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The Other Weed With Roots In Hell?
Disclaimer: I am not advocating the use of tobacco products to anyone. It's smelly, expensive and inconvenient, so it's already struck out even before we get to the part about how it confuses the hell out of doctors (particularly those who only have time to look up some half-baked dogma about it) and you do not want the person whose life your hands may be in to be confused about your workings.

All the same, it doesn't help that confusion for tobacco to be given a bad rap in any respect if a patient uses it (all the self-abuse I gave myself at my doctor's encouragement for lighting up didn't really help a lot either but hey, everybody knows smoking will kill you, right?), and I'm getting reminded somehow of both the horribly ugly propaganda that's been thrown around with Cannabis ("Reefer Madness" "The Weed With Roots In Hell" etc etc), and how every time I see a spot for "" and their anti-tobacco campaign, it's propaganda and not information. If the truth will suffice, why resort to propaganda? 

[Image: marihuana-weed-with-roots-in-hell.jpg]

I myself now have 3 "smoking-related" diseases and have a hard time quitting largely because smoking less actually makes some if not all of these conditions worse and their management can be extremely delicate. I was nearly hospitalized by my last attempt to just cut my nicotine intake by 50%, and hospitalization was quickly but narrowly averted only by resuming my usual level of consumption. More importantly, having examined bacteriological studies of my diagnoses, they seem to have at least one very important common microbial denominator, and it certainly makes one wonder just how deep the rabbit hole goes concerning tobacco being blamed for what could actually be the work of microbes that no one thought to look for, or may have been particularly hard to detect.

Obviously, if any beneficial effects of tobacco are being mediated through impact on microbes, or if a patient seems to be using tobacco in the management of infection, antimicrobials are in order, but I've had a hard time convincing caregivers of this, thus far they are either unequipped or skeptical. So they are sitting there thinking, "My God what an idiot, he just doesn't get that those things are killing him" and I'm sitting there thinking "My God what idiots, they have no idea what it means if the same infection is common denominator to three different diagnoses, or how these microbes could be causing these symptoms, even when it's fairly obvious to me".

In one of my diagnoses, they have most definitely had little business blaming tobacco. One paper was published attempting to name the pathology in honor of smoking, and the premier authority on the disease thankfully stepped in and gave the authors a good slap for it, then went on to point on how in what may be a closely related disease, acne vulgaris, the data shows heavier smokers having decreased disease burden, clearly implying that patients may be gravitating toward tobacco for whatever relief or assistance with disease management it might provide. Although the high statistical percentage of smokers in "that one study" is often referred to even in the latest literature, little if any actual support other than that seems to have materialized.

Doctors seem to adapt this etiology mainly because for years the Mayo Clinic has had a presentation on their website where the percentages of patients with infections were flipped on their heads so that it came out "It's probably not infection because we don't usually find infection" which is to the best of my knowledge the opposite of what the data said. It was a hard error to trace because the Mayo Clinic doesn't provide references, but I do think I traced it correctly back to source. Discouraged from considering or exploring the role of infection in the diagnosis (even though antibiotics remain weapon of choice!) doctors seem to grab whatever's handy (which is a high percentage of patients being smokers) and just jump right on the old soapbox.

I'm inclined to think some of these effects may involve other components of tobacco than nicotine itself since nicotine replacement therapy doesn't seem to make an effective substitute for tobacco use in my case but I'm still having trouble being certain of that. I have a lot more information I can add if I get to it but I bumped into these today and this seemed like a handy place to start. For context, I have never gone looking for items like this to try to defend myself or prove a point, thus far these find me. I do find these particularly interesting since my first and last trip to an infectious diseases specialist resulted in no acceptable offer of therapy and being informed yet again that all my problems were due to "inflammation from smoking" even after the specialist acknowledged the presence of infection.

Nicotine and inflammatory neurological disorders
Piao WH, Campagnolo D, Dayao C, Lukas RJ, Wu J, Shi FD.
Acta Pharmacol Sin. 2009 Jun;30(6):715-22. doi: 10.1038/aps.2009.67. Epub 2009 May 18.
Cigarette smoke is a major health risk factor which significantly increases the incidence of diseases including lung cancer and respiratory infections. However, there is increasing evidence that smokers have a lower incidence of some inflammatory and neurodegenerative diseases. Nicotine is the main immunosuppressive constituent of cigarette smoke, which inhibits both the innate and adaptive immune responses. Unlike cigarette smoke, nicotine is not yet considered to be a carcinogen and may, in fact, have therapeutic potential as a neuroprotective and anti-inflammatory agent. This review provides a synopsis summarizing the effects of nicotine on the immune system and its (nicotine) influences on various neurological diseases.

Immunosuppressive and anti-inflammatory effects of nicotine administered by patch in an animal model.
Kalra R1, Singh SP, Pena-Philippides JC, Langley RJ, Razani-Boroujerdi S, Sopori ML.
Clin Diagn Lab Immunol. 2004 May;11(3):563-8.
Abstract - To study the immunological effects of nicotine, there are several rodent models for chronic nicotine administration. These models include subcutaneously implanted miniosmotic pumps, nicotine-spiked drinking water, and self-administration via jugular cannulae. Administration of nicotine via these routes affects the immune system. Smokers frequently use nicotine patches to quit smoking, and the immunological effects of nicotine patches are largely unknown. To determine whether the nicotine patch affects the immune system, nicotine patches were affixed daily onto the backs of Lewis rats for 3 to 4 weeks. The patches efficiently raised the levels of nicotine and cotinine in serum and strongly inhibited the antibody-forming cell response of spleen cells to sheep red blood cells. The nicotine patch also suppressed the concanavalin A-induced T-cell proliferation and mobilization of intracellular Ca(2+) by spleen cells, as well as the fever response of animals to subcutaneous administration of turpentine. Moreover, immunosuppression was associated with chronic activation of protein tyrosine kinase and phospholipase C-gamma1 activities. Thus, in this animal model of nicotine administration, the nicotine patch efficiently raises the levels of nicotine and cotinine in serum and impairs both the immune and inflammatory responses.
PMID: 15138183 [PubMed - indexed for MEDLINE] PMCID: PMC404586 Free PMC Article

[PDF] Nicotine, an anti-inflammation molecule - Smart Science Technology
Nicotine, as one of the most important components of cigarette smoke and the key contributor of initiating and maintaining tobacco dependence, has anti-inflammatory effect in the cells of both nervous system and immune system. Among the different types of subunits of nicotinic acetylcholine receptors (nAChR), α7 nAChR is related to the immune response. Nicotine exerts anti-inflammatory effect through cholinergic anti-inflammatory pathway by binding to α7 nAChR. In this review, we summarized the molecular mechanisms of the anti-inflammatory effect of nicotine via binding to the α7 nAChR. We also reviewed the current findings of the nicotinic anti-inflammatory effect in various diseases and disorders. Especially, we focused on the nicotinic anti-inflammatory effect on influenza A virus infection.

Anti-inflammatory effects of nicotine in obesity and ulcerative colitis
Shaheen E Lakhan and Annette Kirchgessner
J Transl Med. 2011; 9: 129. doi: 10.1186/1479-5876-9-129
Cigarette smoke is a major risk factor for a number of diseases including lung cancer and respiratory infections. Paradoxically, it also contains nicotine, an anti-inflammatory alkaloid. There is increasing evidence that smokers have a lower incidence of some inflammatory diseases, including ulcerative colitis, and the protective effect involves the activation of a cholinergic anti-inflammatory pathway that requires the α7 nicotinic acetylcholine receptor (α7nAChR) on immune cells. Obesity is characterized by chronic low-grade inflammation, which contributes to insulin resistance. Nicotine significantly improves glucose homeostasis and insulin sensitivity in genetically obese and diet-induced obese mice, which is associated with suppressed adipose tissue inflammation. Inflammation that results in disruption of the epithelial barrier is a hallmark of inflammatory bowel disease, and nicotine is protective in ulcerative colitis. This article summarizes current evidence for the anti-inflammatory effects of nicotine in obesity and ulcerative colitis. Selective agonists for the α7nAChR could represent a promising pharmacological strategy for the treatment of inflammation in obesity and ulcerative colitis. Nevertheless, we should keep in mind that the anti-inflammatory effects of nicotine could be mediated via the expression of several nAChRs on a particular target cell.
Keywords: α7-nicotinic acetylcholine receptor, ulcerative colitis, enteric nervous system, pro-inflammatory cytokines

Can Nicotine be Used Medicinally in Parkinson's Disease?
Claire Thiriez; Gabriel Villafane; Frédérique Grapin; Gilles Fenelon; Philippe Remy; Pierre Cesaro
Expert Rev Clin Pharmacol. 2011;4(4):429-436.
...There is now robust experimental evidence for a neuroprotective effect of nicotine upon dopaminergic neurons. By contrast, in animal models of Parkinson's disease, nicotine alone has slight or no motor effects. However, nicotine may modulate dopamine transmission and has clear motor effects when associated with L-DOPA, reducing L-DOPA-induced dyskinesias.

FoxFeed Blog: Nicotine Patches to Stop… Parkinson’s Disease?
Posted by Nate Herpich, January 18, 2013
...And there’s still much to learn about possible biological connections between nicotine and PD. To date, most human-based data around nicotine and Parkinson’s has been purely epidemiological, says Maurizio Facheris, MD, MSc. This means that there might be other ways to describe the relationship between nicotine and PD that aren’t “brain chemically-based.”

The Michael J. Fox Foundation: Anti-inflammatory Effects of Nicotine in Parkinson's Disease.
Community Fast Track, 2003.
...Based on the recent observations that macrophage-mediated, peripheral tissue inflammation is suppressed by nicotine, we will evaluate a hypothesis that nicotine similarly can suppress the pro-inflammatory activity of microglia in the brain. Suppression of the microglial-mediated neuroinflammation by nicotine could be a mechanism through which nicotine exerts its reported, long-term neuroprotective effects in animal models of PD and may explain the reduced incidence or delayed onset of PD in cigarette smokers. A confirmation of anti-inflammatory effects of nicotine in the brain, might provide the basis for development of new drug treatments designed to mitigate chronic neuroinflammation and thereby slow the progression of Parkinson's disease.
Janusz B. Suszkiw, PhD
Professor of Molecular and Cellular Physiology at University of Cincinnati Medical School

Chronic polysystemic candidiasis as a possible contributor to onset of idiopathic Parkinson's disease.
Epp LM, Mravec B.
Bratisl Lek Listy. 2006;107(6-7):227-30.
The underlying cause of Parkinson's disease is still enigma. Several mechanisms have been implicated in the etiopathogenesis of PD including oxidative damage, environmental toxins, genetic predisposition, and accelerated aging. Recent research suggests that salsolinol, a derivate of dopamine, is an important contributing factor. In the presence of acetaldehyde dopamine is converted into salsolinol, a neurotoxin involved in apoptosis of dopaminergic neurons. Increased production of acetaldehyde is associated with chronic polysystemic candidiasis (CPC). Chronically elevated levels of acetaldehyde in patients with CPC might participate in the formation of salsolinol and its metabolites in the brain contributing to the destruction of dopaminergic cells in substantia nigra. Clinical mental symptoms of PD often correspond with the mental manifestations of CPC. This hypothesis may constitute basis for further scientific and clinical research of PD etiopathogenesis (Fig. 1, Ref. 29).
PMID: 17051898 [Indexed for MEDLINE] pubmed/17051898
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
I hate to actually name my diagnoses because if you look them up in Google, the pictures are generally not pretty. I have one where tobacco use makes my hands and feet turn red (it also features cramping in the extremities in response to activity and ultimately leads to much worse things). Since the word "vasoconstriction" permeates the literature on this pathology, doctors may be quick to blame this discoloration on "vasoconstriction caused by nicotine" and picture it as if I'd tied rubber bands around my wrists so my hands are starting to turn purple, which is exactly what my doctor did.

It turns out that medical-grade cannabis has the exact same effect even in much smaller doses (where's the nicotine?) and that there may be several vasodilators at work in the picture which may be offsetting any vasoconstrictive effects of lifestyle components. Next we might assume I'm reacting to smoke, but (not that I'm trying it) smokeless tobacco also turns out to be a known trigger of the symptoms of this pathology.

What I proposed originally is that this "red-handed" effect may be histamine-induced flushing similar to the "Asian flushing" effect that some Asians experience on exposure to alcohol due to having variant of genes for alcohol- or acetaldehyde-detoxifying enzymes, and that getting acetaldehyde exposure from chronic Candida may be able to simulate this by overwhelming more competent versions of these enzymes so they are unable, if only temporarily, to effectively deal with aldehyde challenges such as acetaldehyde from tobacco or cannabis smoke, or formaldehyde from smokeless tobacco.

However, while cleaning a dusty corner, I recently discovered that I may be reactive to dust mites. It appears to be a recently acquired sensitivity. First thought in my mind is that there is chitin in the cell wall of fungi and in the exoskeleton of dust mites, so why couldn't dust mite reactivity originate with a Candida infection? Chitin-modifying enzymes (chitinases) do seem to be recognized allergens of these organisms (for example, and there may be potential for cross-sensitization between the two. As I started looking at Candida allergens, I noticed that the first one on the list (Cand a 1 - is an aldehyde dehydrogenase

I am not much of an allergist, but I can only assume that if Cand a 1 is an allergen, that people may become allergic to it, and if we are talking about allergies then I presume we are also talking about histamine. I'm also assuming that as allergens go, compared to a couple of grains of pollen floating by, having a live allergen source multiplying on your person may be bad news, even if you have not yet developed cross-reactivity between this aldehyde dehydrogenase allergen and any of your own multiple versions of aldehyde dehydrogenase.

I haven't found any research yet that sorts it out either way whether such cross-reactivity is possible, but this seems like a very sobering possibility since the major detoxification pathway for histamine in Homo sapiens appears to be diamine oxidase --> aldehyde dehydrogenase. The potential to thus get histamine from an allergic reaction to the enzyme that detoxifies histamine sort of sounds like a possible vicious cycle or a recipe for anaphyllaxis or sudden, severe respiratory attacks. Even without that extreme, however, I don't quite see in this picture where Candida couldn't cause asthma, COPD, or even emphysema. 

To make matters worse, inhalers for these diseases may almost invariably contain corticosteroids which are well-known to promote Candida growth.

But that's silly - everyone knows that yeast infections are just a harmless girlie disease and tobacco kills people, and that doctors would never ignorantly give you medications that might make your condition worse (even while potentially masking the fact they are doing so), right? 

Thank Goddess no one has to hear this from the likes of me:

Tracheobronchial mycosis in a retrospective case-series study of five status asthmaticus patients.
Mak G1, Porter PC, Bandi V, Kheradmand F, Corry DB.
Clin Immunol. 2013 Feb;146(2):77-83. doi: 10.1016/j.clim.2012.11.005. Epub 2012 Nov 27.
The etiology of status asthmaticus (SA), a complication of severe asthma, is unknown. Fungal exposure, as measured by fungal atopy, is a major risk factor for developing asthma, but the relationship of fungi in SA per se has not previously been reported. In this five patient retrospective case series study, lower respiratory tract cultures were performed on bronchoalveolar lavage or tracheal aspirate fluid, comparing standard clinical laboratory cultures with a specialized technique in which respiratory mucus was removed prior to culture. We show that mucolytic treatment allows an increased detection of fungal growth, especially yeast, from the lower airways of all SA patients. We also demonstrate that inhalation of the yeast Candida albicans readily induces asthma-like disease in mice. Our observations suggest that SA may represent a fungal infectious process, and support additional prospective studies utilizing anti-fungal therapy to supplement conventional therapy, broad-spectrum antibiotics and high-dose glucocorticoids, which can promote fungal overgrowth.
PMID: 23280490 PMCID: PMC3569972 DOI: 10.1016/j.clim.2012.11.005
[Indexed for MEDLINE] Free PMC Article
Candida albicans inhalation causes of asthma-like disease in mice.
Mucolysis and incubation at room and body temperature increased fungal recovery.
Glucocorticoid and antibacterial therapy may aid fungal growth and exacerbate disease.
Anti-fungal use in status asthmaticus should be considered in some cases.
1. Introduction
Status Asthmaticus (SA), also referred to as acute severe asthma or severe asthma exacerbation, is a relatively rare, pre-morbid complication of asthma that requires aggressive medical treatment, frequently in an intensive care unit setting and systemic immunosuppression using glucocorticoids. Unlike conventional asthma attacks, the major symptom of SA is profound dyspnea that responds poorly to therapy.
3.3 Experimental infection with Candida albicans
The overwhelming presence of C. albicans in the lower airways of our patients suggested this organism might contribute to disease. To determine experimentally if this is possible, mice were intranasally (i.n.) inoculated with 25,000 viable or heat killed yeast cultured from a clinical isolate of C. albicans and the resulting immune and airway physiological responses were measured. After 8 i.n. exposures over an 18 day period, wild-type C57Black6 mice developed significant increases in airway hyperreactivity, a canonical marker of the asthma phenotype, in response to viable C. albicans as compared to vehicle (phosphate buffer saline: PBS) or heat inactivated yeast challenged animals (Fig. 1b). Viable yeast-challenged mice additionally showed significantly increased allergic inflammation including increased total BAL fluid cellularity composed primarily of eosinophils (Fig. 1c), and predominance of IL-4 secreting cells in the lungs accompanied by increases in IL-17A-secreting cells as compared to controls as analyzed by ELISpot technique (Fig. 1d). Dose-dependant inhalation experiments were also performed and showed an increase in asthma phenotype endpoints with an increase in yeast exposure (Supplementary Fig. 1). Inhalation of dead yeast allergen triggered mild inflammation without Th1 or Th2 dominance (Fig. 1b-d). Thus, the yeast C. albicans potently induces allergic lung disease in normal mice suggesting C. albicans airway infection could cause or exacerbate asthma and status asthmaticus.
Profound immunosuppression related to the taking of immune modulating medications and underlying immunosuppressive illnesses are known risk factors for tracheobronchial candidiasis leading to severe, invasive disease. In contrast, isolation of yeast from the respiratory tract specimens of immunologically competent individuals is generally perceived as representing contamination, innocuous colonization, or a relatively mild disease process such as thrush that does not warrant specific therapy [17]. However, the abundant quantities of yeast present in the lower airways of our patients having no known constitutive immunodeficiency suggested that this organism could also be contributing to or in fact causing the SA. To investigate this possibility, the allergic potential of viable C. albicans was determined directly in mice. Indeed, our studies demonstrate that C. albicans inhalation is as capable of inducing de novo allergic lung disease in normal, naïve mice as filamentous fungi spore inhalation [7,8].
A possible explanation of the abudant yield of Candida spp. in these patients appears to be the nosocomial administration of systemic corticosteroids and broad-spectrum antibiotics. Immunosuppression of many kinds, but especially the use of systemic glucocorticoids, is linked to Candida overgrowth on mucosal surfaces [18–20]. Broad-spectrum antibiotic use has also long been associated with yeast overgrowth in the human gut and oropharynx [21–23]. Antibiotics are theoretically useful in asthma exacerbated by bacterial infection, but studies with sufficient power to detect a beneficial effect are lacking, and for this reason the empiric use of antibiotics in SA is not universally recommended [24]. However, neither the use of antibiotics nor glucocorticoids has been linked to lower respiratory tract candidiasis and actual worsening of disease. In contrast, our findings suggest that the combined use of broad-spectrum antibiotics and high dose glucocorticoids might be particularly hazardous with the potential to cause or exacerbate tracheobronchial mycosis in asthma. Together, our findings suggest that standard therapy for severe asthma might predispose to tracheobronchial mycosis that if sufficiently severe, might lead to or exacerbate SA.

Well, we could hardly blame the medical establishment because no one suspected any of this before, right?

Pulmonary mycotic infections; allergic and immunologic factors.
Calif Med. 1954 Dec;81(6):367-78.
The mechanisms of immunity and allergy, at play in every infectious disease, must be comprehended before the pathogenesis of an infection can be appreciated...
Clinical expressions of allergy may appear in coccidioidomycosis, histoplasmosis and moniliasis. Pulmonary mycoses are divided into three groups, that is, the endogenous mycoses (actinomycosis, moniliasis [Candidiasis], geotrichosis), the endogenous-exogenous mycoses (cryptococcosis, aspergillosis, mucormycosis) and the exogenous mycoses (nocardiosis, coccidioidomycosis, histoplasmosis, North American blastomycosis). The diagnosis and treatment of the important mycotic infections that invade lung tissue are discussed.
PMID: 13209369 PMCID: PMC1532351
[Indexed for MEDLINE] Free PMC Article
The various mycoses in which pulmonary disease is an important feature will now be discussed individually. No longer do these infections play an unimportant and remote position in medicine and public health. Mycotic infections occur with sufficient frequency to justify consideration of them in the differential diagnosis of every difficult and complicated pulmonary infection, and even, under certain circumstances, in supposedly benign and simple respiratory diseases. 
Pulmonary moniliasis is the term for infections of the parenchyma of the lungs. While the parenchymal is not so common as the bronchial infection, it is more serious. Pulmonary moniliasis may resemble miliary tuberculosis with cough, fever, dyspnea, pain in the chest, hemoptysis and night sweats. There may be signs of pleural thickening. Areas of consolidation resembling bronchopneumonia may be scattered throughout two or more lobes and, infrequently, there may be lobar consolidation
Clinical manifestations of allergic reaction of the immediate type may develop during the course of a C. albicans infection. Bronchial asthma was reported by the author to have followed a bronchial infection. The asthmatic symptoms completely disappeared with the alleviation of the infection. The author has also observed the development of urticaria in a patient with cutaneous moniliasis. 
Eczematoid dermatitis of the face and certain cases of miliaria are thought to be allergic reactions to Candida infections... 
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
Quote:All the same, it doesn't help that confusion for tobacco to be given a bad rap in any respect if a patient uses it (all the self-abuse I gave myself at my doctor's encouragement for lighting up didn't really help a lot either but hey, everybody knows smoking will kill you, right?), and I'm getting reminded somehow of both the horribly ugly propaganda that's been thrown around with Cannabis ("Reefer Madness" "The Weed With Roots In Hell" etc etc), and how every time I see a spot for "" and their anti-tobacco campaign, it's propaganda and not information. If the truth will suffice, why resort to propaganda?

1st Welcome to HMF, I want to ask where you " see a spot for """ ???

There is NO website at that domain, much less any truth or propaganda  Nonono

Bob... Ninja  Bong7bp
"The Morning Light, No sensation to compare to this, suspended animation, state of bliss, I keep my eyes on the circling sky, tongue tied and twisted just and Earth Bound Martian I" Learning to Fly Pink Floyd [Video:]
Your ISP or antivirus might have blocked you? I'm finding in Google with a big red McAfee warning not to go there. Wikipedia knows them I'm not seeing any evidence now that there's a .org at the end but I'm almost certain I've seen it written that way on their TV spots before.

They do TV ads all the time. One of them has a giant dog and a giant cat on top of these huge transparent cylinders with fake urine and feces coming out of them to emphasize that, like tobacco, urine and feces contain urea and methane. This might be propaganda because the take-away message I got, was to get rid of my cats because the catbox must be fifty times more dangerous than tobacco. :-)

I think this is the one (The award winning video, "Poop vs Pee")...

At the end of that one, it gives the url as but that url gets me a hardware page...

Sorry, my bad. This unfortunately seems to work...
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
your long dissertation was summed up quickly with candida Whip
implies all fungal sinus or lung infections actually

if this is the culprit of infection, then an antibiotic will not work,
you have to go to a silver based product

it would be one that covered both bacterial spectrum and fungal infections

silvadene is good for topical, 
and I know that somehow it can be applied in the sinus.
I don;t know how that would go in the lungs,
but that would be the type of combination drug

it would be this ... but not in a cream --- an inhaler spray

silver sulfadiazine

cleans up on candiada and a large host of bacteria
I think that article from 1954 suggests potassium iodide but God only knows if that will still work on any particular specimen after it's done being mutated and modified by various factors, same with antifungals. Might explain why I didn't get anything decisive out of potassium iodide drops? Best recommendation I found is linked off the CDC's Candida page and in the fine print it says not to take anything for granted about antifungal susceptibility and to perform cultures and susceptibility testing. Not surprising since the treatment recommendations for Candida glabrata are also all over the place, ranging from "diflucan ought to work" to "don't waste your time, no azole antifungal has ever worked on C. glabrata because it's born with CDR1 and/or other efflux pumps".

There are some suggestions it may have gotten into my blood and set up a biofilm that's playing host to some gram-negative gut bugs, which could turn out to be the bulk of what's producing the "red-handed" business. That's the hardest thing for me to confirm is that Candida is part of the problem for other patients with the diagnosis, because I'm not sure any researchers have ever actually looked for it, they may have focused entirely on periodontal bacteria so far. They did say they were only able to find those by subjecting surgically-extracted pieces of vasculature to PCR methods, blood cultures failed - which is one of the things that makes me suspicious of a biofilm.

Something along these lines quite possibly

Anaerobic bacteria grow within Candida albicans biofilms and induce biofilm formation in suspension cultures.
Fox EP1, Cowley ES2, Nobile CJ3, Hartooni N4, Newman DK2, Johnson AD5.
Curr Biol. 2014 Oct 20;24(20):2411-6. doi: 10.1016/j.cub.2014.08.057. Epub 2014 Oct 9.
The human microbiome contains diverse microorganisms, which share and compete for the same environmental niches. A major microbial growth form in the human body is the biofilm state, where tightly packed bacterial, archaeal, and fungal cells must cooperate and/or compete for resources in order to survive. We examined mixed biofilms composed of the major fungal species of the gut microbiome, Candida albicans, and each of five prevalent bacterial gastrointestinal inhabitants: Bacteroides fragilis, Clostridium perfringens, Escherichia coli, Klebsiella pneumoniae, and Enterococcus faecalis. We observed that biofilms formed by C. albicans provide a hypoxic microenvironment that supports the growth of two anaerobic bacteria, even when cultured in ambient oxic conditions that are normally toxic to the bacteria. We also found that coculture with bacteria in biofilms induces massive gene expression changes in C. albicans, including upregulation of WOR1, which encodes a transcription regulator that controls a phenotypic switch in C. albicans, from the "white" cell type to the "opaque" cell type. Finally, we observed that in suspension cultures, C. perfringens induces aggregation of C. albicans into "mini-biofilms," which allow C. perfringens cells to survive in a normally toxic environment. This work indicates that bacteria and C. albicans interactions modulate the local chemistry of their environment in multiple ways to create niches favorable to their growth and survival.
Comment in
Biofilms: five-star accommodations for the aerobically challenged. [Curr Biol. 2014]
PMID: 25308076 PMCID: PMC4252622 DOI: 10.1016/j.cub.2014.08.057
[Indexed for MEDLINE] Free PMC Article

I do have questions about whether it can be kept away for long even if it can be killed easily enough, or whether the best thing to do is learn to live in harmony with it. A lot of recommendations for Candida co-existence may not apply to systemic infections, which doesn't help much. Candida seems like a pretty fiendishly complex organism, which also doesn't help a lot. Right now I'm just trying not to make any sudden moves that might piss it off. I don't think mine has Clostridium in it but there's something where I do NOT want to find out the hard way that I'm wrong.
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
my full post ... disappeared  Hmm2

it ended as such:

it would be this ... but not in a cream --- an inhaler spray:

silver sulfadiazinine

I was able to stop smoking cigarettes
by switching to an e-cig
using 18 mg menthol tobacco e-juice.
It's very addictive but it works.
The recharger cable hangs off the computer.
You have to use the USB unit that comes with the e-cig for safety.
Besides the discoloration in the hands, this spiffy little circulatory disease of mine comes with coldness in the hands, and acute sensitivity to cold. Literally, if the temperature in the room goes down five degrees, I feel like somebody just poured a bucket of icewater over me. Suddenly all I can think about is how did I get that way and how do I make it stop (A related disease, Raynaud's phenomenon, also features this sensitivity to cold and discoloration in the extremities). Really not practical to turn the thermostat up to 95* for my comfort and drive everyone else out of the house and put the heating bill through the roof. Unfortunately this is another one where it seems way too easy for doctors to just imagine that I have "poor circulation to the extremities from vasoconstriction caused by nicotine" - except as already mentioned there may be multiple vasodilators already at work compensating.

Naturally lot of people have suggestions how I should get off my lazy ass and get my blood moving and my metabolism going, but the worst trouble I had was when I was doing exactly that. I've been on every hiking trail in 20 miles in recent years, and just when I was working the hardest at "doing everything right" that way, I got so sick that I just hauled off and put all my whiny little symptoms into Google - "Alright Google, if you're so damned omniscient, let's see you find a disease that features this laundry list" and Google comes back with Hashimoto's Thyroiditis - I think I had every symptom except goiter. The doctor runs T4 and T3 tests after I prodded him to give me the later, and everything looks normal. Other than testosterone in the low ranges, everything on the general blood panel looks ok, so the inquiry is dropped. I go home and load up on thyroid hormone precursors and manage to stop wanting to scream but the benefits never manage to exceed that, and life forges onward.

I buy some of these books like "Stop the Thyroid Madness," ripping doctors for being out to lunch on thyroid problems and suggesting that I should vampirize some porcine thyroid gland extracts from Armour like I should want to buy medicines from a slaughterhouse, but these are really not much help if they can't offer any scenarios that are plausible in the long run. However, every winter I'm motivated by the ambient temperature to Google "sensitivity to cold" and 9 out of 10 returns continue to suggest some form of hypothyroidism.

The term cellular hypothyroidism has come up in my reading a few times, generally without any actual details or mechanisms, but it does sort of point one in the direction of the cellular milieu where there are a number of other chapters in the life story of thyroid hormone. Each of these steps may be a link in the chain that might theoretically be broken, resulting in various kinds of hypothyroid problems that there aren't even names for. 

As I understand it, the cellular conversion of T4 into the more potent T3 involves an enzymatic reaction which relies on the enzyme cofactor dithiothreitol. Curiously, as notably important a function this may be, while I can find countless scientific reports which involve the use of dithiothreitol as a chemical reducing agent, I have found zero literature describing what dithiothreitol is doing in Homo sapiens (dietary intake or biosynthesis?), how to tell if you might be deficient, or what to do about it if you were. There are a couple of reactions related to quinones or CoQ10 it may be involved in, and that's the sum of it so far.

While trying to dissect the life story of thyroid hormones in target cells and trying to figure out how to troubleshoot the various steps in the proceedings, I came across a curious article based on animal studies, casting aspersions at overactivity of cellular ODC (ornithine decarboxylase, a human version of the same enzyme that can be used to distinguish between nasty yellow Staphylococci). According to these researchers, the substrates of ODC include the heat-producing (thermogenic) thyroid hormones T2 and T4 - ODC can convert them into the anti-thyroid, anti-thermogenic, torpor-provoking, hypothermia-inducing metabolite T1AM (3-iodothyronamine).

It's a little disturbing to see the TAAR receptor there because TAAR may be implicated in addiction, which is a little spooky when you have a condition where the room temperature is making you so miserable that you would literally use your own grandparents for firewood to make it stop. More so when you suspect you may already be swimming in excess cellular cAMP, and:

"3-Iodothyronamine (T1AM) is an endogenous thyronamine. T1AM is a high-affinity ligand for the trace amine-associated receptor TAAR1 (TAR1, TA1), a recently discovered G protein-coupled receptor.[1][2] T1AM is the most potent endogenous TAAR1 agonist yet discovered.[3] Activation of TAAR1 by T1AM results in the production of large amounts of cAMP. This effect is coupled with decreased body temperature and cardiac output.[4] Wu et al. have pointed out that this relationship is not typical of the endocrine system, indicating that TAAR1 activity may not be coupled to G-proteins in some tissues, or that T1AM may interact with other receptor subtypes.[3] T1AM may be part of a signaling pathway to modulate cardiac function, as the compound can induce negative inotropic effects and decrease cardiac output.[5]"

(Let me guess, any resultant decreased cardiac output will likely be mistaken by doctors for cardiovascular insufficiency, that good old "vasoconstriction caused by nicotine"?)

Minireview: 3-Iodothyronamine (T1AM): a new player on the thyroid endocrine team?
Scanlan TS1.
Endocrinology. 2009 Mar;150(3):1108-11. doi: 10.1210/en.2008-1596.
3-Iodothyronamine (T(1)AM) is an endogenous compound with chemical features that are similar to thyroid hormone. T(1)AM has a carbon skeleton identical to that of T(4) and contains a single carbon-iodine bond. Theoretically, T(1)AM could be produced from T(4) by enzymatic decarboxylation and deiodination. Recent studies show that T(1)AM and higher iodinated thyronamines are subject to similar metabolic processing as iodothyronines such as T(4), suggesting a biological linkage between iodothyronines and iodothyronamines. In addition, single doses of T(1)AM administered to rodents induce a hypometabolic state that in certain ways resembles hibernation and is opposite to the effects of excess T(4). This review will discuss the latest developments on this recently discovered thyroid hormone derivative.
PMID: 19116337 PMCID: PMC2654747 DOI: 10.1210/en.2008-1596 [PubMed - indexed for MEDLINE] Free PMC Article

ODC is subject to an elaborate regulation system involving antizymes and antiantizymes or some such absurdly complex workings, but if there are problems and one can therefore assume that the regulation has somehow been lost, it might default to naturally occurring ODC inhibitors such as arginine, to keep ODC from making mincemeat out of your thyroid hormones.

As with the great big mystery of dithiothreitol, I'm not really sure what goes on here either, but literature may offer what are hopefully a couple useful considerations - namely, that adenosine is given credit in literature for being able to promote hypothermia, and that adenosine may be given some credit in literature for shifting the metabolism of target cells into a more anaerobic state. 

(This is how things seem to work with microbes - the biofilm state is characterized by a shift toward an anaerobic state, to the point where biofilm organisms may go so far as to forfeit the use of the citric acid cycle in respiration. This may happen whether or not the microbe is actively making biofilm at the time - for all I can be certain, it's this biofilm metabolism more than biofilm production that might best characterize many biofilm microbes).

Now of course mammals have an anaerobic respiration mode, which produces lactate as a by-product and so forth. (lactate accumulation is often credited with being able to promote muscle fatigue), but perhaps almost as obscure as dithiothreitol is whether humans can operative an anaerobic mode of metabolism that does NOT sacrifice the citric acid cycle, but instead switches from oxygen being the electron acceptor in the electron transport chain to a different one, such as just maybe nitric oxide).

One reason I say this is because is such a thing were actually possible, this putative nitric oxide source may depend on various nitric oxide synthases - iNOS, eNOS, nNOS - which make nitric oxide from arginine. The other reason I say this is because if there is anything in my supplement cupboard which actually seems to help the feeling of being the constant victim of a bucket of icewater, it's arginine. For me, it's like ginseng without the side-effects, and it's potent - 500 milligrams of free-form arginine will put a stop to that, offset sore muscle and lung complaints, and you name it, often clear into the next day. It's hard for me to exceed that because if I do, side-effects will start to happen, and if I take it for 2-4 days in a row, it may start to backfire (possibly because arginine is what microbes make putrefaction out of), but I'm of course wondering why I shouldn't at least take this to be a possible indicator of a T1AM problem even if it's not a real solution. (There's not a lot of elaboration why, but arginine does also already appear on a list of things that may be of advantage in this particular diagnosis).

I'm having a little trouble at the moment with the idea of making an appointment to say "Doctor, I think microbes are making me switch from oxygen to nitrogen compounds, I'm not sure how much I'm an aerobic organism anymore" because I'm guessing I can likely expect to be given some antipsychotics. 

I also can't quite explain very comfortably why 500 mg of free form arginine outperforms 3-4 grams of arginine that might be in dietary protein. "It is written" that free-form aminos are more effective because there's less competition for uptake (although the fact it is it will usually go right to work within 15 minutes even if I take it on top of a full meal's worth of competition). I also don't know why bodybuilders can boast of taking 9000 mg or more of arginine daily and I can't tolerate more than 500 mg, but there it is... 

(Perhaps one other possibility might involve the role of copper as a co-factor in intracellular thyroid hormone metabolism. With all the references to cAMP in the picture, which in another thread I've pointed out as a generator of amyloid proteins, I'm reminded of several Australian researchers who proposed that the role of amyloid is as a "bioflocculant" because of all the things that stick to it or end up incorporated into its structure, particularly copper. No other data I can think of that might imply whether excessive cellular amyloid production could result in cellular copper deficiency like that, but copper supplements have no decisive helpful properties here).

The things that might be realized or discovered if science can keep from blaming everything on tobacco for all of five effing minutes.

The question remains how to convince any medical professionals of any of this, if the Mayo Clinic didn't tell them it might be worth thinking about. Unless I want to dink around some more without medical supervision, which I don't think it a very good idea, they'd need to try and get on the same page - even if everything I've said on this subject so far may all be another way of saying that if you have a chronic infection, you might get chills, you might feel like crap, you might not feel like getting out of your chair, and maybe you should lie down, cover up, stay warm and rest. It's just that I really don't want to spend the rest of my life in bed, especially after as much of my life has already been pissed away while doctors stand around scratching their heads and blaming me for my predicaments.

As usual, chronic infections seem to be the elephant in the room that nobody wants to talk about, or look for.

I could be wrong about any of all of this, it IS some tricky stuff - but for whatever it's worth, maybe any of this will help someone else somewhere someday - again it occurs to me that, for example, there may be thyroid problems that there aren't even names for yet. I don't know where in literature anyone has ever proposed before that arginine depletion might promote or simulate a thyroid deficiency, and I didn't quite feel like waiting another 10 years for them to think of it, so ready or not...

Just more stuff I learned while doctors were making me do their homework for them, so they could argue with my findings. Don't really know how to get them on the same page this many pages of medical literature later, as I'm probably not likely to explain much of this in the five minutes allotted.
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
No matter WHAT illness there is ONE CURE for ALL of them:

Bob... Ninja Alien2
"The Morning Light, No sensation to compare to this, suspended animation, state of bliss, I keep my eyes on the circling sky, tongue tied and twisted just and Earth Bound Martian I" Learning to Fly Pink Floyd [Video:]
I'm increasingly getting into stuff that may be harder to support with existing literature, but what may be interesting about any of that, particularly the stuff about T1AM, is that it may be a look into how microbes can trick someone's body into doing some of the microbial dirty work for the microbes. 

This may also go for adenosine, it's referred to as a biological "danger signal," which may mean not only that it's able to trick the body because it normally is a legitimate signal, which might also mean it has certain priority, and in a worst-case scenario, say a very small colony of microbes sets off a puff of excess adenosine, and before you know it some of your cells have been tricked into sounding the alarm by producing additional adenosine. 

I don't know the lexicon at work here, but the least reach might be to say that it's signalling to conserve energy, which may be point of the shift in metabolic mode. Is this where chronic fatigue might come from? Maybe you won't feel too physically ambitious if you end up with the metabolism of a hibernating bear?

It may also be remotely possible for, say, a Candida infection, if it manages to set up the right immunoreactivities or enzymatic dysfunctions, to manipulate the host into producing more acetaldehyde than the microbes themselves might otherwise be capable of? I'm getting a little suspicious that some fraction of what would normally have been lactate production could be manipulated into coming out acetaldehyde.

Here are a FEW papers on adenosine from my collection. It's probably important to remember that while enzymes like adenosine deaminase (ADA) are intended to deal with excessive adenosine, that infections like Candida and others may be able to inhibit ADA by also generating inosine at the expense of the host (and in turn, cleanup of excess inosine might be blocked by microbes and etc, for them to enjoy success). Also, it can be difficult to sort out whether adenosine (again, it's a legitimate part of life) is friend or foe without being more specific whether we are talking about normal levels or excessive levels.

At any rate, I don't know how many of the following accusations against adenosine could possibly be levelled at tobacco, so as usual I'd like to know what business medicine has BLAMING TOBACCO when THEY have already provided such ample reason to BLAME MICROBES.

[Image: zsruwxjowztpthb1fxo3.jpg]
Responsible citizens everywhere have a sacred duty to
blame the wrong thing.


Adenosine's Greatest Hits, Volume 1

Adenosine and osteopontin contribute to the development of chronic obstructive pulmonary disease.
Schneider DJ1, Lindsay JC, Zhou Y, Molina JG, Blackburn MR.
FASEB J. 2010 Jan;24(1):70-80. doi: 10.1096/fj.09-140772. Epub 2009 Aug 31.
Chronic obstructive pulmonary disease (COPD) is a major health concern. Adenosine, a signaling molecule generated in response to cell stress, contributes to the pathogenesis of COPD. An established model of adenosine-mediated lung injury is the adenosine deaminase-deficient (Ada(-/-)) mouse...
PMID: 19720619 PMCID: PMC2797041 DOI: 10.1096/fj.09-140772 [PubMed - indexed for MEDLINE] Free PMC Article

Acetate causes alcohol hangover headache in rats.
Maxwell CR1, Spangenberg RJ, Hoek JB, Silberstein SD, Oshinsky ML.
PLoS One. 2010 Dec 31;5(12):e15963. doi: 10.1371/journal.pone.0015963.
...Since adenosine accumulation is a result of acetate formation, we administered an adenosine antagonist that blocked hypersensitivity...
...Increased serum acetate levels lead to accumulation of adenosine in many tissues including the brain, and administration of the adenosine receptor antagonist caffeine to rats after ethanol was found to decrease nociceptive behavior.[6][7]...

A2B adenosine receptor blockade enhances macrophage-mediated bacterial phagocytosis and improves polymicrobial sepsis survival in mice.
Belikoff BG1, Hatfield S, Georgiev P, Ohta A, Lukashev D, Buras JA, Remick DG, Sitkovsky M.
J Immunol. 2011 Feb 15;186(4):2444-53. doi: 10.4049/jimmunol.1001567. Epub 2011 Jan 17.
Pharmacological blockade of A2BR even 32 h after the onset of sepsis increased survival by 65% in those mice predicted to die. Thus, even the late treatment with an A2BR antagonist significantly improved survival of mice (ICR/CD-1) that were otherwise determined to die according to plasma IL-6 levels. Our findings of enhanced bacterial clearance and host survival suggest that antagonism of A2BRs offers a therapeutic target to improve macrophage function in a late treatment protocol that improves sepsis survival.
PMID: 21242513 PMCID: PMC3708265 DOI: 10.4049/jimmunol.1001567 [Indexed for MEDLINE] Free PMC Article

TNF-alpha upregulates the A2B adenosine receptor gene: The role of NAD(P)H oxidase 4.
St Hilaire C1, Koupenova M, Carroll SH, Smith BD, Ravid K.
Biochem Biophys Res Commun. 2008 Oct 24;375(3):292-6. doi: 10.1016/j.bbrc.2008.07.059. Epub 2008 Jul 21.
Proliferation of vascular smooth muscle cells (VSMC), oxidative stress, and elevated inflammatory cytokines are some of the components that contribute to plaque formation in the vasculature. The cytokine tumor necrosis factor-alpha (TNF-alpha) is released during vascular injury, and contributes to lesion formation also by affecting VSMC proliferation. Recently, an A(2B) adenosine receptor (A(2B)AR) knockout mouse illustrated that this receptor is a tissue protector, in that it inhibits VSMC proliferation and attenuates the inflammatory response following injury, including the release of TNF-alpha. Here, we show a regulatory loop by which TNF-alpha upregulates the A(2B)AR in VSMC in vitro and in vivo. The effect of this cytokine is mimicked by its known downstream target, NAD(P)H oxidase 4 (Nox4). Nox4 upregulates the A(2B)AR, and Nox inhibitors dampen the effect of TNF-alpha. Hence, our study is the first to show that signaling associated with Nox4 is also able to upregulate the tissue protecting A(2B)AR.
PMID: 18647598 PMCID: PMC2583397 DOI: 10.1016/j.bbrc.2008.07.059 [Indexed for MEDLINE] Free PMC Article

Immunological alterations mediated by adenosine during host-microbial interactions.
Drygiannakis I1, Ernst PB, Lowe D, Glomski IJ.
Immunol Res. 2011 May;50(1):69-77. doi: 10.1007/s12026-011-8207-0.
Adenosine accumulates in inflammation and ischemia but it is more than an end-product of ATP catabolism. Signaling through different receptors with distinct, cell-specific cytoplasmic pathways, adenosine is now recognized as an inducible switch that regulates the immune system. By acting through the A(2A)AR, adenosine shapes T cell function...
PMID: 21479929 PMCID: PMC3361322 DOI: 10.1007/s12026-011-8207-0 [PubMed - indexed for MEDLINE] Free PMC Article

Adenosine A(2B) receptor deficiency promotes host defenses against gram-negative bacterial pneumonia.
Barletta KE1, Cagnina RE, Burdick MD, Linden J, Mehrad B.
Am J Respir Crit Care Med. 2012 Nov 15;186(10):1044-50. doi: 10.1164/rccm.201204-0622OC. Epub 2012 Sep 20.
PMID: 22997203 PMCID: PMC3530209 DOI: 10.1164/rccm.201204-0622OC [Indexed for MEDLINE] Free PMC Article

A2 adenosine receptors and vascular pathologies.
Johnston-Cox HA1, Koupenova M, Ravid K.
Arterioscler Thromb Vasc Biol. 2012 Apr;32(4):870-8. doi: 10.1161/ATVBAHA.112.246181.
Cardiovascular disease, a leading cause of death and morbidity, is regulated, among various factors, by inflammation. The level of the metabolite adenosine is augmented under stress, including inflammatory, hypoxic, or injurious events. Adenosine has been shown to affect various physiological and pathological processes, largely through 1 or more of its 4 types of receptors: the A1 and A3 adenylyl cyclase inhibitory receptors and the A2A and A2B adenylyl cyclase stimulatory receptors
PMID: 22423039 DOI: 10.1161/ATVBAHA.112.246181 [PubMed - indexed for MEDLINE] Free full text 

Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice.
Haskó G1, Szabó C, Németh ZH, Kvetan V, Pastores SM, Vizi ES.
J Immunol. 1996 Nov 15;157:4634–4640 
PMID: 8906843 [PubMed - indexed for MEDLINE]

Adenosine: a physiological modulator of superoxide anion generation by human neutrophils.
Cronstein BN, Kramer SB, Weissmann G, Hirschhorn R.
J Exp Med. 1983 Oct 1;158(4):1160-77.
The effects of adenosine were studied on human neutrophils with respect to their generation of superoxide anion, degranulation, and aggregation in response to soluble stimuli. Adenosine markedly inhibited superoxide anion generation by neutrophils stimulated with N-formyl methionyl leucyl phenylalanine (FMLP), concanavalin A (Con A), calcium ionophore A23187, and zymosan-treated serum; it inhibited this response to PMA to a far lesser extent. The effects of adenosine were evident at concentrations ranging from 1 to 1,000 microM with maximal inhibition at 100 microM. Cellular uptake of adenosine was not required for adenosine-induced inhibition since inhibition was maintained despite the addition of dipyridamole, which blocks nucleoside uptake. Nor was metabolism of adenosine required, since both deoxycoformycin (DCF) and erythro-9-(2-hydroxy-3-nonyl) adenine did not interfere with adenosine inhibition of superoxide anion generation. The finding that 2-chloroadenosine, which is not metabolized, resembled adenosine in its ability to inhibit superoxide anion generation added further evidence that adenosine metabolism was not required for inhibition of superoxide anion generation by neutrophils. Unexpectedly, endogenously generated adenosine was present in supernatants of neutrophil suspensions at 0.14-0.28 microM. Removal of endogenous adenosine by incubation of neutrophils with exogenous adenosine deaminase (ADA) led to marked enhancement of superoxide anion generation in response to FMLP...
These data indicate that adenosine (at concentrations that are present in plasma) acting via cell surface receptors is a specific modulator of superoxide anion generation by neutrophils.
PMID: 6311934 PMCID: PMC2187367 [PubMed - indexed for MEDLINE] Free PMC Article

Antimicrobial Mechanisms of Macrophages and the Immune Evasion Strategies of Staphylococcus aureus.
Flannagan RS1, Heit B2,3, Heinrichs DE4,5.
Pathogens. 2015 Nov 27;4(4):826-68. doi: 10.3390/pathogens4040826.
...The S. aureus effectors that mediate this response are a secreted nuclease that that can degrade DNA and RNA to generate a pool of 3' nucleotides that can be metabolized by the adenosine synthetase AdsA, which catalyzes the formation of deoxyadenosine molecules [220,221]. Previous studies had implicated both the secreted nuclease and AdsA in S. aureus pathogenesis and provided evidence to indicate that AdsA contributed to the evasion of phagocyte driven bacterial clearance however, the mechanism suppressing phagocyte function was attributed to the production of adenosine not deoxyadenosine [221].

Immunosuppression - How staph thwarts attack
Amy Maxmen
J Exp Med. 2009 Oct 26; 206(11): 2304–2305. doi: 10.1084/jem.20611iti3 PMCID: PMC2768856
Staphylococcus aureus stifles its host's immune response by producing an immunosuppressive molecule, report Thammavongsa and colleagues. The new study reveals that without the cell wall enzyme adenosine synthase A (AdsA), most staphylococci fail to thrive and cause severe disease in mice. The gene encoding AdsA contains a 5'-nucleotidase domain, making it similar to a family of mammalian enzymes that convert adenosine monophosphate into adenosine. Adenosine has many immune-dampening effects including blunting T cell proliferation, inhibiting cytokine production, and blocking neutrophil degranulation and superoxide production. 
...Now it appears that at least two strains of staph (including one methicillin-resistant strain) and the anthrax pathogen Bacillus anthracis use AdsA to tap into the adenosine system. Bacteria with intact adsA survived longer in whole blood from rodents and humans than did adsA-deficient bacteria. And mice infected with adsA-deficient strains cleared infection quickly and rarely developed the abscesses characteristic of progressive staph infections. The virulence of adsA-deficient staph could be regained by genetically restoring the enzyme. With AdsA around, adenosine levels were higher, presumably allowing staph to escape destruction by neutrophils. 
Manipulating the adenosine pathway may turn out to be a widespread phenomenon, as the authors also identified putative 5'-nucleotidase–encoding genes in a variety of gram-positive bacteria.

Extracellular adenosine mediates a systemic metabolic switch during immune response.
Bajgar A, Kucerova K, Jonatova L, Tomcala A, Schneedorferova I, Okrouhlik J, Dolezal 
PLoS Biol. 2015 Apr 27;13(4):e1002135. doi: 10.1371/journal.pbio.1002135. eCollection 2015.
Adenosine thus serves as a signal that the "selfish" immune cells send during infection to secure more energy at the expense of other tissues.
PMID: 25915062 PMCID: PMC4411001 DOI: 10.1371/journal.pbio.1002135 [PubMed - indexed for MEDLINE] Free PMC Article
...Extracellular adenosine (e-Ado) is a signal originating from damaged or stressed tissues. Acting as an energy sensor, e-Ado is released from metabolically stressed cells with depleted ATP [22,23] or made from extracellular ATP leaking from damaged tissues [24]. e-Ado then works as a local or systemic hormone, adjusting metabolism by acting either via adenosine receptors or by the uptake into the cells and conversion to AMP activating AMP-activated protein kinase (AMPK) [24,25]. These actions lead to a suppression of energy consuming processes [22,26–29] and to a release of energy from stores [30].

Adenosine 5'-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation.
Bours MJ1, Swennen EL, Di Virgilio F, Cronstein BN, Dagnelie PC.
Pharmacol Ther. 2006 Nov;112(2):358-404. Epub 2006 Jun 19.
Although the role of ATP and Ado during the course of inflammatory and immune responses in vivo appears to be extremely complex, we propose that their immunological role is both interdependent and multifaceted, meaning that the nature of their effects may shift from immunostimulatory to immunoregulatory or vice versa depending on extracellular concentrations as well as on expression patterns of purinergic receptors and ecto-enzymes. 
PMID: 16784779 DOI: 10.1016/j.pharmthera.2005.04.013 [Indexed for MEDLINE]

Adenosine: a selfish-immunity signal?
Tomas Dolezal
Oncotarget. 2015 Oct 20; 6(32): 32307–32308. doi: 10.18632/oncotarget.4685. PMCID: PMC4741691
It is long known that immune response is energy-demanding. It has become clear in recent years [1] that pretty much any immune cell in our body undergoes, upon its activation, a metabolic shift resembling the Warburg effect originally described for cancer cells. Immune cells increase glucose consumption and produce a significant portion of ATP by glycolysis ending with lactate even under oxygenated conditions; increased glycolysis is required for the generation of intermediate metabolites associated with the activation of the immune cell.
Increased energy consumption by immune cells requires a metabolic adaptation of the whole organism. During trauma or infection, the organism vitally depends on the immune system, which is therefore privileged in energy/nutrient allocation. According to Rainer Straub [2], insulin resistance caused by pro-inflammatory cytokines is a physiological way of the immune system to usurp energy/nutrients during acute stress from the rest of the organism because immune cells themselves do not become insulin resistant. Such selfish behavior of the immune system may be crucial for an effective immune response.
Increased plasma levels of adenosine were associated with chronic fatigue syndrome and adenosine was shown to mediate an exercise-induced fatigue [5]. Fatigue is a hallmark of sickness and thus it is tempting to speculate that adenosine may cause fatigue in proportion to tissue damage and the energy needs of immune cells. Fatigue and suppressing the overall activity of the organism could form, together with insulin resistance, a complex program to conserve energy for the immune system.
PMID: 26427038 PMCID: PMC4741691 DOI: 10.18632/oncotarget.4685 [Indexed for MEDLINE] Free PMC Article

In vitro, Candida albicans releases the immune modulator adenosine and a second, high-molecular weight agent that blocks neutrophil killing.
J Immunol. 1992 Jun 1;148(11):3588-95.
Smail EH1, Cronstein BN, Meshulam T, Esposito AL, Ruggeri RW, Diamond RD.
PMID: 1316920 [PubMed - indexed for MEDLINE]

Characterization of the adenosine receptors mediating hypothermia in the conscious mouse.
Anderson R1, Sheehan MJ, Strong P.
Br J Pharmacol. 1994 Dec;113(4):1386-90.
...These data suggest that hypothermia induced by adenosine analogues in the conscious mouse is mediated via adenosine A1 receptors, which are probably located in the CNS.
PMID: 7889296 PMCID: PMC1510495 [PubMed - indexed for MEDLINE] Free PMC Article

Caffeine inhibits the activation of hepatic stellate cells induced by acetaldehyde via adenosine A2A receptor mediated by the cAMP/PKA/SRC/ERK1/2/P38 MAPK signal pathway.
Wang H1, Guan W2, Yang W3, Wang Q1, Zhao H1, Yang F1, Lv X1, Li J1.
PLoS One. 2014 Mar 28;9(3):e92482. doi: 10.1371/journal.pone.0092482. eCollection 2014.
Caffeine significantly inhibited acetaldehyde-induced HSC-T6 cells activation by distinct A2AR mediated signal pathway via inhibition of cAMP-PKA-SRC-ERK1/2 for procollagen type I and via P38 MAPK for procollagen type III.
PMID: 24682220 PMCID: PMC3969328 DOI: 10.1371/journal.pone.0092482 [Indexed for MEDLINE] Free PMC Article

Adenosine-mediated mast cell degranulation in adenosine deaminase-deficient mice.
Zhong H1, Chunn JL, Volmer JB, Fozard JR, Blackburn MR.
J Pharmacol Exp Ther. 2001 Aug;298(2):433-40.
Adenosine levels are elevated in the lungs of asthmatics, further implicating this molecule in the regulation of lung inflammation and suggesting that animal models exhibiting endogenous increases in adenosine will be useful for the analysis of adenosine function. Adenosine deaminase (ADA) is a purine catabolic enzyme responsible for regulating the levels of adenosine in tissues and cells. ADA-deficient mice develop lung inflammation and damage reminiscent of that seen in asthma in association with elevated adenosine levels. In the current study, we investigated the status of mast cells in ADA-deficient lungs. ADA-deficient mice exhibited extensive lung mast cell degranulation concurrent with elevated adenosine levels. ADA enzyme therapy prevented the accumulation of lung adenosine as well as mast cell degranulation, suggesting that this process was dependent on elevated lung adenosine levels. Consistent with this, treatment of ADA-deficient mice with broad spectrum adenosine receptor antagonists attenuated degranulation by 30 to 40%, supporting the involvement of adenosine receptor signaling. Moreover, these studies demonstrate the ability of endogenously generated adenosine to influence lung mast cell degranulation in a receptor-mediated manner and establish ADA-deficient mice as a model system to investigate the specific adenosine receptor responses involved in the degranulation of lung mast cells.
PMID: 11454903 [PubMed - indexed for MEDLINE] Free full text

The role of activated adenosine receptors in degranulation of human LAD2 mast cells.
Leung CT1, Li A, Banerjee J, Gao ZG, Kambayashi T, Jacobson KA, Civan MM.
Purinergic Signal. 2014 Sep;10(3):465-75. doi: 10.1007/s11302-014-9409-4. Epub 2014 Mar 5.
PMID: 24595664 PMCID: PMC4152452 DOI: 10.1007/s11302-014-9409-4 [PubMed - indexed for MEDLINE] Free PMC Article

Mast cell adenosine receptors function: a focus on the a3 adenosine receptor and inflammation.
Rudich N1, Ravid K, Sagi-Eisenberg R.
Front Immunol. 2012 Jun 4;3:134. doi: 10.3389/fimmu.2012.00134. eCollection 2012.
Adenosine is a metabolite, which has long been implicated in a variety of inflammatory processes. Inhaled adenosine provokes bronchoconstriction in asthmatics or chronic obstructive pulmonary disease patients, but not in non-asthmatics. This hyper responsiveness to adenosine appears to be mediated by mast cell activation
PMID: 22675325 PMCID: PMC3366457 DOI: 10.3389/fimmu.2012.00134 [PubMed] Free PMC Article

Adenosine A2B receptor and hyaluronan modulate pulmonary hypertension associated with chronic obstructive pulmonary disease.
Karmouty-Quintana H1, Weng T, Garcia-Morales LJ, Chen NY, Pedroza M, Zhong H, Molina JG, Bunge R, Bruckner BA, Xia Y, Johnston RA, Loebe M, Zeng D, Seethamraju H, Belardinelli L, Blackburn MR.
Am J Respir Cell Mol Biol. 2013 Dec;49(6):1038-47. doi: 10.1165/rcmb.2013-0089OC.
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. The development of pulmonary hypertension (PH) in patients with COPD is strongly associated with increased mortality. Chronic inflammation and changes to the lung extracellular matrix (ECM) have been implicated in the pathogenesis of COPD, yet the mechanisms that lead to PH secondary to COPD remain unknown. Our experiments using human lung tissue show increased expression levels of the adenosine A2B receptor (ADORA2B) and a heightened deposition of hyaluronan (HA; a component of the ECM) in remodeled vessels of patients with PH associated with COPD. We also demonstrate that the expression of HA synthase 2 correlates with mean pulmonary arterial pressures in patients with COPD, with and without a secondary diagnosis of PH. Using an animal model of airspace enlargement and PH, we show that the blockade of ADORA2B is able to attenuate the development of a PH phenotype that correlates with reduced levels of HA deposition in the vessels and the down-regulation of genes involved in the synthesis of HA.
PMID: 23855769 DOI: 10.1165/rcmb.2013-0089OC [Indexed for MEDLINE]

A3 adenosine receptor signaling contributes to airway inflammation and mucus production in adenosine deaminase-deficient mice. 
Young HW, Molina JG, Dimina D, Zhong H, Jacobson M, Chan LN, Chan TS, Lee JJ, Blackburn MR. 
Journal of Immunology (Baltimore, Md. : 1950). 173: 1380-9. PMID 15240734 0.84
PMID: 15240734 [Indexed for MEDLINE] Free full text

A(2B) adenosine receptors increase cytokine release by bronchial smooth muscle cells. 
Zhong H, Belardinelli L, Maa T, Feoktistov I, Biaggioni I, Zeng D.
American Journal of Respiratory Cell and Molecular Biology. 30: 118-25. PMID 12855406 DOI: 10.1165/rcmb.2003-0118OC 0.84

The use of enzyme therapy to regulate the metabolic and phenotypic consequences of adenosine deaminase deficiency in mice. Differential impact on pulmonary and immunologic abnormalities.
Blackburn MR1, Aldrich M, Volmer JB, Chen W, Zhong H, Kelly S, Hershfield MS, Datta SK, Kellems RE.
J Biol Chem. 2000 Oct 13;275(41):32114-21.
PMID: 10908569 DOI: 10.1074/jbc.M005153200 [Indexed for MEDLINE] Free full text

Regulation of neutrophil function by adenosine.
Barletta KE1, Ley K, Mehrad B.
Arterioscler Thromb Vasc Biol. 2012 Apr;32(4):856-64. doi: 10.1161/ATVBAHA.111.226845.
PMID: 22423037 PMCID: PMC3353547 DOI: 10.1161/ATVBAHA.111.226845 [PubMed - indexed for MEDLINE] Free PMC Article

Endothelial catabolism of extracellular adenosine during hypoxia: the role of surface adenosine deaminase and CD26.
Eltzschig HK1, Faigle M, Knapp S, Karhausen J, Ibla J, Rosenberger P, Odegard KC, Laussen PC, Thompson LF, Colgan SP.
Blood. 2006 Sep 1;108(5):1602-10. Epub 2006 May 2.
Extracellular levels of adenosine increase during hypoxia. While acute increases in adenosine are important to counterbalance excessive inflammation or vascular leakage, chronically elevated adenosine levels may be toxic. 
PMID: 16670267 PMCID: PMC1895500 DOI: 10.1182/blood-2006-02-001016 [Indexed for MEDLINE] Free PMC Article

Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion.
Huang S1, Apasov S, Koshiba M, Sitkovsky M.
Accumulation of adenosine and of deoxyadenosine in the absence of adenosine deaminase activity (ADA) activity results in lymphocyte depletion and in severe combined immunodeficiency (ADA SCID), which is currently explained by direct cell death-causing effects of intracellular products of adenosine metabolism. 
PMID: 9269779 [PubMed - indexed for MEDLINE] Free full text

Role of pulmonary adenosine during hypoxia: extracellular generation, signaling and metabolism by surface adenosine deaminase/CD26.
Van Linden A1, Eltzschig HK.
Expert Opin Biol Ther. 2007 Sep;7(9):1437-47.
Numerous parallels exist between limited oxygen availability (hypoxia) and acute inflammation. The lungs in particular are prone to acute inflammation during hypoxia, resulting in pulmonary edema, vascular leakage and neutrophil infiltration. The innate response elicited by hypoxia is associated with increased extracellular adenosine effects. Although studies on acute pulmonary hypoxia show a protective role of extracellular adenosine by attenuating pulmonary edema and excessive inflammation, chronic elevation of pulmonary adenosine may be detrimental. Adenosine deaminase (ADA)-deficient mice, for example, develop signs of chronic pulmonary injury in association with highly elevated levels of adenosine. Thus, the authors hypothesized the existence of hypoxia-elicited clearance mechanisms to offset deleterious influences of chronically elevated adenosine. Such studies indicated a second response to hypoxia characterized by pulmonary induction of ADA and CD26. In fact, hypoxia-inducible ADA is enzymatically active and tethered on the outside of the membrane via CD26 to form a complex capable of degrading extracellular adenosine to inosine. This paper reviews metabolic and transcriptional changes of extracellular adenosine generation, signaling and degradation during acute and prolonged pulmonary hypoxia.
PMID: 17727332 DOI: 10.1517/14712598.7.9.1437 [PubMed - indexed for MEDLINE]

The Danger Signal Adenosine Induces Persistence of Chlamydial Infection through Stimulation of A2b Receptors
Matthew A. Pettengill, Verissa W. Lam, and David M. Ojcius* Jean Kanellopoulos, Editor
PLoS One. 2009; 4(12): e8299. Published online 2009 Dec 14. doi: 10.1371/journal.pone.0008299 PMCID: PMC2788228 

The Role of Adenosine in Alzheimer's Disease
Anisur Rahman*
Long-term administration of caffeine in transgenic animal models showed a reduced amyloid burden in brain with better cognitive performance. Antagonists of adenosine A2A receptors mimic these beneficial effects of caffeine on cognitive function. Neuronal cell cultures with amyloid beta in the presence of an A2A receptor antagonist completely prevented amyloid beta-induced neurotoxicity.

Adenosine receptor signaling in the brain immune system
György Haskó,1,2 Pál Pacher,3 E. Sylvester Vizi,2 and Peter Illes4
Trends Pharmacol Sci. 2005 Oct; 26(10): 511–516. doi: 10.1016/
Abstract - The brain immune system, which consists mainly of astrocytes, microglia and infiltrating immune cells, is quiescent normally, but it is activated in response to pathophysiological events such as ischemia, trauma, inflammation and infection. Adenosine is an endogenous purine nucleoside that is generated at sites that are subjected to these ‘stressful’ conditions. Adenosine interacts with specific G-protein-coupled receptors on astrocytes, microglia and infiltrating immune cells to regulate the function of the immune system in the brain. Although many of the effects of adenosine on immune-competent cells in the brain protect neuronal integrity, adenosine might also aggravate neuronal injury by promoting inflammatory processes.

Adenosine receptor signaling: a key to opening the blood-brain door
Margaret S. Bynoe,corresponding author Christophe Viret, Angela Yan, and Do-Geun Kim
...Extracellular adenosine, which is efficiently generated through the catabolism of ATP via the CD39/CD73 ecto-nucleotidase axis, promotes BBB permeability by signaling through A1 and A2A ARs expressed on BBB cells. In line with this hypothesis, induction of AR signaling by selective agonists efficiently augments BBB permeability in a transient manner and promotes the entry of macromolecules into the CNS. Conversely, antagonism of AR signaling blocks the entry of inflammatory cells and soluble factors into the brain.

Adenosine: essential for life but licensed to kill.
Gama V1, Deshmukh M.
Mol Cell. 2013 May 9;50(3):307-8. doi: 10.1016/j.molcel.2013.04.020.
PMID: 23664374 PMCID: PMC3682465 DOI: 10.1016/j.molcel.2013.04.020 [PubMed] Free PMC Article
For many years the notion that cells could release an essential molecule such as adenosine triphosphate (ATP) was received with considerable skepticism. It is now evident, however, that the release of purines and pyrimidines is a fundamental intercellular communication mechanism in a variety of cell types and organisms (Stagg and Smyth, 2010)...
Not surprisingly, adenosine accumulates in the extracellular tissue surrounding tumors because the tumor microenvironment is hypoxic and can trigger a strong inflammatory response (Di Virgilio, 2012). The mechanism by which normal and cancer cells sense and respond to increased levels of adenosine is not completely understood, and the implications of an adenosine-sensing mechanism in cancer have been unclear.

Adenosine signalling in diabetes mellitus--pathophysiology and therapeutic considerations.
Antonioli L1, Blandizzi C1, Csóka B2, Pacher P3, Haskó G2.
Nat Rev Endocrinol. 2015 Apr;11(4):228-41. doi: 10.1038/nrendo.2015.10. 
Furthermore, adenosine is emerging as a major regulator of insulin responsiveness by controlling insulin signalling in adipose tissue, muscle and liver; adenosine also indirectly mediates effects on inflammatory and/or immune cells in these tissues. 
PMID: 25687993 DOI: 10.1038/nrendo.2015.10 [Indexed for MEDLINE]

Staphylococcus aureus synthesizes adenosine to escape host immune responses.
Thammavongsa V1, Kern JW, Missiakas DM, Schneewind O.
J Exp Med. 2009 Oct 26;206(11):2417-27. doi: 10.1084/jem.20090097. Epub 2009 Sep 28.
Staphylococcus aureus infects hospitalized or healthy individuals and represents the most frequent cause of bacteremia, treatment of which is complicated by the emergence of methicillin-resistant S. aureus. We examined the ability of S. aureus to escape phagocytic clearance in blood and identified adenosine synthase A (AdsA), a cell wall-anchored enzyme that converts adenosine monophosphate to adenosine, as a critical virulence factor. Staphylococcal synthesis of adenosine in blood, escape from phagocytic clearance, and subsequent formation of organ abscesses were all dependent on adsA and could be rescued by an exogenous supply of adenosine. An AdsA homologue was identified in the anthrax pathogen, and adenosine synthesis also enabled escape of Bacillus anthracis from phagocytic clearance. Collectively, these results suggest that staphylococci and other bacterial pathogens exploit the immunomodulatory attributes of adenosine to escape host immune responses.
PMID: 19808256 PMCID: PMC2768845 DOI: 10.1084/jem.20090097 [Indexed for MEDLINE] Free PMC Article

Adenosine signaling during acute and chronic disease states.
Karmouty-Quintana H1, Xia Y, Blackburn MR.
J Mol Med (Berl). 2013 Feb;91(2):173-81. doi: 10.1007/s00109-013-0997-1. Epub 2013 Jan 23.
Adenosine is a signaling nucleoside that is produced following tissue injury, particularly injury involving ischemia and hypoxia. The production of extracellular adenosine and its subsequent signaling through adenosine receptors plays an important role in orchestrating injury responses in multiple organs. There are four adenosine receptors that are widely distributed on immune, epithelial, endothelial, neuronal,and stromal cells throughout the body. Interestingly, these receptors are subject to altered regulation following injury. Studies in mouse models and human cells and tissues have identified that the production of adenosine and its subsequent signaling through its receptors plays largely beneficial roles in acute disease states, with the exception of brain injury. In contrast, if elevated adenosine levels are sustained beyond the acute injury phase, adenosine responses can become detrimental by activating pathways that promote tissue injury and fibrosis. Understanding when during the course of disease adenosine signaling is beneficial as opposed to detrimental and defining the mechanisms involved will be critical for the advancement of adenosine-based therapies for acute and chronic diseases. The purpose of this review is to discuss key observations that define the beneficial and detrimental aspects of adenosine signaling during acute and chronic disease states with an emphasis on cellular processes, such as inflammatory cell regulation, vascular barrier function, and tissue fibrosis.
PMID: 23340998 PMCID: PMC3606047 DOI: 10.1007/s00109-013-0997-1 [PubMed - indexed for MEDLINE] Free PMC Article
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
In earlier posts, I mentioned possible similarities between my "smoking-related" thrombotic disease (Thromboangiitis obliterans, TAO) and what may be tobacco-induced flushing, and "Asian flush syndrome". In addition to the noted prevalence of the "Asian flushing" in certain Asian populations, there may also be a prevalence of this "tobacco-related" thrombotic disease in Asian populations. As important as it may be to determine whether reduced clearance of aldehyde may promote infections which may underlie the thrombotic pathology, what I do not have is data showing whether these two groups actually intersect. I have one account of a person whose Asian flush symptoms include olfactory sensitivity to alcohol (specifically, breaking out with flushing after smelling the cap from a bottle of Boone's Farm Strawberry Hill), which may not be well accounted for by either genetics or ordinary models of Asian flush syndrome. 

It might be noted that some of the protein sequence searches I've run looking for possible cross-reactivity arising from Candida allergens have brought up at least three olfactory receptor proteins of unknown function. Possibly these are involved in olfactory detection of alcohols and aldehydes, and possibly olfactory detection of these substances is intended to prime one's physiology for detoxification of alcohols and aldehydes in anticipation of a more acute alcohol or aldehyde challenge. In the context of possible sensitization to one's own aldehyde dehydrogenase (as well as impaired clearance of histamine), perhaps this points in the direction of an accounting for individuals who are so acutely sensitized to fragrances (frequently alcohols and aldehydes) that they require their being banned from the workplace. It might also help to account for sensitization to tobacco or other smoke in non-smokers.

In addition to the obvious fire safety concerns relating to therapeutic use of oxygen in respiratory pathologies, several other concerns may arise. One is whether the metabolic or respiratory effects of adenosine may induce relative indifference to oxygen. As previously noted, doctors may tend to frame symptoms as indicative of oxygen insufficiency due to vascular or pulmonary insufficiency, as opposed to as a possible reduced metabolic ability to effectively utilize oxygen regardless of abundance. Another possible concern is that although tobacco may by no means be the only lifestyle or dietary factor with this ability, tobacco use has been credited with the ability to induce pathogens into a biofilm state which may in fact account for some medicinal benefits of tobacco in the context of infection, and biofilm colonies are associated with (and may be furthered by) an anaerobic character, in spite of the participation of aerobic organisms.

Thus supplemental oxygen might in theory promote possible reversion of this biofilm induction and restore the microbial planktonic state and accompanying increased virulence, or may increase environmental stress on microbes and induce elevation in pathogenic responses, since a number of environmental stress factors may have already been implicated in the modulation of microbial phenotypes. The possible outcome of oxygen therapy in the absence of antibiotic intervention, or any diminishing therapeutic returns associated with therapeutic use of oxygen, may therefore be critical to consider.
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
Adenosine's Greatest Hits, Volume 2

Links Between Insulin Resistance, Adenosine A2B Receptors, and Inflammatory Markers in Mice and Humans
Robert A. Figler1, Guoquan Wang2, Susseela Srinivasan1, Dae Young Jung3, Zhiyou Zhang3, James S. Pankow4, Katya Ravid5, Bertil Fredholm6, Catherine C. Hedrick1, Stephen S. Rich7, Jason K. Kim3, Kathryn F. LaNoue5 and Joel Linden1
Diabetes 2011 Feb; 60(2): 669-679.
CONCLUSIONS Diabetes affects the production of adenosine and the expression of A2BRs that stimulate IL-6 and CRP production, insulin resistance, and the association between ADORA2B SNPs and inflammatory markers. We hypothesize that increased A2BR signaling in diabetes increases insulin resistance in part by elevating proinflammatory mediators. Selective A2BR blockers may be useful to treat insulin resistance...
Several studies have linked adenosine receptor blockade with reversal of insulin resistance. Challis et al. reported that adenosine receptor antagonists (6) or degradation of adenosine with adenosine deaminase (7) reverse insulin resistance in skeletal muscle isolated from diabetic animals. After a lengthy delay before the development of bioavailable adenosine receptor antagonists, the A1/A2B orally active antagonist, BW-1433, was found to persistently reverse insulin resistance in obese insulin-resistant Zucker rats (8–10). 

Staphylococcal Protein A Promotes Colonization and Immune Evasion of the Epidemic Healthcare-Associated MRSA ST239
Xufen Hong, Juanxiu Qin, Tianming Li, Yingxin Dai, Yanan Wang, Qian Liu, Lei He, Huiying Lu, Qianqian Gao, Yong Lin, and Min Li.
Front Microbiol. 2016; 7: 951. Published online 2016 Jun 27. doi: 10.3389/fmicb.2016.00951 PMCID: PMC4922140
Two mutants, with mutations in staphylococcal nuclease (nuc) or in adenosine synthase A (adsA) were selected. Abscesses that had been caused by the nuc mutant harbored staphylococci surrounded by a cuff of neutrophils and with infiltrates of F4/80-positive macrophages at the periphery of the immune cell cuff, but not in the central part of the abscess (Fig. 1F,I). In contrast, abscesses caused by the adsA mutant were characterized by diffuse infiltrates of F4/80-positive macrophages throughout the neutrophil cuff (Fig. 1G,J)...
Taken together, these results indicate that macrophages are excluded from S. aureus-induced abscesses by mechanisms requiring staphylococcal secretion of nuclease and AdsA. 
Nuclease is a DNA cleavage enzyme with endo- and exonuclease activity (11) 
Nucleases are further described by addition of the prefix "endo" or "exo" to the name: The term "endonuclease" applies to nucleases that break nucleic acid chains somewhere in the interior, rather than at the ends, of the molecule. A nuclease that functions by removing nucleotides from the ends of the DNA molecule is called an exonuclease.

Staphylococcus aureus Adenosine Inhibits sPLA2-IIA-Mediated Host Killing in the Airways.
Pernet E, Brunet J, Guillemot L, Chignard M, Touqui L, Wu Y.
J Immunol. 2015 Jun 1;194(11):5312-9. doi: 10.4049/jimmunol.1402665. Epub 2015 Apr 22.
Abstract - Staphylococcus aureus is a common cause of bacterial infections in respiratory diseases. It secretes molecules to dampen host immunity, and the recently identified adenosine is one of these molecules... S. aureus adenosine (wild-type and adsA-complemented strains) and exogenous adenosine downregulated S. aureus phagocytosis by alveolar macrophages, leading to inhibition of sPLA2-IIA expression. This occurred through inhibition of p38 phosphorylation via adenosine receptors A2a-, A2b-, and protein kinase A-dependent pathways. Taken together, our studies suggest that, in the airway, S. aureus escapes sPLA2-IIA-mediated killing through adenosine-mediated inhibition of phagocytosis and sPLA2-IIA expression.
PMID: 25904549 DOI: 10.4049/jimmunol.1402665 [PubMed - indexed for MEDLINE] Free full text

Staphylococcus aureus degrades neutrophil extracellular traps to promote immune cell death. 
Thammavongsa V1, Missiakas DM, Schneewind O.
Science. 2013 Nov 15;342(6160):863-6. doi: 10.1126/science.1242255.
Abstract - Bacterial invasion of host tissues triggers polymorphonuclear leukocytes to release DNA [neutrophil extracellular traps (NETs)], thereby immobilizing microbes for subsequent clearance by innate defenses including macrophage phagocytosis. We report here that Staphylococcus aureus escapes these defenses by converting NETs to deoxyadenosine, which triggers the caspase-3-mediated death of immune cells. Conversion of NETs to deoxyadenosine requires two enzymes, nuclease and adenosine synthase, that are secreted by S. aureus and are necessary for the exclusion of macrophages from staphylococcal abscesses. Thus, the pathogenesis of S. aureus infections has evolved to anticipate host defenses and to repurpose them for the destruction of the immune system.
Comment in
Entrapment exploited. [Trends Microbiol. 2014]
Infection: microbial nucleases turn immune cells against each other. [Curr Biol. 2014]
Bacterial pathogenesis: Staphylococcus slips through the net. [Nat Rev Microbiol. 2014]
PMID: 24233725 PMCID: PMC4026193 DOI: 10.1126/science.1242255
[PubMed - indexed for MEDLINE] Free PMC Article
...The vast spectrum of human morbidity and mortality has been attributed to the unique ability of staphylococci to evade innate and adaptive immune responses (2). The hallmark of S. aureus infection is the formation of abscesses, which comprise a bacterial community surrounded by fibrin deposits and a cuff of host immune cells (3) (Fig. 1 and fig. S1). Such lesions evolve by the infiltration of neutrophils, which release their DNA, also known as neutrophil extracellular traps (NETs) that immobilize the pathogen and enhance the bactericidal activity of antimicrobial peptides (4)...
Earlier work has reported that staphylococcal nuclease, secreted by S. aureus, degrades NETs (9). Thus, staphylococci persist and replicate within abscesses and seed new lesions at different sites or disseminate to other hosts via the purulent exudate (3).

Extracellular Adenosine Generation in the Regulation of Pro-Inflammatory Responses and Pathogen Colonization
Alam MS, Costales MG, Cavanaugh C, Williams K Biomolecules 2015, 5(2), 775-792; doi:10.3390/biom5020775
Abstract: Adenosine, an immunomodulatory biomolecule, is produced by the ecto-enzymes CD39 (nucleoside triphosphate dephosphorylase) and CD73 (ecto-5'-nucleotidase) by dephosphorylation of extracellular ATP. CD73 is expressed by many cell types during injury, infection and during steady-state conditions. Besides host cells, many bacteria also have CD39-CD73-like machinery, which helps the pathogen subvert the host inflammatory response. The major function for adenosine is anti-inflammatory, and most recent research has focused on adenosine’s control of inflammatory mechanisms underlying various autoimmune diseases (e.g., colitis, arthritis). Although adenosine generated through CD73 provides a feedback to control tissue damage mediated by a host immune response, it can also contribute to immunosuppression. Thus, inflammation can be a double-edged sword: it may harm the host but eventually helps by killing the invading pathogen...
...Besides host cells, many pathogens (e.g., Escherichia coli, Staphylococcus aureus, Streptococcus agalactiae, Toxoplasma gondii, and Trichomonas vaginalis) are armed with CD39/CD73-like machinery, that can aid pathogen colonization and dissemination [37,38,39,40]. Further, Staphylococcus aureus adapts to exploit immunosuppressive pathways to increase its own survival [39]. Reports suggest that pathogens produce adenosine from AMP via adenosine synthase A (AdsA), an extracellular ectonucleotidase expressed on the surface of the cell wall of bacterium which allows evasion of host immune surveillance [39]. Other studies demonstrate the existence of bacterial ectotriphosphate diphophohydrolase, similar to human CD39, which is critical for the intracellular multiplication of Legionella pneumophila [41,42]. Recently, a second eukaryotic-type NTPDase, Lpg0971, from L. pneumophila was reported, which gives the pathogen the ability to hydrolyze ATP within an intracellular compartment [43]. By contrast, in certain situations, CD39 and CD73 can also control infections and associated inflammation and mortality [44,45]. This evidence suggests that pathogens can also manipulate the host’s adenosine signaling pathways for its own benefit as a strategy to subvert the immune system...
In a sepsis model, A2BAR blockade or A2BAR gene-deleted mice are resistant to cecal ligation and puncture (CLP) mortality and showed enhanced bacterial clearance [76]. Additionally, the absence of A2B receptor promoted antimicrobial activity against Gram-negative bacterial pneumonia [77]... Further, some pathogens acclimate to exploit immunosuppressive pathways in order to increase their own survival, leading to the possibility that adenosine may favor the survival of pathogen if it is present at the right time and context...
A previous report suggests that macrophages express A2BAR, and A2BAR blockade enhances bacterial phagocytosis [76]. As with Th cells, the expression of CD39 and CD73 in the macrophage are not well studied. Recent reports suggest that murine peritoneal macrophages mainly express CD39 and it has been found that cAMP upregulates CD39 transcription in murine macrophages [82]. The increase of CD39 mRNA expression in the murine macrophage cell line, RAW 264.7, by cAMP is dependent on protein kinase A (PKA), phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) [82]...
Recently, Barletta et al. [77,91] reported that neutrophils from A2BAR-KO showed six-fold greater bactericidal activities and enhanced production of neutrophil extracellular traps compared to WT mice when incubated with Klebsiella pneumoniae, thus promoting host defense against Gram-negative bacterial pneumonia... 
Figure 1. ATP is catabolized by CD39/CD73 expressed in immune cells to generate extracellular adenosine that regulates the outcome of inflammatory response and pathogen persistence during infection. In the normal situation (center), infection-induced immune activation increases the extracellular adenosine level. When immune activation takes place in an adenosine-enriched environment (right side), effector functions of immune cells are insufficient to eliminate pathogens due to poor pro-inflammatory responses; therefore, outgrowth of infectious agents may result. Contrary to this, in the absence or reduced levels of CD39/CD73-Ado (left side), an increased inflammatory response may help the host to clear pathogens. At the same time, uncontrolled activation may lead to collateral tissue destruction. Any unregulated intervention to increase the expression of CD39/CD73 may dampen inflammation and impair immunity to infection. ...
Xiang et al. [109] recently reported that ATP helps fight against bacterial infection in mice...
A cAMP/PKA/CREB/HIF-1a signaling pathway downstream A2A receptor is activated, which results in up-regulation of pro-IL1ß and NLRP3 and greater caspase-1 activation. It is also reported that the inflammasome promotes a pro-inflammatory response which can be dependent on ROS generation [111]. ...
5. Conclusions
Adenosine is one of the many biomolecules that accumulate in the inflammatory milieu, conferring pleiotropic effects which can be beneficial or harmful. Extracellular adenosine produced by catabolizing enzymes, like CD39 and CD73, can add to the local adenosine pool. Adenosine generated through CD73 can provide feedback to control the tissue damage mediated by the host immune response. At the same time, during bacterial infection, it can also contribute to a harmful degree of immunosuppression leading to increased pathogen load (Figure 1). The studies outlined in this short review support the notion that adenosine production through the CD39/CD73-axis, and the ability of extracellular adenosine to limit inflammation may favor bacterial survival, thereby broadening the impact of infection.

Proteomic and transcriptomic profiling of Staphylococcus aureus surface LPXTG-proteins: correlation with agr genotypes and adherence phenotypes 
AdsA. Adenosine synthase. Agr. Accessory gene regulator. ClfA. Clumping ...
Proteomic and transcriptomic profiling of Staphylococcus aureus
surface LPXTG-proteins: correlation with agr genotypes and adherence phenotypes
Apart from these differences, some other proteins also demonstrated differential regulation between TSB and RPMI, including genes of the iron-capturing isd locus, as well as sizable increases in SasD and SasH in iron starvation. The increase in isd genes is expected in low iron medium [32,33]. On the other hand, the reason for the increase in SasD and SasH is more difficult to interpret. While the physiological role of SasD is as yet unclear, SasH (recently renamed AdsA [59]) is a cell wall associated adenosine synthase that converts adenosine-monophosphate into adenosine, a strong immunomodulator helping staphylococci to escape phagocyte-induced killing. Hence, SasH (or AdsA) could well be co-regulated with the siderophore locus isd, which expression is induced in experimental S. aureus nasal colonization [11]. In this setting, expression of isd could be required for survival in the low-iron mucosal environment, while SasH could be required to damper host defenses and promote bacterial persistence. Eventually, the mRNA of Srap was detected but its encoded protein was not, suggesting the possible lack of access to trypsin shaving. ...

Danger signal adenosine via adenosine 2a receptor stimulates growth of Porphyromonas gingivalis in primary gingival epithelial cells.
Spooner R1, DeGuzman J, Lee KL, Yilmaz O.
Mol Oral Microbiol. 2014 Apr;29(2):67-78. doi: 10.1111/omi.12045. Epub 2014 Feb 12.
Extracellular signaling during inflammation and chronic diseases involves molecules referred to as 'Danger Signals' (DS), including the small molecule adenosine. We demonstrate that primary gingival epithelial cells (GEC) express a family of G-protein coupled receptors known as adenosine receptors, including the high-affinity receptors A1 and A2a and low-affinity receptors A2b and A3. Treatment of Porphyromonas gingivalis-infected GEC with the A2a receptor-specific agonist CGS-21680 resulted in elevated intracellular bacterial replication as determined by fluorescence microscopy and antibiotic protection assay. Additionally, A2a receptor antagonism and knockdown via RNA interference significantly reduced metabolically active intracellular P. gingivalis. Furthermore, analysis of anti-inflammatory mediator cyclic AMP (cAMP) following A2a receptor selective agonist CGS-21680 stimulation induced significantly higher levels of cAMP during P. gingivalis infection, indicating that adenosine signaling may attenuate inflammatory processes associated with bacterial infection. This study reveals that the GEC express functional A2a receptor and P. gingivalis may use the A2a receptor coupled DS adenosine signaling as a means to establish successful persistence in the oral mucosa, possibly via downregulation of the pro-inflammatory response.
KEYWORDS: A2a receptor; epithelial mucosa; periodontal disease; persistence; purinergic signaling
PMID: 24517244 PMCID: PMC3960722 DOI: 10.1111/omi.12045
[Indexed for MEDLINE] Free PMC Article
Feb 12, 2014 - Furthermore, macrophages have been shown to upregulate A2a receptor mRNA ... For the opportunistic pathogens, Staphylococcus aureus and Bacillus .....
The study found that adenosine synthase homologues have 5' ... 

Ecto-5'-nucleotidase: a candidate virulence factor in Streptococcus sanguinis experimental endocarditis.
Fan J1, Zhang Y, Chuang-Smith ON, Frank KL, Guenther BD, Kern M, Schlievert PM, Herzberg MC.
PLoS One. 2012;7(6):e38059. doi: 10.1371/journal.pone.0038059. Epub 2012 Jun 7.
Abstract Streptococcus sanguinis is the most common cause of infective endocarditis (IE). Since the molecular basis of virulence of this oral commensal bacterium remains unclear, we searched the genome of S. sanguinis for previously unidentified virulence factors. We identified a cell surface ecto-5'-nucleotidase (Nt5e), as a candidate virulence factor. By colorimetric phosphate assay, we showed that S. sanguinis Nt5e can hydrolyze extracellular adenosine triphosphate to generate adenosine. Moreover, a nt5e deletion mutant showed significantly shorter lag time (P<0.05) to onset of platelet aggregation than the wild-type strain, without affecting platelet-bacterial adhesion in vitro (P=0.98). In the absence of nt5e, S. sanguinis caused IE (4 d) in a rabbit model with significantly decreased mass of vegetations (P<0.01) and recovered bacterial loads (log(10)CFU, P=0.01), suggesting that Nt5e contributes to the virulence of S. sanguinis in vivo. As a virulence factor, Nt5e may function by (i) hydrolyzing ATP, a pro-inflammatory molecule, and generating adenosine, an immunosuppressive molecule to inhibit phagocytic monocytes/macrophages associated with valvular vegetations. (ii) Nt5e-mediated inhibition of platelet aggregation could also delay presentation of platelet microbicidal proteins to infecting bacteria on heart valves. Both plausible Nt5e-dependent mechanisms would promote survival of infecting S. sanguinis. In conclusion, we now show for the first time that streptococcal Nt5e modulates S. sanguinis-induced platelet aggregation and may contribute to the virulence of streptococci in experimental IE.
PMID: 22685551 PMCID: PMC3369921 DOI: 10.1371/journal.pone.0038059
[PubMed - indexed for MEDLINE] Free PMC Article 

Extracellular nucleotide catabolism by the Group B Streptococcus ectonucleotidase NudP increases bacterial survival in blood.
Firon A1, Dinis M, Raynal B, Poyart C, Trieu-Cuot P, Kaminski PA.
J Biol Chem. 2014 Feb 28;289(9):5479-89. doi: 10.1074/jbc.M113.545632. Epub 2014 Jan 15.
Abstract - Streptococcus agalactiae (Group B Streptococcus) is a commensal of the human intestine and vagina of adult women but is the leading cause of invasive infection in neonates. This Gram-positive bacterium displays a set of virulence-associated surface proteins involved in the interaction with the host, such as adhesion to host cells, invasion of tissues, or subversion of the immune system. In this study, we characterized a cell wall-localized protein as an ecto-5'-nucleoside diphosphate phosphohydrolase (NudP) involved in the degradation of extracellular nucleotides which are central mediators of the immune response. Biochemical characterization of recombinant NudP revealed a Mn(2+)-dependent ecto-5'-nucleotidase activity on ribo- and deoxyribonucleoside 5'-mono- and 5'-diphosphates with a substrate specificity different from that of known orthologous enzymes. Deletion of the gene coding the housekeeping enzyme sortase A led to the release of NudP into the culture supernatant, confirming that this enzyme is anchored to the cell wall by its non-canonical LPXTN motif. The NudP ecto-5'-nucleotidase activity is reminiscent of the reactions performed by the mammalian ectonucleotidases CD39 and CD73 involved in regulating the extracellular level of ATP and adenosine. We further demonstrated that the absence of NudP activity decreases bacterial survival in mouse blood, a process dependent on extracellular adenosine. In vivo assays in animal models of infection showed that NudP activity is critical for virulence. These results demonstrate that Group B Streptococcus expresses a specific ecto-5'-nucleotidase necessary for its pathogenicity and highlight the diversity of reactions performed by this enzyme family. These results suggest that bacterial pathogens have developed specialized strategies to subvert the mammalian immune response controlled by the extracellular nucleotide signaling pathways.
KEYWORDS: Adenosine; Bacterial Pathogenesis; Enzyme Catalysis; Enzymes; Host-Pathogen Interactions; Metalloenzymes; Nucleoside Nucleotide Metabolism; Streptococcus
PMID: 24429288 PMCID: PMC3937624 DOI: 10.1074/jbc.M113.545632 [PubMed - indexed for MEDLINE] Free PMC Article
More recently, ecto-5-nucleotidases in bacterial pathogens have been identified, including the S. aureus AdsA enzyme (18–20). AdsA was first described as an adenosine synthase because of its ability to hydrolyze AMP into adenosine (18), whereas further characterization demonstrated that AdsA is an eN enzyme that also hydrolyzes ADP, ATP, GTP, GDP, and GMP as well as 2-deoxyadenosine 3-monophosphate (19, 20). Homologues of ecto-5-nucleotidases are present in several Gram-positive pathogens, including Enterococcus faecalis, Bacillus anthracis, Listeria monocytogenes, Streptococcus pyogenes (18), and Streptococcus sanguinis (21) but absent in the related human pathogen Streptococcus pneumoniae
In S. aureus, it was proposed that the main activity of the AdsA ectonucleotidase is to synthesize adenosine to dampen the proinflammatory response mediated by neutrophils (18) and very recently to inhibit macrophage recruitment and promote immune cell apoptosis following synthesis of deoxyadenosine (20)... A key difference between the S. aureus AdsA and the S. agalactiae NudP, apart from the pH range and the metal requirement, is the inability of NudP to hydrolyze deoxynucleoside 3-phosphate. Therefore, although the two bacterial species secrete a nuclease involved in neutrophil extracellular trap degradation (20, 54), the deoxyadenosine 3-phosphate resulting from DNA degradation can be used as a substrate by AdsA but not by NudP.

Purinergic signaling during inflammation.
Eltzschig HK1, Sitkovsky MV, Robson SC.
N Engl J Med. 2012 Dec 13;367(24):2322-33. doi: 10.1056/NEJMra1205750.
Comment in
Purinergic signaling during inflammation. [N Engl J Med. 2013]
PMID: 23234515 PMCID: PMC3675791 DOI: 10.1056/NEJMra1205750
[Indexed for MEDLINE] Free PMC Article
Purines are heterocyclic aromatic molecules that are among the oldest and most influential biochemical compounds in evolutionary history.1 The purine nucleotide adenosine triphosphate (ATP) is the universal energy currency of intracellular biologic reactions on which mammalian life is based. Here we examine the roles that purines play as extracellular signaling molecules, with a particular focus on ATP, adenosine diphosphate (ADP), and adenosine.

A2b Adenosine Receptor Regulates Hyperlipidemia and Atherosclerosis
Milka Koupenova, Hillary Johnston-Cox, Alexander Vezeridis, Haralambos Gavras, Dan Yang, Vassilis Zannis, Katya Ravid
Circulation. 2012;125:354-363 Originally published January 16, 2012
Background—The cAMP-elevating A2b adenosine receptor (A2bAR) controls inflammation via its expression in bone marrow cells...
Conclusion—This study provides the first evidence that the A2bAR regulates liver SREBP-1, hyperlipidemia, and atherosclerosis, suggesting that this receptor may be an effective therapeutic target.

Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation.
Jin X1, Shepherd RK, Duling BR, Linden J.
J Clin Invest. 1997 Dec 1;100(11):2849-57.
We investigated the mechanism by which inosine, a metabolite of adenosine that accumulates to > 1 mM levels in ischemic tissues, triggers mast cell degranulation... Inosine differs from adenosine in not activating A2AARs that dilate vascular smooth muscle and inhibit mast cell degranulation. The A3 selectivity of inosine may explain why it elicits a monophasic arteriolar constrictor response distinct from the multiphasic dilator/constrictor response to adenosine. Nucleoside accumulation and an increase in the ratio of inosine to adenosine may provide a physiologic stimulus for mast cell degranulation in ischemic or inflamed tissues.
PMID: 9389751 PMCID: PMC508491 DOI: 10.1172/JCI119833
[PubMed - indexed for MEDLINE] Free PMC Article
Inosine differs from adenosine in not activating A2AARs that dilate vascular smooth 
muscle and inhibit mast cell degranulation. The A3 selectivity of inosine may ...

Targeting adenosine receptors: novel therapeutic targets in asthma and chronic obstructive pulmonary disease.
Rorke S1, Holgate ST.
Am J Respir Med. 2002;1(2):99-105.
Adenosine, an endogenous signaling nucleoside that modulates many physiological processes has been implicated in playing an ever increasingly important role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). All cells contain adenosine and adenine nucleotides and the cellular production of adenosine is greatly enhanced under conditions of local hypoxia as may occur in inflammatory conditions such as asthma and COPD. In 1983, it was first reported that inhaled adenosine causes dose-related bronchoconstriction in patients with both allergic and non-allergic asthma but not in healthy volunteers. This hyperresponsiveness was also reported in patients with COPD, with those patients who smoked exhibiting a significantly greater response. This bronchoconstrictor effect of adenosine is orchestrated through the stimulation of specific cell membrane receptors and involves an important inflammatory cell, the mast cell. There is substantial evidence which suggests that mast cell activation is central to this unique response to adenosine. Mast cell mediator release makes a significant contribution towards airflow obstruction and the consequent symptoms in patients with asthma...
PMID: 14720064 [Indexed for MEDLINE]

Characterization of extracellular nucleotide metabolism in Candida albicans.
Rodrigues L1, Russo-Abrahão T2, Cunha RA1, Gonçalves T3, Meyer-Fernandes JR2.
FEMS Microbiol Lett. 2016 Jan;363(1):fnv212. doi: 10.1093/femsle/fnv212. 
Candida albicans is the most frequent agent of human disseminated fungal infection. Ectophosphatase and ectonucleotidase activities are known to influence the infectious potential of several microbes, including other non-albicans species of Candida. With the present work we aim to characterize these ecto-enzymatic activities in C. albicans. We found that C. albicans does not have a classical ecto-5'-nucleotidase enzyme and 5'AMP is cleaved by a phosphatase instead of exclusively by a nucleotidase that also can use 3'AMP as a substrate. Moreover, these enzymatic activities are not dependent on secreted soluble enzymes and change when the yeast cells are under infection conditions, including low pH, and higher temperature and CO2 content.
KEYWORDS: AMP; Candida albicans; adenosine; enzyme; nucleotide; purines
PMID: 26538575 DOI: 10.1093/femsle/fnv212 [PubMed - indexed for MEDLINE]
Undoubtedly, ecto-enzymes attached to the cell membrane or secreted to extracellular milieu represent important virulence factors, contributing to adhesion, invasion and residence inside phagosomes (e.g. Schaller et al. 2005; Frohner et al. 2009; Bhat et al. 2011)...  Indeed, several studies have revealed that the conversion of extracellular ATP into adenosine is determinant in the effciency of microorganism infection (Kas-Deelen et al. 2001; Romio et al. 2011; Mahamed et al. 2012), affecting pathogen interaction (KifferMoreira et al. 2007; Russo-Abrahao˜ et al. 2011) and adhesion to different host cells (Kiffer-Moreira et al. 2010; Portela et al. 2010; Kneipp et al. 2012; Cosentino-Gomes et al. 2013) and being a correlate of their pathogenicity (de Jesus et al. 2002; Bisaggio et al. 2003; Pinheiro et al. 2006; Sansom et al. 2007; Figueiredo et al. 2012). In that context, various proteins involved in the complex machinery of the ATP–ADP–AMP–adenosine cascade, with active sites facing the external medium, have been highlighted in host–pathogen interactions. In Streptococcus agalactiae it was recently described that the absence of ecto-5'-nucleotidase leads to decreased viability of bacteria in blood and that this effect is mediated by adenosine (Firon et al. 2014)... Thammavongsa and colleagues (Thammavongsa et al. 2009) have shown that some pathogens, such as Staphylococcus aureus and Bacillus anthracis, can use adenosine to overcome host immune responses...
The presence of ectonucleotidase activity in C. albicans was confrmed during this work by the fact that in different assay conditions intact yeast cells were able to hydrolyse 5'AMP...
Moreover, the putative C. albicans ecto-5'-nucleotidase enzyme was affected by several phosphatase inhibitors, reinforcing the doubts about this enzyme’s specificity. In fact, nucleotidase activity was inhibited by potent phosphatase inhibitors such as sodium orthovanadate, sodium fluoride and zinc chloride (Fig. 3B).
The specificity of substrates of yeast ecto-5'-nucleotidase was further investigated. Intact C. albicans cells were able to hydrolyse all monophosphate substrates tested (AMP, CMP, GMP, IMP and UMP), with slight differences, not statistically signifcant, between them, as well as the corresponding di- and triphosphate substrates, as indicated in Fig. 4A, B and C. In particular, it should be noted that C. albicans cells were able to hydrolyse 3'AMP (Fig. 4A). Aligned with the fndings that phosphatase inhibitors affect the C. albicans ecto-5'-nucleotidase, we also observed that sodium orthovanadate, at two different concentrations (0.1 and 1 mM), was able to inhibit nucleotidase activity by about 60% and 80%, respectively (Fig. 4D).
The extracellular metabolism of ATP has been identifed as controlling several homeostasis processes from thermogenesis and homeothermy, along with hormonal regulation (Silva 2006), to multiple mechanisms of cellular energy supply, of undoubted importance, for instance, to sustaining skeletal and cardiac muscle (Hochachka and McClelland 1997; Dzeja and Terzic 2003).
In microbes, the understanding was that ectophosphatase activity was important as a means of obtaining nutrients from the environment. Recently the importance of this metabolism has become apparent in human pathogens. Leishmania donovani, Cryptococcus neoformans, Candida parapsilosis or Staphylococcus aureus were described as having ectophosphatases and ectonucleotidases that are considered as determinants in their virulence (Gomes, Lopes and Meyer-Fernandes 2011; Russo-Abrahao˜ et al. 2011; Freitas-Mesquita and Meyer-Fernandes 2014). As an example, while ectophosphatases were described as being present in C. neoformans, ecto-5'-nucleotidase was found to be important in Saccharomyces cerevisiae (Itoh 1994; CollopyJunior et al. 2006). However, in Leishmania spp. or C. parapsilosis (with ecto-ATPase, ecto-ADPase) both types of enzymes can be found (Kiffer-Moreira et al. 2007, 2010; Russo-Abrahao˜ et al. 2011; Paletta-Silva and Meyer-Fernandes 2012). Taking this information into account, we now characterized C. albicans with respect to both ectophosphatase and ecto-5'-nucleotidase activities...
Hence, we believe that this maximal activity at a pH lower than in other pathogenic yeasts might be relevant to C. albicans cells’ survival/escape to the phagolysosome when infecting host cells, a key feature contributing to its success as a facultative intracellular pathogen. On the other hand, ecto-5'-nucleotidase activity decreases with a temperature of 37?C and with 5% CO2, the ambient conditions with which C. albicans copes when colonizing the host. Moreover, yeast cells grown in the absence of oxygen and left to grow until late stationary (batch culture, no oxygenation, 48 h) have lower activity (results not shown). So, taken together, all these results prompt us to wonder if during infection, when the yeast cells are inside the host cells, in particular inside acidic compartments, yeasts are more prone to hydrolyse these substrates than during extracellular life (either under non-infectious conditions or infecting the host but extracellularly, as observed when yeast cells are colonizing mucosal surfaces).
As described previously, it was reported that C. parapsilosis possesses both ectophosphatases and ecto-5'-nucleotidase enzymes, with specifc properties associated with each type of enzyme (Kiffer-Moreira et al. 2007; Russo-Abrahao˜ et al. 2011). Nevertheless, it seems that C. albicans does not have a classical ecto-5' -nucleotidase enzyme, as described in other organisms. C. albicans ectonucleotidases are able to use 5' AMP as substrate, but contrary to what was observed in C. parapsilosis, this enzyme is inhibited by several phosphatase inhibitors, revealing an unlike enzymatic profle. In addition to this, C. albicans ectonucleotidases are also able to use numerous other substrates, among which 3'AMP is particularly important. In fact, a 3'-nucleotidase/nuclease activity was observed in Leishmania spp., related to different aspects of parasite virulence, from nutrition to infection and escape to neutrophil extracellular traps (NETs) (Paletta-Silva and Meyer-Fernandes 2012; Guimaraes-Costa  et al. 2014). This activity was not described in other yeasts until now, but since it is known that this substrate, together with cAMP (3',5'-cyclic adenosine monophosphate), are involved and determinant to the yeast-to-hypha transition of C. albicans (Sabie and Gadd 1992; Sudbery 2011), we can speculate on the importance of this enzymatic activity in yeast survival and persistence either in the epithelial surfaces and/or once internalized by phagocytic cells... 

Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors.
Carlin JL, Tosh DK, Xiao C, Piñol RA, Chen Z, Salvemini D, Gavrilova O, Jacobson KA, Reitman ML.
J Pharmacol Exp Ther. 2016 Feb;356(2):474-82. doi: 10.1124/jpet.115.229872. 
Adenosine can induce hypothermia, as previously demonstrated for adenosine A1 receptor A1AR) agonists. Here we use the potent, specific A3AR agonists MRS5698, MRS5841, and MRS5980 to show that adenosine also induces hypothermia via the A3AR. The hypothermic effect of A3AR agonists is independent of A1AR activation, as the effect was fully intact in mice lacking A1AR but abolished in mice lacking A3AR. A3AR agonist-induced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A3AR hypothermia is mediated, at least in part, via mast cells. Central agonist dosing had no clear hypothermic effect, whereas peripheral dosing of a non-brain-penetrant agonist caused hypothermia, suggesting that peripheral A3AR-expressing cells drive the hypothermia. Mast cells release histamine, and blocking central histamine H1 (but not H2 or H4) receptors prevented the hypothermia. The hypothermia was preceded by hypometabolism and mice with hypothermia preferred a cooler environmental temperature, demonstrating that the hypothermic state is a coordinated physiologic response with a reduced body temperature set point. Importantly, hypothermia is not required for the analgesic effects of A3AR agonists, which occur with lower agonist doses. These results support a mechanistic model for hypothermia in which A3AR agonists act on peripheral mast cells, causing histamine release, which stimulates central histamine H1 receptors to induce hypothermia. This mechanism suggests that A3AR agonists will probably not be useful for clinical induction of hypothermia.
U.S. Government work not protected by U.S. copyright.
PMID: 26606937 PMCID: PMC4746492 DOI: 10.1124/jpet.115.229872
[PubMed - indexed for MEDLINE] Free PMC Article

Central activation of the A1 adenosine receptor (A1AR) induces a hypothermic, torpor-like state in the rat.
Tupone D1, Madden CJ, Morrison SF.
Since central activation of A1 adenosine receptors (A1ARs) plays an important role in the induction of the hypothermic and hypometabolic torpid state in hibernating mammals, we investigated the potential for the A1AR agonist N6-cyclohexyladenosine to induce a hypothermic, torpor-like state in the (nonhibernating) rat...
In rats exposed to a cool (15°C) ambient temperature, central A1AR stimulation produced a torpor-like state similar to that in hibernating species and characterized by a marked fall in body temperature due to an inhibition of brown adipose tissue and shivering thermogenesis that is mediated by neurons in the nucleus of the solitary tract. During the induced hypothermia, EEG amplitude and heart rate were markedly reduced. Skipped heartbeats and transient bradycardias occurring during the hypothermia were vagally mediated since they were eliminated by systemic muscarinic receptor blockade. These findings demonstrate that a deeply hypothermic, torpor-like state can be pharmacologically induced in a nonhibernating mammal and that recovery of normothermic homeostasis ensues upon rewarming. These results support the potential for central activation of A1ARs to be used in the induction of a hypothermic, therapeutically beneficial state in humans.
PMID: 24005302 PMCID: PMC3761054 DOI: 10.1523/JNEUROSCI.1980-13.2013
[PubMed - indexed for MEDLINE] Free PMC Article

Bacterial immune evasion
Posted on October 26, 2009 by AJ Cann
Staphylococcus aureus In mammals, adenosine assumes an essential role in regulating innate and acquired immune responses. Strong or excessive host inflammatory responses, e.g. in response to bacterial infection, exacerbate the tissue damage inflicted by invading pathogens. Successful immune clearance of microbes therefore involves the balancing of pro- and anti-inflammatory mediators. The cytokines IL-4, IL-10, IL-13, and TGF-β play a role in restricting excessive inflammation, but only adenosine is able to completely suppress immune responses. The immunoregulatory attributes of adenosine are mediated via four transmembrane adenosine receptors: A1, A2A, A2B, and A3. T lymphocytes express the high affinity A2A receptor as well as the low affinity A2B receptor. Depending on their activation state, macrophages and neutrophils express all four adenosine receptors, whereas B cells harbor only A2A. Engagement of A2A inhibits IL-12 production, increases IL-10 in monocytes and dendritic cells, and decreases cytotoxic attributes and chemokine production in neutrophils. Generation of adenosine at sites of inflammation, hypoxia, organ injury, and traumatic shock is mediated by two sequential enzymes.
Although extracellular adenosine is essential for the suppression of inflammation, build-up of excess adenosine is also detrimental. This is exemplified in patients with a deficiency in adenosine deaminase, an enzyme that converts adenosine to inosine. Adenosine deaminase deficiency causes severe compromised immunodeficiency syndrome, with impaired cellular immunity and severely decreased production of immunoglobulins. As the regulation of extracellular adenosine is critical in maintaining immune homeostasis, perturbation of adenosine levels is likely to affect host immune responses during infection...
Staphylococcal synthesis of adenosine in blood, escape from phagocytic clearance, and subsequent formation of organ abscesses were all dependent on adsA and could be rescued by an exogenous supply of adenosine. An AdsA homologue was identified in the anthrax pathogen Bacillus anthracis, and adenosine synthesis also enabled escape of B. anthracis from phagocytic clearance. Collectively, these results suggest that staphylococci and other bacterial pathogens exploit the immunomodulatory attributes of adenosine to escape host immune responses.

Adenosine's Greatest Hits, Volume 2 - Bonus Tracks

Re: Extracellular Adenosine Generation in the Regulation of Pro-Inflammatory Responses and Pathogen Colonization
Alam MS, Costales MG, Cavanaugh C, Williams K Biomolecules 2015, 5(2), 775-792; doi:10.3390/biom5020775
A cAMP/PKA/CREB/HIF-1a signaling pathway downstream A2A receptor is activated, which results in up-regulation of pro-IL1ß and NLRP3 and greater caspase-1 activation. It is also reported that the inflammasome promotes a pro-inflammatory response which can be dependent on ROS generation [111]...

^HIF-1 = Hypoxia-Inducible Factor-1. The pathway specified here may be a way for adenosine poisoning to trick your body into "thinking" that oxygen is in short supply, and may result in biological responses which could subsequently trick doctors into thinking the patient is suffering hypoxia, when it may not necessarily be the case. This may be a part of how excess adenosine may be able shift a host cell's metabolic mode.

Re: Characterization of extracellular nucleotide metabolism in Candida albicans.
Rodrigues L1, Russo-Abrahão T2, Cunha RA1, Gonçalves T3, Meyer-Fernandes JR2.
FEMS Microbiol Lett. 2016 Jan;363(1):fnv212. doi: 10.1093/femsle/fnv212. 
In fact, nucleotidase activity was inhibited by potent phosphatase inhibitors such as sodium orthovanadate, sodium fluoride and zinc chloride (Fig. 3B).

^Speaking of vanadate (not that it might make a safe choice of medication itself), one the properties of certain vanadium compounds may be to plug up the microbial PIE HOLE... excuse me, the microbial Pi (phosphate) uptake transporter... of various stubborn microbes. The conversion of ATP to adenosine also liberates Pi (phosphate), and using the well-studied Staphylococcus aureus as example, Phosphate uptake transporters may be upregulated along with adenosine / phosphate-liberating enzymes like adenosine synthases or nucleotidases, suggesting that microbes, particularly biofilm microbes, may be stocking up on Pi (phosphate). 

Biofilm organisms give the impression that they may be disassembling host ATP and or GTP, breaking it down and then uptaking the pieces, and using them to construct unusual guanine nucleotides like guanine tetraphosphase and guanine pentaphosphate ((p)ppgpp), which in turn appear to be connected to all sorts of persistance and resistance mechanisms like T/AT (toxin/antitoxin) systems. 

Again, in transforming into the biofilm phenotype, microbes may be going out of the citric acid cycle / aerobic respiration / ATP-making business (they may even be "avoiding" ATP because it could force them to revert to planktonic form, robbing them of stealth and resistance), and if so can probably afford to spit the adenosine produced from host ATP degradation back at the host, resulting in or contributing to the potentially immunosuppressive and inflammatory adenosine excesses decribed above.

I'm partly just guessing, so fingers crossed here that the microbial PI HOLE... excuse me, the microbial Pi (phosphate) uptake transporter... might prove be an Achilles' heel to a number of troublesome and stubborn microbes or their phenotypes. If so, maybe I will live to see the day when I won't have to hear doctors whine about how infections have become so difficult to treat that it isn't worth bothering anymore.
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911

Concission of informational material is sometimes prudent.
Your concern with adenosine may be misplaced, it may be correct. Dunno

Quote:As usual, chronic infections seem to be the elephant in the room that nobody wants to talk about, or look for.

You may want to research mycoplasma infections,
mycoplasma fermentans etc

Fungal {yeast etc} infections can get quite complicated with invasive pathogenic mycoplasma,
which are slow acting,
hide in synovial fluids from antibiotic attack ... 

often pathogenic mycoplasma can require many months of antibiotic doxycycline,
be sure to take your prebiotics and probiotics
Interestingly, theophylline in asthma inhalers may be an adenosine blocker. I've also seen the effects of theophylline and corticosteroid inhalers attributed to phosphodiesterase inhibition, but albuterol is supposed to be just the opposite in that respect. (Arginine and citrulline might also have some phosphodiesterase inhibitor activity as they've been cited as potentially therapeutic for erectile dysfunction). One of the more useful things I've done for myself may be staying heavily caffeinated, and caffeine turns out to be another adenosine blocker as noted in some of the cited works and quoted text. Caffeine may also have some TNF-a properties, which would hopefully support the integrity of the gut barrier and prevent things from getting from gut to blood on an on-going basis, as well as from blood to brain.

Anyway, not meaning to go on about my personal problems, but I think a lot of this research would be helpful and exciting if medical professionals were actually reading some of it, so just sort of taking a big data dump here. It does make me optimistic that a lot of diseases just aren't really that mysterious. I have family that work in respiratory therapy that don't seem to have ever heard of any of this, while also having family who lecture on multi-drug resistant Candida. Hard to get a consultation with them as they are busy little critters, but can't imagine their recommendations would differ from those of the CDC's ref on Candida - i.e., the speciation and susceptibility testing that I haven't succeeded in getting anyone to give me since they apparently still think the worst to come from Candida is feminine itching. Pharmaceutical companies must still think this too with the hurry they don't seem to be in to come up with some new and better antifungals.

You know what is strange after dragging all this stuff about alcohol & aldehyde detoxifying enzymes into the proceedings about thromboangiitis is that for all the screaming about tobacco, I don't think I've read one word yet about the impact that alcohol could have on the disease. Fortunately I'm about 11 years on the wagon, except for that time Jim Miller from Anomaly Hunters happened to be in town and I assisted him with a bottle of vino. Thought I was being sociable and ended up about three sheets to the wind. He probably still thinks I'm an alky.
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911

Quote:since they apparently still think the worst to come from Candida is feminine itching  Lol

Pharmaceutical companies must still think this too Nonono
with the hurry 
they don't seem to be in 
to come up with some new and better antifungals 

Oh, but the pharma terror companies have an interest in secondary fungal infections, 
especially as many go undiagnosed.
Fungal infections stimulate a lot of cancers for cancer drugs to be prescribed for.
Especially lung cancers.
Aspergillus exposure.  etc

Heart infections that are fungal used to require something called Amphoterracin for treatment.
Even the doctors call it --amphoterrible --

Feminine itching is a minor symptom,
but many women have persistent or recurrent vaginal candida infections,
and men can carry it in their sperm.

Keeping gut bacteria consistent alone,
will help keep many other fungal infection vectors to a minimum.

There is an unusual fungal infection that is airborne,
from tree dust and pollens in august - Sept in the Pacific Northwest.
Severe symptoms to long lingering lung infections.
Outbreaks on Vancouver Island.

very interesting reading:
Fungal Disease Spreads Through Pacific Northwest

Quote:So far, 
over the past 11 years there have been about 220 cases reported in British Columbia. 
Since 2004, 
doctors in Washington and Oregon have reported about 50 cases. 
Among the total 270 cases, 
40 people have died from overwhelming infections of the lungs and brain.

yea ... not ... feminine itching Whip

According to at least one source, Amphotericin B is one of the things that Candida infections may be able to reject if they have the appropriate efflux pumps. It's troubling for the idea of the recommended susceptibility testing to seem so foreign to doctors, or for them not to be connected to labs that can do them, because antifungals like that or those that carry a risk of organ damage / failure don't seem like something to be giving the patients if they're not even going to work in the first place.

I'm not entirely sure if I should, but I want to suspect fungi with that kind of resistance equipment whenever traditional or herbal antifungals don't seem to work. I think by species, garlic for example is supposed to be able to knock Candida albicans into next week, but no such luck here.

Also, I've been seeing a lot of stuff where tissue remodeling in pulmonary disease tends to look like collateral damage from immune attacks on something (is this something more likely to be smoke, or a virulent microbial threat?) - and I'm tempted to hope that that's reversible if the pathogen is ever actually cleared (as opposed to killing off everything that isn't a biofilm and leaving biofilm to continue the immunosuppression that may prevent tissue repair). That may be the situation I have with skin infections - lesions that don't heal, and maybe never will until the microbes are actually killed.

It might also be in some cases that some immune cells aren't going to go into repair mode while they see cause to remain in attack mode.

(I was surprised to read that the ability of certain amphibians to regenerate limbs can be alleviated by knocking out their macrophages, if I understood that correctly).

They're still doing some things in antibiotics for my skin complaint that may not be very bright in this respect - I'm beginning to wonder if researchers' habit of trying to kill everything at once that may be in a lesion is proving counterproductive. The best and the brightest still haven't succeeded in making much permanent progress, and I'm starting to think it may be because every time they've incorporated metronidazole into the antibiotic regimens to provide coverage for gram-negatives - the only other things they've done consistently are prescribe rifampicin which is made to sound almost foolproof against Staph even as biofilm, and fail - but what if antibiotics co-administered with metronidazole are being denatured by its DNA-denaturing activities when the antibiotics convene in the target microbial cell?

Since metronidazole is a prodrug modified in the target microbe in order to become microbicidal, if there are any telltale metabolites to evidence it degrading co-administered antibiotics, they may only be formed in microbes and may be therefore be produced in small quantities.

But yes, the guidelines for Candida treatment seem very strange, they may go as far as to say that if Candida colonizes any part of a person, it's cause for concern - then we get to the lung, and all of the sudden it's harmless - "nothing to see here, folks, move along"...

FWIW, I know a number of asthmatics - both early and late onset asthma - that may be having some small symptoms that may be suggestive of Candida, or who may be in high-risk groups for Candida "overgrowth" (use of miscellaneous steroidal medications or etc).

I'm having a little trouble feeling sure that things are proceeding through the gut on an ongoing basis. Yogurt also seems to be failing and it's actually starting to piss me off that there may be requirements by law to add probiotics that I suspect may not be well-understood by the people making the laws. Then there is kefir, the yogurt drink gaining in popularity which is made with Candida kefyr, one of the known disease-producing species of Candida. (Even if it's dead it might have a lot of Candida antigens in it for all anyone seems to know), and cases of disease resulting from use of probiotics containing Saccharomyces. 

I imagine that all it might take to have systemic Candidiasis is a one-time infiltration of the blood stream - one episode of bleeding gums, or your cat gives you a good scratch and you reflexively stick your gashed finger in your mouth before declaring "Damn, that hurts!"

Re: Cryptococcus, I'd need to doublecheck but I have a data table I made that says that Cryptococcus neoformans and Cryptococcus gattei have genes for adenylate cyclase (something that Aspergillus seem to consistently have), in possible contrast to some other Cryptococcus species.
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
I'm about to go over my literature again and try to come up with a more concise list on Candida, allergies, asthma and COPD as I just did for adenosine here (wish me luck). The first thing I'm reminded of is that some of these authors seem to be confused what fungal sensitized patients are reacting to - Alternaria and Cladosporium are frequently mentioned (aldehyde dehydrogenases Alt a10 UniProt: P42041 and Cla h3 UniProt: P40108 respectively?), but these may be organisms where cross-reactivity between Candida's aldehyde dehydrogenase and theirs is already noted?

I suppose it's worth asking when wondering which of these could have created the sensitization, which one is most likely to be already colonizing the patient? Unfortunately, they may be even more easily confused by Malassezia but I can't seem to think offhand of anyone establishing cross-reactivity involving its aldehyde dehydrogenase?

Sensitization to fungal allergens: Resolved and unresolved issues.
Fukutomi Y1, Taniguchi M2.
Allergol Int. 2015 Oct;64(4):321-31. doi: 10.1016/j.alit.2015.05.007. Epub 2015 Jun 9.
Despite its importance in the management of allergic diseases, precise recognition of species-specific IgE sensitization to fungal allergens is often challenging because the majority of fungal extracts exhibit broad cross-reactivity with taxonomically unrelated fungi. Recent progress in gene technology has contributed to the identification of specific and cross-reactive allergen components from different fungal sources.
Several allergenic proteins from fungi of the genus Candida have been approved by the WHO/IUIS Allergen Nomenclature Subcommittee. Cand a 1 is a 40-kD alcohol dehydrogenase from C. albicans. Using sera from 30 asthmatic patients with a positive skin test and IgE Abs to C. albicans, IgE immunoblotting of C. albicans extract showed that Cand a 1 had the highest frequency, being recognized by 23 (77%) patients.164 Cand a 3 is 20-kD peroxisomal protein, which has 62% sequence identity with a hypothetical protein (YDR533c) from Saccharomyces cerevisiae. 165
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
Some known efflux pumps of certain Candida specimens (from an unfinished data sheet I put together):

Candida albicans
CDR1 (CaCdr1p) (UniProt: P43071)
CDR2 (CaCdr2p) (UniProt: P78595?)
MDR1 (BEN; CaMdr1p) (UniProt: Q5ABU7? Q09GR1?)
FLU (UniProt: Q9HF77? G1UB37?)
MLT1 (UniProt: Q9UW87? Q5A762?)

Candida glabrata
CDR1 (CgCdr1p)
PDH2 (CgPdh1p)


Multidrug transporters CaCdr1p and CaMdr1p of Candida albicans display different lipid specificities: both ergosterol and sphingolipids are essential for targeting of CaCdr1p to membrane rafts.
Antimicrob Agents Chemother. 2008 Feb;52(2):694-704. Epub 2007 Dec 3.
Pasrija R, Panwar SL, Prasad R.

Efflux in fungi: la pièce de résistance.
Coleman JJ, Mylonakis E.
PLoS Pathog. 2009 Jun;5(6):e1000486. doi: 10.1371/journal.ppat.1000486. Epub 2009 Jun 26.

The only leads I may currently have for reversal of resistance in Candida by efflux pump inhibition are:

The monoamine oxidase A inhibitor clorgyline is a broad-spectrum inhibitor of fungal ABC and MFS transporter efflux pump activities which reverses the azole resistance of Candida albicans and Candida glabrata clinical isolates.
Holmes AR1, Keniya MV, Ivnitski-Steele I, Monk BC, Lamping E, Sklar LA, Cannon RD.
Antimicrob Agents Chemother. 2012 Mar;56(3):1508-15. doi: 10.1128/AAC.05706-11. Epub 2011 Dec 27.

Ibuprofen reverts antifungal resistance on Candida albicans showing overexpression of CDR genes.
Ricardo E1, Costa-de-Oliveira S, Dias AS, Guerra J, Rodrigues AG, Pina-Vaz C.
FEMS Yeast Res. 2009 Jun;9(4):618-25. doi: 10.1111/j.1567-1364.2009.00504.x. Epub 2009 Mar 30.

However, I'd have to go back and read the fine print to see whether the required doses are safe or attainable in humans in vivo. There are a lot of promising herbal resources for Candida until you go back and read the fine print about the MIC required and find out that it's not realistic in actual therapeutic practice.

An interesting fact on Candida that I need to do more research on is that supposedly, the more benign (?) yeast form is overlooked by the immune system, whereas the reproductive hyphal phase is not. This may raise certain questions about the efficacy of both Candidastatics and Candidacides, and certain Candida management programs, depending on the specific treatment goal?

Also, there are some initial murmurings that the idea of Candida "overgrowth" caused by "antibiotics killing off the competition" may involve x amount of dogma... (I have some of my own questions about the origins of certain Candida specimens or their behavior, such as what if the two oral Candida microbes that survived the alcohol onslaught of a mouthwash - or a swig of Everclear? - and went on to dominate the oral microbiome might have to have been mutants with a genetic disposition for making extra alcohol- and aldehyde-detoxifying enzymes. Since aldehyde dehydrogenase is a known Candida albicans allergen, could this result in Candida populations which are more highly allergenic?)

Tetracycline Effects on Candida Albicans Virulence Factors
Logan McCool, Hanh Mai, Michael Essmann, and Bryan Larsen
Infect Dis Obstet Gynecol. 2008; 2008: 493508. Published online 2008 May 29. doi:  10.1155/2008/493508 PMCID: PMC2408679
Object. To determine if tetracycline, previously reported to increase the probability of developing symptomatic vaginal yeast infections, has a direct effect on Candida albicans growth or induction of virulent phenotypes. 
Method. In vitro, clinical isolates of yeast were cultivated with sublethal concentrations of tetracycline and yeast cell counts, hyphal formation, drug efflux pump activity, biofilm production, and hemolysin production were determined by previously reported methods. 
Results. Tetracycline concentrations above 150 µg/mL inhibited Candida albicans, but at submicrogram/mL, a modest growth increase during the early hours of the growth curve was observed. Tetracycline did not inhibit hyphal formation at sublethal concentrations. Hypha formation appeared augmented by exposure to tetracycline in the presence of chemically defined medium and especially in the presence of human serum. Efflux pump CDR1 was upregulated and a nonsignificant trend toward increased biofilm formation was noted. 
Conclusion. Tetracycline appears to have a small growth enhancing effect and may influence virulence through augmentation of hypha formation, and a modest effect on drug efflux and biofilm formation, although tetracycline did not affect hemolysin. It is not clear if the magnitude of the effect is sufficient to attribute vaginitis following tetracycline treatment to direct action of tetracycline on yeast.
Epidemiological studies purport that the use of certain antibiotics during pregnancy increases susceptibility to vulvo-vaginal candidiasis [1, 2]. This condition is generally believed to result from the suppression of a bacterial flora in the face of antibacterial drugs that fail to inhibit Candida, resulting in its overgrowth and subsequent emergence of symptoms. Although this concept is often repeated in textbooks, surprisingly little direct evidence exists to support the concept that vaginal candidiasis is caused by prior antibiotic treatment. A report by Burns et al. [3] provided correlation between antibiotic use and vaginal colonization and candidiasis. Since the role of antibiotics in eliciting yeast vaginitis is medical dogma, there has been little reason to expend effort on developing actual data on the relationship between antibiotics and candidiasis.


Additional references on fungal allergens (aldehyde dehydrogases are only of them)...

Fungal allergens.
Horner WE, Helbling A, Salvaggio JE, Lehrer SB.
Clin Microbiol Rev. 1995 Apr;8(2):161-79.

Mold Allergens in Respiratory Allergy: From Structure to Therapy
Teresa E Twaroch, Mirela Curin, Rudolf Valenta, and Ines Swoboda
Allergy Asthma Immunol Res. 2015 May; 7(3): 205–220.
Published online 2015 Mar 11. doi:  10.4168/aair.2015.7.3.205
PMCID: PMC4397360

Identification of cell surface determinants in Candida albicans reveals Tsa1p, a protein differentially localized in the cell.
Urban C, Sohn K, Lottspeich F, Brunner H, Rupp S.
FEBS Lett. 2003 Jun 5;544(1-3):228-35.

Decoding serological response to Candida cell wall immunome into novel diagnostic, prognostic, and therapeutic candidates for systemic candidiasis by proteomic and bioinformatic analyses.
Pitarch A, Jiménez A, Nombela C, Gil C.
Mol Cell Proteomics. 2006 Jan;5(1):79-96. Epub 2005 Sep 28.

Immunoglobulin G Responses to a Panel of Candida albicans Antigens as Accurate and Early Markers for the Presence of Systemic Candidiasis
Cornelius J. Clancy, Minh-Ly Nguyen, Shaoji Cheng, Hong Huang, Guixiang Fan, Reia A. Jaber, John R. Wingard, Christina Cline, and M. Hong Nguyen
J Clin Microbiol. 2008 May; 46(5): 1647–1654.
Published online 2008 Mar 5. doi:  10.1128/JCM.02018-07 PMCID: PMC2395065

The link between fungi and severe asthma: a summary of the evidence.
Denning DW, O'Driscoll BR, Hogaboam CM, Bowyer P, Niven RM.
Eur Respir J. 2006 Mar;27(3):615-26.
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
It's nice to see some of these references concisely displayed for once. My own notes are a total mess due to their sheer volume, the difficulty categorizing multi-subject works, and so forth, and none of the patient forums I belong to have text systems that are friendly to bibliographies.

I'm currently looking for a particular article that tries to assure me that human antibodies to Enolase, a major allergen of Candida, don't cross-react with the human host version. There may still be questions to be asked whether proteolysis by a microbial protease or refolding of the human protein by human or microbial heat shock proteins might be able to expose a cryptic epitope. Candida has at at least six allergens which are involved in metabolic pathways of glycolysis and neoglucogenesis, one of which is Enolase, all of which might show particularly high homology to human versions, which might raise the prospects of cross-reactivity to host proteins.

Detection of IgE antibody against Candida albicans enolase and its crossreactivity to Saccharomyces cerevisiae enolase.
Ito K, Ishiguro A, Kanbe T, Tanaka K, Torii S.
Clin Exp Allergy. 1995 Jun;25(6):522-8.
Candida albicans 46 kDa protein, a glycolytic enolase enzyme, is an important allergen of the yeast. The purpose of the study was to detect circulating IgE and IgG antibodies against C. albicans enolase (CAE). We isolated CAE using sequential DEAE Sephacel and P11 column chromatography from spheroplasts of C. albicans, and detected IgE and IgG antibody against CAE by immunoblotting. Crossreactivity of enolase of C. albicans and Saccharomyces cerevisiae was also examined by immunoblotting and immunoblot inhibition test. Among 54 sera with positive IgE RAST to C. albicans, IgE antibody against CAE was detected in 20 sera (37%) and IgG antibody in 27 sera (50%). The allergenic potency of CAE was confirmed using a skin-prick test in three patients. Simultaneous IgE binding to S. cerevisiae enolase was only observed in four out of 20 sera reacting to CAE. Pre-treatment of sera with CAE completely inhibited IgE binding to S. cerevisiae enolase. Whereas the latter only partially inhibited IgE binding to CAE. These results suggest that CAE shares some crossreacting epitopes with S. cerevisiae enolase, representing minor components of CAE but dominant segments of S. cerevisiae enolase.
PMID: 7648459 [Indexed for MEDLINE]

I'm currently trying to answer the question of whether Candida could create cross reactivity to players in human metabolism like these which could produce histamine or other allergic responses if a sensitized person tried to use metabolic pathways specific to increased work/fuel demands.

"Excercise-induced asthma" does appear to be an actual thing (as is "Alcohol-induced asthma" which seems particularly suspicious given some of the material here?)
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
You go to ask a simple question like "Can a yeast infection make me allergic to dust mites?" and next you know you're doing another flippin' research project... Nothing gets to be simple, does it?

Here is a particularly obscure piece of information that I will file here for future reference...

I'm currently attempting to find a satisfactory homology between any dust mite allergen, and any Candida allergen.

The American House Dust Mite, Dematophagoides farinae, turns out to have an aldehyde dehydrogenase allergen. It is Aldehyde dehydrogenase DEFA_095270 deduced to be 490 amino acids long and having a reported 65.1% homology to the aldehyde dehydrogenase allergen P42041 from Alternaria alternata. 

It does not appear in UniProt searches thus far, nor does it appear to be located by Google searches. I found it in this article and its supplementary materials:

The draft genome, transcriptome, and microbiome of Dermatophagoides farinae reveal a broad spectrum of dust mite allergens.
Chan TF1, Ji KM2, Yim AK3, Liu XY4, Zhou JW5, Li RQ4, Yang KY6, Li J7, Li M4, Law PT1, Wu YL4, Cai ZL4, Qin H3, Bao Y4, Leung RK6, Ng PK5, Zou J4, Zhong XJ4, Ran PX7, Zhong NS8, Liu ZG9, Tsui SK10.
J Allergy Clin Immunol. 2015 Feb;135(2):539-48. doi: 10.1016/j.jaci.2014.09.031. Epub 2014 Oct 31.
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
I'm a lot more concerned with candida and fungal infections than house dust mites.
I was surprised to see that dust mites are in the spider family.
Mosquito's even this far north are getting to be of concern.

Garlic has always been a good food for controlling candida for me.
I eat a half a pumpkin pie a day -- sweetened with blue agave.
Half a key lime pie in the fridge as well right now.
I am drinking beer right now.
But I eat my greek yoghurt and we have fabulous flax blueberry muffins,
so I shit like a king most of the time.

but I also have the handy dandy Probiotic --- called 100 billion ---gotta have it handy to be dandy

The next thing I like to think I'm doing is to scrutinize the Secreted Aspartyl Proteases (SAPs, see also Candidapepsins) of Candida for possible homology to human aldehyde dehydrogenase 3B1 (highly expressed in the lung). Some 10 different types and at least 30 different examples of SAPs are known for Candida albicans. As secreted proteins, SAPs may be eligible allergens even when there may be a possibility that residence in biofilms might render stationary surface proteins of Candida inaccessible to immunoglobins. I also have several references that assert that SAPs are critical to the virulence and success of Candida infections (including "Sensitization to fungal allergens: Resolved and unresolved issues," above).

Unfortunately, I also have literature that may be implying that the production of SAPs may be upregulated in forms of Candida generally considered to be more benign.

This article describes some of the fungal shape-shifting tricks of Candida

Discovery of a "white-gray-opaque" tristable phenotypic switching system in candida albicans: roles of non-genetic diversity in host adaptation.
Tao L1, Du H1, Guan G1, Dai Y1, Nobile CJ2, Liang W3, Cao C3, Zhang Q3, Zhong J4, Huang G1.
PLoS Biol. 2014 Apr 1;12(4):e1001830. doi: 10.1371/journal.pbio.1001830. eCollection 2014.

While advising us of possible varying levels of SAP activity (it seems as if may be difficult to predict what happens in vivo, since SAP output may apparently also depend on the nutrition provided to the specimen):

"White, Gray, and Opaque Cells Exhibit Differential Secreted Aspartyl Protease (Sap) Activity
The transcriptional profiles of the SAP genes, which are known major virulence factors [26], were different in the three cell types. We therefore tested Sap activities using the yeast carbon base (YCB)-bovine serum albumin (BSA) medium assay. As expected, white cells showed lowest Sap activity, which is consistent with low expression levels of the SAP genes. However, we surprisingly found that gray cells exhibited higher Sap activity than opaque cells, indicated by the white halos of precipitated BSA (Figure 4A). Quantitative Sap activity assays verified these results (Figure 4B). This result is inconsistent with the expression profiles of SAP genes in gray and opaque cells. Since the RNA-Seq analysis was performed in Lee's glucose medium (without BSA), we predicted that the YCB-BSA medium induced the expression of SAP genes in gray cells and thus increased Sap activity. To test this hypothesis, we performed quantitative Sap activity assays. As predicted, the Sap activity of opaque cells was higher than that of gray cells in Lee's glucose medium, but was lower than that of gray cells in the YCB-BSA medium. Using a green fluorescent protein (GFP) reporter system (Figure 4C and 4D) and quantitative real-time PCR (Figure 4E) assays, we further found that SAP1 was constitutively expressed in opaque cells in both media. SAP2 exhibited extremely low expression levels in all three cell types in Lee's medium, while its expression level was increased over thousands of times in gray cells cultured in the YCB-BSA medium. Taken together, these results imply that the three cell types are likely to have differential virulence characteristics at different host niches."

(It also seems hard to predict the impact of various influences on Candida in vivo since while there is a wealth of research describing environmental factors that influence the phenotype of Candida, there is also literature that refers to the potential ability of Candida and other pathogenic microbes to manipulate their immediate environs. One article suggests that Candida can self-induce its morphological changes by altering the pH in its vicinity).

Candida albicans secreted aspartyl proteinases: isoenzyme pattern is determined by cell type, and levels are determined by environmental factors.
White TC1, Agabian N.
J Bacteriol. 1995 Sep;177(18):5215-21.
For the pathogenic yeast Candida albicans, secreted aspartyl proteinase (Sap) activity has been correlated with virulence. A family consisting of at least eight SAP genes can be drawn upon to produce Sap enzymatic activity. In this study, the levels of Sap1, Sap2, and Sap3 isoenzymes were monitored under a variety of growth conditions for several strains, including strain WO-1, which alternates between two switch phenotypes, white (W) and opaque (O). When cultured under proteinase-inducing conditions, most strains and W cells produce Sap2, while O cells produce Sap1, Sap2, and Sap3. Both W and O cells of strain WO-1 produce Saps in enriched and defined media that do not induce Saps from other strains. The specific Sap isoenzyme that is produced is determined by the cell type, while the level of Sap production is determined by environmental factors. The levels and temporal regulation of the SAP mRNAs as determined by Northern (RNA) analysis were consistent with Sap protein levels and with previous results. S1 analysis showed that SAP6 is the predominant SAP gene transcribed during hyphal induction at neutral pH. These studies define the culture conditions which control the levels of SAP mRNAs and Sap proteins, and they indicate that both the yeast/hyphal transition and phenotypic switching can determine which of the Sap isoenzymes is produced.
PMID: 7665510 PMCID: PMC177311 [PubMed - indexed for MEDLINE] Free PMC Article

Meanwhile back at adenosine and pals, right or wrong, meaningful or meaningless, I thought it was interesting that while Firon et al (see above) tell us that

"Homologues of ecto-5-nucleotidases are present in several Gram-positive pathogens, including Enterococcus faecalis, Bacillus anthracis, Listeria monocytogenes, Streptococcus pyogenes, and Streptococcus sanguinis but absent in the related human pathogen Streptococcus pneumoniae." 

Zhang, in relating a "yin-yang" model of microbial persistence asserts that 

"For example, Streptococcus pneumoniae seems to have poor ability to form persisters such that its cure by a single antibiotic can be achieved readily in a week or two. In addition, immune clearance of a small number of residual S. pneumonia seems effective, so there is usually no relapse after antibiotic treatment.

Which may or may not be consistent with the proposal that adenosine-generating mechanisms may be directly related to the recalcitrance of certain infections

Persisters, persistent infections and the Yin–Yang model
Ying Zhang
Emerg Microbes Infect. 2014 Jan; 3(1): e3. Published online 2014 Jan 8. doi:  10.1038/emi.2014.3 PMCID: PMC3913823
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
"Could be something, could be nothing" department:

The peptide sequence YGDxxxSxxxL appears in human aldehyde dehydrogenases ALDH3B1 (lung), ALDH3B2 (salivary glands - I've had numerous "bronchitis attacks" accompanied by unexplained hypersalivation so this is intriguing even if ALDH3B2 is not ordinarily supposed to be a protein displayed on the host cell surface, in apparent contrast to ALDH3B1), and in Candida aspartyl proteases SAP1 and SAP2. (It also occurs in human trehalase, but it does not seem to appear in any known Dermatophagoides proteins unless it appears in one of the unpublished allergen sequences).

IF this is a valid epitope recognized by antibodies, then perhaps it is capable of causing selective cross-reactivity between ALDH3B1/2 and SAP1/2? However, literature regarding this question is implied by Google to be potentially non-existent by searches YGDxxxS + epitope or YGDxxxS + antigenic (determinant).

Whatever it means, this peptide sequence also appears in Cannabis limonene synthase TPS1_CANSA

Well, that does seem to be another thing about my possible allergies, is that for whatever reason they may make it difficult to ingest reefer, which should sort of really piss me off since it's finally legal in my state.

Don't let yeast infections take away your freedoms!?!?!

"Could be something, could be nothing" department (2):

This is from an older attempt at this type of question.

The peptide sequences (P)LVGxxxxxxxVV and LAAGxxV are shared by Candida aldehyde dehydrogenase ALDH1 UniProt: P43067 and human aldehyde dehydrogenase ALDH3B1 UniProt: P48448. LAAGxxV also appears in human ALDH3B2, as does the sequence LVGxxxxxxxVV. In these two human aldehyde dehydrogenases, the shorter sequence actually appears inside of the longer one.

IIRC, these homologies were NOT detected by the online BLAST protein comparison program. Rather, I had to detect them myself by playing "word search puzzle" with the data. Curiously, while they do seem rather specific to appearance in only these two (ALDH3B1 and -3B2) among numerous human aldehyde dehydrogenases, both of these sequences may occur in hundreds of different proteins in nature, ultimately making them a possible mismatch for more selective occurrence of symptoms? Hence perhaps YGDxxxSxxxL might be a greener tree to be barking up?

(LVGxxxxxxxVV occurs in @ 430 proteins in Swiss-Prot, Homo sapiens = 26, Candida = 11; LAAGxxV occurs in @ 1440 proteins in Swiss-Prot, Homo sapiens = 53, Candida = 5; LAAGxxVV occurs in @ 153 proteins in Swiss-Prot, Homo sapiens = 7, Candida = 0)

Thus the question may remain, "What constitutes proof that a doctor might accept in order for the patient to gain access to appropriate medical services or treatment?" - while there are plenty of psyllium-slingers on the Internet lecturing on Candida who will all assure me that Candida can make me allergic to dust mites and "all kinds of things," where is the Smoking Epitope?

BTW, I did look in the yellow pages for The Big City, and there are offices offering Candida testing (one of them sounded like it had a drive-thru window), but they also all sound half determined beforehand to give me yogurt enemas about it even if it turns out to be a bloodstream infection. Would my personal physician find these test results credible or actionable?

On a remotely related note, I am seriously pissed at Dr. Phil for the program he had on the other day, along with some guest "expert" who's peddling the idea that commensal microbes are "good for you" and trying to pawn off doctor dogma about how asthma is because your parents won't let you eat dogshit when you're a toddler so your immune system never has a chance to learn anything.

I already know the hard way how easily medical experts are confounded by polymicrobial infections that involve all of TWO (commensal!) microbes, so I have a very hard time believing that anyone has truly mastered understanding of the dynamics of the almost countless microbial varieties that comprise the human gut flora.

So he's got some kid on who's a germ-o-phobe and they're insisting he should run out and eat some dogshit at the first available opportunity because microbes are your little friends and they make great pets and blah blah blah. Here I'm thinking if someone is phobic about germs, maybe their body is telling them they already have a latent, immunosuppressive (biofilm?) infection that really doesn't need to rendezvous with any potential collaborators?

Also, if Dr. Phil is suddenly a credible microbiologist, I'm almost certain that I am too. (I suppose I have to give him a point though for not trying to pound someone else's turds up this poor kid's arse for the sake of "good bugs"?)

"In the United States, the Food and Drug Administration (FDA) has regulated human feces as an experimental drug since 2013."

Or, as it's done on South Park

"Mmm, mmm... Good bugs!"
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
(03-20-2017, 03:28 AM)Vianova Wrote: Garlic has always been a good food for controlling candida for me.
I eat a half a pumpkin pie a day -- sweetened with blue agave.
Half a key lime pie in the fridge as well right now.
I am drinking beer right now.
But I eat my greek yoghurt and we have fabulous flax blueberry muffins,
so I shit like a king most of the time.

Perhaps I've underestimated the powers of PIE? (I usually just watch it floating on by up there...)
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
So here is a curious thing, perhaps it is A CLEW? In spite of all the talk about bronchoconstriction that goes on in the context of pulmonary diseases, I have never once had this complaint. I have a very clear sense that what is happening is metabolic, that it may have an adverse impact on pulmonary-related musculature, and any hyperventilation is all about getting something out (as opposed to struggling to get oxygen in), like some metabolic waste product that isn't finding any other way out of my person and it's imperative to blow it out. 

I don't know who else's problems may be similar, but looking at my case I can see how easy it can be for the observer to mistake one for the other (and this would presumably be very similar to the possible confusion between vasoconstriction and vasodilation in cardiovascular disease discussed here).

If I didn't accidentally already spew out the answer to this somewhere here already, I'm still not sure what to make of this, although this perspective might be a contributor to such crazy ideas of mine like Candida possibly having the potential to hot wire a patient's metabolism so that their body becomes complicit in the production of acetaldehyde.

Apparently vitamins may be able to help intercept acetaldehyde (the other end of the stick being that acetaldehyde may be able to rob you of nutrients in the form of acetaldehyde-nutrient conjugates). Someone on CureZone I think it was did a remarkable job describing some of these conjugates complete with respectable references, but I didn't come away with what vitamins would result in the most innocuous by-products. 

There are also some recommendations I remain wary of, like certain enzyme co-factors such as molybdenum. I'm not entirely sure anyone making the recommendation knows the difference between an aldehyde dehydrogenase and an aldehyde oxidase. Aldehyde oxidase may not be an optimal detox pathway for aldehydes since a by-product of the reaction is peroxide.

Another curious complaint I have is that anything that comes out that is mucus is frothy. Naturally telling my doctor this got me the echocardiogram with the nurse scrolling a mouse thing over my greased tit for an hour because this is suggestive of a heart problem, but when it comes back that I haven't got a heart problem, no one seems to know what to make of this symptom. This may be another clew (and I did find a patient forum with pages and pages of patients having this same unexplained complaint, so apparently I'm not the only one it happens to)?

I might also throw out that almost everything I've seen so far makes it sound like what goes on in pulmonary pathologies that I've read about, may include that the immune system (as opposed to lifestyle) may be eligible to take considerable responsibility for symptoms, including tissue remodeling. Normally we might think things like these (eosinophilia and etc) are "erroneous" over-reactions that should be suppressed, but they might actually turn out to be normal responses to infection (albeit that the pathogen may have worked out ways around normal defenses)?

Anyway, as one might imagine, when ya ain't breathing right, everything else looks like PIE... 

So naturally I am always happy for scientists when they're awarded a gazillion dollars to build a superconducting supercollider the size of the Ukraine so they can try to catch and cage a particle of the God they don't believe in, but it does taste faintly of meringue to my pallette...
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
Several fairly appropriate comments? Does anyone know what these medications actually do, even now?

Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers
Donna Donigi Gale, Linda J Landells, Domenico Spina, Alan J Miller, Kate Smith, Terry Nichols, Yakov Rotshteyn, Alfred Tonelli, Peter Lacouture, Ronald M Burch, Clive P Page, and Brian J O'Connor
Br J Clin Pharmacol. 2002 Nov; 54(5): 478–484. doi:  10.1046/j.1365-2125.2002.01682.x PMCID: PMC1874476
...Recently, the orally active PDE4 selective inhibitors, CDP840 [9] and roflumilast [10] have been demonstrated to modestly attenuate the development of the late asthmatic response in mild asthmatics whilst having no effect on the acute response, with no significant side-effects being reported in comparison with placebo. The ability of these novel selective PDE4 inhibitors to inhibit the late asthmatic response was not associated with bronchodilation, suggesting actions of this drug other than smooth muscle relaxation. Furthermore, another PDE4 inhibitor RPR73401, has also been shown to have no significant effect on allergen-induced bronchoconstriction in allergic asthmatic subjects [11], consistent with the suggestion that PDE3 rather than PDE4 may be the important isoenzyme regulating airway smooth muscle tone in asthmatic subjects. However, recent clinical studies with another orally active PDE4 inhibitor, cilomilast have shown that this drug can attenuate bronchoconstriction following exercise in asthmatic subjects [12], an effect mimicked by 4 weeks of treatment with the selective PDE4 inhibitor rofluminlast [13]. Similarly, cilomilast provided significant clinical improvement in patients with asthma and COPD [14].
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
Was searching for something else entirely... As I say, these things find me...

Health & Drugs: Disease, Prescription & Medication
Nicolae Sfetcu - 2014 
Several types of "Smoker's Paradoxes" [29], i.e. cases where smoking appears to have specific beneficial effects, have been observed; often the actual mechanism remains undetermined. For instance, recent studies suggest that smokers require less frequent repeated revascularization after percutaneous coronary intervention (PCI) [29], [30]. Smoking appears to interfere with the development of Kaposi's sarcoma [31], breast cancer among women carrying the very high risk BRCA gene [32], preeclampsia [33], and atopic disorders such as allergic asthma [34]. A plausible mechanism of action in these cases may be the nicotine in tobacco smoke acting as an anti-inflammatory agent [35] and interfering with the disease process.

Considering what all inflammation might be credited with in pathologies, nicotine might actually be slightly more versatile than that. It's a shame that my doctors seems so easily convinced of the exact opposite - that tobacco is highly inflammatory stuff that made my cilia fall out (he never even looked), my wiener fall off, and kittens hate me.

It's also a shame that it doesn't seem very interesting to find out why it might be an anti-inflammatory or how to replace it. I find it to be supplemental to other anti-inflammatories, and far more able to replace the rest of them than vice-versa. It's another dodgy one in that nicotine receptors, if I understand correctly, are GPCRs that are allegedly going try to RAISE intracellular cAMP where I'm saying that there already be issues with excess there because of other GPCR activity associated with pathologies - adenosine receptors, TAAR, etc. So it wants to sound like it's working FOR pathogens - synergistically with their cAMP-elevating immunosuppressive toxins - when experience (and possibly a significant amount of literature and common sense) implies the opposite.

There's an awful lot that can happen in the fine details concerning receptors, though.

(Lest anyone think I'm as rude and arrogant with my smoking as I often am with my PIE HOLE, I've lit all of 3 cigs in the house in the 18 years I've lived here, and that was when my wife wasn't due back for a week. Like I say, I don't actually recommend the stuff and I know some people are sensitive, because I'm racking my brains to try to figure out why).

Really wish I could find epitope mapping for some of these other allergens as we seem to have for SAP2 here, even if the general rule were to be that the shorter the epitope, the more ubiquitous it may be likely to be, and the less suspicious it might actually be because of that. I'm going through something very much like that with various auto-antibodies in my miscellaneous diagnoses and also with the Candida cross-reactive fungi Alternaria and Cladosporium at the moment - very likely asthma triggers because of how common they are in the air - yet why are more people not sensitized because of their ubiquity?

Epitope mapping Candida albicans proteinase (SAP 2)
Ali Ghadjari, Ruth Christine Matthews, James Peter Burnie
FEMS Immunol Med Microbiol. 1997 Oct;19(2):115-23.
The continuous epitopes of Candida albicans proteinase SAP 2 were derived by epitope mapping with sera from patients with oral candidiasis (n=3), necropsy-proven disseminated candidiasis (n=5), paired sera from patients who had recovered from blood culture-proven disseminated candidiasis (n=3) and infection due to Candida parapsilosis (n=2) and Candida tropicalis (n=2). In C. albicans infection, IgM identified epitopes in amino acid positions 57–61 (QAVPV), 146–151 (SQGTLY) and 346–351 (PYDKCQ) and IgG at position 386–390 (VKYTS). For C. tropicalis IgM and IgG were positive for the same epitopes whilst IgG also detected epitopes at 78–83 (SNNQKL) and 159–164 (GVSIKN). For C. parapsilosis, IgM was positive for SNNQKL and IgG detected no epitopes. Reactivity of two of the epitopes as peptides KTSKRQAVPVTL and SLAQVKYTSASSI was confirmed in an indirect ELISA. At a cut-off optical density of 0.4, IgM against either peptide was associated with survival but present in only about half of the sera (n=60) from patients who recovered from disseminated candidiasis whilst IgG levels were disappointing. Human recombinant antibodies from a patient who had recovered from disseminated candidiasis against either of these peptides had no activity in a lethal mouse model of candidal infection.
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
No, I suffered from too much pie,
and then beer,
to facilitate a bad day digestively yesterday ,which produced overall fatigue.

I smoke too much good weed, and so when key lime pie comes my way,
I have no control,
and part of that is the yeast dictating food consumption,
but the left over key lime pie,
was slathered in yoghurt tonite. 

if you keep your yeast - candida under control in your gut <---
you maintain a stronger resistance to: 
that is pathogenic 
or even toxic that affetcs you.

all your flu and cold resistance,
your cancer resistance,
your fatigue levels,
your stamina,
clarity of mind,
everyday life, 
is improved, balanced, 
and maintained with more inner strength and reserve and resistance to disease,
by keeping your proper gut bacteria at levels to keep yeast under control. 

Off to have a "100 billion" probiotic right now.
To each their own, especially if something actually works for them, but now you know where my aversion to probiotics comes from. :-) (That, and the little I know about the genome of Lactobacillus).

Besides, I had it figured that probiotics just sort of come with the food chain, or out of the air, and would just fill a niche back in like they filled it in the first place unless some surly little mutant keeps kicking them to the curb.

This report seems to harmonize with my suspicion of Candida and Saccharomyces being possible primary sensitizers, even though here it's supposed to be sensitization to mannan at issue instead of aldehyde dehydrogenase.

IgE, IgA, and IgG responses to common yeasts in atopic patients.
Savolainen J1, Kortekangas-Savolainen O, Nermes M, Viander M, Koivikko A, Kalimo K, Terho EO.
Allergy. 1998 May;53(5):506-12.
This study was undertaken to analyze the differences in exposure and sensitization to five common environmental yeasts. The responses of IgG, IgA, and IgE to Candida albicans, C. utilis, Cryptococcus albidus, Rhodotorula rubra, and Saccharomyces cerevisiae and purified S. cerevisiae enolase were analyzed by immunoblotting (IgE-IB), and the cross-reactivity of their IgE-binding components by IgE-IB inhibition. Twenty atopic subjects, with asthma, allergic rhinitis, or atopic dermatitis were included. In skin prick tests (SPT), 12 of the patients showed simultaneous reactivity to at least two of the five yeasts, four reacted to one of the yeasts, and four had no responses. Antigens run in SDS-PAGE and transferred to nitrocellulose were probed with enzyme-labeled IgA-, IgG-, and IgE-specific antibodies. The IgE immunoblotting revealed most IgE-binding bands in C. albicans (11 bands) followed by C. utilis (eight bands), S. cerevisiae (five bands), R. rubra (five bands), and Cr. albidus (four bands). Six of the IgE-binding bands of C. albicans and C. utilis shared molecular weight, and only two bands shared molecular weight with other yeasts. These were the 46-kDa band, shared by all five yeasts, and a 13-kDa band shared by four yeasts. Prominent IgE binding was seen to a 46-kDa band of C. albicans (seven patients), C. utilis (five patients), and S. cerevisiae (one patient) and to corresponding weak bands of Cr. albidus and R. rubra (one patient). The possible cross-reactivity of the 46-kDa band was analyzed by IgE-IB inhibition and densitometry, revealing clear C. albicans inhibition of C. utilis (80%) and enolase (98%) (autoinhibition 100%). The strongest IgG responses were seen against S. cerevisiae and C. albicans. The responses were mainly against mannans of C. albicans and S. cerevisiae, suggesting that most of the exposure is to these yeasts. Yeasts with different types of exposure, from saprophytic growth on human mucous membranes to exposure by air and food, were shown to cross-react at the allergenic level. Atopic patients primarily sensitized by C. albicans and S. cerevisiae may develop allergic symptoms by exposure to other environmental yeasts due to cross-reacting IgE antibodies. 
PMID: 9636810 [Indexed for MEDLINE] Free full text [?]
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
Further dissent among the ranks?

Low virulent oral Candida albicans strains isolated from smokers.
de Azevedo Izidoro AC, Semprebom AM, Baboni FB, Rosa RT, Machado MA, Samaranayake LP, Rosa EA.
Arch Oral Biol. 2012 Feb;57(2):148-53. doi: 10.1016/j.archoralbio.2011.08.016. Epub 2011 Sep 15.
It is widely accepted that tabagism is a predisposing factor to oral candidosis and cumulate data suggest that cigarette compounds may increase candidal virulence. To verify if enhanced virulence occurs in Candida albicans from chronic smokers, a cohort of 42 non-smokers and other of 58 smokers (all with excellent oral conditions and without signs of candidosis) were swabbed on tong dorsum and jugal mucosa. Results showed that oral candidal loads do not differ between smoker and non-smokers. Activities of secreted aspartyl-protease (Sap), phospholipase, chondroitinase, esterase-lipase, and haemolysin secretions were screened for thirty-two C. albicans isolates. There were detected significant increments in phospholipasic and chondroitinasic activities in isolates from non-smokers. For other virulence factors, no differences between both cohorts were achieved.
PMID: 21924704 DOI: 10.1016/j.archoralbio.2011.08.016 [Indexed for MEDLINE]

Of course, whatever the research may suggest, it may always be somewhat short-sighted to speak as if tobacco is the only potential modifier of microbial phenotype that might be present, even if there are also indications that microbes may often enough be more the masters of their immediate environments than at the mercy of them.

The novel Candida albicans transporter Dur31 Is a multi-stage pathogenicity factor.
Mayer FL, Wilson D, Jacobsen ID, Miramón P, Große K, Hube B.
PLoS Pathog. 2012;8(3):e1002592. doi: 10.1371/journal.ppat.1002592. Epub 2012 Mar 15.
Candida albicans is the most frequent cause of oral fungal infections. However, the exact pathogenicity mechanisms that this fungus employs are largely unknown and many of the genes expressed during oral infection are uncharacterized. In this study we sought to functionally characterize 12 previously unknown function genes associated with oral candidiasis. We generated homozygous knockout mutants for all 12 genes and analyzed their interaction with human oral epithelium in vitro. Eleven mutants caused significantly less epithelial damage and, of these, deletion of orf19.6656 (DUR31) elicited the strongest reduction in pathogenicity. Interestingly, DUR31 was not only involved in oral epithelial damage, but in multiple stages of candidiasis, including surviving attack by human neutrophils, endothelial damage and virulence in vivo. In silico analysis indicated that DUR31 encodes a sodium/substrate symporter with 13 transmembrane domains and no human homologue. We provide evidence that Dur31 transports histatin 5. This is one of the very first examples of microbial driven import of this highly cytotoxic antimicrobial peptide. Also, in contrast to wild type C. albicans, dur31-/- was unable to actively increase local environmental pH, suggesting that Dur31 lies in the extracellular alkalinization hyphal auto-induction pathway; and, indeed, DUR31 was required for morphogenesis. In agreement with this observation, dur31-/- was unable to assimilate the polyamine spermidine.

The Fungal Pathogen Candida albicans Autoinduces Hyphal Morphogenesis by Raising Extracellular pH
Slavena Vylkova, Aaron J. Carman, Heather A. Danhof, John R. Collette, Huaijin Zhou, and Michael C. Lorenz
mBio. 2011 May-Jun; 2(3): e00055-11. doi:  10.1128/mBio.00055-11 PMCID: PMC3101780
We show here that C. albicans is able to actively modulate the environmental pH to a remarkable degree, neutralizing media initially at pH 4 to 10. We have focused mostly on the alkalinization of acidic media, which occurs rapidly, with the pH changing from 4 to >7 in less than 24 h in aerated liquid cultures. This glucose-repressible phenomenon occurs on both solid and liquid media of several compositions but requires the presence of exogenous amino acids. Neutral pH has been long recognized as an inducer of hyphal morphogenesis, and cells in alkalinizing media shift to the hyphal form; this is blocked by buffering the medium or addition of glucose. Thus, C. albicans effectively autoinduces morphogenesis under these conditions. The rise in pH is associated with the release of ammonia, a highly basic compound, as has been observed in other fungi.

(Ammonia has also been cited before as a microbial immunosuppressive weapon capable of interfering with phagocytosis).
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911

Quote:Besides, I had it figured that probiotics just sort of come with the food chain, 
or out of the air, 
and would just fill a niche back in like they filled it in the first place 
unless some surly little mutant keeps kicking them to the curb.

Not much of a clue of what you are talking about there.

If you have a candida problem,
rule number one:
get beneficial gut bacteria to high levels to outcompete yeast {candida}.
Once balance is established with beneficial gut bacteria,
all other problems Whip
with candida Whip
are lessened systemically Applause

Of course that goes in tandem with eating habits.
key lime pie
pumpkin pie 

not good

bad behavior Whip

at least we don;t use sugar --- blue agave is better

when I quit drinking beer / alcohol for months at a time,
I get much healthier.

If I stick just to pumpkin pie with blue agave, i generally do well enough,
by just eating a good Greek yoghurt.

The key lime pie is a special made by my GF,
and it is impossible to put down.


Fresh air with exercise is crucial. 
Even just walking for a few hours.
Getting old defrays from this, and I need naps after several hours on the rock bars while jade hunting.

Diet behavior control is key in controlling gut bacteria.
I have not conquered that beahvior defect in my personality {key lime pie Whip }
so I augment with 100 billion probiotic,
when necessary.
It really does help.

Interesting reading on --->feeding your probiotica with "prebiotocs".
This makes sense,
and something I will be looking into. 
(03-22-2017, 02:22 PM)Vianova Wrote: ...

Quote:Besides, I had it figured that probiotics just sort of come with the food chain, 
or out of the air, 
and would just fill a niche back in like they filled it in the first place 
unless some surly little mutant keeps kicking them to the curb.

Not much of a clue of what you are talking about there.

Humans tend to have a gut flora whether they take probiotic products or not, and have had gut flora since before the invention of probiotic products, would be my impression. 

Where did/does this non-probiotic-product-associated gut flora come from prior to or independently of priobiotic products therefore?

Likewise, why does this gut flora become "imbalanced"? It's fashionable to blame antibiotics for "killing off the good bugs" but did dysbiosis never exist before antibiotics were invented? 

And so that's it, if you've ever taken an antibiotic, your "good bugs" are dead forever and you will never ever have a good gut flora again unless you buy some probiotic product? And you not only have to re-inoculate yourself once with probiotics to restore your gut flora following antibiotic use, you have do this day after day after day even when you're not killing off the "good bugs" with antibiotics on a daily basis?

Something doesn't make sense to me here and for the handiest explanation I keep coming up with antibiotics (or possibly household cleaners) doing what nature can, only faster and on an increasingly wider scale - selecting for "badder" versions of "bad bugs" that may be exceptionally and/or increasingly antagonistic to "good bugs," whether they are in the food you eat - which might otherwise probably serve as a probiotic in itself and probably offering greater probiotic diversity than probiotic products? - or whether they come in a capsule. 

That may be exactly what the article above on tetracycline is implying? That antibiotics may be directly affecting unexpected targets like fungi, and helping to make "worse bugs" out of them?

I don't know, I could very easily be wrong - I'm not even sure I have a position here, I'm just trying not to step in any dogma.

Notice though how the last two articles I posted seem imply that very popular notions about both acidic conditions and glucose feeding yeast may contain some dogma, in addition to implying that Candida is going to do whatever the hell it wants anyway?

Meanwhile, I'm not even sure I have much way of knowing if I have ongoing Candida issues, or whether I'm stuck with a bunch of autoimmune BS from some long-ago gut breach. All I can think of at the minute is trying to find the Smoking Antibody so I can declare that yes, this or that Can Actually Happen (and not necessarily just for my own sake). It might simply not be realistic for me to expect probiotics to be able to resolve that, even if they did a lot of good for other people.

I've sort of "been there, done that" with a lot of things, and things that actually help tend to generate plenty of their own enthusiasm. Many things did not do seem to this, probiotics being only one of them.
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911

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