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The Other Weed With Roots In Hell?
#34
...
probiotoics don;t solve the problem ...
they aid your body in dealing with the problem.

Antibiotics are in most meats etc etc

I have had too many infections that would have killed me without antibiotics,
especially with diverticulitis.
So I don't have a lot of choice.
You get a bad case of diverticulitis --- you take Cipro or you might die.
Probiotics and yoghurt help a lot.

So I often augment with probiotics to facilitate a rebalance in gut flora.
Probiotic bacteria --- consume --- yeast and balance out other bad bacteria, 
often consuming them as well.

Another culprit that is probably fucking with gut bacteria is -- GMO foods.

Go Organic -- eliminate bad foods -- etc etc

One guy -- a doctor has made a lot of mileage on eliminating foods.
he pointed to anything with  -- lectins --
and nightshade family foods --
not good
One thing he pointed out was that probiotics are good,
but that you need to feed the probiotic 
with
prebiotics
to solidify the populations of probiotic organisms over the bad ones.

you don't have to use probiotoics every day,
and the prebiotic feeds the populations of probiotics to restabilize a lingering healthy population.

There is no question, probiotics help reduce gut yeast.

Start there, and then augment with whatever else your research provides.

Even if the issue is a later autoimmune response to past problems,
probiotics
can only help,
they certainly cannot hurt
unless you take too much.

this article is pretty good actually

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725482/

Quote:The effects of imbalances in gut microflora are not restricted to the gastrointestinal tract 
and may have an impact on systemic immunity, 
culminating in allergic disorders such as asthma and atopy , 
and autoimmune disease such as type 1 diabetes


the doctor I mentioned earlier is is Dr grundy
here is audio article on lectins'
https://selfhacked.com/2015/12/11/dr-gun...ance-diet/

audio tape --- I cannot find his youtube video
Dr. Gundry: Turning off Autoimmunity with a Lectin Avoidance Diet
https://www.youtube.com/watch?v=AWRkR5fr-Eg


he's making $$$ -- so take with grain of salt

he sells "reds" --- and "prebiothrive"
a cheaper product that is similar is called     miracle reds



if you want to avoid probiotics and prebiotics ... well good luck.
...
Reply
#35
Ah, okay... Thanks, Vi - this is starting to get into familiar territory (not familiar enough though). There seem to be a lot of patients who share my skin disease diagnosis that have lectin sensitivities. A lot of them try to blame that for the disease but the hallmark of the disease seems to be Staphylococcus lugdunensis infection, and I keep trying to point out to them that they're not likely to get the disease without S. lugdunensis, and that if the lectin sensitivity didn't start there, they probably should have noticed sensitization to lectins earlier in life when they were kids drowning their McDonald's fries in ketchup (that's two nightshades in one right there).

I don't think many of them have actually cleared the S. lugdunensis infection with no-nightshade diets if the disease comes right back on them with lectin exposure but then I think my doctor killed my S. lugdunensis once and for all probably by using an old-school protein synthesis inhibitor antibiotic (erythromycin?) that they'd probably never thought to use if they'd realized what I had. I'm still pretty rare in that. Not entirely sure how I got cured of the particular infection because I think it took so long for the results to become firm that nobody associated the improvement with the treatment until I got seriously retrospective about it.

I don't seem to have the same sensitization (at least not in any overt manner) but then my bacteriology doesn't seem to have involved S. lugdunensis for some time now. Typically when someone with this is lectin-sensitive, it's pretty dramatic. A lot of them have become proponents of the Paleo Diet.

I will try to look closer at the materials, there may be some valuable insights at least for some of us. I wish I knew the subject better, but microbes, plants, and humans all make lectins so it got a bit muddy there.

(This still doesn't change my mind that turd transplants may be somebody taking this probiotic thing just a little too far). :-)
"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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#36
Ohhhh... I wonder if this means anything? I was going to post this because it's from a a search for potential ALDH3B1 epitopes that found homology to THREE olfactory proteins for a single sequence whereas I previously had two olfactory proteins as a total from all searches to date... Don't suppose I'd be lucky enough to actually be getting warm for once?

P43353.1 vs P36222.2
Motif: [S][S][A-Z][A-Z][F][C][G]
AL3B1_HUMAN 1 RecName: Full=Aldehyde dehydrogenase family 3 member B1; EC=1.2.1.5; AltName: Full=Aldehyde dehydrogenase 7;
...
O10A6_HUMAN 1 RecName: Full=Olfactory receptor 10A6; AltName: Full=Olfactory receptor OR11-96;
OR6B2_HUMAN 1 RecName: Full=Olfactory receptor 6B2; AltName: Full=Olfactory receptor OR2-1;
OR6B3_HUMAN 1 RecName: Full=Olfactory receptor 6B3; AltName: Full=Olfactory receptor OR2-2;

What is P36222 and how did it end up in my searches? Like fungi and dust mites, Homo sapiens also produces chitinases, perhaps as an antifungal mechanism? I am surprised by the nature of the protein:

http://www.uniprot.org/uniprot/P36222
UniProtKB - P36222 (CH3L1_HUMAN)
Protein Chitinase-3-like protein 1
Gene CHI3L1
Organism Homo sapiens (Human)
Carbohydrate-binding lectin with a preference for chitin. Has no chitinase activity. May play a role in tissue remodeling and in the capacity of cells to respond to and cope with changes in their environment. Plays a role in T-helper cell type 2 (Th2) inflammatory response and IL-13-induced inflammation, regulating allergen sensitization, inflammatory cell apoptosis, dendritic cell accumulation and M2 macrophage differentiation. Facilitates invasion of pathogenic enteric bacteria into colonic mucosa and lymphoid organs. Mediates activation of AKT1 signaling pathway and subsequent IL8 production in colonic epithelial cells. Regulates antibacterial responses in lung by contributing to macrophage bacterial killing, controlling bacterial dissemination and augmenting host tolerance. Also regulates hyperoxia-induced injury, inflammation and epithelial apoptosis in lung

(I'm putting a premium on matches to olfactory proteins because heylianne flushes when she sniffs the cap of Boone's Farm Strawberry Emetic, and also on account of my being banned from government offices for trying not to smell like a locker room. I have no idea yet how typical this may be in Asian Flushing Syndrome, but it may not be entirely accounted for ALDH gene status). 
https://www.youtube.com/watch?v=8P07iXHJbpw

Maybe something, maybe nothing...
"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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#37
This seems like a relatively comprehensive if dated review of some Candida proteins

Cell Wall and Secreted Proteins of Candida albicans: Identification, Function, and Expression
W. Lajean Chaffin, José Luis López-Ribot, Manuel Casanova, Daniel Gozalbo, and José P. Martínez
Microbiol Mol Biol Rev. 1998 Mar; 62(1): 130–180. PMCID: PMC98909
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC98909

Unfortunately not nearly comprehensive enough. I'm going to be shocked if no one's actually done the research...

This epitope database has numerous Candida epitopes but still most are missing 
http://www.iedb.org

I'm only finding data for SAP2 in it out of 10 different Candida secreted aspartyl proteases in.

If "big pharma" are pulling one over on anybody here, maybe they're going to get away with it for a while?

We now return you to your regularly scheduled anti-marijuana propaganda...



And now it's time for Puff the Magic Scapegoat's Statistics Abuse Hour.

Hey, kids - when some scholarly type informs you that if you use tobacco and cannabis both, you're three times as likely to contract pulmonary disease than if you use tobacco alone, is this because

a. 1 + 1 = 3
b. The stress of figuring out how to afford weed and tobacco both can lead to pulmonary disease
c. Who cares? You are going right straight to hell for using either one and you deserve it
d. The scarcity of Cannabis promotes communal usage generally involving methods that may greatly increase the risk of contracting infections that may be suspect in pulmonary pathologies
"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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#38
If I was to mix cannabis and tobacco
I'd do it with Nicotiana rustica (Indian Tobacco).
It's supposed to be > 10x stronger than domestic types
in terms of psyhcoactivity.
Reply
#39
Since I don't have a reliable, user-friendly multi-protein sequence comparison tool at my disposal, I've had a go at doing some the hard way concerning the possibility of autoimmunity to ALDH3B1 resulting from fungal colonization, particularly Candida. I came up with a number of common motifs, but in trying to include fungi potentially cross-reactive with Candida (Alternaria, Cladosporium, or Malassezia) or other fungi that may also be implicated in atopic asthma or atopic dermatitis (Malassezia, Trichophyton), that might restrict the number of eligible candidates. I've been doing this for about a whole week now, trying to compare 50 protein sequences without aid of appropriate tools, often revising the candidate sequences adaptively as I go along when the occasion arises.

Bear in mind that no database I'm using including UniProt has even given complete or reliable enough results that they seem suitable for professional research or drawing confident conclusions (also that the two-protein comparison tool ProteinBLAST denotes matches between different amino acids which have "similar chemical properties" and I'm ignoring those, so I'm playing closer to rather than farther from the cuff in that respect). I also have the issue that my DB is either comprehensive(UniProt)  or permissive of wildcarding (Swiss-Prot interface), but not both, which is also not terribly conducive. Given, however, the data I currently have and hoping I got anywhere near to making the most of it...

The amino acid sequence (E)IFGPILPI seems to be common to human ALDH3 types, and to ALDH enzymes of numerous Candida specimens.

Relaxing the restriction to EIFGPxLPI affords a match to a Malassezia sympodialis ALDH, Mal(a) s4, UniProt M5E7C5
Relaxing the restriction to EIFGPxxxI affords matching to the purportedly cross-reactive ALDH proteins of Alternaria (ALTA10 UniProt P42041), Cladosporium (CLAD10 UniProt P40108) and to at least three more examples of ALDH proteins from various Candida.

Apparently, most of the entries for relevant ALDH proteins in the Epitope Database link given look like those offered by commercial protein or epitope sources, the protein is divided into x number of fragments purported to be "epitopes," rather than critical key motifs that may occur in them actually being identified or isolated.

A related sequence is identified as an epitope of human ALDH3B1 (Epitope ID 466424) IFGPVQPLF 
http://www.iedb.org/epitope/466424 
But as a literal match it may be exclusive of the reported cross-reactivity with related fungal proteins. On account of this epitope being loosely identified by bona-fide research, I'm compromising on EIFGPILPI with IFGPILPI and skipping the glutamic acid (aka Glu aka E) at the beginning.

UniProt finds the predominant form of the epitope in my studies, IFGPILPI, in currently 2276 different proteins. 15 of them are human, all belonging to the human ALDH3 series. Many matching entries from the general Acinetobacter, Bacillus, and Mycobacterium appear, as do a few matching entries from the genera Alteromonas, Paenibacillus, along with several from Mucor, Pichia, and other miscellaneous entries. 22 relatively scant examples of Staphylococcus aureus proteins (including S. aureus MRSA strain USA300), along with more extensive listings for unspecified Staphylococcus specie also appear, and a few instances of Streptococcus pneumoniae, as do 14 examples qualifying representatives of probably a majority of known pathogenic Candida species - C. albicans, C. dubliniensis, C. tropicalis, etc. Anything named in this paragraph might be a potential exacerbating factor of conditions in questions, if they are able to fulfill enough requirements (and for whatever it's worth, I don't recall any species of Nicotiana including N. tabacum making the list).

There is a second possible epitope that may afford accounting for most of what is described relating pulmonary or allergic conditions to fungal candidates, which may perhaps be best represented as LxxVxLELGGxxP.

LTPVxLELGGxxP relates to the sequence LTPVTLELGGKNP found in human ALDH3B1 and ALDH3B2.

Relaxing the restriction to LTPVxLELGGKxP affords matching with numerous Candida ALDH proteins.
Relaxing the restriction to LxxVxLELGGKxP affords matching with ALDH proteins from Alternaria, Cladosporium, and Malassezia.
Relaxing the restriction to LxxVxLELGGxxP affords matching with an ALDH protein from Trichophyton, UniProt F2SDG0.

Unless my Google has been subverted by an inferior imposter, based on sample searches using some of these possible forms of the two sequences, I'm not finding where much attention has been paid to either of them.

HOPEFULLY what is here could serve as a framework for taking the subject more seriously as to the possible role of common commensal fungi as instigators or exacerbators of pulmonary pathologies.

I think I'd like to try to put my ALDH inquiries to rest with this, I started six months ago and was rudely interrupted by many studies of other things, including immunology and microbiology as they relate to thromobotic disease.

Likely the origin of my dust mite reactivity lies elsewhere, probably in chitinases and proteases of dust mites and Candida and their respective homologies, and the possible autoimmune origins of my metabolic complaints are still fairly unfathomable to me, although this latest work may offer a lot of discouragement that they might also originate with autoimmunity to ALDH. At least the homology between those additional Candida allergens and their human counterparts, if they are involved, should be quite a bit more self-explanatory.

Anyway, something I'm looking for here is possible targets of immune testing that indicate potential trouble in the here and now, and ideally, irrespective of the original source of the antibody. Testing positive on a Candida antibody test may neither convince a caregiver that Candida (as opposed to another, potentially cross-reactive commensal organism) is the root of any problem (or, due to cross-reactivity, that Candida is even the origin of the reacting antibody), or that a positive result means that the patient currently has an active Candida infection requiring treatment - so I'd been hoping to milk something out of all this that might have some kind of added indicative value.

I'm skeptical that I personally have much if any IgE to ALDH3B1 per se, partly based on being able to get by thus far without an inhaler, but the subject seems important since, again, ALDHs are involved in detoxification of histamine, which may make any histamine-producing IgE to ALDH particularly problematic for some.

One area I haven't looked at much is any possible post-translational modifications by microbial factors that could affect key enzymes like ALDH3B1, so far this is mainly in response to respectable claims that Candida or other fungal ALDH proteins are allergens, without reference to possible autoimmune consequences, and to my own apparent (and presumably non-ethnically related) aldehyde sensitization.

The other thing I wanted to address with this, is the possibility of having autoimmunity to ALDH because of a past bout with a fungal infection rather than a current one (a possible reason for probiotic failures?) that could be perpetuated by a secondary infection. I'm still not a believer that any resultant autoimmunity from cross-reactivity between human and microbial proteins iis necessarily going to persist if the root cause is alleviated, but this part of the work might afford for autoimmunity to be sustained by the presence of a lesser and presumably less inflammatory fungal infection like Malassezia or Trichophyton. There may be such a thing as having IgE to either one that might not have come about without the likes of a helper like Candida at some point in time, and that may not recede until such cross-reactive secondary infections are tended to also?

Or would I have heard more about how Head & Shoulders or Lotrimin cure asthma if things actually worked that way???
"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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#40
This might be a third one???

PFGGVGxSGxGxYHGxFS

This would match human ALDH 3B1 to numerous Candida ALDH enzymes.

The entire sequence from ALDH 3B1 UniProt P43353 is PFGGVGASGMGRYHGKFS 

Relaxing the restriction to PFGGxGxSGxGxYHGxFS would afford matching to ALDH from Malassezia and Trichophyton.
Relaxing the restriction to PFGGxGxSGxGxYHGxFx (or just PFGGxGxSGxGxYHGxF) would afford matching to human ALDH3B2 and a second Malassezia ALDH.

That level of restriction may also exclude cross-reactivity with a number of remaining human ALDH proteins.
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
Reply
#41
What's this? A subject that researchers AREN'T milking for all its worth?!?

"alcohol induced asthma" = 10,300 hits in Google

"aldehyde induced asthma" = 0 hits in Google = 1 hit in Google for "formaldehyde-induced asthma"
Formaldehyd - Wiley Online Library
http://onlinelibrary.wiley.com/doi/10.10...0d0048/pdf Translate this page
Grammer LC, Harris KE, Cugell DW, Patterson R (1993) Evaluation of a worker with possible form- aldehyde-induced asthma. J Allergy Clin Immunol 92: 29–33.

"acetaldehyde induced asthma" = 1 hit in Google
Inhibitory effect of indomethacin on tachyphylaxis in response to ...
https://www.ncbi.nlm.nih.gov/pubmed/9155828
by M Fujimura - ‎1997 - ‎Cited by 3 - ‎Related articles
J Allergy Clin Immunol. 1997 May;99(5):620-3. Inhibitory effect of indomethacin on tachyphylaxis in response to acetaldehyde-induced bronchoconstriction in ...

"formaldehyde induced asthma" = 913 hits in Google

----

On the other hand, this sounds like about half the story in one paper?

Inhibitory effect of indomethacin on tachyphylaxis in response to acetaldehyde-induced bronchoconstriction in patients with asthma.
Fujimura M1, Myou S, Kamio Y, Matsuda T.
J Allergy Clin Immunol. 1997 May;99(5):620-3.
Abstract
BACKGROUND:Acetaldehyde, a main factor in alcohol-induced asthma, causes bronchoconstriction indirectly through histamine release; and tachyphylaxis in response to repeated inhalation of acetaldehyde is observed in patients with asthma.
OBJECTIVE: The study was designed to clarify the mechanism of tachyphylaxis in response to acetaldehyde-induced bronchoconstriction.
METHODS: We investigated the bronchial response to inhaled acetaldehyde in 10 patients with asthma who were treated with indomethacin in a double-blind, randomized, placebo-controlled, crossover fashion.
RESULTS: The mean acetaldehyde concentration causing a 20% fall in FEV1 with placebo increased significantly from 13.0 mg/ml (geometric SEM = 0.115) to 31.1 mg/ml (geometric SEM = 0.069) over a period of 1 hour (p < 0.01), whereas there was a slight but not significant tachyphylaxis during indomethacin treatment. The tachyphylactic effect, expressed as logarithmic value of the second PC20 minus logarithmic value of the first PC20, was significantly (p < 0.05) reduced from 0.380 (0.066) with placebo treatment to 0.148 (0.094) with indomethacin treatment.
CONCLUSION: These results suggest an important role of cyclooxygenase pathway products in decreased response to repeated inhalation of acetaldehyde in patients with asthma.
PMID: 9155828 [Indexed for MEDLINE]
[[NO CITATIONS IN PUBMED?!?!?]]
Free full text: http://www.jacionline.org/article/S0091-...0023-X/pdf
PDF saved as PIIS009167499770023X.pdf
Bronchial hyperresponsiveness, which is usually measured by histamine, acetylcholine, or methacholine is a main feature of bronchial asthma. Challenges with histamine and acetylcholine cause airway narrowing, mainly through direct action on airway smooth-muscle receptors; whereas exercise-, alcohol-, hyperventilation-, and cold air-induced bronchoconstriction are caused by secondary substances such as endogenously released histamine 1-4. Although Manning et al. 5 demonstrated, in patients with asthma, that tachyphylaxis occurs on repeated challenges with inhaled histamine but not with inhaled acetylcholine, Ruffin et al. 6 reported no change in bronchial responsiveness to inhaled histamine with repeated testing. Currently, although the occurrence of tachyphylaxis in response to exogenously administered histamine has not been clearly established, we have demonstrated that tachyphylaxis in response to histamine is observed only when histamine is released endogenously after inhalation of acetaldehyde. 8
Acetaldehyde, a rapidly generated metabolite of ethanol, is thought to be a main factor in alcohol-induced asthma. Findings indicating that alcohol-induced asthma, which occurs in response to acetaldehyde-produced histamine, is a condition that occurs only as the result of a genetic alteration in the metabolism of alcohol are that: (1) blood acetaldehyde and histamine concentrations increase during alcohol-induced bronchoconstriction 8; (2) inhaled acetaldehyde provokes bronchoconstriction indirectly through histamine release in guinea pigs 9 and patients with asthma 10; (3) both bronchoconstriction induced by inhalation of acetaldehyde 10 and acetaldehyde-induced bronchial hyperresponsiveness 11 occur not only in patients with so-called alcohol-induced asthma but also in virtually all patients with asthma; (4) the activity of aldehyde dehydrogenase, which oxidizes acetaldehyde to acetate, is a major factor in determining exacerbations of asthma after alcohol intake 12; (5) among patients with asthma in Western societies, who usually do not experience bronchoconstriction in response to alcohol, severe asthma attacks follow alcohol intake in those with chronic alcoholism who are taking the aldehyde dehydrogenase inhibitor disulfiram as a component of alcohol abstinence therapy 13; (6) terfenadine, a selective histamine H1-antagonist, completely inhibits alcohol-induced bronchoconstriction. 2

(Some antibiotics such as "Bactrim" may, like disulfuram, be aldehyde dehydrogenase inhibitors, which I presume might make them questionable in some cases of pulmonary infections or related exacerbations?)

And then we get to the stuff about autoimmunity... 

Autoimmunity and chronic obstructive pulmonary disease: thinking beyond cigarette smoke.
Tzouvelekis A, Kostikas K, Bouros D.
Am J Respir Crit Care Med. 2012 Jun 1;185(11):1248-9.
Comment on
Late intervention with a myeloperoxidase inhibitor stops progression of experimental chronic obstructive pulmonary disease. [Am J Respir Crit Care Med. 2012]
PMID: 22661530 DOI: 10.1164/ajrccm.185.11.1248a [PubMed - indexed for MEDLINE]
https://www.ncbi.nlm.nih.gov/pubmed/22661530
...
We therefore believe that selected patients with COPD, especially younger ones presenting with disproportionally severe disease for their smoking exposure, should be subjected to a thorough investigation of their immunologic profile, besides the assessment of a1-antitrypsin levels. Larger studies are sorely needed to prove whether these patients constitute a novel disease phenotype that could benefit from immunomodulatory therapeutic interventions.

About whether or not cessation promotes clearance of potentially responsible microbes

Smoking Cessation and the Microbiome in Induced Sputum Samples from Cigarette Smoking Asthma Patients.
Munck C, Helby J, Westergaard CG, Porsbjerg C, Backer V, Hansen LH.
PMID: 27391160 Free PMC Article
PLoS One. 2016 Jul 8;11(7):e0158622. doi: 10.1371/journal.pone.0158622. eCollection 2016.
Abstract
Asthma is a common disease causing cough, wheezing and shortness of breath. It has been shown that the lung microbiota in asthma patients is different from the lung microbiota in healthy controls suggesting that a connection between asthma and the lung microbiome exists. Individuals with asthma who are also tobacco smokers experience more severe asthma symptoms and smoking cessation is associated with improved asthma control. In the present study we investigated if smoking cessation in asthma patients is associated with a change in the bacterial community in the lungs, examined using induced sputum. We found that while tobacco smokers with asthma have a greater bacterial diversity in the induced sputum compared to non-smoking healthy controls, smoking cessation does not lead to a change in the microbial diversity.
PMID: 27391160 PMCID: PMC4938234 DOI: 10.1371/journal.pone.0158622 [PubMed - in process] Free PMC Article
https://www.ncbi.nlm.nih.gov/pubmed/27391160

Some things on whether to blame tobacco or just smoke in general

Immunological Features of Chronic Obstructive Pulmonary Disease (COPD) Induced by Indoor Pollution and Cigarette Smoke
Esmaeil Mortaz, Peter J. Barnes, Hassan Heidarnazhad, Ian M. Adcock, and Mohammad Reza Masjedi
Tanaffos. 2012; 11(4): 6–17. PMCID: PMC4153225
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153225/
...
Importantly, there were no significant differences in the histopathological findings for emphysema, goblet cell hyperplasia, bronchial wall inflammation, airway smooth muscle hyperplasia, bronchiolitis or aspects of remodelling between patients with WSLD and smokers with COPD.

And last but not least whether perhaps some metabolism-modifying microbes deserve an interrogation. I'll skip the specifics at least until I'm more certain they aren't muddying the waters again - I've got at least one article on pulmonary disease that's tripping all over itself trying to figure out if what they are observing is typical before or after treatment with medication! - but if they are willing to say stuff like this...

Organization of metabolic pathways in vastus lateralis of patients with chronic obstructive pulmonary disease.
Green HJ1, Bombardier E, Burnett M, Iqbal S, D'Arsigny CL, O'Donnell DE, Ouyang J, Webb KA.
Am J Physiol Regul Integr Comp Physiol. 2008 Sep;295(3):R935-41. doi: 10.1152/ajpregu.00167.2008. Epub 2008 Jul 16.
...
PMID: 18635455 DOI: 10.1152/ajpregu.00167.2008 [PubMed - indexed for MEDLINE] Free full text
https://www.ncbi.nlm.nih.gov/pubmed/18635455
http://ajpregu.physiology.org/content/295/3/R935.long
It is now generally accepted that submaximal contractile activity in patients with chronic obstructive pulmonary disease (COPD) is characterized by abnormal reductions in the content of high-energy phosphate bonds (phosphorylation potential) and excessive accumulation of lactic acid in muscle (15). These metabolic changes suggest an overemphasized dependence of high-energy phosphate transfer reactions and glycolysis to satisfy the energy needs of the working muscle (9). Although inadequate delivery of oxygen to the mitochondria secondary to reduced arterial hemoglobin saturation with oxygen represents a potentially important factor to explain the atypical muscle metabolic response (24), there is emerging consensus that deficiencies in the metabolic pathways involved in substrate utilization and energy production may also be involved (15).

Meanwhile, remember kids - if you smoke, you will never grow up to be President.

[Image: obama2.jpeg]
"And can we get somebody to do a study to find out why
these goddam things are taking so long to kill me?"
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
Reply
#42
Hypoxia-inducible factor-1 signalling promotes goblet cell hyperplasia in airway epithelium.
Polosukhin VV1, Cates JM, Lawson WE, Milstone AP, Matafonov AG, Massion PP, Lee JW, Randell SH, Blackwell TS.
J Pathol. 2011 Jun;224(2):203-11. doi: 10.1002/path.2863.
Abstract
Goblet cell hyperplasia is a common feature of chronic obstructive pulmonary disease (COPD) airways, but the mechanisms that underlie this epithelial remodelling in COPD are not understood. Based on our previous finding of hypoxia-inducible factor-1a (HIF-1a) nuclear localization in large airways from patients with COPD, we investigated whether hypoxia-inducible signalling could influence the development of goblet cell hyperplasia. We evaluated large airway samples obtained from 18 lifelong non-smokers and 13 former smokers without COPD, and 45 former smokers with COPD. In these specimens, HIF-1a nuclear staining occurred almost exclusively in COPD patients in areas of airway remodelling. In COPD patients, 93.2 ± 3.9% (range 65-100%) of goblet cells were HIF-1a positive in areas of goblet cell hyperplasia, whereas nuclear HIF-1a was not detected in individuals without COPD or in normal-appearing pseudostratified epithelium from COPD patients. To determine the direct effects of hypoxia-inducible signalling on epithelial cell differentiation in vitro, human bronchial epithelial cells (HBECs) were grown in air-liquid interface cultures under hypoxia (1% O(2)) or following treatment with a selective HIF-1a stabilizer, (2R)-[(4-biphenylylsulphonyl)amino]-N-hydroxy-3-phenyl-propionamide (BiPS). HBECs grown in hypoxia or with BiPS treatment were characterized by HIF-1a activation, carbonic anhydrase IX expression, mucus-producing cell hyperplasia and increased expression of MUC5AC. Analysis of signal transduction pathways in cells with HIF-1a activation showed increased ERK1/2 phosphorylation without activation of epidermal growth factor receptor, Ras, PI3K-Akt or STAT6. These data indicate an important effect of hypoxia-inducible signalling on airway epithelial cell differentiation and identify a new potential target to limit mucus production in COPD.
PMID: 21557221 DOI: 10.1002/path.2863 [Indexed for MEDLINE]
https://www.ncbi.nlm.nih.gov/pubmed/21557221

Increased mitochondrial arginine metabolism supports bioenergetics in asthma.
Xu W, Ghosh S, Comhair SA, Asosingh K, Janocha AJ, Mavrakis DA, Bennett CD, Gruca LL, Graham BB, Queisser KA, Kao CC, Wedes SH, Petrich JM, Tuder RM, Kalhan SC, Erzurum SC.
J Clin Invest. 2016 Jul 1;126(7):2465-81. doi: 10.1172/JCI82925. Epub 2016 May 23.
Abstract
High levels of arginine metabolizing enzymes, including inducible nitric oxide synthase (iNOS) and arginase (ARG), are typical in asthmatic airway epithelium; however, little is known about the metabolic effects of enhanced arginine flux in asthma. Here, we demonstrated that increased metabolism sustains arginine availability in asthmatic airway epithelium with consequences for bioenergetics and inflammation. Expression of iNOS, ARG2, arginine synthetic enzymes, and mitochondrial respiratory complexes III and IV was elevated in asthmatic lung samples compared with healthy controls. ARG2 overexpression in a human bronchial epithelial cell line accelerated oxidative bioenergetic pathways and suppressed hypoxia-inducible factors (HIFs) and phosphorylation of the signal transducer for atopic Th2 inflammation STAT6 (pSTAT6), both of which are implicated in asthma etiology. Arg2-deficient mice had lower mitochondrial membrane potential and greater HIF-2a than WT animals. In an allergen-induced asthma model, mice lacking Arg2 had greater Th2 inflammation than WT mice, as indicated by higher levels of pSTAT6, IL-13, IL-17, eotaxin, and eosinophils and more mucus metaplasia. Bone marrow transplants from Arg2-deficient mice did not affect airway inflammation in recipient mice, supporting resident lung cells as the drivers of elevated Th2 inflammation. These data demonstrate that arginine flux preserves cellular respiration and suppresses pathological signaling events that promote inflammation in asthma.
PMID: 27214549 PMCID: PMC4922712 DOI: 10.1172/JCI82925 Free PMC Article
https://www.ncbi.nlm.nih.gov/pubmed/27214549
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922712
https://www.jci.org/articles/view/82925

l-Arginine administration attenuates airway inflammation by altering l-arginine metabolism in an NC/Nga mouse model of asthma
Ran Zhang,1 Masayuki Kubo,1 Ikuo Murakami,1,2 Heri Setiawan,1 Kei Takemoto,1 Kiyomi Inoue,3 Yoshihisa Fujikura,4 and Keiki Ogino1,*
J Clin Biochem Nutr. 2015 May; 56(3): 201–207.
Published online 2015 Feb 4. doi:  10.3164/jcbn.14-140 PMCID: PMC4454082
Abstract
Changes in l-arginine metabolism, including increased arginase levels and decreased nitric oxide production, are involved in the pathophysiology of asthma. In this study, using an intranasal mite-induced NC/Nga mouse model of asthma, we examined whether administration of l-arginine ameliorated airway hyperresponsiveness and inflammation by altering l-arginine metabolism. Experimental asthma was induced in NC/Nga mice via intranasal administration of mite crude extract (50 µg/day) on 5 consecutive days (days 0–4, sensitization) and on day 11 (challenge). Oral administration of l-arginine (250 mg/kg) was performed twice daily on days 5–10 for prevention or on days 11–13 for therapy. On day 14, we evaluated the inflammatory airway response (airway hyperresponsiveness, the number of cells in the bronchoalveolar lavage fluid, and the changes in pathological inflammation of the lung), arginase expression and activity, l-arginine bioavailability, and the concentration of NOx, the end products of nitric oxide. Treatment with l-arginine ameliorated the mite-induced inflammatory airway response. Furthermore, l-arginine administration attenuated the increases in arginase expression and activity and elevated the NOx levels by enhancing l-arginine bioavailability. These findings indicate that l-arginine administration may contribute to the improvement of asthmatic symptoms by altering l-arginine metabolism.
Keywords: l-arginine, asthma, arginase, nitric oxide, l-arginine paradox
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454082

Arginase: a key enzyme in the pathophysiology of allergic asthma opening novel therapeutic perspectives.
Maarsingh H1, Zaagsma J, Meurs H.
Br J Pharmacol. 2009 Oct;158(3):652-64. doi: 10.1111/j.1476-5381.2009.00374.x. Epub 2009 Aug 24.
Abstract
Allergic asthma is a chronic inflammatory airways' disease, characterized by allergen-induced early and late bronchial obstructive reactions, airway hyperresponsiveness (AHR), airway inflammation and airway remodelling. Recent ex vivo and in vivo studies in animal models and asthmatic patients have indicated that arginase may play a central role in all these features. Thus, increased arginase activity in the airways induces reduced bioavailability of L-arginine to constitutive (cNOS) and inducible (iNOS) nitric oxide synthases, causing a deficiency of bronchodilating and anti-inflammatory NO, as well as increased formation of peroxynitrite, which may be involved in allergen-induced airways obstruction, AHR and inflammation. In addition, both via reduced NO production and enhanced synthesis of L-ornithine, increased arginase activity may be involved in airway remodelling by promoting cell proliferation and collagen deposition in the airway wall. Therefore, arginase inhibitors may have therapeutic potential in the treatment of acute and chronic asthma. This review focuses on the pathophysiological role of arginase in allergic asthma and the emerging effectiveness of arginase inhibitors in the treatment of this disease.
Comment on
Arginase: an emerging key player in the mammalian immune system. [Br J Pharmacol. 2009]
PMID: 19703164 PMCID: PMC2765587 DOI: 10.1111/j.1476-5381.2009.00374.x
[Indexed for MEDLINE] Free PMC Article
https://www.ncbi.nlm.nih.gov/pubmed/19703164
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765587

Increased arginase activity underlies allergen-induced deficiency of cNOS-derived nitric oxide and airway hyperresponsiveness.
Meurs H1, McKay S, Maarsingh H, Hamer MA, Macic L, Molendijk N, Zaagsma J.
Br J Pharmacol. 2002 Jun;136(3):391-8.
Abstract
1. A deficiency of constitutive nitric oxide synthase (cNOS)-derived nitric oxide (NO), due to reduced availability of L-arginine, importantly contributes to allergen-induced airway hyperresponsiveness (AHR) after the early asthmatic reaction (EAR). Since cNOS and arginase use L-arginine as a common substrate, we hypothesized that increased arginase activity is involved in the allergen-induced NO deficiency and AHR. 2. Using a guinea-pig model of allergic asthma, we addressed this hypothesis by examining the effects of the specific arginase inhibitor N(omega)-hydroxy-nor-L-arginine (nor-NOHA) on the responsiveness to methacholine of isolated perfused tracheae from unchallenged control animals and from animals 6 h after ovalbumin challenge. Arginase activity in these preparations was investigated by measuring the conversion of L-[14C]arginine to [14C]urea. 3. Airways from allergen-challenged animals showed a 2 fold (P<0.001) increase in responsiveness to intraluminal (IL) administration of methacholine compared to controls. A similar hyperresponsiveness (1.8 fold, P<0.01) was observed in control airways incubated with the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 0.1 mM, IL), while L-NAME had no further effect on the airways from challenged animals. 4. Remarkably, 5 microM nor-NOHA (IL) normalized the hyperresponsiveness of challenged airways to basal control (P<0.001), and this effect was fully reversed again by 0.1 mM L-NAME (P<0.05). Moreover, arginase activity in homogenates of the hyperresponsive airways was 3.5 fold (P<0.001) enhanced compared to controls. 5. The results indicate that enhanced arginase activity contributes to allergen-induced deficiency of cNOS-derived NO and AHR after the EAR, presumably by competition with cNOS for the common substrate, L-arginine. This is the first demonstration that arginase is involved in the pathophysiology of asthma.
PMID: 12023942 PMCID: PMC1573363 DOI: 10.1038/sj.bjp.0704725 [Indexed for MEDLINE] Free PMC Article
https://www.ncbi.nlm.nih.gov/pubmed/12023942
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1573363

[Arginine metabolism in bronchial asthma] [Article in Polish].
Lewandowicz AM1, Pawliczak R.
Postepy Hig Med Dosw (Online). 2007;61:156-66.
Abstract
Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. Airway inflammation is associated with an enhanced expression of inducible nitric oxide synthase. This increases nitric oxide production and results in higher levels of NO* gas in exhaled air. Measurement of exhaled nitric oxide is a very useful non-invasive method in the diagnosis and treatment monitoring of asthma. However, the role of nitric oxide in asthma, still under intense debate, should not be regarded only as a consequence of its abundance, but rather as an impairment of the mechanisms that regulate its synthesis and activity, including reducing nitric oxide production by neuronal and endothelial synthase. Arginine is a substrate for both nitric oxide synthase and arginase. Arginase expression in the lung is strongly induced by cytokines, in particular IL-4 and IL-13, which are produced at elevated level in asthmatic airways and which activate inflammatory pathways. Arginase modulates nitric oxide synthase activity and provides a precursor for polyamines (putrescine, spermidine, and spermine) and proline, which stimulate cell growth and collagen synthesis, respectively. Therefore, arginase might also be involved in inflammation-induced airway remodeling in chronic asthma. This review presents arginine homeostasis in asthma and focuses not only on inducible nitric oxide synthase, but also on impairment of constitutive nitric oxide synthase activity and the overproduction of arginase downstream products.
PMID: 17410056 [Indexed for MEDLINE] Free full text [in Polish]
https://www.ncbi.nlm.nih.gov/pubmed/17410056

Arginine homeostasis in allergic asthma.
Maarsingh H, Zaagsma J, Meurs H.
Eur J Pharmacol. 2008 May 13;585(2-3):375-84. doi: 10.1016/j.ejphar.2008.02.096. Epub 2008 Mar 18. Review.
Abstract
Allergic asthma is a chronic disease characterized by early and late asthmatic reactions, airway hyperresponsiveness, airway inflammation and airway remodelling. Changes in l-arginine homeostasis may contribute to all these features of asthma by decreased nitric oxide (NO) production and increased formation of peroxynitrite, polyamines and l-proline. Intracellular l-arginine levels are regulated by at least three distinct mechanisms: (i) cellular uptake by cationic amino acid (CAT) transporters, (ii) metabolism by NO-synthase (NOS) and arginase, and (iii) recycling from l-citrulline. Ex vivo studies using animal models of allergic asthma have indicated that attenuated l-arginine bioavailability to NOS causes deficiency of bronchodilating NO and increased production of procontractile peroxynitrite, which importantly contribute to allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction, respectively. Decreased cellular uptake of l-arginine, due to (eosinophil-derived) polycations inhibiting CATs, as well as increased consumption by increased arginase activity are major causes of substrate limitation to NOS. Increasing substrate availability to NOS by administration of l-arginine, l-citrulline, the polycation scavenger heparin, or an arginase inhibitor alleviates allergen-induced airway hyperresponsiveness by restoring the production of bronchodilating NO. In addition, reduced l-arginine levels may contribute to the airway inflammation associated with the development of airway hyperresponsiveness, which similarly may involve decreased NO synthesis and increased peroxynitrite formation. Increased arginase activity could also contribute to airway remodelling and persistent airway hyperresponsiveness in chronic asthma via increased synthesis of l-ornithine, the precursor of polyamines and l-proline. Drugs that increase the bioavailability of l-arginine in the airways - particularly arginase inhibitors - may have therapeutic potential in allergic asthma.
PMID: 18410920 DOI: 10.1016/j.ejphar.2008.02.096 [Indexed for MEDLINE]
https://www.ncbi.nlm.nih.gov/pubmed/18410920

The arginine-arginase balance in asthma and lung inflammation.
Zimmermann N1, Rothenberg ME.
Eur J Pharmacol. 2006 Mar 8;533(1-3):253-62. Epub 2006 Feb 3.
Abstract
Asthma, a complex chronic inflammatory pulmonary disorder, is on the rise despite intense ongoing research underscoring the need for new scientific inquiry. Using global microarray analysis, we have recently uncovered that asthmatic responses involve metabolism of arginine by arginase. We found that the cationic amino acid transporter (CAT)2, arginase I, and arginase II were particularly prominent among the allergen-induced gene transcripts. These genes are key regulators of critical processes associated with asthma including airway tone, cell hyperplasia and collagen deposition, respectively. Furthermore, systemic arginine levels and arginine metabolism via nitric oxide synthase (NOS) can have profound effect on lung inflammation. This review focuses on the current body of knowledge on l-arginine metabolism in asthma and lung inflammation.
PMID: 16458291 DOI: 10.1016/j.ejphar.2005.12.047 [Indexed for MEDLINE]
https://www.ncbi.nlm.nih.gov/pubmed/16458291

Arginase as a potential target in the treatment of cardiovascular disease: reversal of arginine steal?
Pernow J, Jung C.
Cardiovasc Res. 2013 Jun 1;98(3):334-43. doi: 10.1093/cvr/cvt036. Epub 2013 Feb 14.
Abstract
Functional integrity of the vascular endothelium is of fundamental importance for normal vascular function. A key factor regulating endothelial function is the bioavailability of nitric oxide (NO). Recently, the enzyme arginase has emerged as an important regulator of NO production by competing for l-arginine, which is a substrate for both arginase and NO synthase. Increased activity of arginase may reduce the availability of l-arginine for NO synthase, thus reducing NO production, increasing formation of reactive oxygen species, and leading ultimately to endothelial dysfunction. Increased activity and expression of arginase have been demonstrated in several pathological cardiovascular conditions, including hypertension, pulmonary arterial hypertension, atherosclerosis, myocardial ischaemia, congestive heart failure, and vascular dysfunction in diabetes mellitus. Experimental studies have demonstrated that inhibition of arginase under these conditions increases NO bioavailability, reduces oxidative stress, improves vascular function, and protects against ischaemia-reperfusion injury. Initial clinical interventional studies are also promising. The purpose of this review is to discuss the role of arginase in cardiovascular pathologies, its contribution to the development of several cardiovascular disease states and the feasibility of using arginase inhibition as a therapeutic strategy.
KEYWORDS:
Arginase; Atherosclerosis; Diabetes mellitus; Hypertension; Ischaemia; Nitric oxide; Reactive oxygen species
PMID: 23417041 DOI: 10.1093/cvr/cvt036 [Indexed for MEDLINE]
https://www.ncbi.nlm.nih.gov/pubmed/23417041

Beneficial effects of high dose of L-arginine on airway hyperresponsiveness and airway inflammation in a murine model of asthma.
Mabalirajan U1, Ahmad T, Leishangthem GD, Joseph DA, Dinda AK, Agrawal A, Ghosh B.
J Allergy Clin Immunol. 2010 Mar;125(3):626-35. doi: 10.1016/j.jaci.2009.10.065. Epub 2010 Feb 11.
Abstract
BACKGROUND: Disturbance in the delicate balance between L-arginine-metabolizing enzymes such as nitric oxide synthase (NOS) and arginase may lead to decreased L-arginine availability to constitutive forms of NOS (endothelial NOS), thereby increasing the nitro-oxidative stress and airway hyperresponsiveness (AHR).
OBJECTIVE: In this study, we investigated the effects of high doses of L-arginine on L-arginine-metabolizing enzymes and subsequent biological effects such as cyclic guanosine monophosphate production, lipid peroxidation, peroxynitrite, AHR, and airway inflammation in a murine model of asthma.
METHODS: Different doses of L-arginine were administered to ovalbumin-sensitized and challenged mice. Exhaled nitric oxide, AHR, airway inflammation, T(H)2 cytokines, goblet cell metaplasia, nitro-oxidative stress, and expressions of arginase 1, endothelial NOS, and inducible NOS in lung were determined.
RESULTS: L-arginine significantly reduced AHR and airway inflammation including bronchoalveolar lavage fluid eosinophilia, T(H)2 cytokines, TGF-beta1, goblet cell metaplasia, and subepithelial fibrosis. Further, L-arginine increased ENO levels and cyclic guanosine monophosphate in lung and reduced the markers of nitro-oxidative stress such as nitrotyrosine, 8-isoprostane, and 8-hydroxy-2'-deoxyguanosine. This was associated with reduced activity and expression of arginase 1, increased expression of endothelial NOS, and reduction of inducible NOS in bronchial epithelia.
CONCLUSION: We conclude that L-arginine administration may improve disordered nitric oxide metabolism associated with allergic airway inflammation, and alleviates some features of asthma.
PMID: 20153031 DOI: 10.1016/j.jaci.2009.10.065 [Indexed for MEDLINE]
https://www.ncbi.nlm.nih.gov/pubmed/20153031

Direct inhibition of arginase attenuated airway allergic reactions and inflammation in a Dermatophagoides farinae-induced NC/Nga mouse model.
Takahashi N1, Ogino K, Takemoto K, Hamanishi S, Wang DH, Takigawa T, Shibamori M, Ishiyama H, Fujikura Y.
Am J Physiol Lung Cell Mol Physiol. 2010 Jul;299(1):L17-24. doi: 10.1152/ajplung.00216.2009. Epub 2010 Apr 9.
Abstract
The expression of arginase I has been a focus of research into the pathogenesis of experimental asthma, because arginase deprives nitric oxide synthase (NOS) of arginine and therefore participates in the attenuation of bronchodilators such as nitric oxide (NO). The present study used an intranasal mite-induced NC/Nga mouse model of asthma to investigate the contribution of arginase to the asthma pathogenesis, using an arginase inhibitor, N(omega)-hydroxy-nor-l-arginine (nor-NOHA). The treatment with nor-NOHA inhibited the increase in airway hyperresponsiveness (AHR) and the number of eosinophils in bronchoalveolar lavage fluid. NOx levels in the lung were elevated despite suppressed NOS2 mRNA expression. Accompanied by the attenuated activity of arginase, the expression of arginase I at both the mRNA and protein level was downregulated. The levels of mRNA for T helper 2 cytokines such as IL-4, IL-5, and IL-13, and for chemotactants such as eotaxin-1 and eotaxin-2, were reduced. Moreover, the accumulation of inflammatory cells and the ratio of goblet cells in the bronchiole were decreased. The study concluded that the depletion of NO caused by arginase contributes to AHR and inflammation, and direct administration of an arginase inhibitor to the airway may be beneficial and could be of use in treating asthma due to its anti-inflammatory and airway-relaxing effects, although it is not clear whether the anti-inflammatory effect is direct or indirect.
PMID: 20382750 DOI: 10.1152/ajplung.00216.2009 [Indexed for MEDLINE] Free full text
https://www.ncbi.nlm.nih.gov/pubmed/20382750
http://ajplung.physiology.org/content/299/1/L17.long

The Promise of Plant-Derived Substances as Inhibitors of Arginase.
Girard-Thernier C1, Pham TN, Demougeot C.
Mini Rev Med Chem. 2015;15(10):798-808.
Abstract
The enzyme arginase catalyses the divalent cation dependent hydrolysis of L-arginine to produce L-ornithine and urea. Two isoforms of arginases have been identified in mammalian (including human) cells. Moreover, some infectious pathogens (e.g. Leishmania) synthesize their own arginase. Work over the last decades has revealed that elevated arginase activity both decreases cellular availability in nitric oxide (NO) by competing with NO synthases (NOS) and increases concentration in L-ornithine, a precursor in the biosynthesis of polyamines which are important for cell differentiation and proliferation. From these data emerged the concept that selective arginase inhibitors might be a valuable strategy for treatment of various diseases associated with decreased NO and/or increased polyamines production. Consistent with this, recent research provides compelling evidence supporting the beneficial effects of arginase inhibitors in cardiovascular diseases (hypertension, ischemia reperfusion injury, atherosclerosis, diabetes mellitus), asthma, cancer, immunologically-mediated diseases or leishmaniasis. Despite active programs to identify potent arginase inhibitors, effective chemical compounds with reliable pharmacokinetics and toxicological properties are rare. The present review summarizes available data on the discovery of new arginase inhibitors from natural origin. Current knowledge on plant-derived compounds or extracts with arginase inhibitory properties as well as available data on structure-activity relationship (SAR) will be presented. Lastly, the present review will open up new prospects in order to improve the discovery of novel arginase inhibitors from natural sources.
PMID: 25963565 [Indexed for MEDLINE]
https://www.ncbi.nlm.nih.gov/pubmed/25963565

The described elevation of ornithine may upregulate the activity of ODC? (T2, T4 --ODC--> T1AM)
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
Reply
#43
Why might a HIF protein or its subunits just loiter around in excess being a potential pain to their owner? Some possibilities in this article. If alteration of mitochondrial function could account for it, that might be where I'd want to put my "smart money" out of anything shown here?

Role and regulation of prolyl hydroxylase domain proteins.
Fong GH, Takeda K.
Cell Death Differ. 2008 Apr;15(4):635-41. doi: 10.1038/cdd.2008.10. Epub 2008 Feb 15.
Abstract
Oxygen-dependent hydroxylation of hypoxia-inducible factor (HIF)-alpha subunits by prolyl hydroxylase domain (PHD) proteins signals their polyubiquitination and proteasomal degradation, and plays a critical role in regulating HIF abundance and oxygen homeostasis. While oxygen concentration plays a major role in determining the efficiency of PHD-catalyzed hydroxylation reactions, many other environmental and intracellular factors also significantly modulate PHD activities. In addition, PHDs may also employ hydroxylase-independent mechanisms to modify HIF activity. Interestingly, while PHDs regulate HIF-alpha protein stability, PHD2 and PHD3 themselves are subject to feedback upregulation by HIFs. Functionally, different PHD isoforms may differentially contribute to specific pathophysiological processes, including angiogenesis, erythropoiesis, tumorigenesis, and cell growth, differentiation and survival. Because of diverse roles of PHDs in many different processes, loss of PHD expression or function triggers multi-faceted pathophysiological changes as has been shown in mice lacking different PHD isoforms. Future investigations are needed to explore in vivo specificity of PHDs over different HIF-alpha subunits and differential roles of PHD isoforms in different biological processes.
PMID: 1825920 DOI: 10.1038/cdd.2008.10 [Indexed for MEDLINE] Free full text
https://www.ncbi.nlm.nih.gov/pubmed/18259202
http://www.nature.com/cdd/journal/v15/n4...0810a.html

[Image: cdd200810f1.jpg]


There may also be a role for reactive oxygen species, and...

Regulation of oxygen homeostasis by hypoxia-inducible factor 1.
Semenza GL.
Physiology (Bethesda). 2009 Apr;24:97-106. doi: 10.1152/physiol.00045.2008.
Abstract
Metazoan organisms are dependent on a continuous supply of O(2) for survival. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in development, physiology, and disease. HIF-1 activity is induced in response to continuous hypoxia, intermittent hypoxia, growth factor stimulation, and Ca(2+) signaling. HIF-1 mediates adaptive responses to hypoxia, including erythropoiesis, angiogenesis, and metabolic reprogramming. In each case, HIF-1 regulates the expression of multiple genes encoding key components of the response pathway. HIF-1 also mediates maladaptive responses to chronic continuous and intermittent hypoxia, which underlie the development of pulmonary and systemic hypertension, respectively.
PMID: 19364912 DOI: 10.1152/physiol.00045.2008 [Indexed for MEDLINE] Free full text
https://www.ncbi.nlm.nih.gov/pubmed/19364912
http://physiologyonline.physiology.org/c.../2/97.long
...When cells are acutely subjected to hypoxia, the hydroxylation reactions are inhibited as a result of substrate (O2) deprivation and/or increased mitochondrial production of ROS, which may inhibit the hydroxylases by oxidizing a ferrous ion in the catalytic site (24, 30). The loss of hydroxylase activity increases HIF-1a stability and transactivation function, leading to its dimerization with HIF-1ß, binding of HIF-1 to its recognition sequence 5'-(A/G)CGTG-3' (71) in target genes, and increased transcription of target gene sequences into mRNA.

[Image: F3.large.jpg?width=800&height=600&carousel=1]
("Red numeral indicates process that is inhibited by HIF-1: 5) pyruvate dehydrogenase activity.")
Now THAT looks like a metabolic switch?

...Glucose and energy metabolism
Individual cells must adapt to O2 deprivation by reprogramming their metabolism. The metabolic alterations that are induced by hypoxia are profound (FIGURE 3C?). Perhaps the most subtle adaptation identified thus far is a subunit switch that occurs in cytochrome c oxidase (COX; complex IV), in which the COX4-1 regulatory subunit is replaced by the COX4-2 isoform as a result of HIF-1-mediated transcriptional activation of genes encoding COX4-2 and LON, a mitochondrial protease that is required for the hypoxia-induced degradation of COX4-1 (20). This subunit switch serves to optimize the efficiency with which COX transfers electrons to O2 under hypoxic conditions. Remarkably, the budding yeast Saccharomyces cerevisiae also switches COX subunits in response to hypoxia (40) but does so by a completely different molecular mechanism since yeast do not have a HIF-1 homolog. The similar regulation of COX activity in yeast and human cells indicates that the selection for O2-dependent homeostatic regulation of mitochondrial respiration is ancient and likely to be shared by all eukaryotic organisms (20).
A more drastic alteration is the shunting of pyruvate away from the mitochondria by the HIF-1-mediated activation of the PDK1 gene encoding pyruvate dehydrogenase (PDH) kinase 1 (35, 56), which phosphorylates the catalytic subunit of PDH, the enzyme that converts pyruvate into acetyl coenzyme A (AcCoA) for entry into the mitochondrial tricyclic acid cycle (FIGURE 3C?), which generates reducing equivalents that are donated to the electron transport chain. The reduced delivery of substrate to the mitochondria for oxidative phosphorylation results in reduced ATP synthesis, which must be compensated for by increased glucose uptake via glucose transporters and increased conversion of glucose to lactate by the activity of glycolytic enzymes and lactate dehydrogenase A (FIGURE 3C?), which are all encoded by HIF-1 target genes (27, 67, 69, 71).
Induction of PDK1 expression will inhibit the oxidative metabolism of AcCoA derived from glucose but will not affect the oxidative metabolism of AcCoA derived from fatty acids. The most draconian response to persistent hypoxia is the active destruction of mitochondria by selective mitochondrial autophagy (97). Remarkably, mouse embryo fibroblasts (MEFs) cultured at 1% O2 reduce their mitochondrial mass by ~75% within 48 h through autophagy that is initiated by the HIF-1-dependent expression of BNIP3, a mitochondrial protein that competes with Beclin1 for binding to Bcl2, thereby freeing Beclin1 to trigger autophagy (97).
The adaptive significance of these metabolic responses to hypoxia were revealed by the finding that HIF-1a-deficient MEFs die when cultured under hypoxic conditions for 72 h due to dramatically increased ROS levels (35, 69). The cells can be rescued by overexpression of PDK1 or BNIP3, or by treatment with free-radical scavengers (35, 69). It has long been known that mitochondrial ROS production increases under hyperoxic conditions (87). However, recent studies have demonstrated that acute hypoxia also leads to increased mitochondrial ROS production, which is required for the inhibition of HIF-1a hydroxylase activity (24). Exposure of wild-type (WT) MEFs to hypoxia for 48 h results in reduced ROS levels, in contrast to Hif1a-/- MEFs in which ROS levels are markedly increased (35, 97).
The following conclusions can be drawn regarding the metabolic adaptation to hypoxia. The increase in glycolysis and decrease in respiration that occur in response to hypoxia do not represent a passive effect of substrate (O2) deprivation but instead represent an active response of the cell to counteract the reduced efficiency of respiration under hypoxic conditions, which in the absence of adaptation results in the accumulation of toxic levels of ROS. These studies indicate that a major role of HIF-1 is to establish, at any O2 concentration, the optimal balance between glycolytic and oxidative metabolism that maximizes ATP production without increasing ROS levels. Finally, analysis of lung tissue from non-hypoxic Hif1a+/- mice, which are heterozygous for a HIF-1a-null allele and thus partially HIF-1a deficient, revealed an ~50% decrease in mitochondrial mass compared with WT littermates (97). This remarkable finding indicates that HIF-1 regulates mitochondrial metabolism even in the tissue exposed to the highest PO2, indicating that HIF-1 performs this critical function over the entire range of physiological PO2. Thus HIF-1 maintains the metabolic/redox homeostasis that is essential for metazoan cells to live with O2.

Then there is FIH, whom I have not actually met before this morning...

The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism.
Zhang N, Fu Z, Linke S, Chicher J, Gorman JJ, Visk D, Haddad GG, Poellinger L, Peet DJ, Powell F, Johnson RS.
Cell Metab. 2010 May 5;11(5):364-78. doi: 10.1016/j.cmet.2010.03.001. Epub 2010 Apr 15.n
Abstract
Factor inhibiting HIF-1alpha (FIH) is an asparaginyl hydroxylase. Hydroxylation of HIF-alpha proteins by FIH blocks association of HIFs with the transcriptional coactivators CBP/p300, thus inhibiting transcriptional activation. We have created mice with a null mutation in the FIH gene and found that it has little or no discernable role in mice in altering classical aspects of HIF function, e.g., angiogenesis, erythropoiesis, or development. Rather, it is an essential regulator of metabolism: mice lacking FIH exhibit reduced body weight, elevated metabolic rate, hyperventilation, and improved glucose and lipid homeostasis and are resistant to high-fat-diet-induced weight gain and hepatic steatosis. Neuron-specific loss of FIH phenocopied some of the major metabolic phenotypes of the global null animals: those mice have reduced body weight, increased metabolic rate, and enhanced insulin sensitivity and are also protected against high-fat-diet-induced weight gain. These results demonstrate that FIH acts to a significant degree through the nervous system to regulate metabolism.
PMID: 20399150 PMCID: PMC2893150 DOI: 10.1016/j.cmet.2010.03.001 [Indexed for MEDLINE] Free PMC Article
https://www.ncbi.nlm.nih.gov/pubmed/20399150
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893150

Factor inhibiting HIF-1 (FIH-1) modulates protein interactions of apoptosis-stimulating p53 binding protein 2 (ASPP2).
Janke K, Brockmeier U, Kuhlmann K, Eisenacher M, Nolde J, Meyer HE, Mairbäurl H, Metzen E.
J Cell Sci. 2013 Jun 15;126(Pt 12):2629-40. doi: 10.1242/jcs.117564. Epub 2013 Apr 19.
Abstract
The asparaginyl hydroxylase factor inhibiting HIF-1 (FIH-1) is an important suppressor of hypoxia-inducible factor (HIF) activity. In addition to HIF-a, FIH-1 was previously shown to hydroxylate other substrates within a highly conserved protein interaction domain, termed the ankyrin repeat domain (ARD). However, to date, the biological role of FIH-1-dependent ARD hydroxylation could not be clarified for any ARD-containing substrate. The apoptosis-stimulating p53-binding protein (ASPP) family members were initially identified as highly conserved regulators of the tumour suppressor p53. In addition, ASPP2 was shown to be important for the regulation of cell polarity through interaction with partitioning defective 3 homolog (Par-3). Using mass spectrometry we identified ASPP2 as a new substrate of FIH-1 but inhibitory ASPP (iASPP) was not hydroxylated. We demonstrated that ASPP2 asparagine 986 (N986) is a single hydroxylation site located within the ARD. ASPP2 protein levels and stability were not affected by depletion or inhibition of FIH-1. However, FIH-1 depletion did lead to impaired binding of Par-3 to ASPP2 while the interaction between ASPP2 and p53, apoptosis and proliferation of the cancer cells were not affected. Depletion of FIH-1 and incubation with the hydroxylase inhibitor dimethyloxalylglycine (DMOG) resulted in relocation of ASPP2 from cell-cell contacts to the cytosol. Our data thus demonstrate that protein interactions of ARD-containing substrates can be modified by FIH-1-dependent hydroxylation. The large cellular pool of ARD-containing proteins suggests that FIH-1 can affect a broad range of cellular functions and signalling pathways under certain conditions, for example, in response to severe hypoxia.
KEYWORDS: Cell polarity; Hydroxylation; Hypoxia; Protein interaction
PMID: 23606740 DOI: 10.1242/jcs.117564 [Indexed for MEDLINE] Free full text
https://www.ncbi.nlm.nih.gov/pubmed/23606740
http://jcs.biologists.org/content/126/12/2629.long

The role of factor inhibiting HIF (FIH-1) in inhibiting HIF-1 transcriptional activity in glioblastoma multiforme.
Wang E, Zhang C, Polavaram N, Liu F, Wu G, Schroeder MA, Lau JS, Mukhopadhyay D, Jiang SW, O'Neill BP, Datta K, Li J.
PLoS One. 2014 Jan 23;9(1):e86102. doi: 10.1371/journal.pone.0086102. eCollection 2014.
Abstract
Glioblastoma multiforme (GBM) accounts for about 38% of primary brain tumors in the United States. GBM is characterized by extensive angiogenesis induced by vascular growth factors and cytokines. The transcription of these growth factors and cytokines is regulated by the Hypoxia-Inducible-Factor-1(HIF-1), which is a key regulator mediating the cellular response to hypoxia. It is known that Factor Inhibiting HIF-1, or FIH-1, is also involved in the cellular response to hypoxia and has the capability to physically interact with HIF-1 and block its transcriptional activity under normoxic conditions. Delineation of the regulatory role of FIH-1 will help us to better understand the molecular mechanism responsible for tumor growth and progression and may lead to the design of new therapies targeting cellular pathways in response to hypoxia. Previous studies have shown that the chromosomal region of 10q24 containing the FIH-1 gene is often deleted in GBM, suggesting a role for the FIH-1 in GBM tumorigenesis and progression. In the current study, we found that FIH-1 is able to inhibit HIF-mediated transcription of GLUT1 and VEGF-A, even under hypoxic conditions in human glioblastoma cells. FIH-1 has been found to be more potent in inhibiting HIF function than PTEN. This observation points to the possibility that deletion of 10q23-24 and loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF-1 activity, an alteration of HIF-1 targets such as GLUT-1 and VEGF-A, and may contribute to the survival of cancer cells in hypoxia and the development of hypervascularization observed in GBM. Therefore FIH-1 can be potential therapeutic target for the treatment of GBM patients with poor prognosis.
PMID: 24465898 PMCID: PMC3900478 DOI: 10.1371/journal.pone.0086102 [Indexed for MEDLINE] Free PMC Article
https://www.ncbi.nlm.nih.gov/pubmed/24465898
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900478

It will be a neat trick if an infection that may be able to make you cross-allergic to your own glycolytic enzymes can also manipulate your metabolism to be that much more dependent on them?

I'll throw in this one for good measure. By this time, let me guess, there's potential airway hyperreactivity to CO2, plenty of CO2 coming off fermentative respiration, and mobilization of HIF-upregulated CA IX at the possible expense of proper pH homeostasis? (Reminder, CAs may be the fastest enzymes ever discovered in nature. If they're tricked into doing anything, they may be able to do a lot of it, fast?)

Dexamethasone downregulates expression of carbonic anhydrase IX via HIF-1a and NF-kB-dependent mechanisms
Veronika Simko, Martina Takacova, Michaela Debreova, Katarina Laposova, Elena Ondriskova-Panisova, Silvia Pastorekova, Lucia Csaderova, and Jaromir Pastorek
Int J Oncol. 2016 Oct; 49(4): 1277–1288. Published online 2016 Jul 14. doi:  10.3892/ijo.2016.3621 PMCID: PMC5021256
Abstract
Dexamethasone is a synthetic glucocorticoid frequently used to suppress side-effects of anticancer chemotherapy. In the present study, we showed that dexamethasone treatment leads to concentration-dependent downregulation of cancer-associated marker, carbonic anhydrase IX (CA IX), at the level of promoter activity, mRNA and protein expression in 2D and 3D cancer cell models. The effect of dexamethasone on CA IX expression under hypoxic conditions is predominantly mediated by impaired transcriptional activity and decreased protein level of the main hypoxic transcription factor HIF-1a. In addition, CA9 downregulation can be caused by protein-protein interactions between activated glucocorticoid receptors, major effectors of glucocorticoid action, and transcription factors that trigger CA9 transcription (e.g. AP-1). Moreover, we identified a potential NF-kB binding site in the CA9 promoter and propose the involvement of NF-kB in the dexamethasone-mediated inhibition of CA9 transcription. As high level of CA IX is often linked to aggressive tumor behavior, poor prognosis and chemo- and radiotherapy resistance, uncovering its reduction after dexa-methasone treatment and implication of additional regulatory mechanisms can be relevant for the CA IX-related clinical applications.
Keywords: dexamethasone, hypoxia-inducible factor-1a, carbonic anhydrase IX, transcriptional regulation, nuclear factor-kappaB
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021256
Hypoxia as a consequence of low oxygenation caused by impaired and aberrant vascularization is a common feature of many malignant tumors. Hypoxia leads to reduced apoptosis, increased proliferation and angiogenesis predominantly via altered gene expression. The main factor mediating this oxygen sensitive response is the hypoxia-inducible factor-1 (HIF-1) that consists of a constitutive ß subunit and an oxygen-sensitive a subunit that is regulated through O2-dependent degradation by prolyl hydroxylation. Oxygenation of cells results in the binding of the von Hippel-Lindau tumor-suppressor protein specifically to hydroxylated HIF-1a which ensures its ubiquitylation and rapid proteasomal degradation (1). During hypoxia these processes are inhibited, HIF-1a accumulates, dimerizes with HIF-1ß to generate the functional HIF-1 that regulates many genes responsible for adaptive responses, which are important for cell survival at low oxygen levels (2).
One of the proteins, which support adaptation of tumor cells to hypoxia is carbonic anhydrase IX (CA IX). CA IX is a tumor-associated, membrane located metalloenzyme catalyzing the reversible conversion of carbon dioxide to bicarbonate ion and proton (reviewed in ref. 3). Its activity, dependent on the phosphorylation of Thr443 residue by protein kinase A contributes to intracellular pH maintenance (4), supporting cancer cell survival in the conditions of hypoxia and related acidosis and promoting their migration and invasion (5). Moreover, through its unique extracellular proteoglycan domain it is involved in cell adhesion and spreading (6). Transcription of CA9 gene is primarily regulated by the hypoxia-inducible HIF-1 transcription factor that binds to the hypoxia response element (HRE) located next to the transcription initiation site (7) and CA IX is considered as a marker of tumor hypoxia. CA IX is expressed in a broad range of tumors where its strong expression often associates with worse prognosis. Due to its tumor-related expression and its role in pro-survival and pro-metastatic processes of tumor cells CA IX represents a promising target for antitumor therapy (8).
Recently, it was described that hypoxia also occurs as a result of the inflammation when HIF-1a can be regulated independently of the vascularization level induced by growth factors, pro-inflammatory cytokines, reactive oxygen and nitrogen species or mitochondrial stress (9). Moreover, hypoxia can actively participate in the development of the inflammatory microenvironment through the promotion of many pro-inflammatory genes (10) governed by nuclear factor-kappaB transcription factor (NF-kB) (11,12). Mammalian NF-kB family consists of: NF-kB1 (p50/p105), NF-kB2 (p52/p100), RelA (p65), RelB and c-Rel. The active NF-kB is a heterodimer typically consisting of NF-kB1 and RelA subunits. In unstimulated cells, a latent protein complex is sequestered in the cytoplasm by the associated inhibitor IkB. The activation of the NF-kB is initiated by the phosphorylation of IkB proteins mediated via the signal-induced activation of IkB kinase (IKK). This leads to the ubiquitylation and degradation of I?B in the proteasome which results in a release of the NF-kB complex and its subsequent relocation to the nucleus (13,14). Transcriptional targets of NF-kB transcription factor include mostly pro-inflammatory genes encoding cytokines, chemokines, adhesion molecules as well as angiogenic factors and key enzymes involved in prostaglandin synthase or nitric oxide synthase pathways. In this way, NF-kB directly contributes to the development of inflammation. A number of studies provided evidence on aberrant regulation of NF-kB in many cancers where it actively participates in tumor initiation and progression (15).

I guess lastly there's the part where human adenylate cyclase 10 (ADCY10 aka sAC aka soluble adenylate cyclase) is a bicarbonate sensor. Could the appropriate manipulation of cellular bicarbonate result in hijacking of this enzyme? Sounds like AC and CA might make for a rather mischievous pair in certain situations on certain days?

Soluble Adenylyl Cyclase - Wikipedia
A truncated form of the enzyme only includes the C1 and C2 domains and it is refers to as the minimal functional sAC variant.[4][9] This sAC-truncated form has cAMP-forming activity much higher than its full-length type. These sAC variants are stimulated by HCO3- and respond to all known selective sAC inhibitors.[5] Crystal structures of this sAC variant comprising only the catalytic core, in apo form and in as complex with various substrate analogs, products, and regulators, reveal a generic Class III AC architecture with sAC-specific features.[10] The structurally related domains C1 and C2 form the typical pseudo-heterodimer, with one active site.[5] The pseudo-symmetric site accommodates the sAC-specific activator HCO3-, which activates by triggering a rearrangement of Arg176, a residue connecting both sites. The anionic sAC inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) acts as a blocker for the entrance to active site and bicarbonate binding pocket.[10]
...
Sources of bicarbonate (HCO-3)and calcium (Ca2+):
-bicarbonate derived from carbonic anhydrase (CA)-dependent hydration.
-CO2 metabolism
-Enters through membrane-transporting proteins or cystic fibrosis transmembrane conductance regulators.
-Calcium enters by voltage-dependent Ca2+ channels or by release from the endoplasmic reticulum.
-Hydrogen carbonate and calcium activates sAC in the nucleus.
-sAC inside mitochondria is activated by metabolically generated CO2 through carbonic anhydrase.

Any MORE trouble that adenosine needs to be in a position to cause before "the medical profession" will consider blaming a nucleotidase-bearing microbe first instead of last?
"Work and pray, live on hay, you'll get Pie In The Sky when you die." - Joe Hill, "The Preacher and the Slave" 1911
Reply
#44
Involvement of hypoxia-inducible factor-1 HiF(1alpha) in IgE-mediated primary human basophil responses.
Sumbayev VV1, Nicholas SA, Streatfield CL, Gibbs BF.
Eur J Immunol. 2009 Dec;39(12):3511-9. doi: 10.1002/eji.200939370.
Abstract
Basophils play a pivotal role in regulating chronic allergic inflammation as well as angiogenesis. Here, we show for the first time that IgE-mediated activation of primary human basophils results in protein accumulation of the alpha-subunit of hypoxia-inducible factor 1alpha (HIF-1alpha), which is differentially regulated compared with signals controlling histamine release. HIF-1 facilitates cellular adaptation to hypoxic conditions such as inflammation and tumour growth by controlling glycolysis, angiogenesis and cell adhesion. ERK and p38 MAPK, but not reactive oxygen species (ROS), ASK1 or PI 3-kinase, were critical for IgE-mediated accumulation of HIF-1alpha, although the latter crucially affected degranulation. Abrogating HIF-1alpha expression in basophils using siRNA demonstrated that this protein is essential for vascular endothelial growth factor (VEGF) mRNA expression and, consequently, release of VEGF protein. In addition, HIF-1alpha protein alters IgE-induced ATP depletion in basophils, thus also supporting the production of the pro-allergic cytokine IL-4.
PMID: 19768695 DOI: 10.1002/eji.200939370 [Indexed for MEDLINE] Free full text
https://www.ncbi.nlm.nih.gov/pubmed/19768695
http://onlinelibrary.wiley.com/doi/10.10...39370/epdf

Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide.
Kimura H1, Weisz A, Kurashima Y, Hashimoto K, Ogura T, D'Acquisto F, Addeo R, Makuuchi M, Esumi H.
Blood. 2000 Jan 1;95(1):189-97.
Abstract
Nitric oxide (NO) regulates production of vascular endothelial growth factor (VEGF) by normal and transformed cells. We demonstrate that NO donors may up-regulate the activity of the human VEGF promoter in normoxic human glioblastoma and hepatoma cells independent of a cyclic guanosine monophosphate-mediated pathway. Deletion and mutation analysis of the VEGF promoter indicates that the NO-responsive cis-elements are the hypoxia-inducible factor-1 (HIF-1) binding site and an adjacent ancillary sequence that is located immediately downstream within the hypoxia-response element (HRE). This work demonstrates that the HRE of this promoter is the primary target of NO. In addition, VEGF gene regulation by NO, as well as by hypoxia, is potentiated by the AP-1 element of the gene. Our study also reveals that NO and hypoxia induce an increase in HIF-1 binding activity and HIF-1alpha protein levels, both in the nucleus and the whole cell. These results suggest that there are common features of the NO and hypoxic pathways of VEGF induction, while in part, NO mediates gene transcription by a mechanism distinct from hypoxia. This is demonstrated by a difference in sensitivity to guanylate cyclase inhibitors and a different pattern of HIF-1 binding. These results show that there is a primary role for NO in the control of VEGF synthesis and in cell adaptations to hypoxia. (Blood. 2000;95:189-197)
PMID: 10607702 [Indexed for MEDLINE] Free full text
https://www.ncbi.nlm.nih.gov/pubmed/10607702
http://www.bloodjournal.org/content/95/1/189.long

Activation of hypoxia-inducible factor-1 regulates human histidine decarboxylase expression.
Jeong HJ1, Moon PD, Kim SJ, Seo JU, Kang TH, Kim JJ, Kang IC, Um JY, Kim HM, Hong SH.
Cell Mol Life Sci. 2009 Apr;66(7):1309-19. doi: 10.1007/s00018-009-9001-1.
Abstract
Histidine decarboxylase (HDC) catalyzes the formation of histamine from histidine. Histamine has various effects in physiological and pathological reactions, such as inflammation, cell growth, and neuro-transmission. We investigated the role of hypoxia-inducible factor (HIF)-1 on hypoxia-induced HDC expression in human mast cell line, HMC-1 cells and mouse bone marrow-derived mast cells (BMMCs). Hypoxia significantly increased histamine production. HDC expression and activity were induced by hypoxia. Additionally, when cells were transfected with a native form of HIF-1alpha, hypoxia could induce higher HDC expression than in the nontransfected cell. HIF-1 binding activity for HDC 5' flanking region (HFR) was similar to that for the hypoxia-responsive element. Using HDC promoter deletion analysis, we also demonstrated that HFR was regulated by HIF-1 activation. In addition, depletion of HIF-1alpha prevents hypoxic induction of HDC in BMMCs. In conclusion, these results demonstrate that hypoxia induces HDC expression by transcriptional mechanisms dependent upon HIF-1.
PMID: 19266161 DOI: 10.1007/s00018-009-9001-1 [Indexed for MEDLINE]
https://www.ncbi.nlm.nih.gov/pubmed/19266161

The critical role of mast cell-derived hypoxia-inducible factor-1a in human and mice melanoma growth.
Jeong HJ1, Oh HA, Nam SY, Han NR, Kim YS, Kim JH, Lee SJ, Kim MH, Moon PD, Kim HM, Oh HA.
Int J Cancer. 2013 Jun 1;132(11):2492-501. doi: 10.1002/ijc.27937. Epub 2012 Dec 3.
Abstract
Mast cells play an important role in tumorigenesis. Histamine released from mast cells stimulates new vessel formation by acting through the histamine1 (H1) receptor. Despite the evidence of the role of mast cells in tumor growth and angiogenesis, the potential mechanism remains to be elucidated. Therefore, we investigated the role of mast cell-derived HIF-1a in melanoma growth. Here, we identify that the most positive cells for HIF-1a staining are seen in mast cells of human and animal melanoma tissue. The number of the stromal cell types (fibroblasts, macrophages and endothelial cells) was also increased in melanoma tissues. In activated bone marrow-derived mast cells (BMMCs), expressions of HIF-1a and VEGF were increased. Histamine also induced the expressions of HIF-1a and VEGF in BMMCs. H1 receptor antagonists significantly improved overall survival rates and substantially suppressed tumor growth as well as the infiltration of mast cells and levels of VEGF through the inhibition of HIF-1a expression in B16F10 melanoma-bearing mice. Furthermore, the injection of HIF-1a depleted BMMCs markedly inhibited the growth of tumors and migration of mast cells and increased the survival rate of the mice. These findings emphasize that the growth of melanoma can actually be exacerbated by mast cell-derived HIF-1a. In aggregate, our results reveal a novel role for mast cell-derived HIF-1a in the melanoma microenvironment and have important implications for the design of therapeutic strategies.
PMID: 23161568 DOI: 10.1002/ijc.27937 [Indexed for MEDLINE] Free full text 
https://www.ncbi.nlm.nih.gov/pubmed/23161568
http://onlinelibrary.wiley.com/doi/10.10....27937/pdf

Mast cell degranulation and de novo histamine formation contribute to sustained postexercise vasodilation in humans.
Romero SA1, McCord JL1, Ely MR1, Sieck DC1, Buck TM1, Luttrell MJ1, MacLean DA2, Halliwill JR3.
J Appl Physiol (1985). 2017 Mar 1;122(3):603-610. doi: 10.1152/japplphysiol.00633.2016. Epub 2016 Aug 25.
Abstract
In humans, acute aerobic exercise elicits a sustained postexercise vasodilation within previously active skeletal muscle. This response is dependent on activation of histamine H1 and H2 receptors, but the source of intramuscular histamine remains unclear. We tested the hypothesis that interstitial histamine in skeletal muscle would be increased with exercise and would be dependent on de novo formation via the inducible enzyme histidine decarboxylase and/or mast cell degranulation. Subjects performed 1 h of unilateral dynamic knee-extension exercise or sham (seated rest). We measured the interstitial histamine concentration and local blood flow (ethanol washout) via skeletal muscle microdialysis of the vastus lateralis. In some probes, we infused either a-fluoromethylhistidine hydrochloride (a-FMH), a potent inhibitor of histidine decarboxylase, or histamine H1/H2-receptor blockers. We also measured interstitial tryptase concentrations, a biomarker of mast cell degranulation. Compared with preexercise, histamine was increased after exercise by a change (?) of 4.2 ± 1.8 ng/ml (P < 0.05), but not when a-FMH was administered (?-0.3 ± 1.3 ng/ml, P = 0.9). Likewise, local blood flow after exercise was reduced to preexercise levels by both a-FMH and H1/H2 blockade. In addition, tryptase was elevated during exercise by ?6.8 ± 1.1 ng/ml (P < 0.05). Taken together, these data suggest that interstitial histamine in skeletal muscle increases with exercise and results from both de novo formation and mast cell degranulation. This suggests that exercise produces an anaphylactoid signal, which affects recovery, and may influence skeletal muscle blood flow during exercise. NEW & NOTEWORTHY Blood flow to previously active skeletal muscle remains elevated following an acute bout of aerobic exercise and is dependent on activation of histamine H1 and H2 receptors. The intramuscular source of histamine that drives this response to exercise has not been identified. Using intramuscular microdialysis in exercising humans, we show both mast cell degranulation and formation of histamine by histidine decarboxylase contributes to the histamine-mediated vasodilation that occurs following a bout of aerobic exercise.
KEYWORDS: extracellular fluid; histamine; microdialysis; postexercise hypotension; regional blood flow
PMID: 27562843 DOI: 10.1152/japplphysiol.00633.2016
https://www.ncbi.nlm.nih.gov/pubmed/27562843

Natural product-derived small molecule activators of hypoxia-inducible factor-1 (HIF-1).
Nagle DG1, Zhou YD.
Curr Pharm Des. 2006;12(21):2673-88.
Abstract
Hypoxia-inducible factor-1 (HIF-1) is a key mediator of oxygen homeostasis that was first identified as a transcription factor that is induced and activated by decreased oxygen tension. Upon activation, HIF-1 upregulates the transcription of genes that promote adaptation and survival under hypoxic conditions. HIF-1 is a heterodimer composed of an oxygen-regulated subunit known as HIF-1alpha and a constitutively expressed HIF-1beta subunit. In general, the availability and activity of the HIF-1alpha subunit determines the activity of HIF-1. Subsequent studies have revealed that HIF-1 is also activated by environmental and physiological stimuli that range from iron chelators to hormones. Preclinical studies suggest that HIF-1 activation may be a valuable therapeutic approach to treat tissue ischemia and other ischemia/hypoxia-related disorders. The focus of this review is natural product-derived small molecule HIF-1 activators. Natural products, relatively low molecular weight organic compounds produced by plants, animals, and microbes, have been and continue to be a major source of new drugs and molecular probes. The majority of known natural product-derived HIF-1 activators were discovered through the pharmacological evaluation of specifically selected individual compounds. On the other hand, the combination of natural products chemistry with appropriate high-throughput screening bioassays may yield novel natural product-derived HIF-1 activators. Potent natural product-derived HIF-1 activators that exhibit a low level of toxicity and side effects hold promise as new treatment options for diseases such as myocardial and peripheral ischemia, and as chemopreventative agents that could be used to reduce the level of ischemia/reperfusion injury following heart attack and stroke.
PMID: 16842166 PMCID: PMC2907550 [Indexed for MEDLINE] Free PMC Article
https://www.ncbi.nlm.nih.gov/pubmed/16842166
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907550
Introduction
Over the course of time, multicellular organisms have evolved tightly regulated oxygen delivery systems to ensure oxygen dependent energy production. In the human body, high levels of oxygen (hyperoxia) can cause oxygen toxicity while low levels (hypoxia) are associated with hypoxia/ischemia-related diseases such as ischemic and neoplastic disorders. At the organism level, the body responds to changes in oxygen levels by altering respiration rate and blood flow. At the cellular level, changes in oxygen levels can trigger responses from a network of signaling pathways that lead to alterations in gene expression patterns.
Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that is activated by hypoxic conditions [1]. It is composed of a HIF-1a subunit and a HIF-1ß (also known as aryl hydrocarbon receptor nuclear translocator or ARNT) subunit, both are members of the basic helix-loop-helix (bHLH) PER-ARNT-SIM (PAS) family of transcription factors [2]. Over seventy genes have been identified as HIF-1 target genes and the list is still growing [3]. These genes encode proteins that are involved in many aspects of cellular physiology, ranging from cellular metabolism, cell proliferation/survival/death, cytoskeletal structure, cell adhesion/motility, angiogenesis, erythropoiesis, vascular tone, to drug resistance. It is no surprise that HIF-1 plays a crucial role in development, physiological processes such as wound healing, and pathological processes such as tumor progression and tissue ischemia [3–5].
...
One group of amino acid-derived natural products that activate HIF-1 is nitric oxide (NO) donors. Initial studies revealed that NO inhibits HIF-1 activation under hypoxic conditions [55–57]. Later, Kumara and coworkers discovered that the HIF-1 binding site in the human VEGF promoter actually mediates NO-induced activation of VEGF transcription under normoxic conditions [58]. The NO donor S-nitroso-N-acetyl-D,L-penicillamine (15, SNAP) induced HIF-1a protein accumulation, HIF-1 binding activities, and activated transcription from the VEGF promoter in A-172 human glioblastoma and Hep3B cells. Another NO donor, 3-(hydroxy-1-(1-methylethyl)-2-nitrosohydrazino)-1-propanamine (NOC5) also activated the VEGF promoter in a cell-based reporter assay. In bovine pulmonary artery endothelial and rat aortic smooth muscle cells, the NO donor diazen-1-ium-1,2-diolate (NOC-18), induced HIF-1a protein and HIF-1 DNA binding, augmented HIF-1ß protein expression, and activated expression of the HIF-1 target gene heme oxygenase-1 (HO-1) [59]. The induction of HIF-1 by NOC-18 is both dose- and time-dependent (optimal induction: 500 µM, 3–4 h). It was observed that Angeli's salt (a NO donor that generates NO-, nitroxyl equivalents) failed to induce HIF-1 activity, while 
S-nitrosoglutathione (16, GSNO) (an endogenous NO donor that generates NO-, nitrosonium equivalents) exerted a similar ability to induce HIF-1 as NOC-18. This indicates that a NO- equivalent-mediated electrophilic nitrosylation reaction may take place during NO-induced HIF-1 activation. Reversal of NOC-18-induced HIF-1 activation by dithiothreitol (DTT) suggests a mechanism that involves intracellular 
S-nitrosylation or oxidation of protein thiols. Subsequent studies have revealed that S-nitrosylation stabilizes HIF-1a protein and S-nitrosylation of Cys-800 promotes the interaction between HIF-1a protein and the co-activator p300, thus enhancing HIF-1 activation [60, 61]. Diazenium diolate NO donors that include spermine NONOate (17, a complex of NO with the natural product spermine), diethylamine NONOate, and diethyltryamine NONOate each induced HIF-1a protein in a dose- and time-dependent manner in multiple cell lines (proximal tubular LLC-PK1, human breast carcinoma MCF-7, MB231, and MB157) [62, 63]. Using a combination of NO donors that activate HIF-1 and pharmacological inhibitors of selected pathways, studies from numerous groups have revealed that NO donor-induced HIF-1 activation requires the presence of NO, is independent of the guanylate cyclase/guanosine 3',5'-monophosphate (cGMP) pathway, activates the PI3K/AKT/mTOR (phosphoinositol 3-kinase/protein kinase B/mammalian target of rapamycin) pathway to increase the synthesis of HIF-1a protein, and is sensitive to alterations in the cellular redox environment [59, 63–66]. Biochemical studies indicate that NO can bind to the iron in the active sites of HIF hydroxylases, block O2 binding and inhibit the hydroxylation reaction [23]. Inhibition of the hydroxylases that destabilize and inactivate HIF-1a protein may also contribute to NO-mediated HIF-1 activation in cell-based studies. Both the concentration and duration of NO released by structurally different NO donors should be considered when interpreting the results of these HIF-1 activation studies. Various NO concentration thresholds have been demonstrated to activate different signaling pathways under normoxic conditions [63]. The activation of HIF-1 by NO is most likely the overall outcome of modulating distinct pathways with different mechanisms.
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The testosterone metabolite dihydrotestosterone (26, 1 nM) induces HIF-1a protein and activates HIF-1 in androgen-dependent LNCaP cells, but not in androgen-independent PC-3 cells [86]. Similar effects were observed in the presence of the metabolically stable synthetic androgen methyltrienolone (27, R1881) at a concentration of 0.1 nM. Androgens activate HIF-1 by inducing growth factors such as epidermal growth factor (EGF), that in turn enhance the synthesis of HIF-1a protein via the activation of the receptor kinase/PI3K/AKT/mTOR pathway. Since androgens are not direct stimuli for HIF-1 activation, this response requires an extended incubation time in contrast to the action of direct stimuli such as hypoxia or iron chelators.
...
Prostaglandin E2 (PGE2)
Prostaglandin E2 (29, PGE2) was demonstrated to induce HIF-1a protein in human colon carcinoma HCT116 cells in a dose- and time-dependent manner [93]. Although modest in comparison to that triggered by hypoxia, maximal induction was observed after an 18–32 hr incubation in the presence of 29 (100 µM) . Prostaglandin E2 (29) induces HIF-1a protein by increasing HIF-1a protein synthesis. Pathway studies that employed pharmacological agents suggest that 29 activates the G-protein coupled receptor EP1, which then activates MEK/ERK and the v-src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (c-src), followed by the activation of the PI3K/AKT/mTOR pathway, and leads to increased HIF-1a protein synthesis. The induction of HIF-1a protein by 29 is accompanied by an increase in the level of VEGF mRNA. In PC-3ML (a subline of PC-3) cells, 29 (1 µM) induced nuclear HIF-1a protein accumulation within 4 hr and 29 appears to be more potent than hypoxia (1% O2) at inducing HIF-1a protein [94]. The effects of PGE2 (29) on HIF-1a protein were mediated by EP2 and EP4 receptor subtypes, through activation of the MAPK and PI3K/AKT pathways.. The enzyme cyclooxygenase-2 (COX-2) has been identified as a mediator for the induction of HIF-1 and VEGF by the proinflammatory cytokine IL-1ß in both A549 and colon carcinoma Caco-2 cells [95]. In A549 cells, PGE2 (one of the major products of COX-2 catalyzed metabolism of arachidonic acid) induced nuclear HIF-1a protein accumulation at concentrations as low as 0.1 µM within 1 hr. These results suggest that the effect of 29 on HIF-1 and its target genes can be mediated by more than one pathway, depending on which specific tumor type is involved. Due to the wide range of concentrations and incubation times required in different cell lines to elicit a HIF-1 response from PGE2 (29), particular caution should be taken when extrapolating these laboratory findings to the clinical setting.
Carbohydrates and Glycolysis Products
Hypoxic conditions and a state of aerobic glycolysis are commonly found in solid tumors. One group of HIF-1 target genes is glucose transporters and the glycolytic enzymes that promote glycolysis [3]. Identification of glucose and the glycolytic end products pyruvate and lactate as HIF-1 stimuli has helped construct a two-way connection between hypoxia and aerobic glycolysis [96]. In human glioma cells (U87, U373, and U251), glucose (30), pyruvate (31), and lactate (32) were each shown to induce nuclear HIF-1a protein accumulation in a dose- and time-dependent manner. Further study using pharmacological inhibitors identified pyruvate as the key glycolytic metabolite that induces HIF-1a protein by preventing its degradation. Activation of HIF-1 targets that include VEGF, EPO, GLUT3, and aldolase A was observed in the presence of either glucose or pyruvate [96]. At the final stage of glucose oxidation, reactions in the Krebs cycle (TCA cycle or citric acid cycle) oxidize the acetyl group of acetyl CoA into CO2. One intermediate of the TCA cycle, oxaloacetate (33), induces HIF-1a protein, activates HIF-1, and induces the expression of HIF-1 target genes in U87 and U251 cells [97]. Induction of the HIF prolyl hydroxylases (HPH) HPH-1 and HPH-2 mRNAs was also observed in the presence of these endogenous 2-oxoacids (31 and 33), as well as by the other known HIF-1 stimuli that include hypoxia (1% O2), the iron chelator DFO (1), the transition metal Co2+, and the 2-oxoglutarate (2OG) analogue dimethyl-N-oxalylglycine (6) [97]. This suggests the involvement of a potential negative feedback loop that regulates HIF-1 activity. In an effort to identify the link between succinate dehydrogenase (SDH) mutations and tumor formation, Selak and coworkers revealed that succinate (34) links mitochondrial dysfunction to oncogenesis via the activation of HIF-1 [98]. The enzyme SDH is localized to the inner mitochondrial membrane and catalyzes the conversion of 34 to fumarate. Both 34 and fumarate are intermediates of the TCA cycle. Inhibition of SDH leads to an increase in 34, which is transported from mitochondria to the cytosol. Succinate (34) is the product of 2OG-dependent oxygenases and a weak inhibitor of these enzymes. Succinate (34) inhibits HIF prolyl hydroxylases in the cytosol, stabilizes HIF-1a protein, and subsequently activates HIF-1. The concentrations of 34 that were shown to inhibit HPH activity in HEK293 cell extracts are within the range of 34 found in succinate dehydrogenase deficient cells. This SDH-succinate-HIF-1 link is supported by results from clinical studies that have demonstrated that SDH mutation-related tumors such as pheochromocytoma and renal cell carcinoma are highly vascular and have activated hypoxic signaling pathways [99].
...
There is increasing evidence that supports HIF-1 as a general regulator of cellular responses to environmental, extracellular, and intracellular signals. Non-hypoxic physiological stimuli such as growth factors, cytokines, and hormones can also induce HIF-1a protein and activate HIF-1. Activation of HIF-1 by insulin, insulin-like growth factor (IGF)-1 and IGF-2 leads to an increased expression of HIF-1 target genes such as IGF-2, IGF-binding protein (IGFBP)-2 and IGFBP-3 and forms an autocrine loop that promotes proliferation [111, 112]. Other growth factors that include EGF, basic fibroblast growth factor (bFGF), and heregulin have all been shown to activate HIF-1 in various cell lines [88, 112–114]. Both PI3K and MAPK signaling pathways are involved in mediating the induction and activation of HIF-1 by growth factors [112–117]. Activation of the PI3K/AKT/mTOR pathway relieves translational inhibition and enhances translation of HIF-1a mRNA [113]. These growth factors activate HIF-1 by increasing HIF-1a protein synthesis, in contrast to the mechanism of stimuli such as hypoxia and iron chelators that inhibit the degradation of HIF-1a protein. Cytokines such as tumor necrosis factor alpha (TNFa) and interleukin-1 beta (IL-1ß) induce HIF-1a protein under normoxic conditions and the induction can be augmented by hypoxic treatments [118, 119]. TNFa-induced HIF-1a protein stabilization and HIF-1 activation involve reactive oxygen species (ROS)-sensitive pathways, activation of the PI3K/AKT and MAPK pathways, and receptor-interacting protein (RIP)-dependent activation of NF?B [65, 91, 120, 121]. A recent study demonstrated that TNFa increases HIF-1a protein synthesis [122]. Activation of HIF-1 by IL-1ß requires pathways similar to those used by TNFa [95, 115, 123, 124]. Most of the studies indicate that IL-1ß induces HIF-1a protein accumulation. One study demonstrated that IL-1 also rapidly increases HIF-1a mRNA levels [125]. The vascular hormones angiotensin II and thrombin activate HIF-1 via stimulation of both HIF-1a transcription and translation [126–128]. The mechanisms used by these hormones to activate HIF-1 were summarized in a recent review [129]. Recently, thyroid hormone and follicle-stimulating hormone were added to the list of hormones that activate HIF-1 [130, 131]. Other physiological factors such as the redox protein thioredoxin-1 (Trx-1) and oxidized low-density lipoprotein (oxLDL) can also induce HIF-1a protein and activate HIF-1, suggesting that HIF-1 may play a role in tumors that over-express Trx-1 and diseases related to oxLDL such as atherosclerosis [132, 133].

So this is interesting because in a pathological context, thyroid hormone might exacerbate hyper-HIF activity, and low and behold, nature may have already tended to that concern (much to my continual dismay). How many other legitimate factors that might exacerbate a hyper-HIF condition might be similarly attenuated by hyper-HIF? It's also interesting that DHT comes up here, as 5-a-reductase inhibitors were greenlighted for my diagnosis that most certainly seems to result from infection. I already had the discussion a year ago with my doctor that the capability of certain infections to degrade testosterone via 5-a-reductase or equivalent enzymes might make me a candidate for an antibiotic before it makes me a candidate for a 5-a-reductase inhibitor, although there may be hints here and there that perhaps like thyroid hormone may be, androgens might also be downregulated in response to HIF)?

I left out the parts in this last article about green tea and quercetin and their effects on HIF-1, because in context their inclusion suggests implication in pathology and I tend to disagree with that, so I again wonder if any of these people really understand what they're saying (I also wonder why they keep wandering off the beaten path when that alone probably provides ample explanation). On the other hand, it might at least help to explain why these supplements may not be particularly helpful?

I have some new material that I think wants to make me sound hypochondriacal in it's apparently suggesting that the signalling events typically discussed here are well-organised via cellular microstructures or some such, as if to imply that wholesale hot-rodding of some of these signalling pathways were unlikely, but I'm not sure that such provisions are expected to win out in many pathological scenarios (starting with the classic examples of debilitating Cholera toxin impact on phagocytes), and I have some suspicions that such intercellular suborganization may sooner or later itself come under attack from certain toxins or factors in question. I'm not really expecting that much out of, for example, conjugated actin-ATP structures if a cell's ATP may have already been plundered.

Perhaps it's a little more likely for dysfunctions along these lines to make hypochondriacs out of people in the sense that there are so many possible exacerbatory influences in the developing picture that may correspond in real life to an increasing number of sensitivities?

For what it's worth, if the association of NO and VEGF is meant to serve as an explanation for angiogenesis, there may be an additional complication somewhere in the picture since thomboangiitis may nonetheless involve impediment of angiogenesis? I'm wondering if something like p53 might be the safety switch for... well, all the pro-HIF-1 literature makes it sound as if resultant angiogenesis is a beneficial response to genuine hypoxia, as if it is somehow attempting to correct hypoxia by generating compensatory vascular structure (?), and if I wonder how this system is going to distinguish oncologically-related hypoxia so as to refrain from providing metastasis to cancer cells, it might be something like that? Several years and too many papers ago now but IIRC p53 and some of the IkB proteins were linked though interactions with products of a large number of cancer-related genes? I guess next question might be which of those many proteins might be tricked into action to inhibit angiogenesis, if they are actually capable of such interference with the mechanisms that might be in question?

For now, this has given me a massive headache. I think all the parts are here but it might help quite a bit to be able to piece them together and come up with a complete picture of, for example, exactly what arginine is doing to be helpful. (There may be some other possibilities, like its possible participation in correction of ATP deficits via creatine or creatinine?) Still don't know if I've seen anything that suggests arginine metabolism or supplementation might more than a stop-gap measure actually, though. Might also be nice if I had a clearer picture of the effects of histamine and HIF-1 on each other, it keeps looking to me like they may be able to form an unhealthy feedback loop but I'm still not very sure of that. HOPEFULLY, this thread (or this thread plus the Regeneration thread?) does already contain enough pieces to lay out the barest bones of relevant pathological models?
"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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#45
Just a reminder kids, do not start smoking anything, ever. If you have birthdays, don't get candles that smoke when you blow them out, and remember to burn only smokeless wood for home and outdoor heating. Smoke is bad, mmmk? If you smoke, your doctor will be sure that whatever you are smoking is the cause of any and all of your health problems.

Went back to see my doctor to get an inhaler for emergencies. Inquired if I might possibly be asthmatic and was informed I'd already been listed as having asthma-slash-COPD without having been previously informed that I may be asthmatic. Maybe they just didn't want it to look like I'd gotten to a diagnosis before they did AGAIN, I've no idea what goes through their minds.

Apparently my doctor has learned nothing from misplacing blame on tobacco for at least two diagnoses, and seems to have no clue that infections can be more lung-damaging that tobacco many times over.

Since when is the question "Which will kill you quicker, smoking or pneumonia" too hard for doctors? Every one I go to acts like tobacco is the most dangerous thing in the room, and seems to act like either they're hiding something, or trying to conceal the fact that the Almightly Mayo Clinic will take another 20 years to tell them how to be of help for anything that isn't killing you this week.

I attempted to express my concern as also noted in the literature about inhaled corticosteroids having the potential to stealthily exacerbate the severity of pulmonary disease while masking the fact it's doing so by mediating the outward severity of symptoms, and my doctor informed me that Candida is "just a harmless commensal" and that they'd just watched a four-hour presentation from Princeton that apparently assures everyone it's just a harmless girlie thing.

I am of course furious that my doctor seems to have learned nothing from our last visit, and seems to have no clue that it's not a good idea to rub shit in a wound even if they're "just commensals" and "make great pets and blah blah blah". I was also furious to be offered an antibiotic after complaining of possible lung infection, since I can't give them to give me an antibiotic for a skin disease even when they have acknowledged active infection and when antibiotics remain the weapon of choice against the disease, because they "might make superbugs" - but can turn around and give me an antibiotic for an unconfirmed lung infection without even stopping to ask if the infection is viral, bacterial or fungal. 

And at the risk of sounding utterly sarcastic, which I don't think is intended (?), in my experience mycology is the last sort of microbiology where anyone is going to acquire relevant expertise in the course of four whole hours. I have yet to find an authority that I think has even half mastered the absurdly diverse behaviors of Candida. Probably should have commended my doctor for even taking the time but I involuntarily retorted that I'd spent a bare minimum of four months studying the subject, but apparently your doctor is an expert on everything and you are not, because of two whole paragraphs they read at the Mayo Clinic website. Your doctor will always know best, even on subjects they admittedly know next to nothing about.

Maybe they're such busy little critters distracted by exploding patient rosters that they aren't aware of it, but from this patient's perspective it all sounds like the most pernicious kind of doubletalk and denial of basic essential services. At least they let me into the building so they can tap my insurance for doing nothing for me, rather than just locking the front doors, that's quite thoughtful of them.

So there you go, boys and girls, this is all part of what you get if you smoke anything. Also if you're asthmatic, so don't ever start being asthmatic either. In fact, if you smoke, you may not even get the option of being asthmatic - you may automatically be diagnosed with COPD simply because you smoke anything, or at least until you bring up the subject of asthma yourself. (Again, I have no idea what is going through their minds). Whatever it takes for it to be all the fault of you the patient, and not the fault of the doctor's ignorance and apathy concerning microbiology and antibiotics, and as long as it serves to distract from the fact if your doctor knew what the feck they were doing with either one, you could probably smoke whatever you like and not have to be chronically ill.

Also, it may greatly exacerbate your level of resultant insanity if you have a domestic partner with medical views that are the least bit conservative. Every time you light up you may hear some smug remark to the effect of "I know what YOUR problem is" which is kind of like having your doctor move in with you. Side effects of having your doctor move in with you may include social evasiveness, decreased libido, frequent involuntary beating of your head against inanimate objects, and thoughts of suicide.

Smoking - not as relaxing as you might have thought.
"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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#46
...

Simple equations.

Hmm2   plus  Nonono   equals   Slap2

Don't smoke anything when you have a lung infection.

Don't smoke cigarettes.

Smoke weed.
You will invariably smoke less Lol

Close windows when any form of smoke is incoming.
Especially wood and diesel smoke.

Avoid other peoples colds and allergies at all times.

Avoid the doctor and the clinics at all costs.

Intentionally smoke more weed in the living room,
the next time that your "domestic partner" purposely domesticates Whip  you.

Hi

...
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