Monday, September 28, 2009
Glutamine as an Energy Substrate in the Liver
But I was going to mention that there are also lots of articles showing that glutamine can prevent or ameliorate experimental liver disease and pancreatic exocrine dysfunction in animals, etc. [see this article and the related articles, etc.: (http://www.ncbi.nlm.nih.gov/pubmed/1971031)]. The different effects probably depend on a lot of different variables, such as the dosage and availability of phosphate and uridine, the degree of damage to the mitochondria, the degree of insulin resistance, and other factors. That's part of the reason something like glutamine would probably be more likely to be useful in diffuse brain injuries, such as traumatic brain injuries induced by concussive traumas, or milder ischemia, rather than as an adjunctive approach in severe strokes that are characterized by "raging" cores of necrotic tissue with no functional mitochondria that could oxidize glutamine-derived 2-oxoglutarate, etc. In contrast, purine nucleotides would be expected to be more "durable" in terms of their usefulness in damaged cells, given that purine nucleotides can provide ribose-5-phosphate for the formation of glycolytic intermediates and activate phosphofructokinase in the cytosol and be degraded into uric acid, etc. That presupposes that adenosine receptor activation isn't so deranged as to preclude their usefulness, but a lot of the research on adenosine in strokes doesn't make a distinction between the intracellular and extracellular actions and metabolic fates of adenosine-derived nucleotides. Adenosine that isn't infused too rapidly is not going to just behave like an A1 adenosine receptor agonist, for many reasons that I can't get into. But there are some situations in which there's severe damage or derangement of adenosine receptor signalling, and rapidly-administered, intravenous adenosine can be detrimental under those extreme circumstances. But obviously one would want to discuss these things with one's doctor, even though no one's talking about using intravenous adenosine in a willy-nilly fashion.
Glutamine and Uridine in Hexosamine Biosynthesis and Glycosylation Reactions
There are lots of interesting articles that have shown the roles that glutamine (GLN)-mediated increases in the O-glycosylation, with beta-N-acetylglucosamine, of serine and threonine residues on proteins can play in mediating either the protective effects or undesirable effects of GLN (http://scholar.google.com/scholar?q=glutamine+hexosamine+ischemia&hl=en). GLN is a substrate of glutamine: fructose-6-phosphate amidotransferase (GFAT), and that enzyme forms glucosamine-6-phosphate and glutamate [Broschat et al., 2002: (http://www.jbc.org/content/277/17/14764.full)(http://www.ncbi.nlm.nih.gov/pubmed/11842094?dopt=Abstract)]. In any case, the overall point is that some of the GLN-mediated protection against damage due to ischemia have been shown to be a result of the augmentation of hexosamine formation by GLN (see that first search), but I've also seen articles showing that GLN can sometimes worsen the course of experimental fatty liver disease or the courses of other disease states, in animals, in which insulin resistance features prominently. There's a large amount of research showing that glucosamine can cause insulin resistance in animals (http://scholar.google.com/scholar?hl=en&q=glucosamine+liver+OR+insulin+OR+ATP) and other undesirable effects, but, under normal circumstances, I remember reading that only about 3 percent of the intracellular GLN in cells in the liver is metabolized into glucosamine. As I've discussed in past postings, the formation of uridine diphosphohexosamines can sometimes sequester large amounts of uridine in ways that is undesirable, in animal models of liver disease, and GLN can also serve as a substrate for de novo uridine biosynthesis. That's not generally something that one wants to accelerate in an unregulated way. But my point would be that, at reasonable dosages, the formation of glucosamine or carbamoyl phosphate, as a precursor of orotate and uridine, from GLN would be processes that would be subject to substantially more regulation than the formation of hexosamines and orotate from exogenous glucosamine and...orotate would be.
Another important point is that it's necessary to take into account the potential for GLN-mediated decreases in glutamine synthetase (GS) activity, with regard to the supposed ATP-sparing effects of that suppression, to occur and to consider the effects of GLN-derived 2-oxoglutarate on mitochondrial ATP formation. One can say that the effects of GLN are mediated by glycosylation during ischemia, but how was the uridine pool preserved during ischemia? The GLN-mediated preservation of ATP could indirectly preserve the UDP-N-acetylglucosamine and overall UDP-hexosamine pools during ischemia, given that ATP depletion tends to lead to loss of pyrimidine nucleosides, either by export or degradation. That's only one example. Not surprisingly, there's actually some research showing that some of the protective effects of uridine in cultured astrocytes, or something like that, are mediated by glycosylation of various proteins, and I remember downloading a paper that shows that glycosaminoglycan formation is more sensitive to increases in uridine availability than other UDP-sugar-dependent or UDP-hexosamine-dependent glycosylation reactions are. Again, however, one has to consider the increases in glucose uptake that exogenous uridine can produce. Did the uridine-induced increases in protein glycosylation exert protective effects by increasing the glucose uptake, or did the uridine-induced increases in glycogen formation, in the face of increase in glucose uptake by other mechanisms, buffer ATP levels and thereby maintain the normal, relative amounts of different UDP-hexosamines that are required for glycosylation reactions that produce other protective effects? Similarly, one can't look at an article on GFAT overexpression in mice, see a lot of adverse effects, and conclude that GLN is going to produce the same effects as GFAT overexpression will (for the reasons I discussed above, involving energy metabolism, primarily). But another important point is that, in some of those articles using high doses of GLN, one has to consider the cumulative, potentially-depleting effects of GLN-induced hexosamine and UDP-hexosamine formation on the intracellular and even plasma inorganic phosphate pools. I have at least one article showing that exogenous uridine can deplete the inorganic phosphate pool, and I'll try to put it up. Another thing to consider would be the use of uridine, glutamine, and inorganic phosphate in some sort of combination approach. The uridine could suppress de novo pyrimidine biosynthesis and avoid some of the undesirable effects of a high rate of de novo pyrimidine (uridine) formation (as discussed in past postings, orotate has tended to lead to ATP depletion in animal experiments) and also prevent the sequestration of uridine, some of which is obviously required for glycogen formation, in UDP-hexosamines. But the goal, in my opinion, should really be to normalize the availability of GLN to the brain or skeletal muscles, in order to prevent unnecessary exercise-induced ATP depletion, etc. There can be a significant increase in ATP turnover in the brain and, obviously, skeletal muscles during high-intensity exercise. That's separate, to a large extent, from the issue of ischemia.
Another important point is that it's necessary to take into account the potential for GLN-mediated decreases in glutamine synthetase (GS) activity, with regard to the supposed ATP-sparing effects of that suppression, to occur and to consider the effects of GLN-derived 2-oxoglutarate on mitochondrial ATP formation. One can say that the effects of GLN are mediated by glycosylation during ischemia, but how was the uridine pool preserved during ischemia? The GLN-mediated preservation of ATP could indirectly preserve the UDP-N-acetylglucosamine and overall UDP-hexosamine pools during ischemia, given that ATP depletion tends to lead to loss of pyrimidine nucleosides, either by export or degradation. That's only one example. Not surprisingly, there's actually some research showing that some of the protective effects of uridine in cultured astrocytes, or something like that, are mediated by glycosylation of various proteins, and I remember downloading a paper that shows that glycosaminoglycan formation is more sensitive to increases in uridine availability than other UDP-sugar-dependent or UDP-hexosamine-dependent glycosylation reactions are. Again, however, one has to consider the increases in glucose uptake that exogenous uridine can produce. Did the uridine-induced increases in protein glycosylation exert protective effects by increasing the glucose uptake, or did the uridine-induced increases in glycogen formation, in the face of increase in glucose uptake by other mechanisms, buffer ATP levels and thereby maintain the normal, relative amounts of different UDP-hexosamines that are required for glycosylation reactions that produce other protective effects? Similarly, one can't look at an article on GFAT overexpression in mice, see a lot of adverse effects, and conclude that GLN is going to produce the same effects as GFAT overexpression will (for the reasons I discussed above, involving energy metabolism, primarily). But another important point is that, in some of those articles using high doses of GLN, one has to consider the cumulative, potentially-depleting effects of GLN-induced hexosamine and UDP-hexosamine formation on the intracellular and even plasma inorganic phosphate pools. I have at least one article showing that exogenous uridine can deplete the inorganic phosphate pool, and I'll try to put it up. Another thing to consider would be the use of uridine, glutamine, and inorganic phosphate in some sort of combination approach. The uridine could suppress de novo pyrimidine biosynthesis and avoid some of the undesirable effects of a high rate of de novo pyrimidine (uridine) formation (as discussed in past postings, orotate has tended to lead to ATP depletion in animal experiments) and also prevent the sequestration of uridine, some of which is obviously required for glycogen formation, in UDP-hexosamines. But the goal, in my opinion, should really be to normalize the availability of GLN to the brain or skeletal muscles, in order to prevent unnecessary exercise-induced ATP depletion, etc. There can be a significant increase in ATP turnover in the brain and, obviously, skeletal muscles during high-intensity exercise. That's separate, to a large extent, from the issue of ischemia.
Sunday, September 27, 2009
Gone Menthol
This thing (http://www.usatoday.com/news/health/2009-09-27-menthol-cigarettes_N.htm) is about the banning of menthol cigarettes by the FDA. I'm not even certain about what a menthol cigarette is, but I think it's a flavored cigarette. I can't read through the insane quotes in that article. The author of the article quoted people who had made all of these bizarre statements about having "gone menthol" or something. "@#%#, yes, I went menthol." I don't think banning things like that is a good idea. I obviously think smoking is really bad, and I'm not a smoker. But I dunno. The last time they tried to ban high-nicotine cigarettes or something like that, smokers just ended up smoking more cigarettes to compensate. How does taxing smokers into bankruptcy accomplish anything? This is not a very interesting topic, but I should say that, in fact, I don't like the FDA. It's a cliched thing to say, but the FDA has become so cautious about making statements that, in my opinion, a mild or conservatively-worded warning from the FDA is likely to be, "not infrequently," a sign that there's a serious or significant problem. But then, when it comes to things like cigarettes, the FDA isn't afraid to make "statements." What exactly does the FDA do these days. I can't figure out what it is. I can't remember the last time they've done anything decent, but that's just my opinion.
Saturday, September 26, 2009
"Good for Postischemic Damage Control!"
I forget to mention it, but one reason that all of the research on the protection, by GLN and other supposed energy substrates, of the energy charge or adenylate charge during ischemia is "relevant" is that even high-intensity exercise, for example, can cause transient, very mild cerebral ischemia and is well-known to cause metabolic stress in the GI tract that essentially amounts to a low-level ischemia-reperfusion injury. The blood flow to the muscles can increase at the expense of the blood flow to other tissues, etc. But the point is that ischemia can be viewed as being an "everyday event." However, I recently saw some "sports supplement" that contained some questionable messages on the label, such as a "breezy" or even "happy"-looking blurb that read, "Good for preventing ATP depletion after cerebral ischemia!" There was a superscripted star by the "a" of ischemia, and the star referred the reader to the qualifying statement that read "(during your friendly-neighborhood exercise)". So at least there was that. But I still thought that that was in bad taste, just to a small extent. It's fine to face the facts, but...no, there was no such supplement.
In Conclusion
In conclusion, the fact that I've learned that (http://hardcorephysiologyfun.blogspot.com/2009/09/downregulation-of-glutamine-gln.html) is the reason I am, of course, never dismissive of articles, published in the popular press, on influenza, for example.
Downregulation of Glutamine (GLN) Synthetase Activity in Response to GLN: Relevance to Research on GLN as an Energy Substrate and "ATP-Sparing Agent"
In this article [Mignon et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17947599?dopt=Abstract)], Mignon et al. (2007) found that glutamine (GLN) supplementation only produced statistically-significant reductions in the activity of glutamine synthetase (GS), in the skeletal muscles, in the fed state in aged rats and in the fasted state in adult rats. The GLN-induced decreases in GS activity in the other "states" (fasted state in aged rats and fed state in adult rats) were not statistically-significant. It's interesting that the tissue concentrations, which are going to be mainly intracellular, of GLN and glutamate and plasma concentrations of GLN and glutamate did not increase in response to supplementation. Those findings, when viewed in alongside the reductions in GS activity, are consistent with my sense of the way GLN supplementation is likely to exert its supposed therapeutic effects [see here for my bare-bones paper on GLN: (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html)], as discussed below. Mignon et al. (2007) cited research that had shown that hypermetabolic, or "catabolic" states, such as can occur after surgeries or other causes of physiological stress, have generally been associated with an upregulation of GS activity, and researchers have typically attributed those increases in GS activity to glucocorticoid-mediated increases in the mRNA expression of GS or to other factors, etc.
That research by Mignon et al. (2007) is relevant to the use of GLN as an energy substrate, in general, and to its use as an "adjunctive" energy substrate in the treatment of depression, etc. There's only one article on the use of GLN as an adjunctive antidepressant [Cocchi, 1976: (http://hardcorephysiologyfun.blogspot.com/2009/03/gabaergic-effect-of-l-glutamine-in-rats.html)], and its efficacy has obviously not been proven and will never be proven. But that article by Cocchi (1976) is remarkable in the sense that the author's observations are generally consistent with the kinds of effects that one would expect to see, based on all the research that has been done, in response to GLN. The author also noted that the therapeutic window was relatively narrow, and, in my experience, it's extremely narrow and changes in response to changes in exercise intensity and to changes in factors that affect serum calcium (such as vitamin D). All I can do is relate my sense of things, and I don't have a good explanation for the reason the range of therapeutic dosages would be so small. I mean that tiny increases in the dosage can either produce beneficial effects, in terms of the effects that one would ideally expect from an energy substrate, under some conditions, or can cause effects that seem to be consistent with the GABAergic effects that Wang et al. (2007) described [see that past posting for my discussion of this: Wang et al., 2007: (http://www.fasebj.org/cgi/reprint/21/4/1227)(http://www.ncbi.nlm.nih.gov/pubmed/17218538?dopt=Abstract)].
The finding that exogenous GLN can decrease GS activity without increasing the steady-state intracellular GLN concentrations in skeletal muscle myocytes (and satellite cells, etc.) is significant in relation to an understanding of GLN metabolism in general, and the finding can be explained by the fact that exogenous GLN can increase the 26S-proteasomal degradation of the GS enzyme protein [Labow et al., 2001, cited here: (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html)]. That's really important, but there's some sort of resistance to the fact that GLN is likely, as it is, in my opinion, to exert many of its effects by virtue of its capacity to serve as an energy substrate. There are many articles that have shown this, and I'm not going to collect all of them right now [the protection by GLN against damage due to ischemia is basically a result of its capacity to be converted into 2-oxoglutarate and undergo oxidation in the TCA cycle, and here are some of those articles showing protection against ischemic damage: (http://scholar.google.com/scholar?q=glutamine+ischemia&hl=en)]. There's at least one article showing that it improves cardiac function acutely, in humans with heart failure or heart disease [here it is: Khogali et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/11844641)].
The key point, however, is that GS activity consumes enormous amounts of ATP, and very few tissues in the body are characterized by a net formation of GLN. There are all of these articles discussing the fact that the GLN-glutamate-GABA cycle accounts for 70-80 percent of the ATP consumption in the brain, and a lot of articles emphasize the fact that astrocyte-derived GLN is utilized as a major energy substrate for neurons. But the downregulation of GS activity by exogenous GLN is likely to not be accompanied by major increases in either the steady-state extracellular or intracellular GLN or glutamate concentrations, and, following a brain injury, there might not even be any post-infusion, detectable increase in the extracellular-fluid GLN concentrations in the brain [the CNS "parenchymal" interstitial fluid (ISF) concentrations]. This phenomenon has been shown in the liver and in cultured cells, also [see Yudkoff et al., 1988, and Qu et al., 2001, cited here: (http://hardcorephysiologyfun.blogspot.com/2009/05/problems-with-glutamine-research.html)], and I've cited all the research in past postings. The turnover is so rapid and so massive that an infusion of even multi-gram amounts, in the context of the 23 to 60-fold increases in the rate of oxidation of GLN carbons in the TCA cycle that occur in the brain, following ischemia [see here: (http://hardcorephysiologyfun.blogspot.com/2009/05/oxidation-of-glutamate-derived-2.html); Pascual et al., 1998: (http://stroke.ahajournals.org/cgi/content/full/strokeaha;29/5/1048)(http://www.ncbi.nlm.nih.gov/pubmed/9596256)], could easily fail to elevate ISF GLN in the brains of people who have traumatic brain injuries. But the downregulation of GS activity by GLN could, nonetheless, spare significant amounts of ATP, and, of course, ATP depletion is going to occur sooner or later after a brain injury. One can sometimes show no ATP depletion for a little while after an injury, but that's probably because structural damage to the mitochondria takes a couple of days to occur. Another reason that the GLN-mediated decreases in ATP consumption by GS activity would be desirable, in my opinion, is that glutaminase can, especially under those conditions in which the oxidation of GLN carbons is drastically augmented (i.e. after a brain injury or even, arguably, under more mild conditions of deranged energy metabolism), escape feedback inhibition by intramitochondrial glutamate. Essentially, glutamate formed by the glutaminase-mediated deamidation of GLN (in the mitochondria) is likely to be oxidized or otherwise utilized with exceptional rapidity, and that means that the pool of glutamate that is available to exert feedback inhibition of glutaminase activity [see here for discussion: (http://hardcorephysiologyfun.blogspot.com/2009/05/oxidation-of-glutamate-derived-2.html); Brand and Chappell, 1974: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1167992&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/4375961)] is going to be even more limited than it usually is. That change in the normal allosteric regulation of glutaminase could create an ATP-consuming futile cycle, for all practical purposes, in tissues following ischemia, and GLN could be one approach to breaking that futile cycle. Anyway, the point is that GLN could reduce ATP consumption in skeletal muscles ("spare" ATP) or in the brain [it does cross the blood-brain and blood-CSF barriers, and that's apparent and is discussed in articles cited here: (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html)] without necessarily producing drastic or even any changes in the tissue or plasma or ISF GLN concentrations, particularly following ischemia or hypoxia or other physiological stressors that can, as found by Pascual et al. (1998), cited above, increase the percentage (and rate) of the intracellular GLN-derived glutamate pool that is oxidized, upon its metabolism into 2-oxoglutarate, in the TCA cycle. The rates of GLN synthesis, by ATP-consuming GS, and degradation are very high in many tissues, and that's one reason that so few cell groups display an overall, net output of GLN. At very high or otherwise excessive GLN intakes, the adverse effects of the extra ammonia could conceivably outweigh the benefits associated with the supposed ATP-sparing effects. GLN could also interfere with the transport of citrulline or other amino acids or intermediates, as discussed in past postings.
Incidentally, other researchers [Young et al., 1993: (http://www.ncbi.nlm.nih.gov/pubmed/8289407); Morlion et al., 1998: (http://www.pubmedcentral.nih.gov.floyd.lib.umn.edu/picrender.fcgi?artid=1191250&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/9488531)] have reported that people who had been treated with intravenous L-alanyl-L-glutamine (the stable dipeptide "form" of glutamine that can be stored in i.v. solutions in the long term) had noted improvements in "mood" or "well being." It's easy to dismiss things like that, but it's possible to easily dismiss things to the detriment of...oneself. "It's not necessarily *good* to be dismissive of *things*." That's the end of this posting.
That research by Mignon et al. (2007) is relevant to the use of GLN as an energy substrate, in general, and to its use as an "adjunctive" energy substrate in the treatment of depression, etc. There's only one article on the use of GLN as an adjunctive antidepressant [Cocchi, 1976: (http://hardcorephysiologyfun.blogspot.com/2009/03/gabaergic-effect-of-l-glutamine-in-rats.html)], and its efficacy has obviously not been proven and will never be proven. But that article by Cocchi (1976) is remarkable in the sense that the author's observations are generally consistent with the kinds of effects that one would expect to see, based on all the research that has been done, in response to GLN. The author also noted that the therapeutic window was relatively narrow, and, in my experience, it's extremely narrow and changes in response to changes in exercise intensity and to changes in factors that affect serum calcium (such as vitamin D). All I can do is relate my sense of things, and I don't have a good explanation for the reason the range of therapeutic dosages would be so small. I mean that tiny increases in the dosage can either produce beneficial effects, in terms of the effects that one would ideally expect from an energy substrate, under some conditions, or can cause effects that seem to be consistent with the GABAergic effects that Wang et al. (2007) described [see that past posting for my discussion of this: Wang et al., 2007: (http://www.fasebj.org/cgi/reprint/21/4/1227)(http://www.ncbi.nlm.nih.gov/pubmed/17218538?dopt=Abstract)].
The finding that exogenous GLN can decrease GS activity without increasing the steady-state intracellular GLN concentrations in skeletal muscle myocytes (and satellite cells, etc.) is significant in relation to an understanding of GLN metabolism in general, and the finding can be explained by the fact that exogenous GLN can increase the 26S-proteasomal degradation of the GS enzyme protein [Labow et al., 2001, cited here: (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html)]. That's really important, but there's some sort of resistance to the fact that GLN is likely, as it is, in my opinion, to exert many of its effects by virtue of its capacity to serve as an energy substrate. There are many articles that have shown this, and I'm not going to collect all of them right now [the protection by GLN against damage due to ischemia is basically a result of its capacity to be converted into 2-oxoglutarate and undergo oxidation in the TCA cycle, and here are some of those articles showing protection against ischemic damage: (http://scholar.google.com/scholar?q=glutamine+ischemia&hl=en)]. There's at least one article showing that it improves cardiac function acutely, in humans with heart failure or heart disease [here it is: Khogali et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/11844641)].
The key point, however, is that GS activity consumes enormous amounts of ATP, and very few tissues in the body are characterized by a net formation of GLN. There are all of these articles discussing the fact that the GLN-glutamate-GABA cycle accounts for 70-80 percent of the ATP consumption in the brain, and a lot of articles emphasize the fact that astrocyte-derived GLN is utilized as a major energy substrate for neurons. But the downregulation of GS activity by exogenous GLN is likely to not be accompanied by major increases in either the steady-state extracellular or intracellular GLN or glutamate concentrations, and, following a brain injury, there might not even be any post-infusion, detectable increase in the extracellular-fluid GLN concentrations in the brain [the CNS "parenchymal" interstitial fluid (ISF) concentrations]. This phenomenon has been shown in the liver and in cultured cells, also [see Yudkoff et al., 1988, and Qu et al., 2001, cited here: (http://hardcorephysiologyfun.blogspot.com/2009/05/problems-with-glutamine-research.html)], and I've cited all the research in past postings. The turnover is so rapid and so massive that an infusion of even multi-gram amounts, in the context of the 23 to 60-fold increases in the rate of oxidation of GLN carbons in the TCA cycle that occur in the brain, following ischemia [see here: (http://hardcorephysiologyfun.blogspot.com/2009/05/oxidation-of-glutamate-derived-2.html); Pascual et al., 1998: (http://stroke.ahajournals.org/cgi/content/full/strokeaha;29/5/1048)(http://www.ncbi.nlm.nih.gov/pubmed/9596256)], could easily fail to elevate ISF GLN in the brains of people who have traumatic brain injuries. But the downregulation of GS activity by GLN could, nonetheless, spare significant amounts of ATP, and, of course, ATP depletion is going to occur sooner or later after a brain injury. One can sometimes show no ATP depletion for a little while after an injury, but that's probably because structural damage to the mitochondria takes a couple of days to occur. Another reason that the GLN-mediated decreases in ATP consumption by GS activity would be desirable, in my opinion, is that glutaminase can, especially under those conditions in which the oxidation of GLN carbons is drastically augmented (i.e. after a brain injury or even, arguably, under more mild conditions of deranged energy metabolism), escape feedback inhibition by intramitochondrial glutamate. Essentially, glutamate formed by the glutaminase-mediated deamidation of GLN (in the mitochondria) is likely to be oxidized or otherwise utilized with exceptional rapidity, and that means that the pool of glutamate that is available to exert feedback inhibition of glutaminase activity [see here for discussion: (http://hardcorephysiologyfun.blogspot.com/2009/05/oxidation-of-glutamate-derived-2.html); Brand and Chappell, 1974: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1167992&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/4375961)] is going to be even more limited than it usually is. That change in the normal allosteric regulation of glutaminase could create an ATP-consuming futile cycle, for all practical purposes, in tissues following ischemia, and GLN could be one approach to breaking that futile cycle. Anyway, the point is that GLN could reduce ATP consumption in skeletal muscles ("spare" ATP) or in the brain [it does cross the blood-brain and blood-CSF barriers, and that's apparent and is discussed in articles cited here: (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html)] without necessarily producing drastic or even any changes in the tissue or plasma or ISF GLN concentrations, particularly following ischemia or hypoxia or other physiological stressors that can, as found by Pascual et al. (1998), cited above, increase the percentage (and rate) of the intracellular GLN-derived glutamate pool that is oxidized, upon its metabolism into 2-oxoglutarate, in the TCA cycle. The rates of GLN synthesis, by ATP-consuming GS, and degradation are very high in many tissues, and that's one reason that so few cell groups display an overall, net output of GLN. At very high or otherwise excessive GLN intakes, the adverse effects of the extra ammonia could conceivably outweigh the benefits associated with the supposed ATP-sparing effects. GLN could also interfere with the transport of citrulline or other amino acids or intermediates, as discussed in past postings.
Incidentally, other researchers [Young et al., 1993: (http://www.ncbi.nlm.nih.gov/pubmed/8289407); Morlion et al., 1998: (http://www.pubmedcentral.nih.gov.floyd.lib.umn.edu/picrender.fcgi?artid=1191250&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/9488531)] have reported that people who had been treated with intravenous L-alanyl-L-glutamine (the stable dipeptide "form" of glutamine that can be stored in i.v. solutions in the long term) had noted improvements in "mood" or "well being." It's easy to dismiss things like that, but it's possible to easily dismiss things to the detriment of...oneself. "It's not necessarily *good* to be dismissive of *things*." That's the end of this posting.
Friday, September 25, 2009
Hamburger Helper
Here's that olllll' ditty:
http://www.youtube.com/watch?v=c87VzSOdI04
http://www.youtube.com/watch?v=vx3IFMo0Q5M
But don't touch the hamburger helper, for crying out loud(http://hardcorephysiologyfun.blogspot.com/2009/09/rambler-on-magnesium-and-sad-ironies.html). Don't eat it. Use the hamburger helper in a live organism? Huh? Who would want to do that? Are you from a different planet?
http://www.youtube.com/watch?v=c87VzSOdI04
http://www.youtube.com/watch?v=vx3IFMo0Q5M
But don't touch the hamburger helper, for crying out loud(http://hardcorephysiologyfun.blogspot.com/2009/09/rambler-on-magnesium-and-sad-ironies.html). Don't eat it. Use the hamburger helper in a live organism? Huh? Who would want to do that? Are you from a different planet?
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