tag:blogger.com,1999:blog-8550919611653842066.post9051588290019560097..comments2023-10-24T19:10:17.771-07:00Comments on The High-fat Hep C Diet: Naltrexone has TLR-4 activity - is it an "Old Friends" mimic? Unknownnoreply@blogger.comBlogger23125tag:blogger.com,1999:blog-8550919611653842066.post-57204756406039927882015-05-31T21:48:43.239-07:002015-05-31T21:48:43.239-07:00Just noticed your last two comments; that's gr...Just noticed your last two comments; that's great info, thanks.Lou T.https://www.blogger.com/profile/10109091216322863375noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-75192984254034352172014-01-09T23:23:28.867-08:002014-01-09T23:23:28.867-08:00Finally, someone connects exorphins with TLR4 and ...Finally, someone connects exorphins with TLR4 and microglia<br /><br />http://search.informit.com.au/documentSummary;dn=734451123042694;res=IELHEA<br /><br />Pay access, but note the minute fee - $1.80.Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-37579405527541299102013-12-10T23:23:49.145-08:002013-12-10T23:23:49.145-08:00This paper separates TLR4 from endorphins
http://w...This paper separates TLR4 from endorphins<br />http://www.pnas.org/content/109/16/6325<br /><br />Herein, we provide direct evidence that morphine creates neuroinflammation via the activation of an innate immune receptor and not via classic opioid receptors. We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. Small-molecule inhibitors, RNA interference, and genetic knockout validate the TLR4/MD-2 complex as a feasible target for beneficially modifying morphine actions. Disrupting TLR4/MD-2 protein–protein association potentiated morphine analgesia in vivo and abolished morphine-induced proinflammation in vitro, the latter demonstrating that morphine-induced proinflammation only depends on TLR4, despite the presence of opioid receptors.Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-17292102763688370622013-12-10T18:49:47.912-08:002013-12-10T18:49:47.912-08:00I think you might be right, because this effect is...I think you might be right, because this effect is seen consistently with opioids, but I haven't found a reference to endorphins having TLR activity. That is what I was originally looking for when I came across the naltrexone papers.<br />Presumably endorphins don't cause gliosis, hyperalgesia, tolerance and so on, and these are all properties of small molecules with (usually) both endorphin receptor and TLR activity.<br /><br />Some interesting stuff you posted at Cort Johnson about gliadin and green tea. I have read there's an opioid antagonist in coffee. It might be the same thing that can cross-react with gliadin.<br />Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-80279021701199238212013-12-10T16:17:37.060-08:002013-12-10T16:17:37.060-08:00The cited article suggests that "the mu opioi...The cited article suggests that "the mu opioid receptor (MOR) antagonist Naltrexone increases TLR4 levels, thus suggesting a role of the endogenous opioid system in TLR4 regulation." I had been under the impression that the blockade of TLR4 by LDN was a separate effect from its blockade of opioid receptors. For example this study states that "(+)-naltrexone, (+)-naloxone, and (-))-naloxone...we show here to be TLR4 antagonists in vitro on...microglial cell lines."<br /><br />http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588470/Lou T.https://www.blogger.com/profile/10109091216322863375noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-29260213541986796432013-12-10T16:17:26.307-08:002013-12-10T16:17:26.307-08:00This comment has been removed by a blog administrator.Lou T.https://www.blogger.com/profile/10109091216322863375noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-63526121143808532422013-04-01T03:02:54.218-07:002013-04-01T03:02:54.218-07:00From Lucas Tafur's blog:
Hypertriglyceridemia...From Lucas Tafur's blog:<br /><br />Hypertriglyceridemia increases endotoxemia<br /><br />The human body must be able to cope with acute increases in LPS in plasma, attenuating the inflammatory response induced by fat ingestion. Clemente-Postigo, et al. (20) showed that in morbidly obese subjects, endotoxin increases were strongly correlated to the difference between baseline and postprandial triglyceride levels. They also found that baseline triglyceride level was the best variable that predicted basal LPS level in serum. In this regard, very low carbohydrate diets have shown to reduce baseline triglyceride levels and postprandial lipemia (21, 22). In the metabolically healthy, the immune system is capable of attenuating postprandial endotoxemia (as with inflammation induced by any meal). The inflammatory nature of absorption, digestion and metabolism of macronutrients must be coupled with an anti-inflammatory period, such as fasting (depending on the inflammatory load of the diet, an overnight fast might work). By this way, the body's inflammatory balance is maintained in a healthy range. Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-81509886285100425512013-03-30T00:51:31.064-07:002013-03-30T00:51:31.064-07:00It's not the paper you linked to here?
http://...It's not the paper you linked to here?<br />http://high-fat-nutrition.blogspot.co.nz/2009/02/fats-absorbing-endotoxin.html<br />I'm in MacDonalds with a kids computer so I don't have time to follow the links, but if in doubt about this stuff I go to http://www.lucastafur.com/2012/07/nutritional-immunotherapy-dietary-fatty.html which I can see I need to re-read in light of the naltrexone-TLR4-HCV situation.<br />Andrew Kim has also discussed these sorts of papers recently, for example http://www.andrewkimblog.com/2012/12/lipopolysaccharide-physical.html<br />in a breathless but often productive-of-ideas Peatitarian context.Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-5116835676931686552013-03-29T05:30:24.995-07:002013-03-29T05:30:24.995-07:00I've been looking on my hard drive for the &qu...I've been looking on my hard drive for the "high fat meal increases LPS in the bloodstream" paper, part of fat bashing. The one paper I did find suggested that chylomicrons (and LDL) deliver LPS to hepatocytes rather than macrophages in the liver. My assumption was that low fat meals delivered LPS directly to the liver w/o the detox through chylomicrons and might just ramp up inflammation if it was delivered to macrophages. Measuring LPS in the portal vein of human volunteers is not quite as straightforward as looking in peripheral blood... Can't find the paper, argh.Peterhttps://www.blogger.com/profile/14527788116058656094noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-35888262760286697972013-03-27T19:49:09.709-07:002013-03-27T19:49:09.709-07:00I wonder if it's all relevant here that the on...I wonder if it's all relevant here that the only non-opioid intervention that's ever relieved my full-blown withdrawal symptoms has been high-dose I.V. ascorbate.<br /><br />Here's a small connection:<br />http://www.ncbi.nlm.nih.gov/pubmed/12885590?dopt=Abstract<br /><br />In conclusion, strenuous short-term aerobic exercise results in significant increases in plasma LPS levels (endotoxemia) together with increases in markers of oxidative stress. Supplementation with ascorbic acid, however, abolished the increase in LPS and nitrite but led to a significant increase in the ascorbate radical in plasma. <br /><br />This is an interesting view of LPS considered as a kind of hormone: it looks like a good background resource for understanding what TLR4 does in the body (at least in regard to LPS; it has other interesting roles).<br />http://cid.oxfordjournals.org/content/41/Supplement_7/S470.fullPuddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-89165709676688437782013-03-25T02:27:46.905-07:002013-03-25T02:27:46.905-07:00Lovely:
Bacterial peptidoglycan enhances sicknes...Lovely: <br /><br />Bacterial peptidoglycan enhances sickness behaviour induced by<br />bacterial lipopolysaccharide<br />(PDF)<br />http://tinyurl.com/d4weoyv<br /><br />Background: Lipopolysaccharide (LPS) and peptidoglycan are microbial<br />products recognized by Toll-like receptor-4 (TLR4) and nucleotide-binding<br />oligomerization domain 1 (NOD1) and NOD2, respectively. <br /><br />*LPS has been<br />found to cause behavioural alterations indicative of sickness and<br />depressed mood.*<br /><br /> The effect of peptidoglycan on exploratory and affective<br />behaviour has not yet been explored, although it has been reported that it<br />promotes sleep and anorexia. Since NOD1 and NOD2 are activated by two<br />different peptidoglycan components, MurNAc-L-Ala-g-D-Glu-mesodiaminopimelic<br />acid (M-TriDAP) and muramyl dipeptide (MDP),<br />respectively, the effects of both compounds, alone and in combination<br />with LPS, on exploratory and affective behaviour were investigated.<br /><br />I can't wait till someone tests ibogaine for TLR4 activity.Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-77674831098624940152013-03-23T23:15:37.034-07:002013-03-23T23:15:37.034-07:00This 2007 pdf seems to be the earliest paper (from...This 2007 pdf seems to be the earliest paper (from the ever-relevant Hindawi publishing group and a journal I've never heard of called "The Scientific World") to put the full opioid-TLR4-gliosis hypothesis together; it mentions etorphine as an exception to the rule that mu-endorphin receptor agonists cause gliosis (ref 51, but this doesn't seem to be online).<br />downloads.hindawi.com/journals/tswj/2007/746941.pdfPuddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-9204107818754008142013-03-23T18:30:47.113-07:002013-03-23T18:30:47.113-07:00I think of the mitochondria in addiction as runnin...I think of the mitochondria in addiction as running like pressure cookers under the weight of drug interference with the electron chain and membrane potential - when this is lifted the cells boil.<br />My experience of withdrawal, and the fact it could be mitigated by a high-fat diet, reminded me of William Burrough's idea that addiction is a hunger of every cell in the body.<br />It's not just felt in the CNS, but every cell has adapted to the formerly cytotoxic dose, till its removal is even more cytotoxic.Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-49793607196648959422013-03-23T18:23:02.828-07:002013-03-23T18:23:02.828-07:00Very low dose etorphine - surely that would a home...Very low dose etorphine - surely that would a homeopathic concentration, measured in nanograms.<br /><br />Morphine down-regulates glutathione synthesis; more ROS to NF-kappa-beta.<br /><br />http://www.ncbi.nlm.nih.gov/pubmed/2820428<br /><br />Injection of morphine causes an acute increase in liver enzymes and a decrease in hepatic glutathione (GSH) synthesis.12 Recent studies have shown that the opioid antagonist naltrexone decreases liver injury in rats and mice with acute biliary obstruction.<br /><br />http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1603777/<br /><br />So not just gliosis but also hepatotoxicity could be reduced by co-administering LDN.<br />There was a case in N.Z. where a boy died of liver failure after overdosing on methadone. The "experts" testified that "methadone does not cause liver failure" so the coroner ruled natural causes. Just a co-incidence that his previously unexceptionably functioning liver packed in at that particular time apparently. <br /><br />Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-51831784660232394112013-03-23T15:24:31.150-07:002013-03-23T15:24:31.150-07:00George,
Increased receptor numbers gives a lower ...George,<br /><br />Increased receptor numbers gives a lower occupancy % at a given drug concentration. That seems to fit.<br /><br />BTW, just from lurking on poppy.org I recall a poppy tea user commenting that effective opioid usage, ie with slowly increasing dose over the months, led to the complete absence of any cold or flu like symptoms whatever the challenge. Until the time came to deal with the gorilla of course.<br /><br />Our standard analgesic combo is virtually always an NSAID along side the opioid, but we are not performing the sort of surgery where opioids beyond 3 days are needed. Of course the pancreatitis cases often need extended opioids but we get them off of pure agonists and on to bupe as early as they seem comfortable enough. <br /><br />The inclusion of etorphine in the same category as naltrexone is weird, I always thought of it (and used it in my patients) as an ultra potent mu agonist...<br /><br />And gliosis = free radicals to me. I have also long thought of addiction as possibly being mediated by the balance of energy demand by a cell VS oxidative phosphorylation efficiency in said cell. Big demand for ATP might well spew free radicals, especially if running through complex I AND glycerol-3-dehydrogenase. Dunno. Needs a lot of thinking about.<br /><br />PeterPeterhttps://www.blogger.com/profile/14527788116058656094noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-90803382260248494822013-03-23T13:46:01.562-07:002013-03-23T13:46:01.562-07:00The Circadian Clock Controls Toll-like Receptor 9-...The Circadian Clock Controls Toll-like Receptor 9-Mediated Innate and Adaptive Immunity<br />http://www.cell.com/immunity/abstract/S1074-7613(12)00047-7<br /><br />Circadian rhythms refer to biologic processes that oscillate with a period of ∼24 hr. These rhythms are sustained by a molecular clock and provide a temporal matrix that ensures the coordination of homeostatic processes with the periodicity of environmental challenges. We demonstrate the circadian molecular clock controls the expression and function of Toll-like receptor 9 (TLR9). In a vaccination model using TLR9 ligand as adjuvant, mice immunized at the time of enhanced TLR9 responsiveness presented weeks later with an improved adaptive immune response. In a TLR9-dependent mouse model of sepsis, we found that disease severity was dependent on the timing of sepsis induction, coinciding with the daily changes in TLR9 expression and function. These findings unveil a direct molecular link between the circadian and innate immune systems with important implications for immunoprophylaxis and immunotherapy.Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-76432802345890522812013-03-23T02:01:33.776-07:002013-03-23T02:01:33.776-07:00When I used opiates my hay fever disappeared, it c...When I used opiates my hay fever disappeared, it came back as I started withdrawing and was really bad for a while. Many of the more trivial opiate withdrawal symptoms resemble allergy symptoms - yawning, sneezing, runny eyes and nose.<br /><br />It occurs to me there's a duality here: according to wiki naltrexone is the TLR4 antagonist, morphine the agonist, but naltrexone increases expression of TLR4 and morphine suppresses it.<br />in the asthma epidemiology exposure to "old friends" was associated with increased expression of TLR2.<br />How is an increased number of receptors linked to a milder response to their agonist ligands?<br />Or is it only the macrophages that get increased TLRs via exposure to the antagonists?Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-15420416697736010902013-03-22T19:12:54.468-07:002013-03-22T19:12:54.468-07:00" how virtually every drug in my armoury is a..." how virtually every drug in my armoury is a bummer to the immune system"<br />Even on a LC diet I have from time to time(way less frequently than before) to take ergots or opiates for my migraine. Every med for migraine did it for me. Every time it gets my asthma to resurface, even though LCarbing took away the need to refill the prescription for inhalers.Galina L.https://www.blogger.com/profile/09156132815504279615noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-87223976288951906962013-03-22T16:39:11.581-07:002013-03-22T16:39:11.581-07:00Bill, it's amazing how often the really good r...Bill, it's amazing how often the really good research comes out of Italy.<br />You might not want them in your army or your government, but if you're staffing a lab, I'd go for Italians every time.<br /><br />Peter - adjuvants for anaesthesia then?<br />From what I've read it looks like naltrexone can be co-administered with opioids without losing analgesia; it's only in pre-existing dependence that it becomes tricky.<br />For example:<br />http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862024/<br />The development of analgesic tolerance following chronic morphine administration can be a significant clinical problem. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Many studies have also demonstrated that ultra-low doses of naltrexone inhibit the development of spinal morphine antinociceptive tolerance and clinical studies demonstrate that it has opioid sparing effects. In this study we demonstrate that ultra-low dose naltrexone attenuates glial activation, which may contribute to its effects on attenuating tolerance.<br /><br />http://europepmc.org/abstract/MED/9200746<br />Ultra-low doses of naltrexone or etorphine increase morphine's antinociceptive potency and attenuate tolerance/dependence in mice.<br /><br />http://www.ncbi.nlm.nih.gov/pubmed/19443938<br />The findings of the present work suggest that the combination of opioids and NSAIDs has a direct action on spinal nociceptive processing, which may be achieved via mechanisms that are independent of the activation of opioid receptors. The ineffectiveness of naltrexone to reverse the analgesic activity of opioids + NSAIDs combinations indicates that other complex pain regulatory systems are involved in this effect.<br /><br />http://www.sciencedirect.com/science/article/pii/S0165614709001369<br />The “Toll” of Opioid-Induced Glial Activation: Improving the Clinical Efficacy of Opioids by Targeting Glia<br /><br />In farmers' children with low incidence of allergies (hay fever and asthma), there is 3x higher expression of TLR2 (presumed due to "old friends" exposure). Naltrexone increases expression of TLR4. Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-32187389626483600082013-03-22T12:03:39.986-07:002013-03-22T12:03:39.986-07:00As an anaesthetist I find it depressing how virtua...As an anaesthetist I find it depressing how virtually every drug in my armoury is a bummer to the immune system. Maybe I need some naloxone to cheer me up. I have also wondered whether the salvia active ingredient, which looks to be a kappa agonist, mu antagonist (last time I went reading), might do the same. Trip is short, it may well be blocking mu receptors, and it is reported to be antidepressant on long term use.... <br /><br />PeterPeterhttps://www.blogger.com/profile/14527788116058656094noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-62365327344900075342013-03-22T05:45:22.861-07:002013-03-22T05:45:22.861-07:00Lol, the boson.
I've been following the LDN ...Lol, the boson. <br />I've been following the LDN story but felt blindsided after reading your article! This is a crazy & unexpected turn of events - kudos to the researchers involved.<br />best,<br />BillBillhttps://www.blogger.com/profile/05022558754270362782noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-52994885391646142262013-03-22T01:10:52.099-07:002013-03-22T01:10:52.099-07:00Unfortunately everyone I know who tried that exper...Unfortunately everyone I know who tried that experiment was overdosing at the time and expressed mostly ingratitude for the results.<br /><br />Look at the pictures of the healed Crohn's Colitis intestine on the LDN homepage - isn't that what you'd expect after a successful fecal transplant, or a lucky dose of hookworms?<br /><br />Morphine after cancer surgery significantly reduces the chances of remission (tramadol is safer) according to oncology papers on the LEF site. <br /><br />Coley's Toxins certainly had TLR-4 activity. Any anti-cancer effects of LDN are more likely to be due to TLR-4. LDN or VLDN could perhaps be used to block immunosuppressive effects of morphine without compromising analgesia...<br /><br />This discovery pulls together all sorts of scattered findings into a more coherent picture. It's like the Higgs Boson of medicine. Puddleghttps://www.blogger.com/profile/00953398103675945541noreply@blogger.comtag:blogger.com,1999:blog-8550919611653842066.post-87316330872351780002013-03-22T00:27:55.377-07:002013-03-22T00:27:55.377-07:00Great post. I have long wondered whether an iv dos...Great post. I have long wondered whether an iv dose of naloxone would give 10 minutes of deep depression followed by 24h upregulated happiness. The reverese of a bolus of iv alfentanil.... That's before TLRs put in an appearance.<br /><br />PeterPeterhttps://www.blogger.com/profile/14527788116058656094noreply@blogger.com