209 stories
·
0 followers

A Clue to Rheumatoid Arthritis

1 Comment

Rheumatoid arthritis is a complicated disease, as anyone who's tried to do drug discovery work in the area can verify. It's been recognized for a long time as an autoimmune disorder, but given the complexities of the human immune response, knowing that only takes you so far. Most of the therapies available are directed at turning down the immune/inflammation response in the joint tissues, and while these can be very helpful to patients (although not without side effects), the underlying cause of the disease has remained elusive. Which is something you can say about most autoimmune diseases, of course: what exactly sets off lupus, Hashimoto's, Type I diabetes, multiple sclerosis and other such diseases is not an easy question to answer.

In many cases, it's believed that some external antigen could be a cause, and that the immune response to these gets mixed and overlapped with one or more of a person's own biomolecules. You can see this happening in things like Guillian-Barré syndrome, which almost always occurs after some sort of bacterial or viral infection (and yes, rarely after some vaccinations, most notably the 1976 swine flu shot). But even there, we don't know the exact antigens involved and have no good ways to predict who might be more at risk and from which kinds of infections. Campylobacter jejuni bacteria or CMV viral infection (for example) are involved far too often to be due to chance, but we don't know the mechanism by which these set off G-B in susceptible patients - remember, only one in a thousand patients (at most) with either of those infections show any sign of Guillian-Barré. There's the personal variability of the immune system for you. Evolutionarily that's a major feature, but it sure complicates medical practice!

Rheumatoid arthritis is unfortunately a lot more common thatn Guillian-Barré, with up to 1% of the adults in the world affected. We know that risk for developing it increases with age, and that women are at significantly higher risk than men (a pattern seen with many autoimmune diseases). There has been a great deal of effort put into the (very plausible) hypothesis that some environmental cause interacts with an individual's genetic/immune background to set off the disease, and a number of interesting but hard-to-work-with correlations have shown up (for example, with peridontal disease as a risk factor, and clues pointing towards both the oral and intestinal mucosa). There is an uncommon form (reactive arthritis) that's directly linked to infection, for that matter. It's been known for years that there are particular antibody classes that appear in the human blood stream several years before RA symptoms develop, but what are they reacting to? Several different types of bacteria have come under suspicion over the years, but none of them (to the best of my knowledge) can reproduce an RA phenotype in an animal model, or at least one that hasn't been set up to be very susceptible to disease. But here's a new paper that has some very interesting new data on the idea.

The authors used antibodies from the blood of RA patients (dual IgA/IgG types that have recently been described in patients at risk for the disease) to look for cross-reactivity with stains of bacteria found in the human body - especially from families of bacteria that seem to have an elevated profile in people at risk of developing RA. They found a strong hit with particular Subdoligranulum strains: "Isolate 7" in this genus reacted with monoclonal antibodies from those RA patients, and (in the forward-facing experiment), inoculating germ-free mice with these bacteria led to joint swelling, T-cell expansion, and antibody production very reminiscent of wild-type RA. What's more, these changes were shown to be dependent on particular B-cell and T-cell pathways which also fit the disease hypothesis. So that's quite a step forward.

What we don't know is what the antigen is that's associated with these bacteria. The hypothesis is still that there's some particular thing (or maybe more than one) coming from them that kicks the immune response into gear, and you can bet that the authors of this paper are cranking away on an effort to find it. It could be a straight-up surface antigen that's mimicing a human protein, or perhaps these bacteria are producing some sort of excreted factor that's setting things off, and there could be several mechanisms for that as well. One of the main ideas in the field is that there's a "two-hit" mechanism for rheumatoid, with the first being some kind of microbial trigger that's able to go from mucosal immune response to systemic response, and the second being an unidentified process (perhaps associated with a person's genetic background?) that allows things to go on to full-blown arthritis and attack on the synovial tissues. This would indeed be a candidate for the first hit, but a lot of work remains to be done: for example, how prevalent is this Subdoligranulum bacterial species in the general population, and in RA patients versus those with no signs of the disease? Are there other species with this same sort of profile? If there are people with the bacteria and without rheumatoid arthritis, are there any differences we can spot in them that might point to a mechanism? And so on - watching this develop will be interesting.

Read the whole story
tuck
81 days ago
reply
Yeesh. Are there any known endogenous antigens that mimic bacterial infection? And that are *already* known to be involved in Rheumatoid Arthritis?

Beuller... Beuller...
Weston, Connecticut
Share this story
Delete

Evidence of increased sequestration of pro-resolving lipid mediators within brain esterified lipid pools of multiple sclerosis patients

1 Comment

Mult Scler Relat Disord. 2022 Oct 9;68:104236. doi: 10.1016/j.msard.2022.104236. Online ahead of print.

ABSTRACT

BACKGROUND: Unresolved inflammation in multiple sclerosis (MS) is associated with progressive demyelination and symptom worsening. In the brain, both inflammation and resolution pathways are mediated by free lipid mediators (i.e., oxylipins) that can be derived from the enzymatic hydrolysis of esterified oxylipins . It is not known whether disturbances in the turnover of free lipid mediators from esterified pools exist in postmortem brain of MS patients. We hypothesized that resolution pathways are impaired in MS patients because of disturbances in the turnover of free pro-resolving lipid mediators from esterified lipids. The objective was to characterize free and esterified oxylipins in postmortem prefrontal cortex of MS and unaffected control participants.

METHODS: Oxylipins in free, neutral lipid and phospholipid pools were extracted from prefrontal cortex of 10 MS participants and 5 unaffected controls, separated by solid phase extraction columns, and quantified by ultra-high-pressure liquid chromatography-tandem mass spectrometry. Significant differences between the control and MS groups were determined by an unpaired t-test with Benjamini and Hochberg False Discovery Rate correction (10%) applied to oxylipins within each lipid pool.

RESULTS: The concentration of 7 esterified pro-resolving fatty acid epoxides within neutral lipids were significantly higher by 126%-285% in postmortem prefrontal cortex of MS compared to control participants. The concentration of esterified linoleic acid-derived 9(10)-epoxy-octadecenoic acid, a pro-inflammatory epoxide, was higher by 206% in MS compared to controls. No significant changes were observed in free or phospholipid-bound oxylipins.

CONCLUSION: In MS, several pro-resolving lipid mediators are trapped within prefrontal cortex neutral lipids, potentially limiting their supply and availability in the free bioactive form. This may explain why inflammation resolution is impaired in MS patients.

PMID:36308971 | DOI:10.1016/j.msard.2022.104236

Read the whole story
tuck
86 days ago
reply
Fascinating.

"RESULTS: The concentration of 7 esterified pro-resolving fatty acid epoxides within neutral lipids were significantly higher by 126%-285% in postmortem prefrontal cortex of MS compared to control participants. The concentration of esterified linoleic acid-derived 9(10)-epoxy-octadecenoic acid, a pro-inflammatory epoxide, was higher by 206% in MS compared to controls. No significant changes were observed in free or phospholipid-bound oxylipins.

"CONCLUSION: In MS, several pro-resolving lipid mediators are trapped within prefrontal cortex neutral lipids, potentially limiting their supply and availability in the free bioactive form. This may explain why inflammation resolution is impaired in MS patients."
Weston, Connecticut
Share this story
Delete

Soluble Epoxide Hydrolase Is Associated with Postprandial Anxiety Decrease in Healthy Adult Women

1 Comment

Int J Mol Sci. 2022 Oct 5;23(19):11798. doi: 10.3390/ijms231911798.

ABSTRACT

The metabolism of bioactive oxylipins by soluble epoxide hydrolase (sEH) plays an important role in inflammation, and sEH may be a risk modifier in various human diseases and disorders. The relationships that sEH has with the risk factors of these diseases remain elusive. Herein, sEH protein expression and activity in white blood cells were characterized before and after a high-fat meal in healthy women (HW) and women with anorexia nervosa (AN). sEH expression and sEH activity were significantly correlated and increased in both groups two hours after consumption of the study meal. Fasting sEH expression and activity were positively associated with body mass index (BMI) in both groups, while an inverse association with age was found in AN only (p value < 0.05). sEH was not associated with anxiety or depression in either group at the fasting timepoint. While the anxiety score decreased after eating in both groups, a higher fasting sEH was associated with a lower postprandial anxiety decrease in HW (p value < 0.05). sEH characterization using direct measurements verified the relationship between the protein expression and in vivo activity of this important oxylipin modulator, while a well-controlled food challenge study design using HW and a clinical control group of women with disordered eating elucidated sEH's role in the health of adult women.

PMID:36233100 | DOI:10.3390/ijms231911798

Read the whole story
tuck
105 days ago
reply
More evidence that metabolism of omega-6 fats (in this case through sEH plays a role in a wide variety of conditions.
Weston, Connecticut
Share this story
Delete

Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors

1 Comment

J Med Chem. 2022 Oct 12. doi: 10.1021/acs.jmedchem.2c00515. Online ahead of print.

ABSTRACT

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field.

PMID:36222708 | DOI:10.1021/acs.jmedchem.2c00515

Read the whole story
tuck
106 days ago
reply
"Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field."
Weston, Connecticut
Share this story
Delete

German Energy Apocalypse Update VI

1 Comment

It was a cold September in central Europe, and about half of German households responded by heating far earlier in the year than usual. This means, as far as energy economisation, that we are already behind schedule:

Germany’s network regulator, which would be in charge of gas rationing in the event of a supply emergency … said that household consumption was too high to be sustainable.

Last week’s [18–24 September] usage of natural gas by German households and small industry was 483 gigawatt hours, up 14.5% above the average for that week over the past four years, the Bundesnetzagentur said.

“The numbers for that week are thus very sobering,” said agency president Klaus Mueller. “Without significant savings in the private area of consumption, it will be difficult to avoid an emergency situation in winter.”

My own energy bills have only about doubled so far, but many commercial consumers are seeing their gas and electricity costs surge four- or even ten-fold:

The rising costs for electricity and gas will have dramatic consequences for industry. The energy crisis is a “total catastrophe” which could threaten the existence of the whole sector, says Julius Wagner, Head Manager of the German Hotel and Restaurant Association in Hessen. “In comparison, the Corona crisis was a walk in the park.”

Around one in six businesses … is facing a fourfold to tenfold increase in electricity costs. Gas is no better. Wagner reported that he knows businesses where the monthly electricity costs have skyrocketed from around 500 to 3,000 Euros a month.

It seems all but certain that many retail establishments will close forever in the coming months, as energy becomes flatly unaffordable and customers are forced to devote every last penny to keeping their homes warm.

Read more



Read the whole story
tuck
111 days ago
reply
Another catastrophe birthed of human arrogance and ignorance.

"The rising costs for electricity and gas will have dramatic consequences for industry. The energy crisis is a “total catastrophe” which could threaten the existence of the whole sector, says Julius Wagner, Head Manager of the German Hotel and Restaurant Association in Hessen. 'In comparison, the Corona crisis was a walk in the park.'"
Weston, Connecticut
Share this story
Delete

Ether lipid deficiency disrupts lipid homeostasis leading to ferroptosis sensitivity

1 Comment

PLoS Genet. 2022 Sep 30;18(9):e1010436. doi: 10.1371/journal.pgen.1010436. Online ahead of print.

ABSTRACT

Ferroptosis is an iron-dependent form of regulated cell death associated with uncontrolled membrane lipid peroxidation and destruction. Previously, we showed that dietary dihomo-gamma-linolenic acid (DGLA; 20: 3(n-6)) triggers ferroptosis in the germ cells of the model organism, Caenorhabditis elegans. We also demonstrated that ether lipid-deficient mutant strains are sensitive to DGLA-induced ferroptosis, suggesting a protective role for ether lipids. The vinyl ether bond unique to plasmalogen lipids has been hypothesized to function as an antioxidant, but this has not been tested in animal models. In this study, we used C. elegans mutants to test the hypothesis that the vinyl ether bond in plasmalogens acts as an antioxidant to protect against germ cell ferroptosis as well as to protect from whole-body tert-butyl hydroperoxide (TBHP)-induced oxidative stress. We found no role for plasmalogens in either process. Instead, we demonstrate that ether lipid-deficiency disrupts lipid homeostasis in C. elegans, leading to altered ratios of saturated and monounsaturated fatty acid (MUFA) content in cellular membranes. We demonstrate that ferroptosis sensitivity in both wild type and ether-lipid deficient mutants can be rescued in several ways that change the relative abundance of saturated fats, MUFAs and specific polyunsaturated fatty acids (PUFAs). Specifically, we reduced ferroptosis sensitivity by (1) using mutant strains unable to synthesize DGLA, (2) using a strain carrying a gain-of-function mutation in the transcriptional mediator MDT-15, or (3) by dietary supplementation of MUFAs. Furthermore, our studies reveal important differences in how dietary lipids influence germ cell ferroptosis versus whole-body peroxide-induced oxidative stress. These studies highlight a potentially beneficial role for endogenous and dietary MUFAs in the prevention of ferroptosis.

PMID:36178986 | DOI:10.1371/journal.pgen.1010436

Read the whole story
tuck
117 days ago
reply
Ferroptosis = omega-6 toxicity. Oleic acid is protective.
Weston, Connecticut
Share this story
Delete
Next Page of Stories