TLR4

Toll样受体4（TLR4）是机体先天性免疫的中枢调节因子，主要能识别细菌的脂多糖细胞壁组分从而诱发细胞因子释放。近日，一篇发表在Nature Communications上题为“RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling”的研究报告中，来自科隆大学等机构的科学家们通过研究发现，膜内蛋白酶RHBDL4或能有效预防机体过度免疫反应的发生。文章中，研究者发现，所谓的膜内蛋白酶对货物受体的切割会减少细胞表面中央免疫受体的定位，从而就会降低机体免疫系统过度反应的风险。膜内蛋白酶（intramembrane proteases）是一种位于细胞膜中的活性蛋白，其能形成一组特殊的蛋白酶，因为其能切割细胞膜内的蛋白质。目前研究人员还没有充分描述其中不寻常的蛋白酶，而且也仅有一些能够进行切割的分子（即所谓的底物），因此其功能还是未知的。其中一种膜内蛋白酶就是RHBDL4，其位于内质网中，而内质网是细胞中一种较大的膜系统，其主要负责对新合成的蛋白质进行正确折叠，随后将其送入分泌通路。在寻找底物和RHBDL4的分子功能时，研究人员发现了调节机体先天性免疫系统的一种机制，其包括切割转运蛋白从而阻断免疫受体向细胞表面的运输。为了初步了解RHBDL4的生理学功能，研究人员利用质谱法分析了组织培养细胞的底物，在候选底物中有多种所谓的货物受体（cargo receptors），其是在分泌途径中特定蛋白的运输所必需的。与长期假设相反的是，大多数蛋白质并不是简单地以非特异性的方式从内质网分泌，而是必须被货物受体选择和运输，其中一种诸如TMED7的货物受体就能被表征为RHBDL4的底物。通过切割这种货物受体，细胞就能精确且快速地控制特定蛋白的运输从而让细胞适应给定的环境条件，目前研究人员还未描述过这种通过膜内蛋白酶切割货物受体从而调节运输过程背后的分子机制。识别出控制机体免疫系统的新型调节性机制图片来源：Nature Communications (2024). DOI:10.1038/s41467-024-45615-2这一研究发现非常有趣，因为货物受体TMED7能将机体先天性免疫系统中的中心免疫受体（TLR4）运输到细胞表面，当TLR4与细菌细胞壁的组分接触时，其就会诱导免疫反应（即防御反应），RHBDL4对货物受体TMED7的切割会导致少量的TLR4分子抵达细胞表面，从而就会减少对细菌细胞壁组分的免疫反应。由于TLR4的过度激活会损伤有机体，甚至促进血液中毒（败血症）的发生，TLR4介导的免疫反应必须受到机体的严格调控，利用小鼠模型进行研究后，研究人员发现，RHBDL4对于预防TLR4的过度激活非常重要，这或许就能保护机体。研究者Lemberg说道，当受体被刺激时，细胞就会产生更多的RHBDL4，这也就是为何会存在一种负反馈回路的原因了，因为这能防止受体所产生的过度免疫反应损伤机体。为了更多地了解RHBDL4进行运输调节的临床相关性，研究人员通过联合研究后发现，当暴露于诸如结核分枝杆菌时，这种调节就显得尤为重要了。此外，研究人员还将蛋白酶RHBDL4中的遗传突变与川崎综合征联系了起来，后者是一种与机体免疫系统过度反应相关的免疫学疾病，其常常会影响儿童的健康。这一研究计划展示了利用诸如组织培养细胞等非常简单的模型来揭示对人类生物学和疾病的新见解。综上，本文研究中，研究人员识别出了RHBDL4所介导的轴或许能作为预防TLR4通路过度激活的“变阻器”。参考文献：Knopf, J.D., Steigleder, S.S., Korn, F. et al. RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling. Nat Commun 15, 1528 (2024). doi：10.1038/s41467-024-45615-2本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

Eating fatty food in the days leading up to surgery may prompt a heightened inflammatory response in the brain that interferes for weeks with memory-related cognitive function in older adults -- and, new research in animals suggests, even in young adults. Eating fatty food in the days leading up to surgery may prompt a heightened inflammatory response in the brain that interferes for weeks with memory-related cognitive function in older adults -- and, new research in animals suggests, even in young adults. The study, building upon previous research from the same lab at The Ohio State University, also showed that taking a DHA omega-3 fatty acid supplement for a month before the unhealthy eating and surgical procedure prevented the effects on memory linked to both the high-fat diet and the surgery in aged and young adult rats. Three days on a high-fat diet alone was detrimental to a specific type of fear-related memory in aged rats for as long as two weeks later -- the same type of impairment seen in younger rats that ate fatty food and had a surgical procedure. The team has traced the brain inflammation behind these effects to a protein that activates the immune response. "These data suggest that these multiple insults have a compounding effect," said senior author Ruth Barrientos, an investigator in Ohio State's Institute for Behavioral Medicine Research and associate professor of psychiatry and behavioral health and neuroscience in the College of Medicine. "We've shown that an unhealthy diet, even in the short term, especially when it's consumed so close to a surgery, which in and of itself will cause an inflammatory response, can have damaging results," Barrientos said. "The high-fat diet alone might increase inflammation in the brain just a little bit, but then you have surgery that does the same thing, and when put together in a short amount of time you get a synergistic response that can set things in motion toward a longer-term memory issue." The study was published recently in the journal Brain, Behavior, and Immunity. Barrientos' lab studies how everyday life events might trigger inflammation in the aging brain as the nervous system responds to signals from the immune system reacting to a threat. Decades of research has suggested that with aging comes long-term "priming" of the brain's inflammatory pro a loss of brain-cell reserve to bounce back. Researchers fed young adult and aged rats a diet high in saturated fat for three days before a procedure resembling exploratory abdominal surgery -- an event already known to cause about a week of cognitive issues in an older brain. Control rats ate regular food and were anesthetized, but had no surgery. (Barrientos' lab has determined anesthesia alone does not cause memory problems in rats.) In this study, as in previous research on aged rats treated with morphine after surgery, the team showed that an immune system receptor called TLR4 was the culprit behind the brain inflammation and related memory problems generated by both surgery and the high-fat diet, said first author Stephanie Muscat, assistant clinical professor of neuroscience at Ohio State. "Blocking the TLR4 signaling pathway prior to the diet and surgery completely prevented that neuroimmune response and memory impairments, which confirmed this specific mechanism," Muscat said. "And as we had found before in another model of an unhealthy diet, we showed that DHA supplementation did mitigate those inflammatory effects and prevent memory deficits after surgery." There were some surprising memory findings in the new work. Different behavioral tasks are used to test two types of memory: contextual memory based in the hippocampus and cued-fear memory based in the amygdala. In contextual memory tests, rats with normal memory freeze when they re-enter a room in which they had an unpleasant experience. Cued-fear memory is evident when rats freeze in a new environment when they hear a sound connected to that previous bad experience. For aged rats in this study, as expected, the combination of a high-fat diet and surgery led to problems with both contextual and cued-fear memory that persisted for at least two weeks -- a longer-lasting effect than the researchers had seen before. The high-fat diet alone also impaired the aging rats' cued-fear memory. And in young adult rats, the combination of the high-fat diet and surgery led to only cued-fear memory deficits, but no problems with memory governed by the hippocampus. "What this is telling us in aged animals, along with the fact we're seeing this same impairment in young animals after the high-fat diet and surgery, is that cued-fear memory is uniquely vulnerable to the effects of diet. And we don't know why," Barrientos said. "One of the things we're hoping to understand in the future is the vulnerability of the amygdala to these unhealthy diet challenges." With increasing evidence suggesting that fatty and highly processed foods can trigger inflammation-related memory problems in brains of all ages, the consistent findings that DHA -- one of two omega-3 fatty acids in fish and other seafood and available in supplement form -- has a protective effect are compelling, Barrientos said. "DHA was really effective at preventing these changes," she said. "And that's amazing -- it really suggests that this could be a potential pretreatment, especially if people know they're going to have surgery and their diet is unhealthy." This work was supported by grants from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke. Co-authors included Michael Butler, Menaz Bettes, James DeMarsh, Emmanuel Scaria and Nicholas Deems, all of Ohio State.

SAN DIEGO--( BUSINESS WIRE )--Revelation Biosciences Inc. (NASDAQ: REVB) (the “Company” or “Revelation”) a clinical-stage life sciences company that is focused on harnessing the power of trained immunity for the prevention and treatment of disease, announced today new preclinical data on the potential therapeutic benefit of Gemini for the prevention of acute kidney injury (AKI) that was presented at the International Conference on Advances in Critical Care Nephrology (AKI & CRRT 2024) taking place in San Diego on March 12-15, 2024. Gemini is the Company’s proprietary formulation of phosphorylated hexaacyl disaccharide (PHAD®), a toll-like receptor 4 (TLR4) agonist, in development for prevention of AKI. A copy of the presentation and poster presented at the AKI and CRRT 2024 Conference can be found on Revelation’s website . Results from Bilateral Rat Model of Ischemia Reperfusion Induced AKI In a clinically relevant bilateral rat model of ischemia reperfusion (I/R) induced acute kidney injury (AKI), animals were dosed intravenously with PHAD at 0.07 or 0.35mg/kg at 24 hours and/or 48 hours prior to I/R surgery. In addition to clinical observation, rats were evaluated for markers of kidney function at 24 and/or 72 hours post-surgery, and markers of kidney damage at 72 hours post-surgery. In this model, Gemini pretreatment (0.35mg/kg) significantly: Preserved kidney function with a more rapid return to base line relative to untreated control animals, with statistically significant reductions in serum creatinine (p<0.01 at 24 hours, p<0.02 at 72 hours) and serum blood urea nitrogen (BUN) (p<0.02 at 72 hours). Reduced overall damage (necrosis) of the cortical (p<0.02) and medullary tubules (p<0.01) relative to the untreated group. Significantly reduced markers of local inflammation at 24 and/or 72 hours as measured by concentrations of urinary and serum c-reactive protein (CRP) (p<0.01) and IL-6 (p<0.05). Significantly reduced markers of cellular inflammation as observed via reduced neutrophilic inflammation with a single dose of 0.35mg/kg (p<0.02). The improved kidney function, reduced necrosis and reduced inflammatory biomarkers observed in this study are attributed to the immunostimulatory preconditioning effect of Gemini which includes strong upregulation of IL-10, a key cytokine responsible for resolution of inflammation. “These results demonstrate that Gemini has the potential to reduce tissue damage and improve kidney function in ischemic reperfusion induced acute kidney injury and potentially other inflammatory diseases,” said James Rolke, Chief Executive Officer of Revelation. “In addition to this, we are excited to have initiated our Phase 1 clinical study with Gemini in February 2024 and we look forward to starting studies in patients later this year.” About Gemini Gemini is a proprietary formulation of phosphorylated hexaacyl disaccharide (PHAD®) for systemic administration. It is being developed for multiple indications including as a pretreatment to prevent or reduce the severity and duration of post-surgical infection (GEMINI-SSI program), and as pretreatment to prevent or reduce the severity and duration of acute kidney injury (GEMINI-AKI program). In addition, Gemini may be a treatment to stop or slow the progression of chronic kidney disease (GEMINI-CKD program). Revelation believes Gemini works through trained immunity, which redirects and attenuates the innate immune response to external stress (infection, trauma, etc.). Revelation has conducted multiple preclinical studies demonstrating the therapeutic potential of Gemini in the target indications. About Revelation Biosciences Inc. Revelation Biosciences, Inc. is a life sciences company focused on harnessing the power of trained immunity for the prevention and treatment of disease using its proprietary formulation, Gemini. Revelation has multiple ongoing programs to evaluate Gemini, including GEMINI-SSI as a prevention for post-surgical infection, GEMINI-AKI as a prevention for acute kidney injury, and GEMINI-CKD for the treatment of chronic kidney disease. For more information on Revelation, please visit www.RevBiosciences.com . Forward-Looking Statements This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts. These forward-looking statements are generally identified by the words "anticipate", "believe", "expect", "estimate", "plan", "outlook", and "project" and other similar expressions. We caution investors that forward-looking statements are based on management’s expectations and are only predictions or statements of current expectations and involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from those anticipated by the forward-looking statements. Revelation cautions readers not to place undue reliance on any such forward looking statements, which speak only as of the date they were made. The following factors, among others, could cause actual results to differ materially from those described in these forward-looking statements: the ability of Revelation to meet its financial and strategic goals, due to, among other things, competition; the ability of Revelation to grow and manage growth profitability and retain its key employees; the possibility that the Revelation may be adversely affected by other economic, business, and/or competitive factors; risks relating to the successful development of Revelation’s product candidates; the ability to successfully complete planned clinical studies of its product candidates; the risk that we may not fully enroll our clinical studies or enrollment will take longer than expected; risks relating to the occurrence of adverse safety events and/or unexpected concerns that may arise from data or analysis from our clinical studies; changes in applicable laws or regulations; expected initiation of the clinical studies, the timing of clinical data; the outcome of the clinical data, including whether the results of such study is positive or whether it can be replicated; the outcome of data collected, including whether the results of such data and/or correlation can be replicated; the timing, costs, conduct and outcome of our other clinical studies; the anticipated treatment of future clinical data by the FDA, the EMA or other regulatory authorities, including whether such data will be sufficient for approval; the success of future development activities for its product candidates; potential indications for which product candidates may be developed; the ability of Revelation to maintain the listing of its securities on NASDAQ; the expected duration over which Revelation’s balances will fund its operations; and other risks and uncertainties described herein, as well as those risks and uncertainties discussed from time to time in other reports and other public filings with the SEC by Revelation.