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Homocysteine promotes atherosclerosis through macrophage pyroptosis via endoplasmic reticulum stress and calcium disorder - Molecular MedicineBackground Elevated plasma homocysteine levels, known as hyperhomocysteinemia, have been identified as an independent risk factor for atherosclerosis and related cardiovascular diseases. Macrophage pyroptosis-mediated inflammation is crucial in the development of atherosclerosis, but the underlying mechanisms remain unclear. Methods A hyperhomocysteinemia atherosclerotic model with ApoE−/− mice fed with a high-methionine diet was constructed to investigate the role of plasma homocysteine in atherosclerosis. THP-1-derived macrophages were used to investigate the mechanisms by which Hcy regulates pyroptosis. Results We found that hyperhomocysteinemia resulted in larger atherosclerotic plaques and more secretion of inflammatory cytokines, while these effects were attenuated in Caspase-1 knockdown mice. Likewise, in vitro experiments demonstrated that treatment of macrophages with homocysteine resulted in NLRP3 inflammasome activation and pyroptosis, as evidenced by cleavage of Caspase-1, production of downstream IL-1β, elevation of lactate dehydrogenase activity, and extensive propidium iodide-positive staining of cells. These were all inhibited by Caspase-1 inhibitor. In addition, excessive generation of reactive oxygen species was associated with mitochondrial dysfunction, characterized by loss of mitochondrial membrane potential and ATP synthesis. Moreover, further experiments revealed that homocysteine induced endoplasmic reticulum stress, enhanced communication between the endoplasmic reticulum and mitochondria, and consequently contributed to calcium disorder. Furthermore, the endoplasmic reticulum stress inhibitor, 4PBA, the calcium chelator, BAPTA, and calcium channel inhibitor, 2-APB significantly improved macrophage pyroptosis. Conclusion Homocysteine accelerates atherosclerosis progression by enhancing macrophages pyroptosis via promoting endoplasmic reticulum stress, endoplasmic reticulum-mitochondria coupling, and disturbing of calcium disorder.
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Study investigates the interplay between acute stress and placebo effects in nauseaStudy investigates the interplay between acute stress and placebo effects in nausea SciReports unisouthampton LMU_Muenchen uconnhealth nausea sickness stress placebo
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Wearable monitor detects stress hormone levels across a full 24-hour dayEarly warning signs of diseases caused by dysfunctional levels of stress hormones can be spotted more easily thanks to a new wearable device developed by endocrine researchers.
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Homeowners left exposed by inadequate mortgage stress testsMortgage holders could be at risk of struggling to make their repayments The issue is that they may have been exposed to high inflation and cost of living pressures due to opaque mortgage affordability testing 🔴 Exclusive from Victoria_Spratt
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Mortal Kombat 1 online stress test - how to sign up, start dateGet over here to find out how you can get hands on with the latest entry in the bloody brawler series ahead of everyone else.
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