Translational research : the journal of laboratory and clinical medicine
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Peripheral artery disease (PAD) causes an ischemic myopathy contributing to patient disability and mortality. Most preclinical models to date use young, healthy rodents with limited translatability to human disease. Although PAD incidence increases with age, and obesity is a common comorbidity, the pathophysiologic association between these risk factors and PAD myopathy is unknown. ⋯ However, the extent of mitochondrial dysfunction and oxidative stress was significantly greater in obese ischemic muscle compared to non-obese ischemic muscle. Moreover, functional impediments, such as delayed post-surgical recovery of limb function and reduced 6-minute walking distance, as well as accelerated intramuscular protein breakdown, inflammation, cytoskeletal damage, and fibrosis were only evident in mice with obesity. As these features are consistent with human PAD myopathy, our model could be a valuable tool to test new therapeutics.
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In hepatocellular carcinoma (HCC), sorafenib (Sora) efficacy is limited by primary and/or acquired resistance. Emerging evidence shows that the inflammatory factor interleukin 6 (IL-6) plays a role in Sora resistance. Norcantharidin (NCTD), a derivative of cantharidine, was identified as a potent IL-6 inhibitor. ⋯ NCTD boosted Sora antiproliferative and apoptotic activities by decreasing Ccnd1 and BCL2 expressions along with increasing BAX and caspase-3 expressions. To our knowledge, this study represents the first study providing evidence for the potential novel therapeutic use of NCTD/Sora combination for HCC. Moreover, no previous studies have reported the effect of NCTD on FGL1.
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The CLU rs11136000C mutation (CLUC) is the third most common risk factor for Alzheimer's disease (AD). However, the mechanism by which CLUC leads to abnormal GABAergic signaling in AD is unclear. To address this question, this study establishes the first chimeric mouse model of CLUC AD. ⋯ The expression of GABA A receptor, subunit alpha 2 (Gabrα2) was higher in chimeric mice. Interestingly, cognitive impairment in chimeric mice was reversed by treatment with pentylenetetrazole, which is a GABA A receptor inhibitor. Taken together, these findings shed light on the pathogenesis of CLUC AD using a novel humanized animal model and suggest sphingolipid signaling over-activation as a potential mechanism of GABAergic signaling disorder.