Irisin reduces ischemia-induced neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotective effect of physical exercise against cerebral ischemia, suggesting that irisin may be a factor linking metabolism and cardio-cerebrovascular diseases.

Abstract-Inflammatory responses are associated with the genesis and progression of end-organ damage (EOD) in hypertension. A role for the ␣7 nicotinic acetylcholine receptor (␣7nAChR) in inflammation has recently been identified. We tested the hypothesis that ␣7nAChR dysfunction contributes to hypertensive EOD. In both spontaneously hypertensive rats (SHRs) and rats with abdominal aorta coarctation-induced hypertension, atropine-induced tachycardia was blunted compared with normotensive controls. Both models of hypertension were associated with deficits in expression of the vesicular acetylcholine transporter and the ␣7nAChR in cardiovascular tissues. In hypertension induced by abdominal aorta coarctation, deficits in aortic vesicular acetylcholine transporter and ␣7nAChR were present both above and below the coarctation site, indicating that they were independent of the level of arterial pressure itself. Hypertension in 40-week-old SHRs was associated with cardiac and aortic hypertrophy. Morphological abnormalities consistent with EOD, along with elevated tissue levels of proinflammatory cytokines (tumor necrosis factor-␣, interleukin-1␤, and interleukin-6) were observed in the heart, kidney, and aorta. Chronic treatment of SHRs with the ␣7nAChR agonist PNU-282987 relieved EOD and inhibited tissue levels of proinflammatory cytokines and activation of nuclear factor B. Greater serum levels of proinflammatory cytokines and more severe damage in the heart, aorta, and kidney were seen in ␣7nAChR Ϫ/Ϫ mice subjected to 2-kidney-1-clip surgery than in wild-type mice. A deficit in the cholinergic anti-inflammatory pathway appears to contribute to the pathogenesis of EOD in models of hypertension of varying etiology. This pathway may provide a new target for preventing cardiovascular disease resulting from hypertension. (Hypertension. 2011;57:298-307.) • Online Data Supplement Key Words: acetylcholine Ⅲ ␣7 nicotinic acetylcholine receptor Ⅲ inflammation Ⅲ hypertension Ⅲ end-organ damage H ypertension is a major risk factor for myocardial infarction, heart failure, stroke, and kidney dysfunction. Endorgan damage (EOD), including cardiac hypertrophy and myocyte dysfunction, vascular remodeling, and renal lesions, is a crucial mediatory link between hypertension and the development of these cardiovascular events. 1 Therefore, a better understanding of the mechanisms leading to hypertensive EOD could provide new avenues for prevention of cardiovascular events. Inflammation is very important in the genesis and development of EOD. 2,3 Furthermore, the reninangiotensin system can contribute to EOD, at least partly by promoting inflammation. 4 -7 However, cardiovascular inflammation and EOD can also occur without renin-angiotensin system activation, 8 so other mechanisms must also operate.Recent evidence indicates that neuronal 9 -11 cholinergic systems influence inflammatory responses by controlling the release of tumor necrosis factor (TNF)-␣, interleukin-(⌱L)-1␤, and IL-6 and that nonneuronal acetylcholine synthesis and rele...

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BackgroundIn developed countries, prostate cancer (PCa) is a frequently diagnosed cancer with the second highest fatality rate. Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs (ncRNAs) stably expressed in cells and involved in a series of carcinomas. However, few research studies have reported on the role of circRNAs in PCa.Material/MethodsWe used qRT-PCR to detect the expression of circMYLK (circRNA ID: hsa_circ_0141940) and miR-29a in PCa tissues and cell lines. MTT, colony formation, and TUNEL assays were performed to analysis the cell viability of PCa cells. Transwell and wound scratch assays were performed to investigate the cell invasion and migration of PCa cells.ResultsIn the present study, we confirmed that circMYLK expression level was significantly higher in PCa samples and PCa cells than in normal tissues and normal prostatic cells. The upregulated circRNA-MYLK promoted PCa cells proliferation, invasion, and migration; however, si-circRNA-MYLK significantly accelerated the PCa cell apoptosis. We also observed that the aforementioned function of circRNA-MYLK on PCa cells was affected through targeting miR-29a.ConclusionsWe confirmed circRNA-MYLK was an oncogene in PCa and revealed a novel mechanism underlying circRNA-MYLK in PC progression.

Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal-regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high-fat diet (HFD)-induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho-ASK1, phospho-MKK3/6, phospho-p38, phospho-MKK4/7, and phospho-JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor-associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein β-arrestin-1 and enabled it to bind to ASK1, which antagonized the TRAFs-mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability.Consistent with these findings, knockout of β-arrestin-1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs-mediated ASK1 deubiquitination and stabilization in a β-arrestin-1 dependent manner. K E Y W O R D SASK1, Deubiquitination, Inflammation, Kupffer cell, melatonin, nonalcoholic fatty liver disease, TRAFs, β-arrestin

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Clear cell sarcoma is a high-grade sarcoma with morphological features resembling those of malignant melanoma. An osteoclast-rich tumor of the gastrointestinal tract with features resembling those of clear cell sarcomas of soft parts is very rare. Herein, we report an unusual stomach tumor with microscopic and immunohistochemical characteristics of an osteoclast-rich tumor of the gastrointestinal tract with features resembling those of clear cell sarcomas of soft parts. The tumor cells were predominantly oval, admixed with some round and spindle elements arranged in nests and fascicles, and admixed with scattered osteoclast-like multinucleated giant cells. Neoplastic cells were positive for S-100 protein, and osteoclast-like multinucleated giant cells were immunoreactive to CD68. The unusual morphology of the tumor caused significant diagnostic difficulties. The differential diagnosis included gastrointestinal stromal tumor, primary or metastatic melanoma, and epithelioid malignant peripheral nerve sheath tumor. To the best of our knowledge, this is possibly the second description of an osteoclast-rich tumor of the gastrointestinal tract with features resembling those of clear cell sarcomas of soft parts.