Hydrogen sulfide (H2S) is a gasotransmitter and a potential therapeutic agent. However, molecular targets relevant to its therapeutic actions remain enigmatic. Sulfide-quinone oxidoreductase (SQR) irreversibly oxidizes H2S. Therefore, SQR is assumed to inhibit H2S signaling. We now report that SQR-mediated oxidation of H2S drives reverse electron transport (RET) at mitochondrial complex I, which, in turn, repurposes mitochondrial function to superoxide production. Unexpectedly, complex I RET, a process dependent on high mitochondrial membrane potential, induces superoxide-dependent mitochondrial uncoupling and downstream activation of adenosine monophosphate–activated protein kinase (AMPK). SQR-induced mitochondrial uncoupling is separated from the inhibition of mitochondrial complex IV by H2S. Moreover, deletion of SQR, complex I, or AMPK abolishes therapeutic effects of H2S following intracerebral hemorrhage. To conclude, SQR mediates H2S signaling and therapeutic effects by targeting mitochondrial electron transport to induce mitochondrial uncoupling. Moreover, SQR is a previously unrecognized target for developing non-protonophore uncouplers with broad clinical implications.
Necroptosis contributes to ischemia-induced brain injury. Tumor necrosis factor (TNF) receptor associated factor 2 (TRAF2) has been reported to suppress necroptotic cell death under several pathological conditions. In this study, we investigated the role of TRAF2 in experimental stroke using a mouse middle cerebral artery occlusion (MCAO) model and in vitro cellular models. TRAF2 expression in the ischemic brain was assessed with western blot and real-time RT-PCR. Gene knockdown of TRAF2 by lentivirus was utilized to investigate the role of TRAF2 in stroke outcomes. The expression of TRAF2 was significantly induced in the ischemic brain at 24 h after reperfusion, and neurons and microglia were two of the cellular sources of TRAF2 induction. Striatal knockdown of TRAF2 increased infarction size, cell death, microglial activation and the expression of pro-inflammatory markers at 24 h after reperfusion. TRAF2 expression and necroptosis were induced in mouse primary microglia treated with conditioned medium collected from neurons subject to oxygen and glucose deprivation (OGD) and in TNFα-treated mouse hippocampal neuronal HT-22 cells in the presence of the pan-caspase inhibitor Z-VAD. In addition, TRAF2 knockdown exacerbated microglial cell death and neuronal cell death under these conditions. Moreover, pre-treatment with a specific necroptosis inhibitor necrostatin-1 (nec-1) suppressed the cell death exacerbated by TRAF2 knockdown in the brain following MCAO, indicating that TRAF2 impacted ischemic brain damage through necroptosis mechanism. Taken together, our results demonstrate that TRAF2 is a novel regulator of cerebral ischemic injury.
Purpose: analyze the pathological features of pancreatic endocrine tumor and discuss the differential diagnosis of pancreatic endocrine tumor and pancreatic acinic cell carcinoma. Method: choose 10 patients of pancreatic endocrine tumor from the Chinese Medicine Hospital of Henan Province and the Tumor Consultation Center of Henan Province during January 2012 to January 2015 as research object to analyze their pathological features; choose another 10 patients of pancreatic acinic cell carcinoma conformed during the same period to make control study, combine the pathological examination and documentations to male differential diagnosis for pancreatic endocrine tumor and pancreatic acinic cell carcinoma. Result: (1)for cell morphology, tumor cells of the pancreatic endocrine tumor are arranged as solid flakes, aciniform and trabecular, its organizational structure is similar with that of pancreatic acinic cell carcinoma, but the organization of pancreatic endocrine tumor has no heterocyst, while the organization of pancreatic acinic cell carcinoma has heterocyst. (2) For the expression of immunohistochemistry, the pan cytokeratin, synaptophysin and chromogranin of the patients of pancreatic endocrine tumor and pancreatic acinic cell carcinoma are all positive, while the expression of vimentin, epithelial membrane antigen and insulin of the two kinds of pancreatic tumor are different. (3) For Clinical biological behavior, only one of the ten pancreatic endocrine tumor was diagnosed to be pancreatic tail neuroendocrine carcinoma, tumor of other nine patients were benign, while ten pancreatic acinar cell carcinoma were all high aggressive malignant tumor. Conclusion: Most of the pancreatic endocrine tumors are benign, while pancreatic acinar cell carcinoma is a kind of malignant tumor, though the cellular morphology of two kinds of tumor are similar, while there is obvious difference on the aspect of biological behavior of two kinds of tumors, clinical differential diagnosis of these two kinds of tumors should be paid attention.
Purpose Observed and analyzed the curative effect of Shenqi two thistles Er Zhi decoction in the treatment of IgA nephropathy of qi-yin deficiency. Method Used 80 cases of IgA nephrosis patients treated in our hospital from January 2012 to January 2014 as the research object, divided into two groups, the experimental group and the conventional group according to the random number method.40 cases of conventional group were treated with clinical treatment, including anti infection, antihypertensive therapy; 40 cases of experimental group were treated with clinic treatment of Shenqi two thistles Er Zhi decoction on the basis of the treatment of conventional group. To analyze the total effective rate, urinary red blood cell count, urine protein quantitative and so on, and compare difference of two groups. Results After clinical treatment, the total effective rate of the experimental group was 90.0%, and the conventional group was 70.0%,which was significantly lower than the experimental group,and there was significant difference between two groups (P < 0.05), and the improvement of urine red blood cell count, urine protein and urine protein in the experimental group was significantly better than that in the conventional group,there was significant difference compared(P < 0.05).Conclusion After clinical treatment of self designed Shenqi two thistles Er Zhi decoction in the treatment of IgA nephropathy patient, the total efficiency of the patients of this group was improved obviously, and the laboratory indicators of urine red blood cell count, urine protein quantitative were improved,so it should be used as a clinical priority to the adoption of treatment, worth further promotion and application.
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