The hypoxic environment imposes severe selective pressure on species living at high altitude. To understand the genetic bases of adaptation to high altitude in dogs, we performed whole-genome sequencing of 60 dogs including five breeds living at continuous altitudes along the Tibetan Plateau from 800 to 5100 m as well as one European breed. More than 1503 sequencing coverage for each breed provides us with a comprehensive assessment of the genetic polymorphisms of the dogs, including Tibetan Mastiffs. Comparison of the breeds from different altitudes reveals strong signals of population differentiation at the locus of hypoxia-related genes including endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) and beta hemoglobin cluster. Notably, four novel nonsynonymous mutations specific to high-altitude dogs are identified at EPAS1, one of which occurred at a quite conserved site in the PAS domain. The association testing between EPAS1 genotypes and blood-related phenotypes on additional high-altitude dogs reveals that the homozygous mutation is associated with decreased blood flow resistance, which may help to improve hemorheologic fitness. Interestingly, EPAS1 was also identified as a selective target in Tibetan highlanders, though no amino acid changes were found. Thus, our results not only indicate parallel evolution of humans and dogs in adaptation to high-altitude hypoxia, but also provide a new opportunity to study the role of EPAS1 in the adaptive processes.
Background and Purpose-Our previous study demonstrated that pretreatment with electroacupuncture (EA) induces rapid tolerance to focal cerebral ischemia. The present study was aimed to investigate the involvement of the endocannabinoid system in the early neuroprotection conferred by EA pretreatment in the animal model of focal cerebral ischemia. Methods-Two hours after the end of EA pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion for 120 minutes in male Sprague-Dawley rats or male C57BL/6 mice. The neurobehavioral scores, infarction volumes, and neuronal apoptosis were evaluated at 24 hours or 7 days after reperfusion in the presence or absence of AM251 (a selective cannabinoid receptor type 1 [CB1] receptor antagonist) or CB1 short interfering RNA. The expression of CB1 receptor and the content of endocannabinoids in the brains were also investigated. Results-EA pretreatment reduced infarct size, improved neurological outcome, and inhibited neuronal apoptosis at 24 hours or 7 days after reperfusion. The beneficial effects were abolished by AM251. CB1 knockdown by CB1 short interfering RNA attenuated EA pretreatment-induced neuroprotection. EA pretreatment upregulated the neuronal expression of CB1 receptor in the rat brains and elevated the brain tissue content of the endocannabinoid 2-arachidonylglycerol and N-arach-idonoylethanolamine-anandamide. Pretreatment with 2-arachidonylglycerol and N-arach-idonoylethanolamine-anandamide also reduced infarct size and improved neurological outcome. Conclusion-We conclude that pretreatment with EA increases the production of endocannabinoid 2-arachidonylglycerol and N-arach-idonoylethanolamine-anandamide, which elicits protective effects against transient cerebral ischemia through CB1 receptors. These results suggest a novel mechanism of EA pretreatment-induced rapid tolerance to focal cerebral ischemia.
Although it is known that tumor necrosis factor-related apoptosis-inducing ligand (TNFSF10/TRAIL) induces autophagy, the mechanism by which autophagy is activated by TNFSF10 is still elusive. In this report, we show evidence that TRAF2- and RIPK1-mediated MAPK8/JNK activation is required for TNFSF10-induced cytoprotective autophagy. TNFSF10 activated autophagy rapidly in cancer cell lines derived from lung, bladder and prostate tumors. Blocking autophagy with either pharmacological inhibitors or siRNAs targeting the key autophagy factors BECN1/Beclin 1 or ATG7 effectively increased TNFSF10-induced apoptotic cytotoxicity, substantiating a cytoprotective role for TNFSF10-induced autophagy. Blocking MAPK8 but not NFκB effectively blocked autophagy, suggesting that MAPK8 is the main pathway for TNFSF10-induced autophagy. In addition, blocking MAPK8 effectively inhibited degradation of BCL2L1/Bcl-xL and reduction of the autophagy-suppressing BCL2L1-BECN1complex. Knockdown of TRAF2 or RIPK1 effectively suppressed TNFSF10-induced MAPK8 activation and autophagy. Furthermore, suppressing autophagy inhibited expression of antiapoptosis factors BIRC2/cIAP1, BIRC3/cIAP2, XIAP and CFLAR/c-FLIP and increased the formation of TNFSF10-induced death-inducing signaling complex (DISC). These results reveal a critical role for the MAPK8 activation pathway through TRAF2 and RIPK1 for TNFSF10-induced autophagy that blunts apoptosis in cancer cells. Thus, suppression of MAPK8-mediated autophagy could be utilized for sensitizing cancer cells to therapy with TNFSF10.
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