The use of opioid analgesics has a long history in clinical settings, although the comprehensive action of opioid receptors is still less understood. Nonetheless, recent studies have generated fresh insights into opioid receptor-mediated functions and their underlying mechanisms. Three major opioid receptors (μ-opioid receptor, MOR; δ-opioid receptor, DOR; and κ-opioid receptor, KOR) have been cloned in many species. Each opioid receptor is functionally sub-classified into several pharmacological subtypes, although, specific gene corresponding each of these receptor subtypes is still unidentified as only a single gene has been isolated for each opioid receptor. In addition to pain modulation and addiction, opioid receptors are widely involved in various physiological and pathophysiological activities, including the regulation of membrane ionic homeostasis, cell proliferation, emotional response, epileptic seizures, immune function, feeding, obesity, respiratory and cardiovascular control as well as some neurodegenerative disorders. In some species, they play an essential role in hibernation. One of the most exciting findings of the past decade is the opioid-receptor, especially DOR, mediated neuroprotection and cardioprotection. The up-regulation of DOR expression and DOR activation increase the neuronal tolerance to hypoxic/ischemic stress. The DOR signal triggers (depending on stress duration and severity) different mechanisms at multiple levels to preserve neuronal survival, including the stabilization of homeostasis and increased pro-survival signaling (e.g., PKC-ERK-Bcl 2) and anti-oxidative capacity. In the heart, PKC and KATP channels are involved in the opioid receptor-mediated cardioprotection. The DOR-mediated neuroprotection and cardioprotection have the potential to significantly alter the clinical pharmacology in terms of prevention and treatment of life-threatening conditions like stroke and myocardial infarction. The main purpose of this article is to review the recent work done on opioids and their receptor functions. It shall provide an informative reference for better understanding the opioid system and further elucidation of the opioid receptor function from a physiological and pharmacological point of view.

Aim: To systematically profile the global m6A modification pattern in clear cell renal cell carcinoma (ccRCC). Methods: m6A modification patterns in ccRCC and normal tissues were described via m6A sequencing and RNA sequencing, followed by bioinformatics analysis. m6A-related RNAs were immunoprecipitated and validated by quantitative real-time PCR (qPCR). Results: In total, 6919 new m6A peaks appeared with the disappearance of 5020 peaks in ccRCC samples. The unique m6A-related genes in ccRCC were associated with cancer-related pathways. We identified differentially expressed mRNA transcripts with hyper-methylated or hypo-methylated m6A peaks in ccRCC. Conclusion: This study presented the first m6A transcriptome-wide map of human ccRCC, which may shed lights on possible mechanisms of m6A-mediated gene expression regulation.

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Mesenchymal stem cell (MSC)-based therapy is a promising approach to treat various inflammatory disorders including multiple sclerosis. However, the fate of MSCs in the inflammatory microenvironment is largely unknown. Experimental autoimmune encephalomyelitis (EAE) is a well-studied animal model of multiple sclerosis. We demonstrated that autophagy occurred in MSCs during their application for EAE treatment. Inflammatory cytokines, e.g., interferon gamma and tumor necrosis factor, induced autophagy in MSCs synergistically by inducing expression of BECN1/Beclin 1. Inhibition of autophagy by knockdown of Becn1 significantly improved the therapeutic effects of MSCs on EAE, which was mainly attributable to enhanced suppression upon activation and expansion of CD4+ T cells. Mechanistically, inhibition of autophagy increased reactive oxygen species generation and mitogen-activated protein kinase 1/3 activation in MSCs, which were essential for PTGS2 (prostaglandin-endoperoxide synthase 2 [prostaglandin G/H synthase and cyclooxygenase]) and downstream prostaglandin E2 expression to exert immunoregulatory function. Furthermore, pharmacological treatment of MSCs to inhibit autophagy increased their immunosuppressive effects on T cell-mediated EAE. Our findings indicate that inflammatory microenvironment-induced autophagy downregulates the immunosuppressive function of MSCs. Therefore, modulation of autophagy in MSCs would provide a novel strategy to improve MSC-based immunotherapy.

PurposeIn the present study, we aimed to evaluate the prognostic significance of the systemic inflammation response index (SIRI), which was defined based on peripheral blood counts of neutrophils, lymphocytes, and monocytes, in patients with localized or locally advanced clear cell renal cell carcinoma (CCRCC).Patients and methodsThe prognostic value of SIRI was evaluated in a primary cohort consisting of 414 patients with localized or locally advanced CCRCC and then further validated in an independent cohort composed of 168 patients.ResultsKaplan–Meier survival analyses of both cohorts revealed that CCRCC patients with high SIRI levels exhibited poorer overall survival (OS) and cancer-specific survival (CSS) compared with those with low SIRI levels. Furthermore, univariate and multivariate analyses identified SIRI as a significant independent predictor for both OS (HR: 4.853; 95% CI: 2.362–9.972; P<0.001) and CSS (HR: 5.913; 95% CI: 2.681–13.040; P<0.001). Following propensity score matching analysis, SIRI remained an excellent predictor for both OS and CSS. The area under the curve for SIRI was larger than that of the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score in both cohorts.ConclusionSIRI might be a better prognostic predictor than PLR, NLR, MLR, and MSKCC score in patients with localized or locally advanced CCRCC.Institutional review board approval number(2010) Scientific Research Project No. 39