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81.
SOCS3是酪氨酸蛋白激酶/信号传导子和转录激活子(JAK/STAT)途径的负反馈调节因子之一,由SOCS盒、SH2结构域和激酶抑制区三个部分组成.SOCS3参与了体内多种信号分子转导的调控.本文结合近年的研究成果对其结构和作用机制进行了综述,并对其中尚存在的问题进行展望. 相似文献
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Tumor‐suppressive miR‐145 co‐repressed by TCF4‐β‐catenin and PRC2 complexes forms double‐negative regulation loops with its negative regulators in colorectal cancer 下载免费PDF全文
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目的探讨人参皂苷Rg3通过影响WNT/β-catenin信号通路中关键蛋白β-catenin从而阻断结肠癌细胞生长机制的研究。方法 MTT法检测不同浓度人参皂苷Rg3对人结肠癌细胞系SW480、HCT116细胞增殖的影响;流式细胞仪检测不同浓度人参皂苷Rg3对SW480、HCT116细胞凋亡及磷酸化β-catenin的影响;RT-PCR和Western blot法检测HCT116细胞中β-catenin及c-myc的表达。结果人参皂苷Rg3具有抑制SW480、HCT116细胞增殖和促进凋亡的能力。一定浓度人参皂苷Rg3能够降低β-catenin蛋白的磷酸化程度,下调β-catenin mRNA的表达,下调β-cetanin和c-myc蛋白的表达。结论人参皂苷Rg3具有一定的抗肿瘤活性,可有效抑制HCT116和SW480细胞生长,且这种作用可能是通过下调β-catenin磷酸化来实现的。 相似文献
86.
Jinglin Wang Haoran Ding Jingchao Zhou Senzhe Xia Xiaolei Shi Haozhen Ren 《临床与转化肝病杂志(英文版)》2022,10(4):669
Background and AimsTransplantation of mesenchymal stem cells (MSCs) derived from bone marrow (BM) is an alternative treatment of acute liver failure (ALF) mainly because of the resulting anti-inflammatory activity. It is not known how MSCs regulate local immune responses and liver regeneration. This study explored the effects of MSCs on hepatic macrophages and the Wnt signaling pathway in ALF.MethodsMSCs were isolated from BM aspirates of C57BL/6J mice, and transplanted in mice with ALF induced by D-galactosamine (D-Gal). The proliferation of hepatocytes was assayed by immunohistochemical (IHC) staining of Ki-67 and proliferating cell nuclear antigen (PCNA). The levels of key proteins in the Wnt signaling pathway were assayed by western blotting and cytokines were determined enzyme-linked immunosorbent assays (ELISAs). A macrophage polarization assay characterized the M1/M2 ratio. The potential role of interleukin-4 (IL-4) in the biological activity of MSCs was determined by silencing of IL-4.ResultsTransplantation of allogeneic MSCs significantly attenuated D-Gal-induced hepatic inflammation and promoted liver regeneration. MSC transplantation significantly promoted a phenotypic switch from proinflamatory M1 macrophages to anti-inflammatory M2 macrophages, leading to significant Wnt-3a induction and activation of the Wnt signaling pathway in mice with D-Gal-induced ALF. Of the paracrine factors secreted by MSCs (G-CSF, IL-6, IL-1 beta, IL-4, and IL-17A), IL-4 was specifically induced following transplantation in the ALF model mice. The silencing of IL-4 significantly abrogated the phenotypic switch to M2 macrophages and the protective effects of MSCs in both the ALF model mice and a co-culture model in an IL-4 dependent manner.ConclusionsIn vivo and in vitro studies showed that MSCs ameliorated ALF through an IL-4-dependent macrophage switch toward the M2 anti-inflammatory phenotype. The findings may have clinical implications in that overexpression of IL-4 may enhance the therapeutic effects of allogeneic MSC transplantation in the treatment of ALF. 相似文献
87.
Xue-gong Fan Si-ya Pei Dan Zhou Peng-cheng Zhou Yan Huang Xing-wang Hu Teng Li Yang Wang Ze-bing Huang Ning Li 《Acta pharmacologica Sinica》2021,42(8):1256-1266
Acute liver failure (ALF) is a fatal clinical syndrome with no special drug. Recent evidence shows that modulation of macrophage to inhibit inflammation may be a promising strategy for ALF treatment. In this study we investigated the potential therapeutic effects of melittin, a major peptide component of bee venom both in mice model of ALF and in LPS-stimulated macrophages in vitro, and elucidated the underlying mechanisms. ALF was induced in mice by intraperitoneal injection of d-galactosamine/LPS. Then the mice were treated with melittin (2, 4, and 8 mg/kg, ip). We showed that melittin treatment markedly improved mortality, attenuated severe symptoms and signs, and alleviated hepatic inflammation in d-galactosamine/LPS-induced ALF mice with the optimal dose being 4 mg/kg. In addition, melittin within the effective doses did not cause significant in vivo toxicity. In LPS-stimulated RAW264.7 macrophages, melittin (0.7 μM) exerted anti-oxidation and anti-inflammation effects. We showed that LPS stimulation promoted aerobic glycolysis of macrophages through increasing glycolytic rate, upregulated the levels of Warburg effect-related enzymes and metabolites including lactate, LDHA, LDH, and GLUT-1, and activated Akt/mTOR/PKM2/HIF-1α signaling. Melittin treatment suppressed M2 isoform of pyruvate kinase (PKM2), thus disrupted the Warburg effect to alleviate inflammation. Molecular docking analysis confirmed that melittin targeted PKM2. In LPS-stimulated RAW264.7 macrophages, knockdown of PKM2 caused similar anti-inflammation effects as melittin did. In d-galactosamine/LPS-induced ALF mice, melittin treatment markedly decreased the expression levels of PKM2 and HIF-1α in liver. This work demonstrates that melittin inhibits macrophage activation-mediated inflammation via inhibition of aerobic glycolysis by targeting PKM2, which highlights a novel strategy of using melittin for ALF treatment. 相似文献
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Bladder cancer (BC) is a common type of cancer worldwide. Currently, the gold standard treatment is transurethral resection of bladder tumor (TUR-Bt) accompanied by intravesical Bacillus Calmette–Guérin (BCG) instillation for patients with middle-to-high-risk non-muscle-invasive bladder cancer (NMIBC). However, intravesical BCG therapy fails in almost 50% of high risk cases, leading to NMIBC persistence or early recurrence. In these patients, the gold standard remains radical cystectomy; however, it can seriously affect the patients’ quality of life. Moreover, for patients with muscle-invasive bladder cancer (MIBC), the 5-year survival rate after radical cystectomy with neoadjuvant chemotherapy remains low. Recent discoveries have paved the way for a new era in BC treatment. Metformin is the most widely used oral hypoglycemic drug in clinical practice, being mostly used in the treatment of type 2 diabetes. Epidemiological studies have demonstrated that metformin exerts a potentially positive effect on reducing the incidence and mortality of cancer; therefore, a increasing number of studies have investigated the potential anticancer effects of metformin and its mechanisms of action. This review aims to summarize the evidence for the role of metformin in bladder cancer therapy, including how metformin mediates bladder cancer cell apoptosis. 相似文献
90.
Chetan S. Patil Hongbin Li Natalie E. Lavine Ruoyang Shi Ankur Bodalia Tabrez J. Siddiqui Michael F. Jackson 《Proceedings of the National Academy of Sciences of the United States of America》2022,119(36)
Pannexin-1 (Panx1) is a large-pore ion and solute permeable channel highly expressed in the nervous system, where it subserves diverse processes, including neurite outgrowth, dendritic spine formation, and N-methyl D-aspartate (NMDA) receptor (NMDAR)-dependent plasticity. Moreover, Panx1 dysregulation contributes to neurological disorders, including neuropathic pain, epilepsy, and excitotoxicity. Despite progress in understanding physiological and pathological functions of Panx1, the mechanisms that regulate its activity, including its ion and solute permeability, remain poorly understood. In this study, we identify endoplasmic reticulum (ER)-resident stromal interaction molecules (STIM1/2), which are Ca2+ sensors that communicate events within the ER to plasma membrane channels, as binding and signaling partners of Panx1. We demonstrate that Panx1 is activated to its large-pore configuration in response to stimuli that recruit STIM1/2 and map the interaction interface to a hydrophobic region within the N terminus of Panx1. We further characterize a Panx1 N terminus–recognizing antibody as a function-blocking tool able to prevent large-pore Panx1 activation by STIM1/2. Using either the function-blocking antibody or re-expression of Panx1 deletion mutants in Panx1 knockout (KO) neurons, we show that STIM recruitment couples Ca2+ entry via NMDARs to Panx1 activation, thereby identifying a model of NMDAR-STIM-Panx1 signaling in neurons. Our study highlights a previously unrecognized and important role of the Panx1 N terminus in regulating channel activation and membrane localization. Considering past work demonstrating an intimate functional relation between NMDARs and Panx1, our study opens avenues for understanding activation modality and context-specific functions of Panx1, including functions linked to diverse STIM-regulated cellular responses.Glutamatergic signaling plays a critical role in diverse processes linked to learning and memory formation. Ca2+ signals generated by the N-methyl D-aspartate (NMDA) subtype of glutamate receptors (NMDARs) are indispensable for several forms of synaptic plasticity, including long-term potentiation (LTP), a prototypic form of plasticity linked to memory formation (1–3). NMDAR-initiated Ca2+ signals (e.g., time course, amplitude, and spatial spread) are shaped by secondary events, including those engendered via the endoplasmic reticulum (ER) (4, 5). Ca2+ entry via NMDARs can promote Ca2+-induced Ca2+ release from ER stores by stimulating ryanodine (RyRs) (6–8) and/or IP3 receptors (IP3Rs) (9). In turn, NMDAR-initiated Ca2+ store depletion recruits ER-resident and Ca2+-sensing STIM proteins (10) to negatively regulate L-type voltage-gated Ca2+ channels (VGCCs) (13). This establishes the notion that Ca2+ entry via NMDARs can stimulate ER- and STIM-dependent cascades that regulate secondary routes of Ca2+ entry, thereby sculpting intracellular Ca2+ dynamics and in turn the cellular functions influenced by them. As part of a broader search to identify candidate Ca2+ channels able to respond to ER signaling dynamics, we found that Pannexin-1 (Panx1) can be activated through ER-based signaling following sarcoendoplasmic reticulum calcium adenosine triphosphatase (ATPase) (SERCA) pump inhibition by thapsigargin. This led us to consider the role of STIM1/2 as a candidate Panx1 activation mechanism.Panx1 is a large-pore nonselective ion and solute permeable channel with prominent central nervous system (CNS) expression (14, 15). Panx1 activation has been linked to pathophysiological disorders, such as excitotoxicity, stroke, migraine, chronic pain, and epilepsy (16–18). However, Panx1 also mediates physiological processes in the CNS, including contributions to neural development (19, 20), spine formation (21, 22), and NMDAR-dependent synaptic plasticity (23, 24). In this context, there remains an important gap in understanding the mechanisms by which Panx1 can mediate such disparate physiological and pathological functions. Intriguingly, evidence suggests that Panx1 ion versus solute permeability may be mediated by distinct channel pore configurations (i.e., small anion vs. large solute permeable) recruited via distinct activation modalities (25). Thus, identifying novel activation mechanisms is fundamental to understanding context- and modality-specific channel function.Here, we uncover a mechanism by which Panx1 is activated in response to ER-initiated signaling, which we demonstrate is dependent on Panx1 interaction with ER-resident STIM1/2. STIM1/2 recruitment and activation stimulates large-pore Panx1 opening, evident on the basis of increased permeability to Ca2+ and the large inorganic ion N-methyl-D-glucamine (NMDG). We map the STIM1/2 binding interface to a hydrophobic region in the N terminus of Panx1, a region not previously linked to channel gating. Our detailed structure-function analysis reveals that the Panx1 N-terminal region is necessary for its STIM1/2 responsiveness, but not for its responsiveness to hypotonic stress, demonstrating that this region mediates modality-specific regulation of Panx1 function. Using reverse genetics, ectopic rescue with Panx1 N-terminal deletion mutants, as well as a function inhibiting antibody targeting the critical N-terminal region of Panx1 identified by us, we demonstrate that NMDARs activate Panx1 in hippocampal neurons in a manner contingent upon ER-initiated signaling and reliant upon STIM proteins. Collectively, our data reveal the molecular mechanism by which STIM1/2 activates Panx1 and establishes a previously unrecognized essential role of its N-terminal region in regulating the transition of Panx1 to its large-pore solute permeable state. Our work will benefit studies aimed at understanding diverse functions of Panx1, including those linked to NMDAR-dependent signaling, stimulated in a modality- and context-specific manner by STIM proteins. 相似文献