镁的内稳态及其与心血管疾病相关性的研究进展

镁是生物体中维持细胞正常生命活动不可缺少的电解质。镁离子(Mg²⁺)转运蛋白TRPM6/7、SLC41A1、Mag T1和CNNM2/3/4等在转运镁的过程中发挥着重要作用。Mg²⁺具有改善内皮功能、血管张力、外周血管阻力、心肌代谢、脂质代谢等功能,它还参与氧化应激及炎症反应的调节过程。镁缺乏会增加动脉粥样硬化、心律失常、高血压、2型糖尿病、胰岛素抵抗、代谢综合征等的发生风险。补充镁能降低血压、动脉硬化、空腹血糖、胰岛素抵抗和术后心律失常等的发生。膳食镁摄入增加可以降低心血管疾病和相关代谢病的发生风险。本文主要对Mg²⁺的生物学作用及其与心血管疾病相关性的研究进展进行综述。     

铜死亡与铜载体药物抗肿瘤机制的研究进展

铜参与诸多生命过程,铜稳态失衡会导致细胞死亡,该过程被称为铜死亡。肿瘤细胞为维持更高的细胞活性,铜负荷较高。利用铜载体及相关药物可以参与诱导肿瘤细胞的铜过载,引发肿瘤细胞铜死亡。现针对铜死亡与肿瘤的关系以及铜载体药物的抗肿瘤机制作一综述。     

肿瘤相关蛋白分子核转运机制研究进展

信号分子的核转运是多种信号传导通路的基础。肿瘤的发生和发展常与多种信号蛋白异常的亚细胞定位相关,因此阐明肿瘤相关蛋白的核转运机制对于研究肿瘤的发病机制和开发新的疗法至关重要。本文介绍了核转运系统的基本组成,并对多种重要的肿瘤相关蛋白的核转运机制进行综述。     

基于炎症因子、雌激素及骨稳态的多向调控研究肉桂-熟地黄防治骨质疏松的分子作用机制

本研究整合组方配伍分析、生物信息学和代谢组学探讨肉桂-熟地黄(Cinnamomi Cortex-Rehmanniae Radix, CR)防治骨质疏松(osteoporosis, OP)的分子作用机制。建立大鼠OP模型,进行Micro-CT指标和病理切片综合评价,结果显示与模型组相比, CR干预后的骨密度、骨体积分数等指标显著回调(P <0.05),骨小梁排列成网状。UHPLC-Q-TOF/MS研究结果主要涉及氨基酸代谢、脂类代谢及雌激素代谢途径。整合生物信息学和代谢组学分析,最终发现:(1)肉桂酸、肉桂酸乙酯抑制TNF、IL-1β、IL-13等炎性因子,进而防治OP;(2) CR多个活性成分靶向作用于ESR2、PPARG、CYP19A1、GABRA1等靶点,调节cAMP的合成、AMPK信号通路及脂类代谢,从而调节雌激素水平来防治OP;(3)油酸、花生四烯酸等作用于AR、VDR等靶点,调控HIF-1、AGE-RAGE信号通路,从而调控成骨、破骨细胞,影响钙磷吸收,维持骨稳态。本研究从炎症因子、雌激素及骨稳态多向调控的角度阐明了CR防治OP的分子机制,为CR的临床应用及复方开发提供...     

调控蛋白质稳态的抗肿瘤新靶点和新策略研究进展

蛋白质稳态失调与恶性肿瘤等多种重大疾病密切相关。造成蛋白质稳态失调的原因包括蛋白质合成改变、蛋白质折叠与翻译后修饰异常、泛素-蛋白酶体系统或自噬-溶酶体系统等蛋白质降解途径紊乱等。近年来,大量研究表明蛋白质稳态失调可引起内质网应激及线粒体等重要细胞器功能异常,并导致促癌蛋白异常累积或抑癌蛋白过度降解,进而促进肿瘤发生发展。鉴于蛋白质稳态非常广泛地涉及肿瘤恶性演进的各个阶段,因此基于蛋白质稳态调控的关键机制或重要功能蛋白发展的靶向干预策略,是重要的抗肿瘤药物研发思路。其中靶向蛋白酶体、E3泛素连接酶的药物已成功上市用于多发性骨髓瘤等恶性肿瘤的治疗,而一系列蛋白降解技术如蛋白水解靶向嵌合体（proteolysis-targeting chimera,PROTAC）、溶酶体靶向嵌合体（lysosome-targeting chimera,LYTAC）等也已成为具有前景的新兴抗肿瘤策略。综述围绕蛋白质稳态调控领域,总结了一系列抗肿瘤靶点和策略的研究进展以及目前已上市或处于临床研究阶段的（候选）药物、靶点和适应证,为深入了解和认识蛋白质稳态调控机制,进一步拓展其在肿瘤治疗中的应用提供思路和参考。     

高原低氧诱导肠稳态失衡的分子机制及中药防治研究进展

低氧是限制人群在高原生存的因素之一,能够引起呕吐腹泻、心慌气短、急性昏迷等症状。患有急性高原病的人约80%至少有一种胃肠道不适的症状,如厌食、恶心、腹泻、呕吐等。研究高原低氧所致肠损伤的病理特点、发病机制及药物防治,有利于高原胃肠道疾病的诊治。因此,本文通过总结相关文献,就高原低氧造成肠道损伤的相关研究进行系统阐述,对高原低氧造成肠道形态学、肠道细胞、肠道菌群等肠稳态的改变,引起肠道炎症、氧化损伤等机制及中药防治进行总结,以期为科研工作者和临床工作者提供借鉴及信息参考。     

脑组织中水转运的分子机制

脑组织中水的代谢平衡对于其正常功能的维持具有极其重要的意义，近年来研究发现水通道蛋白(aquaporin，AQP)和一些离子转运体广泛分布于脑组织，在水的代谢调节过程中发挥了不可忽视的作用。因而，研究脑组织中分布的多种AQP(AQP1，AQP3，AQP4，AQP5，AQP8，AQP9)以及离子转运体的生理功能及调节机制，对揭示脑组织水代谢障碍疾病的病理机制有重要意义，可为临床治疗和新药开发提供理论基础。     

铁转运平衡在“铁-炎”稳态偶联中的研究进展及治疗探讨

铁稳态与炎症稳态具有明确的偶联关系,是机体内环境稳态调节的整合功能单元。通过对细胞内外铁的摄取-释放进行双向调节和跨膜浓度动态管理,“铁转运平衡”成为维系铁稳态的关键机制,更是炎症“促进-消散”平衡的生理基础。病理状态下,以炎症性肠病等疾病为代表,铁转运平衡贯穿炎症“诱发-进展-治疗”的全链条,是疾病炎症微环境复稳的根本前提和有效途径。巨噬细胞是炎症“促-消”稳态的核心调节细胞且密切参与铁转运平衡,是“铁-炎”稳态的重要偶联环节。目前,基于铁转运平衡理论的转化应用明显不足,特别是基于“铁-炎”稳态偶联的药物干预策略无法同时维持二者稳态,显示出较高的复杂性,且尚未得到合理发掘。本综述拟聚焦于巨噬细胞,通过文献挖掘,以表型极化等免疫学过程为窗口,总结、梳理铁转运平衡的理论研究进展;探求、展望基于铁转运平衡进行炎症干预的治疗价值。本综述以铁转运平衡为切入点,将为炎症性肠病、动脉粥样硬化等疾病的药物研发提供必要的知识准备和有益的研究提示。     

生物钟系统调控机体代谢的分子机制及中药干预研究进展

昼夜节律是生物体适应外界环境的昼夜周期性变化的一种内在调控机制,在机体的代谢过程中具有重要的作用,通过参与机体内多个器官的代谢途径来达到调控机体稳态的作用。当饮食时间、作息颠倒、睡眠障碍等外源性因素引起机体的昼夜节律发生紊乱时,机体发生代谢综合征的风险明显提高。本文旨在阐述昼夜节律与机体代谢之间的关系,并总结消化系统、肝脏系统、肾脏系统和胆汁酸的昼夜节律调节分子机制,综述中药干预昼夜节律的研究进展,为后续昼夜节律的中药研究和分子机制研究提供合理的、有价值的参考依据。     

MicroRNA对药物转运蛋白和代谢酶中的调控研究

微小RNA（miRNA）是一类内源性长18～25个核苷酸的非编码小RNA分子,在进化过程中具有高度保守性,在转录后水平调控基因的表达,从而在生物过程中发挥重要的作用。生物信息学分析表明人类全部基因的1/3都受到miRNA的调控。目前的研究表明,miRNA广泛调控机体各种生理和病理过程,可能是药物个体差异的原因,在将来可作为个体化给药分子标志物或指导新药开发。     

Apelin在能量平衡中的作用

新发现的生物活性肽apelin是APJ受体的天然配体,广泛分布于中枢系统和外周组织。研究表明apelin具有广泛的生理作用。该文总结了近几年来关于apelin在摄食、消化、体液平衡、肥胖和糖代谢等方面所取得的最新进展,并结合本实验室的工作,提出了今后的发展趋势。     

The disruption of mitochondrial metabolism and ion homeostasis in chicken hearts exposed to manganese

Exposure to high levels of manganese (Mn) can result in cardiotoxicity in animals. However, little is known about the effect of excess Mn on poultry hearts. The aim of this study was to investigate the effect of dietary Mn on chicken cardiac injuries and the possible mechanisms of this process. In the present study, 400 fifty-day-old Hy-line brown cocks were randomly divided into four groups, and were fed either a commercial diet (containing 100 mg/kg Mn) or a Mn-supplemented diet containing 600 mg/kg, 900 mg/kg, or 1800 mg/kg Mn for 30, 60 or 90 days, respectively. Next, we examined several biomarkers of cardiac injury, including biochemical blood serum analyses, electrocardiogram assays, histological analyses, ultra-structural assays and apoptosis assays. To investigate the possible mechanisms of Mn-induced cardiotoxicity, we examined the effect of MnCl₂ on mitochondrial function and metal ion homeostasis. We found that subchronic MnCl₂ exposure induced damage in chicken hearts. Further investigations indicated that possible mechanisms for Mn-induced chicken cardiac injury included the disruption of mitochondrial metabolism and the alteration of ion homeostasis.     

血管壁稳态促进机制与动脉粥样硬化

脂质经渗漏或有缺陷的血管内皮沉积,在血管壁上是动脉粥样硬化的始动过程.机体通过三大防御机制:内皮祖细胞修复内皮,血管新生,高密度脂蛋白抑制机制,以减少对血管壁的侵害和促进血管壁功能的恢复,维持血管壁内环境稳态.     

The effect of antidepressants on glucose homeostasis and insulin sensitivity: synthesis and mechanisms

Objective: To synthesise results from investigations reporting on the effect of antidepressants on glucose–insulin homeostasis. Method: The authors conducted a MedLine search of all English language articles from 1966 to October 2005 using the keywords: bipolar disorder, major depressive disorder, diabetes mellitus, glucose homeostasis, and the name of each antidepressant that has been indicated for major depression in Canada and the US up to October 2005. The search was supplemented with a manual review of relevant references. Both preclinical and clinical investigations were reviewed. Results: Some serotonergic antidepressants (e.g., fluoxetine) reduce hyperglycaemia, normalise glucose homeostasis and increase insulin sensitivity, whereas some noradrenergic antidepressants (e.g., desipramine) exert opposite effects. Dual-mechanism antidepressants (e.g., duloxetine and venlafaxine) do not appear to disrupt glucose homeostatic dynamics, whereas nonselective hydrazine monoamine oxidase inhibitors (e.g., phenelzine) are associated with hypoglycaemia and an increased glucose disposal rate. Conclusion: Some antidepressants exert a clinically significant effect on metabolism relevant to both therapeutic outcome and adverse events.     

The combined effect of furosemide and propranolol on GSH homeostasis in ACHN renal cells

Objectives: Propranolol, a beta-adrenergic blocker, is used in the treatment of a large number of cardiovascular diseases such as hypertension and arrhythmias. Propranolol, in combination with furosemide, is used to treat hypertensive disorders although their side effect profile is not very obvious. In present study, the effects of the drugs furosemide and propranolol were in corporately investigated both on glutathione homeostasis and their antioxidant effect on ACHN cells.

Methods: The cytoxicities and antioxidant effects of these two clinically important drugs on human kidney cell lines were evaluated using MTT following by the determination of glutathione reductase (GR) and glutathione peroxidase (GPx) activities and measuring the level of reduced glutathione (GSH).

Results: Propranolol induced a significant cytotoxic effect at 100?µM, while furosemide was cytotoxic at doses of 250 and 1000?µg/ml. A slight increase in GPx and GR activities and GSH level was observed with propranolol and furosemide treatment alone, while the two drugs together caused a significant increase in GPx and GR activities (35% and 42%, respectively) and GSH content (35%) in ACHN cell lysates (p?Conclusions: Our results demonstrate that although high doses of furosemide and propranolol are cytotoxic, co-administration of low doses may improve the antioxidant defense in patients undergoing treatment with these two important drugs.     

Molecular mechanisms of deguelin-induced apoptosis in transformed human bronchial epithelial cells

Increasing evidence has demonstrated that the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway plays an important role in cell proliferation, apoptosis, angiogenesis, adhesion, invasion, and migration, functions that are critical to cancer cell survival and metastasis. Increased expression of activated Akt has been observed in the early stages of tobacco-induced lung carcinogenesis. Moreover, blocking the PI3K/Akt pathway specifically inhibits the proliferation of non-small cell lung cancer (NSCLC) cells, indicating that the PI3K/Akt pathway is a potential target for chemoprevention and therapy in lung cancer. The aim of this work is to study the lung cancer chemopreventive potential of PI3K/Akt inhibitors using an in vitro lung carcinogenesis model. We found that genetic or pharmacologic approaches targeting the PI3K/Akt pathway inhibited the proliferation of premalignant and malignant human bronchial epithelial (HBE) cells. After screening several natural products to identify a potential lung cancer chemopreventive agent, we have found that deguelin, a rotenoid isolated from Mundulea sericea (Leguminosae), specifically inhibits the growth of transformed HBE and NSCLC cells by inducing cell-cycle arrest in the G2/M phase and apoptosis, with no detectable toxic effects on normal HBE cells, most likely due to the agent's ability to inhibit PI3K/Akt-mediated signaling pathways. The specific sensitivity of premalignant and malignant HBE and NSCLC cells to deguelin suggests that this drug could be clinically useful for chemoprevention in early-stage lung carcinogenesis and for therapy in confirmed lung cancer.     

镉诱导HEK293细胞胞内钙稳态的失调引发细胞凋亡

目的　研究镉诱导HEK2 93细胞钙稳态失调及其引发细胞凋亡的机制。方法　通过吖啶橙 /溴乙锭双荧光染色法检测细胞凋亡 ,并通过MTT法检测细胞生长抑制 ;以Fluo 3/AM和Fura 2 /AM为探针检测胞浆内游离钙离子浓度 ([Ca2 +]i)的变化 ;使用钙调磷酸酶试剂盒测定镉对钙调磷酸酶活性的影响。结果　镉诱导HEK2 93细胞的凋亡和生长抑制呈浓度依赖性 ;镉通过引发胞内钙库的释放后引起胞外钙离子内流 ;钙信号阻断剂能显著地抑制镉引起的细胞凋亡 ;镉使胞内钙调磷酸酶的活性显著增加。结论　 [Ca2 +]i 升高使钙调磷酸酶活化可能在镉引发细胞凋亡过程中起重要作用。     

Molecular mechanisms of polyamine analogs in cancer cells

The natural polyamines are aliphatic cations with multiple functions and are essential for cell growth. Soon after the critical requirement of polyamines for cell proliferation was recognized, the metabolism of polyamines was pursued as a target for antineoplastic therapy. Initially, much attention was focused on the development of inhibitors of polyamine biosynthesis as a means to inhibit tumor growth. The best-characterized inhibitor is alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase. While compensatory mechanisms in polyamine metabolism reduce the effectiveness of DFMO as a single chemotherapeutic agent, it is currently undergoing extensive testing and clinical trials for chemoprevention and other diseases. There has been increasing interest over the last two decades in the cytotoxic response to agents that target the regulation of polyamine metabolism rather than directly inhibiting the metabolic enzymes in tumor cells. This interest resulted in the development of a number of polyamine analogs that exhibit effective cytotoxicity against tumor growth in preclinical models. The analogs enter cells through a selective polyamine transport system and can be either polyamine antimetabolites that deplete the intracellular polyamines or polyamine mimetics that displace the natural polyamines from binding sites, but do not substitute in terms of growth-promoting function. Synthesis of the first generation of symmetrically substituted bis(alkyl)polyamine analogs in the mid-1980s was based on the theory that polyamines may utilize feedback mechanisms to auto-regulate their synthesis. In the 1990s, unsymmetrically substituted bis(alkyl) polyamine analogs were developed. These compounds display structure-dependent and cell type-specific cellular effects and regulation on polyamine metabolism. More recently, a novel class of analogs has been synthesized, which include conformationally restricted, cyclic and long-chain oligoamine analogs. The development and use of these analogs have provided valuable information for understanding the molecular mechanisms of targeting the polyamine pathway as a means of cancer therapy.