自噬相关通路在糖尿病心肌病中的研究进展

糖尿病心肌病定义为无冠状动脉疾病和高血压的糖尿病患者发生的心肌功能障碍。据报道,糖尿病心肌病的发病机制与炎症、心肌纤维化、线粒体损伤、心肌细胞凋亡、自噬等因素相关。自噬是维持细胞器功能和细胞内营养环境的关键因素,也参与了系统的代谢稳态,这对于维持心脏功能和活性具有重要作用,其调节失调可能造成心肌细胞损伤。自噬相关信号通路包括m TOR信号通路及Beclin-1信号通路。糖尿病心肌病中自噬的影响因素包括高糖血症、游离脂肪酸过度积累、氧化应激、胰岛素抵抗、内质网应激等,该文就自噬相关通路在糖尿病心肌病发病机制中的研究进展进行综述。     

内质网自噬——疾病防治的新靶标

内质网自噬是指内质网功能发生改变时,细胞激活选择性自噬以清除细胞内受损的内质网或内质网片段的过程。其主要的功能是改善细胞内环境,起细胞保护作用。内质网自噬作为选择性自噬研究的新领域,与细胞中其他类型的选择性自噬和细胞凋亡之间关系密切,在疾病发生发展中有重要作用。该文综述了内质网自噬的形成过程,细胞内调控方式,与其他选择性自噬间的相互作用,并阐述了内质网自噬参与糖尿病、神经退行性疾病和肾脏疾病等多种疾病的发生发展,逐步成为疾病防治的新靶标。     

非酒精性脂肪肝与钙稳态关系的研究进展

钙离子（Ca²⁺）是细胞内重要的第二信使,其主要储存在内质网和线粒体中,参与调控细胞多种生理功能及维持内质网、线粒体功能。内质网和线粒体对钙离子的摄取与释放直接影响胞内钙离子水平的变化,继而影响细胞正常生理功能。病理条件下,细胞内钙离子稳态失衡,可引发细胞生理功能异常并进一步影响内质网、线粒体功能。非酒精性脂肪肝（NAFLD）是临床常见病和多发病,其主要病理特征是：肝脏脂肪样变性、内质网应激、线粒体损伤和非特异性炎性反应等。其中持续的内质网应激及线粒体功能障碍是NAFLD发生发展的重要诱因。而细胞内钙稳态的变化可直接导致内质网及线粒体功能异常,继而影响NAFLD的发生发展。本文主要从钙稳态的主要影响因素以及钙稳态变化与NAFLD的关系两方面进行阐述,为寻求和研发防治NAFLD的药物提供新的方向。     

SIRT1在糖尿病心肌病发病中的研究进展

糖尿病心肌病(DCM)是糖尿病患者的一种严重的心血管并发症。去乙酰化酶沉默信息调节因子2同源物1(SIRT1)作为机体重要的细胞内调控蛋白,在许多生物过程中发挥重要作用,包括减轻心肌细胞氧化应激、维持心肌线粒体Ca²⁺稳态、降低心肌内质网应激、改善心肌线粒体功能障碍以及抑制机体肾素-血管紧张素-醛固酮系统的活化等,可能是DCM的潜在治疗靶点,靶向SIRT1进行深入研究能够为DCM的临床治疗提供新的理论依据。就SIRT1在DCM的发病机制中的具体作用及治疗策略进行综述。     

内质网应激与代谢性疾病

内质网是真核细胞内合成代谢的重要场所,细胞内稳态改变可引起内质网应激.适宜的内质网应激有利于细胞内环境的恢复,过度的应激则导致代谢障碍.内质网应激介导的炎症通路及细胞凋亡通路改变与细胞的生长、分化、存活及凋亡有密切联系,在代谢性疾病发生发展过程中起重要作用.维持适当的应激状态,减少过度应激有利于代谢性疾病的恢复,内质网应激为进一步认识和治疗代谢性疾病提供了新的视野和思路.     

糖尿病认知功能障碍的机制及中药干预研究进展

糖尿病认知功能障碍(DCD)是糖尿病患者常见的慢性并发症。DCD的发病机制复杂,尚未完全阐明,其中代谢异常、胰岛素抵抗、内质网应激、神经元钙稳态失衡、炎症反应、血脑屏障损伤、线粒体损伤等均参与其中,共同组成了复杂而相互关联的发病机制。近年来,中药在改善DCD方面取得了较大的进展。该文对DCD的发病机制以及中药在治疗和预防DCD的研究进展予以综述。     

内质网应激相关细胞自噬与心肌缺血再灌注损伤的研究现状

自噬是细胞对自身长寿命蛋白、冗余蛋白或破坏的细胞器进行降解并再利用的过程。内质网应激是细胞的一种适应性机制,通过未折叠蛋白反应等细胞活动来维持内质网的稳态。这两者都具有双刃剑的作用:即适度的激活可以保护细胞;但过度激活则导致细胞死亡。内质网应激可以诱导细胞自噬,且与心肌缺血再灌注损伤关系密切。本文对内质网应激相关自噬在心肌缺血再灌注损伤中的作用机制及研究进展进行综述。     

内质网应激和自噬在骨骼肌再生中的作用研究进展

骨骼肌卫星细胞(muscle satellite/stem cells, MuSCs)介导的再生和修复对骨骼肌损伤后完整肌肉功能的恢复至关重要。在多种病理生理过程中,内质网应激(endoplasmic reticulum stress, ERS)诱导的未折叠蛋白质反应(unfolded protein response, UPR)和自噬能够清除积累的错误折叠的蛋白质,是细胞维持稳态的重要机制。近年来,越来越多的研究发现在骨骼肌再生过程中内质网应激和自噬被激活,且在肌再生过程中发挥重要的调控作用,对损伤后肌肉的修复至关重要。本文主要针对近年来内质网应激和自噬在肌再生过程中的作用的研究进展做一综述,旨在为研发以内质网应激和自噬为靶点改善骨骼肌再生的药物提供理论依据。     

硫氧还蛋白相互作用蛋白介导胰岛β细胞凋亡及功能障碍研究进展

硫氧还蛋白相互作用蛋白(TXNIP)不仅与细胞的氧化还原状态密切相关,在胰岛β细胞功能障碍和细胞凋亡中也扮演了重要角色。高糖通过招募碳水化合物反应元件结合蛋白(ChREBP)到TXNIP的启动子,ChREBP与组蛋白乙酰转移酶p300相互作用,引起TXNIP的转录,TXNIP介导高糖诱发的氧化应激、内质网应激、NOD样受体3炎症小体激活、凋亡和自噬障碍等。可通过诱导微小RNA-204的表达下调鸟类Maf A蛋白哺乳动物同系物而抑制胰岛素基因转录,抑制胰岛素信号转导途径,进而抑制葡萄糖刺激的胰岛素分泌;TXNIP通过抑制硫氧还蛋白系统影响细胞的生存,同时还是介导细胞线粒体凋亡和内质网应激凋亡途径的枢纽分子。抑制TXNIP可能是一个阻止糖尿病进程的有效靶点。本文就TXNIP在胰岛细胞凋亡和胰岛功能障碍方面的相关研究进行回顾和总结分析。     

内质网应激在心室重构中作用的研究进展

内质网是真核细胞的重要细胞器,是蛋白折叠与成熟的加工厂。内质网应激是细胞针对错误折叠或未折叠蛋白质的一种适应性机制,但持续或过强的内质网应激则诱导细胞凋亡与自噬失衡,造成组织损伤。研究显示内质网应激是冠状动脉粥样硬化性心脏病、缺血性心脏病、心力衰竭及糖尿病心肌病等心血管疾病发生、发展的共同通路,可诱导心肌细胞肥大、纤维化、凋亡,致使心室重构的发生。故调控内质网应激可能成为预防心室重构进而治疗相关心血管疾病的新靶点。     

Cytoprotective effects of xanthohumol against methylglyoxal‐induced cytotoxicity in MC3T3‐E1 osteoblastic cells

Methylglyoxal (MG) has been suggested to be a major source of intracellular reactive carbonyl compounds, and has been implicated in increasing the levels of advanced glycation end products in age‐related diseases. Xanthohumol is a prenylated flavonoid found in hops (Humulus lupulus) and beer. In the present study, we investigated the effects of xanthohumol on MG‐induced cytotoxicity in osteoblastic MC3T3‐E1 cells. Xanthohumol attenuated MG‐induced cytotoxicity, as evidenced by improved cell viability, and prevented MG‐induced MG‐protein adducts, inflammatory cytokines, reactive oxygen species and mitochondrial superoxide production. In addition, xanthohumol increased glyoxalase I activity, glutathione, heme oxygenase‐1 and nuclear factor erythroid 2‐related factor 2 levels in the presence of MG. Pretreatment with xanthohumol before MG exposure reduced MG‐induced mitochondrial dysfunction. Furthermore, xanthohumol treatment resulted in a significant reduction in the levels of endoplasmic reticulum stress and autophagy induced by MG. Notably, the autophagy‐reducing effect of xanthohumol was abolished after the addition of Ex527, a selective inhibitor of sirtuin 1, suggesting that xanthohumol is an effective sirtuin 1 activator for reducing autophagy. Taken together, our findings suggest xanthohumol as a promising new strategy for preventing diabetic osteopathy.     

Toxic effects and involved molecular pathways of nanoparticles on cells and subcellular organelles

Owing to the increasing application of engineered nanoparticles (NPs), besides the workplace, human beings are also exposed to NPs from nanoproducts through the skin, respiratory tract, digestive tract and vein injection. This review states pathways of cellular uptake, subcellular distribution and excretion of NPs. The uptake pathways commonly include phagocytosis, micropinocytosis, clathrin- and caveolae-mediated endocytosis, scavenger receptor-related pathway, clathrin- or caveolae-independent pathway, and direct penetration or insertion. Then the ability of NPs to decrease cell viability and metabolic activity, change cell morphology, and destroy cell membrane, cytoskeleton and cell function was presented. In addition, the lowest dose decreasing cell metabolic viability compared with the control or IC₅₀ of silver, titanium dioxide, zinc oxide, carbon black, carbon nanotubes, silica, silicon NPs and cadmium telluride quantum dots to some cell lines was gathered. Next, this review attempts to increase our understanding of NP-caused adverse effects on organelles, which have implications in mitochondrial dysfunction, endoplasmic reticulum stress and lysosomal rupture. In particular, the disturbance of mitochondrial biogenesis and mitochondrial dynamic fusion-fission, mitophagy and cytochrome c-dependent apoptosis are involved. In addition, prolonged endoplasmic reticulum stress will result in apoptosis. Rupture of the lysosomal membrane was associated with inflammation, and both induction of autophagy and blockade of autophagic flow can result in cytotoxicity. Finally, the network mechanism of the combined action of multiple organelle dysfunction, apoptosis, autophagy and oxidative stress was discussed.     

Mitochondrial dysfunction in bipolar disorder]

Phosphorus magnetic resonance spectroscopic studies in bipolar disorder revealed altered brain energy metabolism resembling that of chronic progressive external ophthalmoplegia (CPEO). Mood disorder is one characteristic symptom in several families of CPEO caused by mutations of three genes, ANT1, Twinkle, and POLG. Molecular genetic analysis revealed association of bipolar disorder with mitochondrial DNA (mtDNA) 10398A polymorphism, 3644C mutation, and FDUFV2. In the postmortem brains, increased levels of mtDNA 4977bp deletion and 3243G mutation, and altered expression of mitochondria-related genes were reported. Mitochondria play an important role in neuroplasticity and apoptotic signaling via regulating intracellular calcium homeostasis. Thus, mitochondrial dysfunction may cause altered calcium homeostasis and neuroplasticity, resulting in bipolar disorder. Most molecular genetic findings in bipolar disorder regarding mitochondria and endoplasmic reticulum stress signaling are common to Parkinson's disease and diabetes mellitus. Thus, it is possible that bipolar disorder is also a disease caused by the progressive loss of some neuronal cells.     

The research advances in the mechanism of manganese-induced neurotoxicity

Manganese is an indispensable trace element in the growing process of living creature. However, long-term manganese exposure can cause different levels of damage to multiple organs or systems in the body. It can also cause irreversible damage to the nervous system, causing dysfunction of mental and extrapyramidal system. The exact neurotoxic mechanism of manganese is not yet clear, and this brings difficulties to the early prevention and cure of manganese poisoning. The present research progress of the neurotoxic mechanisms induced by manganese is summarized from the aspects of mitochondrial damage, autophagy, endoplasmic reticulum stress, inflammatory stimulation and neurotransmitter metabolism.     

自噬在药物性肝损伤中的作用研究进展

药物性肝损伤(DILI)是临床上最为常见的一类药源性病变,可导致急性肝衰竭,严重时可造成肝硬化、肝癌甚至死亡.近年来,DILI的发生率呈逐年增加的趋势,成为药物研发失败和已上市药物被撤市的重要原因.自噬是细胞内蛋白质和受损细胞器进行清除的过程,对细胞稳态、质量与数量乃至存活与死亡等调控有着十分重要的意义.越来越多研究表...     

Role of autophagy in the progression from obesity to diabetes and in the control of energy balance

Autophagy plays a crucial role in cellular homeostasis through the degradation and recycling of organelles such as mitochondria or endoplasmic reticulum (ER) that are closely related to the pathogenesis of diabetes. In pancreatic β-cells producing insulin, autophagy helps maintain β-cell mass, structure and function. In mice with β-cell-specific deletion of Atg7 (autophagy-related 7), a critical autophagy gene, reduction of β-cell mass and pancreatic insulin content were observed together with impaired insulin secretory function. Because of such structural and functional defects, β-cell-specific Atg7-null mice showed hypoinsulinemia and hyperglycemia. However, those mice never developed diabetes. Obesity and lipids are physiological ER stressors that can precipitate β-cell dysfunction and insulin resistance. Recent studies showed that β-cell-specific Atg7-null mice, when bred with ob/ob mice, developed severe diabetes, suggesting that autophagy-deficient β-cells can handle basal metabolic stress but have problems dealing with increased metabolic stress. Thus, autophagy deficiency in β-cells could be a factor in the progression from obesity to diabetes due to an inappropriate response to obesity-induced ER stress. Autophagy also appears to play a role in the hypothalamic control of energy expenditure, appetite and body weight. Thus, autophagy is important to body and nutrient metabolism in many ways, and its dysregulation could contribute to the pathogenesis of metabolic disorders and diabetes.     

Genetics of bipolar disorder

Many linkage loci and candidate genes have been reported in molecular genetic studies of bipolar disorder. However, none of these findings have been consistently replicated. Meta-analyses of linkage studies have also reported conflicting results. Among recently reported candidate genes, BDNF, G72, AKT1, GRIN2A, XBP1, GRK3, HTR4, IMPA2 and GABRA1 may have some importance. Study of the possible roles of epigenetics or analysis of genetic diseases, in which bipolar disorder is one of phenotypes, may also be promising. In addition to monoaminergic and intracellular signaling pathways, recent studies have revealed possible roles for mitochondrial dysfunction, for glutamatergic dysfunction and for the endoplasmic reticulum stress pathway.     

Tributyltin induces apoptotic signaling in hepatocytes through pathways involving the endoplasmic reticulum and mitochondria

Tri-n-butyltin is a widespread environmental toxicant, which accumulates in the liver. This study investigates whether tri-n-butyltin induces pro-apoptotic signaling in rat liver hepatocytes through pathways involving the endoplasmic reticulum and mitochondria. Tri-n-butyltin activated the endoplasmic reticulum pathway of apoptosis, which was demonstrated by the activation of the protease calpain, its translocation to the plasma membrane, followed by cleavage of the calpain substrates, cytoskeletal protein vinculin, and caspase-12. Caspase-12 is localized to the cytoplasmic side of the endoplasmic reticulum and is involved in apoptosis mediated by the endoplasmic reticulum. Tri-n-butyltin also caused translocation of the pro-apoptotic proteins Bax and Bad from the cytosol to mitochondria, as well as changes in mitochondrial membrane permeability, events which can activate the mitochondrial death pathway. Tri-n-butyltin induced downstream apoptotic events in rat hepatocytes at the nuclear level, detected by chromatin condensation and by confocal microscopy using acridine orange. We investigated whether the tri-n-butyltin-induced pro-apoptotic events in hepatocytes could be linked to perturbation of intracellular calcium homeostasis, using confocal microscopy. Tri-n-butyltin caused changes in intracellular calcium distribution, which were similar to those induced by thapsigargin. Calcium was released from a subcellular compartment, which is likely to be the endoplasmic reticulum, into the cytosol. Cytosolic acidification, which is known to trigger apoptosis, also occurred and involved the Cl(-)/HCO(3)(-) exchanger. Pro-apoptotic events in hepatocytes were inhibited by the calcium chelator, Bapta-AM, and by a calpain inhibitor, which suggests that changes in intracellular calcium homeostasis are involved in tri-n-butyltin-induced apoptotic signaling in rat hepatocytes.     

Synergism between staurosporine and drugs inducing endoplasmic reticulum stress

Drugs causing endoplasmic reticulum or mitochondrial dysfunction may trigger apoptosis in eukaryotic cells. The thiol reagent dithiothreitol (DTT) belongs to the first group whereas the protein kinases inhibitor staurosporine acts on mitochondria. Since the endoplasmic reticulum and the mitochondrial pathways of apoptosis may converge in common steps, we examined the possibility of synergism between these two drugs. Using the activation of caspase-3 as indicator of apoptosis, we found that in two cell lines, Jurkat and Mono-Mac 6, staurosporine and DTT elicited apoptosis with a different pattern: staurosporine acted rapidly and at nanomolar concentrations while DTT acted slowly and at higher concentrations (1mM). When staurosporine and DTT were combined, the proapoptotic action was increased. This was confirmed examining late apoptotic events such as the translocation of phosphatidylserine across the plasma membrane and the cleavage of the antiapoptotic protein Mcl-1. The use of subthreshold DTT concentrations and isobologram analysis demonstrated the synergic nature of the interaction. Tunicamycin, a drug that, like DTT, inhibits protein folding in the endoplasmic reticulum also increased the proapoptotic effect of staurosporine. In agreement with the interplay between the mitochondrial and the endoplasmic reticulum pathways it was found that both staurosporine and DTT induced cytochrome c release. Furthermore, 90min incubation with DTT did not induce caspase-4 activation while staurosporine alone or in combination with DTT stimulated caspase-4 activity. We conclude that staurosporine is more active in cells undergoing endoplasmic reticulum stress. This synergism may warrant evaluation to establish whether the anticancer activity of staurosporine is also enhanced.