exosome的研究进展

exosome是一种可由多种细胞分泌的纳米量级的膜性小囊泡。经研究后发现,其内含有独特的蛋白质与脂质。这也决定了exosome的生物学功用,如去除细胞生长过程中的废弃蛋白、抗原提呈、信号传导或诱导抗肿瘤免疫反应等。本文就exosome的研究进展做一综述,阐述到目前为止对exosome的生理组成及生物功能的研究成果,并探讨其在生物学应用方面的潜在前景。     

Defects in processing and trafficking of the AE1 Cl<Superscript>−</Superscript>/HCO3<Superscript>−</Superscript> exchanger associated with inherited distal renal tubular acidosis

Distal renal tubular acidosis (dRTA) results from impaired urinary acidification by the renal collecting duct. Acquired dRTA can be secondary to diverse pathological processes, including diabetic, ischemic, fibrosing, or immunological processes; less frequently it presents as a familial disorder with either an autosomal recessive or dominant pattern of transmission. Mutations in the SLC4A1/AE1/band 3 Cl^?/HCO₃ ^? exchanger gene have been identified as causes for both dominant and recessive forms of dRTA. These mutations comprise a group almost entirely distinct from the SLC4A1 mutations that underlie the familial hemolytic anemia of hereditary spherocytosis. Why does one group of mutations express almost exclusively an isolated erythroid phenotype, whereas the second group of mutations expresses almost exclusively a phenotype explicable entirely by defective function of renal collecting duct type A intercalated cells? This review summarizes current research addressing this central question in the pathobiology of inherited dRTA associated with mutations in the SLC4A1 gene. Studying dRTA-associated mutant AE1 polypeptides can provide novel insights into the biology of the intercalated cell and the collecting duct as well as more generally into mechanisms by which epithelial cells generate and maintain functional polarity.     

Pas de deux in groups of four--the biogenesis of KATP channels

The biogenesis of K(ATP) channels provides an interesting example of the assembly of structurally very different membrane protein subunits into a heterooligomeric complex. This review summarizes our current knowledge with respect to the protein domains driving heteromultimeric assembly in the endoplasmic reticulum, quality control, as well as the determinants and kinetics of subcellular sorting of the K(ATP) channel complex. The impact of disease-associated mutations on K(ATP) channel biogenesis is discussed.     

Chronic ethanol-initiated apoptosis in hepatocytes is induced by changes in membrane biogenesis and intracellular transport

The outcome of chronic ethanol consumption recorded in liver by in situ staining of the genomic DNA in fragmented nuclei indicates the course of cellular events that has been coined as apoptosis or programmed cell death. Hence, we designed the study to determine which ethanol-induced modification of the cellular make-up is responsible for the hastening the cell damage. The in vitro assays were performed with cellular organelles and cytosol prepared from hepatocytes derived from rats subjected to 9 weeks of chronic alcohol consumption. The results were compared with the pair-fed controls receiving isocaloric liquid diet. In the initial phase of the studies, we established that the process of apoptosis was not triggered by the aberrant activity of neutral or acidic sphingomyelinase. The hepatocytes derived from alcohol and control diets manifested equal enzymatic activity. The de novo synthesis of sphingoid bases and ceramides in the alcohol-derived sample of endoplasmic reticulum was reduced, but the in situ apoptosis was up to 36-fold higher than in the control. Also, the isolated hepatocytes contained a 2- to 4-fold higher amount of nucleosomal fragments in the cytosolic extracts. The endosomes from liver hepatocytes of ethanol-consuming rats, in the presence of the cytosol and mitochondria from pair-fed controls, disclosed 2 to 3 times higher apoptotic potential than sample consisting of ethanol-derived fractions only, and 3 to 5 times higher than the control-derived fractions. The substantial increase in apoptosis, as recorded in the amount of DNA fragments released to the cytosol from the fresh nuclei, was also recorded when the microsomal membranes of endoplasmic reticulum and Golgi were incubated in the conditions with preserved intracellular transport. The maximal 20-fold increase of apoptotic activity was recorded in the incubation mixtures of ethanol-derived endoplasmic reticulum-Golgi membranes with control-derived cytosol in the presence of the ATP generating system. Results infer that the intracellular transport vesicles, generated from ethanol-modified membranes in the presence of the substrates that are available in the cytosol of the control hepatocytes, activate the apoptotic activity in the in vitro system. This interpretation is supported by the results of analysis of the clathrin-coated transport vesicles that, in contrast to nonclathrin transport vesicles, contain a sizable accumulation of ceramides that are known to induce apoptosis.     

线粒体质量控制系统在脓毒症相关性脑病中作用的研究进展

脓毒症相关性脑病是脓毒症最常见的中枢神经系统并发症,可导致患者远期神经功能异常、预后不良,目前尚无有效的防治策略。线粒体功能障碍是脓毒症相关性脑病的关键病理机制之一,已成为该领域研究热点。线粒体分裂融合、线粒体生物发生、线粒体自噬及线粒体运输等构成了线粒体质量控制系统,进而调节线粒体功能。因此,线粒体质量控制系统在脓毒症相关性脑病发生发展中具有重要作用。本文总结线粒体质量控制系统的主要调控机制及在脓毒症相关性脑病中的研究进展,并探讨线粒体质量控制系统在脓毒症相关性脑病评估和防治中的潜在价值。     

Mitochondrial Targeted Therapies: Where Do We Stand in Mental Disorders?

The neurobiology of psychiatric disorders is still unclear, although changes in multiple neuronal systems, specifically the dopaminergic, glutamatergic, and gamma-aminobutyric acidergic systems as well as abnormalities in synaptic plasticity and neural connectivity, are currently suggested to underlie their pathophysiology. A growing body of evidence suggests multifaceted mitochondrial dysfunction in mental disorders, which is in line with their role in neuronal activity, growth, development, and plasticity. In this review, we describe the main endeavors toward development of treatments that will enhance mitochondrial function and their transition into clinical use in congenital mitochondrial diseases and chronic disorders such as types 1 and 2 diabetes, cardiovascular disorders, and cancer. In addition, we discuss the relevance of mitochondrial targeted treatments to mental disorders and their potential to become a novel therapeutic strategy that will improve the efficiency of the current treatments.     

Short-term caloric restriction,resveratrol, or combined treatment regimens initiated in late-life alter mitochondrial protein expression profiles in a fiber-type specific manner in aged animals

Aging is associated with a loss in muscle known as sarcopenia that is partially attributed to apoptosis. In aging rodents, caloric restriction (CR) increases health and longevity by improving mitochondrial function and the polyphenol resveratrol (RSV) has been reported to have similar benefits. In the present study, we investigated the potential efficacy of using short-term (6 weeks) CR (20%), RSV (50 mg/kg/day), or combined CR + RSV (20% CR and 50 mg/kg/day RSV), initiated at late-life (27 months) to protect muscle against sarcopenia by altering mitochondrial function, biogenesis, content, and apoptotic signaling in both glycolytic white and oxidative red gastrocnemius muscle (WG and RG, respectively) of male Fischer 344 × Brown Norway rats. CR but not RSV attenuated the age-associated loss of muscle mass in both mixed gastrocnemius and soleus muscle, while combined treatment (CR + RSV) paradigms showed a protective effect in the soleus and plantaris muscle (P < 0.05). Sirt1 protein content was increased by 2.6-fold (P < 0.05) in WG but not RG muscle with RSV treatment, while CR or CR + RSV had no effect. PGC-1α levels were higher (2-fold) in the WG from CR-treated animals (P < 0.05) when compared to ad-libitum (AL) animals but no differences were observed in the RG with any treatment. Levels of the anti-apoptotic protein Bcl-2 were significantly higher (1.6-fold) in the WG muscle of RSV and CR + RSV groups compared to AL (P < 0.05) but tended to occur coincident with elevations in the pro-apoptotic protein Bax so that the apoptotic susceptibility as indicated by the Bax to Bcl-2 ratio was unchanged. There were no alterations in DNA fragmentation with any treatment in muscle from older animals. Additionally, mitochondrial respiration measured in permeabilized muscle fibers was unchanged in any treatment group and this paralleled the lack of change in cytochrome c oxidase (COX) activity. These data suggest that short-term moderate CR, RSV, or CR + RSV tended to modestly alter key mitochondrial regulatory and apoptotic signaling pathways in glycolytic muscle and this might contribute to the moderate protective effects against aging-induced muscle loss observed in this study.     

THE MICROBIAL BIOGENESIS OF AQUATIC BIOTOXINS

The biogenesis of small molecular nonprotein poisons has long been a mystery in the world of biotoxicology. The phylogenetic distribution, molecular structure, evidence of biogenesis, and possible mechanisms involving some of these poisons, such as saxitoxin, tetrodotoxin, ciguatoxin, palytoxin, maitotoxin, and brevitoxin, are briefly discussed.