Autophagy and Digestive Disorders: Advances in Understanding and Therapeutic Approaches

The gastrointestinal (GI) tract is a series of hollow organs that is responsible for the digestion and absorption of ingested foods and the excretion of waste. Any changes in the GI tract can lead to GI disorders. GI disorders are highly prevalent in the population and account for substantial morbidity, mortality, and healthcare utilization. GI disorders can be functional, or organic with structural changes. Functional GI disorders include functional dyspepsia and irritable bowel syndrome. Organic GI disorders include inflammation of the GI tract due to chronic infection, drugs, trauma, and other causes. Recent studies have highlighted a new explanatory mechanism for GI disorders. It has been suggested that autophagy, an intracellular homeostatic mechanism, also plays an important role in the pathogenesis of GI disorders. Autophagy has three primary forms: macroautophagy, microautophagy, and chaperone-mediated autophagy. It may affect intestinal homeostasis, host defense against intestinal pathogens, regulation of the gut microbiota, and innate and adaptive immunity. Drugs targeting autophagy could, therefore, have therapeutic potential for treating GI disorders. In this review, we provide an overview of current understanding regarding the evidence for autophagy in GI diseases and updates on potential treatments, including drugs and complementary and alternative medicines.     

自噬信号通路与心血管疾病的研究进展

自噬是指自噬溶酶体将自身的细胞器分解并回收利用的一种细胞降解过程,广泛存在于机体组织中。在正常情况下,自噬活动水平在维持细胞的稳态和功能中发挥着重要作用;过量或不足的自噬通量水平都可能导致疾病的发生。在本文中,我们讨论了自噬的概念分类以及自噬信号通路的研究进展,并阐述了自噬对心血管疾病的影响。     

Autophagy: a target for therapeutic interventions in myocardial pathophysiology

Background: Autophagy is a major degradative and highly conserved process in eukaryotic cells that is activated by stress signals. This self-cannibalisation is activated as a response to changing environmental conditions, cellular remodelling during development and differentiation, and maintenance of homeostasis. Objective: To review autophagy regarding its process, molecular mechanisms and regulation in mammalian cells, and its role in myocardial pathophysiology. Results/conclusion: Autophagy is a multistep process regulated by diverse, intracellular and/or extracellular signalling complexes and pathways. In the heart, normally, autophagy occurs at low basal levels, where it represents a homeostatic mechanism for the maintenance of cardiac function and morphology. However, in the diseased heart the functional role of the enhanced autophagy is unclear and studies have yielded conflicting results. Recently, it was shown that during myocardial ischemia autophagy promotes survival by maintaining energy homeostasis. Also, rapamycin was demonstrated to prevent cardiac hypertrophy. In heart failure, upregulation of autophagy acts as an adaptive response that protects cells from hemodynamic stress. In addition, sirolimus-eluting stents have been shown to lower re-stenosis rates in patients with coronary artery disease after angioplasty. Thus, this mechanism can become a major target for therapeutic intervention in heart pathophysiology.     

细胞凋亡与自噬在心血管疾病中的作用研究

摘 要细胞凋亡与自噬是普遍存在于各种细胞内的生命现象,广泛参与了机体的生理、病理过程,且二者有着多因子、多通路的相互影响,这种错综复杂的关系贯穿于各种心血管疾病的始终,对多种心血管疾病的发生发展转归起重要作用。现对细胞凋亡与自噬及其相互关系进行梳理,并综述其在心血管疾病中的作用。     

Autophagy and mitophagy in the myocardium: therapeutic potential and concerns

The autophagic-lysosomal degradation pathway is critical for cardiac homeostasis, and defects in this pathway are associated with development of cardiomyopathy. Autophagy is responsible for the normal turnover of organelles and long-lived proteins. Autophagy is also rapidly up-regulated in response to stress, where it rapidly clears dysfunctional organelles and cytotoxic protein aggregates in the cell. Autophagy is also important in clearing dysfunctional mitochondria before they can cause harm to the cell. This quality control mechanism is particularly important in cardiac myocytes, which contain a very high volume of mitochondria. The degradation of proteins and organelles also generates free fatty acids and amino acids, which help maintain energy levels in myocytes during stress conditions. Increases in autophagy have been observed in various cardiovascular diseases, but a major question that remains to be answered is whether enhanced autophagy is an adaptive or maladaptive response to stress. This review discusses the regulation and role of autophagy in the myocardium under baseline conditions and in various aetiologies of heart disease. It also discusses whether this pathway represents a new therapeutic target to treat or prevent cardiovascular disease and the concerns associated with modulating autophagy.

Linked Articles

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8     

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...     

Autophagy in toxicology: self‐consumption in times of stress and plenty

Autophagy is a critical cellular process orchestrating the lysosomal degradation of cellular components in order to maintain cellular homeostasis and respond to cellular stress. A growing research effort over the last decade has proven autophagy to be essential for constitutive protein and organelle turnover, for embryonic/neonatal survival and for cell survival during conditions of environmental stress. Emphasizing its biological importance, dysfunctional autophagy contributes to a diverse set of human diseases. Cellular stress induced by xenobiotic exposure typifies environmental stress, and can result in the induction of autophagy as a cytoprotective mechanism. An increasing number of xenobiotics are notable for their ability to modulate the induction or the rate of autophagy. The role of autophagy in normal cellular homeostasis, the intricate relationship between cellular stress and the induction of autophagy, and the identification of specific xenobiotics capable of modulating autophagy, point to the importance of the autophagic process in toxicology. This review will summarize the importance of autophagy and its role in cellular response to stress, including examples in which consideration of autophagy has contributed to a more complete understanding of toxicant‐perturbed systems. Copyright © 2012 John Wiley & Sons, Ltd.     

细胞自噬：糖尿病发生发展中的积极参与者

糖尿病病因复杂,涉及自身免疫、环境及遗传等多种因素。细胞自噬是一种细胞内分解代谢过程,在维持胰岛细胞内环境稳态中发挥重要作用。自噬通过参与内质网应激、线粒体功能障碍以及炎症反应等过程,影响糖尿病的发生发展。本文就糖尿病中自噬和内质网应激、线粒体功能障碍以及炎症的相互作用作一综述,旨在探讨糖尿病的发病机制,寻找防治糖尿病的新策略。     

Clinical significance and potential role of trimethylamine N-oxide in neurological and neuropsychiatric disorders

In the past three decades, research on the gut microbiome and its metabolites, such as trimethylamines (TMA), trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), bile acids, tryptophan and indole derivatives, has attracted the attention of many scientists and industrialists. Among these metabolites, TMAO is produced from dietary choline, phosphatidylcholine, carnitine, and betaine. TMAO and other gut metabolites, such as TMA and SCFAs, reach the brain by crossing the blood–brain barrier (BBB) and are involved in brain development, neurogenesis, and behavior. Gut-microbiota composition is influenced by diet, lifestyle, antibiotics, and age. Several studies have confirmed that altered TMAO levels contribute to metabolic, vascular, psychiatric, and neurodegenerative disorders. This review focuses on how altered TMAO levels impact oxidative stress, microglial activation, and the apoptosis of neurons, and may lead to neuroinflammation, which can subsequently result in the development of psychiatric, cognitive, and behavioral disorders.     

Pharmacological modulation of autophagy for Alzheimer's disease therapy: Opportunities and obstacles

Alzheimer's disease (AD) is a prevalent and deleterious neurodegenerative disorder characterized by an irreversible and progressive impairment of cognitive abilities as well as the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. By far, the precise mechanisms of AD are not fully understood and no interventions are available to effectively slow down progression of the disease. Autophagy is a conserved degradation pathway that is crucial to maintain cellular homeostasis by targeting damaged organelles, pathogens, and disease-prone protein aggregates to lysosome for degradation. Emerging evidence suggests dysfunctional autophagy clearance pathway as a potential cellular mechanism underlying the pathogenesis of AD in affected neurons. Here we summarize the current evidence for autophagy dysfunction in the pathophysiology of AD and discuss the role of autophagy in the regulation of AD-related protein degradation and neuroinflammation in neurons and glial cells. Finally, we review the autophagy modulators reported in the treatment of AD models and discuss the obstacles and opportunities for potential clinical application of the novel autophagy activators for AD therapy.     

Autophagy in ageing and ageing-associated diseases

Autophagy is a cell self-digestion process via lysosomes that clears “cellular waste”, including aberrantly modified proteins or protein aggregates and damaged organelles. Therefore, autophagy is considered a protein and organelle quality control mechanism that maintains normal cellular homeostasis. Dysfunctional autophagy has been observed in ageing tissues and several ageing-associated diseases. Lifespan of model organisms such as yeast, worms, flies, and mice can be extended through promoting autophagy, either by genetic manipulations such as over-expression of Sirtuin 1, or by administrations of rapamycin, resveratrol or spermidine. The evidence supports that autophagy may play an important role in delaying ageing or extending lifespan. In this review, we summarize the current knowledge about autophagy and its regulation, outline recent developments ie the genetic and pharmacological manipulations of autophagy that affects the lifespan, and discuss the role of autophagy in the ageing-related diseases.     

Zearalenone Induces Apoptosis and Autophagy in a Spermatogonia Cell Line

Zearalenone (ZEN), a widely known mycotoxin, is mainly produced by various Fusarium species, and it is a potent estrogenic metabolite that affects reproductive health in livestock and humans. In this study, the molecular mechanisms of toxicity and cell damage induced by ZEN in GC-1 spermatogonia (spg) cells were evaluated. Our results showed that cell viability decreased and apoptosis increased in a dose-dependent manner when GC-1 spg cells were exposed to ZEN. In addition, the key proteins involved in apoptosis, cleaved caspase-3 and -8, BAD, BAX, and phosphorylation of p53 and ERK1/2, were significantly increased in ZEN-exposed GC-1 spg cells for 24 h, and cytochrome c was released from mitochondria by ZEN. Interestingly, ZEN also triggered autophagy in GC-1 spg cells. The expression levels of the autophagy-related genes Atg5, Atg3, Beclin 1, LC3, Ulk1, Bnip 3, and p62 were significantly higher in ZEN-treated GC-1 spg cells, and the protein levels of both LC3A/B and Atg12 were remarkably increased in a dose-dependent manner in ZEN-exposed GC-1 spg cells compared to the control. In addition, immunostaining results showed that ZEN-treated groups showed a remarkable increase in LC 3A/B positive puncta as compared to the control in a dose-dependent manner based on confocal microscopy analysis in GC-1 spg cells. Our findings suggest that ZEN has toxic effects on tGC-1 spg cells and induces both apoptosis and autophagy.     

Benzyl Isothiocyanate-Induced Cytotoxicity via the Inhibition of Autophagy and Lysosomal Function in AGS Cells

Gastric adenocarcinoma is among the top causes of cancer-related death and is one of the most commonly diagnosed carcinomas worldwide. Benzyl isothiocyanate (BITC) has been reported to inhibit the gastric cancer metastasis. In our previous study, BITC induced apoptosis in AGS cells. The purpose of the present study was to investigate the effect of BITC on autophagy mechanism in AGS cells. First, the AGS cells were treated with 5, 10, or 15 μM BITC for 24 h, followed by an analysis of the autophagy mechanism. The expression level of autophagy proteins involved in different steps of autophagy, such as LC3B, p62/SQSTM1, Atg5-Atg12, Beclin1, p-mTOR/mTOR ratio, and class III PI3K was measured in the BITC-treated cells. Lysosomal function was investigated using cathepsin activity and Bafilomycin A1, an autophagy degradation stage inhibitor. Methods including qPCR, western blotting, and immunocytochemistry were employed to detect the protein expression levels. Acridine orange staining and omnicathepsin assay were conducted to analyze the lysosomal function. siRNA transfection was performed to knock down the LC3B gene. BITC reduced the level of autophagy protein such as Beclin 1, class III PI3K, and Atg5-Atg12. BITC also induced lysosomal dysfunction which was shown as reducing cathepsin activity, protein level of cathepsin, and enlargement of acidic vesicle. Overall, the results showed that the BITC-induced AGS cell death mechanism also comprises the inhibition of the cytoprotective autophagy at both initiation and degradation steps.     

Neurological soft signs in bipolar disorder in comparison to healthy controls and schizophrenia: A meta-analysis

Neurological soft signs (NSS) are subtle deficits in motor coordination, sensory integration, and sequencing of complex motor acts. Increased NSS is a well-established feature of patients with schizophrenia but a relatively smaller number of studies have investigated NSS in bipolar disorder (BD). Some authors but not others suggested that NSS can distinguish schizophrenia from BD. We conducted a meta-analysis of 18 studies to quantitatively review NSS in BD in comparison to schizophrenia and healthy controls. The current meta-analysis compared NSS scores of 725 BD patients and 634 healthy controls, and 391 BD and 471 schizophrenia patients. Patients with BD had significantly higher NSS scores (d?=?1.14, CI?=?0.89–1.44) than healthy controls and increased scores in BD was evident in all aspects of NSS (d?=?0.88–0.99). BD was associated with a less severe increase in NSS compared to schizophrenia, however, between-group difference was modest (d?=?0.42, CI?=?0.18–0.65). The results of this meta-analysis demonstrated that BD is characterized by a robust increase in NSS which is only moderately less severe than schizophrenia. Increased NSS is a common feature of both disorders.     

Discovery of Autophagy Inhibitors with Antiproliferative Activity in Lung and Pancreatic Cancer Cells

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Autophagy & Phagocytosis in Neurological Disorders and their Possible Cross-talk

Autophagy and phagocytosis are two important endogenous lysosomal dependent clearing systems in the organism. In some neurological disorders, excessive autophagy or dysfunctional phagocytosis has been shown to contribute to brain injury. Recent studies have revealed that there are underlying interactions between these two processes. However, different studies show inconsistent results for the contribution of autophagy to the phagocytic process in diverse phagocytes and relatively little is known about the link between them especially in the brain. It is critical to understand the role that autophagy plays in phagocytic process in order to promote the clearance of endogenous and exogenous detrimental materials. In this review, we highlight the studies focusing on phagocytosis and autophagy occurring in the brain and summarizing the possible regulatory roles of autophagy in the process of phagocytosis. Balancing the roles of autophagy and phagocytosis may be a promising therapeutic strategy for the treatment of some neurological diseases in the future.