Oxidative stress and antioxidants in hepatic pathogenesis

Long term hepatitis B virus (HBV) infection is a major risk factor in pathogenesis of chronic liver diseases,including hepatocellular carcinoma (HCC). The HBV encod-ed proteins,hepatitis B virus X protein and preS,appear to contribute importantly to the pathogenesis of HCC. Both are associated with oxidative stress,which can damage cellular molecules like lipids,proteins,and DNA during chronic infection. Chronic alcohol use is another important factor that contributes to oxidative stress in the liver. Previous studies reported that treatment with antioxidants,such as curcumin,silymarin,green tea,and vitamins C and E,can protect DNA from damage and regulate liver pathogenesis-related cascades by reducing reactive oxygen species. This review summarizes some of the relationships between oxidative stress and liver pathogenesis,focusing upon HBV and alcohol,and suggests antioxidant therapeutic approaches.     

肝性脑病中氧化应激参与氨中毒的研究进展

肝性脑病是一种严重的肝脏衰竭综合征,临床表现出一系列神经精神病学和神经肌肉上的症状.肝性脑病的病理生理学基础尚不明确,目前普遍认为氨在其中起到关键作用.近年,人们发现氧化应激参与到肝性脑病的病理生理学级联反应中,并与氨中毒学说存在一定的联系.此文将着重就氧化应激与氨中毒学说的研究进展作一综述.     

Evidence for oxidative/nitrosative stress in the pathogenesis of hepatic encephalopathy

Hepatic encephalopathy (HE) is a serious complication of liver failure. HE manifests as a series of neuropsychiatric and neuromuscular symptoms including personality changes, sleep abnormalities, asterixis and muscle rigidity progressing through stupor to coma. The pathophysiologic basis of HE remains unclear. There is general agreement that ammonia plays a key role. In recent years, it has been suggested that oxidative/nitrosative stress constitutes part of the pathophysiologic cascade in HE. Direct evidence for oxidative/nitrosative stress in the pathogenesis of HE has been demonstrated in experimental animal models of acute or chronic liver failure. However, evidence from studies in HE patients is limited. This review summarizes this evidence for a role of oxidative/nitrosative stress in relation to ammonia toxicity and to the pathogenesis of HE.     

Theories of the pathogenesis of hepatic encephalopathy

The earliest hypothesis of the pathogenesis of HE implicated ammonia, although effects of appreciable concentrations of this neurotoxin did not resemble HE. Altered eurotransmission in the brain was suggested by similarities between increased GABA-mediated inhibitory neurotransmission and HE, specifically decreased consciousness and impaired motor function. Evidence of increased GABAergic tone in models of HE has accumulated; potential mechanisms include increased synaptic availability of GABA and accumulation of natural benzodiazepine receptor ligands with agonist properties. Pathophysiological concentrations of ammonia associated with HE, have the potential of enhancing GABAergic tone by mechanisms that involve its interactions with the GABAa receptor complex.     

肝性脑病发病机制的研究进展

肝性脑病(hepatic encephalopathy,HE)是肝功能严重障碍和/或门体分流术后患者发生的以代谢紊乱为基础,神经、精神症状为主要表现的综合征.其症状包括意识混乱、定向力障碍、协调能力降低,甚至昏迷.其发病机制被认为是高氨血症使脑星形胶质细胞内谷氨酰胺浓度升高、钙离子内流启动氧化应激、破坏线粒体功能,干扰能量代谢并诱发炎症反应,破坏血脑屏障使内皮细胞、脑星形胶质细胞对水通透性增加,引发脑水肿.炎症反应又反过来升高脑内氨浓度,增加其中枢神经系统毒性,而锰是参与上述过程的重要组成成分,故目前公认为高氨血症和炎症反应的协同作用导致星形胶质细胞肿胀,进而引起脑水肿导致HE.本文就HE发病机制的研究进展作一综述.     

Oxidative stress and hippocampus in a low‐grade hepatic encephalopathy model: protective effects of curcumin

Aim: The present study was performed on prehepatic portal hypertensive rats, a model of low‐grade hepatic encephalopathy, designed to evaluate whether oxidative stress was a possible pathway implicated in hippocampal damage and if so, the effect of an anti‐oxidant to prevent it. Methods: Prehepatic portal hypertension was induced by a regulated portal vein stricture. Oxidative stress was investigated by assessing related biochemical parameters in rat hippocampus. The effect of the anti‐oxidant curcumin, administered in a single i.p. dose of 100 mg/kg on the seventh, ninth and eleventh days after surgery, was evaluated. Results: Oxidative stress in the rat hippocampal area was documented. Curcumin significantly decreased tissue malondialdehyde levels and significantly increased glutathione peroxidase, catalase and superoxide dismutase activities in the hippocampal tissue of portal hypertensive rats. Conclusion: Oxidative stress was found to be implicated in the hippocampal damage and curcumin protected against this oxidative stress in low‐grade hepatic encephalopathic rats. These protective effects may be attributed to its anti‐oxidant properties.     

Elevated cerebral lactate: Implications in the pathogenesis of hepatic encephalopathy

Hepatic encephalopathy (HE), a complex neuropsychiatric syndrome, is a frequent complication of liver failure/disease. Increased concentrations of lactate are commonly observed in HE patients, in the systemic circulation, but also in the brain. Traditionally, increased cerebral lactate is considered a marker of energy failure/impairment however alterations in lactate homeostasis may also lead to a rise in brain lactate and result in neuronal dysfunction. The latter may involve the development of brain edema. This review will target the significance of increased cerebral lactate in the pathogenesis of HE.     

Oxidative stress in the pathogenesis of asthma

Asthma affects 5% to 10% of the population of the United States. In asthmatics, oxidative stress occurs not only as a result of inflammation but also from environmental exposure to air pollution. The specific localization of antioxidants in the lung and the adaptive changes during asthma underscore the importance of oxidative stress, and therapeutic interventions that decrease exposure to environmental reactive oxygen species or augment endogenous antioxidant defenses might be beneficial as adjunctive therapies in asthmatic patients.     

Oxidative stress in the pathogenesis of diabetic neuropathy

Oxidative stress results from a cell or tissue failing to detoxify the free radicals that are produced during metabolic activity. Diabetes is characterized by chronic hyperglycemia that produces dysregulation of cellular metabolism. This review explores the concept that diabetes overloads glucose metabolic pathways, resulting in excess free radical production and oxidative stress. Evidence is presented to support the idea that both chronic and acute hyperglycemia cause oxidative stress in the peripheral nervous system that can promote the development of diabetic neuropathy. Proteins that are damaged by oxidative stress have decreased biological activity leading to loss of energy metabolism, cell signaling, transport, and, ultimately, to cell death. Examination of the data from animal and cell culture models of diabetes, as well as clinical trials of antioxidants, strongly implicates hyperglycemia-induced oxidative stress in diabetic neuropathy. We conclude that striving for superior antioxidative therapies remains essential for the prevention of neuropathy in diabetic patients.     

The role of methanethiol in the pathogenesis of hepatic encephalopathy

Mixed disulfides of methanethiol represent a relative estimate for an exposure to methanethiol. The concentrations of methanethiol-mixed disulfides, methionine, 4-methylthio-2-oxobutyrate and ammonia were measured in patients with different stages of hepatic encephalopathy, in patients with chronic kidney failure and in healthy subjects. In patients with hepatic encephalopathy, the mean serum concentrations of all these compounds were elevated. However, the elevations of methanethiol-mixed disulfides were small and partly caused by decreased renal function. In addition, the levels of methanethiol-mixed disulfides did not differ significantly between the different grades of hepatic encephalopathy. The concentrations of methanethiol-mixed disulfides were substantially lower than those previously observed in healthy subjects after an oral methionine load or in a patient with a deficiency in methionine adenosyltransferase, the latter without causing encephalopathy. We concluded that the role of methanethiol in the pathogenesis of hepatic encephalopathy is probably minor, if not insignificant. In the patients with hepatic encephalopathy, a significant correlation was found between the concentrations of methionine and 4-methylthio-2-oxobutyrate and between 4-methylthio-2-oxobutyrate and methanethiol-mixed disulfides, supporting the theory that methanethiol is formed by way of the methionine transamination pathway. Evidence is provided that, besides the methionine transsulfuration pathway, the transamination pathway is also impaired in patients with hepatic encephalopathy.     

肝性脑病的病因和防治探讨

肝性脑病至今仍以血液检查所见的生化代谢异常来解释,因不能圆满解释全面情况,需进一步探讨。不加选择收集70例肝硬化死亡者脑组织,分别作HE和免疫组化检查,观察病理改变和HBsAg、HBcAg表达。在70例脑组织标本中免疫组化染色HBsAg、HBcAg阳性者计30例,阳性率42.3%,临床上有肝性脑病表现者阳性率明显高于无表现者,脑组织病理改变较明显者,阳性率亦明显高于较轻者。肝硬化脑组织内出现HBsAg和HBcAg表达,而且阳性率与脑组织病理改变和是否出现临床表现密切有关。提示HBV侵及脑组织,导致病理形态改变可能是肝性脑病的病理基础,生化代谢异常可能仅是肝衰的表现。     

Pannexin1 as a novel cerebral target in pathogenesis of hepatic encephalopathy

Hepatic encephalopathy (HE) represents a nervous system disorder caused due to liver dysfunction. HE is broadly classified as acute/overt and moderate-minimal HE. Since HE syndrome severely affects quality of life of the patients and it may be life threatening, it is important to develop effective therapeutic strategy against HE. Mainly ammonia neurotoxicity is considered accountable for HE. Increased level of ammonia in the brain activates glutamate-NMDA (N-methyl-D-aspartate) receptor (NMDAR) pathway leading to Ca²⁺ influx, energy deficit and oxidative stress in the post synaptic neurons. Moreover, NMDAR blockage has been found to be a poor therapeutic option, as this neurotransmitter receptor plays important role in maintaining normal neurophysiology of the brain. Thus, searching new molecular players in HE pathogenesis is of current concern. There is an evolving concept about roles of the trans-membrane channels in the pathogenesis of a number of neurological complications. Pannexin1 (Panx1) is one of them and has been described to be implicated in stroke, epilepsy and ischemia. Importantly, the pathogenesis of these complications relates to some extent with NMDAR over activation. Thus, it is speculated that HE pathogenesis might also involve Panx1. Indeed, some recent observations in the animal models of HE provide support to this argument. Since opening of Panx1 channel is mostly associated with the neuronal dysfunctions, down regulation of this channel could serve as a relevant therapeutic strategy without producing any serious side effects. In the review article an attempt has been made to summarize the current information on implication of Panx1 in the brain disorders and its prospects for being examined as pharmacological target in HE pathogenesis.     

氧化应激与肝脏保护

活性氧自由基引发的氧化应激是多种肝病发病的共同病理生理基础,在各种慢性肝病的形成和发展过程中起重要作用。本文主要阐述氧化应激与肝脏保护的关系,并根据两者关系阐述了目前保肝抗氧化物质的抗氧化作用机制。     

Ammonia and endogenous benzodiazepine-like compounds in the pathogenesis of hepatic encephalopathy

BACKGROUND: Ammonia and endogenous benzodiazepines (BDZs) are two of the most important agents among those taken into consideration in the pathogenesis of hepatic encephalopathy (HE). METHODS: Venous ammonia and endogenous BDZs sera levels were assayed in 58 liver cirrhosis patients (34 male, 24 female) free of commercial BDZs. Endogenous BDZs were measured by binding assay after high-performance liquid chromatography purification. Ammonia was assessed by colorimetric test. RESULTS: Endogenous BDZs and ammonia were significantly higher in Child-Pugh class C than in class B and class A (P < 0.05), correlating to the severity of the liver dysfunction but not with the degree of HE. A significant difference, in fact, was noted between degree 0 (no HE) versus III-IV of HE (P < 0.05), but not between degrees I-II versus III-IV. Regression analysis performed to find a correlation between the ammonia and BDZ levels in HE resulted negative. CONCLUSION: Clinical evidence is provided in cirrhotic patients that ammonia and endogenous BDZ levels do not correlate with each other in the outcome of HE.     

氧化应激与肝脏损伤

活性氧自由基引发的氧化应激是多种肝病发病的共同病理生理基础.氧化应激主要通过启动膜脂质过氧化改变生物膜功能、与生物大分子共价结合及破坏酶的活性等在细胞因子(如TNF-α、NF-κB)的共同作用下引起不同程度的肝损伤.氧化应激在脂肪肝、病毒性肝炎、肝纤维化等肝病中可产生不容忽视的作用.     

Recent insights into the pathogenesis of hepatic encephalopathy and treatments

Hepatic encephalopathy (HE) encompasses a spectrum of neuropsychiatric disorders related to liver failure. The development of HE can have a profound impact on mortality as well as quality of life for patients and carers. Ammonia is central in the disease process contributing to alteration in neurotransmission, oxidative stress, and cerebral edema and astrocyte swelling in acute liver failure. Inflammation in the presence of ammonia coactively worsens HE. Inflammation can result from hyperammonemic responses, endotoxemia, innate immune dysfunction or concurrent infection. This review summarizes the current processes implicated in the pathogenesis of HE, as well as current and potential treatments. Treatments currently focus on reducing inflammation and/or blood ammonia levels and provide varying degrees of success. Optimization of current treatments and initial testing of novel therapies will provide the basis of improvement of care in the near future.     

Oxidative stress in the pathogenesis of diffuse lung diseases: A review

Oxidative stress is an imbalance between oxidants (reactive oxygen and nitrogen species) and antioxidants that may affect lipids, DNA, carbohydrates and proteins. The lung is continuously exposed to endogenous and exogenous oxidants (cigarette smoke, mineral dust, ozone, radiation). Reactive oxygen and nitrogen species are mainly produced by phagocytes as well as by polymorphonuclear, alveolar, bronchial and endothelial cells. A potential role of oxidative stress in the pathogenesis of diffuse lung diseases (particularly idiopathic pulmonary fibrosis) has been demonstrated. Increased oxidant levels and decreased antioxidant defences can contribute to the progression of idiopathic pulmonary fibrosis and other diffuse lung diseases.The growing number of papers on the different aspects of oxidant/antioxidant imbalance in diffuse lung diseases in the last decade reflects increasing interest in this topic and suggests that specific DLDs may be characterized by specific patterns of oxidation and antioxidant responses. The study of oxidative stress can provide insights into etiopathogenesis and favour the discovery of new treatments. In this review of the literature on oxidants and antioxidants in diffuse lung diseases, the focus is on idiopathic pulmonary fibrosis, sarcoidosis, pneumoconiosis and pulmonary fibrosis associated with systemic sclerosis.