帮帮翻译成中文,谢谢大家,
发布网友
发布时间：2022-04-23 06:21
共4个回答
热心网友
时间：2023-10-04 19:02
INTRODUCTION
Much progress has been made in our understanding of the role of nutritional factors in the pathogenesis of liver disease and its treatment. The basic concept has been that some nutrients are essential because they cannot be synthesized endogenously in the mammalian body and therefore must be provided exogenously in the diet. A classic example is that of the amino acids, 9 of which are essential and therefore are mandatory constituents of any diet. An important one is methionine. Its requirements have been established and its key role in a score of vital functions has been well chartered, as reviewed in the introction to this symposium (1) and elsewhere (2). In addition, to this traditional concept, a new approach has emerged that has changed the use of some of the essential nutrients in pathologic conditions. Indeed, many of these nutrients, including methionine, must first be activated in the liver or in other tissues before they can exert their key functions. This activating process, however, is altered by liver disease and, as a consequence, nutritional requirements change. For instance, methionine has to be converted to S-adenosyl-L-methionine (SAMe) before it can act as the main cellular methyl donor (Figure 1). This function of SAMe is important for the metabolism of nucleic acids and for the structure and function of membranes and many other cellular constituents. These are often disturbed in various liver diseases but cannot be restored by the simple administration of methionine. Indeed, experimentally, it has been shown that even a 7-fold increase in the normal dietary methionine content failed to significantly alter hepatic SAMe (3). This is exacerbated when there is significant liver disease, which is commonly associated with impairment of the enzyme activating methionine to SAMe (4). Therefore, supplementation with methionine is useless in most such circumstances and may even result in toxicity because of its accumulation as a result of nonutilization. Indeed, elevated concentrations of circulating methionine in patients with liver disease have been reported (5–7), and excess methionine was shown to have toxic effects (3), including a decrease in hepatic ATP (8). Accordingly, one must bypass the enzyme deficiency e to liver disease and provide the proct of the defective reaction, namely SAMe, which becomes crucial for the functioning of the cell under these pathologic conditions. Thus, SAMe then becomes the essential nutrient instead of methionine. It is a typical example of a "conditional essential amino acid" (9) and what is now also called a supernutrient, namely an activated nutrient that must be provided to meet the normal cellular requirements when its endogenous synthesis from a nutritional precursor becomes insufficient because of an impairment in the activation process secondary to a pathologic state. Because the essential supernutrient SAMe is key to many basic cellular functions, it is not surprising that its lack is associated with many pathologic manifestations of liver diseases and that these can be corrected by simply providing the missing supernutrient (10).
View larger version (28K):
FIGURE 1. . Lipid peroxidation and other adverse effects resulting from alcoholic liver disease and from free radical generation and acetaldehyde proction by ethanol-inced microsomes and associated cytochrome P4502E1 (CYP2E1) up-regulation. Metabolic blocks caused by liver disease (a and b) or folate (c), vitamin B-12 (c), or vitamin B-6 (d) deficiencies result in corresponding depletions in S-adenosyl-L-methionine, phosphatidylcholine, and glutathione (GSH). New therapeutic approaches include the down-regulation of microsomal enzyme inction, 1, especially of CYP2E1; the trapping of free radicals with antioxidants, 2; the replenishment of S-adenosyl-L-methionine, 3; and the replenishment of phosphatidylcholine, 4. ADH, alcohol dehydrogenase (EC 1.1.1.1). Reprinted with permission from reference 2.
BENEFICIAL EFFECTS OF SAMe ON BASIC MANIFESTATIONS OF LIVER DISEASE
Role of SAMe on oxidative stress
As reviewed elsewhere (11), oxidative stress was shown to play a major pathogenic role in multiple disease states ranging from the hepatotoxicity of alcohol (and other xenobiotics) to the carcinogenicity of many compounds. The major natural defense mechanism against oxidative stress is reced glutathione, which traps the excess of free radicals (Figure 1). Glutathione is a tripeptide, the rate-limiting amino acid being cysteine (12), and SAMe plays a fundamental role in the formation of cysteine.
Role of SAMe in transmethylation and transsulfuration reactions
Another basic cellular activity of SAMe is its role as a methyl donor and enzyme activator in the transmethylation and transsulfuration reactions key to membrane structure and function. For example, SAMe is essential for the transport processes and signal transmission across membranes. One of the important consequences of the failure of these functions is insufficiency of bile formation, a key aspect of many diseases of the liver, resulting in a pathologic state called cholestasis. SAMe opposes successfully many of the cholestatic states, as reviewed elsewhere (13). Given either orally or parenterally, SAMe improves both the pruritus and the biochemical indexes of cholestasis, such as serum bilirubin, alkaline phosphatase (EC 3.1.3.1), and -glutamyltransferase (EC 2.3.2.2). It is noteworthy that in a prospective, multicenter, double-blind, placebo-controlled trial performed in 220 inpatients with chronic liver disease (chronic active hepatitis and cirrhosis, including primary biliary cirrhosis), serum markers of cholestasis and subjective symptoms (eg, pruritus and fatigue) significantly improved after SAMe treatment (14). Cholestasis is not only an important manifestation of various liver disorders, but it also may complicate physiologic states such as pregnancy. SAMe was shown to be a useful therapy for cholestasis ring pregnancy (15) and for cholestasis that is sometimes associated with parenteral nutrition (16).
Role of SAMe in opposing fibrosis
The leading cause of morbidity and mortality in all major liver diseases is an inappropriately excessive healing process with uncontrolled scarring or fibrosis culminating in cirrhosis. Indeed, fibrosis can be viewed as an initially beneficial scarring process that has escaped control and results ultimately in cirrhosis. SAMe was shown to be therapeutically useful in alleviating this process experimentally (17) and for improving the outcome clinically (18).
The most common liver disease for which SAMe has been shown to be useful therapeutically is alcoholic liver injury, which encompasses all the pathologic manifestations discussed above, namely a deficiency in the activation of methionine to SAMe, in the pathogenic role of oxidative stress and glutathione deficiency, in complications of cholestasis, and in the devastating consequences of excessive liver fibrosis (leading to cirrhosis).
SAMe AND THE PATHOGENESIS OF ALCOHOLIC LIVER INJURY
Alcohol causes liver disease through a variety of pathogenic mechanisms that were reviewed in detail elsewhere (19–21). The major mechanisms include interactions with nutrition and toxic manifestations through generation of oxidative stress and proction of the toxic metabolite acetaldehyde.
Interactions of alcohol with nutrition
In addition to its pharmacologic action, alcohol (ethanol) has a considerable energy content (7.1 kcal/g). Thus, its consumption may cause primary malnutrition by displacing other nutrients in the diet because of the high energy content of the alcoholic beverages or because of associated socioeconomic and medical disorders. Secondary malnutrition may result from either maldigestion or malabsorption of nutrients caused by gastrointestinal complications associated with alcoholism. Alcohol also promotes nutrient degradation or impaired activation (see below). Whereas it continues to be important to replenish nutritional deficiencies, it is crucial to recognize that, because of the alcohol-inced disease process, some nutritional requirements change.
Methionine and its utilization in liver diseases
In rats, alcohol consumption is associated with impaired methionine conservation. Consequently, methionine supplementation has been proposed for the treatment of liver diseases, especially the alcoholic variety, but some difficulties have been encountered, which are reviewed in detail elsewhere (22). Indeed, fatty liver and cirrhosis were not prevented in baboons given liberal amounts of methionine and other lipotropes (23, 24), and excess methionine was shown in various studies to have some adverse effects (see above). Whereas in some patients with alcoholic liver disease, circulating methionine concentrations may be normal or even low (25), elevated concentrations have been reported in others (see above). Furthermore, there was a delay in the clearance of plasma methionine after its systemic administration to patients with liver damage (26). Similarly, the blood clearance of methionine after an oral load of this amino acid was slowed (27). Because about one-half of methionine is metabolized by the liver, the above observations suggest the impaired hepatic metabolism of this amino acid. Indeed, Duce et al (4) reported a decrease in SAMe-synthetase activity in cirrhotic livers. As a consequence, methionine supplementation may be ineffective in alcoholic liver disease and SAMe depletion ensues, as was verified in nonhuman primates after long-term ethanol consumption (28). Additional factors that contribute to the decrease in hepatic SAMe are increased glutathione utilization secondary to enhanced free radical and acetaldehyde generation by the inced microsomal ethanol-oxidizing system (see below).
Microsomal ethanol-oxidizing system and SAMe
The microsomal ethanol-oxidizing system has been the subject of extensive research, and is reviewed in detail elsewhere (29, 30). With the use of Western blot technique with specific antibodies against cytochrome P4502E1 (CYP2E1), a 4-fold inction of CYP2E1 was found in liver biopsy samples from recently drinking subjects (31). CYP2E1 activates some xenobiotics (such as acetaminophen) to toxic metabolites (29). It also generates several species of active oxygen (Figures 2 and 3). Glutathione provides one of the cell’s fundamental mechanisms for the scavenging of toxic free radicals (Figure 1), but the generation of active oxygen species by CYP2E1 may overwhelm this antioxidant system with pathogenic consequences requiring new therapeutic approaches (32). Furthermore, acute ethanol administration also inhibits glutathione synthesis and proces an increased loss from the liver (33). Indeed, rats fed ethanol chronically have significantly increased rates of glutathione turnover (34). Such an increased glutathione turnover was also shown indirectly by an increase in -amino-N-butyrate (Figure 1), which has been shown in both nonhuman primates and in humans (35). A depletion in the steady state concentrations of hepatocellular glutathione, in synergy with other conditions, leads to hepatocellular necrosis and liver injury (36). Glutathione is selectively depleted in the mitochondria (37) and may contribute to the striking alcohol-inced alterations of that organelle. In addition, -tocopherol, the major antioxidant in the membranes, is depleted in patients with cirrhosis (38). This deficiency in the defense systems, coupled with increased oxygen and other free radical generation (by the ethanol-inced microsomes; see above) and with acetaldehyde proction (see below), may contribute to liver damage not only via lipid peroxidation but also by enzyme inactivation (39). Replenishment of glutathione can be achieved in acute situations (such as acetaminophen poisoning) by administration of precursors of cysteine (one of the amino acids of glutathione), such as acetylcysteine, or in chronic conditions by SAMe (10, 28). Beneficial effects of SAMe on glutathione were also observed in humans (40, 41). Moreover, experimentally, the ethanol-inced increase in fluidity of mitochondrial membranes was prevented by SAMe but not by N-acetylcysteine supplementation (42).
View larger version (33K):
FIGURE 2. . Pathogenesis of hepatic, nutritional, and metabolic abnormalities after ethanol abuse. Malnutrition, whether primary or secondary, can be differentiated from metabolic changes or direct toxicity, resulting partly from redox changes mediated by alcohol dehydrogenase (ADH; EC 1.1.1.1) or effects secondary to microsomal inction, including increased acetaldehyde proction. L-FABP, L-fatty acid binding protein; FA, fatty acid; GSH, glutathione; MEOS, microsomal ethanol-oxidizing system; 4A1, cytochrome P4504A1. Reprinted with permission from reference 2.
View larger version (14K):
FIGURE 3. . Physiologic and toxic roles of cytochrome P4502E1 (CYP2E1), the main cytochrome P450 of the microsomal ethanol-oxidizing system. Many endogenous and xenobiotic compounds are substrates for CYP2E1 and ince its activity through various mechanisms, resulting in an array of beneficial as well as harmful effects. Reprinted with permission from reference 30.
Toxicity of acetaldehyde
Acetaldehyde, the proct of all pathways of ethanol oxidation, is highly toxic (18) and is rapidly metabolized to acetate, mainly by a mitochondrial aldehyde dehydrogenase, the activity of which is significantly reced by chronic ethanol consumption (43). The decreased capacity of mitochondria in alcoholfed subjects to oxidize acetaldehyde, associated with unaltered or even enhanced rates of ethanol oxidation (and therefore acetaldehyde generation because of the inction of the microsomal ethanol-oxidizing system; see above), results in an imbalance between the proction and disposition of acetaldehyde. The latter causes the elevated acetaldehyde concentrations observed after chronic ethanol consumption in baboons (44) and humans (45).
Acetaldehyde’s toxicity is e, in part, to its capacity to form protein adcts, which results in antibody proction, enzyme inactivation, and decreased DNA repair (19). Moreover, acetaldehyde promotes lipid peroxidation (Figure 1); one mechanism that promotes lipid peroxidation is glutathione depletion. The binding of acetaldehyde with cysteine, glutathione, or both (Figure 1) may contribute to a decrease in liver glutathione (46). Acetaldehyde adcts also promote collagen proction because collagen synthesis by liver stellate cells is released from the feedback inhibition proced by the carboxy terminal propeptide of procollagen through adct formation of acetaldehyde with the latter (47). Thus, acetaldehyde toxicity plays a fundamental role in alcohol-inced liver injury, and glutathione is a key defense mechanism by inactivating the free radicals generated by acetaldehyde and by binding to acetaldehyde itself (Figure 1). SAMe, in turn, serves as the main support for the maintenance of adequate glutathione concentrations.
BENEFICIAL EFFECTS OF SAMe IN ALCOHOLIC LIVER DISEASE
Experimental studies
Although it has been claimed that the liver does not take up SAMe from the bloodstream, other results indicate its uptake by isolated hepatocytes; results in baboons (28) also clearly showed hepatic uptake of exogenous SAMe in vivo, associated with beneficial effects on liver function and structure. In these baboons, correction of the ethanol-inced hepatic SAMe depletion with oral SAMe administration (28) resulted in a corresponding attenuation of ethanol-inced liver injury, as shown by a less-striking glutathione depletion and lesser increases in plasma aspartate transaminase (EC 2.6.1.1). The number of alcohol-inced megamitochondria (documented by electron microscopy) was markedly reced (28). The latter was associated with a lesser leakage of the mitochondrial enzyme glutamic dehydrogenase into the bloodstream. In rats, SAMe also decreased ethanol-inced fat accumulation (48). Thus, SAMe was shown to be useful for opposing the oxidative stress and the alcohol-inced liver injury.
Membrane alterations are common in alcoholic liver injury and are also associated with a decrease in phosphatidylcholine, the backbone of the membranes. One pathway for the maintenance and preservation of adequate phosphatidylcholine concentrations in the liver membranes is the methylation of phosphatidylethanolamine to phosphatidylcholine through the action of SAMe (Figure 1). This vital function is impaired in alcoholic liver disease because, under these conditions, the activity of phosphatidylethanolamine methyltransferase (EC 2.1.1.17) is depressed (4, 49). This deficiency is exacerbated if SAMe is depleted (Figure 1). These metabolic considerations may explain, at least in part, some of the beneficial effects of SAMe on alcohol-inced liver injury in baboons (28) through the restoration of some of the phosphatidylcholine proction or through the positive effects of the supplementation with phosphatidylcholine (50), the depleted proct of the reaction (Figure 1).
Clinical trial
A significant therapeutic success in alcoholic liver disease was achieved in a recent long-term randomized, placebo-controlled, double-blind, multicenter clinical trial of SAMe in patients with alcoholic liver cirrhosis in whom SAMe improved survival or delayed liver transplantation (18).
CONCLUSIONS
Liver disorders, including alcoholic liver disease, are associated with and result in part from impaired activation of methionine to SAMe or from alcohol-inced oxidative stress, which results in the increased utilization of SAMe, a key precursor of cysteine—the rate-limiting amino acid of the tripeptide glutathione. Depletion of SAMe, the main methylating agent of the liver, and associated liver pathology can be corrected by the administration of this safe, yet therapeutically effective nutrient.
热心网友
时间：2023-10-04 19:02
摘要
S - Adenosyl - L -氨基甲硫基丁酸(同样)施加在肝脏的许多关键作用，包括起一个前体作用对于半胱氨酸， 1谷胱甘肽— 3氨基酸主要生理防御机制反对氧化重音。 同样是特别重要在反对各种各样的病原生物引起的自由氧气基础毒力，包括酒精，主要导致氧化重音由细胞色素P4502E1 (CYP2E1)归纳和由它的代谢产物乙醛。 同样也作为在肝脏的主要甲基化的代理。 同样的前体是氨基甲硫基丁酸，其中一基本氨基酸，同样合成酶激活(EC 2.5.1.6)。 不幸地，作为肝脏病结果，这酵素的活动显著被减少。 由于减少的运用，氨基甲硫基丁酸，同时，积累，并且有在获取根本营养素的状态并且必须提供外生地作为supernutrient补尝它的缺乏的同样的减退。 管理这在许多有利作用的无害supernutrient结果以各种各样的组织，主要在肝脏和特别是在线粒体。 这显示了在酒精哺养的狒狒和在肝脏伤其他实验性模型和在临床试验，一些在这个问题的其他文章上被回顾。
supernutrient是不是拼错了？？？？？？
热心网友
时间：2023-10-04 19:03
摘要
S -腺苷- L -蛋氨酸（同）施加许多关键职能肝脏，包括担任的先导半胱氨酸， 1 3氨基酸谷胱甘肽的主要生理防御机制对氧化应激。同样特别重要的，反对的毒性氧自由基产生的各种病原体，包括酒精，造成主要由氧化应激诱导的细胞色素P4502E1 （ CYP2E1基因）及其代谢产物乙醛。也是如此行为作为主要甲基化剂在肝脏中。的前身也是蛋氨酸，其中必需氨基酸，这是激活的同合成酶（欧共体2.5.1.6 ） 。不幸的是，这种酶的活性显着下降是由于肝脏疾病。由于减少利用，蛋氨酸和积累，同时，有减少的一样，获得的地位的一个重要养分，因此必须提供外部作为一个supernutrient ，以弥补其不足。管理本无害supernutrient结果在许多有益的影响在各组织，主要是在肝脏，尤其是在线粒体。这是显示在酒精美联储狒狒和其他实验模型的肝损伤和临床试验，其中一些是在其他条款审查这一问题。
热心网友
时间：2023-10-04 19:03
你好 本来是翻译的
但是你是不是打错了某些单词 所以变得无法翻译~~
