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| 1 | Alcoholic pancreatitis:New insights into the pathogenesisand treatment显示文摘Acute pancreatitis is a necro-inflammatory disease of the exocrine pancreas that is characterized by inappropriate activation of zymogens, infiltration of the pancreas by inflammatory cells, and destruction of the pancreatic exocrine cells. Acute pancreatitis can progress to a severe life-threatening disease. Currently there is no pharmacotherapy to prevent or treat acute pancreatitis. One of the more common factors associated with acute pancreatitis is alcohol abuse. Although commonly associated with pancreatitis alcohol alone is unable to cause pancreatitis. Instead, it appears that alcohol and its metabolic by-products predispose the pancreas to damage from agents that normally do not cause pancreatitis, or to more severe disease from agents that normally cause mild pancreatic damage. Over the last 10 to 20 years, a tremendous amount of work has defined a number of alcohol-mediated biochemical changes in pancreatic cells. Among these changes are: Sustained levels of intracellular calcium, activation of the mitochondrial permeability transition pore, endoplasmic reticulum stress, impairment in autophagy, alteration in the activity of transcriptional activators, and colocalization of lysosomal and pancreatic digestive enzymes. Elucidation of these changes has led to a deeper understanding of the mechanisms by which ethanol predisposes acinar cells to damage. This greater understanding has revealed a number of promising targets for therapeutic intervention. It is hoped that further investigation of these targets will lead to the development of pharmacotherapy that is effective in treating and preventing the progression of acute pancreatitis. | Dahn L Clemens Katrina J Schneider Christopher K Arkfeld Jaclyn R Grode Mark A Wells Shailender Singh | 2016 | World Journal of Gastrointestinal Pathophysiology2016，7，1： | 10 |
| 2 | Alcoholic pancreatitis:Lessons from the liver显示文摘The association between alcohol consumption and pancreatitis has been recognized for over 100 years. Despite the fact that this association is well recognized, the mechanisms by which alcohol abuse leads to pancreatic tissue damage are not entirely clear. Alcohol abuse is the major factor associated with pancreatitis in the Western world. Interestingly, although most cases of chronic pancreatitis and many cases of acute pancreatitis are associated with alcohol abuse, only a small percentage of individuals who abuse alcohol develop this disease. This situation is reminiscent of the association between alcohol abuse and the incidence of alcoholic liver disease. The liver and the pancreas are developmentally very closely related. Even though these two organs are quite different, they exhibit a number of general structural and functional similarities. Furthermore, the diseases mediated by alcohol abuse in these organs exhibit some striking similarities. The diseases in both organs are characterized by parenchymal cell damage, activation of stellate cells, aberrant wound healing, and fibrosis. Because of the similarities between the liver and the pancreas, and the alcohol-associated diseases of these organs, we may be able to apply much of the knowledge that we have gained regarding the effects of alcohol on the liver to the pancreas. | Dahn L Clemens Katrina J Mahan | 2010 | World Journal of Gastroenterology2010，16，11： | 5 |
| 3 | High omega arachidonic acid/docosahexaenoic acid ratio induces mitochondrial dysfunction and altered lipid metabolism in human hepatoma cells显示文摘BACKGROUND Non-alcoholic fatty liver disease(NAFLD) is a common cause of liver disease worldwide and is a growing epidemic. A high ratio of omega-6 fatty acids to omega-3 fatty acids in the diet has been implicated in the development of NAFLD. However, the inflicted cellular pathology remains unknown. A high ratio may promote lipogenic pathways and contribute to reactive oxygen species(ROS)-mediated damage, perhaps leading to mitochondrial dysfunction.Therefore, these parameters were investigated to understand their contribution to NAFLD development.AIM To examine the effect of increasing ratios of omega-6:3 fatty acids on mitochondrial function and lipid metabolism mediators.METHODS Hep G2-derived VL-17 A cells were treated with normal(1:1, 4:1) and high(15:1,25:1) ratios of omega-6: omega-3 fatty acids [arachidonic acid(AA):docosahexaenoic acid(DHA)] at various time points. Mitochondrial activity and function were examined via MTT assay and Seahorse XF24 analyzer, respectively.Triglyceride accumulation was determined by using Enzy Chrom? and levels of ROS were measured by fluorescence intensity. Protein expression of the mediators of lipogenic, lipolytic and endocannabinoid pathways was assessed by Western blotting.RESULTS High AA:DHA ratio decreased mitochondrial activity(P < 0.01;up to 80%) and promoted intracellular triglyceride accumulation(P < 0.05;40%-70%).Mechanistically, it altered the mediators of lipid metabolism;increased the expression of stearoyl-Co A desaturase(P < 0.05;22%-35%), decreased the expression of peroxisome proliferator-activated receptor-alpha(P < 0.05;30%-40%) and increased the expression of cannabinoid receptor 1(P < 0.05;31%).Furthermore, the high ratio increased ROS production(P < 0.01;74%-115%) and reduced mitochondrial respiratory functions such as basal and maximal respiration, ATP production, spare respiratory capacity and proton leak(P < 0.01;35%-68%).CONCLUSION High AA:DHA ratio induced triglyceride accumulation, increased oxidative stress and disrupted mitochondrial functions. Stimulation of lipogenic and steroidal transcription factors may partly mediate these effects and contribute to NAFLD development. | Reem Ghazali Kosha J Mehta SW Annie Bligh Ihab Tewfik Dahn Clemens Vinood B Patel | 2020 | World Journal of Hepatology2020，12，3： | 2 |
| 4 | Autophagy Reduces Acute Ethanol-Induced Hepatotoxicity and Steatosis in Mice显示文摘 | Wen–Xing Ding Min Li Xiaoyun Chen Hong–Min Ni Chih–Wen Lin Wentao Gao Binfeng Lu Donna B. Stolz Dahn L. Clemens Xiao–Ming Yin | 2010 | Gastroenterology2010，，5： | 1 |
| 5 | Autophagy Reduces Acute Ethanol-Induced Hepatotoxicity and Steatosis in Mice显示文摘 | Wen–Xing Ding Min Li Xiaoyun Chen Hong–Min Ni Chih–Wen Lin Wentao Gao Binfeng Lu Donna B. Stolz Dahn L. Clemens Xiao–Ming Yin | 2010 | Gastroenterology2010，，5： | 1 |
| 6 | Effects of ethanol on hepatic cellular replication and cell cycleprogression显示文摘Ethanol is a hepatotoxin. It appears that the liver is the target of ethanol induced toxicity primarily because it is the major site of ethanol metabolism. Metabolism of ethanol results in a number of biochemical changes that are thought to mediate the toxicity associated with ethanol abuse. These include the production of acetaldehyde and reactive oxygen species, as well as an accumulation of nicotinamide adenine dinucleotide (NADH). These biochemical changes are associated with the accumulation of fat and mitochondrial dysfunction in the liver. If these changes are severe enough they can themselves cause hepatotoxicity, or they can sensitize the liver to more severe damage by other hepatotoxins. Whether liver damage is the result of ethanol metabolism or some other hepatotoxin, recovery of the liver from damage requires replacement of cells that have been destroyed. It is now apparent that ethanol metabolism not only causes hepatotoxicity but also impairs the replication of normal hepatocytes. This impairment has been shown to occur at both the G1/S, and the G2/M transitions of the cell cycle. These impairments may be the result of activation of the checkpoint kinases, which can mediate cell cycle arrest at both of these transitions. Conversely, because ethanol metabolism results in a number of biochemical changes, there may be a number of mechanisms by which ethanol metabolism impairs cellular replication. It is the goal of this article to review the mechanisms by which ethanol metabolism mediates impairment of hepatic replication. | Dahn L Clemens | 2007 | World Journal of Gastroenterology2007，13，37： | 0 |
| 7 | Molecular mechanisms of alcohol associated pancreatitis显示文摘Alcohol abuse is commonly associated with the development of both acute and chronic pancreatitis. Despite this close association, the fact that only a small percentage of human beings who abuse alcohol develop pancreatitis indicates that alcohol abuse alone is not sufficient to initiate clinical pancreatitis. This contention is further supported by the fact that administration of ethanol to experimental animals does not cause pancreatitis. Because of these findings, it is widely believed that ethanol sensitizes the pancreas to injury and additional factors trigger the development of overt pancreatitis. How ethanol sensitizes the pancreas to pancreatitis is not entirely known. Numerous studies have demonstrated that ethanol and its metabolites have a number of deleterious effects on acinar cells. Important acinar cells properties that are affected by ethanol include: calcium signaling, secretion of zymogens, autophagy, cellular regeneration, the unfolded protein response, and mitochondrial membrane integrity. In addition to the actions of ethanol on acinar cells, it is apparent that ethanol also affects pancreatic stellatecells. Pancreatic stellate cells have a critical role in normal tissue repair and the pathologic fibrotic response. Given that ethanol and its metabolites affect so many pancreatic functions, and that all of these effects occur simultaneously, it is likely that none of these effects is 'THE' effect. Instead, it is most likely that the cumulative effect of ethanol on the pancreas predisposes the organ to pancreatitis. The focus of this article is to highlight some of the important mechanisms by which ethanol alters pancreatic functions and may predispose the pancreas to disease. | Dahn L Clemens Mark A Wells Katrina J Schneider Shailender Singh | 2014 | World Journal of Gastrointestinal Pathophysiology2014，5，3： | 0 |
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