Processes exacerbating apoptosis in non-alcoholic steatohepatitis

2019 ◽  
Vol 133 (22) ◽  
pp. 2245-2264 ◽  
Author(s):  
Marta B. Afonso ◽  
Rui E. Castro ◽  
Cecília M. P. Rodrigues
Keyword(s):  
Molecular Mechanisms ◽  
Health Concern ◽  
Alcoholic Fatty Liver ◽  
Intrinsic Signals ◽  
Alcoholic Steatohepatitis ◽  
Significant Public Health Concern ◽  
High Prevalence ◽  
Significant Public Health ◽  
Alcoholic Fatty Liver Disease

Abstract Non-alcoholic fatty liver disease (NAFLD) is a significant public health concern, owing to its high prevalence, progressive nature and lack of effective medical therapies. NAFLD is a complex and multifactorial disease involving the progressive and concerted action of factors that contribute to the development of liver inflammation and eventually fibrosis. Here, we summarize fundamental molecular mechanisms underlying the pathogenesis of non-alcoholic steatohepatitis (NASH), how they are interrelated and possible translation to clinical applications. We focus on processes triggering and exacerbating apoptotic signalling in the liver of NAFLD patients and their metabolic and pathological implications. Indeed, liver injury and inflammation are cardinal histopathological features of NASH, a duo in which derailment of apoptosis is of paramount importance. In turn, the liver houses a very high number of mitochondria, crucial metabolic unifiers of both extrinsic and intrinsic signals that converge in apoptosis activation. The role of lifestyle options is also dissected, highlighting the management of modifiable risk factors, such as obesity and harmful alcohol consumption, influencing apoptosis signalling in the liver and ultimately NAFLD progression. Integrating NAFLD-associated pathologic mechanisms in the cell death context could provide clues for a more profound understating of the disease and pave the way for novel rational therapies.

scholarly journals Natural Progression of Non-Alcoholic Steatohepatitis to Hepatocellular Carcinoma

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 184
Author(s):  
Daryl Ramai ◽  
Waqqas Tai ◽  
Michelle Rivera ◽  
Antonio Facciorusso ◽  
Nicola Tartaglia ◽  
...  
Keyword(s):  
Public Health ◽  
Hepatocellular Carcinoma ◽  
Lipid Peroxidation ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Natural Progression ◽  
Public Health Threat ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic steatohepatitis (NASH) is a chronic and progressive form of non-alcoholic fatty liver disease (NAFLD). Its global incidence is increasing which makes NASH an epidemic and a public health threat. Due to repeated insults to the liver, patients are at risk for developing hepatocellular carcinoma (HCC). The progression of NASH to HCC was initially defined according to a two-hit model which involved the development of steatosis, followed by lipid peroxidation and inflammation. However, current research defines a “multi-hit” or “multi-parallel hit” model which synthesizes several contributing pathways involved in progressive fibrosis and oncogenesis. This perspective considers the effects of cellular, genetic, immunologic, metabolic, and endocrine pathways leading up to HCC which underscores the complexity of this condition. This article will provide an updated review of the pathogenic mechanisms leading from NASH to HCC as well as an exploration of the role of biomarkers and screening.

scholarly journals The Role of the Histone Methyltransferase EZH2 in Liver Inflammation and Fibrosis in STAM NASH Mice

Biology ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 93 ◽  
Author(s):  
Seul Lee ◽  
Dong-Cheol Woo ◽  
Jeeheon Kang ◽  
Moonjin Ra ◽  
Ki Hyun Kim ◽  
...  
Keyword(s):  
Liver Disease ◽  
Epigenetic Modification ◽  
Treatment Options ◽  
Histone Methyltransferase ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Promising Therapeutic Target ◽  
Alcoholic Fatty Liver Disease ◽  
Potential Therapeutics

Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease, with few biomarkers and treatment options currently available. Non-alcoholic steatohepatitis (NASH), a progressive disease of NAFLD, may lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Epigenetic modification can contribute to the progression of NAFLD causing non-alcoholic steatohepatitis (NASH), in which the exact role of epigenetics remains poorly understood. To identify potential therapeutics for NASH, we tested small-molecule inhibitors of the epigenetic target histone methyltransferase EZH2, Tazemetostat (EPZ-6438), and UNC1999 in STAM NASH mice. The results demonstrate that treatment with EZH2 inhibitors decreased serum TNF-alpha in NASH. In this study, we investigated that inhibition of EZH2 reduced mRNA expression of inflammatory cytokines and fibrosis markers in NASH mice. In conclusion, these results suggest that EZH2 may present a promising therapeutic target in the treatment of NASH.

scholarly journals Hypoxia-Inducible Factors as Key Players in the Pathogenesis of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis

2021 ◽  
Vol 8 ◽  
Author(s):  
Lorenz M. W. Holzner ◽  
Andrew J. Murray
Keyword(s):  
Transcription Factors ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Treatment Options ◽  
Redox Homeostasis ◽  
Health Concern ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) and its more severe form non-alcoholic steatohepatitis (NASH) are a major public health concern with high and increasing global prevalence, and a significant disease burden owing to its progression to more severe forms of liver disease and the associated risk of cardiovascular disease. Treatment options, however, remain scarce, and a better understanding of the pathological and physiological processes involved could enable the development of new therapeutic strategies. One process implicated in the pathology of NAFLD and NASH is cellular oxygen sensing, coordinated largely by the hypoxia-inducible factor (HIF) family of transcription factors. Activation of HIFs has been demonstrated in patients and mouse models of NAFLD and NASH and studies of activation and inhibition of HIFs using pharmacological and genetic tools point toward important roles for these transcription factors in modulating central aspects of the disease. HIFs appear to act in several cell types in the liver to worsen steatosis, inflammation, and fibrosis, but may nevertheless improve insulin sensitivity. Moreover, in liver and other tissues, HIF activation alters mitochondrial respiratory function and metabolism, having an impact on energetic and redox homeostasis. This article aims to provide an overview of current understanding of the roles of HIFs in NAFLD, highlighting areas where further research is needed.

scholarly journals Chronic Inflammation in Non-Alcoholic Steatohepatitis: Molecular Mechanisms and Therapeutic Strategies

2020 ◽  
Vol 11 ◽  
Author(s):  
Carmelo Luci ◽  
Manon Bourinet ◽  
Pierre S. Leclère ◽  
Rodolphe Anty ◽  
Philippe Gual
Keyword(s):  
Endothelial Cells ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Therapeutic Strategies ◽  
Innate Immune ◽  
Lymphoid Cells ◽  
Liver Sinusoidal Endothelial Cells ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Alcoholic Fatty Liver Disease

Non-Alcoholic Steatohepatitis (NASH) is the progressive form of Non-Alcoholic Fatty Liver Disease (NAFLD), the main cause of chronic liver complications. The development of NASH is the consequence of aberrant activation of hepatic conventional immune, parenchymal, and endothelial cells in response to inflammatory mediators from the liver, adipose tissue, and gut. Hepatocytes, Kupffer cells and liver sinusoidal endothelial cells contribute to the significant accumulation of bone-marrow derived-macrophages and neutrophils in the liver, a hallmark of NASH. The aberrant activation of these immune cells elicits harmful inflammation and liver injury, leading to NASH progression. In this review, we highlight the processes triggering the recruitment and/or activation of hepatic innate immune cells, with a focus on macrophages, neutrophils, and innate lymphoid cells as well as the contribution of hepatocytes and endothelial cells in driving liver inflammation/fibrosis. On-going studies and preliminary results from global and specific therapeutic strategies to manage this NASH-related inflammation will also be discussed.

The role of effective diagnosis for the control of gonorrhoea in high prevalence populations

1998 ◽  
Vol 9 (8) ◽  
pp. 435-443 ◽  
Author(s):  
P O Davies ◽  
C A Ison
Keyword(s):  
Health Concern ◽  
Clinical Settings ◽  
Significant Public Health Concern ◽  
High Prevalence ◽  
Significant Public Health ◽  
Clinical Environments ◽  
Sufficient Intensity ◽  
Effective Diagnosis ◽  
The Uk ◽  
Spread Of Infection

Gonorrhoea in the UK is now a highly focal problem that is localized to certain inner city areas where it presents a significant public health concern. However, the majority of men and a proportion of women infested with Neisseria gonorrhoeae do not experience symptoms of sufficient intensity to prompt them to seek medical advice and the current strategy of treating symptomatic individuals in specialist clinics with subsequent tracing of sexual partners is therefore failing to control the spread of infection in these areas. One method for addressing this problem would be the extension of effective diagnostic services into the clinical environments most likely to be accessed by these high risk individuals. This paper reviews the scientific literature examining the various methodologies available for the identification of N. gonorrhoeae and assesses their suitability for the diagnosis of gonorrhoea in these alternative clinical settings.

scholarly journals Autophagy in Hepatic Steatosis: A Structured Review

2021 ◽  
Vol 9 ◽  
Author(s):  
Vitor de Miranda Ramos ◽  
Alicia J. Kowaltowski ◽  
Pamela A. Kakimoto
Keyword(s):  
Molecular Mechanisms ◽  
Neutral Lipids ◽  
Hepatic Lipid Metabolism ◽  
Pharmacological Interventions ◽  
Alcoholic Fatty Liver ◽  
Amino Acid Contents ◽  
Related Proteins ◽  
Precise Role ◽  
Alcoholic Fatty Liver Disease

Steatosis is the accumulation of neutral lipids in the cytoplasm. In the liver, it is associated with overeating and a sedentary lifestyle, but may also be a result of xenobiotic toxicity and genetics. Non-alcoholic fatty liver disease (NAFLD) defines an array of liver conditions varying from simple steatosis to inflammation and fibrosis. Over the last years, autophagic processes have been shown to be directly associated with the development and progression of these conditions. However, the precise role of autophagy in steatosis development is still unclear. Specifically, autophagy is necessary for the regulation of basic metabolism in hepatocytes, such as glycogenolysis and gluconeogenesis, response to insulin and glucagon signaling, and cellular responses to free amino acid contents. Also, genetic knockout models for autophagy-related proteins suggest a critical relationship between autophagy and hepatic lipid metabolism, but some results are still ambiguous. While autophagy may seem necessary to support lipid oxidation in some contexts, other evidence suggests that autophagic activity can lead to lipid accumulation instead. This structured literature review aims to critically discuss, compare, and organize results over the last 10 years regarding rodent steatosis models that measured several autophagy markers, with genetic and pharmacological interventions that may help elucidate the molecular mechanisms involved.

Impact of the Opioid/Fentanyl Epidemic on the Toxicology Laboratory’s Workload: The CMCVAMC Experience

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S90-S90
Author(s):  
Jeffrey Petersen ◽  
Thomas George ◽  
Darshana Jhala
Keyword(s):  
Public Health ◽  
Clinical Care ◽  
Health Concern ◽  
Fiscal Year ◽  
Opioid Epidemic ◽  
Public Health Concern ◽  
Significant Public Health Concern ◽  
Significant Public Health ◽  
Gas Chromatography Mass Spectroscopy

Abstract Introduction Opiates have long been used by both the population at large and the veteran population as a drug of abuse. However, recently, fentanyl—a synthetic opioid—has risen in prominence in this opioid drug abuse epidemic as a drug used by suppliers to “cut” heroin, to masquerade for another opiate, or for direct usage. As this is a recent phenomenon, the new increasing need to test for fentanyl for clinical reasons has a major impact on the toxicology laboratory’s workload. Method Quality assurance/improvement data were obtained to determine the number of fentanyl tests by gas chromatography/mass spectroscopy (GC/MS) performed by the toxicology laboratory since quarter 1 of 2011 (October-December 2010) to quarter 1 of 2018 (October-December 2017). The numbers of tests required for clinical care in each quarter were tabulated and compared in a graph. Quarters for each year begin and end in October. Results The total number of GC/MS tests for fentanyl needed for clinical care has been drastically increasing recently. From 2011 to 2015, the yearly number of tests clinically needed has ranged from 83 to 92. In 2016, the total number of clinically needed tests for fentanyl spiked to 167 and by fiscal year 2017 included 1,108 fentanyl GC/MS tests. The last examined quarter (quarter 1 of fiscal year 2018) included 527 tests, which is more than the highest number from 2017 (377 in quarter 4 of 2017). Conclusion The increasing use of fentanyl in the opioid epidemic appears to have played a role in significantly increasing the clinical need to test for fentanyl by GC/MS, increasing the volume by over 10 to 15 times. The role of fentanyl in the opioid epidemic remains a significant public health concern.

scholarly journals The gut microbial metabolome: modulation of cancer risk in obese individuals

2012 ◽  
Vol 72 (1) ◽  
pp. 178-188 ◽  
Author(s):  
Wendy R. Russell ◽  
Sylvia H. Duncan ◽  
Harry J. Flint
Keyword(s):  
Gut Microbiota ◽  
Genetic Factors ◽  
Microbial Metabolism ◽  
Health Concern ◽  
Human Gut ◽  
Alcoholic Fatty Liver ◽  
Health And Disease ◽  
Diet And Lifestyle ◽  
Alcoholic Fatty Liver Disease

Obesity is a critical health concern and although genetic factors may predispose an individual to become obese, changes in diet and lifestyle over the last few decades are likely to be significant contributors. Even so, it has been suggested that the causes of the current obesity crisis are not simply explained by changes in eating and exercise habits. Evidence suggests that the gut microbiota may play an important role in obesity and may be a factor in the development of associated disease including diabetes, CVD, non-alcoholic fatty liver disease and cancer. There have been tremendous advances in knowledge regarding the composition of human gut microbiota, but less is known about their function and role within the human host. It is becoming widely accepted that the products of microbial metabolism influence human health and disease, particularly with respect to immune response and inflammation. However, in most cases, the products of microbial metabolism are uncharacterised and their mechanism of action remains unknown. This review addresses the role of the metabolites produced by gut microbiota in cancer and obesity. It is clear that only if the link between microbial diversity and metabolic functionality is firmly established, will the mechanism by which gut microbiota maintains health or contributes to disease development be elucidated.

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