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American Journal of Physiology.... Jun 2017Intermediate filament proteins (IFs), such as cytoplasmic keratins in epithelial cells and vimentin in mesenchymal cells and the nuclear lamins, make up one of the three... (Review)
Review
Intermediate filament proteins (IFs), such as cytoplasmic keratins in epithelial cells and vimentin in mesenchymal cells and the nuclear lamins, make up one of the three major cytoskeletal protein families. Whether in digestive organs or other tissues, IFs share several unique features including stress-inducible overexpression, abundance, cell-selective and differentiation state expression, and association with >80 human diseases when mutated. Whereas most IF mutations cause disease, mutations in simple epithelial keratins 8, 18, or 19 or in lamin A/C predispose to liver disease with or without other tissue manifestations. Keratins serve major functions including protection from apoptosis, providing cellular and subcellular mechanical integrity, protein targeting to subcellular compartments, and scaffolding and regulation of cell-signaling processes. Keratins are essential for Mallory-Denk body aggregate formation that occurs in association with several liver diseases, whereas an alternate type of keratin and lamin aggregation occurs upon liver involvement in porphyria. IF-associated diseases have no known directed therapy, but high-throughput drug screening to identify potential therapies is an appealing ongoing approach. Despite the extensive current knowledge base, much remains to be discovered regarding IF physiology and pathophysiology in digestive and nondigestive organs.
Topics: Animals; Digestive System; Digestive System Diseases; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Intermediate Filament Proteins; Intermediate Filaments; Mallory Bodies; Mutation; Phenotype; Polymorphism, Genetic
PubMed: 28360031
DOI: 10.1152/ajpgi.00455.2016 -
Experimental and Molecular Pathology Jun 2016There is a possibility that the aggresomes that form in the brain in neurodegenerative diseases like Alzheimer's disease (AD) and in the liver where aggresomes like... (Review)
Review
There is a possibility that the aggresomes that form in the brain in neurodegenerative diseases like Alzheimer's disease (AD) and in the liver where aggresomes like Mallory-Denk Bodies (MDB) form, share mechanisms. MDBs can be prevented by feeding mice sadenosylmethionine (SAMe) or betaine. Possibly these proteins could prevent AD. We compared the literature on MDBs and AD pathogenesis, which include roles played by p62, ubiquitin UBB +1, HSPs70, 90, 104, FAT10, NEDD8, VCP/97, and the protein quality control mechanisms including the 26s proteasome, the IPOD and JUNQ and autophagosome pathways.
Topics: Alzheimer Disease; Animals; Autophagosomes; Humans; Mallory Bodies; Models, Biological; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Protein Aggregates; Protein Aggregation, Pathological
PubMed: 27068270
DOI: 10.1016/j.yexmp.2016.03.010 -
World Journal of Gastroenterology May 2011Mallory-Denk Bodies (MDB) are important as investigators, suggesting MDB as an indicator of the histologic severity of chronic hepatitis, causes of which include... (Review)
Review
Mallory-Denk Bodies (MDB) are important as investigators, suggesting MDB as an indicator of the histologic severity of chronic hepatitis, causes of which include hepatitis C, primary biliary cirrhosis (PBC), and nonalcoholic fatty liver disease (NAFLD). Matteoni et al scored MDB in patients with NAFLD as none, rare and many, and reported that MDB plays a prominent role in this classification scheme in an earlier classification system. In this study, we evaluated 258 patients with chronic hepatitis due to metabolic, autoimmune and viral etiologies. Liver biopsy samples were evaluated with hematoxylin and eosin, periodic acid-Schiff-diastase, Gordon and Sweet's reticulin, Masson's trichrome, and iron stains. Both staging and grading were performed. Additionally, MDB were evaluated and discussed for each disease. We examined patients with nonalcoholic steatohepatitis (NASH; 50 patients), alcoholic hepatitis (10 patients), PBC (50 patients), Wilson disease (WD; 20 patients), hepatitis B (50 patients), hepatitis C (50 patients) and hepatocellular carcinoma (HCC; 30 patients). Frequency of MDB was as follows; NASH: 10 patients with mild in 60% and moderate in 40% and observed in every stage of the disease and frequently seen in zone 3. PBC: 11 patients with mild in 10%, moderate in 70%, and cirrhosis in 20%, and frequently seen in zone 1. WD: 16 patients with moderate and severe in 60% and cirrhosis in 40% and frequently seen in zone 1. Hep B: 3 patients with mild in 66% and severe in 34%. Hep C: 7 patients with mild in 40% and moderate in 60% and observed in every stage. HCC: 3 patients with hep B in 2 patients. We found that there is no relationship between MDB and any form of chronic hepatitis regarding histologic severity such as alcoholic steatohepatitis and NAFLD and variable zone distribution by etiology.
Topics: Cytoplasm; Fatty Liver; Hepatitis, Chronic; Hepatocytes; Humans; Inclusion Bodies; Protein Folding; Proteins; Ubiquitination
PubMed: 21633525
DOI: 10.3748/wjg.v17.i17.2172 -
LGBT Health 2021Sexual minority youth (SMY), particularly bisexual youth and youth unsure of their sexual identity, are at greater risk of poor mental and sexual health outcomes than...
Sexual minority youth (SMY), particularly bisexual youth and youth unsure of their sexual identity, are at greater risk of poor mental and sexual health outcomes than heterosexual youth. The purpose of this study was to examine disparities in intimate partner violence (IPV) and mental and sexual health for Black and Latino/a bisexual and unsure youth compared with their White bisexual and unsure and Black and Latino/a heterosexual peers. We used aggregated state and school district 2015 Youth Risk Behavior Survey data to demonstrate differences in mental health (e.g., depressive symptoms and suicidality), sexual health (e.g., number of sexual partners and contraceptive use), and physical and sexual IPV between Black and Latino/a bisexual and unsure youth, and their White bisexual and unsure and Black and Latino/a heterosexual peers. Bisexual and unsure youth had higher odds of depressive symptoms, suicidal ideation and plans, and physical IPV than their same-race heterosexual peers. Black and Latina bisexual and unsure females were more likely to report sexual health risk behaviors than Black and Latina heterosexual females. There were few differences between bisexual and unsure youth of color and White youth. We add to a growing body of literature showing disparities in IPV and mental and sexual health among bisexual and unsure youth of color. Pronounced risk for poor health outcomes among bisexual and unsure females of color needs to be especially addressed by prevention and intervention efforts. We encourage further research on the health of SMY with multiple marginalized identities.
Topics: Adolescent; Black or African American; Female; Health Status Disparities; Heterosexuality; Hispanic or Latino; Humans; Intimate Partner Violence; Male; Mental Health; Sexual Health; Sexual and Gender Minorities
PubMed: 33861625
DOI: 10.1089/lgbt.2020.0374 -
FEBS Letters Aug 2016p62/SQSTM1 is a multifunctional signaling hub and autophagy adaptor with many binding partners, which allow it to activate mTORC1-dependent nutrient sensing,... (Review)
Review
p62/SQSTM1 is a multifunctional signaling hub and autophagy adaptor with many binding partners, which allow it to activate mTORC1-dependent nutrient sensing, NF-κB-mediated inflammatory responses, and the NRF2-activated antioxidant defense. p62 recognizes polyubiquitin chains via its C-terminal domain and binds to LC3 via its LIR motif, thereby promoting the autophagic degradation of ubiquitinated cargos. p62 accumulates in many human liver diseases, including nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), where it is a component of Mallory-Denk bodies and intracellular hyaline bodies. Chronic p62 elevation contributes to HCC development by preventing oncogene-induced senescence and death of cancer-initiating cells and enhancing their proliferation. In this review, we discuss p62-mediated signaling pathways and their roles in liver pathophysiology, especially NASH and HCC.
Topics: Carcinoma, Hepatocellular; Food; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Liver Neoplasms; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; NF-kappa B; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Sequestosome-1 Protein; TOR Serine-Threonine Kinases
PubMed: 27404485
DOI: 10.1002/1873-3468.12301 -
The FEBS Journal Feb 2023p62/Sequestosome-1 (SQSTM1) is a selective autophagy receptor that recruits and delivers intracellular substrates for bulk clearance through the autophagy lysosomal... (Review)
Review
p62/Sequestosome-1 (SQSTM1) is a selective autophagy receptor that recruits and delivers intracellular substrates for bulk clearance through the autophagy lysosomal pathway. Interestingly, p62 also serves as a signaling scaffold to participate in the regulation of multiple physiological processes, including oxidative stress response, metabolism, inflammation, and programmed cell death. Perturbation of p62 activity has been frequently found to be associated with the pathogenesis of many liver diseases. p62 has been identified as a critical component of protein aggregates in the forms of Mallory-Denk bodies (MDBs) or intracellular hyaline bodies (IHBs), which are known to be frequently detected in biopsy samples from alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC) patients. Importantly, abundance of these p62 inclusion bodies is increasingly recognized as a biomarker for NASH and HCC. Although the level of p62 bodies seems to predict the progression and prognosis of these liver diseases, understanding of the underlying mechanisms by which p62 regulates and contributes to the development and progression of these diseases remains incomplete. In this review, we will focus on the function and regulation of p62, and its pathophysiological roles in the liver, by critically reviewing the findings from preclinical models that recapitulate the pathogenesis and manifestation of these liver diseases in humans. In addition, we will also explore the suitability of p62 as a predictive biomarker and a potential therapeutic target for the treatment of liver diseases, including NASH and HCC, as well as recent development of small-molecule compounds for targeting the p62 signaling axis.
Topics: Humans; Carcinoma, Hepatocellular; Sequestosome-1 Protein; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Liver; Biomarkers; Autophagy
PubMed: 34882306
DOI: 10.1111/febs.16317 -
Arquivos Brasileiros de Cirurgia... 2012Roux-en-Y gastric bypass may result in stenosis of the gastrojejunal anastomosis. There is currently no well-defined management protocol for this complication. (Review)
Review
INTRODUCTION
Roux-en-Y gastric bypass may result in stenosis of the gastrojejunal anastomosis. There is currently no well-defined management protocol for this complication.
AIM
Through systematic review, to analyze the results of endoscopic dilation in patients with stenosis, including complication and success rates.
METHODS
The PubMed database was searched for relevant studies published each year from 1988 to 2010, and 23 studies were identified for analysis. Only papers describing the treatment of anastomotic stricture after Roux-en-Y gastric bypass were included, and case reports featuring less than three patients were excluded.
RESULTS
The mean age of the trial populations was 42.3 years and mean preoperative body mass index was 48.8 kg/m². A total of 1,298 procedures were undertaken in 760 patients (81% female), performing 1.7 dilations per patient. Through-the-scope balloons were used in 16 studies (69.5%) and Savary-Gilliard bougies in four. Only 2% of patients required surgical revision after dilation; the reported complication rate was 2.5% (n=19). Annual success rate was greater than 98% each year from 1992 to 2010, except for a 73% success rate in 2004. Seven studies reported complications, being perforation the most common, reported in 14 patients (1.82%) and requiring immediate operation in two patients. Other complications were also reported: one esophageal hematoma, one Mallory-Weiss tear, one case of severe nausea and vomiting, and two cases of severe abdominal pain.
CONCLUSION
Endoscopic treatment of stenosis is safe and effective; however, further high-quality randomized controlled trials should be conducted to confirm these findings.
Topics: Anastomosis, Surgical; Constriction, Pathologic; Endoscopy, Gastrointestinal; Gastric Bypass; Humans; Jejunum; Postoperative Complications; Stomach
PubMed: 23411930
DOI: 10.1590/s0102-67202012000400014 -
Experimental and Molecular Pathology Feb 2017This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25,... (Review)
Review
This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25, 2016 at New Orleans, Louisiana, USA. The integrative symposium investigated different aspects of alcohol-induced liver disease (ALD) as well as non-alcohol-induced liver disease (NAFLD) and possible repair. We revealed the basic aspects of alcohol metabolism that may be responsible for the development of liver disease as well as the factors that determine the amount, frequency and which type of alcohol misuse leads to liver and gastrointestinal diseases. We aimed to (1) describe the immuno-pathology of ALD, (2) examine the role of genetics in the development of alcoholic hepatitis (ASH) and NAFLD, (3) propose diagnostic markers of ASH and non-alcoholic steatohepatitis (NASH), (4) examine age and ethnic differences as well as analyze the validity of some models, (5) develop common research tools and biomarkers to study alcohol-induced effects, 6) examine the role of alcohol in oral health and colon and gastrointestinal cancer and (7) focus on factors that aggravate the severity of organ-damage. The present review includes pre-clinical, translational and clinical research that characterizes ALD and NAFLD. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD with simple fatty infiltrations and chronic alcoholic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes and cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human deficiency virus were discussed. Dysregulation of metabolism, as a result of ethanol exposure, in the intestine leads to colon carcinogenesis. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota have been suggested. The clinical aspects of NASH, as part of the metabolic syndrome in the aging population, have been presented. The symposium addressed mechanisms and biomarkers of alcohol induced damage to different organs, as well as the role of the microbiome in this dialog. The microbiota regulates and acts as a key element in harmonizing immune responses at intestinal mucosal surfaces. It is known that microbiota is an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. The signals at the sites of inflammation mediate recruitment and differentiation in order to remove inflammatory inducers and promote tissue homeostasis restoration. The change in the intestinal microbiota also influences the change in obesity and regresses the liver steatosis. Evidence on the positive role of moderate alcohol consumption on heart and metabolic diseases as well on reducing steatosis have been looked up. Moreover nutrition as a therapeutic intervention in alcoholic liver disease has been discussed. In addition to the original data, we searched the literature (2008-2016) for the latest publication on the described subjects. In order to obtain the updated data we used the usual engines (Pub Med and Google Scholar). The intention of the eighth symposia was to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.
Topics: Alcoholism; Congresses as Topic; Cytochrome P-450 CYP2E1; Hepatitis, Alcoholic; Humans; Life Style; Liver Diseases, Alcoholic; Microbiota; Non-alcoholic Fatty Liver Disease; Polymorphism, Genetic
PubMed: 28077318
DOI: 10.1016/j.yexmp.2017.01.003 -
World Journal of Hepatology Aug 2010This editorial reviews the recent evidence showing that Mallory-Denk bodies (MDBs) form in hepatocytes as the result of a drug-induced shift from the 26s proteasome...
This editorial reviews the recent evidence showing that Mallory-Denk bodies (MDBs) form in hepatocytes as the result of a drug-induced shift from the 26s proteasome formation to the immunoproteasome formation. The shift is the result of changes in gene expression induced in promoter activation, which is induced by the IFNγ and TNFα signaling pathway. This activates TLR 2 and 4 receptors. The TLR signaling pathway stimulates both the induction of a cytokine proinflammatory response and an up regulation of growth factors. The MDB- forming hepatocytes proliferate as a result of the increase in growth factor expression by the MDB- forming cells, which selectively proliferate in response to drug toxicity. All of these mechanisms are induced by drug toxicity, and are prevented by feeding the methyl donors SAMe and betaine, supporting the epigenetic response of MDB formation.
PubMed: 21161012
DOI: 10.4254/wjh.v2.i8.295 -
The Journal of Adolescent Health :... Jun 2021To synthesize the diverse body of literature on sexual and gender minority youth (SGMY) and sexual health education. (Review)
Review
PURPOSE
To synthesize the diverse body of literature on sexual and gender minority youth (SGMY) and sexual health education.
METHODS
We conducted a systematic search of the literature on SGMY and sexual health education, including SGMY perspectives on sexual health education, the acceptability or effectiveness of programs designed for SGMY, and SGMY-specific results of sexual health education programs delivered to general youth populations.
RESULTS
A total of 32 articles were included. Sixteen qualitative studies with SGMY highlight key perspectives underscoring how youth gained inadequate knowledge from sexual health education experiences and received content that excluded their identities and behaviors. Thirteen studies examined the acceptability or effectiveness of sexual health interventions designed for SGMY from which key characteristics of inclusive sexual health education relating to development, content, and delivery emerged. One study found a sexual health education program delivered to a general population of youth was also acceptable for a subsample of sexual minority girls.
CONCLUSIONS
Future research on SGMY experiences should incorporate populations understudied, including younger adolescents, sexual minority girls, and transgender persons. Further, the effectiveness of inclusive sexual health education in general population settings requires further study.
Topics: Adolescent; Female; Humans; Sex Education; Sexual Behavior; Sexual Health; Sexual and Gender Minorities; Transgender Persons
PubMed: 33162290
DOI: 10.1016/j.jadohealth.2020.09.032