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1
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Sabet NH, Wyatt TA. The alcohol exposome. Alcohol 2025; 122:81-89. [PMID: 39722409 PMCID: PMC11918757 DOI: 10.1016/j.alcohol.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 12/05/2024] [Accepted: 12/07/2024] [Indexed: 12/28/2024]
Abstract
Science is now in a new era of exposome research that strives to build a more all-inclusive, panoramic view in the quest for answers; this is especially true in the field of toxicology. Alcohol exposure researchers have been examining the multivariate co-exposures that may either exacerbate or initiate alcohol-related tissue/organ injuries. This manuscript presents selected key variables that represent the Alcohol Exposome. The primary variables that make up the Alcohol Exposome can include comorbidities such as cigarettes, poor diet, occupational hazards, environmental hazards, infectious agents, and aging. In addition to representing multiple factors, the Alcohol Exposome examines the various types of intercellular communications that are carried from one organ system to another and may greatly impact the types of injuries and metabolites caused by alcohol exposure. The intent of defining the Alcohol Exposome is to bring the newly expanded definition of Exposomics, meaning the study of the exposome, to the field of alcohol research and to emphasize the need for examining research results in a non-isolated environment representing a more relevant manner in which all human physiology exists.
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Affiliation(s)
- Nousha H Sabet
- Department of Internal Medicine, Division of Pulmonary, Critical Care & Sleep, University of Nebraska Medical Center, Omaha, NE, USA; Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE', USA
| | - Todd A Wyatt
- Department of Internal Medicine, Division of Pulmonary, Critical Care & Sleep, University of Nebraska Medical Center, Omaha, NE, USA; Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE', USA; Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
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2
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Hu Y, Schnabl B, Stärkel P. Origin, Function, and Implications of Intestinal and Hepatic Macrophages in the Pathogenesis of Alcohol-Associated Liver Disease. Cells 2025; 14:207. [PMID: 39936998 PMCID: PMC11816606 DOI: 10.3390/cells14030207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 01/12/2025] [Accepted: 01/15/2025] [Indexed: 02/13/2025] Open
Abstract
Macrophages are members of the human innate immune system, and the majority reside in the liver. In recent years, they have been recognized as essential players in the maintenance of liver and intestinal homeostasis as well as key guardians of their respective immune systems, and they are increasingly being recognized as such. Paradoxically, they are also likely involved in chronic pathologies of the gastrointestinal tract and potentially in the alteration of the gut-liver axis in alcohol use disorder (AUD) and alcohol-associated liver disease (ALD). To date, the causal relationship between macrophages, the pathogenesis of ALD, and the immune dysregulation of the gut remains unclear. In this review, we will discuss our current understanding of the heterogeneity of intestinal and hepatic macrophages, their ontogeny, the potential factors that regulate their origin, and the evidence of how they are associated with the manifestation of chronic inflammation. We will also illustrate how the micro-environment of the intestine shapes the phenotypes and functionality of the macrophage compartment in both the intestines and liver and how they change during chronic alcohol abuse. Finally, we highlight the obstacles to current research and the prospects for this field.
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Affiliation(s)
- Yifan Hu
- Laboratory of Hepato-Gastroenterology, Institute of Clinical and Experimental Research, Université Catholique de Louvain, 1200 Brussels, Belgium;
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA 92161, USA;
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, USA
| | - Peter Stärkel
- Laboratory of Hepato-Gastroenterology, Institute of Clinical and Experimental Research, Université Catholique de Louvain, 1200 Brussels, Belgium;
- Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium
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3
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Peng Q, Zheng H, Quan L, Li S, Huang J, Li J, Xie G. Therapeutic Potential of Foodborne Indole Derived from Chinese Stinky Tofu in Reducing Intestinal Inflammation and Enhancing Barrier Function to Mitigate Alcoholic Liver Injury. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:21829-21842. [PMID: 39300777 DOI: 10.1021/acs.jafc.4c06203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/22/2024]
Abstract
Indole, a compound in Chinese stinky tofu (ST), acts as a ligand for the aryl hydrocarbon receptor (AHR). Despite extensive research on prebiotic compounds, indole's specific role in ST remains unexplored. This study used an ethanol gavage method to create an ALD (alcoholic liver disease) mouse model and investigate dietary indole's effects on the intestinal barrier. Our findings indicate that after 6 weeks of being fed ST, the indole present (2 mg/day) robustly activated the intestinal AHR, upregulating its target gene, CYP1A1 (cytochrome P450 1A1 enzyme). This activation significantly reduced intestinal permeability, mitigated alcohol-induced oxidative stress and inflammation, and restored intestinal barrier function. Consequently, the study demonstrates that foodborne indole substantially reduces alcohol absorption and lowers the expression levels of liver inflammation-related factors, thereby slowing the progression of ALD. These results highlight indole's therapeutic potential for treating ALD and its role in developing functional foods.
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Affiliation(s)
- Qi Peng
- National Engineering Research Center for Chinese CRW (branch center), School of Life and Environmental Sciences, Shaoxing University, Shaoxing 312000, Zhejiang, China
| | - Huajun Zheng
- National Engineering Research Center for Chinese CRW (branch center), School of Life and Environmental Sciences, Shaoxing University, Shaoxing 312000, Zhejiang, China
| | - Leping Quan
- National Engineering Research Center for Chinese CRW (branch center), School of Life and Environmental Sciences, Shaoxing University, Shaoxing 312000, Zhejiang, China
| | - Shanshan Li
- National Engineering Research Center for Chinese CRW (branch center), School of Life and Environmental Sciences, Shaoxing University, Shaoxing 312000, Zhejiang, China
| | - Jiaxin Huang
- National Engineering Research Center for Chinese CRW (branch center), School of Life and Environmental Sciences, Shaoxing University, Shaoxing 312000, Zhejiang, China
| | - Jiachen Li
- National Engineering Research Center for Chinese CRW (branch center), School of Life and Environmental Sciences, Shaoxing University, Shaoxing 312000, Zhejiang, China
| | - Guangfa Xie
- Key Laboratory of Pollution Exposure and Health Intervention of Zhejiang Province, College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310015, China
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Ramadan YN, Kamel AM, Medhat MA, Hetta HF. MicroRNA signatures in the pathogenesis and therapy of inflammatory bowel disease. Clin Exp Med 2024; 24:217. [PMID: 39259390 PMCID: PMC11390904 DOI: 10.1007/s10238-024-01476-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 08/20/2024] [Indexed: 09/13/2024]
Abstract
Inflammatory bowel disease (IBD) is a persistent inflammatory illness of the gastrointestinal tract (GIT) triggered by an inappropriate immune response to environmental stimuli in genetically predisposed persons. Unfortunately, IBD patients' quality of life is negatively impacted by the symptoms associated with the disease. The exact etiology of IBD pathogenesis is not fully understood, but the emerging research indicated that the microRNA (miRNA) plays an important role. miRNAs have been documented to possess a significant role in regulating pro- and anti-inflammatory pathways, in addition to their roles in several physiological processes, including cell growth, proliferation, and apoptosis. Variations in the miRNA profiles might be a helpful prognostic indicator and a valuable tool in the differential diagnosis of IBD. Most interestingly, these miRNAs have a promising therapeutic target in several pre-clinical animal studies and phase 2 clinical studies to alleviate inflammation and improve patient's quality of life. This comprehensive review discusses the current knowledge about the significant physiological role of different miRNAs in the health of the intestinal immune system and addresses the role of the most relevant differentially expressed miRNAs in IBD, identify their potential targets, and emphasize their diagnostic and therapeutic potential for future research.
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Affiliation(s)
- Yasmin N Ramadan
- Department of Microbiology and Immunology, Faculty of Pharmacy, Assiut University, Assiut, 71515, Egypt.
| | - Ayat M Kamel
- Department of Microbiology and Immunology, Faculty of Pharmacy, Assiut University, Assiut, 71515, Egypt
| | - Mohammed A Medhat
- Tropical Medicine and Gastroenterology Department, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
| | - Helal F Hetta
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, 71491, Tabuk, Saudi Arabia
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5
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Nelaturi P, Kademani SP, Nallagangula KS, Ravikumar S. Role of MicroRNAs in Alcohol-Related Liver Disease. ALCOHOLISM TREATMENT QUARTERLY 2024; 42:115-137. [DOI: 10.1080/07347324.2023.2256756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Affiliation(s)
- Prabhudas Nelaturi
- Multi-Disciplinary Centre for Biomedical Research, Aarupadai Veedu Medical College and Hospital, Vinayaka Mission’s Research Foundation (Deemed to be University), Puducherry, India
| | - Sangeetha P Kademani
- Multi-Disciplinary Centre for Biomedical Research, Aarupadai Veedu Medical College and Hospital, Vinayaka Mission’s Research Foundation (Deemed to be University), Puducherry, India
| | | | - Sambandam Ravikumar
- Multi-Disciplinary Centre for Biomedical Research, Aarupadai Veedu Medical College and Hospital, Vinayaka Mission’s Research Foundation (Deemed to be University), Puducherry, India
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6
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Jouve M, Carpentier R, Kraiem S, Legrand N, Sobolewski C. MiRNAs in Alcohol-Related Liver Diseases and Hepatocellular Carcinoma: A Step toward New Therapeutic Approaches? Cancers (Basel) 2023; 15:5557. [PMID: 38067261 PMCID: PMC10705678 DOI: 10.3390/cancers15235557] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 11/15/2023] [Accepted: 11/17/2023] [Indexed: 06/29/2024] Open
Abstract
Alcohol-related Liver Disease (ALD) is the primary cause of chronic liver disorders and hepatocellular carcinoma (HCC) development in developed countries and thus represents a major public health concern. Unfortunately, few therapeutic options are available for ALD and HCC, except liver transplantation or tumor resection for HCC. Deciphering the molecular mechanisms underlying the development of these diseases is therefore of major importance to identify early biomarkers and to design efficient therapeutic options. Increasing evidence indicate that epigenetic alterations play a central role in the development of ALD and HCC. Among them, microRNA importantly contribute to the development of this disease by controlling the expression of several genes involved in hepatic metabolism, inflammation, fibrosis, and carcinogenesis at the post-transcriptional level. In this review, we discuss the current knowledge about miRNAs' functions in the different stages of ALD and their role in the progression toward carcinogenesis. We highlight that each stage of ALD is associated with deregulated miRNAs involved in hepatic carcinogenesis, and thus represent HCC-priming miRNAs. By using in silico approaches, we have uncovered new miRNAs potentially involved in HCC. Finally, we discuss the therapeutic potential of targeting miRNAs for the treatment of these diseases.
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Affiliation(s)
- Mickaël Jouve
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Rodolphe Carpentier
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Sarra Kraiem
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Noémie Legrand
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Cyril Sobolewski
- Univ. Lille, Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, F-59000 Lille, France
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7
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Rungratanawanich W, Ballway JW, Wang X, Won KJ, Hardwick JP, Song BJ. Post-translational modifications of histone and non-histone proteins in epigenetic regulation and translational applications in alcohol-associated liver disease: Challenges and research opportunities. Pharmacol Ther 2023; 251:108547. [PMID: 37838219 DOI: 10.1016/j.pharmthera.2023.108547] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 09/30/2023] [Accepted: 10/05/2023] [Indexed: 10/16/2023]
Abstract
Epigenetic regulation is a process that takes place through adaptive cellular pathways influenced by environmental factors and metabolic changes to modulate gene activity with heritable phenotypic variations without altering the DNA sequences of many target genes. Epigenetic regulation can be facilitated by diverse mechanisms: many different types of post-translational modifications (PTMs) of histone and non-histone nuclear proteins, DNA methylation, altered levels of noncoding RNAs, incorporation of histone variants, nucleosomal positioning, chromatin remodeling, etc. These factors modulate chromatin structure and stability with or without the involvement of metabolic products, depending on the cellular context of target cells or environmental stimuli, such as intake of alcohol (ethanol) or Western-style high-fat diets. Alterations of epigenetics have been actively studied, since they are frequently associated with multiple disease states. Consequently, explorations of epigenetic regulation have recently shed light on the pathogenesis and progression of alcohol-associated disorders. In this review, we highlight the roles of various types of PTMs, including less-characterized modifications of nuclear histone and non-histone proteins, in the epigenetic regulation of alcohol-associated liver disease (ALD) and other disorders. We also describe challenges in characterizing specific PTMs and suggest future opportunities for basic and translational research to prevent or treat ALD and many other disease states.
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Affiliation(s)
- Wiramon Rungratanawanich
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892, USA
| | - Jacob W Ballway
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892, USA
| | - Xin Wang
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Kyoung-Jae Won
- Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, CA, 90069, USA
| | - James P Hardwick
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
| | - Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892, USA.
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Anand SK, Ahmad MH, Sahu MR, Subba R, Mondal AC. Detrimental Effects of Alcohol-Induced Inflammation on Brain Health: From Neurogenesis to Neurodegeneration. Cell Mol Neurobiol 2023; 43:1885-1904. [PMID: 36436159 PMCID: PMC11412203 DOI: 10.1007/s10571-022-01308-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 11/11/2022] [Indexed: 11/28/2022]
Abstract
Alcohol consumption is known to cause several brain anomalies. The pathophysiological changes associated with alcohol intoxication are mediated by various factors, most notable being inflammation. Alcohol intoxication may cause inflammation through several molecular mechanisms in multiple organs, including the brain, liver and gut. Alcohol-induced inflammation in the brain and gut are intricately connected. In the gut, alcohol consumption leads to the weakening of the intestinal barrier, resulting in bacteria and bacterial endotoxins permeating into the bloodstream. These bacterial endotoxins can infiltrate other organs, including the brain, where they cause cognitive dysfunction and neuroinflammation. Alcohol can also directly affect the brain by activating immune cells such as microglia, triggering the release of pro-inflammatory cytokines and neuroinflammation. Since alcohol causes the death of neural cells, it has been correlated to an increased risk of neurodegenerative diseases. Besides, alcohol intoxication has also negatively affected neural stem cells, affecting adult neurogenesis and causing hippocampal dysfunctions. This review provides an overview of alcohol-induced brain anomalies and how inflammation plays a crucial mechanistic role in alcohol-associated pathophysiology.
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Affiliation(s)
- Surendra Kumar Anand
- Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi, 110067, India
| | - Mir Hilal Ahmad
- Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi, 110067, India
| | - Manas Ranjan Sahu
- Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi, 110067, India
| | - Rhea Subba
- Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi, 110067, India
| | - Amal Chandra Mondal
- Laboratory of Cellular and Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi, 110067, India.
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9
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Alfaifi J, Germain A, Heba AC, Arnone D, Gailly L, Ndiaye NC, Viennois E, Caron B, Peyrin-Biroulet L, Dreumont N. Deep Dive Into MicroRNAs in Inflammatory Bowel Disease. Inflamm Bowel Dis 2023; 29:986-999. [PMID: 36545755 DOI: 10.1093/ibd/izac250] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Indexed: 06/02/2023]
Abstract
Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, is thought to develop in genetically predisposed individuals as a consequence of complex interactions between dysregulated inflammatory stimuli, immunological responses, and environmental factors. The pathogenesis of IBD has yet to be fully understood. The global increase in the incidence of IBD suggests a gap in the current understanding of the disease. The development of a new diagnostic tool for inflammatory bowel disease that is both less invasive and more cost-effective would allow for better management of this condition. MicroRNAs (miRNAs) are a class of noncoding RNAs with important roles as posttranscriptional regulators of gene expression, which has led to new insights into understanding IBD. Using techniques such as microarrays and real-time polymerase chain reactions, researchers have investigated the patterns in which patients with Crohn's disease and ulcerative colitis show alterations in the expression of miRNA in tissue, blood, and feces. These miRNAs are found to be differentially expressed in IBD and implicated in its pathogenesis through alterations in autophagy, intestinal barrier, and immune homeostasis. In this review, we discuss the miRNA expression profiles associated with IBD in tissue, peripheral blood, and feces and provide an overview of the miRNA mechanisms involved in IBD.
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Affiliation(s)
- Jaber Alfaifi
- Department of Hepatobiliary, Colorectal, and Digestive Surgery, Nancy University Hospital, University of Lorraine, Nancy, France
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Adeline Germain
- Department of Hepatobiliary, Colorectal, and Digestive Surgery, Nancy University Hospital, University of Lorraine, Nancy, France
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Anne-Charlotte Heba
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Djésia Arnone
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Laura Gailly
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Ndeye Coumba Ndiaye
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
| | - Emilie Viennois
- INSERM U1149, Center of Research on Inflammation, Université de Paris, Paris, France
| | - Bénédicte Caron
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France
| | - Laurent Peyrin-Biroulet
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France
| | - Natacha Dreumont
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), INSERM, University of Lorraine, Nancy, France
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Abstract
BACKGROUND Autoimmune hepatitis has an unknown cause and genetic associations that are not disease-specific or always present. Clarification of its missing causality and heritability could improve prevention and management strategies. AIMS Describe the key epigenetic and genetic mechanisms that could account for missing causality and heritability in autoimmune hepatitis; indicate the prospects of these mechanisms as pivotal factors; and encourage investigations of their pathogenic role and therapeutic potential. METHODS English abstracts were identified in PubMed using multiple key search phases. Several hundred abstracts and 210 full-length articles were reviewed. RESULTS Environmental induction of epigenetic changes is the prime candidate for explaining the missing causality of autoimmune hepatitis. Environmental factors (diet, toxic exposures) can alter chromatin structure and the production of micro-ribonucleic acids that affect gene expression. Epistatic interaction between unsuspected genes is the prime candidate for explaining the missing heritability. The non-additive, interactive effects of multiple genes could enhance their impact on the propensity and phenotype of autoimmune hepatitis. Transgenerational inheritance of acquired epigenetic marks constitutes another mechanism of transmitting parental adaptations that could affect susceptibility. Management strategies could range from lifestyle adjustments and nutritional supplements to precision editing of the epigenetic landscape. CONCLUSIONS Autoimmune hepatitis has a missing causality that might be explained by epigenetic changes induced by environmental factors and a missing heritability that might reflect epistatic gene interactions or transgenerational transmission of acquired epigenetic marks. These unassessed or under-evaluated areas warrant investigation.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA.
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Luo L, Chang Y, Sheng L. Gut-liver axis in the progression of nonalcoholic fatty liver disease: From the microbial derivatives-centered perspective. Life Sci 2023; 321:121614. [PMID: 36965522 DOI: 10.1016/j.lfs.2023.121614] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/16/2023] [Accepted: 03/18/2023] [Indexed: 03/27/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the world's most common chronic liver diseases. However, its pathogenesis remains unclear. With the deepening of research, NAFLD is considered a metabolic syndrome associated with the environment, heredity, and metabolic disorders. Recently, the close relationship between the intestinal microbiome and NAFLD has been discovered, and the theory of the "gut-liver axis" has been proposed. In short, the gut bacteria directly reach the liver via the portal vein through the damaged intestinal wall or indirectly participate in the development of NAFLD through signaling pathways mediated by their components and metabolites. This review focuses on the roles of microbiota-derived lipopolysaccharide, DNA, peptidoglycan, bile acids, short-chain fatty acids, endogenous ethanol, choline and its metabolites, indole and its derivatives, and bilirubin and its metabolites in the progression of NAFLD, which may provide significative insights into the pathogenesis, diagnosis, and treatment for this highly prevalent liver disease.
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Affiliation(s)
- Lijun Luo
- Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China; Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
| | - Yongchun Chang
- Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China; Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
| | - Li Sheng
- Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China; Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
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12
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Guo C, Zheng L, Chen S, Liang X, Song X, Wang Y, Hua B, Qiu L. Thymol ameliorates ethanol-induced hepatotoxicity via regulating metabolism and autophagy. Chem Biol Interact 2023; 370:110308. [PMID: 36535314 DOI: 10.1016/j.cbi.2022.110308] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 11/22/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022]
Abstract
Alcoholic liver disease represents a serious threat to human health. In terms of safety and acceptability, thymol is widely used in or on foodstuffs to generate odour and taste. The present study aimed to investigate the therapeutic effect and mechanism of thymol against ethanol-induced injury in liver cells. Here we found that thymol is an effective agent for reducing ethanol-induced reactive oxygen species production in mouse liver cells. Thymol improves ethanol-induced lipid accumulation, and this corresponded to altered DGAT2 mRNA expression levels. Metabolomics data analysis showed that thymol alleviated ethanol-induced changes in the levels of thirty-four metabolites including nicotinic acid and l-arginine. By utilizing pathway enrichment analysis, altered metabolites in cells treated with ethanol and ethanol plus thymol were enriched in fourteen pathways including metabolic pathways and arginine and proline metabolism. We further confirmed the alleviation of overdose nitric oxide production in cells treated with ethanol plus thymol compared with that in ethanol-treated cells. It was interesting that up-regulated LC3-II/LC3-I ratio together with higher SQSTM1 protein abundance in ethanol-treated cells were attenuated by treatment with ethanol plus thymol. Thymol ameliorated ethanol-induced reduction of HSPA8 protein abundance. In addition, chloroquine-treated cells exhibited lower HSPA8 protein abundance compared with cells simulated with ethanol plus thymol. These data reveal that improving effect of thymol on ethanol-induced metabolic alteration is related to autophagic flux restoration. Our findings indicate that thymol is an attractive option for treating ethanol-induced liver damage.
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Affiliation(s)
- Chang Guo
- School of Life Sciences, Longyan University, Longyan, 364012, PR China; Fujian Provincial Key Laboratory for the Prevention and Control of Animal Infectious Diseases and Biotechnology, Longyan, 364012, PR China; Key Laboratory of Preventive Veterinary Medicine and Biotechnology (Longyan University), Fujian Province University, Longyan, 364012, PR China
| | - Linyan Zheng
- School of Life Sciences, Longyan University, Longyan, 364012, PR China
| | - Shuyu Chen
- School of Life Sciences, Longyan University, Longyan, 364012, PR China
| | - Xuxuan Liang
- School of Life Sciences, Longyan University, Longyan, 364012, PR China
| | - Xue Song
- School of Life Sciences, Longyan University, Longyan, 364012, PR China
| | - Yue Wang
- School of Life Sciences, Longyan University, Longyan, 364012, PR China
| | - Baoyu Hua
- School of Life Sciences, Longyan University, Longyan, 364012, PR China; Fujian Provincial Key Laboratory for the Prevention and Control of Animal Infectious Diseases and Biotechnology, Longyan, 364012, PR China; Key Laboratory of Preventive Veterinary Medicine and Biotechnology (Longyan University), Fujian Province University, Longyan, 364012, PR China
| | - Longxin Qiu
- School of Life Sciences, Longyan University, Longyan, 364012, PR China; Fujian Provincial Key Laboratory for the Prevention and Control of Animal Infectious Diseases and Biotechnology, Longyan, 364012, PR China; Key Laboratory of Preventive Veterinary Medicine and Biotechnology (Longyan University), Fujian Province University, Longyan, 364012, PR China.
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Liu X, Yu S, Zhang Y, Zhang W, Zhong H, Lu X, Guan R. A review on the protective effect of active components in Antrodia camphorata against alcoholic liver injury. JOURNAL OF ETHNOPHARMACOLOGY 2023; 300:115740. [PMID: 36162549 DOI: 10.1016/j.jep.2022.115740] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 09/02/2022] [Accepted: 09/15/2022] [Indexed: 06/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Antrodia camphorata is a genus of wood-rot basidiomycete in the family Fomitopsidaceae. It is a valuable medicinal fungus in China that contains more than 78 kinds of active compounds. A. camphorata has good protection effects on the liver, especially on alcoholic liver injury (ALI). AIM This paper summarizes the complex occurrence and development of alcoholic liver disease (ALD). In addition, the effect of ALD on the intestine through the gut-liver axis is summarized. The protective mechanism of A. camphorata on ALI is reviewed to reveal its therapeutic potential, offering insights into future research. MATERIALS AND METHODS A comprehensive search in the literature was obtained from books and online databases such as Web of Science, Google Scholar, PubMed, Scopus, Science direct, ACS Publications and Baidu Scholar. RESULTS The pathogenesis of ALD mainly includes oxidative stress injury, intestinal microflora imbalance, inflammatory mediator injury and nutritional imbalance. A. camphorata contains rich active components (e.g. polysaccharides, triterpenoids, maleic and succinic acid derivatives, amino acids, superoxide dismutase, vitamins, lignin and sterols). These components have good antioxidant, anti-inflammatory and intestinal protection activities. Therefore, A. camphorata has a wide application in the prevention and treatment of ALI. CONCLUSIONS ALD develops from a mild disease to alcoholic hepatitis and cirrhosis, which is the main reason of global morbidity and mortality. At present, there is no effective drug for the treatment of ALD. A. camphorata, as a valuable medicinal fungus unique to Taiwan, has a great protective effect on the liver. It is expected to be an effective drug for ALI treatment. Although many studies have performed the protective effects of A. camphorata on ALI, its regulatory effects on the gut-liver axis of ALD patients need to be further explored.
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Affiliation(s)
- Xiaofeng Liu
- College of Food Science and Technology, Zhejiang University of Technology, Zhejiang, Hangzhou, 310014, China.
| | - Shuzhen Yu
- College of Food Science and Technology, Zhejiang University of Technology, Zhejiang, Hangzhou, 310014, China.
| | - Yao Zhang
- Zhejiang Provincial Key Lab for Chem and Bio Processing Technology of Farm Produces, School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Zhejiang, Hangzhou, 310023, China.
| | - Wei Zhang
- College of Food Science and Technology, Zhejiang University of Technology, Zhejiang, Hangzhou, 310014, China.
| | - Hao Zhong
- College of Food Science and Technology, Zhejiang University of Technology, Zhejiang, Hangzhou, 310014, China.
| | - Xiaoqin Lu
- College of Food Science and Technology, Zhejiang University of Technology, Zhejiang, Hangzhou, 310014, China.
| | - Rongfa Guan
- College of Food Science and Technology, Zhejiang University of Technology, Zhejiang, Hangzhou, 310014, China.
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14
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Nikolaieva N, Sevcikova A, Omelka R, Martiniakova M, Mego M, Ciernikova S. Gut Microbiota-MicroRNA Interactions in Intestinal Homeostasis and Cancer Development. Microorganisms 2022; 11:microorganisms11010107. [PMID: 36677399 PMCID: PMC9867529 DOI: 10.3390/microorganisms11010107] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/21/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023] Open
Abstract
Pre-clinical models and clinical studies highlight the significant impact of the host-microbiota relationship on cancer development and treatment, supporting the emerging trend for a microbiota-based approach in clinical oncology. Importantly, the presence of polymorphic microbes is considered one of the hallmarks of cancer. The epigenetic regulation of gene expression by microRNAs affects crucial biological processes, including proliferation, differentiation, metabolism, and cell death. Recent evidence has documented the existence of bidirectional gut microbiota-microRNA interactions that play a critical role in intestinal homeostasis. Importantly, alterations in microRNA-modulated gene expression are known to be associated with inflammatory responses and dysbiosis in gastrointestinal disorders. In this review, we summarize the current findings about miRNA expression in the intestine and focus on specific gut microbiota-miRNA interactions linked to intestinal homeostasis, the immune system, and cancer development. We discuss the potential clinical utility of fecal miRNA profiling as a diagnostic and prognostic tool in colorectal cancer, and demonstrate how the emerging trend of gut microbiota modulation, together with the use of personalized microRNA therapeutics, might bring improvements in outcomes for patients with gastrointestinal cancer in the era of precision medicine.
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Affiliation(s)
- Nataliia Nikolaieva
- Department of Genetics, Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, 845 05 Bratislava, Slovakia
| | - Aneta Sevcikova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, 845 05 Bratislava, Slovakia
| | - Radoslav Omelka
- Department of Botany and Genetics, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, 949 74 Nitra, Slovakia
| | - Monika Martiniakova
- Department of Zoology and Anthropology, Faculty of Natural Sciences and Informatics, Constantine the Philosopher University in Nitra, 949 74 Nitra, Slovakia
| | - Michal Mego
- National Cancer Institute and Faculty of Medicine, Comenius University, 813 72 Bratislava, Slovakia
| | - Sona Ciernikova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, 845 05 Bratislava, Slovakia
- Correspondence: ; Tel.: +421-02-3229519
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15
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Redox and Metabolic Regulation of Intestinal Barrier Function and Associated Disorders. Int J Mol Sci 2022; 23:ijms232214463. [PMID: 36430939 PMCID: PMC9699094 DOI: 10.3390/ijms232214463] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/11/2022] [Accepted: 11/14/2022] [Indexed: 11/23/2022] Open
Abstract
The intestinal epithelium forms a physical barrier assembled by intercellular junctions, preventing luminal pathogens and toxins from crossing it. The integrity of tight junctions is critical for maintaining intestinal health as the breakdown of tight junction proteins leads to various disorders. Redox reactions are closely associated with energy metabolism. Understanding the regulation of tight junctions by cellular metabolism and redox status in cells may lead to the identification of potential targets for therapeutic interventions. In vitro and in vivo models have been utilized in investigating intestinal barrier dysfunction and in particular the free-living soil nematode, Caenorhabditis elegans, may be an important alternative to mammalian models because of its convenience of culture, transparent body for microscopy, short generation time, invariant cell lineage and tractable genetics.
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16
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Czaja AJ. Epigenetic Aspects and Prospects in Autoimmune Hepatitis. Front Immunol 2022; 13:921765. [PMID: 35844554 PMCID: PMC9281562 DOI: 10.3389/fimmu.2022.921765] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 05/12/2022] [Indexed: 12/12/2022] Open
Abstract
The observed risk of autoimmune hepatitis exceeds its genetic risk, and epigenetic factors that alter gene expression without changing nucleotide sequence may help explain the disparity. Key objectives of this review are to describe the epigenetic modifications that affect gene expression, discuss how they can affect autoimmune hepatitis, and indicate prospects for improved management. Multiple hypo-methylated genes have been described in the CD4+ and CD19+ T lymphocytes of patients with autoimmune hepatitis, and the circulating micro-ribonucleic acids, miR-21 and miR-122, have correlated with laboratory and histological features of liver inflammation. Both epigenetic agents have also correlated inversely with the stage of liver fibrosis. The reduced hepatic concentration of miR-122 in cirrhosis suggests that its deficiency may de-repress the pro-fibrotic prolyl-4-hydroxylase subunit alpha-1 gene. Conversely, miR-155 is over-expressed in the liver tissue of patients with autoimmune hepatitis, and it may signify active immune-mediated liver injury. Different epigenetic findings have been described in diverse autoimmune and non-autoimmune liver diseases, and these changes may have disease-specificity. They may also be responses to environmental cues or heritable adaptations that distinguish the diseases. Advances in epigenetic editing and methods for blocking micro-ribonucleic acids have improved opportunities to prove causality and develop site-specific, therapeutic interventions. In conclusion, the role of epigenetics in affecting the risk, clinical phenotype, and outcome of autoimmune hepatitis is under-evaluated. Full definition of the epigenome of autoimmune hepatitis promises to enhance understanding of pathogenic mechanisms and satisfy the unmet clinical need to improve therapy for refractory disease.
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Affiliation(s)
- Albert J. Czaja
- *Correspondence: Albert J. Czaja, ; orcid.org/0000-0002-5024-3065
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17
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Ram AK, Vairappan B. Role of zonula occludens in gastrointestinal and liver cancers. World J Clin Cases 2022; 10:3647-3661. [PMID: 35647143 PMCID: PMC9100728 DOI: 10.12998/wjcc.v10.i12.3647] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 08/08/2021] [Accepted: 03/04/2022] [Indexed: 02/06/2023] Open
Abstract
A growing body of evidence suggests that tight junction (TJ) proteins play a crucial role in the pathogenesis of various diseases, including gastrointestinal (GI) cancer and hepatocellular carcinoma (HCC). TJ proteins primarily maintain the epithelial and endothelial cells intact together through integral proteins however, recent reports suggest that they also regulate gene expression necessary for cell proliferation, angiogenesis, and metastasis through adapter proteins such as zonula occludens (ZO). ZO proteins are membrane-associated cytosolic scaffolding proteins that modulate cell proliferation by interacting with several transcription factors. Reduced ZO proteins in GI cancer and HCC are correlated with tumor development and poor prognosis. Pubmed has searched for using the keyword ZO and gastric cancer, ZO and cancer, and ZO and HCC for the last ten years to date. This review summarized the role of ZO proteins in cell proliferation and their expression in GI cancer and HCC. Furthermore, therapeutic interventions targeting ZO in GI and liver cancers are reviewed.
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Affiliation(s)
- Amit Kumar Ram
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India
| | - Balasubramaniyan Vairappan
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India
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18
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Sun N, Zhu B, Xin J, Li L, Gan B, Cao X, Fang J, Pan K, Jing B, Zeng Y, Lv C, Zhao L, Zeng D, Xu P, Wang H, Ni X. Psychoactive Effects of Lactobacillus johnsonii BS15 on Preventing Memory Dysfunction Induced by Acute Ethanol Exposure Through Modulating Intestinal Microenvironment and Improving Alcohol Metabolic Level. Front Microbiol 2022; 13:847468. [PMID: 35432260 PMCID: PMC9011001 DOI: 10.3389/fmicb.2022.847468] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 02/28/2022] [Indexed: 12/12/2022] Open
Abstract
The negative effects of ethanol (EtOH) abuse on the body have been widely reported in recent years. Building on the microbiota-gut-brain axis hypothesis, our study aimed to demonstrate the potential psychobiotic role of Lactobacillus johnsonii BS15 in the preventive effects of acute EtOH intake on memory impairment. We also determined whether L. johnsonii BS15 intake could effectively improve resistance to acute drinking and alleviate the adverse effects of EtOH. Male mice were fed L. johnsonii BS15 orally with (Probiotic group) or without (Control and Alcohol groups) daily dose of 0.2 × 109 CFU/ml per mouse for 28 days. Gavage with L. johnsonii BS15 significantly modified the ileal microbial ecosystem (assessed by 16S rRNA gene sequencing) in favor of Firmicutes and Lactobacillus, indicating the ability of BS15 to restore the gut microbiota. The acute EtOH exposure model (7 g/kg EtOH per mice) was established by gavage, which was administered to the alcohol and probiotic groups on day 28 of the experiment. The L. johnsonii BS15 intake effectively reduced alcohol unconsciousness time, blood alcohol concentration, and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Meanwhile, the improvement of ethanol resistance time and the activities of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the liver were shown by BS15 in acute alcohol-induced mice. We found that acute EtOH exposure reduced the exploration ratio (assessed by the novel object recognition test), escape latency, number of errors (assessed by passive avoidance test), and spontaneous exploration (assessed by T-maze test) in mice, which were obviously improved by L. johnsonii BS15. In the hippocampus, L. johnsonii BS15 significantly reversed the decrease in antioxidant capacity of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) and mRNA expression of memory-related functional proteins of brain-derived neurotrophic factor (BDNF) and cyclic ampresponse element binding protein (CREB) in the hippocampal tissue after acute EtOH exposure. In conclusion, L. johnsonii BS15 intake appears as a promising psychoactive therapy to ameliorate alcohol-mediated memory impairment by increasing EtOH metabolic levels.
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Affiliation(s)
- Ning Sun
- Animal Microecology Institute, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Bin Zhu
- MOE Key Laboratory for Neuroinformation, Center for Information in Medicine, The School of Life Sciences and Technology, Clinical Hospital of Chengdu Brain Science Institute, University of Electronic Science and Technology of China, Chengdu, China
| | - Jinge Xin
- Animal Microecology Institute, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
- Guangzhou Beneco Biotechnology Co., Ltd., Guangzhou, China
| | - Lianxin Li
- Animal Microecology Institute, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Baoxing Gan
- Animal Microecology Institute, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xi Cao
- Animal Microecology Institute, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Jing Fang
- Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Kangcheng Pan
- Animal Microecology Institute, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Bo Jing
- Animal Microecology Institute, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yan Zeng
- Animal Microecology Institute, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Cheng Lv
- Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Ling Zhao
- Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Dong Zeng
- Animal Microecology Institute, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Peng Xu
- MOE Key Laboratory for Neuroinformation, Center for Information in Medicine, The School of Life Sciences and Technology, Clinical Hospital of Chengdu Brain Science Institute, University of Electronic Science and Technology of China, Chengdu, China
| | - Hesong Wang
- Guangzhou Beneco Biotechnology Co., Ltd., Guangzhou, China
| | - Xueqin Ni
- Animal Microecology Institute, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
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19
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Liu F, Gao X, Li Z, Zhang X, Fan H, Yu G, Bello BK, Feng X, Li D, Teng D, Chen Y, Zhao P, Fu M, Dong J. Protective Effects of Scutellarin on Acute Alcohol Intestinal Injury. Chem Biodivers 2022; 19:e202100856. [PMID: 35263019 DOI: 10.1002/cbdv.202100856] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/09/2022] [Indexed: 11/09/2022]
Abstract
The present study aims to investigate the roles of scutellarin (SCU) on acute alcohol intestinal injury. Mice were divided into six groups: alcohol, three administration, negative control and positive drug bifendate control. The administration group mice were intraperitoneally injected with SCU for 3 consecutive days followed by alcohol gavage at an interval of 1 h. After the mice were sacrificed, colon tissue damage was evaluated by histopathological examination; the activities of inducible nitric oxide synthase (iNOS) and catalase (CAT), as well as the content of malondialdehyde (MDA) were detected using biochemical kits; the levels of inflammatory cytokines mRNA were determined by real-time fluorescence quantitative PCR; the protein expression levels of hemeoxygenase-1 (HO-1) and phosphorylated nuclear factor-ĸB p65 were measured via western blotting. The results showed that alcohol induced severe colon morphological degradation, epithelia atrophy, and more inflammatory cells infiltration in the submucosa. SCU treatment prevented this process, especially in the middle and high dose groups. Alcohol treatment caused excessive lipid peroxidation product accumulation of MDA, restrained the activity of antioxidant enzyme CAT, induced HO-1 expression in the colon, whereas low dose SCU treatment significantly down-regulated the MDA level, enhanced the CAT level, and accelerated HO-1 signals. SCU prevented alcohol stimulation triggered inflammatory response in colon tissues through significantly downregulating the iNOS activity, transcript levels of Tnf-α, Il-1β and Il-6, and phosphorylation levels of NF-κB p65. These findings suggest that SCU protects the colon via antioxidant and anti-inflammatory mechanisms, making it a promising drug against alcohol-induced colon damage.
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Affiliation(s)
- Feixue Liu
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Xuzhu Gao
- Department of Central Laboratory, The Second People's Hospital of Lianyungang City, Lianyungang, 222000, China
| | - Zhixing Li
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Xiao Zhang
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Hui Fan
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Guili Yu
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Babatunde Kazeem Bello
- State Key Laboratory of Rice Biology, Lianyungang Academy of Agricultural Sciences, Lianyungang, 222000, China
| | - Xin Feng
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Debang Li
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Daoyang Teng
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Yi Chen
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - PanPan Zhao
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Mian Fu
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Jingquan Dong
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, Jiangsu Ocean University, Lianyungang, 222005, China
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20
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Pareek S, Sanchenkova X, Sakaguchi T, Murakami M, Okumura R, Kayama H, Kawauchi S, Motooka D, Nakamura S, Okuzaki D, Kishimoto T, Takeda K. Epithelial miR‐215 negatively modulates Th17‐dominant inflammation by inhibiting CXCL12 production in the small intestine. Genes Cells 2022; 27:243-253. [DOI: 10.1111/gtc.12922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/17/2022] [Accepted: 01/20/2022] [Indexed: 11/27/2022]
Affiliation(s)
- Siddhika Pareek
- Regenerative Medicine Institute Cedars‐Sinai Medical Center Los Angeles CA 90048 USA
| | - Xenia Sanchenkova
- WPI Immunology Frontier Research Center Osaka University Osaka 5650871 Japan
| | - Taiki Sakaguchi
- WPI Immunology Frontier Research Center Osaka University Osaka 5650871 Japan
- Laboratory of Immune Regulation Department of Microbiology and Immunology Graduate School of Medicine Osaka University Osaka 5650871 Japan
| | - Mari Murakami
- WPI Immunology Frontier Research Center Osaka University Osaka 5650871 Japan
- Laboratory of Immune Regulation Department of Microbiology and Immunology Graduate School of Medicine Osaka University Osaka 5650871 Japan
| | - Ryu Okumura
- WPI Immunology Frontier Research Center Osaka University Osaka 5650871 Japan
- Laboratory of Immune Regulation Department of Microbiology and Immunology Graduate School of Medicine Osaka University Osaka 5650871 Japan
| | - Hisako Kayama
- WPI Immunology Frontier Research Center Osaka University Osaka 5650871 Japan
- Laboratory of Immune Regulation Department of Microbiology and Immunology Graduate School of Medicine Osaka University Osaka 5650871 Japan
- Institute for Advanced Co‐Creation Studies Osaka University Osaka 5650871 Japan
| | - Saya Kawauchi
- WPI Immunology Frontier Research Center Osaka University Osaka 5650871 Japan
- Laboratory of Immune Regulation Department of Microbiology and Immunology Graduate School of Medicine Osaka University Osaka 5650871 Japan
| | - Daisuke Motooka
- WPI Immunology Frontier Research Center Osaka University Osaka 5650871 Japan
- Genome Information Research Center Research Institute for Microbial Diseases Osaka University Osaka 5650871 Japan
| | - Shota Nakamura
- WPI Immunology Frontier Research Center Osaka University Osaka 5650871 Japan
- Genome Information Research Center Research Institute for Microbial Diseases Osaka University Osaka 5650871 Japan
| | - Daisuke Okuzaki
- WPI Immunology Frontier Research Center Osaka University Osaka 5650871 Japan
- Genome Information Research Center Research Institute for Microbial Diseases Osaka University Osaka 5650871 Japan
| | - Tadamitsu Kishimoto
- WPI Immunology Frontier Research Center Osaka University Osaka 5650871 Japan
| | - Kiyoshi Takeda
- WPI Immunology Frontier Research Center Osaka University Osaka 5650871 Japan
- Laboratory of Immune Regulation Department of Microbiology and Immunology Graduate School of Medicine Osaka University Osaka 5650871 Japan
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21
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Baumann A, Rajcic D, Brandt A, Sánchez V, Jung F, Staltner R, Nier A, Trauner M, Staufer K, Bergheim I. Alterations of nitric oxide homeostasis as trigger of intestinal barrier dysfunction in non-alcoholic fatty liver disease. J Cell Mol Med 2022; 26:1206-1218. [PMID: 35029027 PMCID: PMC8831936 DOI: 10.1111/jcmm.17175] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/20/2021] [Accepted: 12/23/2021] [Indexed: 02/07/2023] Open
Abstract
Changes in intestinal nitric oxide metabolism are discussed to contribute for the development of intestinal barrier dysfunction in non‐alcoholic fatty liver disease (NAFLD). To induce steatosis, female C57BL/6J mice were pair‐fed with a liquid control diet (C) or a fat‐, fructose‐ and cholesterol‐rich diet (FFC) for 8 weeks. Mice received the diets ± 2.49 g L‐arginine/kg bw/day for additional 5 weeks. Furthermore, mice fed C or FFC ± L‐arginine/kg bw/day for 8 weeks were concomitantly treated with the arginase inhibitor Nω‐hydroxy‐nor‐L‐arginine (nor‐NOHA, 0.01 g/kg bw). Liver damage, intestinal barrier function, nitric oxide levels and arginase activity in small intestine were assessed. Also, arginase activity was measured in serum from 13 patients with steatosis (NAFL) and 14 controls. The development of steatosis with beginning inflammation was associated with impaired intestinal barrier function, increased nitric oxide levels and a loss of arginase activity in small intestine in mice. L‐arginine supplementation abolished the latter along with an improvement of intestinal barrier dysfunction; nor‐NOHA attenuated these effects. In patients with NAFL, arginase activity in serum was significantly lower than in healthy controls. Our data suggest that increased formation of nitric oxide and a loss of intestinal arginase activity is critical in NAFLD‐associated intestinal barrier dysfunction.
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Affiliation(s)
- Anja Baumann
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Dragana Rajcic
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Annette Brandt
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Victor Sánchez
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Finn Jung
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Raphaela Staltner
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Anika Nier
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Katharina Staufer
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.,Department of Surgery Division of Transplantation, Medical University of Vienna, Vienna, Austria
| | - Ina Bergheim
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Vienna, Austria
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22
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Yan J, Ouyang J, Isnard S, Zhou X, Harypursat V, Routy JP, Chen Y. Alcohol Use and Abuse Conspires With HIV Infection to Aggravate Intestinal Dysbiosis and Increase Microbial Translocation in People Living With HIV: A Review. Front Immunol 2021; 12:741658. [PMID: 34975838 PMCID: PMC8718428 DOI: 10.3389/fimmu.2021.741658] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 11/30/2021] [Indexed: 12/12/2022] Open
Abstract
The intestinal microbiome is an essential so-called human "organ", vital for the induction of innate immunity, for metabolizing nutrients, and for maintenance of the structural integrity of the intestinal barrier. HIV infection adversely influences the richness and diversity of the intestinal microbiome, resulting in structural and functional impairment of the intestinal barrier and an increased intestinal permeability. Pathogens and metabolites may thus cross the "leaky" intestinal barrier and enter the systemic circulation, which is a significant factor accounting for the persistent underlying chronic inflammatory state present in people living with HIV (PLWH). Additionally, alcohol use and abuse has been found to be prevalent in PLWH and has been strongly associated with the incidence and progression of HIV/AIDS. Recently, converging evidence has indicated that the mechanism underlying this phenomenon is related to intestinal microbiome and barrier function through numerous pathways. Alcohol acts as a "partner" with HIV in disrupting microbiome ecology, and thus impairing of the intestinal barrier. Optimizing the microbiome and restoring the integrity of the intestinal barrier is likely to be an effective adjunctive therapeutic strategy for PLWH. We herein critically review the interplay among HIV, alcohol, and the gut barrier, thus setting the scene with regards to development of effective strategies to counteract the dysregulated gut microbiome and the reduction of microbial translocation and inflammation in PLWH.
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Affiliation(s)
- Jiangyu Yan
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Jing Ouyang
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Stéphane Isnard
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Canadian HIV Trials Network (CTN), Canadian Institutes of Health Research (CIHR), Vancouver, BC, Canada
| | - Xin Zhou
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Vijay Harypursat
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Division of Hematology, McGill University Health Centre, Montréal, QC, Canada
| | - Yaokai Chen
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
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Yadav M, Chauhan NS. Microbiome therapeutics: exploring the present scenario and challenges. Gastroenterol Rep (Oxf) 2021; 10:goab046. [PMID: 35382166 PMCID: PMC8972995 DOI: 10.1093/gastro/goab046] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 12/11/2022] Open
Abstract
Human gut-microbiome explorations have enriched our understanding of microbial colonization, maturation, and dysbiosis in health-and-disease subsets. The enormous metabolic potential of gut microbes and their role in the maintenance of human health is emerging, with new avenues to use them as therapeutic agents to overcome human disorders. Microbiome therapeutics are aimed at engineering the gut microbiome using additive, subtractive, or modulatory therapy with an application of native or engineered microbes, antibiotics, bacteriophages, and bacteriocins. This approach could overcome the limitation of conventional therapeutics by providing personalized, harmonized, reliable, and sustainable treatment. Its huge economic potential has been shown in the global therapeutics market. Despite the therapeutic and economical potential, microbiome therapeutics is still in the developing stage and is facing various technical and administrative issues that require research attention. This review aims to address the current knowledge and landscape of microbiome therapeutics, provides an overview of existing health-and-disease applications, and discusses the potential future directions of microbiome modulations.
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Affiliation(s)
- Monika Yadav
- Department of Biochemistry, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Nar Singh Chauhan
- Department of Biochemistry, Maharshi Dayanand University, Rohtak, Haryana, India
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24
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Kuracha MR, Thomas P, Tobi M, McVicker BL. Role of cell-free network communication in alcohol-associated disorders and liver metastasis. World J Gastroenterol 2021; 27:7080-7099. [PMID: 34887629 PMCID: PMC8613644 DOI: 10.3748/wjg.v27.i41.7080] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/02/2021] [Accepted: 09/30/2021] [Indexed: 02/06/2023] Open
Abstract
The aberrant use of alcohol is a major factor in cancer progression and metastasis. Contributing mechanisms include the systemic effects of alcohol and the exchange of bioactive molecules between cancerous and non-cancerous cells along the brain-gut-liver axis. Such interplay leads to changes in molecular, cellular, and biological functions resulting in cancer progression. Recent investigations have examined the role of extracellular vesicles (EVs) in cancer mechanisms in addition to their contribution as diagnostic biomarkers. Also, EVs are emerging as novel cell-free mediators in pathophysiological scenarios including alcohol-mediated gut microbiome dysbiosis and the release of nanosized EVs into the circulatory system. Interestingly, EVs in cancer patients are enriched with oncogenes, miRNA, lipids, and glycoproteins whose delivery into the hepatic microenvironment may be enhanced by the detrimental effects of alcohol. Proof-of-concept studies indicate that alcohol-associated liver disease is impacted by the effects of exosomes, including altered immune responses, reprogramming of stromal cells, and remodeling of the extracellular matrix. Moreover, the culmination of alcohol-related changes in the liver likely contributes to enhanced hepatic metastases and poor outcomes for cancer patients. This review summarizes the numerous aspects of exosome communications between organs with emphasis on the relationship of EVs in alcohol-associated diseases and cancer metastasis. The potential impact of EV cargo and release along a multi-organ axis is highly relevant to the promotion of tumorigenic mechanisms and metastatic disease. It is hypothesized that EVs target recipient tissues to initiate the formation of prometastatic niches and cancer progression. The study of alcohol-associated mechanisms in metastatic cancers is expected to reveal a better understanding of factors involved in the growth of secondary malignancies as well as novel approaches for therapeutic interventions.
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Affiliation(s)
- Murali R Kuracha
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Peter Thomas
- Department of Surgery, Creighton University School of Medicine, Omaha, NE 68178, United States
| | - Martin Tobi
- Research and Development Service, Detroit VAMC, Detroit, MI 48201, United States
- Department of Medicine, Central Michigan University College of Medicine, Detroit, MI 48201, United States
| | - Benita L McVicker
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Research Service, Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
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25
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Kim HG, Cho JH, Kim J, Kim SJ. The Role of Epigenetic Changes in the Progression of Alcoholic Steatohepatitis. Front Physiol 2021; 12:691738. [PMID: 34335299 PMCID: PMC8323660 DOI: 10.3389/fphys.2021.691738] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022] Open
Abstract
Alcoholic steatohepatitis (ASH) is a progression hepatitis with severe fatty liver and its mortality rate for 30-days in patients are over 30%. Additionally, ASH is well known for one-fifth all alcoholic related liver diseases in the world. Excessive chronic alcohol consumption is one of the most common causes of the progression of ASH and is associated with poor prognosis and liver failure. Alcohol abuse dysregulates the lipid homeostasis and causes oxidative stress and inflammation in the liver. Consequently, metabolic pathways stimulating hepatic accumulation of excessive lipid droplets are induced. Recently, many studies have indicated a link between ASH and epigenetic changes, showing differential expression of alcohol-induced epigenetic genes in the liver. However, the specific mechanisms underlying the pathogenesis of ASH remain elusive. Thus, we here summarize the current knowledge about the roles of epigenetics in lipogenesis, inflammation, and apoptosis in the context of ASH pathophysiology. Especially, we highlight the latest findings on the roles of Sirtuins, a conserved family of class-III histone deacetylases, in ASH. Additionally, we discuss the involvement of DNA methylation, histone modifications, and miRNAs in ASH as well as the ongoing efforts for the clinical translation of the findings in ASH-related epigenetic changes.
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Affiliation(s)
- Hyeong Geug Kim
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Jung-Hyo Cho
- Department of East & West Cancer Center, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon, South Korea
| | - Jeongkyu Kim
- Department of Life Science, Chung-Ang University, Seoul, South Korea
| | - Seung-Jin Kim
- Kangwon Institute of Inclusive Technology, Kangwon National University, Chuncheon, South Korea
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26
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Calleja-Conde J, Echeverry-Alzate V, Bühler KM, Durán-González P, Morales-García JÁ, Segovia-Rodríguez L, Rodríguez de Fonseca F, Giné E, López-Moreno JA. The Immune System through the Lens of Alcohol Intake and Gut Microbiota. Int J Mol Sci 2021; 22:ijms22147485. [PMID: 34299105 PMCID: PMC8303153 DOI: 10.3390/ijms22147485] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/05/2021] [Accepted: 07/07/2021] [Indexed: 02/08/2023] Open
Abstract
The human gut is the largest organ with immune function in our body, responsible for regulating the homeostasis of the intestinal barrier. A diverse, complex and dynamic population of microorganisms, called microbiota, which exert a significant impact on the host during homeostasis and disease, supports this role. In fact, intestinal bacteria maintain immune and metabolic homeostasis, protecting our organism against pathogens. The development of numerous inflammatory disorders and infections has been linked to altered gut bacterial composition or dysbiosis. Multiple factors contribute to the establishment of the human gut microbiota. For instance, diet is considered as one of the many drivers in shaping the gut microbiota across the lifetime. By contrast, alcohol is one of the many factors that disrupt the proper functioning of the gut, leading to a disruption of the intestinal barrier integrity that increases the permeability of the mucosa, with the final result of a disrupted mucosal immunity. This damage to the permeability of the intestinal membrane allows bacteria and their components to enter the blood tissue, reaching other organs such as the liver or the brain. Although chronic heavy drinking has harmful effects on the immune system cells at the systemic level, this review focuses on the effect produced on gut, brain and liver, because of their significance in the link between alcohol consumption, gut microbiota and the immune system.
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Affiliation(s)
- Javier Calleja-Conde
- Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, 28223 Madrid, Spain; (J.C.-C.); (V.E.-A.); (K.-M.B.); (P.D.-G.); (L.S.-R.)
| | - Victor Echeverry-Alzate
- Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, 28223 Madrid, Spain; (J.C.-C.); (V.E.-A.); (K.-M.B.); (P.D.-G.); (L.S.-R.)
- Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Malaga University, 29010 Málaga, Spain;
- Universidad Nebrija, Campus Madrid-Princesa, 28015 Madrid, Spain
| | - Kora-Mareen Bühler
- Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, 28223 Madrid, Spain; (J.C.-C.); (V.E.-A.); (K.-M.B.); (P.D.-G.); (L.S.-R.)
| | - Pedro Durán-González
- Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, 28223 Madrid, Spain; (J.C.-C.); (V.E.-A.); (K.-M.B.); (P.D.-G.); (L.S.-R.)
| | - Jose Ángel Morales-García
- Instituto de Investigaciones Biomédicas (CSIC-UAM) “Alberto Sols” (CSIC-UAM), 28029 Madrid, Spain;
- Departamento de Biología Celular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain;
- Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
| | - Lucía Segovia-Rodríguez
- Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, 28223 Madrid, Spain; (J.C.-C.); (V.E.-A.); (K.-M.B.); (P.D.-G.); (L.S.-R.)
| | - Fernando Rodríguez de Fonseca
- Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Malaga University, 29010 Málaga, Spain;
| | - Elena Giné
- Departamento de Biología Celular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain;
| | - Jose Antonio López-Moreno
- Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, 28223 Madrid, Spain; (J.C.-C.); (V.E.-A.); (K.-M.B.); (P.D.-G.); (L.S.-R.)
- Correspondence:
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27
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Michalak A, Lach T, Cichoż-Lach H. Oxidative Stress-A Key Player in the Course of Alcohol-Related Liver Disease. J Clin Med 2021; 10:3011. [PMID: 34300175 PMCID: PMC8303854 DOI: 10.3390/jcm10143011] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/04/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress is known to be an inseparable factor involved in the presentation of liver disorders. Free radicals interfere with DNA, proteins, and lipids, which are crucial in liver metabolism, changing their expression and biological functions. Additionally, oxidative stress modifies the function of micro-RNAs, impairing the metabolism of hepatocytes. Free radicals have also been proven to influence the function of certain transcriptional factors and to alter the cell cycle. The pathological appearance of alcohol-related liver disease (ALD) constitutes an ideal example of harmful effects due to the redox state. Finally, ethanol-induced toxicity and overproduction of free radicals provoke irreversible changes within liver parenchyma. Understanding the underlying mechanisms associated with the redox state in the course of ALD creates new possibilities of treatment for patients. The future of hepatology may become directly dependent on the effective action against reactive oxygen species. This review summarizes current data on the redox state in the natural history of ALD, highlighting the newest reports on this topic.
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Affiliation(s)
- Agata Michalak
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
| | - Tomasz Lach
- Department of Orthopedics and Traumatology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
| | - Halina Cichoż-Lach
- Department of Gastroenterology with Endoscopy Unit, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland;
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28
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Jung H, Kim JS, Lee KH, Tizaoui K, Terrazzino S, Cargnin S, Smith L, Koyanagi A, Jacob L, Li H, Hong SH, Yon DK, Lee SW, Kim MS, Wasuwanich P, Karnsakul W, Shin JI, Kronbichler A. Roles of microRNAs in inflammatory bowel disease. Int J Biol Sci 2021; 17:2112-2123. [PMID: 34131410 PMCID: PMC8193269 DOI: 10.7150/ijbs.59904] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 05/08/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract that mainly affects young people. IBD is associated with various gastrointestinal symptoms, and thus, affects the quality of life of patients. Currently, the pathogenesis of IBD is poorly understood. Although intestinal bacteria and host immune response are thought to be major factors in its pathogenesis, a sufficient explanation of their role in its pathophysiologic mechanism has not been presented. MicroRNAs (miRNAs), which are small RNA molecules that regulate gene expression, have gained attention as they are known to participate in the molecular interactions of IBD. Recent studies have confirmed the important role of miRNAs in targeting certain molecules in signaling pathways that regulate the homeostasis of the intestinal barrier, inflammatory reactions, and autophagy of the intestinal epithelium. Several studies have identified the specific miRNAs associated with IBD from colon tissues or serum samples of IBD patients and have attempted to use them as useful diagnostic biomarkers. Furthermore, some studies have attempted to treat IBD through intracolonic administration of specific miRNAs in the form of nanoparticle. This review summarizes the latest findings on the role of miRNAs in the pathogenesis, diagnosis, and treatment of IBD.
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Affiliation(s)
- HyunTaek Jung
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Seok Kim
- Department of Nephrology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kalthoum Tizaoui
- Laboratory Microorganisms and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Salvatore Terrazzino
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Sarah Cargnin
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Lee Smith
- The Cambridge Centre for Sport and Exercise Science, Anglia Ruskin University, Cambridge, CB1 1PT, UK
| | - Ai Koyanagi
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, 08830 Barcelona, Spain.,ICREA, Pg. Lluis Companys 23, 08010 Barcelona, Spain
| | - Louis Jacob
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, 08830 Barcelona, Spain.,Faculty of Medicine, University of Versailles Saint-Quentin-en-Yvelines, 78000 Versailles, France
| | - Han Li
- University of Florida College of Medicine, Gainesville, FL 32610, USA
| | - Sung Hwi Hong
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dong Keon Yon
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seung Won Lee
- Department of Data Science, Sejong University College of Software Convergence, Seoul, Republic of Korea
| | - Min Seo Kim
- Korea University, College of Medicine, Seoul, Republic of Korea
| | - Paul Wasuwanich
- University of Florida College of Medicine, Gainesville, FL 32610, USA
| | - Wikrom Karnsakul
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
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Liu SY, Tsai IT, Hsu YC. Alcohol-Related Liver Disease: Basic Mechanisms and Clinical Perspectives. Int J Mol Sci 2021; 22:5170. [PMID: 34068269 PMCID: PMC8153142 DOI: 10.3390/ijms22105170] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 05/07/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022] Open
Abstract
Alcohol-related liver disease (ALD) refers to the liver damage occurring due to excessive alcohol consumption and involves a broad spectrum of diseases that includes liver steatosis, steatohepatitis, hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The progression of ALD is mainly associated with the amount and duration of alcohol usage; however, it is also influenced by genetic, epigenetic, and environmental factors. The definite diagnosis of ALD is based on a liver biopsy, although several non-invasive diagnostic tools and serum biomarkers have emerging roles in the early detection of ALD. While alcohol abstinence and nutritional support remain the cornerstone of ALD treatment, growing evidence has revealed that the therapeutic agents that target oxidative stress or gut-liver axis, inflammatory response inhibition, and liver regeneration enhancement also play a role in ALD management. Furthermore, microRNAs modulation and mesenchymal stem cell-based therapy have emerging potential as ALD therapeutic options. This review summarizes the updated understanding of the pathophysiology, diagnosis, and novel therapeutic approaches for ALD.
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Affiliation(s)
- Szu-Yi Liu
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (S.-Y.L.); (I.-T.T.)
| | - I-Ting Tsai
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (S.-Y.L.); (I.-T.T.)
- School of Medicine for International Student, I-Shou University, Kaohsiung 82445, Taiwan
| | - Yin-Chou Hsu
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (S.-Y.L.); (I.-T.T.)
- School of Medicine for International Student, I-Shou University, Kaohsiung 82445, Taiwan
- School of Chinese Medicine for Post Baccalaureate, I-Shou University, Kaohsiung 82445, Taiwan
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30
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Feng D, Christensen JT, Yetman AT, Lindsey ML, Singh AB, Salomon JD. The microbiome’s relationship with congenital heart disease: more than a gut feeling. JOURNAL OF CONGENITAL CARDIOLOGY 2021. [DOI: 10.1186/s40949-021-00060-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AbstractPatients with congenital heart disease (CHD) are at risk for developing intestinal dysbiosis and intestinal epithelial barrier dysfunction due to abnormal gut perfusion or hypoxemia in the context of low cardiac output or cyanosis. Intestinal dysbiosis may contribute to systemic inflammation thereby worsening clinical outcomes in this patient population. Despite significant advances in the management and survival of patients with CHD, morbidity remains significant and questions have arisen as to the role of the microbiome in the inflammatory process. Intestinal dysbiosis and barrier dysfunction experienced in this patient population are increasingly implicated in critical illness. This review highlights possible CHD-microbiome interactions, illustrates underlying signaling mechanisms, and discusses future directions and therapeutic translation of the basic research.
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31
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Yuan J, Che S, Zhang L, Ruan Z. Reparative Effects of Ethanol-Induced Intestinal Barrier Injury by Flavonoid Luteolin via MAPK/NF-κB/MLCK and Nrf2 Signaling Pathways. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:4101-4110. [PMID: 33749262 DOI: 10.1021/acs.jafc.1c00199] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Luteolin, a dietary flavonoid, has gained increasing interest as an intestinal protectant. This study aimed to evaluate the reparative effect of luteolin against ethanol-induced intestinal barrier damage in a Caco-2 cell monolayer model and the potential mechanisms. Luteolin attenuated ethanol-induced intestinal barrier injury, by increasing transepithelial monolayer resistance (TEER, 27.75 ± 14.75% of the ethanol group, p < 0.01), reducing Lucifer yellow flux (13.21 ± 1.23% of ethanol group, p < 0.01), and upregulating the expression of tight junction (TJ) proteins zonulin occludin-1 (ZO-1), occludin, and claudin-1 (37.963 ± 8.62%, 17.69 ± 7.35%, and 29.40 ± 8.08% of the ethanol group, respectively, p < 0.01). Further mechanistic studies showed that luteolin suppressed myosin light chain 2 (MLC) phosphorylation, myosin light chain kinase (MLCK) activation, nuclear factor kappa-B (NF-κB) nuclear translocation, and mitogen-activated-protein-kinase (MAPK) phosphorylation. Moreover, luteolin also acted as antioxidants indirectly by upregulating antioxidant-responsive-element (ARE) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation to relieve ethanol-induced oxidative damage and TJ dysfunction. The results of the study indicate that luteolin may play an effective role in relieving intestinal barrier damage, and this effect is at least partially due to its indirect antioxidant capacity.
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Affiliation(s)
- Jinwen Yuan
- State Key Laboratory of Food Science and Technology, Nanchang Key Laboratory of Fruits and Vegetables Nutrition and Processing, Institute of Nutrition and School of Food Science, Nanchang University, Nanchang 330047, China
| | - Siyan Che
- State Key Laboratory of Food Science and Technology, Nanchang Key Laboratory of Fruits and Vegetables Nutrition and Processing, Institute of Nutrition and School of Food Science, Nanchang University, Nanchang 330047, China
| | - Li Zhang
- State Key Laboratory of Food Science and Technology, Nanchang Key Laboratory of Fruits and Vegetables Nutrition and Processing, Institute of Nutrition and School of Food Science, Nanchang University, Nanchang 330047, China
| | - Zheng Ruan
- State Key Laboratory of Food Science and Technology, Nanchang Key Laboratory of Fruits and Vegetables Nutrition and Processing, Institute of Nutrition and School of Food Science, Nanchang University, Nanchang 330047, China
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Translational Approaches with Antioxidant Phytochemicals against Alcohol-Mediated Oxidative Stress, Gut Dysbiosis, Intestinal Barrier Dysfunction, and Fatty Liver Disease. Antioxidants (Basel) 2021; 10:antiox10030384. [PMID: 33806556 PMCID: PMC8000766 DOI: 10.3390/antiox10030384] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022] Open
Abstract
Emerging data demonstrate the important roles of altered gut microbiomes (dysbiosis) in many disease states in the peripheral tissues and the central nervous system. Gut dysbiosis with decreased ratios of Bacteroidetes/Firmicutes and other changes are reported to be caused by many disease states and various environmental factors, such as ethanol (e.g., alcohol drinking), Western-style high-fat diets, high fructose, etc. It is also caused by genetic factors, including genetic polymorphisms and epigenetic changes in different individuals. Gut dysbiosis, impaired intestinal barrier function, and elevated serum endotoxin levels can be observed in human patients and/or experimental rodent models exposed to these factors or with certain disease states. However, gut dysbiosis and leaky gut can be normalized through lifestyle alterations such as increased consumption of healthy diets with various fruits and vegetables containing many different kinds of antioxidant phytochemicals. In this review, we describe the mechanisms of gut dysbiosis, leaky gut, endotoxemia, and fatty liver disease with a specific focus on the alcohol-associated pathways. We also mention translational approaches by discussing the benefits of many antioxidant phytochemicals and/or their metabolites against alcohol-mediated oxidative stress, gut dysbiosis, intestinal barrier dysfunction, and fatty liver disease.
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Qin C, Hu J, Wan Y, Cai M, Wang Z, Peng Z, Liao Y, Li D, Yao P, Liu L, Rong S, Bao W, Xu G, Yang W. Narrative review on potential role of gut microbiota in certain substance addiction. Prog Neuropsychopharmacol Biol Psychiatry 2021; 106:110093. [PMID: 32898589 DOI: 10.1016/j.pnpbp.2020.110093] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 08/22/2020] [Accepted: 08/30/2020] [Indexed: 12/14/2022]
Abstract
As a neuropsychiatric disorder, substance addiction represents a major public health issue with high prevalence and mortality in many countries. Recently, gut microbiota has been certified to play a part in substance addiction through various mechanisms. Hence, we mainly focused on three substance including alcohol, cocaine and methamphetamine in this review, and summarized their relationships with gut microbiota, respectively. Besides, we also concluded the possible treatments for substance addiction from the perspective of applying gut microbiota. This review aims to build a bridge between substance addiction and gut microbiota according to existing evidences, so as to excavate the possible bi-directional function of microbiota-gut-brain axis in substance addiction for developing therapeutic strategies in the future.
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Affiliation(s)
- Chenyuan Qin
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Jiawei Hu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Yiming Wan
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Mengyao Cai
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Zhenting Wang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Zhao Peng
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Yuxiao Liao
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Dan Li
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Ping Yao
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Liegang Liu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China
| | - Shuang Rong
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene, School of Public Health, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China
| | - Wei Bao
- Department of Epidemiology, College of Public Health, University of Iowa, IA 52242, USA
| | - Guifeng Xu
- Department of Epidemiology, College of Public Health, University of Iowa, IA 52242, USA; Center for Disabilities and Development, University of Iowa Stead Family Children's Hospital, Iowa City, IA 52242, USA
| | - Wei Yang
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China; Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, 430030 Wuhan, China.
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Morris NL, Choudhry MA. Maintenance of gut barrier integrity after injury: Trust your gut microRNAs. J Leukoc Biol 2021; 110:979-986. [PMID: 33577717 DOI: 10.1002/jlb.3ru0120-090rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 01/20/2021] [Accepted: 01/21/2021] [Indexed: 12/11/2022] Open
Abstract
The gastrointestinal (GI) tract is a highly dynamic structure essential for digestion, nutrient absorption, and providing an interface to prevent gut bacterial translocation. In order to maintain the barrier function, the gut utilizes many defense mechanisms including proliferation, apoptosis, and apical junctional complexes. Disruption of any of these parameters due to injury or disease could negatively impact the intestinal barrier function and homeostasis resulting in increased intestine inflammation, permeability, bacterial dysbiosis, and tissue damage. MicroRNAs are small noncoding RNA sequences that are master regulators of normal cellular homeostasis. These regulatory molecules affect cellular signaling pathways and potentially serve as candidates for providing a mechanism of impaired gut barrier integrity following GI-related pathologic conditions, ethanol exposure, or trauma such as burn injury. MicroRNAs influence cellular apoptosis, proliferation, apical junction complex expression, inflammation, and the microbiome. Due to their widespread functional affiliations, altered expression of microRNAs are associated with many pathologic conditions. This review explores the role of microRNAs in regulation of intestinal barrier integrity. The studies reviewed demonstrate that microRNAs largely impact intestine barrier function and provide insight behind the observed adverse effects following ethanol and burn injury. Furthermore, these studies suggest that microRNAs are excellent candidates for therapeutic intervention or for biomarkers to manage gut barrier integrity following trauma such as burn injury and other GI-related pathologic conditions.
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Affiliation(s)
- Niya L Morris
- Alcohol Research Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Integrative Cell Biology Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Current address: Department of Medicine: Pulmonary, Allergy, Critical Care and Sleep, Emory University/Atlanta VA Medical Center, Decatur, Geogia, USA
| | - Mashkoor A Choudhry
- Alcohol Research Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Burn & Shock Trauma Research Institute, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Integrative Cell Biology Program, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA.,Department of Surgery, Loyola University Chicago Health Sciences Division, Maywood, Illinois, USA
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35
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Impact of drinking alcohol on gut microbiota: recent perspectives on ethanol and alcoholic beverage. Curr Opin Food Sci 2021. [DOI: 10.1016/j.cofs.2020.10.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Devall M, Plummer SJ, Bryant J, Jennelle LT, Eaton S, Dampier CH, Huyghe JR, Peters U, Powell SM, Casey G. Ethanol exposure drives colon location specific cell composition changes in a normal colon crypt 3D organoid model. Sci Rep 2021; 11:432. [PMID: 33432071 PMCID: PMC7801615 DOI: 10.1038/s41598-020-80240-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 12/14/2020] [Indexed: 12/15/2022] Open
Abstract
Alcohol is a consistently identified risk factor for colon cancer. However, the molecular mechanism underlying its effect on normal colon crypt cells remains poorly understood. We employed RNA-sequencing to asses transcriptomic response to ethanol exposure (0.2% vol:vol) in 3D organoid lines derived from healthy colon (n = 34). Paired regression analysis identified 2,162 differentially expressed genes in response to ethanol. When stratified by colon location, a far greater number of differentially expressed genes were identified in organoids derived from the left versus right colon, many of which corresponded to cell-type specific markers. To test the hypothesis that the effects of ethanol treatment on colon organoid populations were in part due to differential cell composition, we incorporated external single cell RNA-sequencing data from normal colon biopsies to estimate cellular proportions following single cell deconvolution. We inferred cell-type-specific changes, and observed an increase in transit amplifying cells following ethanol exposure that was greater in organoids from the left than right colon, with a concomitant decrease in more differentiated cells. If this occurs in the colon following alcohol consumption, this would lead to an increased zone of cells in the lower crypt where conditions are optimal for cell division and the potential to develop mutations.
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Affiliation(s)
- Matthew Devall
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Sarah J Plummer
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Jennifer Bryant
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Lucas T Jennelle
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Stephen Eaton
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Christopher H Dampier
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.,Department of Surgery, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Jeroen R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Center Research Institute, Seattle, WA, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Center Research Institute, Seattle, WA, USA
| | - Steven M Powell
- Digestive Health Center, University of Virginia, Charlottesville, VA, USA
| | - Graham Casey
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
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Bi K, Zhang X, Chen W, Diao H. MicroRNAs Regulate Intestinal Immunity and Gut Microbiota for Gastrointestinal Health: A Comprehensive Review. Genes (Basel) 2020; 11:genes11091075. [PMID: 32932716 PMCID: PMC7564790 DOI: 10.3390/genes11091075] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 08/24/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs are small non-coding RNAs regulating gene expression at the post-transcriptional level. The regulation of microRNA expression in the gut intestine is gradually recognized as one of the crucial contributors of intestinal homeostasis and overall health. Recent studies indicated that both the microRNAs endogenous in the gut intestine and exogenous from diets could play influential roles in modulating microbial colonization and intestinal immunity. In this review, we discuss the biological functions of microRNAs in regulating intestinal homeostasis by modulating intestinal immune responses and gut microbiota. We particularly focus on addressing the microRNA-dependent communication and interactions among microRNA, gut microbiota, and intestinal immune system. Besides, we also summarize the roles of diet-derived microRNAs in host-microbiome homeostasis and their benefits on intestinal health. A better understanding of the relationships among intestinal disorders, microRNAs, and other factors influencing intestinal health can facilitate the application of microRNA-based therapeutics for gastrointestinal diseases.
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Ramamoorthy K, Anandam KY, Yasujima T, Srinivasan P, Said HM. Posttranscriptional regulation of thiamin transporter-1 expression by microRNA-200a-3p in pancreatic acinar cells. Am J Physiol Gastrointest Liver Physiol 2020; 319:G323-G332. [PMID: 32683950 PMCID: PMC7509260 DOI: 10.1152/ajpgi.00178.2020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The water-soluble vitamin B1 (thiamin) plays essential roles in normal metabolism and function of all human/mammalian cells, including the pancreatic acinar cells (PACs). PACs obtain thiamin from their surrounding circulation via transport across the plasma membrane, a process that is mediated by thiamin transporter (THTR)-1 and THTR-2. We have previously characterized different aspects of thiamin uptake by mouse and human primary PACs, but little is known about posttranscriptional regulation of the uptake event. We addressed this by focusing on the predominant thiamin transporter THTR-1 (encoded by SLC19A2 gene) in PACs. Transfecting pmirGLO-SLC19A2 3'-untranslated region (UTR) into mouse-derived PAC 266-6 cells leads to a significant reduction in luciferase activity compared with cells transfected with empty vector. Subjecting the SLC19A2 3'-UTR to different in silico algorithms identified multiple putative microRNA binding sites in this region. Focusing on miR-200a-3p (since it is highly expressed in mouse and human pancreas), we found that transfecting PAC 266-6 and human primary PACs (hPACs) with mimic miR-200a-3p leads to a significant inhibition of THTR-1 expression (both protein and mRNA levels) and in thiamin uptake. In contrast, transfection by miR-200a-3p inhibitor leads to an increase in THTR-1 expression and thiamin uptake. Additionally, truncating the region carrying miR-200a-3p binding site in SLC19A2 3'-UTR and mutating the binding site lead to abrogation in the inhibitory effect of this microRNA on luciferase activity in PAC 266-6. These results demonstrate that expression of THTR-1 and thiamin uptake in PACs is subject to posttranscriptional regulation by microRNAs.NEW & NOTEWORTHY The findings of this study show, for the first time, that the membrane transporter of vitamin B1, i.e., thiamin transporter-1 (THTR-1), is subject to regulation by microRNAs (specifically miR-200a-3p) in mouse and human primary pancreatic acinar cells (PACs). The results also show that this posttranscriptional regulation has functional consequences on the ability of PACs to take in the essential micronutrient thiamin.
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Affiliation(s)
- Kalidas Ramamoorthy
- 1Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California
| | - Kasin Yadunandam Anandam
- 1Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California,3Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California
| | - Tomoya Yasujima
- 4Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Japan
| | - Padmanabhan Srinivasan
- 1Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California,3Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California
| | - Hamid M. Said
- 1Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California,2Department of Medicine, School of Medicine, University of California, Irvine, California,3Department of Medical Research, Veterans Affairs Medical Center, Long Beach, California
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Li M, Zhao J, Cao M, Liu R, Chen G, Li S, Xie Y, Xie J, Cheng Y, Huang L, Su M, Xu Y, Zheng M, Zou K, Geng L, Xu W, Gong S. Mast cells-derived MiR-223 destroys intestinal barrier function by inhibition of CLDN8 expression in intestinal epithelial cells. Biol Res 2020; 53:12. [PMID: 32209121 PMCID: PMC7092522 DOI: 10.1186/s40659-020-00279-2] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 03/09/2020] [Indexed: 12/19/2022] Open
Abstract
Background Mast cells (MCs) have been found to play a critical role during development of inflammatory bowel disease (IBD) that characterized by dysregulation of inflammation and impaired intestinal barrier function. However, the function of MCs in IBD remains to be fully elucidated. Results In our study, we used exosomes isolated from human mast cells-1 (HMCs-1) to culture with NCM460, HT-29 or CaCO2 of intestinal epithelial cells (IECs) to investigate the communication between MCs and IECs. We found that MCs-derived exosomes significantly increased intestinal epithelial permeability and destroyed intestinal barrier function, which is attributed to exosome-mediated functional miRNAs were transferred from HMCs-1 into IECs, leading to inhibit tight junction-related proteins expression, including tight junction proteins 1 (TJP1, ZO-1), Occludin (OCLN), Claudin 8 (CLDN8). Microarray and bioinformatic analysis have further revealed that a panel of miRNAs target different tight junction-related proteins. Interestingly, miR-223 is enriched in mast cell-derived exosome, which inhibit CLDN8 expression in IECs, while treatment with miR-223 inhibitor in HT-29 cells significantly reversed the inhibitory effect of HMCs-1-derived exosomes on CLDN 8 expression. Most importantly, enrichment of MCs accumulation in intestinal mucosa of patients with IBD compared with those healthy control. Conclusions These results indicated that enrichment of exosomal miR-223 from HMCs-1 inhibited CLDN8 expression, leading to destroy intestinal barrier function. These finding provided a novel insight of MCs as a new target for therapeutic treatment of IBD.
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Affiliation(s)
- Musheng Li
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Junhong Zhao
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Meiwan Cao
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Ruitao Liu
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Guanhua Chen
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Songyu Li
- Department of Clinical Laboratory, Qionghai Hospital of Traditional Chinese Medicine, Qionghai, 571400, China
| | - Yuanwen Xie
- Department of Anorectal, Qionghai Hospital of Traditional Chinese Medicine, Qionghai, 571400, China
| | - Jing Xie
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Yang Cheng
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Ling Huang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China
| | - Mingmin Su
- Department of Cancer Biology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales, CF103AT, UK
| | - Yuxin Xu
- Department of Preventive Medicine, School of School of Public Health, Fujian Medical University, Fuzhou, 350122, China
| | - Mingyue Zheng
- School of Marine Life Sciences, Ocean University of China, Qingdao, Shandong, 266003, China
| | - Kejian Zou
- Department of General Surgery, Hainan General Hospital, Haikou, China
| | - Lanlan Geng
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. .,Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
| | - Wanfu Xu
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. .,Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
| | - Sitang Gong
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. .,Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
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Protocatechuic Acid-Mediated miR-219a-5p Activation Inhibits the p66shc Oxidant Pathway to Alleviate Alcoholic Liver Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:3527809. [PMID: 31428222 PMCID: PMC6683775 DOI: 10.1155/2019/3527809] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 02/22/2019] [Accepted: 06/25/2019] [Indexed: 12/13/2022]
Abstract
Alcohol abuse has become common worldwide and has been recognized as a major cause of chronic alcoholic liver disease (ALD). ALD encompasses a complex process that includes a broad scope of hepatic lesions, ranging from steatosis to cirrhosis. In particular, reactive oxygen species (ROS) are mainly involved. Numerous studies have shown that p66shc plays a significant role in ALD. Protocatechuic acid (PCA), a dihydroxybenzoic acid that is naturally found in green tea, vegetables, and fruits, has efficient free radical scavenging effects. In this study, we aimed to assess the protective effect of PCA on ALD and to evaluate the microRNA- (miRNA-) p66shc-mediated reduction of ROS formation in ALD. Our results demonstrated that PCA treatment significantly decreased p66shc expression and downstream ROS formation in ALD. miR-219a-5p, which was identified by bioinformatics and experimental analysis, was enhanced by PCA and subsequently suppressed p66shc expression. Importantly, p66shc played an essential role in the protection of PCA-stimulated miR-219a-5p overexpression. Overall, these findings show that PCA-stimulated miR-219a-5p expression mitigates ALD by reducing p66shc-mediated ROS formation. This study may contribute to the development of therapeutic interventions for ALD.
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Webb DL. Tests of intestinal mucosal hyperpermeability: Many diseases, many biomarkers and a bright future. Best Pract Res Clin Gastroenterol 2019; 40-41:101636. [PMID: 31594645 DOI: 10.1016/j.bpg.2019.101636] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 07/18/2019] [Indexed: 01/31/2023]
Abstract
The number of disorders now linked to increased intestinal mucosal permeability implies that a substantial percent of the population is affected. Drug interventions targeting reduced tight junctional permeability are being pursued. Although hyper-permeability in itself is not a clinically recognized disease entity, its relationship to disease processes has driven interest in measuring, and even monitoring mucosal permeability in vivo. Along with improved knowledge of gut barrier physiology, advances have been made in tests and biomarkers of barrier function. Drawing from our experiences in the past decade, considerations and challenges faced in assessing in vivo intestinal permeability are discussed herein, along with indications of what the future might hold.
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Affiliation(s)
- Dominic-Luc Webb
- Gastroenterology and Hepatology Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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42
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Mu K, Yu S, Kitts DD. The Role of Nitric Oxide in Regulating Intestinal Redox Status and Intestinal Epithelial Cell Functionality. Int J Mol Sci 2019; 20:E1755. [PMID: 30970667 PMCID: PMC6479862 DOI: 10.3390/ijms20071755] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 03/29/2019] [Accepted: 04/03/2019] [Indexed: 12/11/2022] Open
Abstract
Important functions of intestinal epithelial cells (IECs) include enabling nutrient absorption to occur passively and acting as a defense barrier against potential xenobiotic components and pathogens. A compromise to IEC function can result in the translocation of bacteria, toxins, and allergens that lead to the onset of disease. Thus, the maintenance and optimal function of IECs are critically important to ensure health. Endogenous biosynthesis of nitric oxide (NO) regulates IEC functionality both directly, through free radical activity, and indirectly through cell signaling mechanisms that impact tight junction protein expression. In this paper, we review the current knowledge on factors that regulate inducible nitric oxide synthase (iNOS) and the subsequent roles that NO has on maintaining IECs' intestinal epithelial barrier structure, functions, and associated mechanisms of action. We also summarize important findings on the effects of bioactive dietary food components that interact with NO production and affect downstream intestinal epithelium integrity.
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Affiliation(s)
- Kaiwen Mu
- Faculty of Land and Food Systems, The University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
| | - Shengwu Yu
- Faculty of Land and Food Systems, The University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
| | - David D Kitts
- Faculty of Land and Food Systems, The University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
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Tolefree JA, Garcia AJ, Farrell J, Meadows V, Kennedy L, Hargrove L, Demieville J, Francis N, Mirabel J, Francis H. Alcoholic liver disease and mast cells: What's your gut got to do with it? LIVER RESEARCH 2019. [DOI: 10.1016/j.livres.2019.02.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Role of HIF-1α in Alcohol-Mediated Multiple Organ Dysfunction. Biomolecules 2018; 8:biom8040170. [PMID: 30544759 PMCID: PMC6316086 DOI: 10.3390/biom8040170] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/30/2018] [Accepted: 12/06/2018] [Indexed: 12/12/2022] Open
Abstract
Excess alcohol consumption is a global crisis contributing to over 3 million alcohol-related deaths per year worldwide and economic costs exceeding $200 billion dollars, which include productivity losses, healthcare, and other effects (e.g., property damages). Both clinical and experimental models have shown that excessive alcohol consumption results in multiple organ injury. Although alcohol metabolism occurs primarily in the liver, alcohol exposure can lead to pathophysiological conditions in multiple organs and tissues, including the brain, lungs, adipose, liver, and intestines. Understanding the mechanisms by which alcohol-mediated organ dysfunction occurs could help to identify new therapeutic approaches to mitigate the detrimental effects of alcohol misuse. Hypoxia-inducible factor (HIF)-1 is a transcription factor comprised of HIF-1α and HIF-1β subunits that play a critical role in alcohol-mediated organ dysfunction. This review provides a comprehensive analysis of recent studies examining the relationship between HIF-1α and alcohol consumption as it relates to multiple organ injury and potential therapies to mitigate alcohol’s effects.
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45
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Moein S, Vaghari-Tabari M, Qujeq D, Majidinia M, Nabavi SM, Yousefi B. MiRNAs and inflammatory bowel disease: An interesting new story. J Cell Physiol 2018; 234:3277-3293. [PMID: 30417350 DOI: 10.1002/jcp.27173] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 07/17/2018] [Indexed: 02/06/2023]
Abstract
Inflammatory bowel disease (IBD), as a chronic and recurrent inflammatory disorder, is caused by a dysregulated and aberrant immune response to exposed environmental factors in genetically susceptible individuals. Despite huge efforts in determining the molecular pathogenesis of IBD, an increasing worldwide incidence of IBD has been reported. MicroRNAs (miRNAs) are a set of noncoding RNA molecules that are about 22 nucleotides long, and these molecules are involved in the regulation of the gene expression. By clarifying the important role of miRNAs in a number of diseases, their role was also considered in IBD; numerous studies have been performed on this topic. In this review, we attempt to summarize a number of studies and discuss some of the recent developments in the roles of miRNAs in the pathophysiology, diagnosis, and treatment of IBD.
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Affiliation(s)
- Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Mostafa Vaghari-Tabari
- Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Irantab.,Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Bahman Yousefi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Cho YE, Yu LR, Abdelmegeed MA, Yoo SH, Song BJ. Apoptosis of enterocytes and nitration of junctional complex proteins promote alcohol-induced gut leakiness and liver injury. J Hepatol 2018; 69:142-153. [PMID: 29458168 PMCID: PMC6008177 DOI: 10.1016/j.jhep.2018.02.005] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 02/07/2018] [Accepted: 02/07/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Binge alcohol exposure causes gut leakiness, contributing to increased endotoxemia and inflammatory liver injury, although the molecular mechanisms are still elusive. This study was aimed at investigating the roles of apoptosis of enterocytes and nitration followed by degradation of intestinal tight junction (TJ) and adherens junction (AJ) proteins in binge alcohol-induced gut leakiness. METHODS The levels of intestinal (ileum) junctional complex proteins, oxidative stress markers and apoptosis-related proteins in rodents, T84 colonic cells and autopsied human ileums were determined by immunoblot, immunoprecipitation, immunofluorescence, and mass-spectral analyses. RESULTS Binge alcohol exposure caused apoptosis of gut enterocytes with elevated serum endotoxin and liver injury. The levels of intestinal CYP2E1, iNOS, nitrated proteins and apoptosis-related marker proteins were significantly elevated in binge alcohol-exposed rodents. Differential, quantitative mass-spectral analyses of the TJ-enriched fractions of intestinal epithelial layers revealed that several TJ, AJ and desmosome proteins were decreased in binge alcohol-exposed rats compared to controls. Consistently, the levels of TJ proteins (claudin-1, claudin-4, occludin and zonula occludens-1), AJ proteins (β-catenin and E-cadherin) and desmosome plakoglobin were very low in binge alcohol-exposed rats, wild-type mice, and autopsied human ileums but not in Cyp2e1-null mice. Additionally, pretreatment with specific inhibitors of CYP2E1 and iNOS prevented disorganization and/or degradation of TJ proteins in alcohol-exposed T84 colonic cells. Furthermore, immunoprecipitation followed by immunoblot confirmed that intestinal TJ and AJ proteins were nitrated and degraded via ubiquitin-dependent proteolysis, resulting in their decreased levels. CONCLUSIONS These results demonstrated for the first time the critical roles of CYP2E1, apoptosis of enterocytes, and nitration followed by ubiquitin-dependent proteolytic degradation of the junctional complex proteins, in promoting binge alcohol-induced gut leakiness and endotoxemia, contributing to inflammatory liver disease. LAY SUMMARY Binge alcohol exposure causes gut leakiness, contributing to increased endotoxemia and inflammatory liver injury. Our results demonstrated for the first time the critical roles of apoptosis of enterocytes and nitration followed by ubiquitin-dependent proteolytic degradation of the junctional complex proteins in promoting this gut leakiness and endotoxemia. These results provide insight into the molecular mechanisms of alcohol-induced inflammatory liver disease.
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Affiliation(s)
- Young-Eun Cho
- Section of Molecular Pharmacology & Toxicology, Laboratory of Membrane Biochemistry, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892 USA
| | - Li-Rong Yu
- Biomarkers and Alternative Models Branch, Division of Systems Biology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079, USA
| | - Mohamed A. Abdelmegeed
- Section of Molecular Pharmacology & Toxicology, Laboratory of Membrane Biochemistry, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892 USA
| | - Seong-Ho Yoo
- Department of Forensic Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Byoung-Joon Song
- Section of Molecular Pharmacology & Toxicology, Laboratory of Membrane Biochemistry, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA.
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Miao C, Xie Z, Chang J. Critical Roles of microRNAs in the Pathogenesis of Fatty Liver: New Advances, Challenges, and Potential Directions. Biochem Genet 2018; 56:423-449. [PMID: 29951838 DOI: 10.1007/s10528-018-9870-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 06/20/2018] [Indexed: 12/17/2022]
Abstract
In this review, we summarize the current understanding of microRNA (miRNA)-mediated modulation of the gene expression in the fatty liver as well as related signaling pathways. Because of the breadth and diversity of miRNAs, miRNAs may have a very wide variety of biological functions, and much evidence has confirmed that miRNAs are involved in the pathogenesis of fatty liver. In the pathophysiological mechanism of fatty liver, miRNAs may be regulated by upstream regulators, and have their own regulatory targets. miRNAs display important roles in the pathological mechanisms of alcoholic liver disease and non-alcoholic fatty liver disease. At present, most of the miRNA studies are focused on cell and tissue levels, and in vivo studies will help us elucidate the regulation of miRNAs and help us evaluate the potential of miRNAs as diagnostic markers and therapeutic targets. Furthermore, there is evidence that miRNAs are involved in the mechanism of natural medicine treatment in fatty liver. Given the important roles of miRNAs in the pathogenesis of fatty liver, we predict that studies of miRNAs in the pathogenesis of fatty liver will contribute to the elucidation of fatty liver pathology and the treatment of fatty liver patients.
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Affiliation(s)
- Chenggui Miao
- Department of Pharmacy, School of Life and Health Science, Anhui Science and Technology University, Fengyang, 233100, China
| | - Zhongwen Xie
- State Key Laboratory of Tea Biochemistry and Biotechnology, School of Science and Technology of Tea and Food, Anhui Agricultural University, No. 130, Changjiang West Road, Hefei, 230036, Anhui, China.
| | - Jun Chang
- Fourth Affiliated Hospital, Anhui Medical University, Hefei, 230032, China
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Deal RA, Tang Y, Fletcher R, Torquati A, Omotosho P. Understanding intestinal glucose transporter expression in obese compared to non-obese subjects. Surg Endosc 2017; 32:1755-1761. [PMID: 28936585 DOI: 10.1007/s00464-017-5858-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 08/22/2017] [Indexed: 01/06/2023]
Abstract
INTRODUCTION The impact of Roux-en-Y gastric bypass (RYGB) on weight loss and co-morbid disease resolution is well established. However, the mechanisms underlying the procedure remain incompletely understood. Intestinal remodeling involving glucose transporters (GLUTs) may play a crucial role. Rat studies have demonstrated morphological adaptation of GLUTs within adipose and intestinal cells in association with the reprogramming of glucose metabolism. There is a limited understanding of the variations in expression amongst GLUT family receptors in the human intestine. The aim of this study was to evaluate and describe jejunal GLUT expression patterns in the obese versus non-obese. METHODS Tissue samples were collected from 19 adults (age ≥18) patients with morbid obesity undergoing elective RYGB. Specimens were obtained from excess jejunum removed during the stapled jejuno-jejunal anastomosis. All subjects met National Institutes of Health criteria for bariatric surgery (body mass index or BMI ≥40 or ≥35 with obesity-related comorbidities). Exclusion criteria included age less than 18, age greater than 65, patients undergoing a revision procedure, and the presence of a seizure disorder (possible association with GLUT-1 deficiency syndrome). Five samples were obtained from non-obese subjects (average BMI 26.7) without diabetes who were consenting organ donors after brain death. Samples of jejunum from non-obese individuals were obtained at the time of organ procurement. Institutional Review Board and Gift of Hope approval was obtained. Specimens underwent quantitative real-time PCR and Western blotting. Western blot densitometry was performed using Image J software. Student T test was performed using SPSS statistics software. RESULTS GLUT-1 and GLUT-7 expression were not detected in the jejunum of either group. No difference in expression pattern was observed for GLUT-2, GLUT-4, and GLUT-9 between the groups. Western blot band density of GLUT-5 to loading control (GADPH) mean ratio was 0.21 (SD = 0.20) in obese specimens compared to 0.56 (SD = 0.17) in non-obese. Densitometry revealed GLUT-5 levels in the jejunum of the obese were significantly lower than non-obese specimens (P < 0.05). CONCLUSION The absence of GLUT-1 expression in both the obese and non-obese groups is consistent with the established view of GLUT-1 being abundantly present in fetal intestine but diminished to negligible levels by adulthood. Decreased GLUT-5 expression in samples from subjects with obesity compared to non-obese samples may represent a down-regulation of gene expression amongst the obese. The differential expression of GLUT-5 suggests a possible role in obesity. Studies of GLUT family expression will aid in understanding the impact of intestinal remodeling on obesity.
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Affiliation(s)
- Rebecca A Deal
- Division of Minimally Invasive and Bariatric Surgery, Department of-Surgery, Rush University Medical Center, Chicago, IL, 60612, USA.
| | - Yueming Tang
- Division of Minimally Invasive and Bariatric Surgery, Department of-Surgery, Rush University Medical Center, Chicago, IL, 60612, USA
| | - Reid Fletcher
- Division of Minimally Invasive and Bariatric Surgery, Department of-Surgery, Rush University Medical Center, Chicago, IL, 60612, USA
| | - Alfonso Torquati
- Division of Minimally Invasive and Bariatric Surgery, Department of-Surgery, Rush University Medical Center, Chicago, IL, 60612, USA
| | - Philip Omotosho
- Division of Minimally Invasive and Bariatric Surgery, Department of-Surgery, Rush University Medical Center, Chicago, IL, 60612, USA
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Brandt A, Jin CJ, Nolte K, Sellmann C, Engstler AJ, Bergheim I. Short-Term Intake of a Fructose-, Fat- and Cholesterol-Rich Diet Causes Hepatic Steatosis in Mice: Effect of Antibiotic Treatment. Nutrients 2017; 9:nu9091013. [PMID: 28906444 PMCID: PMC5622773 DOI: 10.3390/nu9091013] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 08/31/2017] [Accepted: 09/11/2017] [Indexed: 02/07/2023] Open
Abstract
Intestinal microbiota and barrier functions seem to play an important role in the development of non-alcoholic fatty liver disease (NAFLD). However, whether these changes are an early event in the development of NAFLD or are primarily associated with later stages of the disease, has not yet been clarified. Using a pair-feeding model, we determined the effects of a short-term intake of a fat-, fructose- and cholesterol-rich diet (FFC) on the development of early hepatic steatosis and markers of intestinal barrier function in mice treated with and without non-resorbable antibiotics (AB). For four days, C57BL/6J mice were either pair-fed a control diet or a FFC diet ± AB (92 mg/kg body weight (BW) polymyxin B and 216 mg/kg BW neomycin). Hepatic steatosis and markers of inflammation, lipidperoxidation and intestinal barrier function were assessed. Lipid accumulation and early signs of inflammation found in the livers of FFC-fed mice were markedly attenuated in FFC + AB-fed animals. In FFC-fed mice the development of NAFLD was associated with a significant loss of tight junction proteins and an induction of matrix metalloproteinase-13 in the upper parts of the small intestine as well as significantly higher portal endotoxin levels and an induction of dependent signaling cascades in the liver. As expected, portal endotoxin levels and the expression of dependent signaling cascades in liver tissue were almost at the level of controls in FFC + AB-fed mice. However, FFC + AB-fed mice were also protected from the loss of zonula occludens-1 and partially of occludin protein in small intestine. Our data suggest that the development of early diet-induced hepatic steatosis in mice at least in part results from alterations of intestinal barrier function.
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Affiliation(s)
- Annette Brandt
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, A-1090 Vienna, Austria.
- Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.
| | - Cheng Jun Jin
- Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.
| | - Katja Nolte
- Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.
| | - Cathrin Sellmann
- Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.
| | - Anna Janina Engstler
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, A-1090 Vienna, Austria.
- Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.
| | - Ina Bergheim
- Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, A-1090 Vienna, Austria.
- Institute of Nutritional Sciences, SD Model Systems of Molecular Nutrition, Friedrich-Schiller-University Jena, D-07743 Jena, Germany.
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Organ-Organ Crosstalk and Alcoholic Liver Disease. Biomolecules 2017; 7:biom7030062. [PMID: 28812994 PMCID: PMC5618243 DOI: 10.3390/biom7030062] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 08/10/2017] [Accepted: 08/11/2017] [Indexed: 02/06/2023] Open
Abstract
Alcohol consumption is a common custom worldwide, and the toxic effects of alcohol on several target organs are well-understood. Given the poor prognosis of treating clinically-relevant alcoholic liver disease (ALD) (i.e., alcoholic hepatitis (AH) and cirrhosis), additional research is required to develop more effective therapies. While the stages of ALD have been well-characterized, targeted therapies to prevent or reverse this process in humans are still needed. Better understanding of risk factors and mechanisms underlying disease progression can lead to the development of rational therapies to prevent or reverse ALD in the clinic. A potential area of targeted therapy for ALD may be organ–organ communication in the early stages of the disease. In contrast to AH and end-stage liver diseases, the involvement of multiple organs in the development of ALD is less understood. The impact of these changes on pathology to the liver and other organs may not only influence disease progression during the development of the disease, but also outcomes of end stages diseases. The purpose of this review is to summarize the established and proposed communication between the liver and other organ systems that may contribute to the development and progression of liver disease, as well as to other organs. Potential mechanisms of this organ–organ communication are also discussed.
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