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Jiang Z, Chen L, Dou X. Glutathionylation and metabolic dysfunction-associated steatotic liver disease. Biochimie 2025; 234:10-19. [PMID: 40147581 DOI: 10.1016/j.biochi.2025.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 02/26/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Affiliation(s)
- Zhe Jiang
- Department of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China
| | - Lin Chen
- Department of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China
| | - Xiaobing Dou
- Department of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China.
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Lin K, Wei L, Wang R, Li L, Song S, Wang F, He M, Pu W, Wang J, Wazir J, Cao W, Yang X, Treuter E, Fan R, Wang Y, Huang Z, Wang H. Disrupted methionine cycle triggers muscle atrophy in cancer cachexia through epigenetic regulation of REDD1. Cell Metab 2025; 37:460-476.e8. [PMID: 39729999 DOI: 10.1016/j.cmet.2024.10.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 09/19/2024] [Accepted: 10/19/2024] [Indexed: 12/29/2024]
Abstract
The essential amino acid methionine plays a pivotal role in one-carbon metabolism, facilitating the production of S-adenosylmethionine (SAM), a critical supplier for DNA methylation and thereby a modulator of gene expression. Here, we report that the methionine cycle is disrupted in skeletal muscle during cancer cachexia, leading to endoplasmic reticulum stress and DNA hypomethylation-induced expression of the DNA damage inducible transcript 4 (Ddit4) gene, encoding the regulated in development and DNA damage response 1 (REDD1) protein. Targeting DNA methylation by depletion or pharmacological inhibition of DNA methyltransferase 3A (DNMT3A) exacerbates cachexia, while restoring DNMT3A expression or REDD1 knockout alleviates cancer cachexia-induced skeletal muscle atrophy in mice. Methionine supplementation restores DNA methylation of the Ddit4 promoter in a DNMT3A-dependent manner, thereby inhibiting activating transcription factor 4 (ATF4)-mediated Ddit4 transcription. Thus, with the identification of the methionine/SAM-DNMT3A/DNA hypomethylation-Ddit4/REDD1 axis, our study provides molecular insights into an epigenetic mechanism underlying cancer cachexia, and it suggests nutrient supplementation as a promising therapeutic strategy to prevent or reverse cachectic muscle atrophy.
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Affiliation(s)
- Kai Lin
- State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
| | - Lulu Wei
- State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China; Department of Pathology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an 223399, China
| | - Ranran Wang
- State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
| | - Li Li
- State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
| | - Shiyu Song
- State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China; Nanjing Lupine (YuShanDou) Biomedical Research Institute Co. Ltd, Nanjing 210046, China
| | - Fei Wang
- State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
| | - Meiwei He
- State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
| | - Wenyuan Pu
- State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
| | - Jinglin Wang
- Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210093, Jiangsu, China
| | - Junaid Wazir
- State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
| | - Wangsen Cao
- State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China
| | - Xiaozhong Yang
- Department of Gastroenterology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an 223399, China
| | - Eckardt Treuter
- Department of Medicine Huddinge, Biosciences and Nutrition Unit, Karolinska Institutet, 14183 Huddinge, Sweden
| | - Rongrong Fan
- Department of Medicine Huddinge, Biosciences and Nutrition Unit, Karolinska Institutet, 14183 Huddinge, Sweden
| | - Yongxiang Wang
- Department of Orthopedics, Northern Jiangsu People's Hospital, Clinical Teaching Hospital of Medical School, Nanjing University, 98 West Nantong Road, Yangzhou 225001, China.
| | - Zhiqiang Huang
- State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China.
| | - Hongwei Wang
- State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210093, China.
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Marginean CM, Pirscoveanu D, Cazacu SM, Popescu MS, Marginean IC, Iacob GA, Popescu M. Non-Alcoholic Fatty Liver Disease, Awareness of a Diagnostic Challenge—A Clinician’s Perspective. GASTROENTEROLOGY INSIGHTS 2024; 15:1028-1053. [DOI: 10.3390/gastroent15040071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease globally. NAFLD is a complex pathology, considered to be the hepatic expression of metabolic syndrome (MetS). It is supposed to become the main indication for liver transplantation in the coming years and is estimated to affect 57.5–74.0% of obese people, 22.5% of children and 52.8% of obese children, with 50% of individuals with type 2 diabetes being diagnosed with NAFLD. Recent research has proved that an increase in adipose tissue insulin resistance index is an important marker of liver injury in patients with NAFLD. Despite being the main underlying cause of incidental liver damage and a growing worldwide health problem, NAFLD is mostly under-appreciated. Currently, NAFLD is considered a multifactorial disease, with various factors contributing to its pathogenesis, associated with insulin resistance and diabetes mellitus, but also with cardiovascular, kidney and endocrine disorders (polycystic ovary syndrome, hypothyroidism, growth hormone deficiency). Hepatitis B and hepatitis C, sleep apnea, inflammatory bowel diseases, cystic fibrosis, viral infections, autoimmune liver diseases and malnutrition are some other conditions in which NAFLD can be found. The aim of this review is to emphasize that, from the clinician’s perspective, NAFLD is an actual and valuable key diagnosis factor for multiple conditions; thus, efforts need to be made in order to increase recognition of the disease and its consequences. Although there is no global consensus, physicians should consider screening people who are at risk of NAFLD. A large dissemination of current concepts on NAFLD and an extensive collaboration between physicians, such as gastroenterologists, internists, cardiologists, diabetologists, nutritionists and endocrinologists, is equally needed to ensure we have the knowledge and resources to address this public health challenge.
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Affiliation(s)
- Cristina Maria Marginean
- Internal Medicine Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Denisa Pirscoveanu
- Neurology Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Sergiu Marian Cazacu
- Research Center of Gastroenterology and Hepatology, Gastroenterology Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Marian Sorin Popescu
- Internal Medicine Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | | | - George Alexandru Iacob
- Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mihaela Popescu
- Endocrinology Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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Torres S, Hardesty J, Barrios M, Garcia-Ruiz C, Fernandez-Checa JC, Singal AK. Mitochondria and Alcohol-Associated Liver Disease: Pathogenic Role and Target for Therapy. Semin Liver Dis 2024. [PMID: 39317216 DOI: 10.1055/a-2421-5658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/26/2024]
Abstract
Alcohol-associated liver disease (ALD) is one of the leading causes of chronic liver disease and a major cause of liver-related death. ALD is a multifactorial disease triggered by the oxidative metabolism of alcohol which leads to the activation of multiple factors that promote the progression from steatosis to more advanced stages like alcohol-associated steatohepatitis (AH) that culminate in alcohol-associated cirrhosis and hepatocellular carcinoma. Poor understanding of the complex heterogeneous pathology of ALD has limited drug development for this disease. Alterations in mitochondrial performance are considered a crucial event in paving the progression of ALD due to the crucial role of mitochondria in energy production, intermediate metabolism, calcium homeostasis, and cell fate decisions. Therefore, understanding the role of mitochondria in eliciting steatosis and progression toward AH may open the door to new opportunities for treatment. In this review, we will cover the physiological function of mitochondria, its contribution to ALD in experimental models and human disease, and explore whether targeting mitochondria may represent a game changer in the treatment of ALD.
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Affiliation(s)
- Sandra Torres
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Unidad Associada IMIM/IIBB-CSIC, Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Josiah Hardesty
- Division of Gastroenterology and Hepatology, University of Louisville, Louisville, Kentucky
- Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Louisville, Kentucky
| | - Monica Barrios
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Unidad Associada IMIM/IIBB-CSIC, Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Carmen Garcia-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Unidad Associada IMIM/IIBB-CSIC, Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Jose C Fernandez-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Unidad Associada IMIM/IIBB-CSIC, Barcelona, Spain
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Unidad Associada IMIM/IIBB-CSIC, Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Ashwani K Singal
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Unidad Associada IMIM/IIBB-CSIC, Barcelona, Spain
- Division of Gastroenterology and Hepatology, University of Louisville, Louisville, Kentucky
- Transplant Hepatology, Trager Transplant Center and Jewish Hospital, University of Health, Louisville, Kentucky
- Department of Clinical Research, Robley Rex VA Medical Center, Louisville, Kentucky
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Jiang L, Ni Y, Zhao C, Gao D, Gai X, Xiong K, Wang J. Folic acid protects against isoniazid-induced liver injury via the m 6A RNA methylation of cytochrome P450 2E1 in mice. Front Nutr 2024; 11:1389684. [PMID: 38798770 PMCID: PMC11116731 DOI: 10.3389/fnut.2024.1389684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 04/23/2024] [Indexed: 05/29/2024] Open
Abstract
Background Cytochrome P450 2E1 (CYP2E1) converts isoniazid (INH) to toxic metabolites and is critical in INH-induced liver injury. The aim is to investigate the effect of folic acid (FA) on CYP2E1 and INH-induced liver injury. Methods Male Balb/c mice were used. The mice in the control group only received an AIN-93M diet. The AIN-93M diet was supplemented with 0.66 g INH/kg diet for the mice in the INH and FA groups. The mice in the FA group were treated with additional 0.01 g FA/kg diet. The one-carbon cycle metabolites, the expressions of CYP2E1 and the DNA and RNA methylation levels were detected to reveal the potential mechanism. Results FA treatment significantly reduced the alanine aminotransferase level and alleviated the liver necrosis. The mRNA and protein expressions of CYP2E1 were significantly lower in the FA group than those in the INH group. The N6-methyladenosine RNA methylation level of Cyp2e1 significantly increased in the FA group compared with the INH group, while the DNA methylation levels of Cyp2e1 were similar between groups. Additionally, the liver S-adenosyl methionine (SAM)/S-adenosyl homocysteine (SAH) was elevated in the FA group and tended to be positively correlated with the RNA methylation level of Cyp2e1. Conclusion FA alleviated INH-induced liver injury which was potentially attributed to its inhibitory effect on CYP2E1 expressions through enhancing liver SAM/SAH and RNA methylation.
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Affiliation(s)
| | | | | | | | | | | | - Jinyu Wang
- Institute of Nutrition and Health, School of Public Health, Qingdao University, Qingdao, China
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Saleh AA, El-Tahan HM, Shaban M, Morsy WA, Genedy S, Alzawqari MH, El-Tahan HM, Shukry M, Ebeid TA, El-Keredy A, Alwutayd K, Alhotan RA, Al-Badwi MAA, Sewlim Hussein EO, Kim IH, Cho S, Eid Abdel-Moneim AM. Effect of dietary supplementation of betaine and organic minerals on growth performance, serum biochemical parameters, nutrients digestibility, and growth-related genes in broilers under heat stress. Poult Sci 2023; 102:103051. [PMID: 37774520 PMCID: PMC10550832 DOI: 10.1016/j.psj.2023.103051] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/15/2023] [Accepted: 08/17/2023] [Indexed: 10/01/2023] Open
Abstract
Global warming and climate changes have a detrimental impact on poultry production, causing substantial economic losses. This study investigated the effects of incorporating dietary betaine (BT) and organic minerals (OMs) on broilers' performance as well as their potential to mitigate the negative impacts of heat stress (HS). Six hundred 1-day-old Ross 308 chicks were randomly allocated to 12 experimental treatments with 5 replicates of 10 birds each (5 male + 5 female). The birds were provided with diets containing BT (0 and 2,000 ppm) and OMs (0, 250, and 500 ppm), either individually or in combination, under both thermoneutral and HS-inducing temperatures. The HS conditions involved exposing the birds to cyclic periods of elevated temperature (35°C ± 2°C) for 6 h daily, from 10:00 am to 4:00 pm, starting from d 10 and continuing until d 35. The exposure to HS deteriorated birds' growth performance; however, dietary BT and OMs inclusion improved the growth performance parameters bringing them close to normal levels. Carcass traits were not affected by dietary supplementation of BT, OMs, HS, or their interaction. Interestingly, while HS led to increased (P < 0.05) levels of total cholesterol, LDL-cholesterol, and hepatic malondialdehyde (MDA), these adverse effects were mitigated (P < 0.05) by the addition of BT and OMs. Moreover, dietary BT supplementation led to elevated serum total protein and globulin concentrations. Cyclic HS did not alter Mn, Zn, and Cu contents in the pectoral muscle. However, the incorporation of OMs at both levels increased concentrations of these minerals. Notably, the combination of 500 ppm OMs and 2,000 ppm BT improved Mn, Zn, Cu, and Fe digestibility, which has been compromised under HS conditions. Cyclic HS upregulated gene expression of interleukin-1β, heat shock protein 70, and Toll-like receptor-4 while downregulated the expression of claudin-1, uncoupling protein, growth hormone receptor, superoxide dismutase 1, glutathione peroxidase 1 and insulin-like growth factor 1. The aforementioned gene expressions were reversed by the combination of higher dietary levels of BT and OMs. In conclusion, the dietary supplementation of 500 ppm OMs along with 2,000 ppm BT yielded significant improvements in growth performance and mineral digestibility among broiler chickens, regardless of thermal conditions. Moreover, this combination effectively restored the expression of growth-related genes even under heat-stress conditions.
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Affiliation(s)
- Ahmed A Saleh
- Department of Poultry Production, Faculty of Agriculture, Kafrelsheikh University, 333516 Kafrelsheikh, Egypt
| | - Hossam M El-Tahan
- Animal Resource and Science Department, Dankook University, Cheonan 31116, Republic of Korea; Animal Production Research Institute (APRI), Agricultural Research Center (ARC), Ministry of Agriculture, Dokki, 12611, Egypt.
| | - Mohammed Shaban
- Department of Poultry Production, Faculty of Agriculture, Kafrelsheikh University, 333516 Kafrelsheikh, Egypt
| | - Wael A Morsy
- Animal Production Research Institute (APRI), Agricultural Research Center (ARC), Ministry of Agriculture, Dokki, 12611, Egypt
| | - Salwa Genedy
- Department of Poultry Production, Faculty of Agriculture, Kafrelsheikh University, 333516 Kafrelsheikh, Egypt
| | - Mohammed H Alzawqari
- Department of Poultry Production, Faculty of Agriculture, Kafrelsheikh University, 333516 Kafrelsheikh, Egypt; Department of Animal Production, Faculty of Agriculture and Food Sciences, Ibb University, 70270 Ibb, Yemen
| | - Hatem M El-Tahan
- Animal Production Research Institute (APRI), Agricultural Research Center (ARC), Ministry of Agriculture, Dokki, 12611, Egypt
| | - Mustafa Shukry
- Department of Physiology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 333516, Egypt
| | - Tarek A Ebeid
- Department of Poultry Production, Faculty of Agriculture, Kafrelsheikh University, 333516 Kafrelsheikh, Egypt; Department of Animal Production and Breeding, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia
| | - Amira El-Keredy
- Department of Genetics, Faculty of Agriculture, Tanta University, Tanta, Egypt
| | - Khairiah Alwutayd
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia
| | - Rashed A Alhotan
- Department of Animal Production, College of Food & Agriculture Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammed A A Al-Badwi
- Department of Animal Production, College of Food & Agriculture Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | | | - In Ho Kim
- Animal Resource and Science Department, Dankook University, Cheonan 31116, Republic of Korea.
| | - Sungbo Cho
- Animal Resource and Science Department, Dankook University, Cheonan 31116, Republic of Korea.
| | - Abdel-Moneim Eid Abdel-Moneim
- Biological Applications Department, Nuclear Research Center, Egyptian Atomic Energy Authority, Abu-Zaabal 13759, Egypt
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Li D, Li BX, Zhang Y, Li X, Li JY, Zhang XY, Ye XW, Zhang C. SAM protects against alveolar septal cell apoptosis in autoimmune emphysema rats. Eur J Med Res 2023; 28:460. [PMID: 37880804 PMCID: PMC10601109 DOI: 10.1186/s40001-023-01396-w] [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: 11/25/2021] [Accepted: 09/25/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Hypomethylation of the perforin gene promoter in CD4 + T cells, inflammation and oxidative stress, might be involved in alveolar septal cell apoptosis associated with emphysema in rats. This study aimed to investigate the effects of S-adenosylmethionine (SAM) on this kind of apoptosis in rats with autoimmune emphysema. METHODS Twenty-four rats were randomly divided into three groups: a normal control group, a model group, and a SAM group. Pathological changes in lung tissues were observed, and the mean linear intercept (MLI) and mean alveolar number (MAN) were measured. The levels of anti-endothelial cell antibodies (AECA) in serum, alveolar septal cell apoptosis, perforin gene promotor methylation in CD4 + T cells in the spleen, and the levels of cytokines, malondialdehyde (MDA), and glutathione (GSH) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in bronchoalveolar lavage fluid (BALF) were investigated. RESULTS The MLI, apoptosis index (AI) of alveolar septal cells, levels of AECA in serum, and levels of tumour necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP-9) and MDA in BALF were increased, while the MAN, methylation levels, and the activities of GSH, SOD and GSH-Px in BALF were decreased in the model group compared with those in the normal control group and the SAM group (all P < 0.05). The levels of interleukin-8 (IL-8) in BALF were greater in the model group than in the normal control group (P < 0.05). CONCLUSIONS SAM protects against alveolar septal cell apoptosis, airway inflammation and oxidative stress in rats with autoimmune emphysema possibly by partly reversing the hypomethylation of the perforin gene promoter in CD4 + T cells.
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Affiliation(s)
- Dan Li
- Department of Respiratory Medicine, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang, Guizhou, China
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China
| | - Ben-Xue Li
- Department of Respiratory Medicine, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang, Guizhou, China
- Panzhou People's Hospital, Panzhou, Guizhou, China
| | - Ye Zhang
- Department of Respiratory Medicine, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang, Guizhou, China
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China
| | - Xia Li
- Department of Respiratory Medicine, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang, Guizhou, China
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China
| | - Jia-Yi Li
- Department of Respiratory Medicine, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang, Guizhou, China
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China
| | - Xiang-Yan Zhang
- Department of Respiratory Medicine, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang, Guizhou, China
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China
| | - Xian-Wei Ye
- Department of Respiratory Medicine, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang, Guizhou, China.
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China.
| | - Cheng Zhang
- Department of Respiratory Medicine, Guizhou Provincial People's Hospital, No. 83, Zhongshan East Road, Guiyang, Guizhou, China.
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China.
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8
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Aghara H, Chadha P, Zala D, Mandal P. Stress mechanism involved in the progression of alcoholic liver disease and the therapeutic efficacy of nanoparticles. Front Immunol 2023; 14:1205821. [PMID: 37841267 PMCID: PMC10570533 DOI: 10.3389/fimmu.2023.1205821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 09/07/2023] [Indexed: 10/17/2023] Open
Abstract
Alcoholic liver disease (ALD) poses a significant threat to human health, with excessive alcohol intake disrupting the immunotolerant environment of the liver and initiating a cascade of pathological events. This progressive disease unfolds through fat deposition, proinflammatory cytokine upregulation, activation of hepatic stellate cells, and eventual development of end-stage liver disease, known as hepatocellular carcinoma (HCC). ALD is intricately intertwined with stress mechanisms such as oxidative stress mediated by reactive oxygen species, endoplasmic reticulum stress, and alcohol-induced gut dysbiosis, culminating in increased inflammation. While the initial stages of ALD can be reversible with diligent care and abstinence, further progression necessitates alternative treatment approaches. Herbal medicines have shown promise, albeit limited by their poor water solubility and subsequent lack of extensive exploration. Consequently, researchers have embarked on a quest to overcome these challenges by delving into the potential of nanoparticle-mediated therapy. Nanoparticle-based treatments are being explored for liver diseases that share similar mechanisms with alcoholic liver disease. It underscores the potential of these innovative approaches to counteract the complex pathogenesis of ALD, providing new avenues for therapeutic intervention. Nevertheless, further investigations are imperative to fully unravel the therapeutic potential and unlock the promise of nanoparticle-mediated therapy specifically tailored for ALD treatment.
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Affiliation(s)
| | | | | | - Palash Mandal
- P D Patel Institute of Applied Sciences, Charotar University of Science and Technology, Anand, Gujarat, India
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9
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Aghara H, Chadha P, Zala D, Mandal P. Stress mechanism involved in the progression of alcoholic liver disease and the therapeutic efficacy of nanoparticles. Front Immunol 2023; 14. [DOI: https:/doi.org/10.3389/fimmu.2023.1205821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023] Open
Abstract
Alcoholic liver disease (ALD) poses a significant threat to human health, with excessive alcohol intake disrupting the immunotolerant environment of the liver and initiating a cascade of pathological events. This progressive disease unfolds through fat deposition, proinflammatory cytokine upregulation, activation of hepatic stellate cells, and eventual development of end-stage liver disease, known as hepatocellular carcinoma (HCC). ALD is intricately intertwined with stress mechanisms such as oxidative stress mediated by reactive oxygen species, endoplasmic reticulum stress, and alcohol-induced gut dysbiosis, culminating in increased inflammation. While the initial stages of ALD can be reversible with diligent care and abstinence, further progression necessitates alternative treatment approaches. Herbal medicines have shown promise, albeit limited by their poor water solubility and subsequent lack of extensive exploration. Consequently, researchers have embarked on a quest to overcome these challenges by delving into the potential of nanoparticle-mediated therapy. Nanoparticle-based treatments are being explored for liver diseases that share similar mechanisms with alcoholic liver disease. It underscores the potential of these innovative approaches to counteract the complex pathogenesis of ALD, providing new avenues for therapeutic intervention. Nevertheless, further investigations are imperative to fully unravel the therapeutic potential and unlock the promise of nanoparticle-mediated therapy specifically tailored for ALD treatment.
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Zhou R, Yang M, Yue C, Shi Y, Tan Y, Zha L, Zhang J, Chen S. Association between Dietary Choline Intake and Cardiovascular Diseases: National Health and Nutrition Examination Survey 2011-2016. Nutrients 2023; 15:4036. [PMID: 37764819 PMCID: PMC10534328 DOI: 10.3390/nu15184036] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/06/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Choline is an essential nutrient for human body, but dietary choline is metabolized into the hazard metabolite for the cardiovascular system. Because of the conflicting results between dietary choline intake and cardiovascular disease (CVD) risk in previous studies, we aimed to investigate this in US adults. Non-pregnant participants and those aged >20 years from National Health and Nutrition Examination Survey 2011-2016, with CVD assessment and reliable dietary recall status, were included. The dietary choline intake was assessed as a mean value of two total dietary choline intakes, including dietary choline intake and supplemental choline intake, in 24-h dietary recall interviews. The association between dietary choline intake and the presence of CVD was examined using logistic regression. We enrolled 14,323 participants. The participants without CVD had substantially higher dietary choline intakes (318.4 mg/d vs. 297.2 mg/d) compared to those with CVD (p < 0.05). After multivariable adjustments, the highest quartile of dietary choline intake was associated with a lower CVD risk, OR 0.693, 95%CI [0.520, 0.923], when compared to the lowest quartile. Consistent results were also found for stroke. Subgroup analyses also supported these, especially in participants aged ≥60 years and in those with BMI < 30 kg/m2. We found that a higher dietary choline intake was associated with a lower CVD risk, especially the risk of stroke. Further clinical trials are needed in order to confirm this finding and to provide dietary suggestions for the appropriate amount of choline intake.
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Affiliation(s)
- Rong Zhou
- Department of Intensive Medicine, Qujing First People’s Hospital, Qujing 655000, China; (R.Z.); (M.Y.); (C.Y.)
| | - Mei Yang
- Department of Intensive Medicine, Qujing First People’s Hospital, Qujing 655000, China; (R.Z.); (M.Y.); (C.Y.)
| | - Chaofu Yue
- Department of Intensive Medicine, Qujing First People’s Hospital, Qujing 655000, China; (R.Z.); (M.Y.); (C.Y.)
| | - Yi Shi
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (Y.S.); (Y.T.); (S.C.)
| | - Yanan Tan
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (Y.S.); (Y.T.); (S.C.)
| | - Lingfeng Zha
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Junxia Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (Y.S.); (Y.T.); (S.C.)
| | - Shaoliang Chen
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (Y.S.); (Y.T.); (S.C.)
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11
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Cruise TM, Kotlo K, Malovic E, Pandey SC. Advances in DNA, histone, and RNA methylation mechanisms in the pathophysiology of alcohol use disorder. ADVANCES IN DRUG AND ALCOHOL RESEARCH 2023; 3:10871. [PMID: 38389820 PMCID: PMC10880780 DOI: 10.3389/adar.2023.10871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 01/25/2023] [Indexed: 02/24/2024]
Abstract
Alcohol use disorder (AUD) has a complex, multifactorial etiology involving dysregulation across several brain regions and peripheral organs. Acute and chronic alcohol consumption cause epigenetic modifications in these systems, which underlie changes in gene expression and subsequently, the emergence of pathophysiological phenotypes associated with AUD. One such epigenetic mechanism is methylation, which can occur on DNA, histones, and RNA. Methylation relies on one carbon metabolism to generate methyl groups, which can then be transferred to acceptor substrates. While DNA methylation of particular genes generally represses transcription, methylation of histones and RNA can have bidirectional effects on gene expression. This review summarizes one carbon metabolism and the mechanisms behind methylation of DNA, histones, and RNA. We discuss the field's findings regarding alcohol's global and gene-specific effects on methylation in the brain and liver and the resulting phenotypes characteristic of AUD.
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Affiliation(s)
- Tara M. Cruise
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, United States
| | - Kumar Kotlo
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, United States
| | - Emir Malovic
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, United States
| | - Subhash C. Pandey
- Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, United States
- Jesse Brown Veterans Affairs Medical Center, Chicago, IL, United States
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12
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Alarcón-Vila C, Insausti-Urkia N, Torres S, Segalés-Rovira P, Conde de la Rosa L, Nuñez S, Fucho R, Fernández-Checa JC, García-Ruiz C. Dietary and genetic disruption of hepatic methionine metabolism induce acid sphingomyelinase to promote steatohepatitis. Redox Biol 2023; 59:102596. [PMID: 36610223 PMCID: PMC9827379 DOI: 10.1016/j.redox.2022.102596] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023] Open
Abstract
Alcoholic (ASH) and nonalcoholic. (NASH).steatohepatitis are advanced.stages.of.fatty.liver.disease.Methionine adenosyltransferase 1A (MAT1A) plays a key role in hepatic methionine metabolism and germline Mat1a deletion in mice promotes NASH. Acid sphingomyelinase (ASMase) triggers hepatocellular apoptosis and liver fibrosis and has been shown to downregulate MAT1A expression in the context of fulminant liver failure. Given the role of ASMase in steatohepatitis development, we investigated the status of ASMase in Mat1a-/- mice and the regulation of ASMase by SAM/SAH. Consistent with its role in NASH, Mat1a-/- mice fed a choline-deficient (CD) diet exhibited macrosteatosis, inflammation, fibrosis and liver injury as well as reduced total and mitochondrial GSH levels. Our data uncovered an increased basal expression and activity of ASMase but not neutral SMase in Mat1a-/- mice, which further increased upon CD feeding. Interestingly, adenovirus-mediated shRNA expression targeting ASMase reduced ASMase activity and protected Mat1a-/- mice against CD diet-induced NASH. Similar results were observed in CD fed Mat1a-/- mice by pharmacological inhibition of ASMase with amitriptyline. Moreover, Mat1a/ASMase double knockout mice were resistant to CD-induced NASH. ASMase knockdown protected wild type mice against NASH induced by feeding a diet deficient in methionine and choline. Furthermore, Mat1a-/- mice developed acute-on-chronic ASH and this outcome was ameliorated by amitriptyline treatment. In vitro data in primary mouse hepatocytes revealed that decreased SAM/SAH ratio increased ASMase mRNA level and activity. MAT1A and ASMase mRNA levels exhibited an inverse correlation in liver samples from patients with ASH and NASH. Thus, disruption of methionine metabolism sensitizes to steatohepatitis by ASMase activation via decreased SAM/SAH. These findings imply that MAT1A deletion and ASMase activation engage in a self-sustained loop of relevance for steatohepatitis.
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Affiliation(s)
- Cristina Alarcón-Vila
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
| | - Naroa Insausti-Urkia
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
| | - Sandra Torres
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
| | - Paula Segalés-Rovira
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
| | - Laura Conde de la Rosa
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
| | - Susana Nuñez
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
| | - Raquel Fucho
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain
| | - Jose C Fernández-Checa
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain; University of Southern California Research Center for Liver Diseases, Keck School of Medicine, USC, Los Angeles, CA, USA.
| | - Carmen García-Ruiz
- Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC, Barcelona, Spain; Liver Unit, Hospital Clínic I Provincial, IDIBAPS, Barcelona, Spain; CIBERehd, University of Barcelona, Spain; University of Southern California Research Center for Liver Diseases, Keck School of Medicine, USC, Los Angeles, CA, USA.
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13
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Starek-Świechowicz B, Budziszewska B, Starek A. Alcohol and breast cancer. Pharmacol Rep 2023; 75:69-84. [PMID: 36310188 PMCID: PMC9889462 DOI: 10.1007/s43440-022-00426-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 10/05/2022] [Accepted: 10/06/2022] [Indexed: 02/04/2023]
Abstract
Breast cancer is one of the main causes of death in women worldwide. In women, breast cancer includes over half of all tumours caused by alcohol. This paper discusses both ethanol metabolism and the mechanisms of mammary tumourigenesis caused by alcohol. Numerous signalling pathways in neoplastic transformation following alcohol consumption in women have been presented. In addition, primary and secondary prevention, phytochemicals, synthetic chemicals, specific inhibitors of enzymes and selective receptor modulators have been described.
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Affiliation(s)
- Beata Starek-Świechowicz
- Department of Biochemical Toxicology, Chair of Toxicology, Medical College, Jagiellonian University, Medyczna 9, 30-688 Kraków, Poland
| | - Bogusława Budziszewska
- Department of Biochemical Toxicology, Chair of Toxicology, Medical College, Jagiellonian University, Medyczna 9, 30-688 Kraków, Poland
| | - Andrzej Starek
- Department of Biochemical Toxicology, Chair of Toxicology, Medical College, Jagiellonian University, Medyczna 9, 30-688 Kraków, Poland
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14
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Li K, Huang W, Wang Z, Nie Q. m 6A demethylase FTO regulate CTNNB1 to promote adipogenesis of chicken preadipocyte. J Anim Sci Biotechnol 2022; 13:147. [PMID: 36461116 PMCID: PMC9716549 DOI: 10.1186/s40104-022-00795-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 10/11/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND N6-methyladenosine (m6A) is an abundant post-transcriptional RNA modification that affects various biological processes. The fat mass and obesity-associated (FTO) protein, a demethylase encoded by the FTO gene, has been found to regulate adipocyte development in an m6A-dependent manner in multiple species. However, the effects of the m6A methylation and FTO demethylation functions on chicken adipogenesis remain unclear. This study aims to explore the association between m6A modification and chicken adipogenesis and the underlying mechanism by which FTO affects chicken preadipocyte development. RESULTS The association between m6A modification and chicken lipogenesis was assessed by treating chicken preadipocytes with different doses of methyl donor betaine and methylation inhibitor cycloleucine. The results showed that betaine significantly increased methylation levels and inhibited lipogenesis, and the inverse effect was found in preadipocytes after cycloleucine treatment. Overexpression of FTO significantly inhibited m6A levels and promoted proliferation and differentiation of chicken preadipocytes. Silencing FTO showed opposite results. Mechanistically, FTO overexpression increased the expression of catenin beta 1 (CTNNB1) by improving RNA stability in an m6A-dependent manner, and we proved that FTO could directly target CTNNB1. Furthermore, CTNNB1 may be a positive regulator of adipogenesis in chicken preadipocytes. CONCLUSIONS m6A methylation of RNA was negatively associated with adipogenesis of chicken preadipocytes. FTO could regulate CTNNB1 expression in a demethylation manner to promote lipogenesis.
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Affiliation(s)
- Kan Li
- grid.20561.300000 0000 9546 5767Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642 China ,grid.418524.e0000 0004 0369 6250National-Local Joint Engineering Research Center for Livestock Breeding, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642 China
| | - Weichen Huang
- grid.20561.300000 0000 9546 5767Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642 China ,grid.418524.e0000 0004 0369 6250National-Local Joint Engineering Research Center for Livestock Breeding, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642 China
| | - Zhijun Wang
- grid.20561.300000 0000 9546 5767Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642 China ,grid.418524.e0000 0004 0369 6250National-Local Joint Engineering Research Center for Livestock Breeding, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642 China
| | - Qinghua Nie
- grid.20561.300000 0000 9546 5767Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642 China ,grid.418524.e0000 0004 0369 6250National-Local Joint Engineering Research Center for Livestock Breeding, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, and Key Laboratory of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642 China
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15
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Mai B, Han L, Zhong J, Shu J, Cao Z, Fang J, Zhang X, Gao Z, Xiao F. Rhoifolin Alleviates Alcoholic Liver Disease In Vivo and In Vitro via Inhibition of the TLR4/NF-κB Signaling Pathway. Front Pharmacol 2022; 13:878898. [PMID: 35685625 PMCID: PMC9171502 DOI: 10.3389/fphar.2022.878898] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/13/2022] [Indexed: 01/16/2023] Open
Abstract
Background: Alcoholic liver disease (ALD) is a common chronic liver disorder worldwide, which is detrimental to human health. A preliminary study showed that the total flavonoids within Citrus grandis “Tomentosa” exerted a remarkable effect on the treatment of experimental ALD. However, the active substances of Citrus grandis “Tomentosa” were not elucidated. Rhoifolin (ROF) is a flavonoid component present in high levels. Therefore, this research aimed to evaluate the hepatoprotective effects of ROF and its possible mechanisms. Methods: Molecular docking was performed to analyze the binding energy of ROF to the main target proteins related to ALD. Subsequently, mice were fed ethanol (ETH) for 49 days to establish the chronic alcoholic liver injury models. The liver pathological injury, serum aminotransferase levels, and oxidative stress levels in the liver tissue were measured. Human normal hepatocytes (LO2 cells) were incubated with ETH to construct the alcoholic liver cell model. The inflammatory markers and apoptosis factors were evaluated using real-time PCR and flow cytometry. Finally, the effects of ROF on the CYP2E1 and NF-κB signaling pathways were tested in vitro and in vivo. Results: Molecular docking results demonstrated that ROF was able to successfully dock with the target proteins associated with ALD. In animal studies, ROF attenuated ETH-induced liver damage in mice by decreasing the serum concentrations of AST and ALT, reducing the expression of inflammatory cytokines, and maintaining antioxidant balance in the liver tissue. The in vitro experiments demonstrated that ROF suppressed ETH-induced apoptosis in LO2 cells by promoting Bcl-2 mRNA and inhibiting Bax mRNA and caspase 3 protein expression. ROF decreased the level of LDH, ALT, AST, ROS, and MDA in the supernatant; induced the activity of GSH and SOD; and inhibited TNF-α, IL-6, and IL-1β expression levels. Mechanistically, ROF could significantly downregulate the expression levels of CYP2E1, TLR4, and NF-κB phosphorylation. Conclusion: This study indicates that ROF is the active component within the total flavonoids, which may alleviate ETH-induced liver injury by inhibiting NF-κB phosphorylation. Therefore, ROF may serve as a promising compound for treating ALD.
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Affiliation(s)
- Baoyu Mai
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ling Han
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, China
- Guangdong Provincial Clinical Medicine Research Center for Chinese Medicine Dermatology, Guangzhou, China
| | - Jiarui Zhong
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingqi Shu
- College of Acumox and Tuina, Jiangxi University of Chinese Medicine, Jiangxi, China
| | - Zelin Cao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, China
| | - Jiaqi Fang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaoying Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zelin Gao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fengxia Xiao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Maoming, China
- *Correspondence: Fengxia Xiao,
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16
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Ornoy A, Weinstein-Fudim L, Becker M. SAMe, Choline, and Valproic Acid as Possible Epigenetic Drugs: Their Effects in Pregnancy with a Special Emphasis on Animal Studies. Pharmaceuticals (Basel) 2022; 15:192. [PMID: 35215304 PMCID: PMC8879727 DOI: 10.3390/ph15020192] [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: 12/28/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 11/29/2022] Open
Abstract
In this review, we discuss the functions and main effects on pregnancy outcomes of three agents that have the ability to induce epigenetic modifications: valproic acid (VPA), a well-known teratogen that is a histone deacetylase inhibitor; S-adenosylmethionine (SAMe), the most effective methyl donor; and choline, an important micronutrient involved in the one methyl group cycle and in the synthesis of SAMe. Our aim was to describe the possible effects of these compounds when administered during pregnancy on the developing embryo and fetus or, if administered postnatally, their effects on the developing child. These substances are able to modify gene expression and possibly alleviate neurobehavioral changes in disturbances that have epigenetic origins, such as autism spectrum disorder (ASD), depression, Rett syndrome, and fetal alcohol spectrum disorder (FASD). Valproic acid and SAMe are antagonistic epigenetic modulators whether administered in utero or postnatally. However, VPA is a major human teratogen and, whenever possible, should not be used by pregnant women. Most currently relevant data come from experimental animal studies that aimed to explore the possibility of using these substances as epigenetic modifiers and possible therapeutic agents. In experimental animals, each of these substances was able to alleviate the severity of several well-known diseases by inducing changes in the expression of affected genes or by other yet unknown mechanisms. We believe that additional studies are needed to further explore the possibility of using these substances, and similar compounds, for the treatment of "epigenetic human diseases".
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Affiliation(s)
- Asher Ornoy
- Adelson School of Medicine, Ariel University, Ariel 40700, Israel;
- Department of Medical Neurobiology, Hebrew University Hadassah Medical School, Jerusalem 9112102, Israel;
| | - Liza Weinstein-Fudim
- Department of Medical Neurobiology, Hebrew University Hadassah Medical School, Jerusalem 9112102, Israel;
| | - Maria Becker
- Adelson School of Medicine, Ariel University, Ariel 40700, Israel;
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17
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Weckerle J, Picart-Armada S, Klee S, Bretschneider T, Luippold AH, Rist W, Haslinger C, Schlüter H, Thomas MJ, Krawczyk B, Fernandez-Albert F, Kästle M, Veyel D. Mapping the metabolomic and lipidomic changes in the Bleomycin model of pulmonary fibrosis in young and aged mice. Dis Model Mech 2021; 15:274099. [PMID: 34845494 PMCID: PMC8807555 DOI: 10.1242/dmm.049105] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 11/17/2021] [Indexed: 11/20/2022] Open
Abstract
Alterations in metabolic pathways were recently recognized as potential underlying drivers of idiopathic pulmonary fibrosis (IPF), translating into novel therapeutic targets. However, knowledge of metabolic and lipid regulation in fibrotic lungs is limited. To comprehensively characterize metabolic perturbations in the bleomycin mouse model of IPF, we analyzed the metabolome and lipidome by mass spectrometry. We identified increased tissue turnover and repair, evident by enhanced breakdown of proteins, nucleic acids and lipids and extracellular matrix turnover. Energy production was upregulated, including glycolysis, the tricarboxylic acid cycle, glutaminolysis, lactate production and fatty acid oxidation. Higher eicosanoid synthesis indicated inflammatory processes. Because the risk of IPF increases with age, we investigated how age influences metabolomic and lipidomic changes in the bleomycin-induced pulmonary fibrosis model. Surprisingly, except for cytidine, we did not detect any significantly differential metabolites or lipids between old and young bleomycin-treated lungs. Together, we identified metabolomic and lipidomic changes in fibrosis that reflect higher energy demand, proliferation, tissue remodeling, collagen deposition and inflammation, which might serve to improve diagnostic and therapeutic options for fibrotic lung diseases in the future. Editor's choice: Using bleomycin-induced lung injury as a mouse model for idiopathic pulmonary fibrosis, this study identifies metabolomic and lipidomic changes in fibrosis reflecting higher energy demand, proliferation, tissue remodeling, collagen deposition and inflammation.
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Affiliation(s)
- Jelena Weckerle
- Boehringer Ingelheim Pharma GmbH & Co. KG, Department Immunology and Respiratory Disease research, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany
| | - Sergio Picart-Armada
- Boehringer Ingelheim Pharma GmbH & Co. KG, Global Computational Biology and Digital Sciences, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany
| | - Stephan Klee
- Boehringer Ingelheim Pharma GmbH & Co. KG, Department Immunology and Respiratory Disease research, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany
| | - Tom Bretschneider
- Boehringer Ingelheim Pharma GmbH & Co. KG, Department Drug Discovery Sciences, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany
| | - Andreas H Luippold
- Boehringer Ingelheim Pharma GmbH & Co. KG, Department Drug Discovery Sciences, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany
| | - Wolfgang Rist
- Boehringer Ingelheim Pharma GmbH & Co. KG, Department Drug Discovery Sciences, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany
| | - Christian Haslinger
- Boehringer Ingelheim Pharma GmbH & Co. KG, Global Computational Biology and Digital Sciences, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany
| | - Holger Schlüter
- Boehringer Ingelheim Pharma GmbH & Co. KG, Department Immunology and Respiratory Disease research, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany
| | - Matthew J Thomas
- Boehringer Ingelheim Pharma GmbH & Co. KG, Department Immunology and Respiratory Disease research, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany
| | - Bartlomiej Krawczyk
- Boehringer Ingelheim Pharma GmbH & Co. KG, Department Drug Discovery Sciences, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany
| | - Francesc Fernandez-Albert
- Boehringer Ingelheim Pharma GmbH & Co. KG, Global Computational Biology and Digital Sciences, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany
| | - Marc Kästle
- Boehringer Ingelheim Pharma GmbH & Co. KG, Department Immunology and Respiratory Disease research, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany
| | - Daniel Veyel
- Boehringer Ingelheim Pharma GmbH & Co. KG, Department Drug Discovery Sciences, Birkendorfer Straße 65, 88397 Biberach an der Riß, Germany
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18
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Rehman A, Mehta KJ. Betaine in ameliorating alcohol-induced hepatic steatosis. Eur J Nutr 2021; 61:1167-1176. [PMID: 34817678 PMCID: PMC8921017 DOI: 10.1007/s00394-021-02738-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/03/2021] [Indexed: 01/15/2023]
Abstract
Alcohol-associated liver disease (AALD) is one of most common chronic liver diseases. Hepatic steatosis is the earliest stage in AALD pathological spectrum, reversible by alcohol abstinence. Untreated steatosis can progress to steatohepatitis, fibrosis and/or cirrhosis. Considering the difficulties in achieving complete abstinence, challenges in disease reversal at advanced stages, high costs of AALD management and lack of standardised prescribed medications for treatment, it is essential to explore low-cost natural compounds that can target AALD at an early stage and halt or decelerate disease progression. Betaine is a non-hazardous naturally occurring nutrient. Here, we address the mechanisms of alcohol-induced hepatic steatosis, the role of betaine in reversing the effects i.e., its action against hepatic steatosis in animal models and humans, and the associated cellular and molecular processes. Accordingly, the review discusses how betaine restores the alcohol-induced reduction in methylation potential by elevating the levels of S-adenosylmethionine and methionine. It details how betaine reinstates alcohol-induced alterations in the expressions and/or activities of protein phosphtase-2A, FOXO1, PPAR-α, AMPK, SREBP-1c, fatty acid synthase, diacylglycerol transferase-2, adiponectin and nitric oxide. Interrelationships between these factors in preventing de novo lipogenesis, reducing hepatic uptake of adipose-tissue-derived free fatty acids, promoting VLDL synthesis and secretion, and restoring β-oxidation of fatty acids to attenuate hepatic triglyceride accumulation are elaborated. Despite its therapeutic potential, very few clinical trials have examined betaine’s effect on alcohol-induced hepatic lipid accumulation. This review will provide further confidence to conduct randomised control trials to enable maximum utilisation of betaine’s remedial properties to treat alcohol-induced hepatic steatosis.
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Affiliation(s)
- Aisha Rehman
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Kosha J Mehta
- Centre for Education, Faculty of Life Sciences and Medicine, King's College London, London, UK.
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Song Y, Chen R, Yang M, Liu Q, Zhou Y, Zhuang S. Dietary betaine supplementation improves growth performance, digestive function, intestinal integrity, immunity, and antioxidant capacity of yellow-feathered broilers. ITALIAN JOURNAL OF ANIMAL SCIENCE 2021. [DOI: 10.1080/1828051x.2021.1986681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Yuduo Song
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Rui Chen
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Mi Yang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Qiang Liu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Yanmin Zhou
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Su Zhuang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
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20
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Zhong C, Miao M, Che B, Du J, Wang A, Peng H, Bu X, Zhang J, Ju Z, Xu T, He J, Zhang Y. Plasma choline and betaine and risks of cardiovascular events and recurrent stroke after ischemic stroke. Am J Clin Nutr 2021; 114:1351-1359. [PMID: 34159355 DOI: 10.1093/ajcn/nqab199] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 05/25/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Choline and betaine have been suggested to play a pivotal role in neurotransmitter synthesis, cell membrane integrity, and methyl-group metabolism, exerting neuroprotective effects in patients with various neurological disorders. However, population-based evidence on choline and betaine with subsequent cardiovascular events after stroke is rare. OBJECTIVES We aimed to prospectively investigate the relationships of circulating choline and betaine with cardiovascular events and recurrent stroke in patients with ischemic stroke. METHODS We performed a nested case-control study within the China Antihypertensive Trial in Acute Ischemic Stroke. A total of 323 cardiovascular events (including 264 recurrent strokes) and 323 controls (free of recurrent cardiovascular events) matched for age (±1 y), sex, and treatment group were included. The primary endpoint was a composite of cardiovascular events after ischemic stroke. Plasma choline and betaine were measured at baseline by ultra-high-performance LC-MS/MS. Conditional logistic regression models were applied, and discrimination, reclassification, and calibration of models with choline pathway metabolites were evaluated. RESULTS Plasma choline and betaine were inversely associated with cardiovascular events and recurrent stroke after ischemic stroke. Specifically, in fully adjusted models, each additional SD of choline and betaine was associated with 35% (95% CI: 20%-48%) and 30% (95% CI: 14%-43%) decreased risks of subsequent cardiovascular events, respectively, and 34% (95% CI: 16%-48%) and 29% (95% CI: 12%-43%) decreased risks of recurrent stroke, respectively. In addition, both choline and betaine offered substantial risk discrimination and reclassification improvement for cardiovascular events and recurrent stroke beyond traditional risk factors, as evidenced by an increase in C statistics, the net reclassification index, and integrated discrimination improvement. CONCLUSIONS Plasma choline pathway metabolites, including choline and betaine, were associated with decreased risks of cardiovascular events and recurrent stroke and provided incremental value in risk discrimination and stratification in patients with ischemic stroke. This nested case-control study was based on the China Antihypertensive Trial in Acute Ischemic Stroke, which is registered at clinicaltrials.gov as NCT01840072.
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Affiliation(s)
- Chongke Zhong
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, China
| | - Mengyuan Miao
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, China
| | - Bizhong Che
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, China
| | - Jigang Du
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, China
| | - Aili Wang
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, China
| | - Hao Peng
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, China
| | - Xiaoqing Bu
- Department of Epidemiology, School of Public Health, Chongqing Medical University, Chongqing, China
| | - Jintao Zhang
- Department of Neurology, The 88th Hospital of PLA, Shandong, China
| | - Zhong Ju
- Department of Neurology, Kerqin District First People's Hospital of Tongliao City, Tongliao, China
| | - Tan Xu
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, China
| | - Jiang He
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
| | - Yonghong Zhang
- Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, China
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21
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Korochanskaya NV, Durleshter VM, Bacenko MA. S-ademetionine in the treatment of non-alcoholic fatty liver disease (NAFLD). EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2021:68-73. [DOI: 10.31146/1682-8658-ecg-191-7-68-73] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The experimental and clinic data supporting S- ademetionin application in NAFLD complex therapy were presented. The therapy corrects an oxidative stress in hepatocytes and transforms the nutrition behavior in patients with excessive body weight when depressive syndrome is developed.
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Affiliation(s)
- N. V. Korochanskaya
- FSBEI HE “Kuban state medical university MHC RF”; SBIHC “Region clinic hospital N 2” MHC of Krasnodar region
| | - V. M. Durleshter
- FSBEI HE “Kuban state medical university MHC RF”; SBIHC “Region clinic hospital N 2” MHC of Krasnodar region
| | - M. A. Bacenko
- FSBEI HE “Kuban state medical university MHC RF”; SBIHC “Region clinic hospital N 2” MHC of Krasnodar region
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22
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Birková A, Hubková B, Čižmárová B, Bolerázska B. Current View on the Mechanisms of Alcohol-Mediated Toxicity. Int J Mol Sci 2021; 22:9686. [PMID: 34575850 PMCID: PMC8472195 DOI: 10.3390/ijms22189686] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 02/07/2023] Open
Abstract
Alcohol is a psychoactive substance that is widely used and, unfortunately, often abused. In addition to acute effects such as intoxication, it may cause many chronic pathological conditions. Some of the effects are very well described and explained, but there are still gaps in the explanation of empirically co-founded dysfunction in many alcohol-related conditions. This work focuses on reviewing actual knowledge about the toxic effects of ethanol and its degradation products.
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Affiliation(s)
- Anna Birková
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, 04011 Kosice, Slovakia
| | - Beáta Hubková
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, 04011 Kosice, Slovakia
| | - Beáta Čižmárová
- Department of Medical and Clinical Biochemistry, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, 04011 Kosice, Slovakia
| | - Beáta Bolerázska
- 1st Department of Stomatology, Faculty of Medicine, Pavol Jozef Šafárik University in Košice, 04011 Kosice, Slovakia
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23
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Chao X, Wang S, Yang L, Ni HM, Ding WX. Trehalose activates hepatic transcription factor EB (TFEB) but fails to ameliorate alcohol-impaired TFEB and liver injury in mice. Alcohol Clin Exp Res 2021; 45:1950-1964. [PMID: 34486131 DOI: 10.1111/acer.14695] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/27/2021] [Accepted: 08/04/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND Recent evidence demonstrates that alcohol activates the mechanistic target of rapamycin (mTOR) and impairs hepatic transcription factor EB (TFEB) reducing autophagy and contributing to alcohol-induced liver injury. Trehalose, a disaccharide, activates TFEB and protects against diet-induced nonalcoholic fatty liver disease in mice. The aim of the present study was to investigate whether trehalose would reverse the impairment of TFEB induced by alcohol and protect against alcohol-induced liver injury. METHODS Male C57BL/6J mice were subjected to chronic-plus-binge (Gao-binge) alcohol feeding with and without trehalose supplementation. Some mice were also administrered Alda-1, an aldehyde dehydrogenase 2 agonist. RESULTS We found that Alda-1 did not affect Gao-binge alcohol-induced mTOR activation and impaired TFEB in mouse livers. Trehalose increased TFEB nuclear translocation, elevated levels of LC3-II and lysosomal proteins in mouse livers and cultured AML12 cells, confirming the activation of TFEB by trehalose. However, trehalose did not improve the impairment in TFEB induced by Gao-binge alcohol. Both Alda-1 and trehalose failed to protect against Gao-binge alcohol-induced steatosis and liver injury, based on the serum levels of alanine aminotransferase (ALT), histological analysis, and levels of hepatic triglyceride. Interestingly, trehalose increased expression of pro-inflammatory genes in mouse macrophage RAW264.7 cells and slightly increased the infiltration of hepatic neutrophils and inflammatory cytokine gene expression in Gao-binge alcohol-fed mice livers. CONCLUSIONS Trehalose fails to improve the impaired TFEB induced by Gao-binge alcohol and does not protect against alcohol-induced liver injury.
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Affiliation(s)
- Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Ling Yang
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, The Pappajohn Biomedical Institute, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
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24
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Hou X, Shi Y, Yang M, Yu S, Fan X, Liang J, Pan X, Wang X. Fabrication of poly( t-butyl betaine carboxylate)-based nanoparticles and study on their in vivo biosecurity. JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION 2021; 32:2387-2401. [PMID: 34428381 DOI: 10.1080/09205063.2021.1971822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The purpose of this article was to fabricate the novel poly(t-butyl betaine carboxylate)-S-S-poly (1, 3-dioxan-2-one) nanoparticles (PCB-tBU-S-S-PDI NPs) and study their in vivo biosecurity. The poly(t-butyl betaine carboxylate) (PCB-tBU) segment was conjugated to the poly(1, 3-dioxan-2-one)(PDI) moity with a disulfide bond to obtain the copolymer PCB-tBU-S-S-PDI. Hydrogen nuclear magnetic resonance (1H NMR) and Fourier transform infrared spectroscopy (FTIR) spectra were applied to study the structure of PCB-tBU-S-S-PDI. The cargo-free NPs were administrated to Sprague-Dawley (SD) rats by intraperitoneal injection every 3 days for 30 days. Then, the blood routine examination, blood biochemistry, and histologic slides of rat's organs were carried out to monitor the in vivo biosecurity of cargo-free PCB-tBU-S-S-PDI NPs. 1H NMR and FTIR spectra confirmed the successfully synthesis of PCB-tBU-S-S-PDI. The cargo-free NPs showed spherical morphology with an average of 139.8 ± 0.26 nm. The results of blood biochemistry and blood routine examination suggested that the cargo-free PCB-tBU-S-S-PDI NPs did not show any influence on the liver and renal functions of treated rats. Significantly, the physiological slides of treated rat's organs did not show any physiological and pathological changes. These phenomena suggested that the PCB-tBU-S-S-PDI NPs had good biosecurity, and it could be used as a vehicle for antineoplastic drug delivery.
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Affiliation(s)
- Xueyan Hou
- College of pharmacy, Xinxiang Medical University, Xinxiang, P.R. China
| | - Yongli Shi
- College of pharmacy, Xinxiang Medical University, Xinxiang, P.R. China
| | - Mingbo Yang
- College of pharmacy, Xinxiang Medical University, Xinxiang, P.R. China
| | - Shasha Yu
- College of pharmacy, Xinxiang Medical University, Xinxiang, P.R. China
| | - Xue Fan
- College of pharmacy, Xinxiang Medical University, Xinxiang, P.R. China
| | - Jinna Liang
- College of pharmacy, Xinxiang Medical University, Xinxiang, P.R. China
| | - Xiaofei Pan
- College of pharmacy, Xinxiang Medical University, Xinxiang, P.R. China
| | - Xiao Wang
- College of pharmacy, Xinxiang Medical University, Xinxiang, P.R. China
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25
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Das A, Sanyal T, Bhattacharjee P, Bhattacharjee P. Depletion of S-adenosylmethionine pool and promoter hypermethylation of Arsenite methyltransferase in arsenic-induced skin lesion individuals: A case-control study from West Bengal, India. ENVIRONMENTAL RESEARCH 2021; 198:111184. [PMID: 33894237 DOI: 10.1016/j.envres.2021.111184] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 04/09/2021] [Accepted: 04/10/2021] [Indexed: 06/12/2023]
Abstract
Methylation of arsenic compounds in the human body occurs following a series of biochemical reactions in the presence of methyl donor S-adenosylmethionine (SAM) and catalyzed by arsenite methyltransferase (AS3MT). However, the extent and pattern of methylation differs among the arsenic exposed individuals leading to differential susceptibility. The mechanism for such inter-individual difference is enigmatic. In the present case-control study we recruited exposed individuals with and without arsenic induced skin lesion (WSL and WOSL), and an unexposed cohort, each having 120 individuals. Using ELISA, we observed a reduction in SAM levels (p < 0.05) in WSL compared to WOSL. Linear regression analysis revealed a negative correlation between urinary arsenic concentration and SAM concentration between the study groups. qRT-PCR revealed a significant down-regulation (p < 0.01) of key regulatory genes like MTHFR, MTR, MAT2A and MAT2B of SAM biogenesis pathway in WSL cohort. Methylation-specific PCR revealed significant promoter hypermethylation of AS3MT (WSL vs. WOSL: p < 0.01) which resulted in its subsequent transcriptional repression (WSL vs. WOSL: p < 0.001). Linear regression analysis also showed a negative correlation between SAM concentration and percentage of promoter methylation. Taken together, these results indicate that reduction in SAM biogenesis along with a higher utilization of SAM results in a decreased availability of methyl donor. These along with epigenetic down-regulation of AS3MT may be responsible for higher susceptibility in arsenic exposed individuals.
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Affiliation(s)
- Ankita Das
- Department of Environmental Science, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, West Bengal, India
| | - Tamalika Sanyal
- Department of Environmental Science, University of Calcutta and Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, West Bengal, India
| | - Pritha Bhattacharjee
- Department of Environmental Science, University of Calcutta and Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, West Bengal, India
| | - Pritha Bhattacharjee
- Department of Environmental Science, University of Calcutta, 35, Ballygunge Circular Road, Kolkata, 700019, West Bengal, India.
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Arumugam MK, Paal MC, Donohue TM, Ganesan M, Osna NA, Kharbanda KK. Beneficial Effects of Betaine: A Comprehensive Review. BIOLOGY 2021; 10:456. [PMID: 34067313 PMCID: PMC8224793 DOI: 10.3390/biology10060456] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/06/2021] [Accepted: 05/19/2021] [Indexed: 02/05/2023]
Abstract
Medicinal herbs and many food ingredients possess favorable biological properties that contribute to their therapeutic activities. One such natural product is betaine, a stable, nontoxic natural substance that is present in animals, plants, and microorganisms. Betaine is also endogenously synthesized through the metabolism of choline or exogenously consumed through dietary intake. Betaine mainly functions as (i) an osmolyte and (ii) a methyl-group donor. This review describes the major physiological effects of betaine in whole-body health and its ability to protect against both liver- as well as non-liver-related diseases and conditions. Betaine's role in preventing/attenuating both alcohol-induced and metabolic-associated liver diseases has been well studied and is extensively reviewed here. Several studies show that betaine protects against the development of alcohol-induced hepatic steatosis, apoptosis, and accumulation of damaged proteins. Additionally, it can significantly prevent/attenuate progressive liver injury by preserving gut integrity and adipose function. The protective effects are primarily associated with the regulation of methionine metabolism through removing homocysteine and maintaining cellular SAM:SAH ratios. Similarly, betaine prevents metabolic-associated fatty liver disease and its progression. In addition, betaine has a neuroprotective role, preserves myocardial function, and prevents pancreatic steatosis. Betaine also attenuates oxidant stress, endoplasmic reticulum stress, inflammation, and cancer development. To conclude, betaine exerts significant therapeutic and biological effects that are potentially beneficial for alleviating a diverse number of human diseases and conditions.
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Affiliation(s)
- Madan Kumar Arumugam
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Matthew C. Paal
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Terrence M. Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (MK.A.); (M.C.P.); (T.M.D.J.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Thapa K, Grewal AS, Kanojia N, Rani L, Sharma N, Singh S. Alcoholic and Non-Alcoholic Liver Diseases: Promising Molecular Drug Targets and their Clinical Development. Curr Drug Discov Technol 2021; 18:333-353. [PMID: 31965945 DOI: 10.2174/1570163817666200121143959] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 11/25/2019] [Accepted: 12/04/2019] [Indexed: 11/22/2022]
Abstract
Alcoholic and non-alcoholic fatty liver diseases have become a serious concern worldwide. Both these liver diseases have an identical pathology, starting from simple steatosis to cirrhosis and, ultimately to hepatocellular carcinoma. Treatment options for alcoholic liver disease (ALD) are still the same as they were 50 years ago which include corticosteroids, pentoxifylline, antioxidants, nutritional support and abstinence; and for non-alcoholic fatty liver disease (NAFLD), weight loss, insulin sensitizers, lipid-lowering agents and anti-oxidants are the only treatment options. Despite broad research in understanding the disease pathophysiology, limited treatments are available for clinical use. Some therapeutic strategies based on targeting a specific molecule have been developed to lessen the consequences of disease and are under clinical investigation. Therefore, focus on multiple molecular targets will help develop an efficient therapeutic strategy. This review comprises a brief overview of the pathogenesis of ALD and NAFLD; recent molecular drug targets explored for ALD and NAFLD that may prove to be effective for multiple therapeutic regimens and also the clinical status of these promising drug targets for liver diseases.
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Affiliation(s)
- Komal Thapa
- Chitkara University School of Basic Sciences, Chitkara University, Himachal Pradesh, India
| | - Ajmer Singh Grewal
- Chitkara University School of Basic Sciences, Chitkara University, Himachal Pradesh, India
| | - Neha Kanojia
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Lata Rani
- Chitkara University School of Basic Sciences, Chitkara University, Himachal Pradesh, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
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Vairetti M, Di Pasqua LG, Cagna M, Richelmi P, Ferrigno A, Berardo C. Changes in Glutathione Content in Liver Diseases: An Update. Antioxidants (Basel) 2021; 10:364. [PMID: 33670839 PMCID: PMC7997318 DOI: 10.3390/antiox10030364] [Citation(s) in RCA: 136] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/22/2021] [Accepted: 02/24/2021] [Indexed: 02/07/2023] Open
Abstract
Glutathione (GSH), a tripeptide particularly concentrated in the liver, is the most important thiol reducing agent involved in the modulation of redox processes. It has also been demonstrated that GSH cannot be considered only as a mere free radical scavenger but that it takes part in the network governing the choice between survival, necrosis and apoptosis as well as in altering the function of signal transduction and transcription factor molecules. The purpose of the present review is to provide an overview on the molecular biology of the GSH system; therefore, GSH synthesis, metabolism and regulation will be reviewed. The multiple GSH functions will be described, as well as the importance of GSH compartmentalization into distinct subcellular pools and inter-organ transfer. Furthermore, we will highlight the close relationship existing between GSH content and the pathogenesis of liver disease, such as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), chronic cholestatic injury, ischemia/reperfusion damage, hepatitis C virus (HCV), hepatitis B virus (HBV) and hepatocellular carcinoma. Finally, the potential therapeutic benefits of GSH and GSH-related medications, will be described for each liver disorder taken into account.
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Affiliation(s)
| | - Laura Giuseppina Di Pasqua
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (M.V.); (M.C.); (P.R.); (C.B.)
| | | | | | - Andrea Ferrigno
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy; (M.V.); (M.C.); (P.R.); (C.B.)
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29
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Rasineni K, Lee SML, McVicker BL, Osna NA, Casey CA, Kharbanda KK. Susceptibility of Asialoglycoprotein Receptor-Deficient Mice to Lps/Galactosamine Liver Injury and Protection by Betaine Administration. BIOLOGY 2020; 10:19. [PMID: 33396223 PMCID: PMC7823640 DOI: 10.3390/biology10010019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 12/27/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Work from our laboratory has shown that the ethanol-induced increase in apoptotic hepatocellular death is closely related to the impairment in the ability of the asialoglycoprotein receptor (ASGP-R) to remove neighboring apoptotic cells. In this study, we assessed the role of ASGP-R in fulminant liver failure and investigated whether prior treatment with betaine (a naturally occurring tertiary amine) is protective. METHODS Lipopolysaccharide (LPS; 50 μg/kg BW) and galactosamine (GalN; 350 mg/kg BW) were injected together to wild-type and ASGP-R-deficient mice that were treated for two weeks prior with or without 2% betaine in drinking water. The mice were sacrificed 1.5, 3, or 4.5 h post-injection, and tissue samples were collected. RESULTS LPS/GalN injection generate distinct molecular processes, which includes increased production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), thus causing apoptosis as evident by increased caspase-3 activity. ASGP-R deficient animals showed increased liver caspase activities, serum TNF-α and IL-6 levels, as well as more pronounced liver damage compared with the wild-type control animals after intraperitoneal injection of LPS/GalN. In addition, prior administration of betaine was found to significantly attenuate the LPS/GalN-induced increases in liver injury parameters. CONCLUSION Our work underscores the importance of normal functioning of ASGP-R in preventing severe liver damage and signifies a therapeutic role of betaine in prevention of liver injuries from toxin-induced fulminant liver failure.
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Affiliation(s)
- Karuna Rasineni
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Serene M. L. Lee
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Benita L. McVicker
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Natalia A. Osna
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Carol A. Casey
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans’ Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (K.R.); (B.L.M.); (N.A.O.); (C.A.C.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
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30
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Immunological mechanisms and therapeutic targets of fatty liver diseases. Cell Mol Immunol 2020; 18:73-91. [PMID: 33268887 PMCID: PMC7852578 DOI: 10.1038/s41423-020-00579-3] [Citation(s) in RCA: 129] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are the two major types of chronic liver disease worldwide. Inflammatory processes play key roles in the pathogeneses of fatty liver diseases, and continuous inflammation promotes the progression of alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH). Although both ALD and NAFLD are closely related to inflammation, their respective developmental mechanisms differ to some extent. Here, we review the roles of multiple immunological mechanisms and therapeutic targets related to the inflammation associated with fatty liver diseases and the differences in the progression of ASH and NASH. Multiple cell types in the liver, including macrophages, neutrophils, other immune cell types and hepatocytes, are involved in fatty liver disease inflammation. In addition, microRNAs (miRNAs), extracellular vesicles (EVs), and complement also contribute to the inflammatory process, as does intertissue crosstalk between the liver and the intestine, adipose tissue, and the nervous system. We point out that inflammation also plays important roles in promoting liver repair and controlling bacterial infections. Understanding the complex regulatory process of disrupted homeostasis during the development of fatty liver diseases may lead to the development of improved targeted therapeutic intervention strategies.
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Wen B, Zhang C, Zhou J, Zhang Z, Che Q, Cao H, Bai Y, Guo J, Su Z. Targeted treatment of alcoholic liver disease based on inflammatory signalling pathways. Pharmacol Ther 2020; 222:107752. [PMID: 33253739 DOI: 10.1016/j.pharmthera.2020.107752] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/15/2020] [Accepted: 11/20/2020] [Indexed: 02/06/2023]
Abstract
Targeted therapy is an emerging treatment strategy for alcoholic liver disease (ALD). Inflammation plays an important role in the occurrence and development of ALD, and is a key choice for its targeted treatment, and anti-inflammatory treatment has been considered beneficial for liver disease. Surprisingly, immune checkpoint inhibitors have become important therapeutic agents for hepatocellular carcinoma (HCC). Moreover, studies have shown that the combination of inflammatory molecule inhibitors and immune checkpoint inhibitors can exert better effects than either alone in mouse models of HCC. This review discusses the mechanism of hepatic ethanol metabolism and the conditions under which inflammation occurs. In addition, we focus on the potential molecular targets in inflammatory signalling pathways and summarize the potential targeted inhibitors and immune checkpoint inhibitors, providing a theoretical basis for the targeted treatment of ALD and the development of new combination therapy strategies for HCC.
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Affiliation(s)
- Bingjian Wen
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Chengcheng Zhang
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jingwen Zhou
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Zhengyan Zhang
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd., Guangzhou 510663, China
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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Larionova VB, Snegovoy AV. Possibilities of supportive therapy in patients with blood system tumors and malignant neoplasms. ONCOHEMATOLOGY 2020; 15:107-127. [DOI: 10.17650/1818-8346-2020-15-3-107-127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Finding opportunities to improve treatment outcomes of cancer patients remains a difficult and unresolved problem. Modern anticancer treatment due to the intensity and molecular biological orientation allows achieving higher efficiency and theoretically reducing the complications frequency. At the same time, the “increase in efficiency” in the modern oncology really exists, but a “decrease in the incidence of complications” is far from its solution. In many ways, the problems of diagnosis, treatment and monitoring of complications are associated with the impact on complex physiological processes in the body of an oncological patient. Timely implementation of modern and adequate programs for the prevention and treatment of these complications defines the concept of “supportive therapy”, which provides at least half of the effectiveness of anticancer treatment.The Multinational Association of Supportive Care in Cancer (MASCC) was formed in 1990. The main tasks of the association were the creation of supportive care system, its popularization and accumulation of scientific data. The MASCC was used not only oncologists experience, but also of specialists working in almost all areas of medicine. Supportive therapy provides prevention and treatment of complications from the moment of malignant disease develops, at all stages of anticancer treatment, during the rehabilitation period, and in patients in the terminal phase.An important stage in the development of maintenance care in Russia was the holding of annual conferences in Moscow with the support of MASCC. Russia is included in the European MASCC group and in working group on supportive therapy and palliative care of the Chemotherapists Society (ESMO). The Russian Society of Supportive care in Oncology (RASSC) was organized In Russia on June 1, 2017. In recent years, the main directions of supportive care have been developed in our country. Today, supportive therapy is an obligatory component of anticancer programs, which allows the patient to cope with severe but potentially reversible disorders of vital organs at all stages of treatment. This is a real way to increase the treatment efficacy and improve the quality of life of cancer patients.
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Affiliation(s)
- V. B. Larionova
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - A. V. Snegovoy
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
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Mukherjee S. Role of betaine in liver disease-worth revisiting or has the die been cast? World J Gastroenterol 2020; 26:5745-5748. [PMID: 33132631 PMCID: PMC7579752 DOI: 10.3748/wjg.v26.i38.5745] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 08/25/2020] [Accepted: 09/16/2020] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is an important indication for liver transplantation in many Western countries due to the epidemic of obesity and insulin resistance. Unfortunately, no medication is approved for NASH and risk factor modification is often advised. Over the last decade, several clinical trials on NASH have been conducted with several ongoing and the future looks promising. Although betaine (trimethyl glycine) was evaluated for NASH, results were mixed in the clinical trials in large part due to the quality of the studies. It seems reasonable to re-evaluate betaine in clinical trials for NASH and alcoholic liver disease due to its low cost, tolerability and mechanism of action.
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Affiliation(s)
- Sandeep Mukherjee
- Department of Medicine, Creighton University Medical Center, Division of Gastroenterology, Omaha, NE 68124, United States
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Sun Y, Li C, Pang S, Yao Q, Chen L, Li Y, Zeng R. Kinase-substrate Edge Biomarkers Provide a More Accurate Prognostic Prediction in ER-negative Breast Cancer. GENOMICS, PROTEOMICS & BIOINFORMATICS 2020; 18:525-538. [PMID: 33450402 PMCID: PMC8377385 DOI: 10.1016/j.gpb.2019.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 08/27/2019] [Accepted: 11/11/2019] [Indexed: 11/19/2022]
Abstract
The estrogen receptor (ER)-negative breast cancer subtype is aggressive with few treatment options available. To identify specific prognostic factors for ER-negative breast cancer, this study included 705,729 and 1034 breast invasive cancer patients from the Surveillance, Epidemiology, and End Results (SEER) and The Cancer Genome Atlas (TCGA) databases, respectively. To identify key differential kinase-substrate node and edge biomarkers between ER-negative and ER-positive breast cancer patients, we adopted a network-based method using correlation coefficients between molecular pairs in the kinase regulatory network. Integrated analysis of the clinical and molecular data revealed the significant prognostic power of kinase-substrate node and edge features for both subtypes of breast cancer. Two promising kinase-substrate edge features, CSNK1A1-NFATC3 and SRC-OCLN, were identified for more accurate prognostic prediction in ER-negative breast cancer patients.
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Affiliation(s)
- Yidi Sun
- CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Chen Li
- CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Shichao Pang
- Deptartment of Statistics, School of Mathematical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Qianlan Yao
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Luonan Chen
- CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Department of Life Sciences, ShanghaiTech University, Shanghai 201210, China; CAS Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China.
| | - Yixue Li
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China; Department of Life Sciences, ShanghaiTech University, Shanghai 201210, China; Bio-Med Big Data Center, Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai 200032, China; Shanghai Center for Bioinformation Technology, Shanghai Academy of Science & Technology, Shanghai 201203, China.
| | - Rong Zeng
- CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Department of Life Sciences, ShanghaiTech University, Shanghai 201210, China.
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S-Adenosine Methionine (SAMe) and Valproic Acid (VPA) as Epigenetic Modulators: Special Emphasis on their Interactions Affecting Nervous Tissue during Pregnancy. Int J Mol Sci 2020; 21:ijms21103721. [PMID: 32466248 PMCID: PMC7279375 DOI: 10.3390/ijms21103721] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 05/19/2020] [Accepted: 05/22/2020] [Indexed: 12/15/2022] Open
Abstract
S-adenosylmethionine (SAMe) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the N-methyl-D-aspartate (NMDA) receptor. Due to its important role as an epigenetic modulator, we discuss in some length the process of DNA methylation and demethylation and the critical periods of epigenetic modifications in the embryo, fetus, and thereafter. We also discuss the effects of SAMe deficiency and the attempts to use SAMe for therapeutic purposes such as the treatment of major depressive disorder, Alzheimer disease, and other neuropsychiatric disorders. SAMe is an approved food additive and as such is also used during pregnancy. Yet, there seems to scanty data on the possible effects of SAMe on the developing embryo and fetus. Valproic acid (VPA) is a well-tolerated and effective antiepileptic drug that is also used as a mood stabilizer. Due to its high teratogenicity, it is contraindicated in pregnancy. A major mechanism of its action is histone deacetylase inhibition, and therefore, it acts as an epigenetic modulator, mainly on the brain. This prompted clinical trials using VPA for additional indications i.e., treating degenerative brain disease such as Alzheimer disease, dementia, HIV, and even cancer. Therefore, we discuss the possible effects of VPA and SAMe on the conceptus and early postnatally, during periods of susceptibility to epigenetic modifications. VPA is also used as an inducer of autistic-like behavior in rodents and was found by us to modify gene expression when administered during the first postnatal week but not when administered to the pregnant dams on day 12 of gestation. In contrast, SAMe modified gene expression when administered on day 12 of pregnancy but not postnatally. If administered together, VPA prevented the changes in gene expression induced by prenatal SAMe administration, and SAMe prevented the gene expression changes and autistic-like behavior induced by early postnatal VPA. It is concluded that both VPA and SAMe are powerful epigenetic modifiers with antagonistic actions on the brain that will probably be used in the future more extensively for the treatment of a variety of epigenetic diseases of the nervous system.
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Hagar H, Husain S, Fadda LM, Attia NM, Attia MMA, Ali HM. Inhibition of NF-κB and the oxidative stress -dependent caspase-3 apoptotic pathway by betaine supplementation attenuates hepatic injury mediated by cisplatin in rats. Pharmacol Rep 2019; 71:1025-1033. [PMID: 31590115 DOI: 10.1016/j.pharep.2019.06.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/08/2019] [Accepted: 06/05/2019] [Indexed: 12/31/2022]
Abstract
BACKGROUND Cisplatin is a major anti-cancer drug commonly used in the treatment of various cancers; nevertheless, the associated hepatotoxicity has limited its clinical application. The aim of this investigation is to test the impact of betaine supplementation on cisplatin-induced hepatotoxicity. METHODS Animals were allocated into four groups; normal control group (control betaine group (250 mg/kg/day, po for twenty six days), cisplatin group (single injection of 7 mg/kg, ip) and betaine + cisplatin group (received betaine for twenty one days before cisplatin injection and daily after cisplatin for five days). RESULTS Cisplatin-induced liver injury was confirmed by increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Cisplatin elevated lipid peroxides, and reduced the concentrations of reduced glutathione (GSH), glutathione peroxidase (GSH-Px), catalase and superoxide dismutase (SOD) in hepatic tissues. Cisplatin increased the inflammatory mediators; nitrite and tumor necrosis factor-α (TNF- α) in hepatic tissues. Increased gene expressions of the apoptotic marker, caspase-3 and nuclear factor-kappa B (NF-κB) were observed in hepatic tissues of cisplatin-treated rats. All these changes were further confirmed by histopathological findings in cisplatin group. Pre-treatment with betaine reduced serum aminotransferases (ALT and AST), and lowered hepatic concentrations of lipid peroxides, nitrite and TNF-α while increased SOD, GSH, catalase, and GSH-Px concentrations. Moreover, the histological and immunohistochemical changes were improved. CONCLUSION The suppression of NF-κβ-mediated inflammation, oxidative stress, and caspase-3 induced apoptosis are possible mechanisms to the observed hepatoprotective effect of betaine.
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Affiliation(s)
- Hanan Hagar
- Pharmacology Unit, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia; Department of Pharmacology and Toxicology, Pharmacy College, Zagazig University, Egypt.
| | - Sufia Husain
- Department of Pathology, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Laila Mohamed Fadda
- Department of Pharmacology, Faculty of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | | | | | - Hanaa Mahmoud Ali
- Department of Genetic and Cytology, National Research Center, Dokki, Egypt; Common First Year Deanship, King Saud University, Riyadh, Saudi Arabia
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Protective Effect of Glutathione against Oxidative Stress-induced Cytotoxicity in RAW 264.7 Macrophages through Activating the Nuclear Factor Erythroid 2-Related Factor-2/Heme Oxygenase-1 Pathway. Antioxidants (Basel) 2019; 8:antiox8040082. [PMID: 30939721 PMCID: PMC6523540 DOI: 10.3390/antiox8040082] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 03/26/2019] [Accepted: 03/27/2019] [Indexed: 01/23/2023] Open
Abstract
Reactive oxygen species (ROS), products of oxidative stress, contribute to the initiation and progression of the pathogenesis of various diseases. Glutathione is a major antioxidant that can help prevent the process through the removal of ROS. The aim of this study was to evaluate the protective effect of glutathione on ROS-mediated DNA damage and apoptosis caused by hydrogen peroxide, H2O2, in RAW 264.7 macrophages and to investigate the role of the nuclear factor erythroid 2-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. The results showed that the decrease in the survival rate of RAW 264.7 cells treated with H2O2 was due to the induction of DNA damage and apoptosis accompanied by the increased production of ROS. However, H2O2-induced cytotoxicity and ROS generation were significantly reversed by glutathione. In addition, the H2O2-induced loss of mitochondrial membrane potential was related to a decrease in adenosine triphosphate (ATP) levels, and these changes were also significantly attenuated in the presence of glutathione. These protective actions were accompanied by a increase in the expression rate of B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X protein (Bax) and poly(ADP-ribose) polymerase cleavage by the inactivation of caspase-3. Moreover, glutathione-mediated cytoprotective properties were associated with an increased activation of Nrf2 and expression of HO-1; however, the inhibition of the HO-1 function using an HO-1 specific inhibitor, zinc protoporphyrin IX, significantly weakened the cytoprotective effects of glutathione. Collectively, the results demonstrate that the exogenous administration of glutathione is able to protect RAW 264.7 cells against oxidative stress-induced mitochondria-mediated apoptosis along with the activity of the Nrf2/HO-1 signaling pathway.
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Kitagawa E, Ota Y, Hasegawa M, Nakagawa T, Hayakawa T. Accumulation of Liver Lipids Induced by Vitamin B 6 Deficiency Was Effectively Ameliorated by Choline and, to a Lesser Extent, Betaine. J Nutr Sci Vitaminol (Tokyo) 2019; 65:94-101. [PMID: 30814419 DOI: 10.3177/jnsv.65.94] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Despite previous studies suggesting that choline and betaine ameliorate lipid accumulation in rat livers, the relative effectiveness of the two nutrients is unclear. We examined the efficacy of dietary supplementation with choline or betaine in ameliorating lipid accumulation induced by vitamin B6 (B6) deficiency in the rat liver. Male Wistar rats were fed control, B6-deficient, choline-supplemented B6-deficient, betaine-supplemented B6-deficient, or both choline and betaine-supplemented B6-deficient diets (all containing 9 g of l-methionine (Met)/kg) for 35 d. Two experiments were performed, i.e., one using 17 mmol/kg diet choline bitartrate, betaine anhydrous, and the combination and another using 8.5 mmol/kg diet. Rats fed a B6-deficient diet developed lipid accumulation in the liver with a reduction of plasma lipids induced by the disruption of Met metabolism. However, the addition of 17 mmol/kg diet choline or betaine was sufficient to ameliorate the disruptions of lipid and Met metabolism. Additionally, 8.5 mmol/kg diet choline ameliorated liver lipid deposition, while the same amount of betaine had no significant effects on liver or plasma lipid profiles. Supplementation with choline resulted in a higher liver betaine than that found using the same amount of betaine alone, although the overall liver betaine content was reduced in B6-deficient rats. Our findings indicate that choline is more effective than betaine in ameliorating B6 deficiency-related disruptions in Met metabolism and liver lipid accumulation by increasing liver betaine levels.
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Affiliation(s)
- Erina Kitagawa
- The United Graduate School of Agricultural Science, Gifu University.,Faculty of Health and Human Life, Nagoya Bunri University
| | - Yuki Ota
- The Graduate School of Applied Biological Sciences, Gifu University
| | - Maki Hasegawa
- Faculty of Applied Biological Sciences, Gifu University
| | - Tomoyuki Nakagawa
- The United Graduate School of Agricultural Science, Gifu University.,The Graduate School of Applied Biological Sciences, Gifu University.,Faculty of Applied Biological Sciences, Gifu University
| | - Takashi Hayakawa
- The United Graduate School of Agricultural Science, Gifu University.,The Graduate School of Applied Biological Sciences, Gifu University.,Faculty of Applied Biological Sciences, Gifu University
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Evaluating the therapeutic potential of one-carbon donors in nonalcoholic fatty liver disease. Eur J Pharmacol 2019; 847:72-82. [DOI: 10.1016/j.ejphar.2019.01.039] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 01/18/2019] [Accepted: 01/24/2019] [Indexed: 12/11/2022]
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Hepatic accumulation of S-adenosylmethionine in hamsters with non-alcoholic fatty liver disease associated with metabolic syndrome under selenium and vitamin E deficiency. Clin Sci (Lond) 2019; 133:409-423. [PMID: 29122967 DOI: 10.1042/cs20171039] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 10/27/2017] [Accepted: 11/09/2017] [Indexed: 12/13/2022]
Abstract
Progression of non-alcoholic fatty liver disease (NAFLD) in the context of metabolic syndrome (MetS) is only partially explored due to the lack of preclinical models. In order to study the alterations in hepatic metabolism that accompany this condition, we developed a model of MetS accompanied by the onset of steatohepatitis (NASH) by challenging golden hamsters with a high-fat diet low in vitamin E and selenium (HFD), since combined deficiency results in hepatic necroinflammation in rodents. Metabolomics and transcriptomics integrated analyses of livers revealed an unexpected accumulation of hepatic S-Adenosylmethionine (SAM) when compared with healthy livers likely due to diminished methylation reactions and repression of GNMT. SAM plays a key role in the maintenance of cellular homeostasis and cell cycle control. In agreement, analysis of over-represented transcription factors revealed a central role of c-myc and c-Jun pathways accompanied by negative correlations between SAM concentration, MYC expression and AMPK phosphorylation. These findings point to a drift of cell cycle control toward senescence in livers of HFD animals, which could explain the onset of NASH in this model. In contrast, hamsters with NAFLD induced by a conventional high-fat diet did not show SAM accumulation, suggesting a key role of selenium and vitamin E in SAM homeostasis. In conclusion, our results suggest that progression of NAFLD in the context of MetS can take place even in a situation of hepatic SAM excess and that selenium and vitamin E status might be considered in current therapies against NASH based on SAM supplementation.
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Fagundes M, Yang S, Eun JS, Hall J, Moon J, Park J. Influence of supplementing a methionine derivative, N-acetyl-l-methionine, in dairy diets on production and ruminal fermentation by lactating cows during early to mid lactation. J Dairy Sci 2018; 101:7082-7094. [DOI: 10.3168/jds.2017-14130] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Accepted: 03/25/2018] [Indexed: 01/06/2023]
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Chronic liver diseases and the potential use of S-adenosyl-L-methionine as a hepatoprotector. Eur J Gastroenterol Hepatol 2018; 30:893-900. [PMID: 29683981 DOI: 10.1097/meg.0000000000001141] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chronic liver diseases result in overall deterioration of health status and changes in metabolism. The search for strategies to control and combat these hepatic diseases has witnessed a great boom in the last decades. Nutritional therapy for controlling and managing liver diseases may be a positive influence as it improves the function of the liver. In this review, we focus mainly on describing liver conditions such as nonalcoholic fatty liver disease, and intrahepatic cholestasis as well as using S-adenosyl-L-methionine as a dietary supplement and its potential alternative therapeutic effect to correct the hepatic dysfunction associated with these conditions.
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Kharbanda KK, Ronis MJJ, Shearn CT, Petersen DR, Zakhari S, Warner DR, Feldstein AE, McClain CJ, Kirpich IA. Role of Nutrition in Alcoholic Liver Disease: Summary of the Symposium at the ESBRA 2017 Congress. Biomolecules 2018; 8:16. [PMID: 29587455 PMCID: PMC6022870 DOI: 10.3390/biom8020016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 03/20/2018] [Accepted: 03/20/2018] [Indexed: 02/06/2023] Open
Abstract
The symposium, "Role of Nutrition in Alcoholic Liver Disease", was held at the European Society for Biomedical Research on Alcoholism Congress on 9 October 2017 in Crete, Greece. The goal of the symposium was to highlight recent advances and developments in the field of alcohol and nutrition. The symposium was focused on experimental and clinical aspects in relation to the role of different types of dietary nutrients and malnutrition in the pathogenesis of alcoholic liver disease (ALD). The following is a summary of key research presented at this session. The speakers discussed the role of dietary fats and carbohydrates in the development and progression of alcohol-induced multi-organ pathology in animal models of ALD, analyzed novel nutrition-related therapeutics (specifically, betaine and zinc) in the treatment of ALD, and addressed clinical relevance of malnutrition and nutrition support in ALD. This summary of the symposium will benefit junior and senior faculty currently investigating alcohol-induced organ pathology as well as undergraduate, graduate, and post-graduate students and fellows.
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Affiliation(s)
- Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA.
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA.
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68105, USA.
| | - Martin J J Ronis
- Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Colin T Shearn
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Denver, CO 80045, USA.
| | - Dennis R Petersen
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Denver, CO 80045, USA.
| | - Samir Zakhari
- Distilled Spirits Council, Washington, DC 20005, USA.
| | - Dennis R Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
| | - Ariel E Feldstein
- Division of Gastroenterology, Department of Pediatrics, University of California, San Diego, CA 92037, USA.
| | - Craig J McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 402202, USA;.
- University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY 40202, USA.
- Robley Rex Veterans Medical Center, Louisville, KY 40202, USA.
- Hepatobiology and Toxicology Program, University of Louisville, Louisville, KY 402202, USA.
| | - Irina A Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY 40202, USA.
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 402202, USA;.
- University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY 40202, USA.
- Hepatobiology and Toxicology Program, University of Louisville, Louisville, KY 402202, USA.
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Millard HR, Musani SK, Dibaba DT, Talegawkar SA, Taylor HA, Tucker KL, Bidulescu A. Dietary choline and betaine; associations with subclinical markers of cardiovascular disease risk and incidence of CVD, coronary heart disease and stroke: the Jackson Heart Study. Eur J Nutr 2018; 57:51-60. [PMID: 27550622 PMCID: PMC5931705 DOI: 10.1007/s00394-016-1296-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 08/11/2016] [Indexed: 01/08/2023]
Abstract
PURPOSE Several mechanisms have been described through which dietary intake of choline and its derivative betaine may be associated in both directions with subclinical atherosclerosis. We assessed the association of dietary intake of choline and betaine with cardiovascular risk and markers of subclinical cardiovascular disease. METHODS Data from 3924 Jackson Heart Study (JHS) African-American participants with complete food frequency questionnaire at baseline and follow-up measurements of heart disease measures were used. Multivariable linear regression models were employed to assess associations between choline and betaine intake with carotid intima-media thickness, coronary artery calcium, abdominal aortic calcium and left ventricular mass. Cox proportional hazards regression models were used to estimate associations with time to incident coronary heart disease (CHD), ischemic stroke and cardiovascular disease (CVD). RESULTS During an average nine years of follow-up, 124 incident CHD events, 75 incident stroke events and 153 incident CVD events were documented. In women, greater choline intake was associated with lower left ventricular mass (p = 0.0006 for trend across choline quartiles) and with abdominal aortic calcium score. Among all JHS participants, there was a statistically significant inverse association between dietary choline intake and incident stroke, β = -0.33 (p = 0.04). Betaine intake was associated with greater risk of incident CHD when comparing the third quartile of intake with the lowest quartile of intake (HR 1.89, 95 % CI 1.14, 3.15). CONCLUSIONS Among our African-American participants, higher dietary choline intake was associated with a lower risk of incident ischemic stroke, and thus putative dietary benefits. Higher dietary betaine intake was associated with a nonlinear higher risk of incident CHD.
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Affiliation(s)
- Heather R Millard
- Department of Epidemiology and Biostatistics, Indiana University School of Public Health, 1025 E. 7th Street, C102, Bloomington, IN, USA
| | - Solomon K Musani
- University of Mississippi Medical Center and Jackson Heart Study, Jackson, MS, USA
| | - Daniel T Dibaba
- Department of Epidemiology and Biostatistics, Indiana University School of Public Health, 1025 E. 7th Street, C102, Bloomington, IN, USA
| | | | | | | | - Aurelian Bidulescu
- Department of Epidemiology and Biostatistics, Indiana University School of Public Health, 1025 E. 7th Street, C102, Bloomington, IN, USA.
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Fernando H, Bhopale KK, Kondraganti SS, Kaphalia BS, Ansari GAS. Alcohol-Induced Hepatic Steatosis: A Comparative Study to Identify Possible Indicator(s) of Alcoholic Fatty Liver Disease. ACTA ACUST UNITED AC 2018; 7. [PMID: 31032137 DOI: 10.4303/jdar/236040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Background Fatty liver is an early sign of both nonalcoholic and alcoholic fatty liver diseases. Ethanol feeding using a Lieber-DeCarli liquid diet (LD) model which contains 35% fat to rats or mice is a well-established model for alcoholic fatty liver. However, LD diet alone can also induce fatty liver and its differential metabolic profile may be able to differentiate steatosis induced by LD versus LD plus ethanol. Purpose We investigated the lipidomic differences in the livers of Sprague-Dawley (SD) rats fed a pellet diet (PD), LD and liquid ethanol diet (LED) for six weeks. Study Design Male Sprague Dawley rats were fed with nonalcoholic diets PD, LD or LED (ethanol in LD) for six weeks. Lipids were extracted and analyzed by nuclear magnetic resonance (NMR)- based metabolomics. The NMR data obtained was analyzed by multivariate Principal Component Analysis (PCA) and Spotfire DecisionSite 9.0 software to compare PD versus LD and LD versus LED groups. Results PCA of the NMR spectral data of livers of both comparisons showed a clear separation of PD from LD group and LD from LED group indicating differences in lipid profiles which corresponded with changes in total lipid weights. LD showed increases for cholesterol, esterified cholesterol, cholesterol acetate and triglycerides with decreases for fatty acyl chain, diallylic and allylic protons, while the LED showed increases in esterified cholesterol, cholesterol acetate, fatty acid methyl esters, allylic protons and some triglyceride protons with decreases in free cholesterol and phosphatidylcholine (PC). Conclusion Our data suggest that altered lipid signature or PC levels could be an indicator to differentiate between nonalcoholic versus alcoholic fatty liver.
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Affiliation(s)
- Harshica Fernando
- Department of Chemistry, Prairie View A & M University, 100 University Dr, Prairie View, TX 77446, USA
| | - Kamlesh K Bhopale
- Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, TX, 77555, USA
| | | | - Bhupendra S Kaphalia
- Department of Pathology, The University of Texas Medical Branch at Galveston, Galveston, TX, 77555, USA
| | - G A Shakeel Ansari
- Department of Pathology, The University of Texas Medical Branch at Galveston, Galveston, TX, 77555, USA
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Cronje PB. Essential role of methyl donors in animal productivity. ANIMAL PRODUCTION SCIENCE 2018. [DOI: 10.1071/an15729] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Dietary requirements for the methyl donors, choline, betaine and folate, in livestock species are poorly defined and have not been included in diet formulation software or simulation models for animals. A deficiency of methyl donors may promote an inflammatory state, which is significant for the livestock industry because chronic low-grade inflammation is widespread among livestock under commercial conditions. Furthermore, recent evidence showing that methyl donors activate adenosine monophosphate-activated protein kinase, an anti-inflammatory master switch, indicates that dietary methyl-donor supplementation could be used to prevent or ameliorate chronic inflammation and its sequelae in livestock, which include fatty liver disease in dairy cows, fatty liver and kidney syndrome in broilers, fatty liver haemorrhagic syndrome in layers, gut ulcers in pigs, liver abscesses in feedlot cattle, enteritis in poultry and susceptibility to heat stress in all species. Because of the complexity of interactions among methyl donors, a modelling approach inclusive of a supporting research effort will be required to harness the potential of methyl-donor supplementation in livestock production.
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Glutathione and Transsulfuration in Alcohol-Associated Tissue Injury and Carcinogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1032:37-53. [PMID: 30362089 DOI: 10.1007/978-3-319-98788-0_3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Glutathione (GSH) is the most abundant non-protein thiol, attaining cellular concentrations in the millimolar range. GSH functions to protect cells against endogenous and exogenous electrophiles. In addition, GSH serves as a cofactor for the GSH peroxidase family of enzymes which metabolize H2O2 as well as lipid peroxides. Through the action of glutathione S-transferase family of enzymes, GSH is conjugated to a variety of electrophilic endogenous compounds and exogenous chemicals, and thereby facilitates their efficient and safe elimination. Through the transsulfuration pathway, GSH biosynthesis is metabolically linked with cellular methylation, which is pivotal for epigenetic gene regulation. Accumulating evidence suggests that the underlying mechanisms of alcohol-associated tissue injury and carcinogenesis involve: (i) generation of the electrophilic metabolite acetaldehyde, (ii) induction of CYP2E1 leading to the formation of reactive oxygen species and pro-carcinogen activation, and (iii) nutritional deficiencies, such as methyl groups, resulting in enhanced susceptibility to cancer development. In this context, clinical and experimental investigations suggest an intimate involvement of GSH and related enzymes in the development of alcohol-induced pathological conditions. The aim of this review is to provide an overview of the GSH biosynthesis, cellular transsulfuration/transmethylation pathways, and their implications in the pathogenesis and treatment of alcohol-related disease and cancer.
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Auta J, Zhang H, Pandey SC, Guidotti A. Chronic Alcohol Exposure Differentially Alters One-Carbon Metabolism in Rat Liver and Brain. Alcohol Clin Exp Res 2017; 41:1105-1111. [PMID: 28369960 DOI: 10.1111/acer.13382] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 03/22/2017] [Indexed: 01/13/2023]
Abstract
BACKGROUND Epigenetic mechanisms such as DNA methylation play an important role in regulating the pathophysiology of alcoholism. Chronic alcohol exposure leads to behavioral changes as well as decreased expression of genes associated with synaptic plasticity. In the liver, it has been documented that chronic alcohol exposure impairs methionine synthase (Ms) activity leading to a decrease in S-adenosyl methionine/S-adenosyl homocysteine (SAM/SAH) ratio which results in DNA hypomethylation; however, it is not known whether similar alterations of SAM and SAH levels are also produced in brain. METHODS Male adult Sprague Dawley rats were fed chronically with Lieber-DeCarli ethanol (EtOH) (9% v/v) or control diet. The EtOH-diet-fed rats were withdrawn for 0 and 24 hours. The cerebellum and liver tissues were dissected and used to investigate changes in one-carbon metabolism, SAM, and SAH levels. RESULTS We found that chronic EtOH exposure decreased SAM levels, SAM/SAH ratio, Ms, methylene tetrahydrofolate reductase, and betaine homocysteine methyltransferase (Bhmt) expression and increased methionine adenosyltransferase-2b (Mat2b) but not Mat2a expression in the liver. In contrast, chronic EtOH exposure decreased SAH levels, increased SAM/SAH ratio and the expression of Mat2a and S-adenosyl homocysteine hydrolase, while the levels of SAM or Bhmt expression in cerebellum remained unaltered. However, in both liver and cerebellum, chronic EtOH exposure decreased the expression of Ms and increased Mat2b expression. All chronic EtOH-induced changes of one-carbon metabolism in cerebellum, but not liver, returned to near-normal levels during EtOH withdrawal. CONCLUSIONS These results indicate a decreased "methylation index" in liver and an increased "methylation index" in cerebellum. The opposing changes of the "methylation index" suggest altered DNA methylation in liver and cerebellum, thus implicating one-carbon metabolism in the pathophysiology of alcoholism.
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Affiliation(s)
- James Auta
- Center for Alcohol Research in Epigenetics , Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Huaibo Zhang
- Center for Alcohol Research in Epigenetics , Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Subhash C Pandey
- Center for Alcohol Research in Epigenetics , Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.,Jesse Brown VA Medical Center , Chicago, Illinois
| | - Alessandro Guidotti
- Center for Alcohol Research in Epigenetics , Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois
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Maternal Betaine Supplementation throughout Gestation and Lactation Modifies Hepatic Cholesterol Metabolic Genes in Weaning Piglets via AMPK/LXR-Mediated Pathway and Histone Modification. Nutrients 2016; 8:nu8100646. [PMID: 27763549 PMCID: PMC5084033 DOI: 10.3390/nu8100646] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 09/20/2016] [Accepted: 10/02/2016] [Indexed: 11/16/2022] Open
Abstract
Betaine serves as an animal and human nutrient which has been heavily investigated in glucose and lipid metabolic regulation, yet the underlying mechanisms are still elusive. In this study, feeding sows with betaine-supplemented diets during pregnancy and lactation increased cholesterol content and low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SR-BI) gene expression, but decreasing bile acids content and cholesterol-7a-hydroxylase (CYP7a1) expression in the liver of weaning piglets. This was associated with the significantly elevated serum betaine and methionine levels and hepatic S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) content. Concurrently, the hepatic nuclear transcription factor liver X receptor LXR was downregulated along with activated signal protein AMP-activated protein kinase (AMPK). Moreover, a chromatin immunoprecipitation assay showed lower LXR binding on CYP7a1 gene promoter and more enriched activation histone marker H3K4me3 on LDLR and SR-BI promoters. These results suggest that gestational and lactational betaine supplementation modulates hepatic gene expression involved in cholesterol metabolism via an AMPK/LXR pathway and histone modification in the weaning offspring.
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Kitagawa E, Yamamoto T, Fujishita M, Ota Y, Yamamoto K, Nakagawa T, Hayakawa T. Choline and betaine ameliorate liver lipid accumulation induced by vitamin B 6 deficiency in rats. Biosci Biotechnol Biochem 2016; 81:316-322. [PMID: 27696964 DOI: 10.1080/09168451.2016.1240604] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
We investigated the efficacy of supplementing the diet with choline or betaine in ameliorating lipid accumulation induced by vitamin B6 (B6) deficiency in rat liver. Male Wistar rats were fed a control, B6-deficient, choline-supplemented (2, 4, or 6 g choline bitartrate/kg diet) B6-deficient diet or betaine-supplemented (1, 2, or 4 g betaine anhydrous/kg diet) B6-deficient diet for 35 d; all diets contained 9 g L-methionine (Met)/kg diet. Choline or betaine supplementation attenuated liver lipid deposition and restored plasma lipid profiles to control levels. These treatments restored the disruptions in Met metabolism and the phosphatidylcholine (PC)/phosphatidylethanolamine (PE) ratio induced by B6 deficiency in liver microsomes. These results suggest that choline and betaine ameliorated liver lipid accumulation induced by B6 deficiency via recovery of Met metabolism and very low-density lipoprotein secretion by restoring the supply of PC derived from PE.
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Affiliation(s)
- Erina Kitagawa
- a The United Graduate School of Agricultural Science , Gifu University , Gifu , Japan.,b Faculty of Health and Human Life , Nagoya Bunri University , Inazawa , Japan
| | - Tatsuya Yamamoto
- c The Graduate School of Applied Biological Sciences , Gifu University , Gifu , Japan
| | - Mayuko Fujishita
- c The Graduate School of Applied Biological Sciences , Gifu University , Gifu , Japan
| | - Yuki Ota
- c The Graduate School of Applied Biological Sciences , Gifu University , Gifu , Japan
| | - Kohei Yamamoto
- a The United Graduate School of Agricultural Science , Gifu University , Gifu , Japan
| | - Tomoyuki Nakagawa
- a The United Graduate School of Agricultural Science , Gifu University , Gifu , Japan.,c The Graduate School of Applied Biological Sciences , Gifu University , Gifu , Japan.,d Faculty of Applied Biological Sciences , Gifu University , Gifu , Japan
| | - Takashi Hayakawa
- a The United Graduate School of Agricultural Science , Gifu University , Gifu , Japan.,c The Graduate School of Applied Biological Sciences , Gifu University , Gifu , Japan.,d Faculty of Applied Biological Sciences , Gifu University , Gifu , Japan
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