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Perumal SK, Arumugam MK, Osna NA, Rasineni K, Kharbanda KK. Betaine regulates the gut-liver axis: a therapeutic approach for chronic liver diseases. Front Nutr 2025; 12:1478542. [PMID: 40196019 PMCID: PMC11973089 DOI: 10.3389/fnut.2025.1478542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 03/03/2025] [Indexed: 04/09/2025] Open
Abstract
Chronic liver disease is defined by persistent harm to the liver that might result in decreased liver function. The two prevalent chronic liver diseases are alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD). There is ample evidence that the pathogenesis of these two chronic liver diseases is closely linked to gastrointestinal dysfunctions that alters the gut-liver crosstalk. These alterations are mediated through the imbalances in the gut microbiota composition/function that combined with disruption in the gut barrier integrity allows for harmful gut microbes and their toxins to enter the portal circulation and reach the liver to elicit an inflammatory response. This leads to further recruitment of systemic inflammatory cells, such as neutrophils, T-cells, and monocytes into the liver, which perpetuate additional inflammation and the development of progressive liver damage. Many therapeutic modalities, currently used to prevent, attenuate, or treat chronic liver diseases are aimed at modulating gut dysbiosis and improving intestinal barrier function. Betaine is a choline-derived metabolite and a methyl group donor with antioxidant, anti-inflammatory and osmoprotectant properties. Studies have shown that low betaine levels are associated with higher levels of organ damage. There have been several publications demonstrating the role of betaine supplementation in preventing the development of ALD and MASLD. This review explores the protective effects of betaine through its role as a methyl donor and its capacity to regulate the protective gut microbiota and maintain intestinal barrier integrity to prevent the development of these chronic liver diseases. Further studies are needed to enhance our understanding of its therapeutic potential that could pave the way for targeted interventions in the management of not only chronic liver diseases, but other inflammatory bowel diseases or systemic inflammatory conditions.
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Affiliation(s)
- Sathish Kumar Perumal
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Madan Kumar Arumugam
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Cancer Biology Lab, Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Natalia A. Osna
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
| | - Karuna Rasineni
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Kusum K. Kharbanda
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
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Gao G, Liu SM, Hao FB, Wang MJ, Wang QN, Yang RM, Guo QB, Wang XP, Li JJ, Han C, Duan L, Zhang JN. Treatment for moyamoya disease with hyperhomocysteinemia. J Cereb Blood Flow Metab 2025:271678X251325676. [PMID: 40079509 PMCID: PMC11907597 DOI: 10.1177/0271678x251325676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/15/2025]
Abstract
This study aimed to investigate the impact of controlling serum homocysteine on improving surgical outcomes in patients with moyamoya disease (MMD) and hyperhomocysteinemia. In this prospective observational cohort study, 477 patients with MMD post-encephaloduroarteriosynangiosis are divided into the HHcy-MMD post-control group (n = 193), HHcy-MMD uncontrolled group (n = 91), and MMD group (n = 193), with the HHcy-MMD post-control group further subdivided into good (homocysteine 0-10 μmol/L, n = 121) and general (homocysteine 10-15 μmol/L, n = 72) control groups. The differences in imaging and long-term clinical prognosis among the three groups were compared. No significant differences were noted in the Matsushima grade after encephaloduroarteriosynangiosis between the MMD group and HHcy-MMD post-control group (P > 0.05); however, there was a significant difference between the HHcy-MMD post-control group and HHcy-MMD uncontrolled group (P < 0.001). A significant difference was noted between the good and general control groups in the Matsushima grade (P = 0.025) and long-term follow-up clinical outcomes (P = 0.035). The area under the curve of homocysteine levels for predicting adverse clinical outcomes was 85.48% (95% confidence interval: 80.31-90.65%). Effective control of serum Hcy level after EDAS surgery in Moyamoya disease patients with HHcy may lead to better prognosis.Clinical Trial Registration: This study was registered at ClinicalTrials.gov (NCT03613701).
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Affiliation(s)
- Gan Gao
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China
| | - Si-Meng Liu
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China
| | - Fang-Bin Hao
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China
| | - Min-Jie Wang
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China
| | - Qian-Nan Wang
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China
| | - Ri-Miao Yang
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China
| | - Qing-Bao Guo
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China
| | - Xiao-Peng Wang
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China
| | - Jing-Jie Li
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China
| | - Cong Han
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China
| | - Lian Duan
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China
| | - Jian-Ning Zhang
- Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China
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Maekawa M, Iwahori A, Kumondai M, Sato Y, Sato T, Mano N. Determination of Choline-Containing Compounds in Rice Bran Fermented with Aspergillus oryzae Using Liquid Chromatography/Tandem Mass Spectrometry. Mass Spectrom (Tokyo) 2024; 13:A0151. [PMID: 39161737 PMCID: PMC11331278 DOI: 10.5702/massspectrometry.a0151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 07/19/2024] [Indexed: 08/21/2024] Open
Abstract
Choline-containing compounds are essential nutrients for human activity, as they are involved in many biological processes, including cell membrane organization, methyl group donation, neurotransmission, signal transduction, lipid transport, and metabolism. These compounds are normally obtained from food. Fermented brown rice and rice bran with Aspergillus oryzae (FBRA) is a fermented food product derived from rice and rice ingredients. FBRA exhibits a multitude of functional properties with respect to the health sciences. This study has a particular focus on choline-containing compounds. We first developed a simultaneous liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis method for seven choline-containing compounds. The method was subsequently applied to FBRA and its ingredients. Hydrophilic interaction chromatography (HILIC) and selected reaction monitoring were employed for the simultaneous analysis of seven choline-containing compounds. MS ion source conditions were optimized in positive ion mode, and the product ions derived from the choline group were obtained through MS/MS optimization. Under optimized HILIC conditions, the peaks exhibited good shape without peak tailing. Calibration curves demonstrated high linearity across a 300- to 10,000-fold concentration range. The application of the method to FBRA and other ingredients revealed significant differences between food with and without fermentation. In particular, betaine and α-glycerophosphocholine were found to be highest in FBRA and brown rice malt, respectively. The results indicated that the fermentation processing of rice ingredients results in alterations to the choline-containing compounds present in foods. The developed HILIC/MS/MS method proved to be a valuable tool for elucidating the composition of choline-containing compounds in foods.
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Affiliation(s)
- Masamitsu Maekawa
- Department of Pharmaceutical Sciences, Tohoku University Hospital, 1–1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980–8574, Japan
- Faculty of Pharmaceutical Sciences, Tohoku University, 1–1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980–8574, Japan
| | - Anna Iwahori
- Faculty of Pharmaceutical Sciences, Tohoku University, 1–1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980–8574, Japan
| | - Masaki Kumondai
- Department of Pharmaceutical Sciences, Tohoku University Hospital, 1–1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980–8574, Japan
| | - Yu Sato
- Department of Pharmaceutical Sciences, Tohoku University Hospital, 1–1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980–8574, Japan
| | - Toshihiro Sato
- Department of Pharmaceutical Sciences, Tohoku University Hospital, 1–1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980–8574, Japan
| | - Nariyasu Mano
- Department of Pharmaceutical Sciences, Tohoku University Hospital, 1–1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980–8574, Japan
- Faculty of Pharmaceutical Sciences, Tohoku University, 1–1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980–8574, Japan
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Song JE, Jun SH, Ryoo JY, Kang NG. Formulation of Ascorbic Acid and Betaine-based Therapeutic Deep Eutectic System for Enhanced Transdermal Delivery of Ascorbic Acid. Pharmaceutics 2024; 16:687. [PMID: 38794349 PMCID: PMC11124945 DOI: 10.3390/pharmaceutics16050687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 05/10/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
L-ascorbic acid (AA), a potent antioxidant, is commonly used topically in the pharmaceutical and cosmetic fields. However, the incorporation of AA into topical formulations is difficult because of its highly unstable nature and relatively poor skin permeability. In this study, we propose an alternative strategy for improving the solubility and topical delivery of AA through its conversion to a therapeutic deep eutectic system (THEDES). AA and betaine (Bet)-based THEDESs were prepared at certain molar ratios and characterized using polarized optical microscopy, Fourier transform infrared spectroscopy, and differential scanning calorimetry. Solubility tests showed that AA in the form of THEDES was readily soluble in various polyols (glycerin, 1,3-butylene glycol, dipropylene glycol, and 1,3-propanediol) at a high concentration (approximately 40%). Furthermore, compared to AA alone or the physical mixture of AA and Bet, AA-based THEDES significantly enhanced AA delivery through porcine skin. In an in vivo human study, THEDES-containing serum reduced the markers of aging and induced an even skin tone. These findings indicate the utility of AA and Bet-based THEDES as novel transdermal delivery systems for AA. Furthermore, our approach also showed good extension to developing gluconolactone, a well-known natural antioxidant, and Bet-based THEDES, showing potential application in transdermal delivery systems.
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Affiliation(s)
| | - Seung-Hyun Jun
- R&D Center, LG Household and Health Care (LG H&H), 70, Magokjungang 10-ro, Gangseo-gu, Seoul 07795, Republic of Korea; (J.-E.S.); (J.-Y.R.)
| | | | - Nae-Gyu Kang
- R&D Center, LG Household and Health Care (LG H&H), 70, Magokjungang 10-ro, Gangseo-gu, Seoul 07795, Republic of Korea; (J.-E.S.); (J.-Y.R.)
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Yu C, Guo X, Cui X, Su G, Wang H. Functional Food Chemical Ingredient Strategies for Non-alcoholic Fatty Liver Disease (NAFLD) and Hepatic Fibrosis: Chemical Properties, Health Benefits, Action, and Application. Curr Nutr Rep 2024; 13:1-14. [PMID: 38172459 DOI: 10.1007/s13668-023-00514-8] [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] [Accepted: 12/07/2023] [Indexed: 01/05/2024]
Abstract
PURPOSE OF REVIEW The liver is an important digestive gland in the body. Lifestyle and dietary habits are increasingly damaging our liver, leading to various diseases and health problems. Non-alcoholic fatty liver disease (NAFLD) has become one of the most serious liver disease problems in the world. Diet is one of the important factors in maintaining liver health. Functional foods and their components have been identified as novel sources of potential preventive agents in the prevention and treatment of liver disease in daily life. However, the effects of functional components derived from small molecules in food on different types of liver diseases have not been systematically summarized. RECENT FINDINGS The components and related mechanisms in functional foods play a significant role in the development and progression of NAFLD and liver fibrosis. A variety of structural components are found to treat and prevent NAFLD and liver fibrosis through different mechanisms, including flavonoids, alkaloids, polyphenols, polysaccharides, unsaturated fatty acids, and peptides. On the other hand, the relevant mechanisms include oxidative stress, inflammation, and immune regulation, and a large number of literature studies have confirmed a close relationship between the mechanisms. The purpose of this article is to examine the current literature related to functional foods and functional components used for the treatment and protection against NAFLD and hepatic fibrosis, focusing on chemical properties, health benefits, mechanisms of action, and application in vitro and in vivo. The roles of different components in the biological processes of NAFLD and liver fibrosis were also discussed.
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Affiliation(s)
- Chong Yu
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China
| | - Xiaohe Guo
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China
| | - Xiaohang Cui
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China
| | - Guangyue Su
- School of Functional Food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China
| | - Haifeng Wang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
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Li Y, Zheng N, Gao X, Huang W, Wang H, Bao Y, Ge X, Tao X, Sheng L, Li H. The identification of material basis of Si Miao Formula effective for attenuating non-alcoholic fatty liver disease. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:116988. [PMID: 37541401 DOI: 10.1016/j.jep.2023.116988] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/17/2023] [Accepted: 07/30/2023] [Indexed: 08/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The Si Miao Formula (SMF), a traditional Chinese medicine, originated from the "Cheng Fang Bian Du" during the Qing Dynasty and is commonly employed for the treatment of gout and hyperuricemia. We have demonstrated the anti-NAFLD effect of SMF by regulating hepatic lipid metabolism in high fat and high sucrose (HFHS) feeding mice in our previous report. However, the material basis of SMF for its anti-NAFLD effect remains unknown. AIM OF THE STUDY To compare the effeciacy of different components of SMF and identify the material basis for its anti-NAFLD effect. MATERIALS AND METHODS In the present study, a "Leave-one out" strategy was adopted by removing one herb from SMF each time, and the anti-NAFLD effects of four decomposed recipes containing three herbs were evaluated in C57BL/6J mice fed with an HFHS diet for 16 weeks. The chemical components of SMF and the absorbed entities in serum were assayed using UHPLC-Q-Exactive-Orbitrap HRMS. Finally, a new chemical combination with four compounds (berberine, betaine, caffeic acid, p-coumaric acid, 2:2:1:1) were generated (SMF component composition, SMF_CC), and its anti-NAFLD effect was evaluated by comparing with the original SMF in the mouse model. RESULTS Varified effects on NAFLD mice were observed among the decomposed recipes of SMF, while the original SMF showed advantages over its decomposed recipes. A total of 111 chemicals were identified from SMF, and 21 of them were detected in serum after oral administration of SMF. Comparing to SMF, SMF_CC showed comparable anti-NAFLD effect in HFHS-diet-fed mice, which was associated with the inhibition of hepatic fatty acid synthesis and transport, as well as inflammation. CONCLUSION Our current results suggested that the original SMF was better than its decomposed recipes in NAFLD management, and the derived SMF_CC was also effective in inhibiting NAFLD formation, highlighting its potential of being a novel natural agent for NAFLD therapy.
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Affiliation(s)
- Yan Li
- Functional Metabolomics and Gut Microbiome Laboratory, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Ningning Zheng
- Functional Metabolomics and Gut Microbiome Laboratory, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Xinxin Gao
- Functional Metabolomics and Gut Microbiome Laboratory, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Wenjin Huang
- Functional Metabolomics and Gut Microbiome Laboratory, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Hao Wang
- Functional Metabolomics and Gut Microbiome Laboratory, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yiyang Bao
- Functional Metabolomics and Gut Microbiome Laboratory, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Xinyu Ge
- Functional Metabolomics and Gut Microbiome Laboratory, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Xin Tao
- Functional Metabolomics and Gut Microbiome Laboratory, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Lili Sheng
- Functional Metabolomics and Gut Microbiome Laboratory, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Houkai Li
- Functional Metabolomics and Gut Microbiome Laboratory, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Ramos-Tovar E, Muriel P. NLRP3 inflammasome in hepatic diseases: A pharmacological target. Biochem Pharmacol 2023; 217:115861. [PMID: 37863329 DOI: 10.1016/j.bcp.2023.115861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/13/2023] [Accepted: 10/16/2023] [Indexed: 10/22/2023]
Abstract
The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway is mainly responsible for the activation and release of a cascade of proinflammatory mediators that contribute to the development of hepatic diseases. During alcoholic liver disease development, the NLRP3 inflammasome pathway contributes to the maturation of caspase-1, interleukin (IL)-1β, and IL-18, which induce a robust inflammatory response, leading to fibrosis by inducing profibrogenic hepatic stellate cell (HSC) activation. Substantial evidence demonstrates that nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis (NASH) via NLRP3 inflammasome activation, ultimately leading to fibrosis and hepatocellular carcinoma (HCC). Activation of the NLRP3 inflammasome in NASH can be attributed to several factors, such as reactive oxygen species (ROS), gut dysbiosis, leaky gut, which allow triggers such as cardiolipin, cholesterol crystals, endoplasmic reticulum stress, and uric acid to reach the liver. Because inflammation triggers HSC activation, the NLRP3 inflammasome pathway performs a central function in fibrogenesis regardless of the etiology. Chronic hepatic activation of the NLRP3 inflammasome can ultimately lead to HCC; however, inflammation also plays a role in decreasing tumor growth. Some data indicate that NLRP3 inflammasome activation plays an important role in autoimmune hepatitis, but the evidence is scarce. Most researchers have reported that NLRP3 inflammasome activation is essential in liver injury induced by a variety of drugs and hepatotropic virus infection; however, few reports indicate that this pathway can play a beneficial role by inducing liver regeneration. Modulation of the NLRP3 inflammasome appears to be a suitable strategy to treat liver diseases.
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Affiliation(s)
- Erika Ramos-Tovar
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina-IPN, Apartado Postal 11340, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomás, Ciudad de México, México
| | - Pablo Muriel
- Laboratorio de Hepatología Experimental, Departamento de Farmacología, Cinvestav-IPN, Apartado Postal 14-740, Ciudad de México, México.
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Arumugam MK, Gopal T, Kalari Kandy RR, Boopathy LK, Perumal SK, Ganesan M, Rasineni K, Donohue TM, Osna NA, Kharbanda KK. Mitochondrial Dysfunction-Associated Mechanisms in the Development of Chronic Liver Diseases. BIOLOGY 2023; 12:1311. [PMID: 37887021 PMCID: PMC10604291 DOI: 10.3390/biology12101311] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 09/15/2023] [Accepted: 09/25/2023] [Indexed: 10/28/2023]
Abstract
The liver is a major metabolic organ that performs many essential biological functions such as detoxification and the synthesis of proteins and biochemicals necessary for digestion and growth. Any disruption in normal liver function can lead to the development of more severe liver disorders. Overall, about 3 million Americans have some type of liver disease and 5.5 million people have progressive liver disease or cirrhosis, in which scar tissue replaces the healthy liver tissue. An estimated 20% to 30% of adults have excess fat in their livers, a condition called steatosis. The most common etiologies for steatosis development are (1) high caloric intake that causes non-alcoholic fatty liver disease (NAFLD) and (2) excessive alcohol consumption, which results in alcohol-associated liver disease (ALD). NAFLD is now termed "metabolic-dysfunction-associated steatotic liver disease" (MASLD), which reflects its association with the metabolic syndrome and conditions including diabetes, high blood pressure, high cholesterol and obesity. ALD represents a spectrum of liver injury that ranges from hepatic steatosis to more advanced liver pathologies, including alcoholic hepatitis (AH), alcohol-associated cirrhosis (AC) and acute AH, presenting as acute-on-chronic liver failure. The predominant liver cells, hepatocytes, comprise more than 70% of the total liver mass in human adults and are the basic metabolic cells. Mitochondria are intracellular organelles that are the principal sources of energy in hepatocytes and play a major role in oxidative metabolism and sustaining liver cell energy needs. In addition to regulating cellular energy homeostasis, mitochondria perform other key physiologic and metabolic activities, including ion homeostasis, reactive oxygen species (ROS) generation, redox signaling and participation in cell injury/death. Here, we discuss the main mechanism of mitochondrial dysfunction in chronic liver disease and some treatment strategies available for targeting mitochondria.
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Affiliation(s)
- Madan Kumar Arumugam
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.K.P.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Cancer Biology Lab, Centre for Molecular and Nanomedical Sciences, Sathyabama Institute of Science and Technology, Chennai 600119, Tamil Nadu, India
| | - Thiyagarajan Gopal
- Centre for Laboratory Animal Technology and Research, Sathyabama Institute of Science and Technology, Chennai 600119, Tamil Nadu, India; (T.G.); (L.K.B.)
| | | | - Lokesh Kumar Boopathy
- Centre for Laboratory Animal Technology and Research, Sathyabama Institute of Science and Technology, Chennai 600119, Tamil Nadu, India; (T.G.); (L.K.B.)
| | - Sathish Kumar Perumal
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.K.P.); (M.G.); (N.A.O.)
- Department of Internal Medicine, 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; (M.K.A.); (S.K.P.); (M.G.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Karuna Rasineni
- Department of Biochemistry and Molecular Biology, 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; (M.K.A.); (S.K.P.); (M.G.); (N.A.O.)
- 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;
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.K.P.); (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; (M.K.A.); (S.K.P.); (M.G.); (N.A.O.)
- 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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Luo Y, Zeng Y, Peng J, Zhang K, Wang L, Feng T, Nhamdriel T, Fan G. Phytochemicals for the treatment of metabolic diseases: Evidence from clinical studies. Biomed Pharmacother 2023; 165:115274. [PMID: 37542856 DOI: 10.1016/j.biopha.2023.115274] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/29/2023] [Accepted: 07/31/2023] [Indexed: 08/07/2023] Open
Abstract
With the continuous improvement of people's living standard, the incidence of metabolic diseases is gradually increasing in recent years. There is growing interest in finding drugs to treat metabolic diseases from natural compounds due to their good efficacy and limited side effects. Over the past few decades, many phytochemicals derived from natural plants, such as berberine, curcumin, quercetin, resveratrol, rutin, and hesperidin, have been shown to have good pharmacological activity against metabolic diseases in preclinical studies. More importantly, clinical trials using these phytochemicals to treat metabolic diseases have been increasing. This review comprehensively summarizes the clinical progress of phytochemicals derived from natural plants in the treatment of several metabolic diseases, including type 2 diabetes mellitus (T2DM), obesity and non-alcoholic fatty liver disease (NAFLD). Accumulating clinical evidence shows that a total of 18 phytochemicals have good therapeutic effects on the three metabolic diseases by lowering blood glucose and lipid levels, reducing insulin resistance, enhancing insulin sensitivity, increasing energy expenditure, improving liver function, and relieving inflammation and oxidative stress. The information will help us better understand the medicinal value of these phytochemicals and promote their clinical application in the treatment of metabolic diseases.
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Affiliation(s)
- Yuting Luo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yujiao Zeng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jiayan Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Kun Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Lijie Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Tu Feng
- School of Ecological Engineering, Guizhou University of Engineering Science, Bijie 551700, China.
| | - Tsedien Nhamdriel
- Department of Tibetan medicine, University of Tibetan Medicine, Lhasa 850000, China.
| | - Gang Fan
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Meishan Hospital of Chengdu University of Traditional Chinese Medicine, Meishan 620010, China.
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10
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Warrier M, Paules EM, Silva-Gomez J, Friday WB, Bramlett F, Kim H, Zhang K, Trujillo-Gonzalez I. Homocysteine-induced endoplasmic reticulum stress activates FGF21 and is associated with browning and atrophy of white adipose tissue in Bhmt knockout mice. Heliyon 2023; 9:e13216. [PMID: 36755585 PMCID: PMC9900266 DOI: 10.1016/j.heliyon.2023.e13216] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 01/13/2023] [Accepted: 01/20/2023] [Indexed: 01/30/2023] Open
Abstract
Betaine-homocysteine methyltransferase (BHMT) catalyzes the transfer of methyl groups from betaine to homocysteine (Hcy), producing methionine and dimethylglycine. In this work, we characterize Bhmt wild type (Bhmt-WT) and knockout (Bhmt-KO) mice that were fully backcrossed to a C57Bl6/J background. Consistent with our previous findings, Bhmt-KO mice had decreased body weight, fat mass, and adipose tissue weight compared to WT. Histological analyses and gene expression profiling indicate that adipose browning was activated in KO mice and contributed to the adipose atrophy observed. BHMT is not expressed in adipose tissue but is abundant in liver; thus, a signal must originate from the liver that modulates adipose tissue. We found that, in Bhmt-KO mice, homocysteine-induced endoplasmic reticulum (ER) stress is associated with activation of the hepatic transcription factor cyclic AMP response element binding protein (CREBH), and an increase in hepatic and plasma concentrations of fibroblast growth factor 21 (FGF21), which is known to induce adipose browning. Our data indicate that the deletion of a single gene in one-carbon metabolism modifies adipose biology and energy metabolism. Future studies could focus on identifying if functional polymorphisms in BHMT result in a similar adipose atrophy phenotype.
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Affiliation(s)
- Manya Warrier
- Department of Nutrition, UNC Nutrition Research Institute, UNC-Chapel Hill, Kannapolis, NC, USA
| | - Evan M. Paules
- Department of Nutrition, UNC Nutrition Research Institute, UNC-Chapel Hill, Kannapolis, NC, USA
- Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA
| | - Jorge Silva-Gomez
- Department of Nutrition, UNC Nutrition Research Institute, UNC-Chapel Hill, Kannapolis, NC, USA
| | - Walter B. Friday
- Department of Nutrition, UNC Nutrition Research Institute, UNC-Chapel Hill, Kannapolis, NC, USA
| | - Frances Bramlett
- Department of Nutrition, UNC Nutrition Research Institute, UNC-Chapel Hill, Kannapolis, NC, USA
| | - Hyunbae Kim
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
| | - Kezhong Zhang
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
| | - Isis Trujillo-Gonzalez
- Department of Nutrition, UNC Nutrition Research Institute, UNC-Chapel Hill, Kannapolis, NC, USA
- Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA
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11
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Nano Ag/Co 3O 4 Catalyzed Rapid Decomposition of Robinia pseudoacacia Bark for Production Biofuels and Biochemicals. Polymers (Basel) 2022; 15:polym15010114. [PMID: 36616464 PMCID: PMC9824563 DOI: 10.3390/polym15010114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/12/2022] [Accepted: 12/18/2022] [Indexed: 12/29/2022] Open
Abstract
Biomass energy has attracted widespread attention due to its renewable, storage, huge production and clean and pollution-free advantages. Using Robinia pseudoacacia bark (RPB) as raw material, biogas and bio-oil produced by pyrolysis of RPB were detected and analyzed by TG-DTG, TG-FTIR and PY-GC-MS under the action of nanocatalysis. TG results showed that CH4 and CO flammable gases were produced by pyrolysis. PY-GC-MS results showed that RPB was rapidly pyrolyzed to obtain alcohols, ketones, aldehydes and acids bio-oil. The content of phenolic substances was the highest, accounting for 32.18% of all substances.Nanocatalysis has a certain effect on RPB, accelerating the precipitation of pyrolysis products and improving the over-oxidation of bio-oil. In addition, the extracts of RPB were identified and analyzed by FTIR, NMR, GC-MS and LC-Q-TOF-MS, and more than 100 active ingredients, such as Betaine, Epicathin and β-sitosterol, were detected. Their applications as additive energy in other fields were explored. Therefore, Robinia pseudoacacia bark constitutes a fine biofeedstock for biofuels and biochemicals.
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12
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Ilyas A, Wijayasinghe YS, Khan I, El Samaloty NM, Adnan M, Dar TA, Poddar NK, Singh LR, Sharma H, Khan S. Implications of trimethylamine N-oxide (TMAO) and Betaine in Human Health: Beyond Being Osmoprotective Compounds. Front Mol Biosci 2022; 9:964624. [PMID: 36310589 PMCID: PMC9601739 DOI: 10.3389/fmolb.2022.964624] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 07/11/2022] [Indexed: 11/13/2022] Open
Abstract
Osmolytes are naturally occurring small molecular weight organic molecules, which are accumulated in large amounts in all life forms to maintain the stability of cellular proteins and hence preserve their functions during adverse environmental conditions. Trimethylamine N-oxide (TMAO) and N,N,N-trimethylglycine (betaine) are methylamine osmolytes that have been extensively studied for their diverse roles in humans and have demonstrated opposing relations with human health. These osmolytes are obtained from food and synthesized endogenously using dietary constituents like choline and carnitine. Especially, gut microbiota plays a vital role in TMAO synthesis and contributes significantly to plasma TMAO levels. The elevated plasma TMAO has been reported to be correlated with the pathogenesis of numerous human diseases, including cardiovascular disease, heart failure, kidney diseases, metabolic syndrome, etc.; Hence, TMAO has been recognized as a novel biomarker for the detection/prediction of several human diseases. In contrast, betaine acts as a methyl donor in one-carbon metabolism, maintains cellular S-adenosylmethionine levels, and protects the cells from the harmful effects of increased plasma homocysteine. Betaine also demonstrates antioxidant and anti-inflammatory activities and has a promising therapeutic value in several human diseases, including homocystinuria and fatty liver disease. The present review examines the multifarious functions of TMAO and betaine with possible molecular mechanisms towards a better understanding of their emerging and diverging functions with probable implications in the prevention, diagnosis, and treatment of human diseases.
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Affiliation(s)
- Ashal Ilyas
- Department of Biotechnology, Invertis University, Bareilly, Uttar Pradesh, India
| | - Yasanandana Supunsiri Wijayasinghe
- Department of Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka,*Correspondence: Yasanandana Supunsiri Wijayasinghe, , Nitesh Kumar Poddar, , , Shahanavaj Khan,
| | - Ilyas Khan
- Department of Mathematics, College of Science Al-Zulfi, Majmaah University, Al-Majmaah, Saudi Arabia
| | - Nourhan M. El Samaloty
- Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt
| | - Mohd Adnan
- Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia
| | - Tanveer Ali Dar
- Department of Clinical Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir, India
| | - Nitesh Kumar Poddar
- Department of Biosciences, Manipal University Jaipur, Jaipur, Rajasthan, India,*Correspondence: Yasanandana Supunsiri Wijayasinghe, , Nitesh Kumar Poddar, , , Shahanavaj Khan,
| | - Laishram R. Singh
- Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
| | - Hemlata Sharma
- Department of Biosciences, Manipal University Jaipur, Jaipur, Rajasthan, India
| | - Shahanavaj Khan
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia,Department of Medical Lab Technology, Indian Institute of Health and Technology (IIHT), Saharanpur, Uttar Pradesh, India,*Correspondence: Yasanandana Supunsiri Wijayasinghe, , Nitesh Kumar Poddar, , , Shahanavaj Khan,
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13
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Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common disease defined by excess fat deposition in the liver. The course of NAFLD is not fully understood, however, some pathogenic mechanisms have been identified. Accumulation of fat in liver cells is associated with insulin resistance, central obesity, triglyceride accumulation in the liver and hepatic fatty acid metabolism dysregulation that cause steatosis. The other process leads to hepatocyte inflammation and necrosis, which leads to severe hepatic disease; non-alcoholic steatohepatitis. Many clinical studies have underlined the link between NAFLD and atherosclerosis. NAFLD may alter the balance lipid-glucose metabolism as well as increase the risk of hypertension and systemic inflammation. This results in a greater risk of vascular events. The present review considers the link between NAFLD and atherosclerosis.
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Affiliation(s)
- Sevket Balta
- Department of Cardiology, Hayat Hospital, Malatya, Turkey
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14
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Gijbels A, Schutte S, Esser D, Wopereis S, Gonzales GB, Afman LA. Effects of a 12-week whole-grain or refined wheat intervention on plasma acylcarnitines, bile acids and signaling lipids, and association with liver fat: A post-hoc metabolomics study of a randomized controlled trial. Front Nutr 2022; 9:1026213. [PMID: 36330140 PMCID: PMC9624226 DOI: 10.3389/fnut.2022.1026213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 09/14/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND We previously showed that whole-grain wheat (WGW) consumption had beneficial effects on liver fat accumulation, as compared to refined wheat (RW). The mechanisms underlying these effects remain unclear. OBJECTIVE In this study, we investigated the effects of WGW vs. RW consumption on plasma metabolite levels to explore potential underlying mechanisms of the preventive effect of WGW consumption on liver fat accumulation. METHODS Targeted metabolomics of plasma obtained from a concluded 12-week double-blind, randomized controlled trial was performed. Fifty overweight or obese men and women aged 45-70 years with mildly elevated levels of plasma cholesterol were randomized to either 98 g/d of WGW or RW products. Before and after the intervention, a total of 89 fasting plasma metabolite concentrations including acylcarnitines, trimethylamine-N-oxide (TMAO), choline, betaine, bile acids, and signaling lipids were quantified by UPLC-MS/MS. Intrahepatic triglycerides (IHTG) were quantified by 1H-MRS, and multiple liver markers, including circulating levels of β-hydroxybutyrate, alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (γ-GT), serum amyloid A (SAA), and C-reactive protein, were assessed. RESULTS The WGW intervention increased plasma concentrations of four out of 52 signaling lipids-lysophosphatidic acid C18:2, lysophosphatidylethanolamine C18:1 and C18:2, and platelet-activating factor C18:2-and decreased concentrations of the signaling lipid lysophosphatidylglycerol C20:3 as compared to RW intervention, although these results were no longer statistically significant after false discovery rate (FDR) correction. Plasma concentrations of the other metabolites that we quantified were not affected by WGW or RW intervention. Changes in the above-mentioned metabolites were not correlated to change in IHTG upon the intervention. CONCLUSION Plasma acylcarnitines, bile acids, and signaling lipids were not robustly affected by the WGW or RW interventions, which makes them less likely candidates to be directly involved in the mechanisms that underlie the protective effect of WGW consumption or detrimental effect of RW consumption on liver fat accumulation. CLINICAL TRIAL REGISTRATION [www.ClinicalTrials.gov], identifier [NCT02385149].
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Affiliation(s)
- Anouk Gijbels
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, Netherlands
| | - Sophie Schutte
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, Netherlands
| | - Diederik Esser
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, Netherlands
| | - Suzan Wopereis
- Research Group Microbiology and Systems Biology, TNO, Netherlands Organization for Applied Scientific Research, Zeist, Netherlands
| | - Gerard Bryan Gonzales
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, Netherlands
| | - Lydia A. Afman
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, Netherlands
- *Correspondence: Lydia A. Afman,
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15
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Protective effect and mechanism of betaine against hyperosmotic stress in porcine intestinal epithelium. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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16
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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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17
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Frieg B, Görg B, Gohlke H, Häussinger D. Glutamine synthetase as a central element in hepatic glutamine and ammonia metabolism: novel aspects. Biol Chem 2021; 402:1063-1072. [PMID: 33962502 DOI: 10.1515/hsz-2021-0166] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/22/2021] [Indexed: 12/27/2022]
Abstract
Glutamine synthetase (GS) in the liver is expressed in a small perivenous, highly specialized hepatocyte population and is essential for the maintenance of low, non-toxic ammonia levels in the organism. However, GS activity can be impaired by tyrosine nitration of the enzyme in response to oxidative/nitrosative stress in a pH-sensitive way. The underlying molecular mechanism as investigated by combined molecular simulations and in vitro experiments indicates that tyrosine nitration can lead to a fully reversible and pH-sensitive regulation of protein function. This approach was also used to understand the functional consequences of several recently described point mutations of human GS with clinical relevance and to suggest an approach to restore impaired GS activity.
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Affiliation(s)
- Benedikt Frieg
- Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich GmbH, D-52425 Jülich, Germany
| | - Boris Görg
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany
| | - Holger Gohlke
- John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry), and Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, D-52425 Jülich, Germany
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany
| | - Dieter Häussinger
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany
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18
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Liu M, Lai Z, Zhu L, Ding X, Tong X, Wang Z, Bi Q, Tan N. Novel amorphous solid dispersion based on natural deep eutectic solvent for enhancing delivery of anti-tumor RA-XII by oral administration in rats. Eur J Pharm Sci 2021; 166:105931. [PMID: 34256100 DOI: 10.1016/j.ejps.2021.105931] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 06/22/2021] [Accepted: 06/23/2021] [Indexed: 02/08/2023]
Abstract
At present, oral chemotherapy showing the advantages of non-invasiveness, convenience, and high patient compliance, is gradually replacing traditional intravenous chemotherapy to treat patients with cancer. RA-XII, a unique natural cyclopeptide, exhibits various biological activities, such as anti-tumor, anti-angiogenic, and anti-metastatic activities. Designing an orally available formulation of RA-XII is of great importance in the development of clinically useful anticancer agents. However, RA-XII shows low oral bioavailability in rats due to its poor solubility and low permeability. To overcome these limitations, in this work, a natural deep eutectic solvent (NADES) was designed to efficiently deliver RA-XII by oral administration. A novel NADES composed of betaine and mandelic acid in the molar ratio of 1:1 (Bet-Man NADES) was successfully prepared based on a binary phase diagram of Bet and Man. Acute toxicity studies indicated that Bet-Man NADES was well tolerated with acceptable toxicity. In Bet-Man NADES solutions, the solubility of RA-XII was increased by up to 17.54-fold, and the diffusion and permeability of RA-XII carried out in a Franz cell was also significantly improved 10.35 times. In terms of biopharmaceutical classification this is translated into a change for RA-XII from class IV to class II systems. More importantly, Bet-Man NADES was transferred into the solid formulation by the inclusion of a polymer, and amorphous solid dispersions based on Bet-Man NADES (PVP K30/NADES/RA-XII, ASDs) were successfully prepared to improve uniformity, apparent solubility, dissolution, and cytotoxicity in vitro. Consequently, the oral bioavailability of RA-XII in NADES solutions and ASDs was enhanced by approximately 11.58 and 7.56 times compared with that of pure RA-XII in 0.5% CMCNa. Thus, it can be seen that a natural deep eutectic solvent and its modified amorphous solid dispersions are appropriate novel strategies for improving dissolution rate and bioavailability of poor soluble natural products such as RA-XII.
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Affiliation(s)
- Mingyu Liu
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Zhixing Lai
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Lijun Zhu
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Xin Ding
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Xiyang Tong
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Zhen Wang
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Qirui Bi
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Ninghua Tan
- Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
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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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20
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Fawaz R, Jonas MM. Acute and Chronic Hepatitis. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2021:819-837.e6. [DOI: 10.1016/b978-0-323-67293-1.00075-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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21
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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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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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23
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Lee MR, Kim JE, Park JW, Kang MJ, Choi HJ, Bae SJ, Choi YW, Kim KM, Hong JT, Hwang DY. Fermented mulberry (Morus alba) leaves suppress high fat diet-induced hepatic steatosis through amelioration of the inflammatory response and autophagy pathway. BMC Complement Med Ther 2020; 20:283. [PMID: 32948162 PMCID: PMC7501671 DOI: 10.1186/s12906-020-03076-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 09/08/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND A novel extract of mulberry leaves fermented with Cordyceps militaris (EMfC) is reported to exert anti-obesity activity, although their molecular mechanism during hepatic steatosis has not verified. METHODS To investigate the role of inflammation and autophagy during the anti-hepatic steatosis effects of EMfC, we measured alterations in the key parameters for inflammatory response and autophagy pathway in liver tissues of the high fat diet (HFD) treated C57BL/6N mice after exposure to EMfC for 12 weeks. RESULTS Significant anti-hepatic steatosis effects, including decreased number of lipid droplets and expression of Klf2 mRNA, were detected in the liver of the HFD + EMfC treated group. The levels of mast cell infiltration, expression of two inflammatory mediators (iNOS and COX-2), and the MAPK signaling pathway were remarkably decreased in the liver of HFD + EMfC treated group as compared to the HFD + Vehicle treated group. Furthermore, a similar inhibitory effect was measured for the expression levels of pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α and NF-κB. The expression level of members in the AKT/mTOR signaling pathway (a central regulator in autophagy) was recovered after treatment with EMfC, and autophagy-related proteins (Beclin and LC3-II) were remarkably decreased in the HFD + EMfC treated group compared to the HFD + Vehicle treated group. Moreover, the HFD + EMfC treated group showed decreased transcript levels of autophagy-regulated genes including Atg4b, Atg5, Atg7 and Atg12. CONCLUSIONS Taken together, findings of the present study provide novel evidences that the anti-hepatic steatosis of EMfC is tightly linked to the regulation of the inflammatory response and autophagy pathway in the liver tissue of HFD-induced obesity mice.
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Affiliation(s)
- Mi Rim Lee
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, South Korea
| | - Ji Eun Kim
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, South Korea
| | - Ji Won Park
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, South Korea
| | - Mi Ju Kang
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, South Korea
| | - Hyeon Jun Choi
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, South Korea
| | - Su Ji Bae
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, South Korea
| | - Young Whan Choi
- Department of Horticultural Bioscience, College of Natural Resources & Life Science/Life and Industry Convergence Research Institue, Pusan National University, Miryang, 50463, South Korea
| | - Kyung Mi Kim
- Life Science Research Institute, Novarex Co., Ltd, Chungju, 28126, South Korea
| | - Jin Tae Hong
- College of Pharmacy, Chungbuk National University, Chungju, 28644, South Korea
| | - Dae Youn Hwang
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, South Korea.
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Song J, Dongqi S, Hang S, Yongxia F, Wei T. Optimization of ultrasonic extraction of Lycium barbarum polysaccharides using response surface methodology. INTERNATIONAL JOURNAL OF FOOD ENGINEERING 2020. [DOI: 10.1515/ijfe-2020-0153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
AbstractUltrasonic extraction was a new development method to achieve high-efficiency extraction of Lycium barbarum polysaccharides instead of hot water extraction. In this paper, the single factor method combined with the box Behnken design of response surface method was used to study the influence of extraction time, extraction temperature, material liquid ratio and ultrasonic power on the extraction rate of L. barbarum polysaccharide. The results indicated that the best extraction rate of L. barbarum polysaccharide was 12.54 ± 0.12% under the conditions of 80 min for extraction time, 73 °C for extraction temperature, 1 g:38 mL for material to liquid ratio, and 185 W for ultrasonic power. Under the same operating conditions, the yield of L. barbarum polysaccharide using ultrasonic extraction was 83.3%, which was higher than that hot water extraction. Moreover, the extraction time of ultrasonic extraction was only 47% of that using hot water extraction. This suggested that there was great potentials of using ultrasonic extraction in the realization of high-efficiency extraction of L. barbarum polysaccharide. The results of this study could also provide a theoretical basis for the coupling of ultrasonic extraction and ultrasonic concentration process to develop the integrated equipment of both ultrasonic extraction and ultrasonic concentration.
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Affiliation(s)
- Jitian Song
- Tianjin Key Laboratory of Integrated Design and On-line Monitoring for Light Industry & Food Machinery and Equipment, College of Mechanical Engineering, Tianjin University of Science and Technology, 300222, Tianjin, China
- International Science and Technology Cooperation Base of Low-Carbon Green Process Equipment, 300222, Tianjin, China
| | - Shi Dongqi
- Tianjin Key Laboratory of Integrated Design and On-line Monitoring for Light Industry & Food Machinery and Equipment, College of Mechanical Engineering, Tianjin University of Science and Technology, 300222, Tianjin, China
| | - Su Hang
- Tianjin Key Laboratory of Integrated Design and On-line Monitoring for Light Industry & Food Machinery and Equipment, College of Mechanical Engineering, Tianjin University of Science and Technology, 300222, Tianjin, China
| | - Feng Yongxia
- Tianjin Key Laboratory of Integrated Design and On-line Monitoring for Light Industry & Food Machinery and Equipment, College of Mechanical Engineering, Tianjin University of Science and Technology, 300222, Tianjin, China
| | - Tian Wei
- Tianjin Key Laboratory of Integrated Design and On-line Monitoring for Light Industry & Food Machinery and Equipment, College of Mechanical Engineering, Tianjin University of Science and Technology, 300222, Tianjin, China
- International Science and Technology Cooperation Base of Low-Carbon Green Process Equipment, 300222, Tianjin, China
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25
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Schmidt AC, Leroux JC. Treatments of trimethylaminuria: where we are and where we might be heading. Drug Discov Today 2020; 25:1710-1717. [DOI: 10.1016/j.drudis.2020.06.026] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 05/01/2020] [Accepted: 06/23/2020] [Indexed: 02/07/2023]
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26
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Ommati MM, Farshad O, Mousavi K, Jamshidzadeh A, Azmoon M, Heidari S, Azarpira N, Niknahad H, Heidari R. Betaine supplementation mitigates intestinal damage and decreases serum bacterial endotoxin in cirrhotic rats. PHARMANUTRITION 2020. [DOI: 10.1016/j.phanu.2020.100179] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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27
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Li S, Xu S, Zhao Y, Wang H, Feng J. Dietary Betaine Addition Promotes Hepatic Cholesterol Synthesis, Bile Acid Conversion, and Export in Rats. Nutrients 2020; 12:nu12051399. [PMID: 32414094 PMCID: PMC7284822 DOI: 10.3390/nu12051399] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 05/11/2020] [Accepted: 05/11/2020] [Indexed: 12/25/2022] Open
Abstract
It is widely reported how betaine addition regulates lipid metabolism but how betaine affects cholesterol metabolism is still unknown. This study aimed to investigate the role of betaine in hepatic cholesterol metabolism of Sprague-Dawley rats. Rats were randomly allocated to four groups and fed with a basal diet or a high-fat diet with or without 1% betaine. The experiment lasted 28 days. The results showed that dietary betaine supplementation reduced the feed intake of rats with final weight unchanged. Serum low-density-lipoprotein cholesterol was increased with the high-fat diet. The high-fat diet promoted cholesterol synthesis and excretion by enhancing the HMG-CoA reductase and ABCG5/G8, respectively, which lead to a balance of hepatic cholesterol. Rats in betaine groups showed a higher level of hepatic total cholesterol. Dietary betaine addition enhanced cholesterol synthesis as well as conversion of bile acid from cholesterol by increasing the levels of HMGCR and CYP7A1. The high-fat diet decreased the level of bile salt export pump, while dietary betaine addition inhibited this decrease and promoted bile acid efflux and increased total bile acid levels in the intestine. In summary, dietary betaine addition promoted hepatic cholesterol metabolism, including cholesterol synthesis, conversion of bile acids, and bile acid export.
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Affiliation(s)
- Sisi Li
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310027, China; (S.L.); (S.X.); (Y.Z.)
| | - Shuyi Xu
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310027, China; (S.L.); (S.X.); (Y.Z.)
| | - Yang Zhao
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310027, China; (S.L.); (S.X.); (Y.Z.)
| | - Haichao Wang
- Department of Animal Science, College of Life Sciences and Food Engineering, Hebei University of Engineering, Handan 430068, China;
| | - Jie Feng
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, Hangzhou 310027, China; (S.L.); (S.X.); (Y.Z.)
- Correspondence: ; Tel.: +86-571-88982121
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28
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Hernandez GV, Smith VA, Melnyk M, Burd MA, Sprayberry KA, Edwards MS, Peterson DG, Bennet DC, Fanter RK, Columbus DA, Steibel JP, Glanz H, Immoos C, Rice MS, Santiago-Rodriguez TM, Blank J, VanderKelen JJ, Kitts CL, Piccolo BD, La Frano MR, Burrin DG, Maj M, Manjarin R. Dysregulated FXR-FGF19 signaling and choline metabolism are associated with gut dysbiosis and hyperplasia in a novel pig model of pediatric NASH. Am J Physiol Gastrointest Liver Physiol 2020; 318:G582-G609. [PMID: 32003601 PMCID: PMC7099491 DOI: 10.1152/ajpgi.00344.2019] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 01/21/2020] [Accepted: 01/25/2020] [Indexed: 02/08/2023]
Abstract
To investigate the role of bile acids (BAs) in the pathogenesis of diet-induced nonalcoholic steatohepatitis (NASH), we fed a "Western-style diet" [high fructose, high fat (HFF)] enriched with fructose, cholesterol, and saturated fat for 10 wk to juvenile Iberian pigs. We also supplemented probiotics with in vitro BA deconjugating activity to evaluate their potential therapeutic effect in NASH. Liver lipid and function, cytokines, and hormones were analyzed using commercially available kits. Metabolites, BAs, and fatty acids were measured by liquid chromatography-mass spectrometry. Histology and gene and protein expression analyses were performed using standard protocols. HFF-fed pigs developed NASH, cholestasis, and impaired enterohepatic Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling in the absence of obesity and insulin resistance. Choline depletion in HFF livers was associated with decreased lipoprotein and cholesterol in serum and an increase of choline-containing phospholipids in colon contents and trimethylamine-N-oxide in the liver. Additionally, gut dysbiosis and hyperplasia increased with the severity of NASH, and were correlated with increased colonic levels of choline metabolites and secondary BAs. Supplementation of probiotics in the HFF diet enhanced NASH, inhibited hepatic autophagy, increased excretion of taurine and choline, and decreased gut microbial diversity. In conclusion, dysregulation of BA homeostasis was associated with injury and choline depletion in the liver, as well as increased biliary secretion, gut metabolism and excretion of choline-based phospholipids. Choline depletion limited lipoprotein synthesis, resulting in hepatic steatosis, whereas secondary BAs and choline-containing phospholipids in colon may have promoted dysbiosis, hyperplasia, and trimethylamine synthesis, causing further damage to the liver.NEW & NOTEWORTHY Impaired Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling and cholestasis has been described in nonalcoholic fatty liver disease (NAFLD) patients. However, therapeutic interventions with FXR agonists have produced contradictory results. In a swine model of pediatric nonalcoholic steatohepatitis (NASH), we show that the uncoupling of intestinal FXR-FGF19 signaling and a decrease in FGF19 levels are associated with a choline-deficient phenotype of NASH and increased choline excretion in the gut, with the subsequent dysbiosis, colonic hyperplasia, and accumulation of trimethylamine-N-oxide in the liver.
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Affiliation(s)
- Gabriella V Hernandez
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Victoria A Smith
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Megan Melnyk
- Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, California
| | - Matthew A Burd
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Kimberly A Sprayberry
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Mark S Edwards
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Daniel G Peterson
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Darin C Bennet
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
| | - Rob K Fanter
- Center for Health Research, California Polytechnic State University, San Luis Obispo, California
| | | | - Juan P Steibel
- Department of Animal Science and Department of Fisheries and Wildlife, Michigan State University, East Lansing, Michigan
| | - Hunter Glanz
- Department of Statistics, California Polytechnic State University, San Luis Obispo, California
| | - Chad Immoos
- Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California
| | - Margaret S Rice
- Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California
| | | | - Jason Blank
- Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, California
| | - Jennifer J VanderKelen
- Center for Applications in Biotechnology, California Polytechnic State University, San Luis Obispo, California
| | - Christopher L Kitts
- Center for Applications in Biotechnology, California Polytechnic State University, San Luis Obispo, California
| | - Brian D Piccolo
- United States Department of Agriculture-Agricultural Research Services, Arkansas Children's Nutrition Center, Little Rock, Arkansas
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Michael R La Frano
- Department of Food Science and Nutrition, California Polytechnic State University, San Luis Obispo, California
- Center for Health Research, California Polytechnic State University, San Luis Obispo, California
| | - Douglas G Burrin
- United States Department of Agriculture-Agricultural Research Services, Children's Nutrition Research Center, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Magdalena Maj
- Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, California
- Center for Applications in Biotechnology, California Polytechnic State University, San Luis Obispo, California
| | - Rodrigo Manjarin
- Department of Animal Science, California Polytechnic State University, San Luis Obispo, California
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29
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Zawieja EE, Zawieja B, Chmurzynska A. Betaine Supplementation Moderately Increases Total Cholesterol Levels: A Systematic Review and Meta-Analysis. J Diet Suppl 2019; 18:105-117. [DOI: 10.1080/19390211.2019.1699223] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Emilia E. Zawieja
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland
| | - Bogna Zawieja
- Department of Mathematical and Statistical Methods, Poznań University of Life Sciences, Poznań, Poland
| | - Agata Chmurzynska
- Institute of Human Nutrition and Dietetics, Poznań University of Life Sciences, Poznań, Poland
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Abstract
Lifestyle modifications, especially weight loss, are efficient on NASH liver injury, however rarely followed in clinical practice. The target population of pharmacologic treatments is represented by patients with NASH and fibrosis. Out of histological improvement, efficacy of treatments should be assessed through liver morbi-mortality benefit, but also on extrahepatic events, such as cardiovascular. Among anti-diabetic treatments, glitazones et GLP-1 agonists have shown efficacy on histological liver injury. Vitamin E is efficient on liver injury but at the cost of prostate cancer and stroke over risk. About 60 new molecules are under investigation in NASH and have 4 different types of mechanism of action: metabolic, oxidative stress/apoptosis, anti inflammatory and anti fibrotic. A phase 3 trial evaluating obeticholic acid have shown a 72 weeks duration treatment improved significantly fibrosis.
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Affiliation(s)
- Lawrence Serfaty
- Hôpital Hautepierre, service d'hépato-gastroentérologie, 1, avenue Molière, 67200 Strasbourg, France; Université Paris Sorbonne, hôpital Saint-Antoine, Inserm UMR-S938, 67000 Strasbourg, France.
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31
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Li X, Wang L, Ma H. Betaine alleviates high glucose‑induced mesangial cell proliferation by inhibiting cell proliferation and extracellular matrix deposition via the AKT/ERK1/2/p38 MAPK pathway. Mol Med Rep 2019; 20:1754-1760. [PMID: 31257485 PMCID: PMC6625408 DOI: 10.3892/mmr.2019.10391] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 05/14/2019] [Indexed: 12/16/2022] Open
Abstract
Diabetic nephropathy (DN) is a major cause of chronic renal failure in diabetic patients worldwide. Betaine, a zwitterionic quaternary ammonium salt compound, is involved in numerous biological processes. The present study aimed to investigate the effects of betaine on mouse mesangial cells (MMCs) cultured under high glucose (HG) conditions and its underlying mechanisms. MMCs were treated with betaine under HG conditions. Cell proliferation and the cell cycle distribution were investigated with an MTT assay and flow cytometry, respectively. Western blotting and reverse transcription‑quantitative polymerase chain reaction analyses were applied to respectively determine protein and mRNA expression levels. The results suggested that betaine decreased cell proliferation in a dose‑dependent manner, while G1‑phase arrest was significantly induced in MMCs. Compared with the control group, the expression levels of p21 and p27 decreased under HG conditions, but were reversed by betaine. Furthermore, the expression levels of fibronectin and type IV collagen were significantly decreased in cells treated with betaine compared with the HG group. Additionally, betaine decreased the phosphorylation of Akt, extracellular‑signal‑regulated kinase (Erk)1/2 and p38 mitogen‑activated protein kinase (MAPK), but was enhanced under HG conditions. Overall, the results of the present study indicated that betaine serves a protective role in HG‑induced MMCs by inhibiting cell proliferation and extracellular matrix deposition via regulating regulation of the Akt/Erk1/2/p38 MAPK signaling pathway.
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Affiliation(s)
- Xianhui Li
- Department of Traditional Chinese Medicine, Tianjin Key Laboratory of Artificial Cell, Tianjin Institute of Hepatobiliary Disease, Artificial Cell Engineering Technology Research Center of Public Health Ministry, Third Central Hospital of Tianjin, Tianjin 300170, P.R. China
| | - Li Wang
- Department of Basic Medicine, Tianjin Medical College, Tianjin 300222, P.R. China
| | - Huining Ma
- Department of Traditional Chinese Medicine, Tianjin 4th Centre Hospital, Tianjin 300140, P.R. China
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32
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Zhang L, Qi Y, ALuo Z, Liu S, Zhang Z, Zhou L. Betaine increases mitochondrial content and improves hepatic lipid metabolism. Food Funct 2019; 10:216-223. [PMID: 30534761 DOI: 10.1039/c8fo02004c] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The liver plays a critical role in lipid metabolism. Hepatic dysfunction is not only the direct cause of fatty liver disease, but the main risk factor for obesity, diabetes, and other metabolic diseases. So far, therapeutic strategies against fatty liver disease are very limited. Betaine is a methyl donor. Current studies reported that the intake of betaine decreases body fat and is beneficial for treatment of fatty liver disease and metabolic syndrome. However, the underlying mechanisms remain largely unknown. In this study, to investigate the role of betaine on hepatic lipid metabolism and explore the underlying mechanism, HepG2 cells were cultured with fatty acids and betaine. The data indicated that betaine inhibited hepatic fat accumulation and promoted mitochondrial content and activity, suggesting that betaine is involved in the regulation of lipid and energy metabolism. Gene expression analysis implied that betaine inhibits fatty acid synthesis, but stimulates fatty acid oxidation and lipid secretion. Further, to study the mechanism of betaine, FTO (RNA demethylase) and its mutant (loss of demethylase activity) were used. The results showed that FTO blocked the ability of betaine to regulate lipid metabolism and mitochondrial content, but the FTO mutant had no effect, suggesting that betaine influences RNA methylation. This work links betaine administration with mitochondrial activity and RNA methylation, and provides a potential target for the development of new therapeutic strategies for the treatment of fatty liver disease.
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Affiliation(s)
- Lifang Zhang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, College of Animal Science and Technology, Guangxi University, Nanning, P.R. China.
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Gancheva S, Jelenik T, Álvarez-Hernández E, Roden M. Interorgan Metabolic Crosstalk in Human Insulin Resistance. Physiol Rev 2018; 98:1371-1415. [PMID: 29767564 DOI: 10.1152/physrev.00015.2017] [Citation(s) in RCA: 137] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Excessive energy intake and reduced energy expenditure drive the development of insulin resistance and metabolic diseases such as obesity and type 2 diabetes mellitus. Metabolic signals derived from dietary intake or secreted from adipose tissue, gut, and liver contribute to energy homeostasis. Recent metabolomic studies identified novel metabolites and enlarged our knowledge on classic metabolites. This review summarizes the evidence of their roles as mediators of interorgan crosstalk and regulators of insulin sensitivity and energy metabolism. Circulating lipids such as free fatty acids, acetate, and palmitoleate from adipose tissue and short-chain fatty acids from the gut effectively act on liver and skeletal muscle. Intracellular lipids such as diacylglycerols and sphingolipids can serve as lipotoxins by directly inhibiting insulin action in muscle and liver. In contrast, fatty acid esters of hydroxy fatty acids have been recently shown to exert a series of beneficial effects. Also, ketoacids are gaining interest as potent modulators of insulin action and mitochondrial function. Finally, branched-chain amino acids not only predict metabolic diseases, but also inhibit insulin signaling. Here, we focus on the metabolic crosstalk in humans, which regulates insulin sensitivity and energy homeostasis in the main insulin-sensitive tissues, skeletal muscle, liver, and adipose tissue.
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Affiliation(s)
- Sofiya Gancheva
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University , Düsseldorf , Germany ; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University , Düsseldorf , Germany ; and German Center of Diabetes Research (DZD e.V.), Munich- Neuherberg , Germany
| | - Tomas Jelenik
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University , Düsseldorf , Germany ; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University , Düsseldorf , Germany ; and German Center of Diabetes Research (DZD e.V.), Munich- Neuherberg , Germany
| | - Elisa Álvarez-Hernández
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University , Düsseldorf , Germany ; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University , Düsseldorf , Germany ; and German Center of Diabetes Research (DZD e.V.), Munich- Neuherberg , Germany
| | - Michael Roden
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University , Düsseldorf , Germany ; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University , Düsseldorf , Germany ; and German Center of Diabetes Research (DZD e.V.), Munich- Neuherberg , Germany
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34
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Mitochondria protecting amino acids: Application against a wide range of mitochondria-linked complications. PHARMANUTRITION 2018. [DOI: 10.1016/j.phanu.2018.09.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Nonalcoholic fatty liver disease: current concepts, epidemiology and management strategies. Eur J Gastroenterol Hepatol 2018; 30:1103-1115. [PMID: 30113367 DOI: 10.1097/meg.0000000000001235] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is now the most prevalent liver disease in the world. It involves a spectrum of conditions from hepatic steatosis to nonalcoholic steatohepatitis and liver fibrosis, and is a major cause of cirrhosis and hepatocellular carcinoma. It is defined by presence of steatosis in 5% of hepatocytes or more in the absence of other causes of fatty liver. The metabolic syndrome is the major known risk factor for NAFLD. Dietary contributors such as high fructose intake and coffee consumption appear to increase and decrease the risk of disease respectively, but these links are unclear. Genetic associations have also been identified. The estimated prevalence of the disease varies according to diagnostic method and population demographics. It appears to be a major issue in Europe with population studies showing up to 50% of the individuals are affected while in the USA one in three adults are estimated to have NAFLD. Laboratory investigations and ultrasound are typically first-line investigations. Fibrosis may be assessed noninvasively through transient elastography and biomarkers but liver biopsy remains the gold standard to quantify hepatic damage. Associated comorbidities include cardiovascular disease and chronic kidney disease. Weight loss, dietary changes and exercise are recommended in management. Medications should be considered to manage underlying risk factors including insulin resistance. Surgical options include bariatric procedures and liver transplantation. The combination of rising prevalence and significant potential complications warrant further research into NAFLD, particularly in areas with research gaps including Eastern Europe.
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Jung Kim M. Betaine enhances the cellular survival via mitochondrial fusion and fission factors, MFN2 and DRP1. Anim Cells Syst (Seoul) 2018; 22:289-298. [PMID: 30460110 PMCID: PMC6171430 DOI: 10.1080/19768354.2018.1512523] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 08/01/2018] [Accepted: 08/09/2018] [Indexed: 12/19/2022] Open
Abstract
Betaine is a key metabolite of the methionine cycle and known for attenuating alcoholic steatosis in the liver. Recent studies have focused on the protection effect of betaine in mitochondrial regulation through the enhanced oxidative phosphorylation system. However, the mechanisms of its beneficial effects have not been clearly identified yet. Mitochondrial dynamics is important for the maintenance of functional mitochondria and cell homeostasis. A defective mitochondrial dynamics and oxidative phosphorylation system have been closely linked to several pathologies, raising the possibility that novel drugs targeting mitochondrial dynamics may present a therapeutic potential to restore the cellular homeostasis. In this study, we investigated betaine’s effect on mitochondrial morphology and physiology and demonstrated that betaine enhances mitochondrial function by increasing mitochondrial fusion and improves cell survival. Furthermore, it rescued the unbalance of the mitochondrial dynamics from mitochondrial oxidative phosphorylation dysfunction induced by oligomycin and rotenone. The elongation properties by betaine were accompanied by lowering DRP1 and increasing MFN2 expression. These data suggest that betaine could play an important role in remodeling mitochondrial dynamics to enhance mitochondrial function and cell viability.
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Affiliation(s)
- Min Jung Kim
- Department of Biological Sciences, Sookmyung Women's University, Seoul, South Korea
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Grizales AM, Patti ME, Lin AP, Beckman JA, Sahni VA, Cloutier E, Fowler KM, Dreyfuss JM, Pan H, Kozuka C, Lee A, Basu R, Pober DM, Gerszten RE, Goldfine AB. Metabolic Effects of Betaine: A Randomized Clinical Trial of Betaine Supplementation in Prediabetes. J Clin Endocrinol Metab 2018; 103:3038-3049. [PMID: 29860335 PMCID: PMC6692715 DOI: 10.1210/jc.2018-00507] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 05/25/2018] [Indexed: 12/16/2022]
Abstract
CONTEXT Plasma betaine correlates with insulin sensitivity in humans. Betaine supplementation improves metabolic effects in mice fed a high-fat diet. OBJECTIVE To assess metabolic effects of oral betaine in obese participants with prediabetes. DESIGN A 12-week, parallel arm, randomized, double-masked, placebo-controlled trial. SETTING University-affiliated hospital. PARTICIPANTS AND INTERVENTIONS Persons with obesity and prediabetes (N = 27) were randomly assigned to receive betaine 3300 mg orally twice daily for 10 days, then 4950 mg twice daily for 12 weeks, or placebo. MAIN OUTCOME MEASURES Changes from baseline in insulin sensitivity, glycemia, hepatic fat, and endothelial function. RESULTS There was a 16.5-fold increase in plasma dimethylglycine [dimethylglycine (DMG); P < 0.0001] levels, but modest 1.3- and 1.5-fold increases in downstream serine and methionine levels, respectively, in the betaine vs placebo arm. Betaine tended to reduce fasting glucose levels (P = 0.08 vs placebo) but had no other effect on glycemia. Insulin area under curve after oral glucose was reduced for betaine treatment compared with placebo (P = 0.038). Insulin sensitivity, assessed by euglycemic hyperinsulinemic clamp, was not improved. Serum total cholesterol levels increased after betaine treatment compared with placebo (P = 0.032). There were no differences in change in intrahepatic triglyceride or endothelial function between groups. CONCLUSION DMG accumulation supports DMG dehydrogenase as rate limiting for betaine metabolism in persons with prediabetes. Betaine had little metabolic effect. Additional studies may elucidate mechanisms contributing to differences between preclinical and human responses to betaine, and whether supplementation of metabolites downstream of DMG improves metabolism.
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Affiliation(s)
- Ana Maria Grizales
- Harvard Medical School, Boston, Massachusetts
- Research Division, Joslin Diabetes Center, Boston, Massachusetts
| | - Mary-Elizabeth Patti
- Harvard Medical School, Boston, Massachusetts
- Research Division, Joslin Diabetes Center, Boston, Massachusetts
| | - Alexander P Lin
- Harvard Medical School, Boston, Massachusetts
- Brigham and Women’s Hospital, Boston, Massachusetts
| | - Joshua A Beckman
- Brigham and Women’s Hospital, Boston, Massachusetts
- Vanderbilt University Medical Center, Nashville, Tennessee
| | - V Anik Sahni
- Harvard Medical School, Boston, Massachusetts
- Brigham and Women’s Hospital, Boston, Massachusetts
| | - Emilie Cloutier
- Research Division, Joslin Diabetes Center, Boston, Massachusetts
| | - Kristen M Fowler
- Research Division, Joslin Diabetes Center, Boston, Massachusetts
| | | | - Hui Pan
- Research Division, Joslin Diabetes Center, Boston, Massachusetts
| | - Chisayo Kozuka
- Harvard Medical School, Boston, Massachusetts
- Research Division, Joslin Diabetes Center, Boston, Massachusetts
| | - Adrienne Lee
- Brigham and Women’s Hospital, Boston, Massachusetts
| | - Rita Basu
- University of Virginia School of Medicine, Charlottesville, Virginia
| | - David M Pober
- Harvard Medical School, Boston, Massachusetts
- Research Division, Joslin Diabetes Center, Boston, Massachusetts
| | - Robert E Gerszten
- Harvard Medical School, Boston, Massachusetts
- Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Allison B Goldfine
- Harvard Medical School, Boston, Massachusetts
- Research Division, Joslin Diabetes Center, Boston, Massachusetts
- Brigham and Women’s Hospital, Boston, Massachusetts
- Correspondence and Reprint Requests: Allison B. Goldfine, MD, One Joslin Place, Boston, Massachussetts 02215. E-mail:
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38
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Heidari R, Niknahad H, Sadeghi A, Mohammadi H, Ghanbarinejad V, Ommati MM, Hosseini A, Azarpira N, Khodaei F, Farshad O, Rashidi E, Siavashpour A, Najibi A, Ahmadi A, Jamshidzadeh A. Betaine treatment protects liver through regulating mitochondrial function and counteracting oxidative stress in acute and chronic animal models of hepatic injury. Biomed Pharmacother 2018; 103:75-86. [DOI: 10.1016/j.biopha.2018.04.010] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 03/29/2018] [Accepted: 04/02/2018] [Indexed: 12/29/2022] Open
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Tiwari-Heckler S, Gan-Schreier H, Stremmel W, Chamulitrat W, Pathil A. Circulating Phospholipid Patterns in NAFLD Patients Associated with a Combination of Metabolic Risk Factors. Nutrients 2018; 10:nu10050649. [PMID: 29883377 PMCID: PMC5986528 DOI: 10.3390/nu10050649] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 05/11/2018] [Accepted: 05/15/2018] [Indexed: 12/13/2022] Open
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is associated with inefficient macro- and micronutrient metabolism, and alteration of circulating phospholipid compositions defines the signature of NAFLD. This current study aimed to assess the pattern of serum phospholipids in the spectrum of NAFLD, and its related comorbidities and genetic modifications. Methods: 97 patients with diagnosed NAFLD were recruited at a single center during 2013–2016. Based on histological and transient elastography assessment, 69 patients were divided into non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver (NAFL) subgroups. 28 patients served as healthy controls. Serum phospholipids were determined by liquid-chromatography mass spectrometry (LC-MS/MS). Results: The total content of phosphatidylcholine (PC) and sphingomyelin in the serum was significantly increased in NAFL and NASH patients, compared to healthy controls. In addition, serum lysophospatidylethanolamine levels were significantly decreased in NAFL and NASH individuals. Circulating PC species, containing linoleic and α-linolenic acids, were markedly increased in NAFLD patients with hypertension, compared to NAFLD patients without hypertension. The pattern of phospholipids did not differ between NAFLD patients with diabetes and those without diabetes. However, NAFLD patients with hyperglycemia (blood glucose level (BGL) >100 mg/dL) exhibited significantly a higher amount of monounsaturated phosphatidylethanolamine than those with low blood glucose levels. In addition, NAFLD patients with proven GG-genotype of PNPLA3, who were at higher risk for the development of progressive disease with fibrosis, showed lower levels of circulating plasmalogens, especially 16:0, compared to those with CC- and CG-allele. Conclusions: Our extended lipidomic study presents a unique metabolic profile of circulating phospholipids associated with the presence of metabolic risk factors or the genetic background of NAFLD patients.
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Affiliation(s)
- Shilpa Tiwari-Heckler
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
| | - Hongying Gan-Schreier
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
| | - Wolfgang Stremmel
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
| | - Walee Chamulitrat
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
| | - Anita Pathil
- Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
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Vesković M, Labudović-Borović M, Zaletel I, Rakočević J, Mladenović D, Jorgačević B, Vučević D, Radosavljević T. The Effects of Betaine on the Nuclear Fractal Dimension, Chromatin Texture, and Proliferative Activity in Hepatocytes in Mouse Model of Nonalcoholic Fatty Liver Disease. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2018; 24:132-138. [PMID: 29350612 DOI: 10.1017/s1431927617012806] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The effects of betaine on hepatocytes chromatin architecture changes were examined by using fractal and gray-level co-occurrence matrix (GLCM) analysis in methionine/choline-deficient (MCD) diet-induced, nonalcoholic fatty liver disease (NAFLD). Male C57BL/6 mice were divided into groups: (1) Control: standard diet; (2) BET: standard diet and betaine supplementation through drinking water (solution 1.5%); (3) MCD group: MCD diet for 6 weeks; (4) MCD+BET: fed with MCD diet + betaine for 6 weeks. Liver tissue was collected for histopathology, immunohistochemistry, and determination of fractal dimension and GLCM parameters. MCD diet induced diffuse micro- and macrovesicular steatosis accompanied with increased Ki67-positive hepatocyte nuclei. Steatosis and Ki67 immunopositivity were less prominent in the MCD+BET group compared with the MCD group. Angular second moment (ASM) and inverse difference moment (IDM) (textural homogeneity markers) were significantly increased in the MCD+BET group versus the MCD group (p<0.001), even though no difference between the MCD and the control group was evident. Heterogeneity parameters, contrast, and correlation were significantly increased in the MCD group versus the control (p<0.001). On the other hand, betaine treatment significantly reduced correlation, contrast, and entropy compared with the MCD group (p<0.001). Betaine attenuated MCD diet-induced NAFLD by reducing fat accumulation and inhibiting hepatocyte proliferation. Betaine supplementation increased nuclear homogeneity and chromatin complexity with reduction of entropy, contrast, and correlation.
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Affiliation(s)
- Milena Vesković
- 1Institute of Pathophysiology,Ljubodrag Buba Mihailović, Faculty of Medicine,University of Belgrade,11000 Belgrade,Serbia
| | - Milica Labudović-Borović
- 2Institute of Histology and Embryology,Aleksandar Đ. Kostić, Faculty of Medicine,University of Belgrade,11000 Belgrade,Serbia
| | - Ivan Zaletel
- 2Institute of Histology and Embryology,Aleksandar Đ. Kostić, Faculty of Medicine,University of Belgrade,11000 Belgrade,Serbia
| | - Jelena Rakočević
- 2Institute of Histology and Embryology,Aleksandar Đ. Kostić, Faculty of Medicine,University of Belgrade,11000 Belgrade,Serbia
| | - Dušan Mladenović
- 1Institute of Pathophysiology,Ljubodrag Buba Mihailović, Faculty of Medicine,University of Belgrade,11000 Belgrade,Serbia
| | - Bojan Jorgačević
- 1Institute of Pathophysiology,Ljubodrag Buba Mihailović, Faculty of Medicine,University of Belgrade,11000 Belgrade,Serbia
| | - Danijela Vučević
- 1Institute of Pathophysiology,Ljubodrag Buba Mihailović, Faculty of Medicine,University of Belgrade,11000 Belgrade,Serbia
| | - Tatjana Radosavljević
- 1Institute of Pathophysiology,Ljubodrag Buba Mihailović, Faculty of Medicine,University of Belgrade,11000 Belgrade,Serbia
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Zhang D, Jing H, Dou C, Zhang L, Wu X, Wu Q, Song H, Li D, Wu F, Liu Y, Li W, Wang R. Supplement of Betaine into Embryo Culture Medium Can Rescue Injury Effect of Ethanol on Mouse Embryo Development. Sci Rep 2018; 8:1761. [PMID: 29379082 PMCID: PMC5789050 DOI: 10.1038/s41598-018-20175-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 01/15/2018] [Indexed: 02/06/2023] Open
Abstract
Mammal embryos can be impaired by mother’s excessive ethanol uptake, which induces a higher level of reactive oxygen species (ROS) and interferes in one carbon unit metabolism. Here, our analysis by in vitro culture system reveals immediate effect of ethanol in medium on mouse embryo development presents concentration dependent. A preimplantation embryo culture using medium contained 1% ethanol could impact greatly early embryos development, and harmful effect of ethanol on preimplantation embryos would last during the whole development period including of reducing ratio of blastocyst formation and implantation, and deteriorating postimplantation development. Supplement of 50 μg/ml betaine into culture medium can effectively reduce the level of ROS caused by ethanol in embryo cells and rescue embryo development at each stage damaged by ethanol, but supplement of glycine can’t rescue embryo development as does betaine. Results of 5-methylcytosine immunodetection indicate that supplement of betaine into medium can reduce the rising global level of genome DNA methylation in blastocyst cells caused by 1% ethanol, but glycine can’t play the same impact. The current findings demonstrate that betaine can effectively rescue development of embryos harmed by ethanol, and possibly by restoring global level of genome DNA methylation in blastocysts.
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Affiliation(s)
- Di Zhang
- School of Biological and Food Engineering, Fuyang Teachers College, Fuyang, 236037, China. .,Key Laboratory of Embryo Development and Reproductive Regulation in Anhui, Fuyang, 236037, China.
| | - Huaijiang Jing
- School of Biological and Food Engineering, Fuyang Teachers College, Fuyang, 236037, China.,Key Laboratory of Embryo Development and Reproductive Regulation in Anhui, Fuyang, 236037, China
| | - Changfeng Dou
- School of Biological and Food Engineering, Fuyang Teachers College, Fuyang, 236037, China.,Key Laboratory of Embryo Development and Reproductive Regulation in Anhui, Fuyang, 236037, China
| | - Ling Zhang
- School of Biological and Food Engineering, Fuyang Teachers College, Fuyang, 236037, China.,Key Laboratory of Embryo Development and Reproductive Regulation in Anhui, Fuyang, 236037, China
| | - Xiaoqing Wu
- School of Biological and Food Engineering, Fuyang Teachers College, Fuyang, 236037, China.,Key Laboratory of Embryo Development and Reproductive Regulation in Anhui, Fuyang, 236037, China
| | - Qingqing Wu
- School of Biological and Food Engineering, Fuyang Teachers College, Fuyang, 236037, China.,Key Laboratory of Embryo Development and Reproductive Regulation in Anhui, Fuyang, 236037, China
| | - Haoyang Song
- School of Biological and Food Engineering, Fuyang Teachers College, Fuyang, 236037, China.,Key Laboratory of Embryo Development and Reproductive Regulation in Anhui, Fuyang, 236037, China
| | - Dengkun Li
- School of Biological and Food Engineering, Fuyang Teachers College, Fuyang, 236037, China.,Key Laboratory of Embryo Development and Reproductive Regulation in Anhui, Fuyang, 236037, China
| | - Fengrui Wu
- School of Biological and Food Engineering, Fuyang Teachers College, Fuyang, 236037, China.,Key Laboratory of Embryo Development and Reproductive Regulation in Anhui, Fuyang, 236037, China
| | - Yong Liu
- School of Biological and Food Engineering, Fuyang Teachers College, Fuyang, 236037, China.,Key Laboratory of Embryo Development and Reproductive Regulation in Anhui, Fuyang, 236037, China
| | - Wenyong Li
- School of Biological and Food Engineering, Fuyang Teachers College, Fuyang, 236037, China.,Key Laboratory of Embryo Development and Reproductive Regulation in Anhui, Fuyang, 236037, China
| | - Rong Wang
- School of Biological and Food Engineering, Fuyang Teachers College, Fuyang, 236037, China. .,Key Laboratory of Embryo Development and Reproductive Regulation in Anhui, Fuyang, 236037, China.
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Luo C, Liang W, Chen X, Wang J, Deng Z, Zhang H. Pharmaceutical cocrystals of naringenin with improved dissolution performance. CrystEngComm 2018. [DOI: 10.1039/c8ce00341f] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Four pharmaceutical cocrystals of naringenin were obtained, which demonstrate improved dissolution performance.
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Affiliation(s)
- Chun Luo
- College of Chemistry and Chemical Engineering
- Wuhan University of Science and Technology
- Wuhan 430081
- P. R. China
- Laboratory of Magnetic Resonance Spectroscopy and Imaging
| | - Wendong Liang
- College of Chemistry and Chemical Engineering
- Wuhan University of Science and Technology
- Wuhan 430081
- P. R. China
| | - Xin Chen
- Laboratory of Magnetic Resonance Spectroscopy and Imaging
- Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences
- Suzhou 215123
- P. R. China
| | - Jianming Wang
- Crystal Pharmatech
- Suzhou Industrial Park
- Suzhou 215123
- P. R. China
| | - Zongwu Deng
- Laboratory of Magnetic Resonance Spectroscopy and Imaging
- Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences
- Suzhou 215123
- P. R. China
| | - Hailu Zhang
- Laboratory of Magnetic Resonance Spectroscopy and Imaging
- Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences
- Suzhou 215123
- P. R. China
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Serine prevented high-fat diet-induced oxidative stress by activating AMPK and epigenetically modulating the expression of glutathione synthesis-related genes. Biochim Biophys Acta Mol Basis Dis 2017; 1864:488-498. [PMID: 29158183 DOI: 10.1016/j.bbadis.2017.11.009] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 10/26/2017] [Accepted: 11/14/2017] [Indexed: 01/06/2023]
Abstract
Serine deficiency has been observed in patients with nonalcoholic fatty liver disease (NAFLD). Whether serine supplementation has any beneficial effects on the prevention of NAFLD remains unknown. The present study was conducted to investigate the effects of serine supplementation on hepatic oxidative stress and steatosis and its related mechanisms. Forty male C57BL/6J mice (9week-old) were randomly assigned into four groups (n=10) and fed: i) a low-fat diet; ii) a low-fat diet supplemented with 1% (wt:vol) serine; iii) a high-fat (HF) diet; and iv) a HF diet supplemented with 1% serine, respectively. Palmitic acid (PA)-treated primary hepatocytes separated from adult mice were also used to study the effects of serine on oxidative stress. The results showed that serine supplementation increased glucose tolerance and insulin sensitivity, and protected mice from hepatic lipid accumulation, but did not significantly decreased HF diet-induced weight gain. In addition, serine supplementation protected glutathione (GSH) antioxidant system and prevented hypermethylation in the promoters of glutathione synthesis-related genes, while decreasing reactive oxygen species (ROS) in mice fed a HF diet. Moreover, we found that serine supplementation increased phosphorylation and S-glutathionylation of AMP-activated protein kinase α subunit (AMPKα), and decreased ROS, malondialdehyde and triglyceride contents in PA-treated primary hepatocytes. However, while AMPK activity or GSH synthesis was inhibited, the abovementioned effects of serine on PA-treated primary hepatocytes were not observed. Our results suggest that serine supplementation could prevent HF diet-induced oxidative stress and steatosis by epigenetically modulating the expression of glutathione synthesis-related genes and through AMPK activation.
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Shirata Y, Wakasa A, Miura K, Nakamura H, Matsumoto Y, Miyada T. Body heat responsive gelation of methylcellulose formulation containing betaine. Biosci Biotechnol Biochem 2017; 81:1829-1836. [PMID: 28715251 DOI: 10.1080/09168451.2017.1347487] [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: 01/27/2023]
Abstract
We examined a methylcellulose (MC) formulation that gels at body temperature for enteral alimentation. Betaine was found to have a lowering effect on the gelation temperature of the MC solution. The thermal gelation temperature of a body heat-responsive (BHR) gelling MC formulation, consisting of 2% MC, 15% glucose, 1.2% sodium citrate, and 3.5% betaine mixture, was approximately 32 °C, indicating that it could gel in response to body heat. Glucose release from the BHR gels was delayed at 37 °C in an in vitro study. In rats, oral administration of BHR gelling MC formulation delayed an increase in blood glucose and appearance of 13CO2 in expired air in a 13C-acetate breath test in comparison with the control. These results suggested that the BHR gelling MC formulation was gelled in the stomach and delayed gastric emptying after oral administration and glucose in the gels was absorbed slowly.
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Affiliation(s)
- Yoshiaki Shirata
- a Division of Clinical Nutrition, Graduate School of Health Science and Technology , Kawasaki University of Medical Welfare , Kurashiki , Japan
| | - Asami Wakasa
- b Division of Health Science, Graduate School of Health Science and Technology , Kawasaki University of Medical Welfare , Kurashiki , Japan
| | - Kiyoshi Miura
- c Department of Clinical Nutrition, Faculty of Health Science and Technology , Kawasaki University of Medical Welfare , Kurashiki , Japan
| | - Hironori Nakamura
- c Department of Clinical Nutrition, Faculty of Health Science and Technology , Kawasaki University of Medical Welfare , Kurashiki , Japan
| | - Yoshinobu Matsumoto
- c Department of Clinical Nutrition, Faculty of Health Science and Technology , Kawasaki University of Medical Welfare , Kurashiki , Japan
| | - Tomihiro Miyada
- c Department of Clinical Nutrition, Faculty of Health Science and Technology , Kawasaki University of Medical Welfare , Kurashiki , Japan
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Du S, Sun S, Liu L, Zhang Q, Guo F, Li C, Feng R, Sun C. Effects of Histidine Supplementation on Global Serum and Urine 1H NMR-based Metabolomics and Serum Amino Acid Profiles in Obese Women from a Randomized Controlled Study. J Proteome Res 2017; 16:2221-2230. [PMID: 28447460 DOI: 10.1021/acs.jproteome.7b00030] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The aim of current study was to investigate the metabolic changes associated with histidine supplementation in serum and urine metabolic signatures and serum amino acid (AA) profiles. Serum and urine 1H NMR-based metabolomics and serum AA profiles were employed in 32 and 37 obese women with metabolic syndrome (MetS) intervened with placebo or histidine for 12 weeks. Multivariable statistical analysis were conducted to define characteristic metabolites. In serum 1H NMR metabolic profiles, increases in histidine, glutamine, aspartate, glycine, choline, and trimethylamine-N-oxide (TMAO) were observed; meanwhile, decreases in cholesterol, triglycerides, fatty acids and unsaturated lipids, acetone, and α/β-glucose were exhibited after histidine supplement. In urine 1H NMR metabolic profiles, citrate, creatinine/creatine, methylguanidine, and betaine + TMAO were higher, while hippurate was lower in histidine supplement group. In serum AA profiles, 10 AAs changed after histidine supplementation, including increased histidine, glycine, alanine, lysine, asparagine, and tyrosine and decreased leucine, isoleucine, ornithine, and citrulline. The study showed a systemic metabolic response in serum and urine metabolomics and AA profiles to histidine supplementation, showing significantly changed metabolism in AAs, lipid, and glucose in obese women with MetS.
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Affiliation(s)
- Shanshan Du
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University , 157 Baojian Road, Nangang District, Harbin 150086, Heilongjiang Province, China
| | - Shuhong Sun
- Department of Psychiatry, The First Affiliated Hospital of Harbin Medical University , 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China
| | - Liyan Liu
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University , 157 Baojian Road, Nangang District, Harbin 150086, Heilongjiang Province, China
| | - Qiao Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University , 157 Baojian Road, Nangang District, Harbin 150086, Heilongjiang Province, China
| | - Fuchuan Guo
- Department of Nutrition and Food Safety, School of Public Health, Fujian Medical University , No. 1 Xuefu North Road, University Town, Fuzhou 350122, Fujian Province, China
| | - Chunlong Li
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University , 246 Xuefu Road, Nangang District, Harbin 150086, Heilongjiang Province, China
| | - Rennan Feng
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University , 157 Baojian Road, Nangang District, Harbin 150086, Heilongjiang Province, China
| | - Changhao Sun
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University , 157 Baojian Road, Nangang District, Harbin 150086, Heilongjiang Province, China
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Mardinoglu A, Bjornson E, Zhang C, Klevstig M, Söderlund S, Ståhlman M, Adiels M, Hakkarainen A, Lundbom N, Kilicarslan M, Hallström BM, Lundbom J, Vergès B, Barrett PHR, Watts GF, Serlie MJ, Nielsen J, Uhlén M, Smith U, Marschall HU, Taskinen MR, Boren J. Personal model-assisted identification of NAD + and glutathione metabolism as intervention target in NAFLD. Mol Syst Biol 2017; 13:916. [PMID: 28254760 PMCID: PMC5371732 DOI: 10.15252/msb.20167422] [Citation(s) in RCA: 139] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
To elucidate the molecular mechanisms underlying non‐alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome‐scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD+ and glutathione (GSH) in subjects with high HS. Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD+ repletion on the development of NAFLD, we added precursors for GSH and NAD+ biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof‐of‐concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.
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Affiliation(s)
- Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden .,Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
| | - Elias Bjornson
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.,Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Cheng Zhang
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Martina Klevstig
- Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Sanni Söderlund
- Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Marcus Ståhlman
- Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Martin Adiels
- Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Antti Hakkarainen
- Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - Nina Lundbom
- Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - Murat Kilicarslan
- Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Björn M Hallström
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Jesper Lundbom
- Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - Bruno Vergès
- Department of Endocrinology-Diabetology, University Hospital and INSERM CRI 866, Dijon, France
| | - Peter Hugh R Barrett
- Faculty of Engineering, Computing and Mathematics, University of Western Australia, Perth, WA, Australia
| | - Gerald F Watts
- Metabolic Research Centre, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia
| | - Mireille J Serlie
- Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Jens Nielsen
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.,Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
| | - Mathias Uhlén
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Ulf Smith
- Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Marja-Riitta Taskinen
- Research programs Unit, Diabetes and Obesity, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Jan Boren
- Department of Molecular and Clinical Medicine, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden
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Godos J, Federico A, Dallio M, Scazzina F. Mediterranean diet and nonalcoholic fatty liver disease: molecular mechanisms of protection. Int J Food Sci Nutr 2016; 68:18-27. [PMID: 27484357 DOI: 10.1080/09637486.2016.1214239] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Nutritional habits modifications have shown an important impact in preventing and ameliorating metabolic alterations, such as nonalcoholic fatty liver disease (NAFLD). Among several dietary approaches that exert positive effects in NAFLD patients, the Mediterranean dietary pattern has shown notable benefits. This review explores the molecular mechanisms through which the Mediterranean diet would improve risk factors associated with metabolic syndrome and NAFLD. The main features of the Mediterranean diet acting on metabolism are represented by its whole-grain and low glycemic index cereal-based items, its fatty acid profile, and its content in phytochemical compounds. Carbohydrate-rich foods high in dietary fiber inducing low glycemic response are able to interact with glucose and insulin metabolism. Unsaturated fatty acids are associated with better hepatic lipid metabolism. Finally, phytochemical compounds, such as dietary polyphenols, are thought to ameliorate inflammation, which is considered one of the mechanisms through which NALFD may evolve into nonalcoholic steatohepatitis (NASH).
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Affiliation(s)
- Justyna Godos
- a Integrated Cancer Registry of Catania-Messina-Siracusa-Enna , Azienda Universitario Ospedaliera Policlinico "Vittorio Emanuale" , Catania , Italy
| | - Alessandro Federico
- b Hepato-Gastroenterology Division , Second University of Naples , Napoli , Italy
| | - Marcello Dallio
- b Hepato-Gastroenterology Division , Second University of Naples , Napoli , Italy
| | - Francesca Scazzina
- c Human Nutrition Unit, Department of Food Science , University of Parma , Parma, Italy
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48
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Alleviation of hepatic fat accumulation by betaine involves reduction of homocysteine via up-regulation of betaine-homocysteine methyltransferase (BHMT). Biochem Biophys Res Commun 2016; 477:440-7. [DOI: 10.1016/j.bbrc.2016.06.080] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2016] [Accepted: 06/15/2016] [Indexed: 01/08/2023]
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Houben T, Brandsma E, Walenbergh SMA, Hofker MH, Shiri-Sverdlov R. Oxidized LDL at the crossroads of immunity in non-alcoholic steatohepatitis. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1862:416-429. [PMID: 27472963 DOI: 10.1016/j.bbalip.2016.07.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 07/01/2016] [Accepted: 07/21/2016] [Indexed: 02/08/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is viewed as the hepatic manifestation of the metabolic syndrome and is a condition hallmarked by lipid accumulation in the liver (steatosis) along with inflammation (hepatitis). Currently, the etiology and mechanisms leading to obesity-induced hepatic inflammation are not clear and, as a consequence, strategies to diagnose or treat NASH in an accurate manner do not exist. In the current review, we put forward the concept of oxidized lipids as a significant risk factor for NASH. We will focus on the contribution of the different types of oxidized lipids as part of the oxidized low-density lipoprotein (oxLDL) to the hepatic inflammatory response. Furthermore, we will elaborate on the underlying mechanisms linking oxLDL to inflammatory responses in the liver and on how these cascades can be used as therapeutic targets to combat NASH. This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder.
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Affiliation(s)
- T Houben
- Department of Molecular Genetics, Maastricht University, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht, the Netherlands
| | - E Brandsma
- Molecular Genetics Section, Department of Pediatrics, University Medical Center Groningen, University of Groningen, the Netherlands
| | - S M A Walenbergh
- Department of Molecular Genetics, Maastricht University, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht, the Netherlands
| | - M H Hofker
- Molecular Genetics Section, Department of Pediatrics, University Medical Center Groningen, University of Groningen, the Netherlands
| | - R Shiri-Sverdlov
- Department of Molecular Genetics, Maastricht University, School for Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht, the Netherlands.
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50
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Pravastatin-Induced Hepatotoxicity in a Patient With Fatty Liver Disease: A Case Presentation With Literature Review. J Pharm Pract 2016. [DOI: 10.1177/0897190007303052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Purpose. To report a case of biopsy-confirmed pravastatin-induced liver injury in a patient with nonalcoholic fatty liver disease (NAFLD). Second, to review the data regarding hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) use in patients with NAFLD and monitoring that may be required for statin therapy. Literature Search. A PubMed search and review of the reference lists of the articles included in the case report was performed to find human studies from 1965 to the present on statin therapy in patients with NAFLD. To the authors' knowledge, there are no other case reports that parallel the one presented here. Case Report. A 71-year-old female with NAFLD, challenged multiple times on different lipid lowering agents, with a history of elevated liver enzymes post statin therapy, developed drug-induced hepatocellular damage following pravastatin therapy. Discussion. Symptomatic liver injury with statin therapy is rare even in patients with NAFLD. To the authors' knowledge, there are no case reports demonstrating statin-induced hepatocellular damage in a patient with NAFLD. Conclusion. Contrary to numerous pilot studies indicating the benefit and safety of statin therapy in patients with NAFLD, the authors report a patient case with underlying NAFLD that developed drug-induced liver injury post statin therapy. This case highlights the importance of identifying when symptoms associated with liver injury are occurring in patients with comorbid NAFLD, instead of solely relying on routine monitoring of transaminase levels. Health care providers need to closely examine and question NAFLD patients who develop liver enzyme elevations while on statin therapy to determine if they are showing signs of significant liver dysfunction and obtain more detailed laboratory assessments such as indirect bilirubin and prothrombin time. If hepatotoxicity occurs, the statin should be stopped immediately and treated with an alternative lipid-lowering agent per the National Lipid Association Statin Safety Assessment Task Force recommendations.
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