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Saeki T, Yamamoto S, Akaki J, Tanaka T, Nakasone M, Ikeda H, Wang W, Inoue M, Manse Y, Ninomiya K, Morikawa T. Ameliorative effect of bofutsushosan (Fangfengtongshengsan) extract on the progression of aging-induced obesity. J Nat Med 2024; 78:576-589. [PMID: 38662301 PMCID: PMC11937147 DOI: 10.1007/s11418-024-01803-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 03/06/2024] [Indexed: 04/26/2024]
Abstract
This study aimed to compare fat accumulation in young and aged mice raised on a high-fat diet and to characterize the obesity-reducing effects of a Kampo medicine, bofutsushosan (BTS; fangfengtongshengsan in Chinese). Aged mice fed a high-fat diet containing 2% BTS extract for 28 days exhibited a significant reduction in weight gain and accumulation of visceral and subcutaneous fat, which were greater degree of reduction than those of the young mice. When the treatment period was extended to two months, the serum aspartate aminotransferase and alanine aminotransferase levels and the accumulation of fat droplets in the hepatocytes decreased. The mRNA expression of mitochondrial uncoupling protein 1 (UCP1) in the brown adipose tissue was significantly reduced in the aged mice compared to the young mice but increased by 2% in the BTS-treated aged mice. Additionally, the effect of BTS extract on oleic acid-albumin-induced triglyceride accumulation in hepatoblastoma-derived HepG2 cells was significantly inhibited in a concentration-dependent manner. Evaluation of the single crude drug extracts revealed that Forsythia Fruit, Schizonepeta Spike, and Rhubarb were the active components in BTS extract. These results suggest that BTS extract is effective against visceral, subcutaneous, and ectopic fats in the liver, which tend to accumulate with aging. Thus, BTS extract is useful in preventing and ameliorating the development of obesity and metabolic syndrome.
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Affiliation(s)
- Takafumi Saeki
- Central R&D Laboratory, Kobayashi Pharmaceutical Co., Ltd, 1-30-3 Toyokawa, Ibaraki, Osaka, 567-0057, Japan.
| | - Saya Yamamoto
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka, 577-8502, Japan
| | - Junji Akaki
- Central R&D Laboratory, Kobayashi Pharmaceutical Co., Ltd, 1-30-3 Toyokawa, Ibaraki, Osaka, 567-0057, Japan
| | - Takahiro Tanaka
- Central R&D Laboratory, Kobayashi Pharmaceutical Co., Ltd, 1-30-3 Toyokawa, Ibaraki, Osaka, 567-0057, Japan
| | - Misaki Nakasone
- Central R&D Laboratory, Kobayashi Pharmaceutical Co., Ltd, 1-30-3 Toyokawa, Ibaraki, Osaka, 567-0057, Japan
| | - Hidemasa Ikeda
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka, 577-8502, Japan
| | - Wei Wang
- Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan
| | - Makoto Inoue
- Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan
| | - Yoshiaki Manse
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka, 577-8502, Japan
| | - Kiyofumi Ninomiya
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka, 577-8502, Japan
- School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama, 703-8516, Japan
| | - Toshio Morikawa
- Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka, 577-8502, Japan.
- Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka, 577-8502, Japan.
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Nishiyama M, Ishizawa S, Nishi A, Taketomi A, Kono T. Bofutsushosan (Fangfengtongshengsan) improves early stages of NASH via the gut–liver axis in diabetes-induced NASH model mice. PHARMACOLOGICAL RESEARCH - MODERN CHINESE MEDICINE 2024; 11:100440. [DOI: 10.1016/j.prmcm.2024.100440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Jian H, Liu Y, Wang X, Dong X, Zou X. Akkermansia muciniphila as a Next-Generation Probiotic in Modulating Human Metabolic Homeostasis and Disease Progression: A Role Mediated by Gut-Liver-Brain Axes? Int J Mol Sci 2023; 24:ijms24043900. [PMID: 36835309 PMCID: PMC9959343 DOI: 10.3390/ijms24043900] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/09/2023] [Accepted: 02/12/2023] [Indexed: 02/17/2023] Open
Abstract
Appreciation of the importance of Akkermansia muciniphila is growing, and it is becoming increasingly relevant to identify preventive and/or therapeutic solutions targeting gut-liver-brain axes for multiple diseases via Akkermansia muciniphila. In recent years, Akkermansia muciniphila and its components such as outer membrane proteins and extracellular vesicles have been known to ameliorate host metabolic health and intestinal homeostasis. However, the impacts of Akkermansia muciniphila on host health and disease are complex, as both potentially beneficial and adverse effects are mediated by Akkermansia muciniphila and its derivatives, and in some cases, these effects are dependent upon the host physiology microenvironment and the forms, genotypes, and strain sources of Akkermansia muciniphila. Therefore, this review aims to summarize the current knowledge of how Akkermansia muciniphila interacts with the host and influences host metabolic homeostasis and disease progression. Details of Akkermansia muciniphila will be discussed including its biological and genetic characteristics; biological functions including anti-obesity, anti-diabetes, anti-metabolic-syndrome, anti-inflammation, anti-aging, anti-neurodegenerative disease, and anti-cancer therapy functions; and strategies to elevate its abundance. Key events will be referred to in some specific disease states, and this knowledge should facilitate the identification of Akkermansia muciniphila-based probiotic therapy targeting multiple diseases via gut-liver-brain axes.
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Fujisaka S, Usui I, Nawaz A, Igarashi Y, Okabe K, Furusawa Y, Watanabe S, Yamamoto S, Sasahara M, Watanabe Y, Nagai Y, Yagi K, Nakagawa T, Tobe K. Bofutsushosan improves gut barrier function with a bloom of Akkermansia muciniphila and improves glucose metabolism in mice with diet-induced obesity. Sci Rep 2020; 10:5544. [PMID: 32218475 PMCID: PMC7099031 DOI: 10.1038/s41598-020-62506-w] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 03/10/2020] [Indexed: 12/25/2022] Open
Abstract
Obesity and insulin resistance are associated with dysbiosis of the gut microbiota and impaired intestinal barrier function. Herein, we report that Bofutsushosan (BFT), a Japanese herbal medicine, Kampo, which has been clinically used for constipation in Asian countries, ameliorates glucose metabolism in mice with diet-induced obesity. A 16S rRNA sequence analysis of fecal samples showed that BFT dramatically increased the relative abundance of Verrucomicrobia, which was mainly associated with a bloom of Akkermansia muciniphila (AKK). BFT decreased the gut permeability as assessed by FITC-dextran gavage assay, associated with increased expression of tight-junction related protein, claudin-1, in the colon. The BFT treatment group also showed significant decreases of the plasma endotoxin level and expression of the hepatic lipopolysaccharide-binding protein. Antibiotic treatment abrogated the metabolic effects of BFT. Moreover, many of these changes could be reproduced when the cecal contents of BFT-treated donors were transferred to antibiotic-pretreated high fat diet-fed mice. These data demonstrate that BFT modifies the gut microbiota with an increase in AKK, which may contribute to improving gut barrier function and preventing metabolic endotoxemia, leading to attenuation of diet-induced inflammation and glucose intolerance. Understanding the interaction between a medicine and the gut microbiota may provide insights into new pharmacological targets to improve glucose metabolism.
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Affiliation(s)
- Shiho Fujisaka
- First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.
| | - Isao Usui
- First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
- Department of Endocrinology and Metabolism, Dokkyo Medical University, Tochigi, Japan
| | - Allah Nawaz
- First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
- Department of Metabolism and Nutrition, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan
| | - Yoshiko Igarashi
- First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Keisuke Okabe
- First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
- Department of community Medical Support, Toyama University Hospital, Toyama, Japan
| | - Yukihiro Furusawa
- Department of Liberal Arts and Sciences, Faculty of Engineering, Toyama Prefectural University, Toyama, Japan
| | - Shiro Watanabe
- Division of Nutritional Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama, Japan
| | - Seiji Yamamoto
- Department of Pathology, University of Toyama, Toyama, Japan
| | | | - Yoshiyuki Watanabe
- First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Yoshinori Nagai
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, Toyama, Japan
| | - Kunimasa Yagi
- First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Takashi Nakagawa
- Department of Metabolism and Nutrition, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan
| | - Kazuyuki Tobe
- First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.
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Increase of Akkermansia muciniphila by a Diet Containing Japanese Traditional Medicine Bofutsushosan in a Mouse Model of Non-Alcoholic Fatty Liver Disease. Nutrients 2020; 12:nu12030839. [PMID: 32245128 PMCID: PMC7146306 DOI: 10.3390/nu12030839] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 03/14/2020] [Accepted: 03/16/2020] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered a worldwide healthcare problem that mirrors the increased prevalence of obesity. Gut microbiota plays a crucial role in the progression and treatment of NAFLD. Bofutsushosan (BTS), a pharmaceutical-grade Japanese traditional medicine, has long been prescribed in Japan for obesity and obesity-related syndrome. Although BTS has been reported to exert an anti-obesity effect in obese patients as well as various obesity-model animals, its effect on gut microbiota is unknown. Here, the effects of BTS on obesity, liver damage, and the gut microbiome in genetically obese mice, ob/ob, were studied. Seven-week-old ob/ob mice were fed a standard diet with (BTS group) or without (CONT group) 5% BTS for 4 weeks. By comparison to the CONT group, the BTS group showed reduced body weight gain and hyperlipidemia as well as improved liver function. Moreover, gut microbiota in the CONT and BTS group formed a significantly different cluster. Specifically, the genera Akkermansia, Bacteroides and an unknown genus of the family Enterobacteriaceae expanded dramatically in the BTS group. Noteworthy, the population of Akkermansia muciniphila, which is reported to elicit an anti-obesity effect and improve various metabolic abnormalities, was markedly increased (93-fold) compared with the CONT group. These results imply that BTS may be a promising agent for treating NAFLD.
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Yan T, Yan N, Wang P, Xia Y, Hao H, Wang G, Gonzalez FJ. Herbal drug discovery for the treatment of nonalcoholic fatty liver disease. Acta Pharm Sin B 2020; 10:3-18. [PMID: 31993304 PMCID: PMC6977016 DOI: 10.1016/j.apsb.2019.11.017] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 09/23/2019] [Accepted: 10/31/2019] [Indexed: 12/11/2022] Open
Abstract
Few medications are available for meeting the increasing disease burden of nonalcoholic fatty liver disease (NAFLD) and its progressive stage, nonalcoholic steatohepatitis (NASH). Traditional herbal medicines (THM) have been used for centuries to treat indigenous people with various symptoms but without clarified modern-defined disease types and mechanisms. In modern times, NAFLD was defined as a common chronic disease leading to more studies to understand NAFLD/NASH pathology and progression. THM have garnered increased attention for providing therapeutic candidates for treating NAFLD. In this review, a new model called “multiple organs-multiple hits” is proposed to explain mechanisms of NASH progression. Against this proposed model, the effects and mechanisms of the frequently-studied THM-yielded single anti-NAFLD drug candidates and multiple herb medicines are reviewed, among which silymarin and berberine are already under U.S. FDA-sanctioned phase 4 clinical studies. Furthermore, experimental designs for anti-NAFLD drug discovery from THM in treating NAFLD are discussed. The opportunities and challenges of reverse pharmacology and reverse pharmacokinetic concepts-guided strategies for THM modernization and its global recognition to treat NAFLD are highlighted. Increasing mechanistic evidence is being generated to support the beneficial role of THM in treating NAFLD and anti-NAFLD drug discovery.
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Affiliation(s)
- Tingting Yan
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Corresponding authors.
| | - Nana Yan
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
| | - Ping Wang
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yangliu Xia
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- School of Life Science and Medicine, Dalian University of Technology, Panjin 124221, China
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
| | - Guangji Wang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
| | - Frank J. Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Corresponding authors.
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Doulberis M, Papaefthymiou A, Polyzos SA, Katsinelos P, Grigoriadis N, Srivastava DS, Kountouras J. Rodent models of obesity. MINERVA ENDOCRINOL 2019; 45:243-263. [PMID: 31738033 DOI: 10.23736/s0391-1977.19.03058-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Obese or overweight people exceed one-third of the global population and obesity along with diabetes mellitus consist basic components of metabolic syndrome, both of which are known cardio-cerebrovascular risk factors with detrimental consequences. These data signify the pandemic character of obesity and the necessity for effective treatments. Substantial advances have been accomplished in preclinical research of obesity by using animal models, which mimic the human disease. In particular, rodent models have been widely used for many decades with success for the elucidation of the pathophysiology of obesity, since they share physiological and genetic components with humans and appear advantageous in their husbandry. The most representative rodents include the laboratory mouse and rat. Within this review, we attempted to consolidate the most widely used mice and rat models of obesity and highlight their strengths as well as weaknesses in a critical way. Our aim was to bridge the gap between laboratory facilities and patient's bed and help the researcher find the appropriate animal model for his/her obesity research. This tactful selection of the appropriate model of obesity may offer more translational derived results. In this regard, we included, the main diet induced models, the chemical/mechanical ones, as well as a selection of monogenic or polygenic models.
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Affiliation(s)
- Michael Doulberis
- Department of Gastroenterology and Hepatology, University of Zurich, Zurich, Switzerland - .,Department of Internal Medicine, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece -
| | | | | | - Panagiotis Katsinelos
- Department of Internal Medicine, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikolaos Grigoriadis
- First Department of Pharmacology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - David S Srivastava
- Second Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Jannis Kountouras
- Department of Internal Medicine, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Nitezki T, Kleuser B, Krämer S. Fatal gastric distension in a gold thioglucose mouse model of obesity. Lab Anim 2018; 53:89-94. [PMID: 30290722 DOI: 10.1177/0023677218803384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
This case report addresses the problem of underreporting negative results and adverse side effects in animal testing. We present our findings regarding a hyperphagic mouse model associated with unforeseen high mortality. The results outline the necessity of reporting detailed information in the literature to avoid duplication. Obese mouse models are essential in the study of obesity, metabolic syndrome and diabetes mellitus. An experimental model of obesity can be induced by the administration of gold thioglucose (GTG). After transcending the blood-brain barrier, the GTG molecule interacts with regions of the ventromedial hypothalamus, thereby primarily targeting glucose-sensitive neurons. When these neurons are impaired, mice become insensitive to the satiety effects of glucose and develop hyperphagia. In a pilot study for optimising dosage and body weight development, C57BL/6 mice were treated with GTG (0.5 mg/g body weight) or saline, respectively. Animals were provided a physiological amount of standard diet (5 g per animal) for the first 24 hours after treatment to prevent gastric dilatation. Within 24 hours after GTG injection, all GTG-treated animals died of gastric overload and subsequent circulatory shock. Animals developed severe attacks of hyperphagia, and as the amount of provided chow was restricted, mice exhibited unforeseen pica and ingested bedding material. These observations strongly suggest that restricted feeding is contraindicated concerning GTG application. Presumably, the impulse of excessive food intake was a strong driving force. Therefore, the actual degree of suffering in the GTG-induced model of hyperphagia should be revised from moderate to severe.
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Affiliation(s)
- Tina Nitezki
- 1 Department of Physiology and Pathophysiology, Institute of Nutritional Science, University of Potsdam, Germany
| | - Burkhard Kleuser
- 2 Department of Toxicology, Institute of Nutritional Science, University of Potsdam, Germany
| | - Stephanie Krämer
- 3 German Institute of Human Nutrition, Germany.,4 Department of Laboratory Animal Science and Animal Welfare, Justus-Liebig University Giessen, Germany
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Kuo YT, Lin CC, Kuo HT, Hung JH, Liu CH, Jassey A, Yen MH, Wu SJ, Lin LT. Identification of baicalin from Bofutsushosan and Daisaikoto as a potent inducer of glucose uptake and modulator of insulin signaling-associated pathways. J Food Drug Anal 2018; 27:240-248. [PMID: 30648577 PMCID: PMC9298638 DOI: 10.1016/j.jfda.2018.07.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 06/20/2018] [Accepted: 07/19/2018] [Indexed: 01/31/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by hyperglycemia that can lead to long-term complications including heart diseases, stroke, retinopathy, and renal failure. Treatment strategies include stimulating glucose uptake and controlling blood glucose level. Bofutsushosan (BOF) and Daisaikoto (DAI) are two herb-based kampo medicines that have been demonstrated to improve metabolism-associated disorders including obesity, hyperlipidemia, and nonalcoholic fatty liver. Given their bioactivities against metabolic syndromes, we explored in this study the effect of BOF and DAI extracts on glucose absorption and used them as source to identify phytochemical stimulator of glucose absorption. Glucose uptake and mechanistic studies were evaluated in differentiated C2C12 skeletal muscle cells, and HPLC analysis was used to determine the molecular bioactive constituents. Our results indicated that the ethanolic extracts of BOF and DAI (BOFEE and DAIEE, respectively) enhanced the glucose uptake ratio in the differentiated C2C12 cells, and further analysis identified the flavone baicalin as a major constituent capable of efficiently stimulating glucose absorption. Mechanistic studies revealed that the effect from baicalin involved the activation of IRS-1 and GLUT-4, and implicated the AMPK, PI3K/Akt, and MAPK/ERK signaling cascades. Due to its potency, we suggest that baicalin merit further evaluation as a potential candidate anti-hyperglycemic agent for the treatment and management of T2DM.
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Affiliation(s)
- Yu-Ting Kuo
- Department of Medical Imaging, Chi Mei Medical Center, No. 901 Zhonghua Road, Yongkang District, Tainan, 710, Taiwan
| | - Chih-Chan Lin
- Department of Medical Research, Chi Mei Medical Center, No. 901 Zhonghua Road, Yongkang District, Tainan, 710, Taiwan
| | - Hsiao-Tzu Kuo
- Department of Nutritional Health, Chia-Nan University of Pharmacy and Science, 60 Erh-Jen 1st Road, Jen-Te Hsiang, Tainan, 717, Taiwan
| | - Jui-Hsiang Hung
- Department of Biotechnology, Chia-Nan University of Pharmacy and Science, 60 Erh-Jen 1st Road, Jen-Te Hsiang, Tainan, 717, Taiwan
| | - Ching-Hsuan Liu
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei, 11031, Taiwan; Department of Microbiology & Immunology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 4R2, Canada
| | - Alagie Jassey
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei, 11031, Taiwan
| | - Ming-Hong Yen
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, No. 100 Shih-Chuan 1st Road, Kaohsiung, 807, Taiwan
| | - Shu-Jing Wu
- Department of Nutritional Health, Chia-Nan University of Pharmacy and Science, 60 Erh-Jen 1st Road, Jen-Te Hsiang, Tainan, 717, Taiwan.
| | - Liang-Tzung Lin
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei, 11031, Taiwan; Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei, 11031, Taiwan.
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Chen YY, Yan Y, Zhao Z, Shi MJ, Zhang YB. Bofutsushosan ameliorates obesity in mice through modulating PGC-1α expression in brown adipose tissues and inhibiting inflammation in white adipose tissues. Chin J Nat Med 2017; 14:449-56. [PMID: 27473963 DOI: 10.1016/s1875-5364(16)30042-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Indexed: 02/07/2023]
Abstract
The inducible co-activator PGC-1α plays a crucial role in adaptive thermogenesis and increases energy expenditure in brown adipose tissue (BAT). Meanwhile, chronic inflammation caused by infiltrated-macrophage in the white adipose tissue (WAT) is a target for the treatment of obesity. Bofutsushosan (BF), a traditional Chinese medicine composed of 17 crude drugs, has been widely used to treat obesity in China, Japan, and other Asia countries. However, the mechanism underlying anti-obesity remains to be elucidated. In the present study, we demonstrated that BF oral administration reduced the body weight of obese mice induced by high-fat diet (HFD) and alleviated the level of biochemical markers (P < 0.05), including blood glucose (Glu), total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C) and insulin. Our further results also indicated that oral BF administration increased the expression of PGC-1α and UCP1 in BAT. Moreover, BF also reduced the expression of inflammatory cytokines in WAT, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). These findings suggested that the mechanism of BF against obesity was at least partially through increasing gene expression of PGC-1α and UCP1 for energy consumption in BAT and inhibiting inflammation in WAT.
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Affiliation(s)
- Ying-Ying Chen
- State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing 210009, China; Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yan Yan
- State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing 210009, China
| | - Zheng Zhao
- Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing 210009, China
| | - Mei-Jing Shi
- State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing 210009, China
| | - Yu-Bin Zhang
- State Key Laboratory of Natural Medicines, Department of Biochemistry, China Pharmaceutical University, Nanjing 210009, China.
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Miyazaki K, Satoh H, Watanabe H, Shiozawa T, Tamura T, Kawaguchi M, Hizawa N. A case study of bofutsushosan-induced pulmonary injury in a patient: Case report. Biomed Rep 2016; 5:758-760. [DOI: 10.3892/br.2016.787] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 09/22/2016] [Indexed: 11/06/2022] Open
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Tan HY, San-Marina S, Wang N, Hong M, Li S, Li L, Cheung F, Wen XY, Feng Y. Preclinical Models for Investigation of Herbal Medicines in Liver Diseases: Update and Perspective. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2016; 2016:4750163. [PMID: 26941826 PMCID: PMC4749812 DOI: 10.1155/2016/4750163] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 12/23/2015] [Accepted: 12/30/2015] [Indexed: 02/07/2023]
Abstract
Liver disease results from a dynamic pathological process associated with cellular and genetic alterations, which may progress stepwise to liver dysfunction. Commonly, liver disease begins with hepatocyte injury, followed by persistent episodes of cellular regeneration, inflammation, and hepatocyte death that may ultimately lead to nonreversible liver failure. For centuries, herbal remedies have been used for a variety of liver diseases and recent studies have identified the active compounds that may interact with liver disease-associated targets. Further study on the herbal remedies may lead to the formulation of next generation medicines with hepatoprotective, antifibrotic, and anticancer properties. Still, the pharmacological actions of vast majority of herbal remedies remain unknown; thus, extensive preclinical studies are important. In this review, we summarize progress made over the last five years of the most commonly used preclinical models of liver diseases that are used to screen for curative herbal medicines for nonalcoholic fatty liver disease, liver fibrosis/cirrhosis, and liver. We also summarize the proposed mechanisms associated with the observed liver-protective, antifibrotic, and anticancer actions of several promising herbal medicines and discuss the challenges faced in this research field.
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Affiliation(s)
- Hor-Yue Tan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Serban San-Marina
- Zebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital and Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Ming Hong
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Sha Li
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Lei Li
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Fan Cheung
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Xiao-Yan Wen
- Zebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital and Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
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Azushima K, Tamura K, Haku S, Wakui H, Kanaoka T, Ohsawa M, Uneda K, Kobayashi R, Ohki K, Dejima T, Maeda A, Hashimoto T, Oshikawa J, Kobayashi Y, Nomura K, Azushima C, Takeshita Y, Fujino R, Uchida K, Shibuya K, Ando D, Tokita Y, Fujikawa T, Toya Y, Umemura S. Effects of the oriental herbal medicine Bofu-tsusho-san in obesity hypertension: A multicenter, randomized, parallel-group controlled trial (ATH-D-14-01021.R2). Atherosclerosis 2015; 240:297-304. [DOI: 10.1016/j.atherosclerosis.2015.01.025] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 01/10/2015] [Accepted: 01/16/2015] [Indexed: 12/20/2022]
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Takahashi Y, Sugimoto K, Inui H, Fukusato T. Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2015; 21:3777-3785. [PMID: 25852263 PMCID: PMC4385525 DOI: 10.3748/wjg.v21.i13.3777] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 01/08/2015] [Accepted: 02/05/2015] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing worldwide. It is currently the most common chronic liver disease. NASH can progress to liver cirrhosis and hepatocellular carcinoma, and may result in liver-related death. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles. The pathogenesis of NAFLD/NASH has not been completely elucidated. However, insulin resistance, inflammatory cytokines, and oxidative stress are thought to be important in the development and/or progression of the disease. Currently, insulin sensitizers (thiazolidinediones) and antioxidants (vitamin E) seem to be the most promising therapeutic agents for NAFLD/NASH, and lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, and n-3 polyunsaturated fatty acids also have promise. However, there is a lack of consensus regarding the most effective and appropriate pharmacotherapy for NAFLD/NASH. Animal experiments suggest that herbal medicines and natural products may be promising therapeutic agents for NAFLD/NASH, but their efficacy and safety are yet to be investigated in human studies. In this paper, we review the existing and potential pharmacological therapies for NAFLD/NASH.
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Qian W, Hasegawa J, Tsuno S, Endo Y, Matsuda A, Miura N. Effects of kampo formulas on the progression of hypercholesterolemia and Fatty liver induced by high-cholesterol diet in rats. Yonago Acta Med 2014; 57:147-158. [PMID: 25901102 PMCID: PMC4404525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 11/10/2014] [Indexed: 06/04/2023]
Abstract
BACKGROUND Bofutsushosan is a well known Kampo, traditional Japanese medicine, based on ancient Chinese medicine mainly used in the treatment of hypercholesterolemia in Japan. We selected two Kampo formulas, Boiogito and Keishibukuryogan mainly used in the treatment of hypercholesterolemia in China to compare with Bofutsushosan and cholesterol absorption inhibitor ezetimibe. METHODS Hypercholesterolemia and fatty liver were induced by high cholesterol (containing 2% cholesterol and 0.5% cholic acid) diet in male Wistar rats for 6 and 12 weeks. Kampo formulas Boiogito, Bofutsushosan, Keishibukuryogan and ezetimibe were added to the high-cholesterol diet, respectively. After 6 and 12 weeks, body and liver weights, blood chemistry, cholesterol concentrations, fat-related and inflammatory-related factors were examined. RESULTS High-cholesterol diet increased body and liver weights, and serum cholesterol concentrations. Boiogito and ezetimibe improved them. Serum ICAM-1 and RBP4 were increased in the high cholesterol diet group. Boiogito and ezetimibe improved them too. In the histological examinations of liver and adipose tissues, we observed a significant improvement after treatment. Immunostaining expression of ICAM-1 in aorta was improved by Boiogito, Bofutsushosan, Keishibukuryogan and ezetimibe. The mRNA expression of RBP4, HFABP, CFABP, MCP1 and CCR2 in liver and adipose tissue were decreased by Boiogito and ezetimibe. CONCLUSION Boiogito has a protective effect on the progression of hypercholesterolemia and fatty liver induced by high-cholesterol diet in rats and more effective than Bofutsushosan and Keishibukuryogan. The lipid-lowering effect of Boiogito is not stronger than ezetimibe. But the anti-inflammatory (MCP1, CCR2) and anti-arteriosclerotic (ICAM-1) effects of Boiogito are more potent than ezetimibe.
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Affiliation(s)
- Weibin Qian
- Division of Pharmacotherapeutics, Department of Pathophysiological and Therapeutic Science, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan
| | - Junichi Hasegawa
- Division of Pharmacotherapeutics, Department of Pathophysiological and Therapeutic Science, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan
| | - Satoshi Tsuno
- Division of Pharmacotherapeutics, Department of Pathophysiological and Therapeutic Science, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan
| | - Yusuke Endo
- Division of Pharmacotherapeutics, Department of Pathophysiological and Therapeutic Science, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan
| | - Akiko Matsuda
- †Department of Fundamental Nursing, School of Health Science, Tottori University Faculty of Medicine, Yonago 683-8503, Japan
| | - Norimasa Miura
- Division of Pharmacotherapeutics, Department of Pathophysiological and Therapeutic Science, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan
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Nonalcoholic Fatty liver disease: pathogenesis and therapeutics from a mitochondria-centric perspective. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:637027. [PMID: 25371775 PMCID: PMC4211163 DOI: 10.1155/2014/637027] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 07/31/2014] [Accepted: 07/31/2014] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of disorders characterized by the accumulation of triglycerides within the liver. The global prevalence of NAFLD has been increasing as the obesity epidemic shows no sign of relenting. Mitochondria play a central role in hepatic lipid metabolism and also are affected by upstream signaling pathways involved in hepatic metabolism. This review will focus on the role of mitochondria in the pathophysiology of NAFLD and touch on some of the therapeutic approaches targeting mitochondria as well as metabolically important signaling pathways. Mitochondria are able to adapt to lipid accumulation in hepatocytes by increasing rates of beta-oxidation; however increased substrate delivery to the mitochondrial electron transport chain (ETC) leads to increased reactive oxygen species (ROS) production and eventually ETC dysfunction. Decreased ETC function combined with increased rates of fatty acid beta-oxidation leads to the accumulation of incomplete products of beta-oxidation, which combined with increased levels of ROS contribute to insulin resistance. Several related signaling pathways, nuclear receptors, and transcription factors also regulate hepatic lipid metabolism, many of which are redox sensitive and regulated by ROS.
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