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Li H, Liang J, Han M, Gao Z. Polyphenols synergistic drugs to ameliorate non-alcoholic fatty liver disease via signal pathway and gut microbiota: A review. J Adv Res 2025; 68:43-62. [PMID: 38471648 PMCID: PMC11785558 DOI: 10.1016/j.jare.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/04/2024] [Accepted: 03/07/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease with an increasing incidence worldwide. Single drug therapy may have toxic side effects and disrupt gut microbiota balance. Polyphenols are widely used in disease intervention due to their distinctive nutritional properties and medicinal value, which a potential gut microbiota modulator. However, there is a lack of comprehensive review to explore the efficacy and mechanism of combined therapy with drugs and polyphenols for NAFLD. AIM OF REVIEW Based on this, this review firstly discusses the link between NAFLD and gut microbiota, and outlines the effects of polyphenols and drugs on gut microbiota. Secondly, it examined recent advances in the treatment and intervention of NAFLD with drugs and polyphenols and the therapeutic effect of the combination of the two. Finally, we highlight the underlying mechanisms of polyphenol combined drug therapy in NAFLD. This is mainly in terms of signaling pathways (NF-κB, AMPK, Nrf2, JAK/STAT, PPAR, SREBP-1c, PI3K/Akt and TLR) and gut microbiota. Furthermore, some emerging mechanisms such as microRNA potential biomarker therapies may provide therapeutic avenues for NAFLD. KEY SCIENTIFIC CONCEPTS OF REVIEW Drawing inspiration from combination drug strategies, the use of active substances in combination with drugs for NAFLD intervention holds transformative and prospective potential, both improve NAFLD and restore gut microbiota balance while reducing the required drug dosage. This review systematically discusses the bidirectional interactions between gut microbiota and NAFLD, and summarizes the potential mechanisms of polyphenol synergistic drugs in the treatment of NAFLD by modulating signaling pathways and gut microbiota. Future researches should develop multi-omics technology to identify patients who benefit from polyphenols combination drugs and devising individualized treatment plans to enhance its therapeutic effect.
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Affiliation(s)
- Hongcai Li
- College of Food Science and Engineering, Northwest A&F University, 712100 Yangling, Shaanxi, People's Republic of China
| | - Jingjing Liang
- College of Food Science and Engineering, Northwest A&F University, 712100 Yangling, Shaanxi, People's Republic of China
| | - Mengzhen Han
- College of Food Science and Engineering, Northwest A&F University, 712100 Yangling, Shaanxi, People's Republic of China
| | - Zhenpeng Gao
- College of Food Science and Engineering, Northwest A&F University, 712100 Yangling, Shaanxi, People's Republic of China.
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2
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Zhao J, Zhao Y, Zhang S, Zhang L, Yang Z. Insights into the chirality-dependent recognition of Danshensu Bingpian Zhi stereoisomers with PPAR γ. Phys Chem Chem Phys 2024; 26:28143-28154. [PMID: 39495487 DOI: 10.1039/d4cp03926b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2024]
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor involved in metabolic processes, inflammation, and energy balance, represents a promising therapeutic target for cardiovascular diseases. Danshensu Bingpian Zhi (DBZ), a chiral compound derived from traditional Chinese medicine, exhibits potential as a PPARγ agonist. Using an ensemble-based docking approach, molecular dynamics (MD) simulations, and the molecular mechanics generalized born surface area (MM/GBSA) methods, we explored the binding modes and energetics of DBZ stereoisomers with the PPARγ ligand-binding domain (LBD). The results indicated that the right-handed stereoisomer (DBZR) binds like a full agonist, while the left-handed stereoisomer (DBZS) binds as a partial agonist with stronger binding energies (ΔGbind), indicating a robust interaction with PPARγ. Both the stereoisomers stabilize the β-sheet region of PPARγ-LBD, potentially protecting Ser245 from phosphorylation by Cdk5, a process implicated in atherosclerosis. Principal component analysis (PCA) and dynamic cross-correlation matrices (DCCM) revealed the complex structural dynamics within the Ω loop, β-sheet, and AF-2 region of PPARγ-LBD upon ligand binding, which may contribute to the unique binding mode and efficacy of DBZS. These findings provide insights into the molecular recognition of PPARγ-LBD by DBZ stereoisomers and their impact on the conformational dynamics of PPARγ, highlighting the therapeutic potential of DBZ and the significance of chirality in drug design.
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Affiliation(s)
- Jiasheng Zhao
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an 710049, China.
| | - Yizhen Zhao
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an 710049, China.
| | - Shengli Zhang
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an 710049, China.
| | - Lei Zhang
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an 710049, China.
| | - Zhiwei Yang
- MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an 710049, China.
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Kirtipal N, Seo Y, Son J, Lee S. Systems Biology of Human Microbiome for the Prediction of Personal Glycaemic Response. Diabetes Metab J 2024; 48:821-836. [PMID: 39313228 PMCID: PMC11449821 DOI: 10.4093/dmj.2024.0382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 08/29/2024] [Indexed: 09/25/2024] Open
Abstract
The human gut microbiota is increasingly recognized as a pivotal factor in diabetes management, playing a significant role in the body's response to treatment. However, it is important to understand that long-term usage of medicines like metformin and other diabetic treatments can result in problems, gastrointestinal discomfort, and dysbiosis of the gut flora. Advanced sequencing technologies have improved our understanding of the gut microbiome's role in diabetes, uncovering complex interactions between microbial composition and metabolic health. We explore how the gut microbiota affects glucose metabolism and insulin sensitivity by examining a variety of -omics data, including genomics, transcriptomics, epigenomics, proteomics, metabolomics, and metagenomics. Machine learning algorithms and genome-scale modeling are now being applied to find microbiological biomarkers associated with diabetes risk, predicted disease progression, and guide customized therapy. This study holds promise for specialized diabetic therapy. Despite significant advances, some concerns remain unanswered, including understanding the complex relationship between diabetes etiology and gut microbiota, as well as developing user-friendly technological innovations. This mini-review explores the relationship between multiomics, precision medicine, and machine learning to improve our understanding of the gut microbiome's function in diabetes. In the era of precision medicine, the ultimate goal is to improve patient outcomes through personalized treatments.
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Affiliation(s)
- Nikhil Kirtipal
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Youngchang Seo
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Jangwon Son
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea
| | - Sunjae Lee
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
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Huang H, Zhao H, Wenqing L, Xu F, Wang X, Yao Y, Huang Y. Prospect of research on anti-atherosclerosis effect of main components of traditional Chinese medicine Yiqi Huoxue Huatan recipe through gut microbiota: A review. Medicine (Baltimore) 2024; 103:e37104. [PMID: 38306512 PMCID: PMC10843552 DOI: 10.1097/md.0000000000037104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 01/08/2024] [Indexed: 02/04/2024] Open
Abstract
The incidence and mortality rates of cardiovascular diseases are on the rise globally, posing a severe threat to human health. Atherosclerosis (AS) is considered a multi-factorial inflammatory disease and the main pathological basis of cardiovascular and cerebrovascular diseases, as well as the leading cause of death. Dysbiosis of the gut microbiota can induce and exacerbate inflammatory reactions, accelerate metabolic disorders and immune function decline, and affect the progression and prognosis of AS-related diseases. The Chinese herbal medicine clinicians frequently utilize Yiqi Huoxue Huatan recipe, an effective therapeutic approach for the management of AS. This article reviews the correlation between the main components of Yiqi Huoxue Huatan recipe and the gut microbiota and AS to provide new directions and a theoretical basis for the prevention and treatment of AS.
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Affiliation(s)
- Hongtao Huang
- Department of Cardiology, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, China
| | - Hanjun Zhao
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lv Wenqing
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Feiyue Xu
- Shanghai Pudong New District Pudong Hospital, Shanghai, China
| | - Xiaolong Wang
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yili Yao
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Huang
- Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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McAleer JP. Obesity and the microbiome in atopic dermatitis: Therapeutic implications for PPAR-γ agonists. FRONTIERS IN ALLERGY 2023; 4:1167800. [PMID: 37051264 PMCID: PMC10083318 DOI: 10.3389/falgy.2023.1167800] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 03/13/2023] [Indexed: 03/29/2023] Open
Abstract
Atopic dermatitis (AD) is an inflammatory skin disease characterized by epidermal barrier disruption, Th2 immune responses to skin allergens and microbial dysbiosis within affected lesions. Studies within the past decade have revealed genetic and environmental factors contributing to AD in children. Obesity is a metabolic disorder that often manifests early in life and is associated with reduced bacterial diversity, leading to skin colonization with lipophilic bacteria and intestinal colonization with pro-inflammatory species. These changes impair epithelial barriers and promote Th17 responses, which may worsen the severity of AD symptoms. While few studies have examined the contribution of microbiota in obesity-induced allergies, there is emerging evidence that PPAR-γ may be an effective therapeutic target. This review discusses the microbiome in pediatric AD, treatment with probiotics, how disease is altered by obesity and potential therapeutic effects of PPAR-γ agonists. While healthy skin contains diverse species adapted for specific niches, lesional skin is highly colonized with Staphylococcus aureus which perpetuates the inflammatory reaction. Treatments for AD should help to restore microbial diversity in the skin and intestine, as well as epithelial barrier function. Pre-clinical models have shown that PPAR-γ agonists can suppress Th17 responses, IgE production and mast cell function, while improving the epidermal barrier and microbial homeostasis. Overall, PPAR-γ agonists may be effective in a subset of patients with AD, and future studies should distinguish their metabolic and anti-inflammatory effects in order to inform the best therapies.
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Werlinger P, Nguyen HT, Gu M, Cho JH, Cheng J, Suh JW. Lactobacillus reuteri MJM60668 Prevent Progression of Non-Alcoholic Fatty Liver Disease through Anti-Adipogenesis and Anti-inflammatory Pathway. Microorganisms 2022; 10:2203. [PMID: 36363795 PMCID: PMC9696116 DOI: 10.3390/microorganisms10112203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 10/18/2022] [Accepted: 11/04/2022] [Indexed: 08/26/2023] Open
Abstract
Non-alcoholic fatty liver disease (NALFD) is a disease characterized by liver steatosis. The liver is a key organ involved in the metabolism of fat, protein, and carbohydrate, enzyme activation, and storage of glycogen, which is closely related to the intestine by the bidirectional relation of the gut-liver axis. Abnormal intestinal microbiota composition can affect energy metabolism and lipogenesis. In this experiment, we investigated the beneficial effect of Lactobacillus reuteri MJM60668 on lipid metabolism and lipogenesis. C57BL/6 mice were fed a high-fat diet (HFD) and orally administrated with MJM60668. Our results showed that mice treated with MJM60668 significantly decreased liver weight and liver/body weight ratio, without affecting food intake. Serum levels of ALT, AST, TG, TCHO, and IL-1β in mice fed with MJM60668 were decreased compared to the HFD group. Investigation of gene and protein expression on the lipogenesis and lipid metabolism showed that the expression of ACC, FAS, and SREBP was decreased, and PPARα and CPT was increased. Furthermore, an increase of adiponectin in serum was shown in our experiment. Moreover, serum IL-1β level was also significantly decreased in the treated mice. These results suggested that MJM60668 can strongly inhibit lipogenesis, enhance fatty acid oxidation, and suppress inflammation. Additionally, supplementation of MJM60668 increased the proportion of Akkermansiaceae and Lachnospiracea, confirming a potential improvement of gut microbiota, which is related to mucus barrier and decrease of triglycerides levels.
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Affiliation(s)
- Pia Werlinger
- Interdisciplinary Program of Biomodulation, Myongji University, Yongin 17058, Korea
| | - Huong Thi Nguyen
- Interdisciplinary Program of Biomodulation, Myongji University, Yongin 17058, Korea
| | - Mingkun Gu
- Interdisciplinary Program of Biomodulation, Myongji University, Yongin 17058, Korea
| | - Joo-Hyung Cho
- Myongji Bioefficacy Research Center, Myongji University, Yongin 17058, Korea
| | - Jinhua Cheng
- Interdisciplinary Program of Biomodulation, Myongji University, Yongin 17058, Korea
- Myongji Bioefficacy Research Center, Myongji University, Yongin 17058, Korea
| | - Joo-Won Suh
- Interdisciplinary Program of Biomodulation, Myongji University, Yongin 17058, Korea
- Myongji Bioefficacy Research Center, Myongji University, Yongin 17058, Korea
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Tanshinone IIA May Inhibit Gastric Cancer via Affecting the Intestinal Microbiome. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:6960304. [PMID: 36199775 PMCID: PMC9529444 DOI: 10.1155/2022/6960304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/05/2022] [Accepted: 09/09/2022] [Indexed: 12/30/2022]
Abstract
Background Gastric cancer (GC) belongs to a type of the most deadly cancer in the world, and the incidence rate of GC will increase in the coming decades. Tanshinone IIA (Tan IIA) is an active component that separated from Danshen. Tan IIA may also exert its therapeutic effects in disease with intestinal dysbacteriosis, at least partially, via regulating the intestinal microbiome. Nevertheless, it is obscure whether Tanshinone IIA affects the intestinal dysbacteriosis and plays antitumor roles. This research was designed to explore Tanshinone IIA potential on the intestinal dysbacteriosis of GC xenograft mice. Methods Mouse xenograft GC tumor models were built and treated by Tan IIA. The tumor growth as well as microbiome in the intestinal were compared. Western blot was used to detect the phosphorylation of the NF-κB and expressions of the downstream cytokines IL-6 and IL-1β. Results Microbiome in the intestinal was changed in xenograft tumor mice in comparison with the control mice. What is more, Tan IIA could influence the microbiome in the intestinal of the tumor mice. Tan IIA hinders the growth of xenograft tumor and change the microbiome in the intestinal, but intestinal dysbacteriosis condition partially blocked Tan IIA-stimulated antitumor effects. In addition, intestinal dysbacteriosis abrogated Tan IIA-stimulated decrease in the NF-κB signaling in xenograft tumor mice. Conclusions Tanshinone IIA may inhibit GC tumor growth via affecting the intestinal microbiome through regulating the NF-κB signaling.
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Sun Y, Jia P, Wei J, Bai Y, Yang L, Bai Y, Zheng X. Simultaneous and rapid analysis of chiral Danshensu and its ester derivatives by supercritical fluid chromatography. J Pharm Biomed Anal 2022; 219:114884. [PMID: 35738121 DOI: 10.1016/j.jpba.2022.114884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/24/2022] [Accepted: 06/07/2022] [Indexed: 11/18/2022]
Abstract
The analysis and separation of chiral compounds with wide polar range by supercritical fluid chromatography is of major importance in the process of drug development and quality control. In this work, a fast and reliable enantioselective method for the simultaneous quantitative determination of 8 DBZ-related enantiomers has been successfully developed by supercritical fluid chromatography using an amylose-based reversed-chiral stationary phase. Within less than seven minutes all target compounds could be baseline resolved, using a mobile phase comprising supercritical carbon dioxide and methanol with 0.05 % H3PO4. The optimum chiral stationary phase showed to be a CHIRALPAK® AD-RH column, operated at flow rate of 3.0 mL/min, back pressure of 150 bar and temperature of 40 °C. Method validation confirmed that the developed procedure was selective, linear (r2 > 0.998), accurate (recovery rates: 98.02-100.02 %), and precise (intra-day: 0.05-1.98 %, inter-day: 0.08-1.98 %); the limit of detection and limit of quantification were 0.13-0.55 μg/mL and 0.37-1.68 μg/mL on column, respectively. After initial evaluation of stability according to the ICH Q1A (R2) guideline, R-DBZ showed good stability. Thus, this developed method can be used for assessing the stability of bulk DBZ samples, dosage forms of DBZ and also for monitoring the synthetic procedures of DBZ.
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Affiliation(s)
- Ying Sun
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, The College of Life Sciences, Northwest University, Xi'an 710069, PR China
| | - Pu Jia
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, The College of Life Sciences, Northwest University, Xi'an 710069, PR China
| | - Jingdong Wei
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, The College of Life Sciences, Northwest University, Xi'an 710069, PR China
| | - Yujun Bai
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, The College of Life Sciences, Northwest University, Xi'an 710069, PR China
| | - Lingjian Yang
- School of Chemistry & Chemical Engineering, Ankang University, Ankang 725000, Shaanxi, PR China
| | - Yajun Bai
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, The College of Life Sciences, Northwest University, Xi'an 710069, PR China; Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi'an 710127, PR China; Hong-taoism Research Institute of Analytical Science and Technology Ltd., Xi'an 710068, Shaanxi, PR China.
| | - Xiaohui Zheng
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, The College of Life Sciences, Northwest University, Xi'an 710069, PR China.
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Liu J, Shi Y, Peng D, Wang L, Yu N, Wang G, Chen W. Salvia miltiorrhiza Bge. (Danshen) in the Treating Non-alcoholic Fatty Liver Disease Based on the Regulator of Metabolic Targets. Front Cardiovasc Med 2022; 9:842980. [PMID: 35528835 PMCID: PMC9072665 DOI: 10.3389/fcvm.2022.842980] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 03/28/2022] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is rapidly prevalent due to its strong association with increased metabolic syndrome such as cardio- and cerebrovascular disorders and diabetes. Few drugs can meet the growing disease burden of NAFLD. Salvia miltiorrhiza Bge. (Danshen) have been used for over 2,000 years in clinical trials to treat NAFLD and metabolic syndrome disease without clarified defined mechanisms. Metabolic targets restored metabolic homeostasis in patients with NAFLD and improved steatosis by reducing the delivery of metabolic substrates to liver as a promising way. Here we systematic review evidence showing that Danshen against NAFLD through diverse and crossing mechanisms based on metabolic targets. A synopsis of the phytochemistry and pharmacokinetic of Danshen and the mechanisms of metabolic targets regulating the progression of NAFLD is initially provided, followed by the pharmacological activity of Danshen in the management NAFLD. And then, the possible mechanisms of Danshen in the management of NAFLD based on metabolic targets are elucidated. Specifically, the metabolic targets c-Jun N-terminal kinases (JNK), sterol regulatory element-binding protein-1c (SREBP-1c), nuclear translocation carbohydrate response element–binding protein (ChREBP) related with lipid metabolism pathway, and peroxisome proliferator-activated receptors (PPARs), cytochrome P450 (CYP) and the others associated with pleiotropic metabolism will be discussed. Finally, providing a critical assessment of the preclinic and clinic model and the molecular mechanism in NAFLD.
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Affiliation(s)
- Jie Liu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China
- Institute of Traditional Chinese Medicine Resources Protection and Development, Anhui Academy of Chinese Medicine, Hefei, China
- Anhui Province Key Laboratory of Traditional Chinese Medicine Decoction Pieces of New Manufacturing Technology, Hefei, China
| | - Yun Shi
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China
- Institute of Traditional Chinese Medicine Resources Protection and Development, Anhui Academy of Chinese Medicine, Hefei, China
| | - Daiyin Peng
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China
- Institute of Traditional Chinese Medicine Resources Protection and Development, Anhui Academy of Chinese Medicine, Hefei, China
| | - Lei Wang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China
- Anhui Province Key Laboratory of Traditional Chinese Medicine Decoction Pieces of New Manufacturing Technology, Hefei, China
- *Correspondence: Lei Wang,
| | - Nianjun Yu
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China
- Institute of Traditional Chinese Medicine Resources Protection and Development, Anhui Academy of Chinese Medicine, Hefei, China
| | - Guokai Wang
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China
- Institute of Traditional Chinese Medicine Resources Protection and Development, Anhui Academy of Chinese Medicine, Hefei, China
| | - Weidong Chen
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China
- Institute of Traditional Chinese Medicine Resources Protection and Development, Anhui Academy of Chinese Medicine, Hefei, China
- Anhui Province Key Laboratory of Traditional Chinese Medicine Decoction Pieces of New Manufacturing Technology, Hefei, China
- Weidong Chen,
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Hirsch GE, Heck TG. Inflammation, oxidative stress and altered heat shock response in type 2 diabetes: the basis for new pharmacological and non-pharmacological interventions. Arch Physiol Biochem 2022; 128:411-425. [PMID: 31746233 DOI: 10.1080/13813455.2019.1687522] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Type 2 diabetes mellitus (DM2) is a chronic disease characterised by variable degrees of insulin resistance and impaired insulin secretion. Besides, several pieces of evidence have shown that chronic inflammation, oxidative stress, and 70 kDa heat shock proteins (HSP70) are strongly involved in DM2 and its complications, and various pharmacological and non-pharmacological treatment alternatives act in these processes/molecules to modulate them and ameliorate the disease. Besides, uncontrolled hyperglycaemia is related to several complications as diabetic retinopathy, neuropathy and hepatic, renal and cardiac complications. In this review, we address discuss the involvement of different inflammatory and pro-oxidant pathways related to DM2, and we described molecular targets modulated by therapeutics currently available to treat DM2.
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Affiliation(s)
- Gabriela Elisa Hirsch
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUÍ), Rua do Comércio, Brazil
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Regional University of Northwestern region of the state of Rio Grande do Sul (UNIJUÍ), Rua do Comércio, Brazil
| | - Thiago Gomes Heck
- Research Group in Physiology, Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUÍ), Rua do Comércio, Brazil
- Postgraduate Program in Integral Attention to Health (PPGAIS-UNIJUÍ/UNICRUZ), Regional University of Northwestern region of the state of Rio Grande do Sul (UNIJUÍ), Rua do Comércio, Brazil
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11
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Wu YL, Lin H, Li HF, Don MJ, King PC, Chen HH. Salvia miltiorrhiza Extract and Individual Synthesized Component Derivatives Induce Activating-Transcription-Factor-3-Mediated Anti-Obesity Effects and Attenuate Obesity-Induced Metabolic Disorder by Suppressing C/EBPα in High-Fat-Induced Obese Mice. Cells 2022; 11:cells11061022. [PMID: 35326476 PMCID: PMC8947163 DOI: 10.3390/cells11061022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/09/2022] [Accepted: 03/15/2022] [Indexed: 12/24/2022] Open
Abstract
Pharmacological studies indicate that Salvia miltiorrhiza extract (SME) can improve cardiac and blood vessel function. However, there is limited knowledge regarding the effects (exerted through epigenetic regulation) of SME and newly derived single compounds, with the exception of tanshinone IIA and IB, on obesity-induced metabolic disorders. In this study, we administered SME or dimethyl sulfoxide (DMSO) as controls to male C57BL/J6 mice after they were fed a high-fat diet (HFD) for 4 weeks. SME treatment significantly reduced body weight, fasting plasma glucose, triglyceride levels, insulin resistance, and adipogenesis/lipogenesis gene expression in treated mice compared with controls. Transcriptome array analysis revealed that the expression of numerous transcriptional factors, including activating transcription factor 3 (ATF3) and C/EBPα homologous protein (CHOP), was significantly higher in the SME group. ST32db, a novel synthetic derivative similar in structure to compounds from S. miltiorrhiza extract, ameliorates obesity and obesity-induced metabolic syndrome in HFD-fed wild-type mice but not ATF3−/− mice. ST32db treatment of 3T3-L1 adipocytes suppresses lipogenesis/adipogenesis through the ATF3 pathway to directly inhibit C/EBPα expression and indirectly inhibit the CHOP pathway. Overall, ST32db, a single compound modified from S. miltiorrhiza extract, has anti-obesity effects through ATF3-mediated C/EBPα downregulation and the CHOP pathway. Thus, SME and ST32db may reduce obesity and diabetes in mice, indicating the potential of both SME and ST32db as therapeutic drugs for the treatment of obesity-induced metabolic syndrome.
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Affiliation(s)
- Yueh-Lin Wu
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (Y.-L.W.); (H.L.)
- Division of Nephrology, Department of Internal Medicine, Wei-Gong Memorial Hospital, Miaoli 350, Taiwan
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 350, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan
- TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei 110, Taiwan
| | - Heng Lin
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (Y.-L.W.); (H.L.)
- Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (H.-F.L.); (P.-C.K.)
| | - Hsiao-Fen Li
- Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (H.-F.L.); (P.-C.K.)
| | - Ming-Jaw Don
- National Research Institute of Chinese Medicine, Taipei 112, Taiwan;
| | - Pei-Chih King
- Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (H.-F.L.); (P.-C.K.)
| | - Hsi-Hsien Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (Y.-L.W.); (H.L.)
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan
- TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei 110, Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: ; Tel.: +886-27372181-3903; Fax: 886-2-5558-9890
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Guo B, Liu J, Wang B, Zhang C, Su Z, Zhao M, Qin L, Zhang W, Zheng R. Withaferin A Promotes White Adipose Browning and Prevents Obesity Through Sympathetic Nerve-Activated Prdm16-FATP1 Axis. Diabetes 2022; 71:249-263. [PMID: 34732538 DOI: 10.2337/db21-0470] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 11/01/2021] [Indexed: 11/13/2022]
Abstract
The increasing prevalence of obesity has resulted in demands for the development of new effective strategies for obesity treatment. Withaferin A (WA) shows a great potential for prevention of obesity by sensitizing leptin signaling in the hypothalamus. However, the mechanism underlying the weight- and adiposity-reducing effects of WA remains to be elucidated. In this study, we report that WA treatment induced white adipose tissue (WAT) browning, elevated energy expenditure, decreased respiratory exchange ratio, and prevented high-fat diet-induced obesity. The sympathetic chemical denervation dampened the WAT browning and also impeded the reduction of adiposity in WA-treated mice. WA markedly upregulated the levels of Prdm16 and FATP1 (Slc27a1) in the inguinal WAT (iWAT), and this was blocked by sympathetic denervation. Prdm16 or FATP1 knockdown in iWAT abrogated the WAT browning-inducing effects of WA and restored the weight gain and adiposity in WA-treated mice. Together, these findings suggest that WA induces WAT browning through the sympathetic nerve-adipose axis, and the adipocytic Prdm16-FATP1 pathway mediates the promotive effects of WA on white adipose browning.
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Affiliation(s)
- Bingbing Guo
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Jiarui Liu
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Bingwei Wang
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Chenyu Zhang
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Zhijie Su
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Miao Zhao
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Lihua Qin
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Weiguang Zhang
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
| | - Ruimao Zheng
- Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, China
- Neuroscience Research Institute, Peking University, Beijing, China
- Key Laboratory for Neuroscience of Ministry of Education, Peking University, Beijing, China
- Key Laboratory for Neuroscience of National Health Commission, Peking University, Beijing, China
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13
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PPARγ Regulates Triclosan Induced Placental Dysfunction. Cells 2021; 11:cells11010086. [PMID: 35011648 PMCID: PMC8750171 DOI: 10.3390/cells11010086] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/14/2022] Open
Abstract
Exposure to the antibacterial agent triclosan (TCS) is associated with abnormal placenta growth and fetal development during pregnancy. Peroxisome proliferator-activated receptor γ (PPARγ) is crucial in placenta development. However, the mechanism of PPARγ in placenta injury induced by TCS remains unknown. Herein, we demonstrated that PPARγ worked as a protector against TCS-induced toxicity. TCS inhibited cell viability, migration, and angiogenesis dose-dependently in HTR-8/SVneo and JEG-3 cells. Furthermore, TCS downregulated expression of PPARγ and its downstream viability, migration, angiogenesis-related genes HMOX1, ANGPTL4, VEGFA, MMP-2, MMP-9, and upregulated inflammatory genes p65, IL-6, IL-1β, and TNF-α in vitro and in vivo. Further investigation showed that overexpression or activation (rosiglitazone) alleviated cell viability, migration, angiogenesis inhibition, and inflammatory response caused by TCS, while knockdown or inhibition (GW9662) of PPARγ had the opposite effect. Moreover, TCS caused placenta dysfunction characterized by the significant decrease in weight and size of the placenta and fetus, while PPARγ agonist rosiglitazone alleviated this damage in mice. Taken together, our results illustrated that TCS-induced placenta dysfunction, which was mediated by the PPARγ pathway. Our findings reveal that activation of PPARγ might be a promising strategy against the adverse effects of TCS exposure on the placenta and fetus.
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14
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Wang R, Wang Z, Sun R, Fu R, Sun Y, Zhu M, Geng Y, Gao D, Tian X, Zhao Y, Yao J. Activation of TAF9 via Danshensu-Induced Upregulation of HDAC1 Expression Alleviates Non-alcoholic Fatty Liver Disease. Front Pharmacol 2021; 12:775528. [PMID: 34925033 PMCID: PMC8678612 DOI: 10.3389/fphar.2021.775528] [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: 09/14/2021] [Accepted: 11/22/2021] [Indexed: 11/17/2022] Open
Abstract
Fatty acid β-oxidation is an essential pathogenic mechanism in nonalcoholic fatty liver disease (NAFLD), and TATA-box binding protein associated factor 9 (TAF9) has been reported to be involved in the regulation of fatty acid β-oxidation. However, the function of TAF9 in NAFLD, as well as the mechanism by which TAF9 is regulated, remains unclear. In this study, we aimed to investigate the signaling mechanism underlying the involvement of TAF9 in NAFLD and the protective effect of the natural phenolic compound Danshensu (DSS) against NAFLD via the HDAC1/TAF9 pathway. An in vivo model of high-fat diet (HFD)-induced NAFLD and a palmitic acid (PA)-treated AML-12 cell model were developed. Pharmacological treatment with DSS significantly increased fatty acid β-oxidation and reduced lipid droplet (LD) accumulation in NAFLD. TAF9 overexpression had the same effects on these processes both in vivo and in vitro. Interestingly, the protective effect of DSS was markedly blocked by TAF9 knockdown. Mechanistically, TAF9 was shown to be deacetylated by HDAC1, which regulates the capacity of TAF9 to mediate fatty acid β-oxidation and LD accumulation during NAFLD. In conclusion, TAF9 is a key regulator in the treatment of NAFLD that acts by increasing fatty acid β-oxidation and reducing LD accumulation, and DSS confers protection against NAFLD through the HDAC1/TAF9 pathway.
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Affiliation(s)
- Ruiwen Wang
- Department of Pharmacology, Dalian Medical University, Dalian, China
| | - Zhecheng Wang
- Department of Pharmacology, Dalian Medical University, Dalian, China
| | - Ruimin Sun
- Department of Pharmacology, Dalian Medical University, Dalian, China
| | - Rong Fu
- Department of Pharmacology, Dalian Medical University, Dalian, China
| | - Yu Sun
- Department of Pharmacology, Dalian Medical University, Dalian, China
| | - Meiyang Zhu
- Department of Pharmacology, Dalian Medical University, Dalian, China
| | - Yunfei Geng
- Department of Pharmacology, Dalian Medical University, Dalian, China
| | - Dongyan Gao
- Department of Pharmacology, Dalian Medical University, Dalian, China
| | - Xiaofeng Tian
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yan Zhao
- Department of Pharmacology, Dalian Medical University, Dalian, China
| | - Jihong Yao
- Department of Pharmacology, Dalian Medical University, Dalian, China
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Chen Y, Wang M. New Insights of Anti-Hyperglycemic Agents and Traditional Chinese Medicine on Gut Microbiota in Type 2 Diabetes. Drug Des Devel Ther 2021; 15:4849-4863. [PMID: 34876807 PMCID: PMC8643148 DOI: 10.2147/dddt.s334325] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 11/19/2021] [Indexed: 12/11/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a widespread metabolic disease characterized by chronic hyperglycemia. Human microbiota, which is regarded as a “hidden organ”, plays an important role in the initiation and development of T2DM. In addition, anti-hyperglycemic agents and traditional Chinese medicine may affect the composition of gut microbiota and consequently improve glucose metabolism. However, the relationship between gut microbiota, T2DM and anti-hyperglycemic agents or traditional Chinese medicine is poorly understood. In this review, we summarized pre-clinical and clinical studies to elucidate the possible underlying mechanism. Some anti-hyperglycemic agents and traditional Chinese medicine may partly exert hypoglycemic effects by altering the gut microbiota composition in ways that reduce metabolic endotoxemia, maintain the integrity of intestinal mucosal barrier, promote the production of short-chain fatty acids (SCFAs), decrease trimethylamine-N-oxide (TMAO) and regulate bile acid metabolism. In conclusion, gut microbiota may provide some new therapeutic targets for treatment of patients with diabetes mellitus.
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Affiliation(s)
- Yanxia Chen
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People's Republic of China
| | - Mian Wang
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People's Republic of China
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Lei W, Li X, Li L, Huang M, Cao Y, Sun X, Jiang M, Zhang B, Zhang H. Compound Danshen Dripping Pill ameliorates post ischemic myocardial inflammation through synergistically regulating MAPK, PI3K/AKT and PPAR signaling pathways. JOURNAL OF ETHNOPHARMACOLOGY 2021; 281:114438. [PMID: 34390798 DOI: 10.1016/j.jep.2021.114438] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 07/13/2021] [Accepted: 07/17/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Compound Danshen Dripping Pill (CDDP), composed of Salvia miltiorrhiza Bunge, Panax notoginseng (Burkill) F.H. Chen and Borneol, is a famous traditional Chinese medicine formula which has made great achievements in the treatment of ischemic heart disease, but the profound mechanism of CDDP improving post ischemic myocardial inflammation hasn't been clearly discussed. AIM OF THE STUDY The aim of this study was to explore the biological mechanism of constituents in CDDP synergistically improving post ischemic myocardial inflammation. MATERIALS AND METHODS The pharmacologic studies were applied to assess the cardio protection effect of CDDP in acute myocardial ischemic rats. To identify the anti-inflammatory ingredients in CDDP, an ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry combined with a dual-luciferase reporter assay for NF-κB inhibition were used. The network pharmacology and molecular docking assay were adopted to predict targets of anti-inflammatory ingredients and then the regulation effects of these active components on their targets were also verified. RESULTS Our results indicated that CDDP exerted an excellent cardio protection effect by reversing echocardiographic abnormalities, attenuating histopathological lesion, ameliorating circulating myocardial markers and inflammation cytokines. Tanshinol, salvianolic acid B (Sal B), tanshinone IIA (Tan IIA) and notoginsenoside R1 (NGR1) were the pivotal anti-inflammatory ingredients in CDDP. The anti-inflammatory mechanism is that tanshinol and Sal B respectively targeted on PPARγ and JNK, while Tan IIA worked on AKT1 and NGR1 bound to PI3K. CONCLUSIONS Our results firstly demonstrated that CDDP effectively ameliorated post ischemic myocardial inflammation through simultaneously modulating MAPK, PI3K/AKT and PPAR pathways in a multi-components synergetic manner.
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Affiliation(s)
- Wei Lei
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District,Tianjin 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiao Li
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District,Tianjin 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Lin Li
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District,Tianjin 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Ming Huang
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District,Tianjin 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yu Cao
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District,Tianjin 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xingyi Sun
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District,Tianjin 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Min Jiang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China
| | - Boli Zhang
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District,Tianjin 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Han Zhang
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District,Tianjin 301617, China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
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Tianwang Buxin Granules Influence the Intestinal Flora in Perimenopausal Insomnia. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9979511. [PMID: 34825005 PMCID: PMC8610686 DOI: 10.1155/2021/9979511] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 09/29/2021] [Accepted: 10/07/2021] [Indexed: 11/18/2022]
Abstract
Methods The subjects included 13 PI patients from the Hubei Provincial Hospital of TCM, Hubei University of TCM, and Wuhan Traditional Chinese Medicine Hospital, and the corresponding noninsomniac spouses of the patients were selected as controls. TWBXG was continuously administered for 4 weeks. The feces of PI patients and their noninsomniac spouses before and after treatment with TWBXG were collected. The intestinal flora composition of each group was detected by metagenomic sequencing, and the efficacy of TWBXG was evaluated by the PSQI scale. Results Compared with the control group, the model group showed an increase in the abundance of Roseburia faecis, Ruminococcus, Prevotella copri, Fusicatenibacter saccharivorans, and Blautia obeum, while those of Bacteroides, fecal Bacteroidetes, and Faecalibacterium prausnitzii were decreased. Compared with pretreatment, the PSQI score was significantly reduced (P < 0.05), the abundance of Bacteroides, fecal Bacteroidetes, and Faecalibacterium prausnitzii increased, and that of Roseburia faecis, Ruminococcus, Prevotella copri, Fusicatenibacter saccharivorans, and Blautia obeum decreased after treatment. However, there was still a certain gap in the abundance of related flora in the treatment group compared with the control. Conclusion PI is associated with disturbances in the intestinal flora and is mainly related to the disorders of Roseburia faecis, Ruminococcus, Prevotella copri, Fusicatenibacter saccharivorans, Blautia obeum, Bacteroides, fecal Bacteroidetes, and Faecalibacterium prausnitzii. TWBXG can effectively treat PI, and its effect may be achieved by regulating the disordered intestinal flora. Clinical Trials. The study was registered in the Chinese clinical trial registry and approved by the World Health Organization clinical trial registration platform (Effects of the modified Tianwang Buxin granule and modified Tianwang Buxin decoction pieces on insomnia: a randomized, controlled trial, ChiCTR-IPR-17011549).
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18
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Xi Y, Xu PF. Diabetes and gut microbiota. World J Diabetes 2021; 12:1693-1703. [PMID: 34754371 PMCID: PMC8554376 DOI: 10.4239/wjd.v12.i10.1693] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 04/20/2021] [Accepted: 08/05/2021] [Indexed: 02/06/2023] Open
Abstract
The prevalence of diabetes has increased rapidly throughout the world in recent years. Currently, approximately 463 million people are living with diabetes, and the number has tripled over the last two decades. Here, we describe the global epidemiology of diabetes in 2019 and forecast the trends to 2030 and 2045 in China, India, USA, and the globally. The gut microbiota plays a major role in metabolic diseases, especially diabetes. In this review, we describe the interaction between diabetes and gut microbiota in three aspects: probiotics, antidiabetic medication, and diet. Recent findings indicate that probiotics, antidiabetic medications, or dietary interventions treat diabetes by shifting the gut microbiome, particularly by raising beneficial bacteria and reducing harmful bacteria. We conclude that targeting the gut microbiota is becoming a novel therapeutic strategy for diabetes.
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Affiliation(s)
- Yue Xi
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Peng-Fei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
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Li Y, Ji X, Wu H, Li X, Zhang H, Tang D. Mechanisms of traditional Chinese medicine in modulating gut microbiota metabolites-mediated lipid metabolism. JOURNAL OF ETHNOPHARMACOLOGY 2021; 278:114207. [PMID: 34000365 DOI: 10.1016/j.jep.2021.114207] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 04/23/2021] [Accepted: 05/11/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The gut microbiome plays an important role in advancing the process of host lipid metabolism directly or indirectly. Traditional Chinese medicine (TCM) can improve the intestinal environment by intervening with gut microbiota metabolites to potentially regulate lipid levels. However, the underlying mechanisms remain unclear. Therefore, we examined the current databases to search for studies related to influence of TCM on the gut microbiota metabolites-mediated lipid metabolism. AIM OF THE STUDY This paper aims to review the TCM that could regulate lipid metabolism mediated by microbial metabolites and their pharmacological targets and provides perspectives for future investigation. METHODS Electronic databases including PubMed, Web of Science, EMBASE, the Cochrane Library, Chinese Biological Medicine Database, and China National Knowledge Infrastructure were searched up to April 2021 to identify eligible studies. RESULTS A total of 30 active compounds, five Chinese herbal formulae, and three proprietary Chinese medicines were included in this review. We found that TCM can effectively improve lipid metabolism by increasing short chain fatty acids (SCFA) levels, regulating bile acid (BA) metabolism, reducing the production of trimethylamine N-oxide (TMAO), alleviating the release of inflammatory factors, and altering branched-chain amino acids (BCAA) biosynthesis. This process is accompanied by changes in the structure of the gut microbiota, blood lipids, and expression of lipid metabolism genes. CONCLUSION In summary, studies on the regulation of lipid metabolism by microbial metabolites in TCM will provide a new approach for better management of dyslipidemia, which may facilitate future clinical treatments.
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Affiliation(s)
- Yingying Li
- Experimental Research Center of China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Xinyu Ji
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Haonan Wu
- Experimental Research Center of China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Xiang Li
- Institute of Information on Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Huamin Zhang
- Institute of Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Danli Tang
- Experimental Research Center of China Academy of Chinese Medical Sciences, Beijing, 100700, China.
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20
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Melatonin Attenuates Dextran Sodium Sulfate Induced Colitis in Obese Mice. Pharmaceuticals (Basel) 2021; 14:ph14080822. [PMID: 34451919 PMCID: PMC8399719 DOI: 10.3390/ph14080822] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 01/03/2023] Open
Abstract
Epidemiological studies have indicated that obesity is an independent risk factor for colitis and that a high-fat diet (HFD) increases the deterioration of colitis-related indicators in mice. Melatonin has multiple anti-inflammatory effects, including inhibiting tumor growth and regulating immune defense. However, the mechanism of its activity in ameliorating obesity-promoted colitis is still unclear. This study explored the possibility that melatonin has beneficial functions in HFD-induced dextran sodium sulfate (DSS)-induced colitis in mice. Here, we revealed that HFD-promoted obesity accelerated DSS-induced colitis, while melatonin intervention improved colitis. Melatonin significantly alleviated inflammation by increasing anti-inflammatory cytokine release and reducing the levels of proinflammatory cytokines in HFD- and DSS-treated mice. Furthermore, melatonin expressed antioxidant activities and reversed intestinal barrier integrity, resulting in improved colitis in DSS-treated obese mice. We also found that melatonin could reduce the ability of inflammatory cells to utilize fatty acids and decrease the growth-promoting effect of lipids by inhibiting autophagy. Taken together, our study indicates that the inhibitory effect of melatonin on autophagy weakens the lipid-mediated prosurvival advantage, which suggests that melatonin-targeted autophagy may provide an opportunity to prevent colitis in obese individuals.
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21
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Chen T, Zhang Y, Dong Y, Zhang D, Xia L, Sun X, Li H, Han C, Wang H, Xu G. Mast cell and heparin promote adipogenesis in superficial fascia of rats. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866:159024. [PMID: 34389520 DOI: 10.1016/j.bbalip.2021.159024] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 07/13/2021] [Accepted: 08/03/2021] [Indexed: 10/20/2022]
Abstract
Fascial adipocytes are recently identified as a unique population of adipose cells, which have different developmental origins, anatomical locations, cytological and functional characteristics compared with subcutaneous or visceral adipocytes. Superficial fascia in rats (also in pigs but not obviously in mice) contains numbers of lineage committed preadipocytes which possess adipogenic potential in vivo. The present study aimed to investigate the physiological factors that contribute to fascial adipogenesis in rats. We detected that mast cells, adipose progenitor cells, and mature adipocytes distributed in certain fascia areas were closely associated with each other, and numerous heparin-loaded granules released from mast cells were distributed around fascial preadipocytes. The culture supernatants of rat peritoneal mast cells and RBL-2H3 mast cells contained 20-30 μg/ml of heparin, effectively activated PPAR-responsive luciferase activity, promoted mRNA and protein expressions of key adipogenic genes, and hence increased adipogenic differentiation of fascia- or epididymal adipose-derived stromal cells. Adipogenic effects of mast cell supernatants were mimicked by heparin but not by histamine or 5-hydroxytryptamine, and were antagonized by protamine sulfate. Adipogenic effects of heparin may relate to its chain length of glucosamine units, because heparin stimulated stronger adipogenesis than dalteparin and enoxaparin with relatively short chains. In rats, local administration of heparin-loaded microspheres for 30 days induced adipogenesis in local areas of superficial fascia. Our findings suggested that mast cell and its granule heparin could serve as the endogenous physiological factors to initiate and accelerate local adipogenesis in superficial fascia, or in adipose tissue with the fascia naturally embedded inside.
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Affiliation(s)
- Tongsheng Chen
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, and Peking University Center for Obesity and Metabolic Disease Research, Beijing 100191, China
| | - Yanfei Zhang
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, and Peking University Center for Obesity and Metabolic Disease Research, Beijing 100191, China
| | - Yingyue Dong
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, and Peking University Center for Obesity and Metabolic Disease Research, Beijing 100191, China
| | - Dandan Zhang
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, and Peking University Center for Obesity and Metabolic Disease Research, Beijing 100191, China
| | - Lisha Xia
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, and Peking University Center for Obesity and Metabolic Disease Research, Beijing 100191, China
| | - Xiaozhe Sun
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, and Peking University Center for Obesity and Metabolic Disease Research, Beijing 100191, China
| | - Hanxiao Li
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, and Peking University Center for Obesity and Metabolic Disease Research, Beijing 100191, China
| | - Chunmiao Han
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, and Peking University Center for Obesity and Metabolic Disease Research, Beijing 100191, China
| | - Huamin Wang
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, and Peking University Center for Obesity and Metabolic Disease Research, Beijing 100191, China
| | - Guoheng Xu
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, and Peking University Center for Obesity and Metabolic Disease Research, Beijing 100191, China.
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22
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Chen YW, Huang YP, Wu PC, Chiang WY, Wang PH, Chen BY. The Functional Vision Protection Effect of Danshensu via Dopamine D1 Receptors: In Vivo Study. Nutrients 2021; 13:nu13030978. [PMID: 33803057 PMCID: PMC8002943 DOI: 10.3390/nu13030978] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/09/2021] [Accepted: 03/15/2021] [Indexed: 12/22/2022] Open
Abstract
Danshensu, a traditional herb-based active component (Salvia miltiorrhiza Bunge), has garnered attention, due to its safety, nutritional value, and antioxidant effects, along with cardiovascular-protective and neuroprotective abilities; however, its effect on the retinal tissues and functional vision has not been fully studied. The objective of this study was to analyze the protective effect of danshensu on retinal tissues and functional vision in vivo in a mouse model of light-induced retinal degeneration. High energy light-evoked visual damage was confirmed by the loss in structural tissue integrity in the retina accompanied by a decline in visual acuity and visual contrast sensitivity function (VCSF), whereas the retina tissue exhibited severe Müller cell gliosis. Although danshensu treatment did not particularly reduce light-evoked damage to the photoreceptors, it significantly prevented Müller cell gliosis. Danshensu exerted protective effects against light-evoked deterioration on low spatial frequency-based VCSF as determined by the behavioral optomotor reflex method. Additionally, the protective effect of danshensu on VCSF can be reversed and blocked by the injection of a dopamine D1 receptor antagonist (SCH 23390). This study demonstrated that the major functional vision promotional effect of danshensu in vivo was through the dopamine D1 receptors enhancement pathway, rather than the structural protection of the retinas.
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Affiliation(s)
- Yun-Wen Chen
- Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 88301, Taiwan; (Y.-W.C.); (P.-C.W.); (W.-Y.C.)
| | - Yun-Ping Huang
- Department of Optometry, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-P.H.); (P.-H.W.)
| | - Pei-Chang Wu
- Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 88301, Taiwan; (Y.-W.C.); (P.-C.W.); (W.-Y.C.)
| | - Wei-Yu Chiang
- Department of Ophthalmology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 88301, Taiwan; (Y.-W.C.); (P.-C.W.); (W.-Y.C.)
| | - Ping-Hsun Wang
- Department of Optometry, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-P.H.); (P.-H.W.)
| | - Bo-Yie Chen
- Department of Optometry, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-P.H.); (P.-H.W.)
- Department of Ophthalmology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
- Correspondence: ; Tel.: +886-4-2473-0022 (ext. 12319)
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Li X, Wu D, Niu J, Sun Y, Wang Q, Yang B, Kuang H. Intestinal Flora: A Pivotal Role in Investigation of Traditional Chinese Medicine. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2021; 49:237-268. [PMID: 33622213 DOI: 10.1142/s0192415x21500130] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Intestinal flora is essential for maintaining host health and plays a unique role in transforming Traditional Chinese Medicine (TCM). TCM, as a bodyguard, has saved countless lives and maintained human health in the long history, especially in this COVID-19 pandemic. Pains of diseases have been removed from the effective TCM therapy, such as TCM preparation, moxibustion, and acupuncture. With the development of life science and technology, the wisdom and foresight of TCM has been more displayed. Furthermore, TCM has been also inherited and developed in innovation to better realize the modernization and globalization. Nowadays, intestinal flora transforming TCM and TCM targeted intestinal flora treating diseases have been important findings in life science. More and more TCM researches showed the significance of intestinal flora. Intestinal flora is also a way to study TCM to elucidate the profound theory of TCM. Processing, compatibility, and properties of TCM are well demonstrated by intestinal flora. Thus, it is no doubt that intestinal flora is a core in TCM study. The interaction between intestinal flora and TCM is so crucial for host health. Therefore, it is necessary to sum up the latest results in time. This paper systematically depicted the profile of TCM and the importance of intestinal flora in host. What is more, we comprehensively summarized and discussed the latest progress of the interplay between TCM and intestinal flora to better reveal the core connotation of TCM.
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Affiliation(s)
- Xiao Li
- Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin 150040, P. R. China
| | - Dan Wu
- Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin 150040, P. R. China
| | - Jingjie Niu
- Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin 150040, P. R. China
| | - Yanping Sun
- Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin 150040, P. R. China
| | - Qiuhong Wang
- Department of Natural Medicinal Chemistry, College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China
| | - Bingyou Yang
- Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin 150040, P. R. China
| | - Haixue Kuang
- Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin 150040, P. R. China
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Zhang HY, Tian JX, Lian FM, Li M, Liu WK, Zhen Z, Liao JQ, Tong XL. Therapeutic mechanisms of traditional Chinese medicine to improve metabolic diseases via the gut microbiota. Biomed Pharmacother 2020; 133:110857. [PMID: 33197760 DOI: 10.1016/j.biopha.2020.110857] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 09/01/2020] [Accepted: 09/10/2020] [Indexed: 12/18/2022] Open
Abstract
Metabolic diseases such as obesity, type 2 diabetes mellitus, and hyperlipidemia are associated with the dysfunction of gut microbiota. Traditional Chinese medicines (TCMs) have shown considerable effects in the treatment of metabolic disorders by regulating the gut microbiota. However, the underlying mechanisms are unclear. Studies have shown that TCMs significantly affect glucose and lipid metabolism by modulating the gut microbiota, particularly mucin-degrading bacteria, bacteria with anti-inflammatory properties, lipopolysaccharide- and short-chain fatty acid (SCFA)-producing bacteria, and bacteria with bile-salt hydrolase activity. In this review, we explored potential mechanisms by which TCM improved metabolic disorders via regulating gut microbiota composition and functional structure. In particular, we focused on the protection of the intestinal barrier function, modulation of metabolic endotoxemia and inflammatory responses, regulation of the effects of SCFAs, modulation of the gut-brain axis, and regulation of bile acid metabolism and tryptophan metabolism as therapeutic mechanisms of TCMs in metabolic diseases.
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Affiliation(s)
- Hai-Yu Zhang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China; Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, 100029, China
| | - Jia-Xing Tian
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
| | - Feng-Mei Lian
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Min Li
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Wen-Ke Liu
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Zhong Zhen
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Jiang-Quan Liao
- Department of National Integrated Traditional and Western Medicine Center for Cardiovascular Disease, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Xiao-Lin Tong
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
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Leonardi BF, Gosmann G, Zimmer AR. Modeling Diet-Induced Metabolic Syndrome in Rodents. Mol Nutr Food Res 2020; 64:e2000249. [PMID: 32978870 DOI: 10.1002/mnfr.202000249] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 08/24/2020] [Indexed: 12/17/2022]
Abstract
Standardized animal models represent one of the most valuable tools available to understand the mechanism underlying the metabolic syndrome (MetS) and to seek for new therapeutic strategies. However, there is considerable variability in the studies conducted with this essential purpose. This review presents an updated discussion of the most recent studies using diverse experimental conditions to induce MetS in rodents with unbalanced diets, discusses the key findings in metabolic outcomes, and critically evaluates what we have been learned from them and how to advance in the field. The study includes scientific reports sourced from the Web of Science and PubMed databases, published between January 2013 and June 2020, which used hypercaloric diets to induce metabolic disorders, and address the impact of the diet on metabolic parameters. The collected data are used as support to discuss variables such as sex, species, and age of the animals, the most favorable type of diet, and the ideal diet length to generate metabolic changes. The experimental characteristics propose herein improve the performance of a preclinical model that resembles the human MetS and will guide researchers to investigate new therapeutic alternatives with confidence and higher translational validity.
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Affiliation(s)
- Bianca F Leonardi
- Phytochemistry and Organic Synthesis Laboratory, Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul (UFRGS), 2752 Ipiranga avenue, Porto Alegre, RS, 90610-000, Brazil
| | - Grace Gosmann
- Phytochemistry and Organic Synthesis Laboratory, Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul (UFRGS), 2752 Ipiranga avenue, Porto Alegre, RS, 90610-000, Brazil
| | - Aline R Zimmer
- Phytochemistry and Organic Synthesis Laboratory, Pharmaceutical Sciences Graduate Program, Faculty of Pharmacy, Federal University of Rio Grande do Sul (UFRGS), 2752 Ipiranga avenue, Porto Alegre, RS, 90610-000, Brazil
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The effect of Faecalibacterium prausnitzii and its extracellular vesicles on the permeability of intestinal epithelial cells and expression of PPARs and ANGPTL4 in the Caco-2 cell culture model. J Diabetes Metab Disord 2020; 19:1061-1069. [PMID: 33520823 DOI: 10.1007/s40200-020-00605-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 07/29/2020] [Accepted: 07/31/2020] [Indexed: 12/12/2022]
Abstract
Background and Objectives Gut microbiota such as Faecalibacterium prausnitzii play a major role in the regulation of gut barrier, inflammation and metabolic functions. Microbiota-derived extracellular vehicles (EVs) have been recently introduced as functional units mediating the eukaryotic and prokaryotic cell-microbiota interactions. In this paper, the effect of F. prausnitzii and its EVs on mRNA expression levels of tight junction genes (ZO1 and OCLN) as well as PPARs and ANGPTL4 genes in the human epithelial colorectal adenocarcinoma (Caco-2) cell line was evaluated. Methods F. prausnitzii was cultured on the Brain Heart Infusion (BHI) broth medium under anaerobic conditions, and its EVs were extracted by ultracentrifugation. This bacterium and its EVs were treated on the Caco-2 cells. After 24 h, the expression of the genes encoding TJ proteins such as ZO1 and OCLN, PPARs and ANGPTL4 was evaluated by quantitative real-time PCR. Results Unlike F. prausnitzii, its EVs significantly increased the expression of ZO1 and OCLN genes, and PPARα, PPARγ and PPARβ/δ genes (except at a concentration of 100 µg/ml) as well as ANGPTL4 gene. Conclusions The results of this study demonstrated that F. prausnitzii-derived EVs increased the intestinal barrier permeability via TJs (ZO1 and OCLN) as well as PPAR-α, PPAR-γ and PPAR β/δ genes and their targeted gene (ANGPTL4) in the Caco-2 cell line. Accordingly, it is suggested that F. prausnitzii-derived EVs can be considered as a new bacterial postbiotic to cure dysbiosis-associated diseases including obesity and its related metabolic dysfunctions, according to the leaky gut hypothesis.
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A novel compound DBZ ameliorates neuroinflammation in LPS-stimulated microglia and ischemic stroke rats: Role of Akt(Ser473)/GSK3β(Ser9)-mediated Nrf2 activation. Redox Biol 2020; 36:101644. [PMID: 32863210 PMCID: PMC7371982 DOI: 10.1016/j.redox.2020.101644] [Citation(s) in RCA: 147] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 06/30/2020] [Accepted: 07/11/2020] [Indexed: 01/07/2023] Open
Abstract
Microglia-mediated neuroinflammation plays a crucial role in the pathophysiological process of multiple neurological disorders such as ischemic stroke, yet lacks effective therapeutic agents. Previously, we discovered one novel synthetic compound, tanshinol borneol ester (DBZ), possesses anti-inflammatory and anti-atherosclerotic activities, whereas little is known about its effects in CNS. Therefore, the present study aims to explore the effects and potential mechanism of DBZ on neuroinflammation and microglial function. Our studies revealed that DBZ significantly inhibited NF-κB activity, suppressed the production of pro-inflammatory mediators meanwhile promoted M2 mediators expression in LPS-stimulated BV2 cells and mouse primary microglia cells. DBZ also exhibited antioxidant activity by enhancing Nrf2 nuclear accumulation and transcriptional activity, increasing HO-1 and NQO1 expression, and inhibiting LPS-induced ROS generation in BV2 cells. Importantly, the anti-neuroinflammatory and antioxidant effects of DBZ above were reversed by Nrf2 knockdown. Additionally, DBZ ameliorated sickness behaviors of neuroinflammatory mice induced by systemic LPS administration, and significantly reduced infract volume, improved sensorimotor and cognitive function in rats subjected to transient middle cerebral artery occlusion (tMCAO); besides, DBZ restored microglia morphological alterations and shifted the M1/M2 polarization in both murine models. Mechanistically, DBZ-induced Nrf2 nuclear accumulation and antioxidant enzymes expression were accompanied by increased level of p-Akt(Ser473) (activation) and p-GSK3β(Ser9) (inactivation), and decreased nuclear level of Fyn both in vitro and in vivo. Pharmacologically inhibiting PI3K or activating GSK3β markedly increased nuclear density of Fyn in microglia cells, which blocked the promoting effect of DBZ on Nrf2 nuclear accumulation and its antioxidant and anti-neuroinflammatory activities. Collectively, these results indicated the effects of DBZ on microglia-mediated neuroinflammation were strongly associated with the nuclear accumulation and stabilization of Nrf2 via the Akt(Ser473)/GSK3β(Ser9)/Fyn pathway. With anti-neuroinflammatory and antioxidant properties, DBZ could be a promising new drug candidate for prevention and/or treatment of cerebral ischemia and other neuroinflammatory disorders.
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Ye P, Xi Y, Huang Z, Xu P. Linking Obesity with Colorectal Cancer: Epidemiology and Mechanistic Insights. Cancers (Basel) 2020; 12:cancers12061408. [PMID: 32486076 PMCID: PMC7352519 DOI: 10.3390/cancers12061408] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 05/24/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023] Open
Abstract
The incidence of obesity and colorectal cancer (CRC) has risen rapidly in recent decades. More than 650 million obese and 2 billion overweight individuals are currently living in the world. CRC is the third most common cancer. Obesity is regarded as one of the key environmental risk factors for the pathogenesis of CRC. In the present review, we mainly focus on the epidemiology of obesity and CRC in the world, the United States, and China. We also summarize the molecular mechanisms linking obesity to CRC in different aspects, including nutriology, adipokines and hormones, inflammation, gut microbiota, and bile acids. The unmet medical needs for obesity-related CRC are still remarkable. Understanding the molecular basis of these associations will help develop novel therapeutic targets and approaches for the treatment of obesity-related CRC.
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Affiliation(s)
- Pengfei Ye
- College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471003, China;
| | - Yue Xi
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA;
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China;
| | - Zhiying Huang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China;
| | - Pengfei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA;
- Correspondence: ; Tel.: +1-412-708-4694
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How gut microbiota relate to the oral antidiabetic treatment of type 2 diabetes. MEDICINE IN MICROECOLOGY 2020. [DOI: 10.1016/j.medmic.2020.100007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Melatonin Orchestrates Lipid Homeostasis through the Hepatointestinal Circadian Clock and Microbiota during Constant Light Exposure. Cells 2020; 9:cells9020489. [PMID: 32093272 PMCID: PMC7072737 DOI: 10.3390/cells9020489] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 02/17/2020] [Accepted: 02/17/2020] [Indexed: 02/07/2023] Open
Abstract
Misalignment between natural light rhythm and modern life activities induces disruption of the circadian rhythm. It is mainly evident that light at night (LAN) interferes with the human endocrine system and contributes to the increasing rates of obesity and lipid metabolic disease. Maintaining hepatointestinal circadian homeostasis is vital for improving lipid homeostasis. Melatonin is a chronobiotic substance that plays a main role in stabilizing bodily rhythm and has shown beneficial effects in protecting against obesity. Based on the dual effect of circadian rhythm regulation and antiobesity, we tested the effect of melatonin in mice under constant light exposure. Exposure to 24-h constant light (LL) increased weight and insulin resistance compared with those of the control group (12-h light–12-h dark cycle, LD), and simultaneous supplementation in the melatonin group (LLM) ameliorated this phenotype. Constant light exposure disturbed the expression pattern of a series of transcripts, including lipid metabolism, circadian regulation and nuclear receptors in the liver. Melatonin also showed beneficial effects in improving lipid metabolism and circadian rhythm homeostasis. Furthermore, the LL group had increased absorption and digestion of lipids in the intestine as evidenced by the elevated influx of lipids in the duodenum and decrease in the efflux of lipids in the jejunum. More interestingly, melatonin ameliorated the gut microbiota dysbiosis and improved lipid efflux from the intestine. Thus, these findings offer a novel clue regarding the obesity-promoting effect attributed to LAN and suggest a possibility for obesity therapy by melatonin in which melatonin could ameliorate rhythm disorder and intestinal dysbiosis.
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An X, Bao Q, Di S, Zhao Y, Zhao S, Zhang H, Lian F, Tong X. The interaction between the gut Microbiota and herbal medicines. Biomed Pharmacother 2019; 118:109252. [DOI: 10.1016/j.biopha.2019.109252] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 07/18/2019] [Accepted: 07/18/2019] [Indexed: 12/14/2022] Open
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Relationship between Changes in Microbiota and Liver Steatosis Induced by High-Fat Feeding-A Review of Rodent Models. Nutrients 2019; 11:nu11092156. [PMID: 31505802 PMCID: PMC6770892 DOI: 10.3390/nu11092156] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 08/15/2019] [Accepted: 08/22/2019] [Indexed: 12/15/2022] Open
Abstract
Several studies have observed that gut microbiota can play a critical role in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) development. The gut microbiota is influenced by different environmental factors, which include diet. The aim of the present review is to summarize the information provided in the literature concerning the impact of changes in gut microbiota on the effects which dietary fat has on liver steatosis in rodent models. Most studies in which high-fat feeding has induced steatosis have reported reduced microbiota diversity, regardless of the percentage of energy provided by fat. At the phylum level, an increase in Firmicutes and a reduction in Bacteroidetes is commonly found, although widely diverging results have been described at class, order, family, and genus levels, likely due to differences in experimental design. Unfortunately, this fact makes it difficult to reach clear conclusions concerning the specific microbiota patterns associated with this feeding pattern. With regard to the relationship between high-fat feeding-induced changes in liver and microbiota composition, although several mechanisms such as alteration of gut integrity and increased permeability, inflammation, and metabolite production have been proposed, more scientific evidence is needed to address this issue and thus further studies are needed.
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Hong F, Pan S, Guo Y, Xu P, Zhai Y. PPARs as Nuclear Receptors for Nutrient and Energy Metabolism. Molecules 2019; 24:molecules24142545. [PMID: 31336903 PMCID: PMC6680900 DOI: 10.3390/molecules24142545] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 07/08/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023] Open
Abstract
It has been more than 36 years since peroxisome proliferator-activated receptors (PPARs) were first recognized as enhancers of peroxisome proliferation. Consequently, many studies in different fields have illustrated that PPARs are nuclear receptors that participate in nutrient and energy metabolism and regulate cellular and whole-body energy homeostasis during lipid and carbohydrate metabolism, cell growth, cancer development, and so on. With increasing challenges to human health, PPARs have attracted much attention for their ability to ameliorate metabolic syndromes. In our previous studies, we found that the complex functions of PPARs may be used as future targets in obesity and atherosclerosis treatments. Here, we review three types of PPARs that play overlapping but distinct roles in nutrient and energy metabolism during different metabolic states and in different organs. Furthermore, research has emerged showing that PPARs also play many other roles in inflammation, central nervous system-related diseases, and cancer. Increasingly, drug development has been based on the use of several selective PPARs as modulators to diminish the adverse effects of the PPAR agonists previously used in clinical practice. In conclusion, the complex roles of PPARs in metabolic networks keep these factors in the forefront of research because it is hoped that they will have potential therapeutic effects in future applications.
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Affiliation(s)
- Fan Hong
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Shijia Pan
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Yuan Guo
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Pengfei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.
| | - Yonggong Zhai
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
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Liao S, Han L, Zheng X, Wang X, Zhang P, Wu J, Liu R, Fu Y, Sun J, Kang X, Liu K, Fan TP, Li S, Zheng X. Tanshinol borneol ester, a novel synthetic small molecule angiogenesis stimulator inspired by botanical formulations for angina pectoris. Br J Pharmacol 2019; 176:3143-3160. [PMID: 31116880 DOI: 10.1111/bph.14714] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 04/16/2019] [Accepted: 05/14/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND AND PURPOSE Tanshinol borneol ester (DBZ) is a novel synthetic compound derived from Dantonic® , a botanical drug approved in 26 countries outside the United States for angina pectoris and currently undergoing FDA Phase III clinical trial. Here, we investigated the angiogenic effects of (S)-DBZ and (R)-DBZ isomers in vitro and in vivo. EXPERIMENTAL APPROACH A network pharmacology approach was used to predict molecular targets of DBZ. The effects of DBZ isomers on proliferation, migration, and tube formation of human endothelial cells were assessed. For in vivo approaches, the transgenic Tg (vegfr2:GFP) zebrafish and C57BL/6 mouse Matrigel plug models were used. ELISA and western blots were used to quantitate the release and expression of relevant target molecules and signalling pathways. KEY RESULTS DBZ produced a biphasic modulation on proliferation and migration of three types of human endothelial cells. Both DBZ isomers induced tube formation in Matrigel assay and a 12-day co-culture model in vitro. Moreover, DBZ promoted Matrigel neovascularization in mice and partially reversed the vascular disruption in zebrafish induced by PTK787. Mechanistically, DBZ enhanced the cellular levels of VEGF, VEGFR2, and MMP-9, as well as activating Akt and MAPK signalling in endothelial cells. Selective inhibition of PI3K and MEK significantly attenuated its angiogenic effects. CONCLUSIONS AND IMPLICATIONS These data reveal, for the first time, that DBZ promotes multiple key steps of angiogenesis, at least in part through Akt and MAPK signalling pathways, and suggest it may be potentially developed further for treating myocardial infarction and other cardiovascular diseases.
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Affiliation(s)
- Sha Liao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Science and Medicine, Northwest University, Xi'an, China.,Angiogenesis and Chinese Medicine Laboratory, Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - Liwen Han
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China
| | - Xiaopu Zheng
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Xin Wang
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRist/Department of Automation, Tsinghua University, Beijing, China
| | - Peng Zhang
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRist/Department of Automation, Tsinghua University, Beijing, China
| | - Jingni Wu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Science and Medicine, Northwest University, Xi'an, China
| | - Ruimin Liu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Science and Medicine, Northwest University, Xi'an, China
| | - Youlan Fu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Science and Medicine, Northwest University, Xi'an, China
| | - Jiaxin Sun
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Science and Medicine, Northwest University, Xi'an, China
| | - Ximeng Kang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Science and Medicine, Northwest University, Xi'an, China
| | - Kechun Liu
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China
| | - Tai-Ping Fan
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Science and Medicine, Northwest University, Xi'an, China.,Angiogenesis and Chinese Medicine Laboratory, Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - Shao Li
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRist/Department of Automation, Tsinghua University, Beijing, China
| | - Xiaohui Zheng
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Science and Medicine, Northwest University, Xi'an, China
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Zhao Z, Bai Y, Xie J, Chen X, He X, Sun Y, Bai Y, Zhang Y, Wu S, Zheng X. Excavating precursors from the traditional Chinese herb Polygala tenuifolia and Gastrodia elata: Synthesis, anticonvulsant activity evaluation of 3,4,5-trimethoxycinnamic acid (TMCA) ester derivatives. Bioorg Chem 2019; 88:102832. [DOI: 10.1016/j.bioorg.2019.03.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 02/27/2019] [Accepted: 03/02/2019] [Indexed: 12/19/2022]
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Zhao Z, Song H, Xie J, Liu T, Zhao X, Chen X, He X, Wu S, Zhang Y, Zheng X. Research progress in the biological activities of 3,4,5-trimethoxycinnamic acid (TMCA) derivatives. Eur J Med Chem 2019; 173:213-227. [PMID: 31009908 PMCID: PMC7115657 DOI: 10.1016/j.ejmech.2019.04.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 04/02/2019] [Accepted: 04/02/2019] [Indexed: 01/02/2023]
Abstract
TMCA (3,4,5-trimethoxycinnamic acid) ester and amide are privileged structural scaffolds in drug discovery which are widely distributed in natural products and consequently produced diverse therapeutically relevant pharmacological functions. Owing to the potential of TMCA ester and amide analogues as therapeutic agents, researches on chemical syntheses and modifications have been carried out to drug-like candidates with broad range of medicinal properties such as antitumor, antiviral, CNS (central nervous system) agents, antimicrobial, anti-inflammatory and hematologic agents for a long time. At the same time, SAR (structure-activity relationship) studies have draw greater attention among medicinal chemists, and many of the lead compounds were derived for various disease targets. However, there is an urgent need for the medicinal chemists to further exploit the precursor in developing chemical entities with promising bioactivity and druggability. This review concisely summarizes the synthesis and biological activity for TMCA ester and amide analogues. It also comprehensively reveals the relationship of significant biological activities along with SAR studies.
3,4,5-Trimethoxycinnamic acid (TMCA) derivatives show applications in different pathophysiological conditions due to its privileged structural scaffolds. Natural derived TMCA analogues and chemically modified TMCA ester and amide analogues and their bioactivities are focused in this review. Additionally, it also comprehensively summarized the relationship of significant biological activities along with SAR studies of synthetic TMCA derivatives.
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Affiliation(s)
- Zefeng Zhao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai Road, Xi'an, 710069, China
| | - Huanhuan Song
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai Road, Xi'an, 710069, China; Biomedicine Key Laboratory of Shaanxi Province, Northwest University, Xi'an, Shaanxi, 710069, China
| | - Jing Xie
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai Road, Xi'an, 710069, China
| | - Tian Liu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai Road, Xi'an, 710069, China
| | - Xue Zhao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai Road, Xi'an, 710069, China
| | - Xufei Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai Road, Xi'an, 710069, China
| | - Xirui He
- Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Shaoping Wu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai Road, Xi'an, 710069, China; Biomedicine Key Laboratory of Shaanxi Province, Northwest University, Xi'an, Shaanxi, 710069, China.
| | - Yongmin Zhang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai Road, Xi'an, 710069, China; Biomedicine Key Laboratory of Shaanxi Province, Northwest University, Xi'an, Shaanxi, 710069, China; Sorbonne Université, Institut Parisien de Chimie Moléculaire, CNRS UMR 8232, 4 place Jussieu, 75005, Paris, France
| | - Xiaohui Zheng
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai Road, Xi'an, 710069, China.
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Anlu W, Dongcheng C, He Z, Qiuyi L, Yan Z, Yu Q, Hao X, Keji C. Using herbal medicine to target the “microbiota-metabolism-immunity” axis as possible therapy for cardiovascular disease. Pharmacol Res 2019; 142:205-222. [DOI: 10.1016/j.phrs.2019.02.018] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 02/18/2019] [Accepted: 02/18/2019] [Indexed: 02/08/2023]
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Interactions between Host PPARs and Gut Microbiota in Health and Disease. Int J Mol Sci 2019; 20:ijms20020387. [PMID: 30658440 PMCID: PMC6359605 DOI: 10.3390/ijms20020387] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 12/28/2018] [Accepted: 01/05/2019] [Indexed: 12/12/2022] Open
Abstract
The human gastrointestinal tract is inhabited by many types of microbiota, including bacteria, viruses, and fungi. Dysregulations of their microenvironment are associated with various health problems, not only limited to gastrointestinal disorders, such as inflammatory bowel disease, but to impacts beyond the intestine. For example, intestinal microbiota can affect the liver in non-alcoholic fatty liver disease, visceral adipose tissue during adipogenesis, and the heart in atherosclerosis. The factors contributing to these pathogeneses involve the gut microbiota and the effector organs of the host, and everything in between. The nuclear receptor peroxisome proliferator-activated receptors (PPARs) are pivotal for the modulation of many of the pathogeneses mentioned above. It is, therefore, conceivable that, in the process of host-microbiota interactions, PPARs play important roles. In this review, we focus on the interactions between host PPARs in different organs and gut microbiota and their impacts on maintaining health and various diseases.
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Gérard C, Vidal H. Impact of Gut Microbiota on Host Glycemic Control. Front Endocrinol (Lausanne) 2019; 10:29. [PMID: 30761090 PMCID: PMC6363653 DOI: 10.3389/fendo.2019.00029] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 01/15/2019] [Indexed: 12/12/2022] Open
Abstract
Given that obesity and associated disorder type II diabetes mellitus have reached epidemic proportions worldwide, the development of efficient prevention and therapeutic interventions is a global public health interest. There is now a large body of evidence suggesting that the micro-organisms colonizing the human gut, known as gut microbiota, play a central role in human physiology and metabolism. Understanding how gut microbiota affects and regulates key metabolic functions such as glucose regulation and insulin resistance is an important health issue. The present review summarizes recent advances in our understanding of how gut bacterial species interfere with host metabolic phenotype. We will examine key biological molecular mechanisms underlying the impact of gut microbiota on host glycemic control including: incretin secretion, short-chain fatty acid production, bile acid metabolism, and adipose tissue regulation. We will highlight how prebiotic/probiotic interventions affect these bacterial processes and are now considered as promising approaches to treat obese and diabetic patients.
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Wu XM, Tan RX. Interaction between gut microbiota and ethnomedicine constituents. Nat Prod Rep 2019; 36:788-809. [DOI: 10.1039/c8np00041g] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This highlight reviews the interaction processes between gut microbiota and ethnomedicine constituents, which may conceptualize future therapeutic strategies.
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Affiliation(s)
- Xue Ming Wu
- State Key Laboratory Cultivation Base for TCM Quality and Efficacy
- Nanjing University of Chinese Medicine
- Nanjing
- China
| | - Ren Xiang Tan
- State Key Laboratory Cultivation Base for TCM Quality and Efficacy
- Nanjing University of Chinese Medicine
- Nanjing
- China
- State Key Laboratory of Pharmaceutical Biotechnology
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Hong F, Xu P, Zhai Y. The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development. Int J Mol Sci 2018; 19:ijms19082189. [PMID: 30060458 PMCID: PMC6121873 DOI: 10.3390/ijms19082189] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 07/16/2018] [Accepted: 07/24/2018] [Indexed: 12/12/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a well-known pharmacological target for the treatment of multiple diseases, including diabetes mellitus, dyslipidemia, cardiovascular diseases and even primary biliary cholangitis, gout, cancer, Alzheimer's disease and ulcerative colitis. The three PPAR isoforms (α, β/δ and γ) have emerged as integrators of glucose and lipid metabolic signaling networks. Typically, PPARα is activated by fibrates, which are commonly used therapeutic agents in the treatment of dyslipidemia. The pharmacological activators of PPARγ include thiazolidinediones (TZDs), which are insulin sensitizers used in the treatment of type 2 diabetes mellitus (T2DM), despite some drawbacks. In this review, we summarize 84 types of PPAR synthetic ligands introduced to date for the treatment of metabolic and other diseases and provide a comprehensive analysis of the current applications and problems of these ligands in clinical drug discovery and development.
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Affiliation(s)
- Fan Hong
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
| | - Pengfei Xu
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
| | - Yonggong Zhai
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
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Panchal SK, Bliss E, Brown L. Capsaicin in Metabolic Syndrome. Nutrients 2018; 10:E630. [PMID: 29772784 PMCID: PMC5986509 DOI: 10.3390/nu10050630] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 05/07/2018] [Accepted: 05/14/2018] [Indexed: 12/21/2022] Open
Abstract
Capsaicin, the major active constituent of chilli, is an agonist on transient receptor potential vanilloid channel 1 (TRPV1). TRPV1 is present on many metabolically active tissues, making it a potentially relevant target for metabolic interventions. Insulin resistance and obesity, being the major components of metabolic syndrome, increase the risk for the development of cardiovascular disease, type 2 diabetes, and non-alcoholic fatty liver disease. In vitro and pre-clinical studies have established the effectiveness of low-dose dietary capsaicin in attenuating metabolic disorders. These responses of capsaicin are mediated through activation of TRPV1, which can then modulate processes such as browning of adipocytes, and activation of metabolic modulators including AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor α (PPARα), uncoupling protein 1 (UCP1), and glucagon-like peptide 1 (GLP-1). Modulation of these pathways by capsaicin can increase fat oxidation, improve insulin sensitivity, decrease body fat, and improve heart and liver function. Identifying suitable ways of administering capsaicin at an effective dose would warrant its clinical use through the activation of TRPV1. This review highlights the mechanistic options to improve metabolic syndrome with capsaicin.
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Affiliation(s)
- Sunil K Panchal
- Functional Foods Research Group, University of Southern Queensland, Toowoomba QLD 4350, Australia.
| | - Edward Bliss
- Functional Foods Research Group, University of Southern Queensland, Toowoomba QLD 4350, Australia.
- School of Health and Wellbeing, University of Southern Queensland, Toowoomba QLD 4350, Australia.
| | - Lindsay Brown
- Functional Foods Research Group, University of Southern Queensland, Toowoomba QLD 4350, Australia.
- School of Health and Wellbeing, University of Southern Queensland, Toowoomba QLD 4350, Australia.
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The Role of PPAR and Its Cross-Talk with CAR and LXR in Obesity and Atherosclerosis. Int J Mol Sci 2018; 19:ijms19041260. [PMID: 29690611 PMCID: PMC5979375 DOI: 10.3390/ijms19041260] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 04/13/2018] [Accepted: 04/19/2018] [Indexed: 02/06/2023] Open
Abstract
The prevalence of obesity and atherosclerosis has substantially increased worldwide over the past several decades. Peroxisome proliferator-activated receptors (PPARs), as fatty acids sensors, have been therapeutic targets in several human lipid metabolic diseases, such as obesity, atherosclerosis, diabetes, hyperlipidaemia, and non-alcoholic fatty liver disease. Constitutive androstane receptor (CAR) and liver X receptors (LXRs) were also reported as potential therapeutic targets for the treatment of obesity and atherosclerosis, respectively. Further clarification of the internal relationships between these three lipid metabolic nuclear receptors is necessary to enable drug discovery. In this review, we mainly summarized the cross-talk of PPARs-CAR in obesity and PPARs-LXRs in atherosclerosis.
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Lv Y, Zhao X, Guo W, Gao Y, Yang S, Li Z, Wang G. The Relationship between Frequently Used Glucose-Lowering Agents and Gut Microbiota in Type 2 Diabetes Mellitus. J Diabetes Res 2018; 2018:1890978. [PMID: 29854817 PMCID: PMC5964532 DOI: 10.1155/2018/1890978] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 02/16/2018] [Accepted: 03/18/2018] [Indexed: 12/11/2022] Open
Abstract
Metabolic diseases, especially diabetes mellitus, have become global health issues. The etiology of diabetes mellitus can be attributed to genetic and/or environmental factors. Current evidence suggests the association of gut microbiota with metabolic diseases. However, the effects of glucose-lowering agents on gut microbiota are poorly understood. Several studies revealed that these agents affect the composition and diversity of gut microbiota and consequently improve glucose metabolism and energy balance. Possible underlying mechanisms include affecting gene expression, lowering levels of inflammatory cytokines, and regulating the production of short-chain fatty acids. In addition, gut microbiota may alleviate adverse effects caused by glucose-lowering agents, and this can be especially beneficial in diabetic patients who experience severe gastrointestinal side effects and have to discontinue these agents. In conclusion, gut microbiota may provide a novel viewpoint for the treatment of patients with diabetes mellitus.
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Affiliation(s)
- You Lv
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xue Zhao
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Weiying Guo
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Ying Gao
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Shuo Yang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Zhuo Li
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Guixia Wang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, China
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Lach G, Schellekens H, Dinan TG, Cryan JF. Anxiety, Depression, and the Microbiome: A Role for Gut Peptides. Neurotherapeutics 2018; 15:36-59. [PMID: 29134359 PMCID: PMC5794698 DOI: 10.1007/s13311-017-0585-0] [Citation(s) in RCA: 358] [Impact Index Per Article: 51.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The complex bidirectional communication between the gut and the brain is finely orchestrated by different systems, including the endocrine, immune, autonomic, and enteric nervous systems. Moreover, increasing evidence supports the role of the microbiome and microbiota-derived molecules in regulating such interactions; however, the mechanisms underpinning such effects are only beginning to be resolved. Microbiota-gut peptide interactions are poised to be of great significance in the regulation of gut-brain signaling. Given the emerging role of the gut-brain axis in a variety of brain disorders, such as anxiety and depression, it is important to understand the contribution of bidirectional interactions between peptide hormones released from the gut and intestinal bacteria in the context of this axis. Indeed, the gastrointestinal tract is the largest endocrine organ in mammals, secreting dozens of different signaling molecules, including peptides. Gut peptides in the systemic circulation can bind cognate receptors on immune cells and vagus nerve terminals thereby enabling indirect gut-brain communication. Gut peptide concentrations are not only modulated by enteric microbiota signals, but also vary according to the composition of the intestinal microbiota. In this review, we will discuss the gut microbiota as a regulator of anxiety and depression, and explore the role of gut-derived peptides as signaling molecules in microbiome-gut-brain communication. Here, we summarize the potential interactions of the microbiota with gut hormones and endocrine peptides, including neuropeptide Y, peptide YY, pancreatic polypeptide, cholecystokinin, glucagon-like peptide, corticotropin-releasing factor, oxytocin, and ghrelin in microbiome-to-brain signaling. Together, gut peptides are important regulators of microbiota-gut-brain signaling in health and stress-related psychiatric illnesses.
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Affiliation(s)
- Gilliard Lach
- APC Microbiome Institute, University College Cork, Cork, Ireland
| | - Harriet Schellekens
- APC Microbiome Institute, University College Cork, Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
- Food for Health Ireland, University College Cork, Cork, Ireland
| | - Timothy G Dinan
- APC Microbiome Institute, University College Cork, Cork, Ireland
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Institute, University College Cork, Cork, Ireland.
- Food for Health Ireland, University College Cork, Cork, Ireland.
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Gut-Bioreactor and Human Health in Future. Indian J Microbiol 2017; 58:3-7. [PMID: 29434391 DOI: 10.1007/s12088-017-0697-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 12/09/2017] [Indexed: 12/22/2022] Open
Abstract
Gut-microbiome provides the complementary metabolic potential to the human system. To understand the active participation and the performance of the microbial community in human health, the concept of gut as a plug-flow reactor with the fed-batch mode of operation can provide better insight. The concept suggests the virtual compartmentalized gut with sequential stratification of the microbial community in response to a typical host genotype. It also provides the analysis plan for gut microbiome; and its relevance in developing health management options under the identified clinical conditions.
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