|
1
|
Gao A, Ni Y, Chen C, Xin W, Wang Y, Zhang W. Covalent binding of Geniposide metabolites to hepatic proteins: A potential mechanism for its hepatotoxicity. Chem Biol Interact 2025; 408:111411. [PMID: 39914502 DOI: 10.1016/j.cbi.2025.111411] [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: 12/13/2024] [Revised: 01/26/2025] [Accepted: 02/04/2025] [Indexed: 02/13/2025]
Abstract
Gardeniae fructus (GF) is a widely used traditional Chinese medicine; however, its application is limited due to the hepatotoxicity of its main active component, Geniposide (GE). To investigate the material basis and mechanisms of GE-induced hepatotoxicity. We utilized an in vitro gastrointestinal model to examine metabolic processes, conducted in vivo experiments to study GE's hepatotoxic effects and performed cellular experiments to verify toxic effects. Results indicated that GE-induced hepatotoxicity is associated with its metabolite Genipin (GP), with GP's hemiacetal structure being a key factor. Upon exposure of the C-1 hydroxyl group of GP, a covalent binding reaction occurs with amino acids. This reaction readily proceeds as a phase II conjugation with the amino group of lysine (LYS), resulting in the formation of genipin-lysine (GP-LYS) adducts. These adducts affect cellular oxidative stress and trigger cascading reactions leading to hepatotoxicity. Our findings not only highlight chemical structure as a crucial factor influencing toxicity but also advance the understanding of GE's toxic action mechanism. This study provides a foundation for guiding rational clinical use of GE and offers valuable insights for the development of novel GE-based pharmaceuticals.
Collapse
Affiliation(s)
- Ai Gao
- Engineering Research Center of Natural Medicine, Ministry of Education, Beijing Normal University, Zhuhai, 519087, China; Beijing Key Laboratory of Traditional Chinese Medicine Protection and Utilization, Faculty of Geographical Science, Beijing Normal University, Beijing, 100875, China
| | - Ying Ni
- Engineering Research Center of Natural Medicine, Ministry of Education, Beijing Normal University, Zhuhai, 519087, China; Beijing Key Laboratory of Traditional Chinese Medicine Protection and Utilization, Faculty of Geographical Science, Beijing Normal University, Beijing, 100875, China
| | - Chao Chen
- Engineering Research Center of Natural Medicine, Ministry of Education, Beijing Normal University, Zhuhai, 519087, China; Beijing Key Laboratory of Traditional Chinese Medicine Protection and Utilization, Faculty of Geographical Science, Beijing Normal University, Beijing, 100875, China
| | - Wenfeng Xin
- College of Notoginseng Medicine and Pharmacy of Wenshan University, Wenshan, 663099, China
| | - Yu Wang
- Engineering Research Center of Natural Medicine, Ministry of Education, Beijing Normal University, Zhuhai, 519087, China; Beijing Key Laboratory of Traditional Chinese Medicine Protection and Utilization, Faculty of Geographical Science, Beijing Normal University, Beijing, 100875, China
| | - Wensheng Zhang
- Engineering Research Center of Natural Medicine, Ministry of Education, Beijing Normal University, Zhuhai, 519087, China; Beijing Key Laboratory of Traditional Chinese Medicine Protection and Utilization, Faculty of Geographical Science, Beijing Normal University, Beijing, 100875, China.
| |
Collapse
|
|
2
|
Yan X, Qin D, Zhang W, Ren Y, Lyu Y, Ma J, Yu Q. Discovering the compatibility of Coptidis Rhizoma and Gardeniae Fructus in attenuating hepatotoxicity through the association rules analysis of related formula. JOURNAL OF ETHNOPHARMACOLOGY 2025; 341:119291. [PMID: 39798674 DOI: 10.1016/j.jep.2024.119291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 12/01/2024] [Accepted: 12/24/2024] [Indexed: 01/15/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Gardenia jasminoides J. Ellis (Gardeniae Fructus, GF) is a widely used herbal medicine in many prescriptions. However, inappropriate application of GF may induce hepatotoxicity, which greatly challenges its clinical application. In the field of Traditional Chinese Medicine, the principle of "Compatibility for Toxicity Attenuation" is a pivotal concept. So far, the basis and mechanisms of compatibility with GF remain unclear. AIMS OF THE STUDY We aimed to investigate the toxicity attenuating effects and potential mechanisms of compatibility of Coptis chinensis Franch (Coptidis Rhizoma, CR) and GF in hepatotoxicity. METHODS AND RESULTS Association rules analysis was performed in 817 GF-related formulas, and 49 associated items were selected, among which CR and GF were ranked in the top two. Network pharmacology was used to elucidate the potential mechanisms of combination of CR and GF in mitigating hepatotoxicity. Nine potential hepatotoxic components of GF and 14 active components of CR were focused on, and 9 common targets for CR and GF were identified. Further GO and KEGG analyses showed that the toxicity attenuating effect of CR on GF-induced hepatotoxicity may be closely correlated with inflammatory response, response to hypoxia, cancer signaling pathways, PI3K-Akt and HIF-1 signaling pathway. The in vitro results indicated that the combined use of CR and GF increased the viability of HepG2 cells. Furthermore, the in vivo data demonstrated that CR inhibited GF-induced increase in serum ALT and AST levels and pathological changes in the livers of KM mice. Besides, CR reduced the accumulation of ROS and MDA, inhibited the release of TNF-α and IL-6, while elevated GSH level in the mouse liver tissues. Finally, the molecular docking results indicated that the active components of CR had strong binding affinity with the monooxygenase cytochrome P450 3A4 (CYP3A4). CR combination restored the expression of CYP3A4 in the liver tissues of mice challenged with GF. CONCLUSION Co-administration with CR effectively reduced GF-induced hepatotoxicity through alleviating oxidative damage, inflammatory response and enhancing CYP3A4 expression.
Collapse
Affiliation(s)
- Xiaodan Yan
- Shenyang Pharmaceutical University, Shenyang, Liaoning, China
| | - Dan Qin
- Beijing University of Chinese Medicine, Beijing, China
| | - Wanting Zhang
- Shenyang Pharmaceutical University, Shenyang, Liaoning, China
| | - Yunyu Ren
- Shenyang Pharmaceutical University, Shenyang, Liaoning, China
| | - Yitong Lyu
- Shenyang Pharmaceutical University, Shenyang, Liaoning, China
| | - Jinyin Ma
- Shenyang Pharmaceutical University, Shenyang, Liaoning, China
| | - Qing Yu
- Shenyang Medical College, Shenyang, Liaoning, China.
| |
Collapse
|
|
3
|
Li D, Li X, Zhang X, Chen J, Wang Z, Yu Z, Wu M, Liu L. Geniposide for treating atherosclerotic cardiovascular disease: a systematic review on its biological characteristics, pharmacology, pharmacokinetics, and toxicology. Chin Med 2024; 19:111. [PMID: 39164773 PMCID: PMC11334348 DOI: 10.1186/s13020-024-00981-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 08/11/2024] [Indexed: 08/22/2024] Open
Abstract
In recent years, the prevalence and fatality rates of atherosclerotic cardiovascular disease have not only shown a consistent rise that cannot be ignored, but have also become a pressing social health problem that requires urgent attention. While interventional surgery and drug therapy offer significant therapeutic results, they often come with common side effects. Geniposide, an active component extracted from the Chinese medicine Gardenia jasminoides Ellis, shows promise in the management of cardiac conditions. This review comprehensively outlines the underlying pharmacological mechanisms by which geniposide exerts its effects on atherosclerosis. Geniposide exhibits a range of beneficial effects including alleviating inflammation, inhibiting the development of macrophage foam cells, improving lipid metabolism, and preventing platelet aggregation and thrombosis. It also demonstrates mitochondrial preservation, anti-apoptotic effects, and modulation of autophagy. Moreover, geniposide shows potential in improving oxidative stress and endoplasmic reticulum stress by maintaining the body's antioxidant and oxidative balance. Additionally, this review comprehensively details the biological properties of geniposide, including methods of extraction and purification, as well as its pharmacokinetics and toxicological characteristics. It further discusses the clinical applications of related biopharmaceuticals, emphasizing the potential of geniposide in the prevention and treatment of atherosclerotic cardiovascular diseases. Furthermore, it highlights the limitations of current research, aiming to provide insights for future studies.
Collapse
Affiliation(s)
- Dexiu Li
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Xiaoya Li
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Xiaonan Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Jiye Chen
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Zeping Wang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Zongliang Yu
- Beijing University of Chinese Medicine, Beijing, China
| | - Min Wu
- Guang'an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Longtao Liu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China.
| |
Collapse
|
|
4
|
Liu S, Tong Y, Shi R, Zeng X, Luo H, Yang P, Cai X, Wang D, Luo H, Wang J. Case report and literature review: Laparoscopic extended right hemicolectomy for a 55-year-old patient with idiopathic mesenteric phlebosclerosis. Front Med (Lausanne) 2024; 11:1382475. [PMID: 39081687 PMCID: PMC11286469 DOI: 10.3389/fmed.2024.1382475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 06/28/2024] [Indexed: 08/02/2024] Open
Abstract
Idiopathic mesenteric phlebosclerosis (IMP) is an extremely rare disease with an unclear pathogenesis and risk factors. The clinical manifestations of IMP are mostly non-specific, mainly consisting of digestive symptoms such as abdominal pain, bloating and diarrhea. The diagnosis of IMP mainly relies on abdominal computed tomography (CT) and colonoscopy. Pathological changes associated with IMP often involve fibrous degeneration of the venous wall, which results in the thickening of the colonic wall and longitudinal calcification of the mesenteric arteries. Currently, there is no standard treatment protocol for IMP, and nonsurgical treatment is the mainstay of most medical centers. In this study, we reported a case of a 55-year-old female patient with IMP whose main clinical presentation was recurrent abdominal pain. The patient's initial diagnosis was considered an incomplete intestinal obstruction and received non-surgical treatments; however, the efficacy of the treatment was unsatisfactory. After completing abdominal CT and colonoscopy, we excluded common diseases of the digestive system (e.g., tumors, Crohn's disease), and finally considered that this patient had a high likelihood of IMP. This patient eventually underwent laparoscopic enlarged right hemicolectomy due to recurrent symptoms and poor outcomes of non-surgical treatment. Postoperative pathological results confirmed the diagnosis of IMP. During the follow-up period, the patient recovered well without recurrence of IMP. Furthermore, we have reviewed the literature related to IMP and summarized the etiology, risk factors, diagnostic methods, treatment options and prognosis of IMP.
Collapse
Affiliation(s)
- Siyu Liu
- Department of Breast Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Yujun Tong
- Department of Breast Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Ruizi Shi
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Xintao Zeng
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Hua Luo
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Pei Yang
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Xianfu Cai
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Decai Wang
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
- NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Huiwen Luo
- NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Jianjun Wang
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
- NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| |
Collapse
|
|
5
|
Li G, Hou Y, Zhang C, Zhou X, Bao F, Yang Y, Chen L, Yu D. Interplay Between Drug-Induced Liver Injury and Gut Microbiota: A Comprehensive Overview. Cell Mol Gastroenterol Hepatol 2024; 18:101355. [PMID: 38729523 PMCID: PMC11260867 DOI: 10.1016/j.jcmgh.2024.05.003] [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: 02/21/2024] [Revised: 05/02/2024] [Accepted: 05/03/2024] [Indexed: 05/12/2024]
Abstract
Drug-induced liver injury is a prevalent severe adverse event in clinical settings, leading to increased medical burdens for patients and presenting challenges for the development and commercialization of novel pharmaceuticals. Research has revealed a close association between gut microbiota and drug-induced liver injury in recent years. However, there has yet to be a consensus on the specific mechanism by which gut microbiota is involved in drug-induced liver injury. Gut microbiota may contribute to drug-induced liver injury by increasing intestinal permeability, disrupting intestinal metabolite homeostasis, and promoting inflammation and oxidative stress. Alterations in gut microbiota were found in drug-induced liver injury caused by antibiotics, psychotropic drugs, acetaminophen, antituberculosis drugs, and antithyroid drugs. Specific gut microbiota and their abundance are associated closely with the severity of drug-induced liver injury. Therefore, gut microbiota is expected to be a new target for the treatment of drug-induced liver injury. This review focuses on the association of gut microbiota with common hepatotoxic drugs and the potential mechanisms by which gut microbiota may contribute to the pathogenesis of drug-induced liver injury, providing a more comprehensive reference for the interaction between drug-induced liver injury and gut microbiota.
Collapse
Affiliation(s)
- Guolin Li
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China; Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yifu Hou
- Department of Organ Transplantation, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China; Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province and Organ Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Changji Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China; Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xiaoshi Zhou
- Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Furong Bao
- Department of Nursing, Guanghan People's Hospital, Guanghan, China
| | - Yong Yang
- Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
| | - Lu Chen
- Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China; Department of Organ Transplantation, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
| | - Dongke Yu
- Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China; Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
| |
Collapse
|
|
6
|
Wang N, Chen L, Huang W, Gao Z, Jin M. Current Advances of Nanomaterial-Based Oral Drug Delivery for Colorectal Cancer Treatment. NANOMATERIALS (BASEL, SWITZERLAND) 2024; 14:557. [PMID: 38607092 PMCID: PMC11013305 DOI: 10.3390/nano14070557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 03/10/2024] [Accepted: 03/20/2024] [Indexed: 04/13/2024]
Abstract
Colorectal cancer (CRC) is a common malignant tumor, and traditional treatments include surgical resection and radiotherapy. However, local recurrence, distal metastasis, and intestinal obstruction are significant problems. Oral nano-formulation is a promising treatment strategy for CRC. This study introduces physiological and environmental factors, the main challenges of CRC treatment, and the need for a novel oral colon-targeted drug delivery system (OCDDS). This study reviews the research progress of controlled-release, responsive, magnetic, targeted, and other oral nano-formulations in the direction of CRC treatment, in addition to the advantages of oral colon-targeted nano-formulations and concerns about the oral delivery of related therapeutic agents to inspire related research.
Collapse
Affiliation(s)
- Nuoya Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; (N.W.); (L.C.); (W.H.)
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Department of Pharmacy, Yanbian University, Yanji 133000, China
| | - Liqing Chen
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; (N.W.); (L.C.); (W.H.)
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Wei Huang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; (N.W.); (L.C.); (W.H.)
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Zhonggao Gao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; (N.W.); (L.C.); (W.H.)
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Mingji Jin
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; (N.W.); (L.C.); (W.H.)
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| |
Collapse
|
|
7
|
Zhang L, Ma XG. A Comprehensive Review on Biotransformation, Interaction, and Health of Gut Microbiota and Bioactive Components. Comb Chem High Throughput Screen 2024; 27:1551-1565. [PMID: 37916626 DOI: 10.2174/0113862073257733231011072004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/25/2023] [Accepted: 09/06/2023] [Indexed: 11/03/2023]
Abstract
BACKGROUND The relationship between gut microbiota and bioactive components has become the research focus in the world. We attempted to clarify the relationship between biotransformation and metabolites of gut microbiota and bioactive components, and explore the metabolic pathway and mechanism of bioactive ingredients in vivo, which will provide an important theoretical basis for the clinical research of bioactive ingredients and rationality of drugs, and also provide an important reference for the development of new drugs with high bioavailability. METHODS The related references of this review on microbiota and bioactive components were collected from both online and offline databases, such as ScienceDirect, PubMed, Elsevier, Willy, SciFinder, Google Scholar, Web of Science, Baidu Scholar, SciHub, Scopus, and CNKI. RESULTS This review summarized the biotransformation of bioactive components under the action of gut microbiota, including flavonoids, terpenoids, phenylpropanoids, alkaloids, steroids, and other compounds. The interaction of bioactive components and gut microbiota is a key link for drug efficacy. Relevant research is crucial to clarify bioactive components and their mechanisms, which involve the complex interaction among bioactive components, gut microbiota, and intestinal epithelial cells. This review also summarized the individualized, precise, and targeted intervention of gut microbiota in the field of intestinal microorganisms from the aspects of dietary fiber, microecological agents, fecal microbiota transplantation, and postbiotics. It will provide an important reference for intestinal microecology in the field of nutrition and health for people. CONCLUSION To sum up, the importance of human gut microbiota in the research of bioactive components metabolism and transformation has attracted the attention of scholars all over the world. It is believed that with the deepening of research, human gut microbiota will be more widely used in the pharmacodynamic basis, drug toxicity relationship, new drug discovery, drug absorption mechanism, and drug transport mechanism in the future.
Collapse
Affiliation(s)
- Lin Zhang
- Department of Medical Nursing, Jiyuan Vocational and Technical College, 459000 Jiyuan, Henan, P.R. China
| | - Xiao-Gen Ma
- Department of Medical Nursing, Jiyuan Vocational and Technical College, 459000 Jiyuan, Henan, P.R. China
| |
Collapse
|
|
8
|
Wang T, Wang YY, Shi MY, Liu L. Mechanisms of action of natural products on type 2 diabetes. World J Diabetes 2023; 14:1603-1620. [DOI: 10.4239/wjd.v14.i11.1603] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/14/2023] [Accepted: 10/23/2023] [Indexed: 11/14/2023] Open
Abstract
Over the past several decades, type 2 diabetes mellitus (T2DM) has been considered a global public health concern. Currently, various therapeutic modalities are available for T2DM management, including dietary modifications, moderate exercise, and use of hypoglycemic agents and lipid-lowering medications. Although the curative effect of most drugs on T2DM is significant, they also exert some adverse side effects. Biologically active substances found in natural medicines are important for T2DM treatment. Several recent studies have reported that active ingredients derived from traditional medicines or foods exert a therapeutic effect on T2DM. This review compiled important articles regarding the therapeutic effects of natural products and their active ingredients on islet β cell function, adipose tissue inflammation, and insulin resistance. Additionally, this review provided an in-depth understanding of the multiple regulatory effects on different targets and signaling pathways of natural medicines in the treatment of T2DM as well as a theoretical basis for clinical effective application.
Collapse
Affiliation(s)
- Tao Wang
- Clinical Molecular Immunology Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Yang-Yang Wang
- Clinical Molecular Immunology Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Meng-Yue Shi
- Clinical Molecular Immunology Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Lian Liu
- Department of Pharmacology, Yangtze University, Jingzhou 434023, Hubei Province, China
| |
Collapse
|
|
9
|
Moreira J, Machado M, Dias-Teixeira M, Ferraz R, Delerue-Matos C, Grosso C. The neuroprotective effect of traditional Chinese medicinal plants-A critical review. Acta Pharm Sin B 2023; 13:3208-3237. [PMID: 37655317 PMCID: PMC10465969 DOI: 10.1016/j.apsb.2023.06.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 03/23/2023] [Accepted: 04/03/2023] [Indexed: 09/02/2023] Open
Abstract
Neurodegenerative and neuropsychiatric diseases are increasingly affecting individuals' quality of life, thus increasing their cost to social and health systems. These diseases have overlapping mechanisms, such as oxidative stress, protein aggregation, neuroinflammation, neurotransmission impairment, mitochondrial dysfunction, and excitotoxicity. Currently, there is no cure for neurodegenerative diseases, and the available therapies have adverse effects and low efficacy. For neuropsychiatric disorders, such as depression, the current therapies are not adequate to one-third of the patients, the so-called treatment-resistant patients. So, searching for new treatments is fundamental. Medicinal plants appear as a strong alternative and complement towards new treatment protocols, as they have been used for health purposes for thousands of years. Thus, the main goal of this review is to revisit the neuroprotective potential of some of the most predominant medicinal plants (and one fungus) used in traditional Chinese medicine (TCM), focusing on their proven mechanisms of action and their chemical compositions, to give clues on how they can be useful against neurodegeneration progression.
Collapse
Affiliation(s)
- João Moreira
- REQUIMTE/LAQV, Instituto Superior de Engenharia do Porto, Instituto Politécnico do Porto, Porto 4249-015, Portugal
| | - Mariana Machado
- Ciências Químicas e das Biomoléculas/CISA, Escola Superior de Saúde—Instituto Politécnico do Porto, Porto 4200-072, Portugal
| | - Mónica Dias-Teixeira
- REQUIMTE/LAQV, Instituto Superior de Engenharia do Porto, Instituto Politécnico do Porto, Porto 4249-015, Portugal
- NICiTeS—Núcleo de Investigação em Ciências e Tecnologias da Saúde, Escola Superior de Saúde Ribeiro Sanches, Lisboa 1950-396, Portugal
| | - Ricardo Ferraz
- Ciências Químicas e das Biomoléculas/CISA, Escola Superior de Saúde—Instituto Politécnico do Porto, Porto 4200-072, Portugal
- REQUIMTE/LAQV, Departamento de Química e Bioquímica Faculdade de Ciências, Universidade do Porto, Porto 4169-007, Portugal
| | - Cristina Delerue-Matos
- REQUIMTE/LAQV, Instituto Superior de Engenharia do Porto, Instituto Politécnico do Porto, Porto 4249-015, Portugal
| | - Clara Grosso
- REQUIMTE/LAQV, Instituto Superior de Engenharia do Porto, Instituto Politécnico do Porto, Porto 4249-015, Portugal
| |
Collapse
|
|
10
|
Zhao Y, Zhong X, Yan J, Sun C, Zhao X, Wang X. Potential roles of gut microbes in biotransformation of natural products: An overview. Front Microbiol 2022; 13:956378. [PMID: 36246222 PMCID: PMC9560768 DOI: 10.3389/fmicb.2022.956378] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 08/29/2022] [Indexed: 11/23/2022] Open
Abstract
Natural products have been extensively applied in clinical practice, characterized by multi-component and multi-target, many pharmacodynamic substances, complex action mechanisms, and various physiological activities. For the oral administration of natural products, the gut microbiota and clinical efficacy are closely related, but this relationship remains unclear. Gut microbes play an important role in the transformation and utilization of natural products caused by the diversity of enzyme systems. Effective components such as flavonoids, alkaloids, lignans, and phenols cannot be metabolized directly through human digestive enzymes but can be transformed by enzymes produced by gut microorganisms and then utilized. Therefore, the focus is paid to the metabolism of natural products through the gut microbiota. In the present study, we systematically reviewed the studies about gut microbiota and their effect on the biotransformation of various components of natural products and highlighted the involved common bacteria, reaction types, pharmacological actions, and research methods. This study aims to provide theoretical support for the clinical application in the prevention and treatment of diseases and provide new ideas for studying natural products based on gut biotransformation.
Collapse
Affiliation(s)
- Yucui Zhao
- Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xinqin Zhong
- Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Junyuan Yan
- Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Congying Sun
- Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xin Zhao
- Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- *Correspondence: Xin Zhao,
| | - Xiaoying Wang
- Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Xiaoying Wang,
| |
Collapse
|
|
11
|
Xia W, Liu B, Tang S, Yasir M, Khan I. The science behind TCM and Gut microbiota interaction-their combinatorial approach holds promising therapeutic applications. Front Cell Infect Microbiol 2022; 12:875513. [PMID: 36176581 PMCID: PMC9513201 DOI: 10.3389/fcimb.2022.875513] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
The trend toward herbal medicine as an alternative treatment for disease medication is increasing worldwide. However, insufficient pharmacologic information is available about the orally taken medicines. Not only herbal medicine, but also Western drugs, when passing through the gastrointestinal tract, interact with trillions of microbes (known as the gut microbiome [GM]) and their enzymes. Gut microbiome enzymes induce massive structural and functional changes to the herbal products and impact the bioavailability and efficacy of the herbal therapeutics. Therefore, traditional Chinese medicine (TCM) researchers extend the horizon of TCM research to the GM to better understand TCM pharmacology and enhance its efficacy and bioavailability. The study investigating the interaction between herbal medicine and gut microbes utilizes the holistic approach, making landmark achievements in the field of disease prognosis and treatment. The effectiveness of TCM is a multipathway modulation, and so is the GM. This review provides an insight into the understanding of a holistic view of TCM and GM interaction. Furthermore, this review briefly describes the mechanism of how the TCM-GM interaction deals with various illnesses.
Collapse
Affiliation(s)
- Wenrui Xia
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Bei Liu
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shiyun Tang
- National Drug Clinical Trial Agency, Teaching Hospital of Chengdu University of Traditional Chinese Medicine (TCM), Chengdu, China
| | - Muhammad Yasir
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Imran Khan
- Department of Biotechnology, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa, Pakistan
| |
Collapse
|
|
12
|
Shan J, Chen F, Yu P. Intestinal obstruction due to idiopathic mesenteric phlebosclerosis colitis: A case report. Front Surg 2022; 9:969154. [PMID: 36061039 PMCID: PMC9428392 DOI: 10.3389/fsurg.2022.969154] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/01/2022] [Indexed: 11/24/2022] Open
Abstract
Introduction Idiopathic mesenteric phlebosclerosis colitis (IMP) is a rare condition that impairs colonic venous blood return owing to mesenteric venous sclerosis and fibrosis. At present, many studies have suggested that long-term intake of Chinese herbal medicines is associated with its pathogenesis. IMP has no characteristic clinical manifestations, and most patients with IMP present with acute intestinal obstruction. As a rare disease, the etiology, pathogenesis, pathophysiology, and treatment of IMP are being explored and studied. Case Description A 60-year-old Chinese male patient with IMP was admitted to our hospital for acute intestinal obstruction, received subtotal colectomy and ileostomy after 10 days of ineffective conservative treatment, and was discharged after postoperative supportive treatment for 1 month. Conclusion There are many causes of intestinal obstruction, and we report a relatively rare one. After failure of conservative treatment, it is necessary to surgically resect part of the diseased bowel.
Collapse
Affiliation(s)
- Jiaqi Shan
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Fangci Chen
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Panpan Yu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Gastrointestinal Surgery, Hangzhou First People’s Hospital, The Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, China
- Correspondence: Panpan Yu
| |
Collapse
|
|
13
|
Yu X, Zheng Q, He Y, Yu D, Chang G, Chen C, Bi L, Lv J, Zhao M, Lin X, Zhu L. Associations of Gut Microbiota and Fatty Metabolism With Immune Thrombocytopenia. Front Med (Lausanne) 2022; 9:810612. [PMID: 35665326 PMCID: PMC9160917 DOI: 10.3389/fmed.2022.810612] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 04/27/2022] [Indexed: 11/30/2022] Open
Abstract
Objective To determine whether gut microbiota, fatty metabolism and cytokines were associated with immune thrombocytopenia (ITP). Methods In total, 29 preliminarily diagnosed ITP patients and 33 healthy volunteers were enrolled. Fecal bacterial were analyzed based on 16S rRNA sequencing. Plasma cytokines and motabolites were analyzed using flow cytometry and liquid chromatography-mass spectrometry (LC-MS), respectively. Results Bacteroides, Phascolarctobacterium, and Lactobacillus were enriched at the genus level in ITP patients, while Ruminococcaceae UCG-002, Eubacterium coprostanoligeues, Megamonas, and Lachnospiraceae NC2004 were depleted. At the phylum level, the relative abundance of Proteobacteria and Chloroflexi increased in ITP patients, while Firmicutes, Actinobacteria, and the Firmicutes/Bacteroidetes ratio decreased. Plasma levels of 5-hydroxyeicosatetraenoic acid (5-HETE), 6-trans-12-epi-leukotriene B4 (6t,12e-LTB4), and resolvin D2 (RvD2) were upregulated, and stachydrine, dowicide A, dodecanoylcarnitine were downregulated in ITP patients. Furthermore, RvD2 is positively correlated with order Bacteroidetes VC2.1 Bac22, 5-HETE is positively correlated with genus Azospirillum, and 6t,12e-LTB4 is positively correlated with genus Cupriavidus. In addition, stachydrine is positively correlated with family Planococcaceae, dowicide A is positively correlated with class MVP-15, and dodecanoylcarnitine is positively correlated with order WCHB1-41. Plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were upregulated in ITP patients. Conclusion Our study revealed a relationship between microbiota and fatty metabolism in ITP. Gut microbiota may participate in the pathogenesis of ITP through affecting cytokine secretion, interfering with fatty metabolism.
Collapse
Affiliation(s)
- Xiaomin Yu
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qingyun Zheng
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Yun He
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Dandan Yu
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guolin Chang
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Cheng Chen
- Department of Hematopathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Laixi Bi
- Department of Hematopathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jia Lv
- Department of Pathology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Misheng Zhao
- Department of Clinical Laboratory, Wenzhou People’s Hospital, Wenzhou, China
- *Correspondence: Misheng Zhao,
| | - Xiangyang Lin
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Xiangyang Lin,
| | - Liqing Zhu
- Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Liqing Zhu,
| |
Collapse
|
|
14
|
Tian J, Qin S, Han J, Meng J, Liang A. A review of the ethnopharmacology, phytochemistry, pharmacology and toxicology of Fructus Gardeniae (Zhi-zi). JOURNAL OF ETHNOPHARMACOLOGY 2022; 289:114984. [PMID: 35066066 DOI: 10.1016/j.jep.2022.114984] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 12/22/2021] [Accepted: 01/06/2022] [Indexed: 05/24/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Fructus Gardeniae (FG) is the dried fruit of Gardenia jasminoides Ellis (GjE), which belongs to the family Rubiaceae. FG has a long history of use as a herb, and was originally recorded in Sheng Nong's herbal classic. FG has also been widely used as both medicine and food. AIM OF STUDY This review aimed to provide a systematic and comprehensive analysis of the current research progress of FG in terms of ethnopharmacology, phytochemistry, pharmacology and toxicity, to provide new insights and extensive field of view for subsequent studies. METHODS Scientific databases, including CNKI, VIP (Chinese literature), PubMed, Science Direct, Elsevier and Google Scholar (English literatures) were searched to gather data about FG and its main active ingredients such as geniposide and genipin (only regarding toxicity). RESULTS Many chemical constituents have been identified from the fruit of GjE, including iridoids, terpenoids, flavonoids, organic acids, volatile oils and others. The constituents of different parts of FG and processed FG are different from those of whole FG. FG extract and its main active constituents have been reported to have pharmacological properties such as hepatoprotective, choleretic, anti-inflammatory, antioxidant, neuroprotective, anti-diabetic, anti-apoptotic and antitumor activities. However, an increasing number of studies have shown that FG induces multiple organ injury, especially causing hepatotoxicity and nephrotoxicity, which could increase the risk during clinical use. The available literature shows that geniposide, a major active component of FG and a critical marker for its quality, is associated with the pharmacology and toxicity of FG. CONCLUSION Although a large number of studies examining FG have been published, issues remain. In the aspect of FG's pharmacology, the traditional efficacy and modern pharmacological effects of FG should be combined, which to broadens clinical application prospects. In addition, few studies have assessed the toxicity of FG. Toxicity assessment of FG should tackle various aspects, including compatibility, processing and the symptom-based prescription theory, in addition to over-dosage or long-term use, for a reasonable clinical use.
Collapse
Affiliation(s)
- Jingzhuo Tian
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, , No. 16 Nanxiaojie, Dongzhimen Nei Ave, Beijing, 100700, China
| | - Shasha Qin
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, , No. 16 Nanxiaojie, Dongzhimen Nei Ave, Beijing, 100700, China
| | - Jiayin Han
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, , No. 16 Nanxiaojie, Dongzhimen Nei Ave, Beijing, 100700, China
| | - Jing Meng
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, , No. 16 Nanxiaojie, Dongzhimen Nei Ave, Beijing, 100700, China
| | - Aihua Liang
- Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, , No. 16 Nanxiaojie, Dongzhimen Nei Ave, Beijing, 100700, China.
| |
Collapse
|
|
15
|
Widespread mesenteric phlebosclerosis presenting as intestinal obstruction due to stenosis of the right-sided colon. Clin J Gastroenterol 2022; 15:717-721. [PMID: 35489002 DOI: 10.1007/s12328-022-01637-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 04/16/2022] [Indexed: 02/07/2023]
Abstract
Mesenteric phlebosclerosis is a rare form of intestinal ischemia characterized by thickening of the right-sided colon and calcification of the mesenteric vein. We describe the case of a 58-year-old woman admitted to our hospital because of abdominal pain and distension. An abdominal computed tomography study revealed remarkable dilatation and fluid collection of the small intestine compatible with intestinal obstruction, which was considered to be the result of stenosis of the ascending colon. The thickened wall of the cecum and ascending colon was associated with calcification of the colonic wall and mesenteric veins. Colonoscopy showed dark purple discoloration of the edematous mucosa from the splenic flexure through the hepatic flexure, at which point the colonoscope could not be advanced further because of stenosis of the ascending colon. Over 10 years previously, the patient had taken an herbal medicine containing gardenia fruit, which can cause mesenteric phlebosclerosis. An extensive colonic resection was performed after intestinal decompression. This case highlights extensive mesenteric phlebosclerosis causing intestinal obstruction from the cecum through the proximal portion of the sigmoid colon, which was treated with extensive colonic resection.
Collapse
|
|
16
|
Microemulsion Delivery System Improves Cellular Uptake of Genipin and Its Protective Effect against Aβ1-42-Induced PC12 Cell Cytotoxicity. Pharmaceutics 2022; 14:pharmaceutics14030617. [PMID: 35335992 PMCID: PMC8950416 DOI: 10.3390/pharmaceutics14030617] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/04/2022] [Accepted: 03/07/2022] [Indexed: 02/04/2023] Open
Abstract
Genipin has attracted much attention for its hepatoprotective, anti-inflammatory, and neuroprotection activities. However, poor water solubility and active chemical properties limit its application in food and pharmaceutical industries. This article aimed to develop a lipid-based microemulsion delivery system to improve the stability and bioavailability of genipin. The excipients for a genipin microemulsion (GME) preparation were screened and a pseudo-ternary phase diagram was established. The droplet size (DS), zeta potential (ZP), polydispersity index (PDI), physical and simulated gastrointestinal digestion stability, and in vitro drug release properties were characterized. Finally, the effect of the microemulsion on its cellular uptake by Caco-2 cells and the protective effect on PC12 cells were investigated. The prepared GME had a transparent appearance with a DS of 16.17 ± 0.27 nm, ZP of −8.11 ± 0.77 mV, and PDI of 0.183 ± 0.013. It exhibited good temperature, pH, ionic strength, and simulated gastrointestinal digestion stability. The in vitro release and cellular uptake data showed that the GME had a lower release rate and better bioavailability compared with that of free genipin. Interestingly, the GME showed a significantly better protective effect against amyloid-β (Aβ1-42)-induced PC12 cell cytotoxicity than that of the unencapsulated genipin. These findings suggest that the lipid-based microemulsion delivery system could serve as a promising approach to improve the application of genipin.
Collapse
|
|
17
|
Yamashita H, Nishiyama M, Ohbuchi K, Kanno H, Tsuchiya K, Yamaguchi J, Mizuno T, Ebata T, Nagino M, Yokoyama Y. Predicting Inchinkoto efficacy, in patients with obstructive jaundice associated with malignant tumors, through pharmacomicrobiomics. Pharmacol Res 2021; 175:105981. [PMID: 34798264 DOI: 10.1016/j.phrs.2021.105981] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 12/14/2022]
Abstract
Inchinkoto (ICKT) is a popular choleretic and hepatoprotective herbal medicine that is widely used in Japan. Geniposide, a major ingredient of ICKT, is metabolized to genipin by gut microbiota, which exerts a choleretic effect. This study investigates the relationship between stool genipin-producing activity and diversity of the clinical effect of ICKT in patients with malignant obstructive jaundice. Fifty-two patients with malignant obstructive jaundice who underwent external biliary drainage were included. ICKT was administered as three packets per day (7.5 g/day) for three days and 2.5 g on the morning of the fourth day. Stool samples were collected before ICKT administration and bile flow was monitored on a daily basis. The microbiome, genipin-producing activity, and organic acids in stools were analyzed. The Shannon-Wiener (SW) index was calculated to evaluate gut microbiome diversity. The stool genipin-producing activity showed a significant positive correlation with the SW index. Stool genipin-producing activity positively correlated with the order Clostridia (obligate anaerobes), but negatively correlated with the order Lactobacillales (facultative anaerobes). Moreover, stool genipin-producing activity was positively correlated to the concentration valeric acid, but negatively correlated to the concentration of lactic acid and succinic acid. The change of bile flow at 2 and 3 days after ICKT administration showed significant positive correlation with genipin-producing activity (correlation coefficient, 0.40 and 0.29, respectively, P < 0.05). An analysis of stool profile, including stool genipin-producing activity, may predict the efficacy of ICKT. Modification of the microbiome may be a target to enhance the therapeutic effect of ICKT.
Collapse
Affiliation(s)
- Hiromasa Yamashita
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Mitsue Nishiyama
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ami-machi, Ibaraki, Japan
| | - Katsuya Ohbuchi
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ami-machi, Ibaraki, Japan
| | - Hitomi Kanno
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ami-machi, Ibaraki, Japan
| | - Kazuaki Tsuchiya
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ami-machi, Ibaraki, Japan
| | - Junpei Yamaguchi
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Takashi Mizuno
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Tomoki Ebata
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Masato Nagino
- Department of Gastrointestinal Surgery, Aichi Cancer Center, Nagoya, Aichi, Japan
| | - Yukihiro Yokoyama
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; Division of Perioperative Medicine, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
| |
Collapse
|
|
18
|
Wang YK, Li WQ, Xia S, Guo L, Miao Y, Zhang BK. Metabolic Activation of the Toxic Natural Products From Herbal and Dietary Supplements Leading to Toxicities. Front Pharmacol 2021; 12:758468. [PMID: 34744736 PMCID: PMC8564355 DOI: 10.3389/fphar.2021.758468] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 10/05/2021] [Indexed: 12/24/2022] Open
Abstract
Currently, herbal and dietary supplements have been widely applied to prevent and treat various diseases. However, the potential toxicities and adverse reactions of herbal and dietary supplements have been increasingly reported, and have gradually attracted widespread attention from clinical pharmacists and physicians. Metabolic activation of specific natural products from herbal and dietary supplements is mediated by hepatic cytochrome P450 or intestinal bacteria, and generates chemical reactive/toxic metabolites that bind to cellular reduced glutathione or macromolecules, and form reactive metabolites-glutathione/protein/DNA adducts, and these protein/DNA adducts can result in toxicities. The present review focuses on the relation between metabolic activation and toxicities of natural products, and provides updated, comprehensive and critical comment on the toxic mechanisms of reactive metabolites. The key inductive role of metabolic activation in toxicity is highlighted, and frequently toxic functional groups of toxic natural products were summarized. The biotransformation of drug cytochrome P450 or intestinal bacteria involved in metabolic activation were clarified, the reactive metabolites-protein adducts were selected as biomarkers for predicting toxicity. And finally, further perspectives between metabolic activation and toxicities of natural products from herbal and dietary supplements are discussed, to provide a reference for the reasonable and safe usage of herbal and dietary supplements.
Collapse
Affiliation(s)
- Yi-Kun Wang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Wen Qun Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Shuang Xia
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Lin Guo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yan Miao
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Bi-Kui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| |
Collapse
|
|
19
|
Cheng L, Deng Y. Characterization by HPLC of p-Hydroxybenzyl Alcohol Biotransformation to Gastrodin In Vivo. Nat Prod Commun 2021. [DOI: 10.1177/1934578x211035069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Gastrodin (GAS) and its aglycone, p-hydroxybenzyl alcohol (HBA), are both bioactive compounds extracted from Gastrodia elata Blume (GEB). In the current Chinese pharmacopoeia, they are regarded as quality control markers for GEB. In this study, we developed a high-performance liquid chromatography method coupled with a diode array detector to quantify GAS and HBA concentrations in plasma following oral ingestion by rats. For the first time, GAS was detected in vivo after HBA administration. GAS and HBA both had similar pharmacological effects, but the influence of the glucose moiety resulted in different pharmacokinetic characteristics. In this study, the effects of GAS and HBA at different administration durations were investigated in zebrafish larvae. These compounds were found to induce a sedative effect but had different onset times. In conclusion, a biotransformation of HBA to GAS could be observed in the rats. This may be a new insight into the pharmacokinetic characteristics of these bioactive compounds and also relates to the different ways in which they take effect.
Collapse
Affiliation(s)
| | - Yang Deng
- Zhaotong Goode Biotechnology Co., Ltd, Zhaotong, China
| |
Collapse
|
|
20
|
Luo Y, Zhang X, Zhang W, Yang Q, You W, Wen J, Zhou T. Compatibility with Semen Sojae Praeparatum attenuates hepatotoxicity of Gardeniae Fructus by regulating the microbiota, promoting butyrate production and activating antioxidant response. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 90:153656. [PMID: 34332844 DOI: 10.1016/j.phymed.2021.153656] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/22/2021] [Accepted: 07/06/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Herb-induced liver injury is a leading cause of drug-induced liver injury in China and its incidence is also increasing worldwide. Gardeniae Fructus (ZZ) has aroused wide concern for hepatotoxicity in recent decades. But when ZZ is administered in combination with Semen Sojae Praeparatum (DDC) to compose a herbal pair Zhizichi Decoction (ZZCD), lower hepatotoxicity is observed. The mechanism involved in the attenuated effect remains to be investigated. HYPOTHESIS/PURPOSE Our previous studies showed that DDC benefited host metabolism by regulating the gut microbiota and it reduced the exposure of major toxic components of ZZ. The present study was aimed to investigate how DDC attenuated hepatotoxicity of ZZ from the perspective of gut microbiota. METHODS Rats received ZZ and ZZCD treatment of different dosages and antibiotic treatment was applied to explore the involvement of gut microbiota. Biochemical assays and histopathological analysis were conducted to evaluate liver injury. Gut microbiota in caecal contents was profiled by 16S rRNA sequencing. Short-chain fatty acids (SCFAs) in caecal contents were measured by gas chromatography mass spectrometry (GCMS). To verify the protective effect of butyrate, it was administered with genipin, the major hepatotoxic metabolite of ZZ, to rats and HepG2 cells. Plasma lipopolysaccharide (LPS) level and colon tissue section were used to evaluate gut permeability. Expression level of Nuclear factor erythroid-derived 2-like 2 (Nrf2) was detected by immunohistochemistry in vitro and by western blot in vivo. RESULTS Our study showed that ZZCD displayed lower hepatotoxicity than ZZ at the same dosage. ZZ induced gut dysbiosis, significantly reducing Lactobacillus and Enterococcus levels and increasing the Parasutterella level. In combination with DDC, these alterations were reversed and beneficial genus including Akkermansia and Prevotella were significantly increased. Besides, butyrate production was diminished by ZZ but was restored when in combination with DDC. Butyrate showed detoxification on genipin-induced liver injury by promoting colon integrity and promoting Nrf2 activation. Besides, it protected genipin-induced hepatocyte damage by promoting Nrf2 activation. CONCLUSION DDC attenuates ZZ-induced liver injury by regulating the microbiota, promoting butyrate production and activating antioxidant response.
Collapse
Affiliation(s)
- Yusha Luo
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China
| | - Xingjie Zhang
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Wen Zhang
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China
| | - Qiliang Yang
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Wei You
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Jun Wen
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China.
| | - Tingting Zhou
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory for Pharmaceutical Metabolite Research, Shanghai 200433, China.
| |
Collapse
|
|
21
|
Zhang W, Zhang F, Hu Q, Xiao X, Ou L, Chen Y, Luo S, Cheng Y, Jiang Y, Ma X, Zhao Y. The emerging possibility of the use of geniposide in the treatment of cerebral diseases: a review. Chin Med 2021; 16:86. [PMID: 34454545 PMCID: PMC8400848 DOI: 10.1186/s13020-021-00486-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/01/2021] [Indexed: 12/19/2022] Open
Abstract
With the advanced discoveries in the field of pathogenesis, a series of cerebral diseases, such as cerebral ischaemia, Alzheimer's disease, and depression, have been found to have multiple signalling targets in the microenvironment. Only a few existing agents have been shown to have curative effects due to this specific circumstance. In recent decades, active ingredients isolated from natural plants have been shown to be crucial for original drug development. Geniposide, mainly extracted from Gardenia jasminoides Ellis, is representative of these natural products. Geniposide demonstrates various biological activities in the treatment of cerebral, cardiovascular, hepatic, tumorous, and other diseases. The multiple protective effects of geniposide on the brain have especially drawn increasing attention. Thus, this article specifically reviews the characteristics of current models of cerebral ischaemia and illustrates the possible effects of geniposide and its pathogenetic mechanisms on these models. Geniposide has been shown to significantly reduce the area of cerebral infarction and alleviate neuronal damage and necrosis mainly by inhibiting inflammatory signals, including NLRP3, TNF-α, IL-6, and IL-1β. Neuronal protection was also involved in activating the PI3K/Akt and Wnt/catenin pathways. Geniposide was able to increase autophagy and inhibit apoptosis by regulating the function of mTOR in treating Alzheimer's disease. Geniposide has also been shown to act as a glucagon-like peptide-1 receptor (GLP-1R) agonist to reduce amyloid plaques and inhibit oxidative stress to alleviate memory impairment as well as synaptic loss. Moreover, geniposide has been shown to exert antidepressant effects primarily by regulating the hypothalamic-pituitary-adrenal (HPA) axis. Detailed explorations have shown that the biological activities of inhibiting inflammatory cytokine secretion, alleviating oxidative stress, and suppressing mitochondrial damage are also involved in the mechanism of action of geniposide. Therefore, geniposide is a promising agent awaiting further exploration for the treatment of cerebral diseases via various phenotypes or signalling pathways.
Collapse
Affiliation(s)
- Wenwen Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Fangling Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Qichao Hu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xiaolin Xiao
- Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Linbo Ou
- College of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yuan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Shiqing Luo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yonghong Cheng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yinxiao Jiang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Yanling Zhao
- Department of Pharmacy, The Fifth Medical Centre of PLA General Hospital, Beijing, 100039, China.
| |
Collapse
|
|
22
|
Mukonowenzou NC, Adeshina KA, Donaldson J, Ibrahim KG, Usman D, Erlwanger KH. Medicinal Plants, Phytochemicals, and Their Impacts on the Maturation of the Gastrointestinal Tract. Front Physiol 2021; 12:684464. [PMID: 34393812 PMCID: PMC8363294 DOI: 10.3389/fphys.2021.684464] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/29/2021] [Indexed: 12/24/2022] Open
Abstract
The gastrointestinal tract (GIT) is the first point of contact for ingested substances and thus represents a direct interface with the external environment. Apart from food processing, this interface plays a significant role in immunity and contributes to the wellbeing of individuals through the brain-gut-microbiota axis. The transition of life from the in utero environment, to suckling and subsequent weaning has to be matched by phased development and maturation of the GIT; from an amniotic fluid occupancy during gestation, to the milk in the suckling state and ultimately solid food ingestion at weaning. This phased maturation of the GIT can be affected by intrinsic and extrinsic factors, including diet. Despite the increasing dietary inclusion of medicinal plants and phytochemicals for health benefits, a dearth of studies addresses their impact on gut maturation. In this review we focus on some recent findings mainly on the positive impact of medicinal plants and phytochemicals in inducing precocious maturation of the GIT, not only in humans but in pertinent animals. We also discuss Paneth cells as mediators and potential markers of GIT maturation.
Collapse
Affiliation(s)
| | - Kehinde Ahmad Adeshina
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, Sokoto, Nigeria
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto, Sokoto, Nigeria
| | - Janine Donaldson
- Faculty of Health Sciences, School of Physiology, University of the Witwatersrand, Johannesburg, Johannesburg, South Africa
| | - Kasimu Ghandi Ibrahim
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, Sokoto, Nigeria
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto, Sokoto, Nigeria
| | - Dawoud Usman
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, Sokoto, Nigeria
- Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto, Sokoto, Nigeria
| | - Kennedy Honey Erlwanger
- Faculty of Health Sciences, School of Physiology, University of the Witwatersrand, Johannesburg, Johannesburg, South Africa
| |
Collapse
|
|
23
|
Wen Y, Chen YW, Meng AH, Zhao M, Fang SH, Ma YQ. Idiopathic mesenteric phlebosclerosis associated with long-term oral intake of geniposide. World J Gastroenterol 2021; 27:3097-3108. [PMID: 34168411 PMCID: PMC8192294 DOI: 10.3748/wjg.v27.i22.3097] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/30/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Idiopathic mesenteric phlebosclerosis (IMP) is a rare disease, and its etiology and risk factors remain uncertain.
AIM To investigate the possible influence of Chinese herbal liquid containing geniposide on IMP.
METHODS The detailed formula of herbal liquid prescriptions of all patients was studied, and the herbal ingredients were compared to identify the toxic agent as a possible etiological factor. Abdominal computed tomography (CT) and colonoscopy images were reviewed to determine the extent and severity of mesenteric phlebosclerosis and the presence of findings regarding colitis. The disease CT score was determined by the distribution of mesenteric vein calcification and colon wall thickening on CT images. The drinking index of medicinal liquor was calculated from the daily quantity and drinking years of Chinese medicinal liquor. Subsequently, Spearman’s correlation analysis was conducted to evaluate the correlation between the drinking index and the CT disease score.
RESULTS The mean age of the 8 enrolled patients was 75.7 years and male predominance was found (all 8 patients were men). The patients had histories of 5-40 years of oral Chinese herbal liquids containing geniposide and exhibited typical imaging characteristics (e.g., threadlike calcifications along the colonic and mesenteric vessels or associated with a thickened colonic wall in CT images). Calcifications were confined to the right-side mesenteric vein in 6 of the 8 patients (75%) and involved the left-side mesenteric vein of 2 cases (25%) and the calcifications extended to the mesorectum in 1 of them. The thickening of colon wall mainly occurred in the right colon and the transverse colon. The median disease CT score was 4.88 (n = 7) and the median drinking index was 5680 (n = 7). After Spearman’s correlation analysis, the median CT score of the disease showed a significant positive correlation with the median drinking index (r = 0.842, P < 0.05).
CONCLUSION Long-term oral intake of Chinese herbal liquid containing geniposide may play a role in the pathogenesis of IMP.
Collapse
Affiliation(s)
- Yang Wen
- Department of Radiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - You-Wei Chen
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Ai-Hong Meng
- Department of Gastroenterology, Hangzhou Yuhang District Hospital of Traditional Chinese Medicine, Hangzhou 311100, Zhejiang Province, China
| | - Ming Zhao
- Department of Pathology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Song-Hua Fang
- Department of Radiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Yan-Qing Ma
- Department of Radiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| |
Collapse
|
|
24
|
Luo Y, Zhou T. Connecting the dots: Targeting the microbiome in drug toxicity. Med Res Rev 2021; 42:83-111. [PMID: 33856076 DOI: 10.1002/med.21805] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/22/2021] [Accepted: 03/31/2021] [Indexed: 12/13/2022]
Abstract
The gut microbiota has a vast influence on human health and its role in initiating, aggravating, or ameliorating diseases is beginning to emerge. Recently, its contribution to heterogeneous toxicological responses is also gaining attention, especially in drug-induced toxicity. Whether they are orally administered or not, drugs may interact with the gut microbiota directly or indirectly, which leads to altered toxicity. Present studies focus more on the unidirectional influence of how xenobiotics disturb intestinal microbial composition and functions, and thus induce altered homeostasis. However, interactions between the gut microbiota and xenobiotics are bidirectional and the impact of the gut microbiota on xenobiotics, especially on drugs, should not be neglected. Thus, in this review, we focus on how the gut microbiota modulates drug toxicity by highlighting the microbiome, microbial enzyme, and microbial metabolites. We connect the dots between drugs, the microbiome, microbial enzymes or metabolites, drug metabolites, and host toxicological responses to facilitate the discovery of microbial targets and mechanisms associated with drug toxicity. Besides this, current mainstream strategies to manipulate drug toxicity by targeting the microbiome are summarized and discussed. The review provides technical reference for the evaluation of medicinal properties in the research and development of innovative drugs, and for the future exploitation of strategies to reduce drug toxicity by targeting the microbiome.
Collapse
Affiliation(s)
- Yusha Luo
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai, China.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Tingting Zhou
- Department of Pharmaceutical Analysis, School of Pharmacy, Second Military Medical University, Shanghai, China.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai, China
| |
Collapse
|
|
25
|
Xia ZS, Hao EW, Wei YT, Hou XT, Chen ZM, Wei M, Du ZC, Deng JG. Genipin induces developmental toxicity through oxidative stress and apoptosis in zebrafish. Comp Biochem Physiol C Toxicol Pharmacol 2021; 241:108951. [PMID: 33316388 DOI: 10.1016/j.cbpc.2020.108951] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/19/2020] [Accepted: 12/06/2020] [Indexed: 12/15/2022]
Abstract
Genipin, an iridoid substance, is mainly derived from Gardenia jasminoides Ellis of the traditional Chinese medicine and is widely used in raw materials for the food additive gardenia blue and biological materials. The developmental toxicity of genipin has not been investigated, and its underlying mechanism is unclear. Therefore, in this study we attempt to investigate the potential developmental toxicity of genipin in zebrafish embryos/larvae. The results showed zebrafish embryos treated with 50 μg/ml dose of genipin display inhibited hatching rates and body length. The pericardial edema was observed. It was also found that genipin could induce cardio-toxicity, hepatotoxicity and nephrotoxicity in zebrafish larvae. After genipin treatment, the suppression of antioxidant capacity and increase of oxidative stress were showed for the triggered generation of ROS and MDA, and decreased activity of SOD. Compared with the 0.5% DMSO group, a number of apoptotic cells in zebrafish were increased after genipin exposure. By measuring marker gene expression with the using of qRT-PCR, we proposed that developmental toxicity after genipin treatment might be associated with oxidative stress and apoptosis increase. Our research offers a better understanding for developmental toxicity of genipin.
Collapse
Affiliation(s)
- Zhong-Shang Xia
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Er-Wei Hao
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning 530200, China; Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning 530200, China
| | - Yan-Ting Wei
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning 530200, China; Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning 530200, China
| | - Xiao-Tao Hou
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning 530200, China; Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning 530200, China; College of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530200, China
| | - Zhang-Mei Chen
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning 530200, China; Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning 530200, China
| | - Man Wei
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning 530200, China; Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning 530200, China
| | - Zheng-Cai Du
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning 530200, China; Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning 530200, China.
| | - Jia-Gang Deng
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning 530200, China; Guangxi Collaborative Innovation Center for Research on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning 530200, China.
| |
Collapse
|
|
26
|
Feng W, Liu J, Huang L, Tan Y, Peng C. Gut microbiota as a target to limit toxic effects of traditional Chinese medicine: Implications for therapy. Biomed Pharmacother 2020; 133:111047. [PMID: 33378954 DOI: 10.1016/j.biopha.2020.111047] [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: 09/21/2020] [Revised: 11/11/2020] [Accepted: 11/19/2020] [Indexed: 12/17/2022] Open
Abstract
Traditional Chinese medicines (TCMs) are medicines that are widely used in oriental countries under the guidance of ancient Chinese medicinal philosophies. With thousands of years of experiences in fighting against diseases, TCMs are gaining increasing importance in the world. Although the efficacy of TCMs is well recognized in clinic, the toxicity of TCMs has become a serious issue around the world in recent years. In general, the toxicity of TCMs is caused by the toxic medicinal compounds and contaminants in TCMs such as pesticides, herbicides, and heavy metals. Recent studies have demonstrated that gut microbiota can interact with TCMs and thus influence the toxicity of TCMs. However, there is no focused review on gut microbiota and the toxicity of TCMs. Here, we summarized the influences of the gut microbiota on the toxicity of medicinal compounds in TCMs and the corresponding mechanisms were offered. Then, we discussed the relationships between gut microbiota and the TCM contaminants. In addition, we discussed the methods of manipulating gut microbiota to reduce the toxicity of TCMs. At the end of this review, the perspectives on gut microbiota and the toxicity of TCMs were also discussed.
Collapse
Affiliation(s)
- Wuwen Feng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China; State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Juan Liu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lihua Huang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China; State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuzhu Tan
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China; State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Cheng Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China; State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| |
Collapse
|
|
27
|
Feng W, Liu J, Ao H, Yue S, Peng C. Targeting gut microbiota for precision medicine: Focusing on the efficacy and toxicity of drugs. Theranostics 2020; 10:11278-11301. [PMID: 33042283 PMCID: PMC7532689 DOI: 10.7150/thno.47289] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
Intra- and interindividual variation in drug responses is one major reason for the failure of drug therapy, drug toxicity, and even the death of patients. Precision medicine, or personalized medicine, is a field of medicine that customizes an individual's medical diagnosis and treatment based on his/her genes, microbiomes, environments, etc. Over the past decade, a large number of studies have demonstrated that gut microbiota can modify the efficacy and toxicity of drugs, and the extent of the modification varies greatly from person to person because of the variability of the gut microbiota. Personalized manipulation of gut microbiota is an important approach to rectify the abnormal drug response. In this review, we aim to improve drug efficacy and reduce drug toxicity by combining precision medicine and gut microbiota. After describing the interactions between gut microbiota and xenobiotics, we discuss (1) the effects of gut microbiota on drug efficacy and toxicity and the corresponding mechanisms, (2) the variability of gut microbiota, which leads to variation in drug responses, (3) the biomarkers used for the patient stratification and treatment decisions before the use of drugs, and (4) the methods used for the personalized manipulation of gut microbiota to improve drug outcomes. Overall, we hope to improve the drug response by incorporating the knowledge of gut microbiota into clinical practice.
Collapse
Affiliation(s)
- Wuwen Feng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Juan Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hui Ao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shijun Yue
- Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi'an, China
| | - Cheng Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
|
28
|
Fan X, Lin L, Cui B, Zhao T, Mao L, Song Y, Wang X, Feng H, Qingxiang Y, Zhang J, Jiang K, Cao X, Wang B, Sun C. Therapeutic potential of genipin in various acute liver injury, fulminant hepatitis, NAFLD and other non-cancer liver diseases: More friend than foe. Pharmacol Res 2020; 159:104945. [PMID: 32454225 DOI: 10.1016/j.phrs.2020.104945] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 05/04/2020] [Accepted: 05/19/2020] [Indexed: 12/14/2022]
Abstract
Genipin is an aglycone derived from the geniposide, the most abundant iridoid glucoside constituent of Gardenia jasminoides Ellis. For decades, genipin is the focus of studies as a versatile compound in the treatment of various pathogenic conditions. In particularly, Gardenia jasminoides Ellis has long been used in traditional Chinese medicine for the prevention and treatment of liver disease. Mounting experimental data has proved genipin possesses therapeutic potential for cholestatic, septic, ischemia/reperfusion-triggered acute liver injury, fulminant hepatitis and NAFLD. This critical review is a reflection on the valuable lessons from decades of research regarding pharmacological activities of genipin. Of note, genipin represents choleretic effect by potentiating bilirubin disposal and enhancement of genes in charge of the efflux of a number of organic anions. The anti-inflammatory capability of genipin is mediated by suppression of the production and function of pro-inflammatory cytokines and inflammasome. Moreover, genipin modulates various transcription factor and signal transduction pathway. Genipin appears to trigger the upregulation of several key genes encoding antioxidant and xenobiotic-metabolizing enzymes. Furthermore, the medicinal impact of genipin extends to modulation of regulated cell death, including autophagic cell death, apoptosis, necroptosis and pyroptosis, and modulation of quality of cellular organelle. Another crucial effect of genipin appears to be linked to dual role in targeting uncoupling protein 2 (UCP2). As a typical UCP2-inhibiting compound, genipin could inhibit AMP-activated protein kinase or NF-κB in circumstance. On the contrary, reactive oxygen species production and cellular lipid deposits mediated by genipin through the upregulation of UCP2 is observed in liver steatosis, suggesting the precise role of genipin is disease-specific. Collectively, we comprehensively summarize the mechanisms and pathways associated with the hepatoprotective activity of genipin and discuss potential toxic impact. Notably, our focus is the direct medicinal effect of genipin itself, whereas its utility as a crosslinking agent in tissue engineering is out of scope for the current review. Further studies are therefore required to disentangle these complicated pharmacological properties to confer this natural agent a far greater potency.
Collapse
Affiliation(s)
- Xiaofei Fan
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Lin Lin
- Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin 300308, China
| | - Binxin Cui
- Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin 300308, China
| | - Tianming Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Lihong Mao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Yan Song
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Xiaoyu Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Hongjuan Feng
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Department of Nutriology, Tianjin Third Central Hospital, Jintang Road 83, Hedong District, Tianjin 300170, China
| | - Yu Qingxiang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Jie Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Kui Jiang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China
| | - Xiaocang Cao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China.
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China.
| | - Chao Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping DisTrict, Tianjin 300052, China; Tianjin Institute of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Tianjin Key Laboratory of Digestive Disease, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin 300308, China.
| |
Collapse
|
|
29
|
Chang R, Liu J, Luo Y, Huang T, Li Q, Wen J, Chen W, Zhou T. Isoflavones' effects on pharmacokinetic profiles of main iridoids from Gardeniae Fructus in rats. J Pharm Anal 2019; 10:571-580. [PMID: 33425451 PMCID: PMC7775847 DOI: 10.1016/j.jpha.2019.11.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 11/01/2019] [Accepted: 11/12/2019] [Indexed: 12/14/2022] Open
Abstract
Gardeniae Fructus (GF) and Semen Sojae Praeparatum (SSP) are both medicine food homologies and widely used in Chinese clinical prescriptions together. The research investigated the pharmacokinetics of four iridoids in normal rats and isolfavones-fed rats, which were administered with isolfavones from SSP for 7, 14, 21 and 28 consecutive days. A validated LC-MS/MS method was developed for determining shanzhiside, genipin-1-gentiobioside, geniposide and their metabolite genipin in rat plasma. Plasma samples were pretreated by solid-phase extraction using paeoniflorin as the internal standard. The chromatographic separation was performed on a Waters Atlantis T3 (4.6 mm × 150 mm, 3 μm) column using a gradient mobile phase consisting of acetonitril and water (containing 0.06% acetic acid). The mass detection was under the multiple reaction monitoring (MRM) mode via polarity switching between negative and positive ionization modes. The calibration curves exhibited good linearity (r > 0.997) for all components. The lower limit of quantitation was in the range of 1–10 ng/mL. The intra-day and inter-day precisions (RSD) at three different levels were both less than 12.2% and the accuracies (RE) ranged from −10.1% to 16.4%. The extraction recovery of them ranged from 53.8% to 99.7%. Pharmacokinetic results indicated the bioavailability of three iridoid glycosides and the metabolite, genipin in normal rats was higher than that in rats exposed to isoflavones. With the longer time of administration of isoflavones, plasma concentrations of iridoids decreased, while genipin sulfate, the phase Ⅱ metabolite of genposide and genipin-1-gentiobioside, appeared the rising exposure. The pharmacokinetic profiles of main iridoids from GF were altered by isoflavones.
A LC-MS/MS method for determination of four iridoids in rat plasma was developed and applied. The bioavailability of four iridoids decreased in rats with their increasing isoflavones exposure time. Isoflavones could alter the fate of iridoids in vivo when GF and SSP were prescribed together to obtain toxicity-reducing.
Collapse
Affiliation(s)
- Ruirui Chang
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.,School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230031, China.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Jialin Liu
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Yusha Luo
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | | | - Qiang Li
- Shimadzu China Co.LTD., Shanghai, 200233, China
| | - Jun Wen
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| | - Weidong Chen
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230031, China
| | - Tingting Zhou
- School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.,Shanghai Key Laboratory for Pharmaceutical Metabolite Research, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
| |
Collapse
|
|
30
|
Screening of the Hepatotoxic Components in Fructus Gardeniae and Their Effects on Rat Liver BRL-3A Cells. Molecules 2019; 24:molecules24213920. [PMID: 31671698 PMCID: PMC6864725 DOI: 10.3390/molecules24213920] [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: 09/17/2019] [Revised: 10/28/2019] [Accepted: 10/29/2019] [Indexed: 02/07/2023] Open
Abstract
Fructus Gardeniae (FG) is a common Chinese medicine and food. However, the toxicity of FG has drawn increasing concern, especially its hepatotoxicity. The purpose of this study was to screen the hepatotoxic components of FG and evaluate their effects on rat liver BRL-3A cells. The chemical composition of FG was determined by HPLC-ESI-MS. CCK-8 assay was used to evaluate the cytotoxicity of ten chemical components from FG, and then the toxic components with significant inhibitory activity were selected for further study. The results showed that geniposide, genipin, genipin-1-gentiobioside, gardenoside, and shanzhiside all suppress cells viability. Apoptosis assays further indicated that geniposide and its metabolite genipin are the main hepatotoxic components of FG. Pretreatment of cells with geniposide or genipin increased the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). The activities of superoxide dismutase (SOD) and glutathione (GSH) were decreased, while the malondialdehyde (MDA) level was increased. The cell contents of tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) were also increased. Molecular docking simulations were used to investigate the mechanism of FG-induced hepatotoxicity, revealing that geniposide and genipin bind strongly to the pro-inflammatory factor TNFR1 receptor of the NF-κB and MAPK signaling pathways. The obtained results strongly indicate that the hepatotoxicity of FG is caused by iridoids compounds. Genipin had the most significant hepatotoxic effect. These toxic substances destroy the cell antioxidant defense system, increasing inflammatory injury to the liver cells and leading to apoptosis and even necrosis. Thus, this study lays a foundation for toxicology research into FG and its rational application.
Collapse
|
|
31
|
Wang Y, Qin S, Jia J, Huang L, Li F, Jin F, Ren Z, Wang Y. Intestinal Microbiota-Associated Metabolites: Crucial Factors in the Effectiveness of Herbal Medicines and Diet Therapies. Front Physiol 2019; 10:1343. [PMID: 31736775 PMCID: PMC6828839 DOI: 10.3389/fphys.2019.01343] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 10/09/2019] [Indexed: 12/14/2022] Open
Abstract
Although the efficacy of herbal medicines (HMs) and traditional Chinese medicines (TCMs) in human diseases has long been recognized, their development has been hindered in part by a lack of a comprehensive understanding of their mechanisms of action. Indeed, most of the compounds extracted from HMs can be metabolized into specific molecules by host microbiota and affect pharmacokinetics and toxicity. Moreover, HMs modulate the constitution of host intestinal microbiota to maintain a healthy gut ecology. Dietary interventions also show great efficacy in treating some refractory diseases, and the commensal microbiota potentially has significant implications for the high inter-individual differences observed in such responses. Herein, we mainly discuss the contribution of the intestinal microbiota to high inter-individual differences in response to HMs and TCMs, and especially the already known metabolites of the HMs produced by the intestinal microbiota. The contribution of commensal microbiota to the inter-individual differences in response to dietary therapy is also briefly discussed. This review highlights the significance of intestinal microbiota-associated metabolites to the efficiency of HMs and dietary interventions. Our review may help further identify the mechanisms leading to the inter-individual differences in the effectiveness of HM and dietary intervention from the perspective of their interactions with the intestinal microbiota.
Collapse
Affiliation(s)
- Yiliang Wang
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
- Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
| | - Shurong Qin
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
- Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Jiaoyan Jia
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
- Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
| | - Lianzhou Huang
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
- Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Feng Li
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
- Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
| | - Fujun Jin
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, China
| | - Zhe Ren
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
- Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
| | - Yifei Wang
- Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
- Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China
- Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China
| |
Collapse
|
|
32
|
Li Y, Pan H, Li X, Jiang N, Huang L, Lu Y, Shi F. Role of intestinal microbiota-mediated genipin dialdehyde intermediate formation in geniposide-induced hepatotoxicity in rats. Toxicol Appl Pharmacol 2019; 377:114624. [DOI: 10.1016/j.taap.2019.114624] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 05/22/2019] [Accepted: 06/10/2019] [Indexed: 02/06/2023]
|
|
33
|
Role of Intestinal Microbiota in Metabolism of Gastrodin In Vitro and In Vivo. Metabolites 2019; 9:metabo9040069. [PMID: 30965644 PMCID: PMC6523420 DOI: 10.3390/metabo9040069] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 04/01/2019] [Accepted: 04/04/2019] [Indexed: 12/19/2022] Open
Abstract
Alteration in the number and composition of intestinal microbiota affects the metabolism of several xenobiotics. Gastrodin, isolated from Gastrodia elata, is prone to be hydrolyzed by intestinal microbiota. In the present study, the role of intestinal microbiota in gastrodin metabolism was investigated in vitro and in vivo. Gastrodin was incubated in an anaerobic condition with intestinal contents prepared from vehicle- and antibiotics-treated rats and the disappearance of gastrodin and formation of 4-hydroxybenzyl alcohol (4-HBA) was measured by liquid chromatography coupled to mass spectroscopy (LC-MS/MS). The results showed that almost all gastrodin incubated with control intestinal contents was metabolized to its aglycone in time- and concentration-dependent manners. In contrast, much less formation of 4-HBA was detected in intestinal contents from antibiotics-treated rats. Subsequently, in vivo pharmacokinetic study revealed that the antibiotic pretreatment of rats significantly affected the metabolism of gastrodin to 4-HBA. When administered orally, gastrodin was rapidly absorbed rapidly into plasma, metabolized to 4-HBA, and disappeared from the body within six hours. Interestingly, the pharmacokinetic parameters of 4-HBA were changed remarkably in antibiotics-treated rats, compared to control rats. The results clearly indicated that the antibiotics treatment of rats suppressed the ability of intestinal microbiota to metabolize gastrodin to 4-HBA and that, thereby, the pharmacodynamic action was significantly modulated.
Collapse
|
|
34
|
Gut microbiota, a new frontier to understand traditional Chinese medicines. Pharmacol Res 2019; 142:176-191. [PMID: 30818043 DOI: 10.1016/j.phrs.2019.02.024] [Citation(s) in RCA: 253] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 02/18/2019] [Accepted: 02/23/2019] [Indexed: 02/06/2023]
Abstract
As an important component of complementary and alternative medicines, traditional Chinese medicines (TCM) are gaining more and more attentions around the world because of the powerful therapeutic effects and less side effects. However, there are still some doubts about TCM because of the questionable TCM theories and unclear biological active compounds. In recent years, gut microbiota has emerged as an important frontier to understand the development and progress of diseases. Together with this trend, an increasing number of studies have indicated that drug molecules can interact with gut microbiota after oral administration. In this context, more and more studies pertaining to TCM have paid attention to gut microbiota and have yield rich information for understanding TCM. After oral administration, TCM can interact with gut microbiota: (1) TCM can modulate the composition of gut microbiota; (2) TCM can modulate the metabolism of gut microbiota; (3) gut microbiota can transform TCM compounds. During the interactions, two types of metabolites can be produced: gut microbiota metabolites (of food and host origin) and gut microbiota transformed TCM compounds. In this review, we summarized the interactions between TCM and gut microbiota, and the pharmacological effects and features of metabolites produced during interactions between TCM and gut microbiota. Then, focusing on gut microbiota and metabolites, we summarized the aspects in which gut microbiota has facilitated our understanding of TCM. At the end of this review, the outlooks for further research of TCM and gut microbiota were also discussed.
Collapse
|
|
35
|
Luo K, Xing Y. Metabolic profile analysis of Zhi-zi-chi decoction in feces of normal and chronic unpredictable mild stress-induced depression rats based on UHPLC-ESI-Q-TOF-MS/MS and multiple analytical strategies. RSC Adv 2019; 9:40037-40050. [PMID: 35541428 PMCID: PMC9076205 DOI: 10.1039/c9ra06486a] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 11/18/2019] [Indexed: 12/24/2022] Open
Abstract
Zhi-zi-chi decoction (ZZCD) has been verified by clinical application that it has definite curative effects and low side effects on depression. Because it is administered orally, the metabolites of ZZCD in the intestinal tract may influence the curative effects significantly. In this study, UHPLC-ESI-Q-TOF-MS/MS was used in combination with untargeted metabolomics-driven strategy, series product ion filtering and diagnostic fragment ion strategy for acquiring the comprehensive metabolic profile of ZZCD in feces of normal and chronic unpredictable mild stress (CUMS)-induced depression rats after oral administration, while the rat depression model was evaluated by behavior tests and plasma biochemical indices. Finally, a total of 56 compounds, including 35 prototype compounds and 21 metabolites, were identified or tentatively characterized in fecal samples. Among these, ten compounds were sieved as potential chemical markers that would reflect the antidepressant effect of ZZCD, which may offer important information for quality assessment, pharmacokinetic study and clinical security. In conclusion, the metabolic profile of ZZCD in normal and CUMS-induced depression rats would be helpful for the further study of anti-depression material basis and mechanism. A total of 56 compounds from ZZCD were identified in feces of normal and depression rats. Then ten compounds were sieved as potential chemical markers that would reflect the antidepressant effect of ZZCD.![]()
Collapse
Affiliation(s)
- Kaiwen Luo
- School of Pharmacy
- Bengbu Medical University
- Bengbu
- China
| | - Yadong Xing
- School of Pharmacy
- Bengbu Medical University
- Bengbu
- China
| |
Collapse
|
|
36
|
Plant-Derived Anticancer Agents: Lessons from the Pharmacology of Geniposide and Its Aglycone, Genipin. Biomedicines 2018; 6:biomedicines6020039. [PMID: 29587429 PMCID: PMC6027249 DOI: 10.3390/biomedicines6020039] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 03/21/2018] [Accepted: 03/22/2018] [Indexed: 12/24/2022] Open
Abstract
For centuries, plants have been exploited by mankind as sources of numerous cancer chemotherapeutic agents. Good examples of anticancer compounds of clinical significance today include the taxanes (e.g., taxol), vincristine, vinblastine, and the podophyllotoxin analogues that all trace their origin to higher plants. While all these drugs, along with the various other available therapeutic options, brought some relief in cancer management, a real breakthrough or cure has not yet been achieved. This critical review is a reflection on the lessons learnt from decades of research on the iridoid glycoside geniposide and its aglycone, genipin, which are currently used as gold standard reference compounds in cancer studies. Their effects on tumour development (carcinogenesis), cancer cell survival, and death, with particular emphasis on their mechanisms of actions, are discussed. Particular attention is also given to mechanisms related to the dual pro-oxidant and antioxidant effects of these compounds, the mitochondrial mechanism of cancer cell killing through reactive oxygen species (ROS), including that generated through the uncoupling protein-2 (UCP-2), the inflammatory mechanism, and cell cycle regulation. The implications of various studies for the evaluation of glycosidic and aglycone forms of natural products in vitro and in vivo through pharmacokinetic scrutiny are also addressed.
Collapse
|
|
37
|
Zhong H, Chen K, Feng M, Shao W, Wu J, Chen K, Liang T, Liu C. Genipin alleviates high-fat diet-induced hyperlipidemia and hepatic lipid accumulation in mice via miR-142a-5p/SREBP-1c axis. FEBS J 2017; 285:501-517. [PMID: 29197188 DOI: 10.1111/febs.14349] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Revised: 11/07/2017] [Accepted: 11/29/2017] [Indexed: 12/13/2022]
Abstract
Hyperlipidemia is a chronic disorder which plays an important role in the development of cardiovascular diseases, type 2 diabetes, atherosclerosis, hypertension, and nonalcoholic fatty liver disease. Genipin (GNP) is a metabolite from genipioside, which is an active component of the traditional Chinese medicine Gardenia jasminoides Ellis, and has been recognized as a beneficial compound against metabolic disorders. However, whether it can correct overnutrition-induced dyslipidemia is still unknown. In this study, the effects of GNP on attenuating hyperlipidemia and hepatic lipid accumulation were investigated using normal and obese mice induced with a high-fat diet (HFD) and primary hepatocytes treated with free fatty acids. We also sought to identify potential targets of GNP to mediate its effects in the liver. We found that obese mice treated with GNP showed a decrease in the body weight, serum lipid levels, as well as hepatic lipid accumulation. Besides, GNP regulated hepatic expression levels of lipid metabolic genes, which are important in maintaining systemic lipid homeostasis. At the molecular level, GNP increased the expression levels of miR-142a-5p, which bound to 3' untranslated region of Srebp-1c, an important regulator of lipogenesis, which thus led to the inhibition of lipogenesis. Collectively, our data demonstrated that GNP effectively antagonized HFD-induced hyperlipidemia and hepatic lipid accumulation in mice. Such effects were achieved by regulating miR-142a-5p/SREBP-1c axis.
Collapse
Affiliation(s)
- Hong Zhong
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Sciences, Nanjing Normal University, China
| | - Ke Chen
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Sciences, Nanjing Normal University, China
| | - Mengyang Feng
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Sciences, Nanjing Normal University, China
| | - Wei Shao
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Sciences, Nanjing Normal University, China
| | - Jun Wu
- Department of Geriatric Cardiology, the First Affiliated Hospital of Nanjing Medical University, China
| | - Kun Chen
- The Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Sciences, Guangzhou University, China
| | - Tingming Liang
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Sciences, Nanjing Normal University, China
| | - Chang Liu
- Jiangsu Key Laboratory for Molecular and Medical Biotechnology, School of Life Sciences, Nanjing Normal University, China.,School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| |
Collapse
|
|
38
|
Ascending colon cancer coincident with mesenteric phlebosclerosis associated with the long-term oral intake of Chinese herb containing gardenia fruit: A case report and literature review. Int Cancer Conf J 2017; 6:70-75. [PMID: 31149474 DOI: 10.1007/s13691-017-0277-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Accepted: 01/05/2017] [Indexed: 12/24/2022] Open
Abstract
Mesenteric phlebosclerosis is a recently discovered rare ischemic colon disease. The relationship between mesenteric phlebosclerosis and the use of herbal medicine containing gardenia fruit was recently reported. Although the relationship between colon cancer and mesenteric phlebosclerosis has not been described, some cases of colorectal cancer coincident with mesenteric phlebosclerosis have been reported. We treated a 63-year-old female who was diagnosed with ascending colon cancer coincident with mesenteric phlebosclerosis. She had been taking a Chinese herb containing gardenia fruit for over 18 years. The ascending colon cancer was clinically diagnosed as T2, N0, and M0 according to Japanese classification of colorectal carcinoma and the mesenteric phlebosclerosis had spread from the cecum to the descending colon. She underwent laparoscopic subtotal colectomy with en bloc removal of the regional lymph nodes, and both the ascending colon cancer and mesenteric phlebosclerosis were completely resected. The microscopic findings show that the tumor was well-differentiated tubular adenocarcinoma invading the muscular propria with no regional lymph node metastasis, and the mesenteric phlebosclerosis lesion was characterized by marked fibrous thickening of the venous walls with calcification, marked transmural fibrosis and deposition of the collagen in the mucosa, accompanied by macrophages within the vessel walls. In literature review, 10 cases with colorectal cancer coincident with mesenteric phlebosclerosis were reported. 9 of 10 cases (90%) had cancer in the right-side colon affected by mesenteric phlebosclerosis, and 5 of 10 cases (50%) were associated with the use of a Chinese herb containing gardenia fruit. It was recently demonstrated that genipin, which is a metabolite bio-transformed from gardenia fruit, possesses carcinogenesis. We speculate that genipin may be associated with not only the development of mesenteric phlebosclerosis but also carcinogenesis in the right-side colon. In conclusion, our findings suggest that the safety of gardenia fruit should be re-evaluated, and gastroenterologists should be aware that gardenia fruit may be risk factor for not only the development of mesenteric phlebosclerosis but also carcinogenesis in the proximal colon.
Collapse
|
|
39
|
Role of Intestinal Microbiota in Baicalin-Induced Drug Interaction and Its Pharmacokinetics. Molecules 2016; 21:337. [PMID: 26978333 PMCID: PMC6273104 DOI: 10.3390/molecules21030337] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 03/02/2016] [Accepted: 03/07/2016] [Indexed: 12/24/2022] Open
Abstract
Since many glycoside compounds in natural products are hydrolyzed by intestinal microbiota when administered orally, it is of interest to know whether their pharmacological effects are derived from the glycoside itself or from the aglycone form in vivo. An interesting example is baicalin versus baicalein, the aglycone of baicalin, which is contained in some herbs from Labiatae including Scutellaria baicalensis Georgi and Scutellaria lateriflora Linne. The herbs have been extensively used for treatment of inflammatory diseases in Asia. Although there have been numerous reports regarding the pharmacological effects of baicalin and baicalein in vivo and in vitro, some reports indicated that the glycoside form would hardly be absorbed in the intestine and that it should be hydrolyzed to baicalein in advance for absorption. Therefore, the role of metabolism by intestinal microbiota should also be considered in the metabolism of baicalin. In addition, baicalin contains a glucuronide moiety in its structure, by which baicalin and baicalein show complex pharmacokinetic behaviors, due to the interconversion between them by phase II enzymes in the body. Recently, concerns about drug interaction with baicalin and/or baicalein have been raised, because of the co-administration of Scutellaria species with certain drugs. Herein, we reviewed the role of intestinal microbiota in pharmacokinetic characteristics of baicalin and baicalein, with regards to their pharmacological and toxicological effects.
Collapse
|
|
40
|
Amidon S, Brown JE, Dave VS. Colon-targeted oral drug delivery systems: design trends and approaches. AAPS PharmSciTech 2015; 16:731-41. [PMID: 26070545 DOI: 10.1208/s12249-015-0350-9] [Citation(s) in RCA: 277] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 06/04/2015] [Indexed: 12/15/2022] Open
Abstract
Colon-specific drug delivery systems (CDDS) are desirable for the treatment of a range of local diseases such as ulcerative colitis, Crohn's disease, irritable bowel syndrome, chronic pancreatitis, and colonic cancer. In addition, the colon can be a potential site for the systemic absorption of several drugs to treat non-colonic conditions. Drugs such as proteins and peptides that are known to degrade in the extreme gastric pH, if delivered to the colon intact, can be systemically absorbed by colonic mucosa. In order to achieve effective therapeutic outcomes, it is imperative that the designed delivery system specifically targets the drugs into the colon. Several formulation approaches have been explored in the development colon-targeted drug delivery systems. These approaches involve the use of formulation components that interact with one or more aspects of gastrointestinal (GI) physiology, such as the difference in the pH along the GI tract, the presence of colonic microflora, and enzymes, to achieve colon targeting. This article highlights the factors influencing colon-specific drug delivery and colonic bioavailability, and the limitations associated with CDDS. Further, the review provides a systematic discussion of various conventional, as well as relatively newer formulation approaches/technologies currently being utilized for the development of CDDS.
Collapse
|
|
41
|
Jin MJ, Kim IS, Kim DH, Yoo HH. Effects of intestinal microbiota on the bioavailability of geniposide in rats. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2014; 62:9632-9636. [PMID: 25257195 DOI: 10.1021/jf502557f] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
This study investigated the effects of intestinal microbiota on the metabolism of geniposide by using a rat model treated with a mixture of antibiotics. The plasma concentration of geniposide was determined after oral administration in control and antibiotics-treated rats by using liquid chromatography-tandem mass spectrometry. The maximum plasma concentrations (Cmax) of geniposide in control and antibiotics-treated rats were 0.91 ± 0.26 and 1.01 ± 0.04 μg/mL, respectively, and the area under the curve (AUC) values were 7.34 ± 3.32 and 11.9 ± 2.1 μg·h/mL (p < 0.05), respectively. The levels of geniposide in rat feces were 0.64 and 15.6 mg, respectively, in the control and antibiotics-treated groups. Thus, the systemic exposure of geniposide was greater in the antibiotics-treated rats. This may be due to the antibiotic-induced suppression of the metabolic activities of the intestinal microbiota. These results suggest that the gut microbiota may have an impact on the bioavailability of geniposide.
Collapse
Affiliation(s)
- Ming Ji Jin
- Institute of Pharmaceutical Science and Technology and College of Pharmacy, Hanyang University , Ansan, Gyeonggi-do, Korea
| | | | | | | |
Collapse
|
|
42
|
Biotransformation of geniposide by Synechocystis sp. PCC 6803 into genipin and its inhibitory effects on BEL-7402, Escherichia coli, and cyanobacteria. ANN MICROBIOL 2014. [DOI: 10.1007/s13213-014-0968-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
|
|
43
|
Malayandi R, Kondamudi PK, Ruby PK, Aggarwal D. Biopharmaceutical considerations and characterizations in development of colon targeted dosage forms for inflammatory bowel disease. Drug Deliv Transl Res 2013; 4:187-202. [DOI: 10.1007/s13346-013-0185-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
|
|
44
|
Jeong HG, Kang MJ, Kim HG, Oh DG, Kim JS, Lee SK, Jeong TC. Role of intestinal microflora in xenobiotic-induced toxicity. Mol Nutr Food Res 2012; 57:84-99. [PMID: 23166009 DOI: 10.1002/mnfr.201200461] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Revised: 09/10/2012] [Accepted: 09/26/2012] [Indexed: 11/09/2022]
Abstract
In addition to its role in digestion of food in the gastrointestinal tract, the intestinal microflora is also capable of biotransforming numerous drugs. Likewise, the intestinal microflora may significantly modulate xenobiotic-induced toxicity by either activating or inactivating xenobiotics via metabolism. To date, most investigations of xenobiotic metabolism have focused not only on metabolism in host tissues, but the modulation of the pharmacological activity of drugs by the intestinal microflora. Despite its importance, the presumed role of intestinal microflora metabolism in xenobiotic-induced toxicity has been understudied. Therefore, it is appropriate to briefly review our current situation, and state which research in xenobiotic metabolism by intestinal microflora, particularly in the field of toxicology, is needed.
Collapse
Affiliation(s)
- Hye Gwang Jeong
- College of Pharmacy, Chungnam National University, Daejeon, South Korea
| | | | | | | | | | | | | |
Collapse
|
|
45
|
Hiramatsu K, Sakata H, Horita Y, Orita N, Kida A, Mizukami A, Miyazawa M, Hirai S, Shimatani A, Matsuda K, Matsuda M, Ogino H, Fujinaga H, Terada I, Shimizu K, Uchiyama A, Ishizawa S, Abo H, Demachi H, Noda Y. Mesenteric phlebosclerosis associated with long-term oral intake of geniposide, an ingredient of herbal medicine. Aliment Pharmacol Ther 2012; 36:575-86. [PMID: 22817400 DOI: 10.1111/j.1365-2036.2012.05221.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2012] [Revised: 06/27/2012] [Accepted: 06/29/2012] [Indexed: 01/13/2023]
Abstract
BACKGROUND Idiopathic mesenteric phlebosclerosis (IMP) is a rare disease, characterised by thickening of the wall of the right hemicolon with calcification of mesenteric veins. However, the aetiology remains unknown. AIM To investigate the possible association of herbal medicines with IMP. METHOD The clinical data of four of our own patients were collected. Furthermore, we searched for previous reports about similar patients with detailed descriptions of herbal prescriptions that they had taken. We compared herbal ingredients to identify the toxic agent as a possible aetiological factor. RESULTS Clinical data on a total of 25 patients were summarised. Mean age was 61.8 years and there was female predominance (6 men and 19 women). The used Kampo prescription, the number of cases, and the mean duration of use were as follows: kamisyoyosan in 12 cases for 12.8 years, inshin-iseihaito in 5 cases for 13.4 years, orengedokuto in 4 cases for 14.3 years, inchinkoto in 1 case for 20 years, kamikihitou in 1 case for 19 years, seijobofuto in 1 case for 10 years and gorinsan in 1 case for an unknown duration. Only one ingredient, sansisi, was common to the herbal medicines of all 25 patients. This crude drug called geniposide in English is a major constituent of the Gardenia fruits. CONCLUSION The long-term use of geniposide in herbal medicines appears to be associated with mesenteric phlebosclerosis.
Collapse
Affiliation(s)
- K Hiramatsu
- Department of Internal Medicine, Toyama Prefectural Central Hospital, Toyama, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|