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Azhdari M, Zur Hausen A. Wnt/β-catenin and notch signaling pathways in cardiovascular disease: Mechanisms and therapeutics approaches. Pharmacol Res 2025; 211:107565. [PMID: 39725339 DOI: 10.1016/j.phrs.2024.107565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 11/30/2024] [Accepted: 12/23/2024] [Indexed: 12/28/2024]
Abstract
Wnt and Notch signaling pathways play crucial roles in the development and homeostasis of the cardiovascular system. These pathways regulate important cellular processes in cardiomyocytes, endothelial cells, and smooth muscle cells, which are the key cell types involved in the structure and function of the heart and vasculature. During embryonic development, Wnt and Notch signaling coordinate cell fate specification, proliferation, differentiation, and morphogenesis of the heart and blood vessels. In the adult cardiovascular system, these pathways continue to maintain tissue homeostasis and arrange adaptive responses to various physiological and pathological stimuli. Dysregulation of Wnt and Notch signaling has been involved in the pathogenesis of numerous cardiovascular diseases, including atherosclerosis, hypertension, myocardial infarction, and heart failure. Abnormal activation or suppression of these pathways in specific cell types can contribute to endothelial dysfunction, vascular remodeling, cardiomyocyte hypertrophy, impaired cardiac contractility and dead. Understanding the complex interplay between Wnt and Notch signaling in the cardiovascular system has led to the investigation of these pathways as potential therapeutic targets in clinical trials. In conclusion, this review summarizes the current knowledge on the roles of Wnt and Notch signaling in the development and homeostasis of cardiomyocytes, endothelial cells, and smooth muscle cells. It further discusses the dysregulation of these pathways in the context of major cardiovascular diseases and the ongoing clinical investigations targeting Wnt and Notch signaling for therapeutic intervention.
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Affiliation(s)
- Manizheh Azhdari
- Pathologie, School for Cardiovascular Diseases, Fac. Health, Medicine and Life Sciences, Maastricht university, MUMC, the Netherland.
| | - Axel Zur Hausen
- Pathologie, School for Cardiovascular Diseases, Fac. Health, Medicine and Life Sciences, Maastricht university, MUMC, the Netherland.
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Jiang M, Xie Y, Wang P, Du M, Wang Y, Yan S. Research Progress of Triptolide Against Fibrosis. Drug Des Devel Ther 2024; 18:3255-3266. [PMID: 39081704 PMCID: PMC11287200 DOI: 10.2147/dddt.s467929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 07/01/2024] [Indexed: 08/02/2024] Open
Abstract
Fibrosis leads to organ failure and death, which is the final stage of many chronic diseases. Triptolide (TPL) is a terpenoid extracted from the traditional Chinese medicine Tripterygium wilfordii Hook. F (TwHF). Triptolide and its derivatives (Omtriptolide, Minnelide, (5R)-5-hydroxytriptolide) have been proven to have a variety of pharmacological effects. This study comprehensively reviewed the antifibrotic mechanism of TPL and its derivatives, and discussed the application of advanced nanoparticles (NPs) drug delivery system in the treatment of fibrotic diseases by TPL. The results show that TPL can inhibit immune inflammatory response, relieve oxidative stress and endoplasmic reticulum stress (ERS), regulate collagen deposition and inhibit myofibroblast production to play an anti-fibrosis effect and reduce organ injury. A low dose of TPL has no obvious toxicity. Under pathological conditions, a toxic dose of TPL has a protective effect on organs. The emergence of TPL derivatives (especially Minnelide) and NPs drug delivery systems promotes the anti-fibrosis effect of TPL and reduces its toxicity, which may be the main direction of anti-fibrosis research in the future.
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Affiliation(s)
- Minmin Jiang
- Department of Endocrinology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China
| | - Yongxia Xie
- Department of Respiratory Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China
| | - Ping Wang
- Department of Endocrinology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China
| | - Mengyu Du
- The First Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China
| | - Ying Wang
- Department of International Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Shuxun Yan
- Department of Endocrinology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China
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Ntampakis G, Pramateftakis MG, Anestiadou E, Bitsianis S, Ioannidis O, Bekiari C, Koliakos G, Karakota M, Tsakona A, Cheva A, Angelopoulos S. Experimental models of high-risk bowel anastomosis in rats: A systematic review. World J Exp Med 2024; 14:94135. [PMID: 38948424 PMCID: PMC11212746 DOI: 10.5493/wjem.v14.i2.94135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/23/2024] [Accepted: 05/10/2024] [Indexed: 06/19/2024] Open
Abstract
BACKGROUND Anastomotic leaks remain one of the most dreaded complications in gastrointestinal surgery causing significant morbidity, that negatively affect the patients' quality of life. Experimental studies play an important role in understanding the pathophysiological background of anastomotic healing and there are still many fields that require further investigation. Knowledge drawn from these studies can lead to interventions or techniques that can reduce the risk of anastomotic leak in patients with high-risk features. Despite the advances in experimental protocols and techniques, designing a high-quality study is still challenging for the investigators as there is a plethora of different models used. AIM To review current state of the art for experimental protocols in high-risk anastomosis in rats. METHODS This systematic review was performed according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. To identify eligible studies, a comprehensive literature search was performed in the electronic databases PubMed (MEDLINE) and Scopus, covering the period from conception until 18 October 2023. RESULTS From our search strategy 102 studies were included and were categorized based on the mechanism used to create a high-risk anastomosis. Methods of assessing anastomotic healing were extracted and were individually appraised. CONCLUSION Anastomotic healing studies have evolved over the last decades, but the findings are yet to be translated into human studies. There is a need for high-quality, well-designed studies that will help to the better understanding of the pathophysiology of anastomotic healing and the effects of various interventions.
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Affiliation(s)
- Georgios Ntampakis
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | | | - Elissavet Anestiadou
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Stefanos Bitsianis
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Orestis Ioannidis
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Chryssa Bekiari
- Laboratory of Anatomy and Histology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
- Experimental and Research Center, Papageorgiou General Hospital of Thessaloniki, Thessaloniki 56403, Greece
| | - George Koliakos
- Laboratory of Biochemistry, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
| | - Maria Karakota
- Laboratory of Biochemistry, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
| | - Anastasia Tsakona
- Department of Pathology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
| | - Angeliki Cheva
- Department of Pathology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
| | - Stamatios Angelopoulos
- Fourth Department of Surgery, Medical School, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
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Geropoulos G, Psarras K, Koimtzis G, Fornasiero M, Anestiadou E, Geropoulos V, Michopoulou A, Papaioannou M, Kouzi-Koliakou K, Galanis I. Knockout Genes in Bowel Anastomoses: A Systematic Review of Literature Outcomes. J Pers Med 2024; 14:553. [PMID: 38929776 PMCID: PMC11205243 DOI: 10.3390/jpm14060553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/12/2024] [Accepted: 04/16/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND The intestinal wound healing process is a complex event of three overlapping phases: exudative, proliferative, and remodeling. Although some mechanisms have been extensively described, the intestinal healing process is still not fully understood. There are some similarities but also some differences compared to other tissues. The aim of this systematic review was to summarize all studies with knockout (KO) experimental models in bowel anastomoses, underline any recent knowledge, and clarify further the cellular and molecular mechanisms of the intestinal healing process. A systematic review protocol was performed. MATERIALS AND METHODS Medline, EMBASE, and Scopus were comprehensively searched. RESULTS a total of eight studies were included. The silenced genes included interleukin-10, the four-and-one-half LIM domain-containing protein 2 (FHL2), cyclooxygenase-2 (COX-2), annexin A1 (ANXA-1), thrombin-activatable fibrinolysis inhibitor (TAFI), and heparin-binding epidermal growth factor (HB-EGF) gene. Surgically, an end-to-end bowel anastomosis was performed in the majority of the studies. Increased inflammatory cell infiltration in the anastomotic site was found in IL-10-, annexin-A1-, and TAFI-deficient mice compared to controls. COX-1 deficiency showed decreased angiogenesis at the anastomotic site. Administration of prostaglandin E2 in COX-2-deficient mice partially improved anastomotic leak rates, while treatment of ANXA1 KO mice with Ac2-26 nanoparticles reduced colitis activity and increased weight recovery following surgery. CONCLUSIONS our findings provide new insights into improving intestinal wound healing by amplifying the aforementioned genes using appropriate gene therapies. Further research is required to clarify further the cellular and micromolecular mechanisms of intestinal healing.
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Affiliation(s)
- Georgios Geropoulos
- 2nd Department of Propaedeutic Surgery, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (G.G.); (G.K.); (V.G.); (A.M.); (I.G.)
| | - Kyriakos Psarras
- 2nd Department of Propaedeutic Surgery, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (G.G.); (G.K.); (V.G.); (A.M.); (I.G.)
| | - Georgios Koimtzis
- 2nd Department of Propaedeutic Surgery, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (G.G.); (G.K.); (V.G.); (A.M.); (I.G.)
| | | | - Elissavet Anestiadou
- Fourth Surgical Department, School of Medicine, Aristotle University of Thessaloniki, 57010 Thessaloniki, Greece;
| | - Vasileios Geropoulos
- 2nd Department of Propaedeutic Surgery, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (G.G.); (G.K.); (V.G.); (A.M.); (I.G.)
| | - Anna Michopoulou
- 2nd Department of Propaedeutic Surgery, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (G.G.); (G.K.); (V.G.); (A.M.); (I.G.)
- Laboratory of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Maria Papaioannou
- Laboratory of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Kokkona Kouzi-Koliakou
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Ioannis Galanis
- 2nd Department of Propaedeutic Surgery, Hippokration Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece; (G.G.); (G.K.); (V.G.); (A.M.); (I.G.)
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Pan W, Yang B, He D, Chen L, Fu C. Functions and targets of miRNAs in pharmacological and toxicological effects of major components of Tripterygium wilfordii Hook F. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1997-2019. [PMID: 37831113 DOI: 10.1007/s00210-023-02764-3] [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: 08/15/2023] [Accepted: 09/29/2023] [Indexed: 10/14/2023]
Abstract
Tripterygium wilfordii Hook F (TwHF) has a long history of use as a traditional Chinese medicine and has been widely administered to treat various inflammatory and autoimmune diseases. MicroRNAs (miRNAs) are endogenous, short, non-coding RNAs that regulate gene expression post-transcriptionally. They participate in the efficacies and even toxicities of the components of TwHF, rendering miRNAs an appealing therapeutic strategy. This review summarizes the recent literature related to the roles and mechanisms of miRNAs in the pharmacological and toxicological effects of main components of TwHF, focusing on two active compounds, triptolide (TP) and celastrol (CEL). Additionally, the prospects for the "You Gu Wu Yun" theory regarding TwHF nephrotoxicity are presented.
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Affiliation(s)
- Wei Pan
- Institute of Pharmacy and Pharmacology, College of Basic Medical Science, Hengyang Medical School, University of South China, Hengyang, 421200, Hunan, People's Republic of China
- The First Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Bo Yang
- The First Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China
| | - Dongxiu He
- Institute of Pharmacy and Pharmacology, College of Basic Medical Science, Hengyang Medical School, University of South China, Hengyang, 421200, Hunan, People's Republic of China
| | - Linxi Chen
- Institute of Pharmacy and Pharmacology, College of Basic Medical Science, Hengyang Medical School, University of South China, Hengyang, 421200, Hunan, People's Republic of China
| | - Chengxiao Fu
- Institute of Pharmacy and Pharmacology, College of Basic Medical Science, Hengyang Medical School, University of South China, Hengyang, 421200, Hunan, People's Republic of China.
- The First Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China.
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Zeng HL, Qiu Q, Fu TX, Deng AP, Xie XY. Development and optimization of sustained release triptolide microspheres. PLoS One 2023; 18:e0292861. [PMID: 37856525 PMCID: PMC10586653 DOI: 10.1371/journal.pone.0292861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 10/02/2023] [Indexed: 10/21/2023] Open
Abstract
Rheumatoid arthritis is considered a chronic systemic autoimmune disorder that may cause joint destruction. Triptolide, an active component isolated from Tripterygium wilfordii Hook.f., is considered to have promising potential for clinical use in treating rheumatoid arthritis. However, its clinical application has been limited by the narrow therapeutic window, side effects associated with plasma drug fluctuations, low oral bioavailability, and poor patient compliance with the long and frequent dosing regimen. An extended drug release preparation may address these limitations. The aim of this work was therefore to develop, formulate and optimize sustained release triptolide microspheres with poly (lactide-co-glycolide) (PLGA). Triptolide-loaded microspheres were prepared using PLGA as the matrix polymer, dichloromethane as the oil phase, and polyvinyl alcohol (PVA) as the matrix forming emulsifier. An oil-in-water (O/W) emulsion solvent evaporation technique was utilized to prepare the microspheres. Surface response methodology (RSM) coupled with central composite design (CCD) was used to optimize the formulation and a total of twenty formulations were prepared. PVA concentration (X1), PLGA concentration (X2), and theoretical drug content (X3) were selected as independent variables; and drug content (Y1), encapsulation efficiency (Y2), mean diameter (Y3) and the initial release during the first day (Y4) were taken as the response variables. The optimized formulation showed mean diameter of 42.36 μm, drug content of 7.96%, encapsulation efficiency of 80.16% and an initial release of 14.48%. The prepared microspheres exhibited a sustained release profile of triptolide in vitro over 4 weeks, which was wellfitted with a Korsmeyer-Peppas equation. However, the initial drug release (~14%) of triptolide-loaded microspheres was very high and should be specifically investigated in future studies. The results indicate that long-term sustained release microspheres of triptolide can be considered a strategy to overcome the low bioavailability and poor patient compliance with conventional triptolide tablets. The issue of initial burst release and in vivo evaluations should be specifically investigated in the future.
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Affiliation(s)
- Hui-lin Zeng
- Department of Pharmacy, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qian Qiu
- Department of Pharmacy, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ting-xiong Fu
- Department of Pharmacy, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ai-ping Deng
- Department of Pharmacy, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiang-yang Xie
- Department of Pharmacy, General Hospital of Central Theater of the PLA, Wuhan, Hubei, China
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Innocenti T, Bigagli E, Lynch EN, Galli A, Dragoni G. MiRNA-Based Therapies for the Treatment of Inflammatory Bowel Disease: What Are We Still Missing? Inflamm Bowel Dis 2023; 29:308-323. [PMID: 35749310 DOI: 10.1093/ibd/izac122] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Indexed: 02/05/2023]
Abstract
Micro-RNAs (miRNAs) are noncoding RNAs usually 24-30 nucleotides long that play a central role in epigenetic mechanisms of inflammatory diseases and cancers. Recently, several studies have assessed the involvement of miRNAs in the pathogenesis of inflammatory bowel disease (IBD) and colitis-associated neoplasia. Particularly, it has been shown that many members of miRNAs family are involved in the pathways of inflammation and fibrogenesis of IBD; therefore, their use as inflammatory and fibrosis biomarkers has been postulated. In light of these results, the role of miRNAs in IBD therapy has been proposed and is currently under investigation with many in vitro and in vivo studies, murine models, and a phase 2a trial. The accumulating data have pushed miRNA-based therapy closer to clinical practice, although many open questions remain. With this systematic review, we discuss the current knowledge about the therapeutic effects of miRNAs mimicking and inhibition, and we explore the new potential targets of miRNA family for the treatment of inflammation and fibrosis in IBD.
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Affiliation(s)
- Tommaso Innocenti
- IBD Referral Center, Gastroenterology Department, Careggi University Hospital, Florence, Italy.,Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Elisabetta Bigagli
- Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | - Erica Nicola Lynch
- IBD Referral Center, Gastroenterology Department, Careggi University Hospital, Florence, Italy.,Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Gabriele Dragoni
- IBD Referral Center, Gastroenterology Department, Careggi University Hospital, Florence, Italy.,Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences "Mario Serio", University of Florence, Florence, Italy
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Vieujean S, Caron B, Haghnejad V, Jouzeau JY, Netter P, Heba AC, Ndiaye NC, Moulin D, Barreto G, Danese S, Peyrin-Biroulet L. Impact of the Exposome on the Epigenome in Inflammatory Bowel Disease Patients and Animal Models. Int J Mol Sci 2022; 23:7611. [PMID: 35886959 PMCID: PMC9321337 DOI: 10.3390/ijms23147611] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that encompass two main phenotypes, namely Crohn's disease and ulcerative colitis. These conditions occur in genetically predisposed individuals in response to environmental factors. Epigenetics, acting by DNA methylation, post-translational histones modifications or by non-coding RNAs, could explain how the exposome (or all environmental influences over the life course, from conception to death) could influence the gene expression to contribute to intestinal inflammation. We performed a scoping search using Medline to identify all the elements of the exposome that may play a role in intestinal inflammation through epigenetic modifications, as well as the underlying mechanisms. The environmental factors epigenetically influencing the occurrence of intestinal inflammation are the maternal lifestyle (mainly diet, the occurrence of infection during pregnancy and smoking); breastfeeding; microbiota; diet (including a low-fiber diet, high-fat diet and deficiency in micronutrients); smoking habits, vitamin D and drugs (e.g., IBD treatments, antibiotics and probiotics). Influenced by both microbiota and diet, short-chain fatty acids are gut microbiota-derived metabolites resulting from the anaerobic fermentation of non-digestible dietary fibers, playing an epigenetically mediated role in the integrity of the epithelial barrier and in the defense against invading microorganisms. Although the impact of some environmental factors has been identified, the exposome-induced epimutations in IBD remain a largely underexplored field. How these environmental exposures induce epigenetic modifications (in terms of duration, frequency and the timing at which they occur) and how other environmental factors associated with IBD modulate epigenetics deserve to be further investigated.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, 4000 Liege, Belgium;
| | - Bénédicte Caron
- Department of Gastroenterology NGERE (INSERM U1256), Nancy University Hospital, University of Lorraine, Vandœuvre-lès-Nancy, F-54052 Nancy, France; (B.C.); (V.H.)
| | - Vincent Haghnejad
- Department of Gastroenterology NGERE (INSERM U1256), Nancy University Hospital, University of Lorraine, Vandœuvre-lès-Nancy, F-54052 Nancy, France; (B.C.); (V.H.)
| | - Jean-Yves Jouzeau
- CNRS (French National Centre for Scientific Research), Laboratoire IMoPA, Université de Lorraine, UMR 7365, F-54000 Nancy, France; (J.-Y.J.); (P.N.); (D.M.); (G.B.)
| | - Patrick Netter
- CNRS (French National Centre for Scientific Research), Laboratoire IMoPA, Université de Lorraine, UMR 7365, F-54000 Nancy, France; (J.-Y.J.); (P.N.); (D.M.); (G.B.)
| | - Anne-Charlotte Heba
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), National Institute of Health and Medical Research, University of Lorraine, F-54000 Nancy, France; (A.-C.H.); (N.C.N.)
| | - Ndeye Coumba Ndiaye
- NGERE (Nutrition-Genetics and Exposure to Environmental Risks), National Institute of Health and Medical Research, University of Lorraine, F-54000 Nancy, France; (A.-C.H.); (N.C.N.)
| | - David Moulin
- CNRS (French National Centre for Scientific Research), Laboratoire IMoPA, Université de Lorraine, UMR 7365, F-54000 Nancy, France; (J.-Y.J.); (P.N.); (D.M.); (G.B.)
| | - Guillermo Barreto
- CNRS (French National Centre for Scientific Research), Laboratoire IMoPA, Université de Lorraine, UMR 7365, F-54000 Nancy, France; (J.-Y.J.); (P.N.); (D.M.); (G.B.)
- Lung Cancer Epigenetics, Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- International Laboratory EPIGEN, Consejo de Ciencia y Tecnología del Estado de Puebla (CONCYTEP), Universidad de la Salud del Estado de Puebla, Puebla 72000, Mexico
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, 20132 Milan, Italy;
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology NGERE (INSERM U1256), Nancy University Hospital, University of Lorraine, Vandœuvre-lès-Nancy, F-54052 Nancy, France; (B.C.); (V.H.)
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Li Y, Guo L, Hou Z, Gong H, Yan M, Zhang B. Role of MicroRNA-155 in Triptolide-induced hepatotoxicity via the Nrf2-Dependent pathway. JOURNAL OF ETHNOPHARMACOLOGY 2021; 281:114489. [PMID: 34363931 DOI: 10.1016/j.jep.2021.114489] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 08/03/2021] [Accepted: 08/03/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Triptolide (TP), the main bioactive and toxic ingredient of Tripterygium wilfordii Hook F, causes severe toxicity, particularly for hepatotoxicity. However, the underlying mechanisms for its hepatotoxicity are not entirely clear. AIM OF THE STUDY The purpose of the study was to explore the role of miR-155, a microRNA closely related to various liver injuries and a regulator of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway, in TP-induced liver injury in vitro and in vivo. MATERIALS AND METHODS First, in vitro L02 cells were treated with different concentrations of TP. The protein levels of Nrf2 and its downstream genes Heme oxygenase1 (HO-1) were determined by Western blot. The mRNA expression of miR-155, Nrf2, NAD(P)H: quinone oxidoreductase 1 (NQO1) and HO-1 were measured using qRT-PCR. And we transfected miR-155 inhibitor and miminc before TP treatment to determine the mRNA and/or protein levels of miR-155, Nrf2 and HO-1. Then, we further confirmed the interaction between miR-155 and Nrf2 pathway in TP-induced hepatic injury in BALB/C mice. The degree of liver injury was determined by HE staining and serum biochemical. The mRNA expression of miR-155 was examined with qRT-PCR and Nrf2 and HO-1 gene expression in liver were evaluated by immunohistochemistry and/or Western blot. RESULTS The results showed that TP significantly induced the expression of miR-155 both in L02 cells and in rodents liver tissue, and the inhibition of miR-155 could mitigate the hepatic damages caused by TP. Further experiments demonstrated that the inhibition of miR-155 reversed the down-regulation of Nrf2 and HO-1 by TP, while the miR-155 mimic enhanced the effects of TP. Animal experiments also showed that the inhibition of miR-155 by miR-155 antagomir reversed the decrease of Nrf2 induced by TP administration. CONCLUSIONS These results indicated that miR-155 played an important role in TP-induced hepatotoxicity by regulating the Nrf2 signaling pathway.
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Affiliation(s)
- Yao Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Lin Guo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Zhenyan Hou
- Department of Pharmacy, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, China
| | - Hui Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
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Zhou K, Chang Y, Han B, Li R, Wei Y. MicroRNAs as crucial mediators in the pharmacological activities of triptolide (Review). Exp Ther Med 2021; 21:499. [PMID: 33791008 PMCID: PMC8005665 DOI: 10.3892/etm.2021.9930] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 02/18/2021] [Indexed: 12/19/2022] Open
Abstract
Triptolide is the main bioactive constituent isolated from the Chinese herb Tripterygium wilfordii Hook F., which possesses a variety of pharmacological properties. MicroRNAs (miRNAs/miRs) are short non-coding RNAs that regulate gene expression post-transcriptionally. miRNAs are implicated in several intracellular processes, whereby their dysregulation contributes to pathogenesis of various diseases. Thus, miRNAs have great potential as biomarkers and therapeutic targets for diseases, and are implicated in drug treatment. Previous studies have reported that specific miRNAs are targeted, and their expression levels can be altered following exposure to triptolide. Thus, miRNAs are emerging as crucial mediators in the pharmacological activities of triptolide. The present review summarizes current literature on miRNAs as target molecules in the pharmacological activities of triptolide, including antitumor, anti-inflammatory, immunosuppressive, renal protective, cardioprotective, antiangiogenesis activities and multiorgan toxicity effects. In addition, the diverse signaling pathways involved are discussed to provide a comprehensive understanding of the underlying molecular mechanisms of triptolide in the regulation of target miRNAs.
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Affiliation(s)
- Kun Zhou
- Shanxi Institute of Energy, Taiyuan, Shanxi 030600, P.R. China
| | - Yinxia Chang
- College of Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, Shanxi 030619, P.R. China
| | - Bo Han
- College of Basic Medicine, Shanxi University of Chinese Medicine, Jinzhong, Shanxi 030619, P.R. China
| | - Rui Li
- College of Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, Shanxi 030619, P.R. China
| | - Yanming Wei
- College of Chinese Medicine and Food Engineering, Shanxi University of Chinese Medicine, Jinzhong, Shanxi 030619, P.R. China
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11
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Tamgue O, Chia JE, Brombacher F. Triptolide Modulates the Expression of Inflammation-Associated lncRNA-PACER and lincRNA-p21 in Mycobacterium tuberculosis-Infected Monocyte-Derived Macrophages. Front Pharmacol 2021; 12:618462. [PMID: 33912039 PMCID: PMC8071990 DOI: 10.3389/fphar.2021.618462] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 02/11/2021] [Indexed: 12/20/2022] Open
Abstract
Triptolide is a diterpene triepoxide, which performs its biological activities via mechanisms including induction of apoptosis, targeting of pro-inflammatory cytokines, and reshaping of the epigenetic landscape of target cells. However, the targeting of long non-coding RNAs (lncRNAs) by triptolide has not yet been investigated, despite their emerging roles as key epigenetic regulators of inflammation and immune cell function during Mycobacterium tuberculosis (Mtb) infection. Hence, we investigated whether triptolide targets inflammation-associated lncRNA-PACER and lincRNA-p21 and how this targeting associates with Mtb killing within monocyte-derived macrophages (MDMs).Using RT-qPCR, we found that triptolide induced the expression of lincRNA-p21 but inhibited the expression of lncRNA-PACER in resting MDMs in a dose- and time-dependent manner. Moreover, Mtb infection induced the expression of lincRNA-p21 and lncRNA-PACER, and exposure to triptolide before or after Mtb infection led to further increase of Mtb-induced expression of these lncRNAs in MDMs. We further found that contrary to lncRNA-PACER, triptolide time- and dose-dependently upregulated Ptgs-2, which is a proximal gene regulated by lncRNA-PACER. Also, low-concentration triptolide inhibited the expression of cytokine IL-6, a known target of lincRNA-p21. Mtb infection induced the expression of IL-6 and Ptgs-2, and triptolide treatment further increased IL-6 but decreased Ptgs-2 expression in Mtb-infected MDMs. The inverse relation between the expression of these lncRNAs and their target genes is concordant with the conception that these lncRNAs mediate, at least partially, the cytotoxic and/or anti-inflammatory activities of triptolide in both resting and activated MDMs. Using the CFU count method, we found that triptolide decreased the intracellular growth of Mtb HN878. The alamarBlue assay showed that this decreased Mtb HN878 growth was not as a result of direct targeting of Mtb HN878 by triptolide, but rather evoking MDMs’ intracellular killing mechanisms which we speculate could include triptolide-induced enhancement of MDMs’ effector killing functions mediated by lncRNA-PACER and lincRNA-p21. Altogether, these results provide proof of the modulation of lncRNA-PACER and lincRNA-p21 expression by triptolide, and a possible link between these lncRNAs, the enhancement of MDMs’ effector killing functions and the intracellular Mtb-killing activities of triptolide. These findings prompt for further investigation of the precise contribution of these lncRNAs to triptolide-induced activities in MDMs.
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Affiliation(s)
- Ousman Tamgue
- Department of Biochemistry, Faculty of Sciences, University of Douala, Douala, Cameroon.,International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.,Department of Pathology, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, University of Cape Town, Cape Town, South Africa
| | - Julius Ebua Chia
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.,Department of Pathology, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, University of Cape Town, Cape Town, South Africa
| | - Frank Brombacher
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.,Department of Pathology, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, University of Cape Town, Cape Town, South Africa.,Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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12
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Xie C, He C, Gao J, Jia S. Efficacy and safety of tripterygium glycosides in the treatment of hyperthyroidism: A systemic review and meta-analysis. Medicine (Baltimore) 2020; 99:e22282. [PMID: 32957384 PMCID: PMC7505354 DOI: 10.1097/md.0000000000022282] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Hyperthyroidism is a condition in which the thyroid gland is overreactive and produces excess amounts of thyroid hormone. Tripterygium glycosides, traditional Chinese medicine has been widely used in the treatment of rheumatoid arthritis, nephrotic syndrome, hyperthyroidism and other diseases due to its anti-inflammatory and immunosuppressive effects. Evidence-based research is becoming popular especially with the application of Chinese traditional medicine. This paper systematically reviews and evaluates existing clinical data on the efficacy and safety of Tripterygium glycosides in the treatment of hyperthyroidism. MATERIALS AND METHODS PubMed, Cochrane library and EMBase, Chinese biomedical literature database (CBM), Chinese journal full-text database (CNKI), Wan fang digital periodical full-text database and China Science and Technology Journal Database (VIP) were searched based on the defined inclusion and exclusion criteria. Data extraction, research quality assessment and meta-analysis were conducted with RevMan5.3 software. Trial sequential analysis (TSA) was used to evaluate information size and treatment benefits. RESULTS Seventeen randomized controlled clinical trials with 1536 participants were included in the systematic review. In the meta-analysis, there were two subgroups: Tripterygium glycosides combined with thiamazole and prednisone group; Tripterygium glycosides combined with thiamazole group. The study results revealed that the degree of exophthalmos, FT3, FT4, BGP, and AKP decreased while TSH, SOD, GSH-PX increased after the addition of Tripterygium glycosides. This study results suggested that Tripterygium glycosides combined with western medicine are an effective therapy for hyperthyroidism. CONCLUSION This study indicates that Tripterygium glycosides enhances the effect of thiamazole and prednisone in the treatment of hyperthyroidism and without increasing the risk of adverse events.
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Affiliation(s)
| | | | - Jun Gao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, PR China
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13
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Triptolide impairs genome integrity by directly blocking the enzymatic activity of DNA-PKcs in human cells. Biomed Pharmacother 2020; 129:110427. [PMID: 32574974 DOI: 10.1016/j.biopha.2020.110427] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 06/09/2020] [Accepted: 06/13/2020] [Indexed: 01/02/2023] Open
Abstract
Triptolide is a multi-functional natural small molecular compound extracted from a traditional Chinese medicinal herb. Triptolide and its derivatives exhibit cytotoxicity through inducing DNA damage, therefore increasing sensitivity to DNA-damage based chemotherapy or radiotherapy in different types of cells. However, the regulatory mechanism of genotoxicity by triptolide, and the loss of genome integrity induced by triptolide are not fully understood. Here, we measured the effects of triptolide on genome integrity in a human fibroblast line HCA2-hTERT using the neutral comet assay. We demonstrated that treating cells with triptolide induced genomic instability in HCA2-hTERT cells. Furthermore, we observed the accumulation of γH2AX foci in triptolide treated cells than control cells at 24 h post ionizing radiation. Further mechanistic studies indicated that triptolide inhibited the enzymatic activity of DNA-PKcs, the critical nonhomologous end joining factor. In vitro kinase activity assays showed that triptolide suppressed the kinase activity of DNA-PKcs and molecular docking also predicted a potential interaction between triptolide and DNA-PKcs. As a consequence, we found that triptolide treatment enhanced the interaction between DNA-PKcs and KU80 and hampered the following recruitment of 53BP1. Altogether, our finding provides a new perspective about the toxicity of triptolide in non-cancer cells and highlights the necessity of taking genome effects of triptolide and its derivatives into consideration in the future clinical and research applications.
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Song CY, Xu YG, Lu YQ. Use of Tripterygium wilfordii Hook F for immune-mediated inflammatory diseases: progress and future prospects. J Zhejiang Univ Sci B 2020; 21:280-290. [PMID: 32253838 PMCID: PMC7183448 DOI: 10.1631/jzus.b1900607] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 12/29/2019] [Indexed: 12/19/2022]
Abstract
Tripterygium wilfordii Hook F has significant anti-inflammatory and immunosuppressive properties and is widely used for treating autoimmune and inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, and kidney disease, especially in traditional Chinese medicine. The mechanisms underlying its effects may be diverse but they remain unclear, and its toxicity and side effects limit its wider clinical application. This review summarizes the clinical application of Tripterygium wilfordii Hook F in recent years, as well as the results of studies into its mechanisms and toxicity, to provide a reference for its future clinical application.
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Affiliation(s)
- Cong-ying Song
- Department of Emergency Medicine, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Department of Geriatric Medicine, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Ying-ge Xu
- Department of Emergency Medicine, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Department of Geriatric Medicine, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Yuan-qiang Lu
- Department of Emergency Medicine, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Department of Geriatric Medicine, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
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15
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Wu H, Rao Q, Ma GC, Yu XH, Zhang CE, Ma ZJ. Effect of Triptolide on Dextran Sodium Sulfate-Induced Ulcerative Colitis and Gut Microbiota in Mice. Front Pharmacol 2020; 10:1652. [PMID: 32063856 PMCID: PMC7000629 DOI: 10.3389/fphar.2019.01652] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 12/17/2019] [Indexed: 12/20/2022] Open
Abstract
Triptolide is beneficial for the treatment of ulcerative colitis (UC), which is closely related to the gut microbiota. However, whether the therapeutic effects of triptolide involve the regulation of the gut microbiota is still unclear. In the present study, animal models of UC mice induced by dextran sodium sulfate (DSS) were established, the changes of gut microbiota in mice were detected by high-throughput sequencing. The effects of triptolide on DSS-induced UC mouse and its gut microbiota were studied. As a result, we found that triptolide exerted anti-inflammatory and therapeutic effects on UC mice. Sequencing results for the gut microbiota showed that the composition of the gut microbiota from DSS group was disordered as compared with that from the control group, consistent with a decrease in the abundance of flora. Triptolide treatment accelerated the recovery of the population of the gut microbiota and significantly improved the microbial diversity. At the phylum level, the population of Bacteroidetes decreased and that of Firmicutes increased. At the genus level, Bacteroides and Lachnospiraceae counts decreased. Thus, triptolide could regulate the composition of the gut microbiota, accelerate the recovery of microbiota, and exert good therapeutic effects in UC mice. Our results also revealed that fecal transplantation from triptolide-treated mice could relieve UC. This study provides a reference for the rational use of triptolide for the treatment of UC.
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Affiliation(s)
- Hao Wu
- The Department of General Surgeryis a part of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Quan Rao
- The Department of General Surgeryis a part of Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Guang-Chao Ma
- The Department of General Surgeryis a part of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiao-Hong Yu
- The Department of General Surgeryis a part of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Cong-En Zhang
- The Department of General Surgeryis a part of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhi-Jie Ma
- The Department of General Surgeryis a part of Beijing Friendship Hospital, Capital Medical University, Beijing, China
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16
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Huang W, Liu C, Xie L, Wang Y, Xu Y, Li Y. Integrated network pharmacology and targeted metabolomics to reveal the mechanism of nephrotoxicity of triptolide. Toxicol Res (Camb) 2019; 8:850-861. [PMID: 32110379 PMCID: PMC7017871 DOI: 10.1039/c9tx00067d] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 08/06/2019] [Indexed: 12/21/2022] Open
Abstract
Triptolide (TP) is one of the important active components in Tripterygium wilfordii Hook. F., which shows strong anti-inflammatory and immunomodulatory effects. However, a large number of literature studies have reported that TP is the main component causing nephrotoxicity, and the mechanism of nephrotoxicity has not yet been revealed. Therefore, it is of great practical significance to clarify the toxicity mechanism of TP. This study integrated network pharmacology and targeted metabolomics to reveal the nephrotoxicity mechanism of TP. Firstly, network pharmacology screening of 61 action targets related to TP induced nephrotoxicity, with 39 direct targets and 22 indirect targets, was performed. Subsequently, based on a large-scale protein-protein interaction (PPI) and molecular docking validation, the core targets were identified. Based on the above targets and enrichment analysis, the purine metabolism, Toll-like receptor signaling pathway and NF-κB signaling pathway were found play a pivotal role in TP-induced nephrotoxicity. Literature investigation showed that purine and pyrimidine metabolism pathways were closely related to kidney diseases. Therefore, by using the quantitative method of determining endogenous purine and pyrimidine previously established in the laboratory, a targeted metabolomic analysis of TP was carried out. Finally, six nephrotoxicity biomarkers, dihydroorotate, thymidine, 2-deoxyinosine, uric acid, adenosine and xanthine, were found. Combining the above results, the mechanisms underlying the nephrotoxicity of TP were speculated to be due to the over-consumption of xanthine and uric acid, which would result in enormous ROS being released in response to oxidative stress in the body. Furthermore, activation of the Toll-like receptor signalling pathway can promotes the phosphorylation of the downstream protein NF-κB and causes an inflammatory response that ultimately leads to nephrotoxicity.
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Affiliation(s)
- Wei Huang
- School of Chinese Materia Medica , Tianjin University of Traditional Chinese Medicine , Jian Kang Chan Ye Yuan , Jinghai Dist. , Tianjin 301617 , China . ; ; ; Tel: +86-22-59596223
| | - Chuanxin Liu
- School of Chinese Materia Medica , Beijing University of Chinese Medicine , Liangxiang Town , Fangshan District , Beijing 102488 , China
| | - Lijuan Xie
- School of Chinese Materia Medica , Tianjin University of Traditional Chinese Medicine , Jian Kang Chan Ye Yuan , Jinghai Dist. , Tianjin 301617 , China . ; ; ; Tel: +86-22-59596223
| | - Yuming Wang
- School of Chinese Materia Medica , Tianjin University of Traditional Chinese Medicine , Jian Kang Chan Ye Yuan , Jinghai Dist. , Tianjin 301617 , China . ; ; ; Tel: +86-22-59596223
| | - Yanyan Xu
- School of Chinese Materia Medica , Tianjin University of Traditional Chinese Medicine , Jian Kang Chan Ye Yuan , Jinghai Dist. , Tianjin 301617 , China . ; ; ; Tel: +86-22-59596223
| | - Yubo Li
- School of Chinese Materia Medica , Tianjin University of Traditional Chinese Medicine , Jian Kang Chan Ye Yuan , Jinghai Dist. , Tianjin 301617 , China . ; ; ; Tel: +86-22-59596223
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Zhang J, Han G, Yu Z. Efficacy and safety of Tripterygium wilfordii Hook F preparations for the treatment of Crohn disease: A systemic review and meta-analysis protocol. Medicine (Baltimore) 2019; 98:e16231. [PMID: 31261581 PMCID: PMC6617484 DOI: 10.1097/md.0000000000016231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Crohn disease (CD) is associated with substantial healthcare related costs and impairment of quality of life. Tripterygium wilfordii Hook F (TwHF) is proved to be effective for CD in animal and human. However, there is no systemic review and meta-analysis regarding the clinical efficacy and safety of TwHF preparation for the treatment of CD. METHODS Six electronic databases (Medline, EMBASE, Cochrane database, Chinese National Knowledge Infrastructure, Wanfang Database and Chongqing VIP Database) will be searched for eligibility studies. Data from the included studies will be extracted and the quality of studies will be assessed. Data synthesis will be performed using Review Manager software. Sensitivity analysis and publication bias assessment will also be carried out. RESULTS This systemic review and meta-analysis will provide synthesized result of clinical efficacy and safety of TwHF preparation for the treatment of CD. CONCLUSION This research will determine the clinical efficacy and safety of TwHF preparation for the treatment of CD.Registration: PROSPERO CRD42019127893.
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Wang XZ, Zhang SY, Xu Y, Zhang LY, Jiang ZZ. The role of neutrophils in triptolide-induced liver injury. Chin J Nat Med 2018; 16:653-664. [PMID: 30269842 DOI: 10.1016/s1875-5364(18)30105-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Indexed: 12/13/2022]
Abstract
Triptolide (TP) induces severe liver injury, but its hepatotoxicity mechanisms are still unclear. Inflammatory responses may be involved in the pathophysiology. Neutrophils are the first-line immune effectors for sterile and non-sterile inflammatory responses. Thus, the aim of the present study was to investigate the neutrophilic inflammatory response in TP-induced liver injury in C57BL/6 mice. Our results showed that neutrophils were recruited and accumulated in the liver, which was parallel to or slightly after the development of liver injury. Neutrophils induced release of myeloperoxidase and up-regulation of CD11b, which caused cytotoxicity and hepatocyte death. Hepatic expressions of CXL1, TNF-α, IL-6, and MCP1 were increased significantly to regulate neutrophils recruitment and activation. Up-regulation of toll like receptors 4 and 9 also facilitated neutrophils infiltration. Moreover, neutrophils depletion using an anti-Gr1 antibody showed mild protection against TP overdose. These results indicated that neutrophils accumulation might be the secondary response, not the cause of TP-induced liver injury. In conclusion, the inflammatory response including neutrophil infiltration may play a role in TP-induced hepatotoxicity, but may not be severe enough to cause additional liver injury.
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Affiliation(s)
- Xin-Zhi Wang
- Jiangsu Key Laboratory of Drug Screening, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Shen-Ye Zhang
- Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
| | - Yao Xu
- Jiangsu Key Laboratory of Drug Screening, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China
| | - Lu-Yong Zhang
- Jiangsu Key Laboratory of Drug Screening, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing 210009, China.
| | - Zhen-Zhou Jiang
- Jiangsu Key Laboratory of Drug Screening, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research, Nanjing 210009, China.
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Yang Y, Zhang LJ, Bai XG, Xu HJ, Jin ZL, Ding M. Synergistic antitumour effects of triptolide plus gemcitabine in bladder cancer. Biomed Pharmacother 2018; 106:1307-1316. [DOI: 10.1016/j.biopha.2018.07.083] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 07/12/2018] [Accepted: 07/15/2018] [Indexed: 01/03/2023] Open
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Zhu J, Wang H, Chen F, Lv H, Xu Z, Fu J, Hou Y, Xu Y, Pi J. Triptolide enhances chemotherapeutic efficacy of antitumor drugs in non-small-cell lung cancer cells by inhibiting Nrf2-ARE activity. Toxicol Appl Pharmacol 2018; 358:1-9. [PMID: 30196066 DOI: 10.1016/j.taap.2018.09.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 08/31/2018] [Accepted: 09/04/2018] [Indexed: 12/20/2022]
Abstract
Non-small cell lung cancer (NSCLC) has a high mortality rate worldwide. Various treatments strategies have been used against NSCLC including individualized chemotherapies, but innate or acquired cancer cell drug resistance remains a major obstacle. Recent studies revealed that the Kelch-like ECH associated protein 1/Nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) pathway is intimately involved in cancer progression and chemoresistance. Thus, antagonizing Nrf2 would seem to be a viable strategy in cancer therapy. In the present study a traditional Chinese medicine, triptolide, was identified that markedly inhibited expression and transcriptional activity of Nrf2 in various cancer cells, including NSCLC and liver cancer cells. Consequently, triptolide made cancer cells more chemosensitivity toward antitumor drugs both in vitro and in a xenograft tumor model system using lung carcinoma cells. These results suggest that triptolide blocks chemoresistance in cancer cells by targeting the Nrf2 pathway. Triptolide should be further investigated in clinical cancer trials.
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Affiliation(s)
- Jiayu Zhu
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New area, Shenyang 110122, China
| | - Huihui Wang
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New area, Shenyang 110122, China.
| | - Feng Chen
- Department of Interventional Radiology, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Road, Heping Area, Shenyang, 110001, China; Interventional Department, Qianfoshan Hospital, Shandong University, No.16766 Jingshi Road, Jinan 250014, China
| | - Hang Lv
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New area, Shenyang 110122, China
| | - Zijin Xu
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New area, Shenyang 110122, China
| | - Jingqi Fu
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New area, Shenyang 110122, China
| | - Yongyong Hou
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New area, Shenyang 110122, China
| | - Yuanyuan Xu
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New area, Shenyang 110122, China
| | - Jingbo Pi
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New area, Shenyang 110122, China.
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Chen SR, Dai Y, Zhao J, Lin L, Wang Y, Wang Y. A Mechanistic Overview of Triptolide and Celastrol, Natural Products from Tripterygium wilfordii Hook F. Front Pharmacol 2018; 9:104. [PMID: 29491837 PMCID: PMC5817256 DOI: 10.3389/fphar.2018.00104] [Citation(s) in RCA: 214] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 01/30/2018] [Indexed: 12/28/2022] Open
Abstract
Triptolide and celastrol are predominantly active natural products isolated from the medicinal plant Tripterygium wilfordii Hook F. These compounds exhibit similar pharmacological activities, including anti-cancer, anti-inflammation, anti-obesity, and anti-diabetic activities. Triptolide and celastrol also provide neuroprotection and prevent cardiovascular and metabolic diseases. However, toxicity restricts the further development of triptolide and celastrol. In this review, we comprehensively review therapeutic targets and mechanisms of action, and translational study of triptolide and celastrol. We systemically discuss the structure-activity-relationship of triptolide, celastrol, and their derivatives. Furthermore, we propose the use of structural derivatives, targeted therapy, and combination treatment as possible solutions to reduce toxicity and increase therapeutic window of these potent natural products from T. wilfordii Hook F.
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Affiliation(s)
- Shao-Ru Chen
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Yan Dai
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Jing Zhao
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Ligen Lin
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Yitao Wang
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Ying Wang
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macau, China
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Kim JH, Park B. Triptolide blocks the STAT3 signaling pathway through induction of protein tyrosine phosphatase SHP-1 in multiple myeloma cells. Int J Mol Med 2017; 40:1566-1572. [DOI: 10.3892/ijmm.2017.3122] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 08/25/2017] [Indexed: 11/06/2022] Open
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Zhang H, Chen W. Interleukin 6 inhibition by triptolide prevents inflammation in a mouse model of ulcerative colitis. Exp Ther Med 2017; 14:2271-2276. [PMID: 28962154 DOI: 10.3892/etm.2017.4778] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 04/21/2017] [Indexed: 12/26/2022] Open
Abstract
The present study aimed to assess interleukin (IL)-6 expression in a murine model of ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) and its potential association with the anti-colitis effects of triptolide (TL). Serum IL-6 levels were measured by ELISA. IL-6 gene expression levels in colonic mucosa specimens were assessed by reverse-transcription quantitative PCR and protein expression was evaluated by western blot analysis and immunohistochemistry. The expression of IL-6 was weak in mucosa specimens from normal control animals and upregulated in DSS-induced mice. In model mice treated with TL (0.4 and 0.6 mg/kg), dexamethasone or mesalazine, IL-6 expression was significantly reduced compared with that in model mice treated with normal saline or propylene glycol (P<0.05), while TL at 0.2 mg/kg did not elicit any significant inhibitory effect. There was no significant difference among TL (0.4 mg/kg and 0.6 mg/kg), mesalazine and dexamethasone treatments (P>0.05) in terms of IL-6 expression or histological score. The results of the present study indicated that IL-6 was overexpressed in a mouse model of UC and was involved in disease progression. In addition, TL exerted therapeutic effects in UC through inhibition of IL-6 expression.
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Affiliation(s)
- Haifeng Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Soochow, Jiangsu 215006, P.R. China.,Department of Infectious Diseases, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Weichang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Soochow, Jiangsu 215006, P.R. China
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24
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Hou HW, Wang JM, Wang D, Wu R, Ji ZL. Triptolide exerts protective effects against fibrosis following ileocolonic anastomosis by mechanisms involving the miR-16-1/HSP70 pathway in IL-10-deficient mice. Int J Mol Med 2017. [PMID: 28627592 PMCID: PMC5505014 DOI: 10.3892/ijmm.2017.3016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Surgeries, particularly ileocecal resection (ICR), are often required in the treatment of Crohn's disease (CD). However, recurrences are common for patients who undergo ICR, and anastomotic fibrosis is the main cause of re-operation. The present study aimed to investigate the therapeutic effects of triptolide (TPL) in ameliorating fibrosis following ileocolonic anastomosis. A model of IL-10−/− mice undergoing ICR was used to study post surgical inflammation and fibrosis of anastomosis. For this purpsose, interleukin (IL)-10−/− mice were randomly divided into 3 groups as follows: the control group, the saline-treated group subjected to ICR (ST-ICR) and the TPL-treated group subjected to ICR (TT-ICR). Wild-type (WT) mice of matching ages were assigned to the WT group. The effects of TPL treatment on ileocolonic anastomosis were determined by histopathological evaluation, western blot analysis and ELISA. The analysis of the effects of TPL treatment on microRNA-16-1 (miR-16-1) and heat shock protein 70 (HSP70) expression was carried out by RT-qPCR and western blot analysis. Compared with the control group, significantly higher inflammation scores following anastomosis were observed in the ST-ICR group (P<0.05), although reversion was observed in the TT-ICR group, which was consistent with changes in the area of CD4+ cell infiltration. The elevated fibrosis scores and the overexpression of procollagen I and III in the ST-ICR group were all inhibited by TPL. With an increase in the severity of inflammation and fibrosis, the levels of IL-6, tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) increased; however, a significant decrease in these levels was observed following treatment with TPL (P<0.05). The results of RT-qPCR revealed that the upregulated miR-16-1 levels in the ST-ICR group were significantly reduced by TPL. HSP70, which can be inhibited by miR-16-1, ameliorates anastomotic inflammation and fibrosis. Thus, the present study demonstrates that TPL exerts a protective effect against fibrosis following anastomosis in CD. The miR-16-1/HSP70 signaling pathway, which can be regulated by TPL, may thus represent a novel therapeutic option in CD that deserves further investigation.
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Affiliation(s)
- Hong-Wei Hou
- Department of General Surgery, Southeast University Medical School, Nanjing, Jiangsu 210009, P.R. China
| | - Jin-Min Wang
- Department of General Surgery, Southeast University Medical School, Nanjing, Jiangsu 210009, P.R. China
| | - Dong Wang
- Department of General Surgery, Southeast University Medical School, Nanjing, Jiangsu 210009, P.R. China
| | - Rong Wu
- Department of General Surgery, Southeast University Medical School, Nanjing, Jiangsu 210009, P.R. China
| | - Zhen-Ling Ji
- Department of General Surgery, Southeast University Medical School, Nanjing, Jiangsu 210009, P.R. China
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25
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Ruan Q, Xu Y, Xu R, Wang J, Hua Y, Wang M, Duan J. The Adverse Effects of Triptolide on the Reproductive System of Caenorhabditis elegans: Oogenesis Impairment and Decreased Oocyte Quality. Int J Mol Sci 2017; 18:E464. [PMID: 28230788 PMCID: PMC5343997 DOI: 10.3390/ijms18020464] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Revised: 02/01/2017] [Accepted: 02/14/2017] [Indexed: 12/15/2022] Open
Abstract
Previous studies have revealed that Triptolide damages female reproductive capacity, but the mechanism is unclear. In this study, we used Caenorhabditis elegans to investigate the effects of Triptolide on the germline and explore its possible mechanisms. Our data show that exposure for 4 h to 50 and 100 mg/L Triptolide reduced C. elegans fertility, led to depletion and inactivation of spermatids with the changes in the expression levels of related genes, and increased the number of unfertilized oocytes through damaging chromosomes and DNA damage repair mechanisms. After 24 and 48 h of the 4 h exposure to 50 and 100 mg/L Triptolide, we observed shrink in distal tip cells, an increase in the number of apoptotic cells, a decrease in the number of mitotic germ cells and oocytes in diakinesis stage, and chromatin aggregates in -1 oocytes. Moreover, expression patterns of the genes associated with mitotic germ cell proliferation, apoptosis, and oocyte quality were altered after Triptolide exposure. Therefore, Triptolide may damage fertility of nematodes by hampering the development of oocytes at different developmental stages. Alterations in the expression patterns of genes involved in oocyte development may explain the corresponding changes in oocyte development in nematodes exposed to Triptolide.
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Affiliation(s)
- Qinli Ruan
- Center for Drug Safety Evaluation and Research, Nanjing University of Chinese Medicine, Nanjing 210023, China.
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Yun Xu
- Center for Drug Safety Evaluation and Research, Nanjing University of Chinese Medicine, Nanjing 210023, China.
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Rui Xu
- Center for Drug Safety Evaluation and Research, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Jiaying Wang
- Center for Drug Safety Evaluation and Research, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Yongqing Hua
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Meng Wang
- Center for Drug Safety Evaluation and Research, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Jinao Duan
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, China.
- Jiangsu Key Laboratory for High Technology Research of Traditional Chinese Medicine Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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26
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Lu ZJ, Wu JJ, Jiang WL, Xiao JH, Tao KZ, Ma L, Zheng P, Wan R, Wang XP. MicroRNA-155 promotes the pathogenesis of experimental colitis by repressing SHIP-1 expression. World J Gastroenterol 2017; 23:976-985. [PMID: 28246471 PMCID: PMC5311107 DOI: 10.3748/wjg.v23.i6.976] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 11/27/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
AIM
To explore the mechanism by which microRNA-155 (miR-155) regulates the pathogenesis of experimental colitis.
METHODS
A luciferase assay was performed to confirm the binding of miR-155 to the SHIP-1 3’-UTR. MiR-155 mimics, negative controls and SHIP-1 expression/knockdown vectors were established and then utilized in gain- and loss-of-function studies performed in raw264.7 cells and primary bone marrow-derived macrophages (BMDMs). Thereafter, dextran sulfate sodium (DSS)-induced colitis mouse model with or without antagomiR-155 treatment was established, and the levels of miR-155 and SHIP-1, as well as the pro-inflammatory capabilities, were measured by western blot, quantitative polymerase chain reaction, and immunohistochemistry.
RESULTS
MiR-155 directly bound to the 3’-UTR of SHIP-1 mRNA and induced a significant decrease in SHIP-1 expression in both raw264.7 cells and primary BMDMs. MiR-155 markedly promoted cell proliferation and pro-inflammatory secretions including IL-6, TNF-α, IL-1β, and IFN-γ, whereas these effects could be reversed by the restoration of SHIP-1 expression. In vivo studies showed that antagomiR-155 administration could alleviate DSS-induced intestinal inflammation in Balb/c mice. Moreover, significantly increased SHIP-1 expression, as well as decreased Akt activation and inflammatory response, were observed in the antagomiR-155-treated mice.
CONCLUSION
MiR-155 promotes experimental colitis by repressing SHIP-1 expression. Thus, the inhibition of miR-155 might be a promising strategy for therapy.
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MESH Headings
- 3' Untranslated Regions
- Animals
- Antagomirs/administration & dosage
- Antagomirs/therapeutic use
- Blotting, Western
- Colitis, Ulcerative/chemically induced
- Colitis, Ulcerative/drug therapy
- Colitis, Ulcerative/metabolism
- Cytokines/metabolism
- Dextran Sulfate/toxicity
- Disease Models, Animal
- Down-Regulation
- Female
- Immunohistochemistry
- Mice
- Mice, Inbred BALB C
- MicroRNAs/metabolism
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases/genetics
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases/metabolism
- Primary Cell Culture
- Proto-Oncogene Proteins c-akt/metabolism
- RAW 264.7 Cells
- RNA Interference
- RNA, Small Interfering
- Signal Transduction
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27
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Li R, Fang L, Pu Q, Lin P, Hoggarth A, Huang H, Li X, Li G, Wu M. Lyn prevents aberrant inflammatory responses to Pseudomonas infection in mammalian systems by repressing a SHIP-1-associated signaling cluster. Signal Transduct Target Ther 2016; 1:16032. [PMID: 29263906 PMCID: PMC5661651 DOI: 10.1038/sigtrans.2016.32] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/18/2016] [Accepted: 11/22/2016] [Indexed: 02/05/2023] Open
Abstract
The pleiotropic Src kinase Lyn has critical roles in host defense in alveolar macrophages against bacterial infection, but the underlying mechanism for Lyn-mediated inflammatory response remains largely elusive. Using mouse Pseudomonas aeruginosa infection models, we observed that Lyn-/- mice manifest severe lung injury and enhanced inflammatory responses, compared with wild-type littermates. We demonstrate that Lyn exerts this immune function through interaction with IL-6 receptor and cytoskeletal protein Ezrin via its SH2 and SH3 domains. Depletion of Lyn results in excessive STAT3 activation, and enhanced the Src homology 2-containing inositol-5-phopsphatase 1 (SHIP-1) expression. Deletion of SHIP-1 in Lyn-/- mice (double knockout) promotes mouse survival and reduces inflammatory responses during P. aeruginosa infection, revealing the rescue of the deadly infectious phenotype in Lyn deficiency. Mechanistically, loss of SHIP-1 reduces NF-κB-dependent cytokine production and dampens MAP kinase activation through a TLR4-independent PI3K/Akt pathway. These findings reveal Lyn as a regulator for host immune response against P. aeruginosa infection through SHIP-1 and IL-6/STAT3 signaling pathway in alveolar macrophages.
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Affiliation(s)
- Rongpeng Li
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, USA.,Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province, Jiangsu Normal University, Xuzhou, Jiangsu 221116, P.R., China
| | - Lizhu Fang
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, USA
| | - Qinqin Pu
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, USA.,State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Ping Lin
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, USA
| | - Austin Hoggarth
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, USA
| | - Huang Huang
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, USA
| | - Xuefeng Li
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, USA.,Institute of Human Virology, Sun Yat-sen University, Guangzhou, China
| | - Guoping Li
- Inflammation and Allergic Disease Research Unit, First Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Min Wu
- Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, USA.,State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
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28
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Gao S, Wu X, Zhang Y, Li K, Wang L, Liu G. Tripterygium wilfordii polyglycosidium ameliorates pouchitis induced by dextran sulfate sodium in rats. Int Immunopharmacol 2016; 43:108-115. [PMID: 27988458 DOI: 10.1016/j.intimp.2016.12.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 11/27/2016] [Accepted: 12/06/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND The aim of this study was to investigate the therapeutic effects of Tripterygium wilfordii polyglycosidium (TWP) to rats with dextran sulfate sodium (DSS)-induced pouchitis and its possible mechanism. METHODS Sprague-Dawley rats underwent surgery of ileal pouch anal anastomosis (IPAA) and pouchitis was induced by DSS. Rats were randomly divided into no intervention (NI), normal saline (NS) and TWP groups. Rats were lavaged with normal saline (3ml/day in NS group) or TWP (12mg/kg/day in TWP group) for 7days. General conditions of animals and histopathological examinations were evaluated. Interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor (TNF)-α mRNA expression was measured. Levels of occludin and Zo-1 proteins were measured by immunohistochemistry. In addition, ALT and AST were assessed. RESULTS TWP significantly attenuated the symptoms of pouchitis characterized by body weight loss, diarrhea, and bloody stool. Furthermore, TWP diminished histological damage compared with other groups. There was a significant reduction in levels of IL-1β, IL-6, and TNF-α, as well as an increase in IL-10 in the TWP group. The expression of tight junction proteins occludin and Zo-1 were increased in the TWP group. There were no statistical differences in serum ALT and AST among the three groups. CONCLUSIONS TWP significantly ameliorated pouchitis and inhibited the production of IL-1β, IL-6, and TNF-α as well as increased the levels of IL-10, occludin, and Zo-1 protein in rats. These findings suggest TWP might be a potential therapeutic agent for patients with pouchitis.
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Affiliation(s)
- Senyang Gao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiaoyan Wu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Yingying Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Kaiyu Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Litian Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Gang Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
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29
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Abstract
BACKGROUND The traditional Chinese medicine, Tripterygium wilfordii Hook F (TwHF) is widely used to treat Crohn's disease (CD) in China. METHODS The authors compared different doses of TwHF with mesalazine in 198 patients with CD over a 52-week period. Subjects were randomized to receive mesalazine (3 g/d), low-dose TwHF (1.5 mg·kg·d), or high-dose TwHF (2.0 mg·kg·d). RESULTS A total of 137 patients completed the study. At week 52, a significant lower proportion of patients in the high-dose TwHF group (7/71) had clinical recurrence compared with patients in the low-dose TwHF (15/68, P = 0.047) or mesalazine group (17/59, P = 0.006), whereas the difference between the low-dose TwHF group and the mesalazine group was not significant (P = 0.503). Patients receiving mesalazine experienced less adverse events than those receiving high-dose TwHF (P = 0.029) and those receiving low-dose TwHF (P = 0.048), but no significant difference was found about drug adverse events resulted withdrawal in the 3 groups (P > 0.05). In addition, compared with low-dose TwHF and mesalazine, the authors also detected significant superiority of high-dose TwHF arm in the decrease of CDAI and SESCD (P < 0.05). CONCLUSION A 2.0 mg/kg daily TwHF was well tolerated and prolonged remission in patients with CD.
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30
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Ngoh EN, Weisser SB, Lo Y, Kozicky LK, Jen R, Brugger HK, Menzies SC, McLarren KW, Nackiewicz D, van Rooijen N, Jacobson K, Ehses JA, Turvey SE, Sly LM. Activity of SHIP, Which Prevents Expression of Interleukin 1β, Is Reduced in Patients With Crohn's Disease. Gastroenterology 2016; 150:465-76. [PMID: 26481854 DOI: 10.1053/j.gastro.2015.09.049] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 09/08/2015] [Accepted: 09/29/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Crohn's disease (CD) is associated with a dysregulated immune response to commensal micro-organisms in the intestine. Mice deficient in inositol polyphosphate 5'-phosphatase D (INPP5D, also known as SHIP) develop intestinal inflammation resembling that of patients with CD. SHIP is a negative regulator of PI3Kp110α activity. We investigated mechanisms of intestinal inflammation in Inpp5d(-/-) mice (SHIP-null mice), and SHIP levels and activity in intestinal tissues of subjects with CD. METHODS We collected intestines from SHIP-null mice, as well as Inpp5d(+/+) mice (controls), and measured levels of cytokines of the interleukin 1 (IL1) family (IL1α, IL1β, IL1ra, and IL6) by enzyme-linked immunosorbent assay. Macrophages were isolated from lamina propria cells of mice, IL1β production was measured, and mechanisms of increased IL1β production were investigated. Macrophages were incubated with pan-phosphatidylinositol 3-kinase inhibitors or PI3Kp110α-specific inhibitors. Some mice were given an antagonist of the IL1 receptor; macrophages were depleted from ilea of mice using clodronate-containing liposomes. We obtained ileal biopsies from sites of inflammation and peripheral blood mononuclear cells (PBMCs) from treatment-naïve subjects with CD or without CD (controls), and measured SHIP levels and activity. PBMCs were incubated with lipopolysaccharide and adenosine triphosphate, and levels of IL1β production were measured. RESULTS Inflamed intestinal tissues and intestinal macrophages from SHIP-null mice produced higher levels of IL1B and IL18 than intestinal tissues from control mice. We found PI3Kp110α to be required for macrophage transcription of Il1b. Macrophage depletion or injection of an IL1 receptor antagonist reduced ileal inflammation in SHIP-null mice. Inflamed ileal tissues and PBMCs from patients with CD had lower levels of SHIP protein than controls (P < .0001 and P < .0002, respectively). There was an inverse correlation between levels of SHIP activity in PBMCs and induction of IL1β production by lipopolysaccharide and adenosine triphosphate (R(2) = .88). CONCLUSIONS Macrophages from SHIP-deficient mice have increased PI3Kp110α-mediated transcription of Il1b, which contributes to spontaneous ileal inflammation. SHIP levels and activity are lower in intestinal tissues and peripheral blood samples from patients with CD than controls. There is an inverse correlation between SHIP activity and induction of IL1β production by lipopolysaccharide and adenosine triphosphate in PBMCs. Strategies to reduce IL1B might be developed to treat patients with CD found to have low SHIP activity.
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Affiliation(s)
- Eyler N Ngoh
- Division of Gastroenterology, Department of Pediatrics, Child & Family Research Institute, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Shelley B Weisser
- Division of Gastroenterology, Department of Pediatrics, Child & Family Research Institute, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Young Lo
- Division of Gastroenterology, Department of Pediatrics, Child & Family Research Institute, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Lisa K Kozicky
- Division of Gastroenterology, Department of Pediatrics, Child & Family Research Institute, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Roger Jen
- Division of Gastroenterology, Department of Pediatrics, Child & Family Research Institute, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Hayley K Brugger
- Division of Gastroenterology, Department of Pediatrics, Child & Family Research Institute, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Susan C Menzies
- Division of Gastroenterology, Department of Pediatrics, Child & Family Research Institute, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Keith W McLarren
- Division of Gastroenterology, Department of Pediatrics, Child & Family Research Institute, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Dominika Nackiewicz
- Department of Surgery, Child & Family Research Institute, and University of British Columbia, Vancouver, British Columbia, Canada
| | - Nico van Rooijen
- Department of Molecular Cell Biology, Vrije Universiteit, Amsterdam, Netherlands
| | - Kevan Jacobson
- Division of Gastroenterology, Department of Pediatrics, Child & Family Research Institute, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jan A Ehses
- Department of Surgery, Child & Family Research Institute, and University of British Columbia, Vancouver, British Columbia, Canada
| | - Stuart E Turvey
- Division of Allergy and Immunology, Department of Pediatrics, Child & Family Research Institute, BC Children's Hospital, and the University of British Columbia, Vancouver, British Columbia, Canada
| | - Laura M Sly
- Division of Gastroenterology, Department of Pediatrics, Child & Family Research Institute, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
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31
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Li JM, Zhang Y, Tang L, Chen YH, Gao Q, Bao MH, Xiang J, Lei DL. Effects of triptolide on hippocampal microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer's disease. Neural Regen Res 2016; 11:1492-1498. [PMID: 27857756 PMCID: PMC5090855 DOI: 10.4103/1673-5374.191224] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The principal pathology of Alzheimer's disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile plaques, which in turn induce neuroinflammation in the brain. Triptolide, a natural extract from the vine-like herb Tripterygium wilfordii Hook F, has potent anti-inflammatory and immunosuppressive efficacy. Therefore, we determined if triptolide can inhibit activation and proliferation of microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer's disease. We used 1 or 5 μg/kg/d triptolide to treat APP/PS1 double transgenic mice (aged 4-4.5 months) for 45 days. Unbiased stereology analysis found that triptolide dose-dependently reduced the total number of microglial cells, and transformed microglial cells into the resting state. Further, triptolide (5 μg/kg/d) also reduced the total number of hippocampal astrocytes. Our in vivo test results indicate that triptolide suppresses activation and proliferation of microglial cells and astrocytes in the hippocampus of APP/PS1 double transgenic mice with Alzheimer's disease.
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Affiliation(s)
- Jian-Ming Li
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China; Department of Anatomy and Neurobiology, Central South University, School of Basic Medical Science, Changsha, Hunan Province, China; Neuroscience Research Center, Changsha Medical University, Changsha, Hunan Province, China; Department of Anatomy, Changsha Medical University, Changsha, Hunan Province, China
| | - Yan Zhang
- Neuroscience Research Center, Changsha Medical University, Changsha, Hunan Province, China
| | - Liang Tang
- Neuroscience Research Center, Changsha Medical University, Changsha, Hunan Province, China
| | - Yong-Heng Chen
- Neuroscience Research Center, Changsha Medical University, Changsha, Hunan Province, China
| | - Qian Gao
- Neuroscience Research Center, Changsha Medical University, Changsha, Hunan Province, China
| | - Mei-Hua Bao
- Neuroscience Research Center, Changsha Medical University, Changsha, Hunan Province, China
| | - Ju Xiang
- Neuroscience Research Center, Changsha Medical University, Changsha, Hunan Province, China
| | - De-Liang Lei
- Department of Anatomy and Neurobiology, Central South University, School of Basic Medical Science, Changsha, Hunan Province, China
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32
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Triptolide: A Critical Review on Antiangiogenesis in Cancer and Scope in Therapeutics. JOURNAL OF BIOMIMETICS BIOMATERIALS AND BIOMEDICAL ENGINEERING 2015. [DOI: 10.4028/www.scientific.net/jbbbe.23.37] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Triptolide (TPL) is a traditional Chinese medicine and an active component of a Chinese herbTripterygium wilfordiiF. (Celastraceae). Triptolide has been used to treat a variety of ailments, including rheumatoid arthritis, nephritic syndrome and Lupus erythematosus. It is also a strong antitumor agent. Several angiogenesis assays in numerous research studies have shown that triptolide is an angiogenesis inhibitor. Numerous preclinical studies have shown that TPL inhibits cell proliferation, induces apoptosis and limits tumor metastasis. TPL also has a synergistic action with other treatment methods whereby, it enhances the effects of other antitumor treatments, as studied in various cancer cell lines. This review summarizes the recent developments and discussion of antiangiogenic mechanisms of TPL in cancer, brief outline of its clinical trials and its future in cancer therapeutics.
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33
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Zhu W, Li Y, Gong J, Zuo L, Zhang W, Cao L, Gu L, Guo Z, Li N, Li J. Tripterygium wilfordii Hook. f. versus azathioprine for prevention of postoperative recurrence in patients with Crohn's disease: a randomized clinical trial. Dig Liver Dis 2015; 47:14-19. [PMID: 25445405 DOI: 10.1016/j.dld.2014.09.008] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Revised: 09/12/2014] [Accepted: 09/14/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Tripterygium wilfordii Hook. f. (TwHF) has been used for many years to induce the remission of Crohn's disease in China. AIMS To compare TwHF versus azathioprine for the prevention of postoperative recurrence in Crohn's disease. METHODS 90 Crohn's disease patients who had undergone resection were treated with TwHF 1.5mg/kg/day or azathioprine 2.0 mg/kg/day. The primary endpoint was clinical recurrence, and the secondary endpoint was endoscopic recurrence. RESULTS 47 patients completed the trial. Clinical recurrence was observed in 6/45 patients in the TwHF group and 4/45 patients in the azathioprine group at week 26 (P=0.74). At week 52, 8/45 azathioprine patients and 12/45 TwHF patients had clinical recurrence (P = 0.45). During the first 26 weeks, 56.8% of the patients in the TwHF group versus 47.7% in the azathioprine group experienced endoscopic recurrence (P = 0.52). However, at week 52, 74.4% of patients in the TwHF group and 50% in the azathioprine group had endoscopic recurrence (P = 0.03). CONCLUSIONS TwHF was less effective in maintaining endoscopic remission at week 52, even though TwHF was comparable to azathioprine for preventing postoperative clinical recurrence.
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Affiliation(s)
- Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China.
| | - Yi Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Jianfeng Gong
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Lugen Zuo
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Wei Zhang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Lei Cao
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Lili Gu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Zhen Guo
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Ning Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
| | - Jieshou Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, PR China
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Yan X, Ke XX, Zhao H, Huang M, Hu R, Cui H. Triptolide inhibits cell proliferation and tumorigenicity of human neuroblastoma cells. Mol Med Rep 2014; 11:791-6. [PMID: 25354591 PMCID: PMC4262511 DOI: 10.3892/mmr.2014.2814] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 07/22/2014] [Indexed: 01/03/2023] Open
Abstract
Triptolide is a diterpene triepoxide, extracted from the Chinese herb Tripterygium wilfordii Hook F, which has been shown to have antitumor activity in a number of cancers. Neuroblastoma is an aggressive extracranial pediatric solid tumor, with significant chemotherapeutic resistance. In this study, triptolide was hypothesized to be a potential therapeutic agent for neuroblastoma. The effects of triptolide on neuroblastoma cell growth and tumor development were investigated. Cell growth and proliferation were evaluated using a cell counting kit-8 assay and a 5-bromo-2-deoxyuridine staining assay. Cell cycle and apoptosis were detected by flow cytometry. Reverse transcription-quantitative polymerase chain reaction was conducted to detect the expression levels of the apoptosis-associated proteins, caspase-3 and caspase-9. The tumorigenicity of neuroblastoma cells was assessed by a soft agar clonogenic assay and an in vivo tumorigenic assay. The results demonstrated that exposure of BE(2)-C human neuroblastoma cells to triptolide resulted in a reduction in cell growth and proliferation, and the induction of cell death and apoptosis, together with cell cycle arrest in the S phase. A soft agar assay indicated that triptolide inhibited the colony-forming ability of BE(2)-C neuroblastoma cells. The xenograft experiment showed that triptolide significantly reduced tumor growth and development in vivo. The data suggested that this Chinese herb may be a potential novel chemotherapeutic agent for neuroblastoma.
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Affiliation(s)
- Xiaomin Yan
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, P.R. China
| | - Xiao-Xue Ke
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, P.R. China
| | - Hailong Zhao
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, P.R. China
| | - Mengying Huang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, P.R. China
| | - Renjian Hu
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, P.R. China
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, P.R. China
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Li XJ, Jiang ZZ, Zhang LY. Triptolide: progress on research in pharmacodynamics and toxicology. JOURNAL OF ETHNOPHARMACOLOGY 2014; 155:67-79. [PMID: 24933225 DOI: 10.1016/j.jep.2014.06.006] [Citation(s) in RCA: 294] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Revised: 06/05/2014] [Accepted: 06/05/2014] [Indexed: 06/03/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Tripterygium wilfordii Hook. f. (Tripterygium wilfordii), also known as Huangteng and gelsemium elegan, is a traditional Chinese medicine that has been marketed in China as Tripterygium wilfordii glycoside tablets. Triptolide (TP), an active component in Tripterygium wilfordii extracts, has been used to treat various diseases, including lupus, cancer, rheumatoid arthritis and nephritic syndrome. This review summarizes recent developments in the research on the pharmacodynamics, pharmacokinetics, pharmacy and toxicology of TP, with a focus on its novel mechanism of reducing toxicity. This review provides insight for future studies on traditional Chinese medicine, a field that is both historically and currently important. MATERIALS AND METHODS We included studies published primarily within the last five years that were available in online academic databases (e.g., PubMed, Google Scholar, CNKI, SciFinder and Web of Science). RESULTS TP has a long history of use in China because it displays multiple pharmacological activities, including anti-rheumatism, anti-inflammatory, anti-tumor and neuroprotective properties. It has been widely used for the treatment of various diseases, such as rheumatoid arthritis, nephritic syndrome, lupus, Behcet׳s disease and central nervous system diseases. Recently, numerous breakthroughs have been made in our understanding of the pharmacological efficacy of TP. Although TP has been marketed as a traditional Chinese medicine, its multi-organ toxicity prevents it from being widely used in clinical practice. CONCLUSIONS Triptolide, a biologically active natural product extracted from the root of Tripterygium wilfordii, has shown promising pharmacological effects, particularly as an anti-tumor agent. Currently, in anti-cancer research, more effort should be devoted to investigating effective anti-tumor targets and confirming the anti-tumor spectrum and clinical indications of novel anti-tumor pro-drugs. To apply TP appropriately, with high efficacy and low toxicity, the safety and non-toxic dose range for specific target organs and diseases should be determined, the altered pathways and mechanisms of exposure need to be clarified, and an early warning system for toxicity needs to be established. With further in-depth study of the efficacy and toxicity of TP, we believe that TP will become a promising multi-use drug with improved clinical efficacy and safety in the future.
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Affiliation(s)
- Xiao-Jiaoyang Li
- Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
| | - Zhen-Zhou Jiang
- Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 210009, China.
| | - Lu-yong Zhang
- Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China.
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