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Wang F, Wen J, Liu J, Xin L, Fang Y, Sun Y, He M. Demethylase FTO mediates m6A modification of ENST00000619282 to promote apoptosis escape in rheumatoid arthritis and the intervention effect of Xinfeng Capsule. Front Immunol 2025; 16:1556764. [PMID: 40181982 PMCID: PMC11966437 DOI: 10.3389/fimmu.2025.1556764] [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: 01/07/2025] [Accepted: 02/24/2025] [Indexed: 04/05/2025] Open
Abstract
Introduction The pathological mechanisms of rheumatoid arthritis (RA) are closely associated with the apoptosis escape of fibroblast-like synoviocytes (FLS). The m6A modification of long non-coding RNAs (lncRNAs) plays a critical regulatory role in RA pathogenesis. Xinfeng Capsule (XFC), a clinically effective traditional Chinese medicine formulation, has been shown to alleviate RA by inhibiting FLS apoptosis escape. However, its molecular mechanisms remain unclear. This study aimed to elucidate the mechanism by which the demethylase FTO promoted FLS apoptosis escape through the m6A modification of lncRNA ENST00000619282 and to reveal the therapeutic targets of XFC in treating RA by intervening in this m6A-dependent pathway. Methods A retrospective analysis was conducted on 1603 RA patients using association rule mining and random walk algorithms to evaluate the efficacy of XFC. The proliferation and apoptosis of co-cultured RA-FLS were assessed using CCK-8, flow cytometry (FCM), and molecular biology techniques. Bioinformatics prediction, MeRIP-qPCR, RIP, and RNA pull-down assays were employed to identify the m6A modification sites of ENST00000619282 and their interactions with FTO/YTHDF1. Additionally, FISH, luciferase reporter assays, and rescue experiments were performed to validate the regulatory role of ENST00000619282 and its sponge-like function in RA-FLS. Clinical samples were analyzed to determine the correlation between FTO/YTHDF1/ENST00000619282/Bax/Bcl-2 and immune-inflammatory markers. Furthermore, the binding affinity of XFC active components to NF-κB was assessed through molecular docking. Results Retrospective data mining demonstrated that XFC significantly improved immune-inflammatory markers in RA patients. Mechanistically, FTO reduced the m6A modification level of ENST00000619282, enhancing its stability and promoting YTHDF1-dependent expression, which in turn inhibited PUF60 and activated the NF-κB pathway, ultimately leading to FLS apoptosis escape. XFC downregulated FTO, increased the m6A modification of ENST00000619282, blocked the NF-κB signaling, inhibited RA-FLS proliferation, as well as induced their apoptosis. Clinical validation revealed that FTO/YTHDF1/ENST00000619282/Bax/Bcl-2 was closely associated with immune-inflammatory markers in RA patients. After XFC treatment, FTO, ENST00000619282, and Bcl-2 expressions were decreased, while YTHDF1 and Bax expressions were increased (all P<0.05). Molecular docking confirmed that the active components of XFC (calycosin-7-O-beta-D-glucoside, calycosin, and formononetin) exhibited strong binding affinity to NF-κB p65. Conclusion FTO promoted FLS apoptosis escape and RA progression by activating the NF-κB pathway through the m6A-dependent ENST00000619282/YTHDF1 axis. XFC inhibited this pathway by modulating FTO-mediated m6A modification, providing a novel RNA epigenetic regulatory strategy for RA treatment.
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Affiliation(s)
- Fanfan Wang
- The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
- Department of Rheumatism Immunity, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Jianting Wen
- The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
- Department of Rheumatism Immunity, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Jian Liu
- The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
- Department of Rheumatism Immunity, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Ling Xin
- Department of Clinical Data Center, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Yanyan Fang
- The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
- Department of Rheumatism Immunity, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Yue Sun
- Department of Rheumatism Immunity, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Mingyu He
- The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
- Department of Rheumatism Immunity, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
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Chen Y, Wang Q, Liu H, Jin L, Feng X, Dai B, Chen M, Xin F, Wei T, Bai B, Fan Z, Li J, Yao Y, Liao R, Zhang J, Jin X, Fu L. The prognostic value of whole-genome DNA methylation in response to Leflunomide in patients with Rheumatoid Arthritis. Front Immunol 2023; 14:1173187. [PMID: 37744384 PMCID: PMC10513488 DOI: 10.3389/fimmu.2023.1173187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 08/14/2023] [Indexed: 09/26/2023] Open
Abstract
Objective Although Leflunomide (LEF) is effective in treating rheumatoid arthritis (RA), there are still a considerable number of patients who respond poorly to LEF treatment. Till date, few LEF efficacy-predicting biomarkers have been identified. Herein, we explored and developed a DNA methylation-based predictive model for LEF-treated RA patient prognosis. Methods Two hundred forty-five RA patients were prospectively enrolled from four participating study centers. A whole-genome DNA methylation profiling was conducted to identify LEF-related response signatures via comparison of 40 samples using Illumina 850k methylation arrays. Furthermore, differentially methylated positions (DMPs) were validated in the 245 RA patients using a targeted bisulfite sequencing assay. Lastly, prognostic models were developed, which included clinical characteristics and DMPs scores, for the prediction of LEF treatment response using machine learning algorithms. Results We recognized a seven-DMP signature consisting of cg17330251, cg19814518, cg20124410, cg21109666, cg22572476, cg23403192, and cg24432675, which was effective in predicting RA patient's LEF response status. In the five machine learning algorithms, the support vector machine (SVM) algorithm provided the best predictive model, with the largest discriminative ability, accuracy, and stability. Lastly, the AUC of the complex model(the 7-DMP scores with the lymphocyte and the diagnostic age) was higher than the simple model (the seven-DMP signature, AUC:0.74 vs 0.73 in the test set). Conclusion In conclusion, we constructed a prognostic model integrating a 7-DMP scores with the clinical patient profile to predict responses to LEF treatment. Our model will be able to effectively guide clinicians in determining whether a patient is LEF treatment sensitive or not.
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Affiliation(s)
- Yulan Chen
- Department of Clinical Epidemiology and Evidence-Based Medicine, the First Affiliated Hospital, China Medical University, Shenyang, China
| | - Qiao Wang
- Department of Clinical Epidemiology and Evidence-Based Medicine, the First Affiliated Hospital, China Medical University, Shenyang, China
| | - Haina Liu
- Department of Rheumatology, The First Affiliated Hospital, China Medical University, Shenyang, China
| | - Lei Jin
- Department of Rheumatology, ShengJing Hospital Affiliated of China Medical University, Shenyang, China
| | - Xin Feng
- Department of Rheumatology, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Bingbing Dai
- Department of Rheumatology and Immunology, Dalian Municipal Central Hospital, Dalian, China
| | - Meng Chen
- Department of Clinical Epidemiology and Evidence-Based Medicine, the First Affiliated Hospital, China Medical University, Shenyang, China
| | - Fangran Xin
- Department of Clinical Epidemiology and Evidence-Based Medicine, the First Affiliated Hospital, China Medical University, Shenyang, China
| | - Tingting Wei
- Department of Clinical Epidemiology and Evidence-Based Medicine, the First Affiliated Hospital, China Medical University, Shenyang, China
| | - Bingqing Bai
- Department of Clinical Epidemiology and Evidence-Based Medicine, the First Affiliated Hospital, China Medical University, Shenyang, China
| | - Zhijun Fan
- Department of Clinical Epidemiology and Evidence-Based Medicine, the First Affiliated Hospital, China Medical University, Shenyang, China
| | - Jiahui Li
- Department of Clinical Epidemiology and Evidence-Based Medicine, the First Affiliated Hospital, China Medical University, Shenyang, China
| | - Yuxin Yao
- Department of Clinical Epidemiology and Evidence-Based Medicine, the First Affiliated Hospital, China Medical University, Shenyang, China
| | - Ruobing Liao
- Department of Clinical Epidemiology and Evidence-Based Medicine, the First Affiliated Hospital, China Medical University, Shenyang, China
| | - Jintao Zhang
- Department of Rheumatology and Immunology, Dalian Municipal Central Hospital, Dalian, China
| | - Xiangnan Jin
- Department of Rheumatology, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Lingyu Fu
- Department of Clinical Epidemiology and Evidence-Based Medicine, the First Affiliated Hospital, China Medical University, Shenyang, China
- Department of Medical Record Management Center, the First Affiliated Hospital, China Medical University, Shenyang, China
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Nafea M, Elharoun M, Abd-Alhaseeb MM, Helmy MW. Leflunomide abrogates neuroinflammatory changes in a rat model of Alzheimer's disease: the role of TNF-α/NF-κB/IL-1β axis inhibition. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:485-498. [PMID: 36385687 PMCID: PMC9898334 DOI: 10.1007/s00210-022-02322-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 11/02/2022] [Indexed: 11/18/2022]
Abstract
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is associated with disrupted cognition and behavior. Neuroinflammatory pathogenesis is the main component that contributes to AD initiation and progression through microglial activation and neuronal damage. Thus, targeting inflammatory pathways may help manage AD. In this study, for the first time, the potential prophylactic and therapeutic effects of leflunomide were investigated either alone or in combination with rivastigmine in aluminum chloride (AlCl3)-induced AD-like rats using behavioral, biochemical, and histological approaches. Thirty-six adult male albino rats were divided into two protocols: the treatment protocol, subdivided into five groups (n = 6)-(1) control group, (2) AlCl3 (50, 70, 100 mg/kg/I.P) group, (3) reference group (rivastigmine 2 mg/kg/P.O.), (4) experimental group (leflunomide 10 mg/kg/P.O.), and (5) combination group (rivastigmine + leflunomide); and the prophylactic protocol (leflunomide 10 mg/kg/P.O.), which started 2 weeks before AlCl3 induction. The results showed that AlCl3 disrupted learning and memory parameters in rats and increased amyloid-β plaque deposition and neurofibrillary tangle aggregation. Moreover, AlCl3 administration markedly elevated acetylcholinesterase activity, nuclear factor-kappa β, tumor necrosis factor-α, and interleukin-1 beta, and marked degenerative changes in the pyramidal neurons. However, administration of leflunomide alone or with rivastigmine in AlCl3-induced AD rats restored most of the behavioral, biochemical, and histological parameters triggered by AlCl3 in rats. Our findings suggest that leflunomide can potentially restore most of the neuronal damage in the hippocampal tissues of AlCl3-induced AD rats. However, these preclinical findings still need to be confirmed in clinical trials.
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Affiliation(s)
- Menna Nafea
- Department of Pharmacology and Biochemistry, College of Pharmacy, Arab Academy for Science, Technology & Maritime Transport, Alexandria, Egypt
| | - Mona Elharoun
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, El-Bahira, Egypt
| | | | - Maged Wasfy Helmy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, El-Bahira, Egypt.
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Aljohani AA, Alqarni YS, Alrashidi MN, Aljuhani MH, Shehata SA, El-Kherbetawy MK, Prabahar K, Alshaman R, Alattar A, Helaly AMN, Ateyya H, Ismail EA, Zaitone SA. The Anti-Rheumatic Drug, Leflunomide, Induces Nephrotoxicity in Mice via Upregulation of TGFβ-Mediated p53/Smad2/3 Signaling. TOXICS 2022; 10:274. [PMID: 35622687 PMCID: PMC9144816 DOI: 10.3390/toxics10050274] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/15/2022] [Accepted: 05/19/2022] [Indexed: 02/01/2023]
Abstract
Recent studies indicated renal toxicity and interstitial nephritis in patients receiving leflunomide (LEFN), but the exact mechanism is still unknown. The transforming growth factor β (TGFβ)/p53/Smad2/3 pathway crucially mediates renal fibrosis. We aimed to assess the nephrotoxic effect of LEFN in mice and the possible role of TGFβ-stimulated p53/SMAD2/3 signaling. The study design involved distributing sixty male albino mice into four groups: (i) vehicle-treated mice, (ii) LEFN (2.5 mg/kg), (iii) LEFN (5 mg/kg), and (iv) LEFN (10 mg/kg). The drug was given orally every 48 h and continued for 8 weeks. Blood samples were then taken from mice for the determination of kidney function parameters. Right kidneys were used for histopathologic staining and immunohistochemistry, whereas left kidneys were frozen and used for Western blot analysis of the target proteins, p-p53 and Smad2/3. Results indicated that chronic administration of LEFN in mice resulted in a four- and nine-fold increase in serum urea and creatinine levels, respectively. Kidney specimens stained with hematoxylin and eosin or periodic acid-Schiff showed significant histopathological manifestations, such as cellular irregularity, interstitial congestion, and moderate lymphocytic inflammatory infiltrate in mice treated with LEFN. Western blotting indicated upregulation of the p-p53/Smad2/3 proteins. LEFN, especially in the highest dose (10 mg/kg), produced prominent nephrotoxicity in mice. This toxicity is mediated through stimulating fibrotic changes through TGFβ-stimulated p53/Smad2/3 signaling and induction of glomerular and tubular apoptosis. An improved understanding of LEFN-induced nephrotoxicity would have great implications in the prediction, prevention, and management of leflunomide-treated rheumatic patients, and may warrant further clinical studies for following up these toxidromes.
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Affiliation(s)
- Alhanouf A. Aljohani
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (A.A.A.); (Y.S.A.); (M.N.A.); (M.H.A.)
| | - Yasmeen S. Alqarni
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (A.A.A.); (Y.S.A.); (M.N.A.); (M.H.A.)
| | - Maram N. Alrashidi
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (A.A.A.); (Y.S.A.); (M.N.A.); (M.H.A.)
| | - Maha H. Aljuhani
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (A.A.A.); (Y.S.A.); (M.N.A.); (M.H.A.)
| | - Shaimaa A. Shehata
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt;
| | | | - Kousalya Prabahar
- Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Reem Alshaman
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.A.); (A.A.)
| | - Abdullah Alattar
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (R.A.); (A.A.)
| | - Ahmed M. N. Helaly
- Department of Forensic Medicine and Toxicology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt;
- Clinical Science, Faculty of Medicine, Yarmouk University, Irbid 566, Jordan
| | - Hayam Ateyya
- Department of Medical Pharmacology, Faculty of Medicine, Cairo University, Giza 11559, Egypt; or
- Department of Pharmacy Practice and Clinical Pharmacy, Faculty of Pharmacy, Future University in Egypt, Cairo 11835, Egypt
| | - Ezzat A. Ismail
- Department of Urology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt;
| | - Sawsan A. Zaitone
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; (A.A.A.); (Y.S.A.); (M.N.A.); (M.H.A.)
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
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5
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Anti-rheumatic drug-induced hepatitis B virus reactivation and preventive strategies for hepatocellular carcinoma. Pharmacol Res 2022; 178:106181. [PMID: 35301112 DOI: 10.1016/j.phrs.2022.106181] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 12/13/2022]
Abstract
To date, an estimated 3 million people worldwide have been infected with chronic hepatitis B virus (HBV). Although anti-HBV therapies have improved the long-term survival profile of chronic carriers, viral reactivation still poses a significant challenge for preventing HBV-related hepatitis, hepatocellular carcinoma (HCC), and death. Immuno-modulating drugs, which are widely applied in managing rheumatic conditions, are commonly associated with HBV reactivation (HBVr) as a result of drug-induced immune suppression. However, there are few reports on the risk of HBVr and the medication management plan for HBV carriers, especially rheumatic patients. In this review, we summarize immuno-modulating drug-induced HBVr during rheumatoid therapy and its preventive strategies for HBVr-induced liver diseases, especially cirrhosis and HCC. These findings will assist with developing treatments for rheumatic patients, and prevent HBV-related cirrhosis and HCC.
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Kabaalioğlu Güner M, Mehra A, Smith WM. Novel strategies for the diagnosis and treatment of scleritis. EXPERT REVIEW OF OPHTHALMOLOGY 2021. [DOI: 10.1080/17469899.2021.1984881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
| | - Ankur Mehra
- Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA
| | - Wendy M. Smith
- Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA
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Zhou Y, Tao L, Zhou X, Zuo Z, Gong J, Liu X, Zhou Y, Liu C, Sang N, Liu H, Zou J, Gou K, Yang X, Zhao Y. DHODH and cancer: promising prospects to be explored. Cancer Metab 2021; 9:22. [PMID: 33971967 PMCID: PMC8107416 DOI: 10.1186/s40170-021-00250-z] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 03/10/2021] [Indexed: 02/08/2023] Open
Abstract
Human dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme catalyzing the fourth step in the de novo pyrimidine synthesis pathway. It is originally a target for the treatment of the non-neoplastic diseases involving in rheumatoid arthritis and multiple sclerosis, and is re-emerging as a validated therapeutic target for cancer therapy. In this review, we mainly unravel the biological function of DHODH in tumor progression, including its crucial role in de novo pyrimidine synthesis and mitochondrial respiratory chain in cancer cells. Moreover, various DHODH inhibitors developing in the past decades are also been displayed, and the specific mechanism between DHODH and its additional effects are illustrated. Collectively, we detailly discuss the association between DHODH and tumors in recent years here, and believe it will provide significant evidences and potential strategies for utilizing DHODH as a potential target in preclinical and clinical cancer therapies.
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Affiliation(s)
- Yue Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Lei Tao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Xia Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Zeping Zuo
- The Laboratory of Anesthesiology and Critical Care Medicine, Translational Neuroscience Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jin Gong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Xiaocong Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Yang Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Chunqi Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Na Sang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Huan Liu
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Jiao Zou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Kun Gou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Xiaowei Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
| | - Yinglan Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China. .,West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
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Zhu J, Han L, Diao Y, Ren X, Xu M, Xu L, Li S, Li Q, Dong D, Huang J, Liu X, Zhao Z, Wang R, Zhu L, Xu Y, Qian X, Li H. Design, Synthesis, X-ray Crystallographic Analysis, and Biological Evaluation of Thiazole Derivatives as Potent and Selective Inhibitors of Human Dihydroorotate Dehydrogenase. J Med Chem 2015; 58:1123-39. [DOI: 10.1021/jm501127s] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Affiliation(s)
- Junsheng Zhu
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Le Han
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Yanyan Diao
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Xiaoli Ren
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Minghao Xu
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Liuxin Xu
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Shiliang Li
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Qiang Li
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Dong Dong
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Jin Huang
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Xiaofeng Liu
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Zhenjiang Zhao
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Rui Wang
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Lili Zhu
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Yufang Xu
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Xuhong Qian
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Honglin Li
- State Key Laboratory
of Bioreactor Engineering, Shanghai Key Laboratory
of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School
of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
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9
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Shih KC, Lee CC, Tsai CN, Lin YS, Tang CY. Development of a human dihydroorotate dehydrogenase (hDHODH) pharma-similarity index approach with scaffold-hopping strategy for the design of novel potential inhibitors. PLoS One 2014; 9:e87960. [PMID: 24504131 PMCID: PMC3913663 DOI: 10.1371/journal.pone.0087960] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Accepted: 01/01/2014] [Indexed: 12/27/2022] Open
Abstract
Human dihydroorotate dehydrogenase (hDHODH) is a class-2 dihydroorotate dehydrogenase. Because it is extensively used by proliferating cells, its inhibition in autoimmune and inflammatory diseases, cancers, and multiple sclerosis is of substantial clinical importance. In this study, we had two aims. The first was to develop an hDHODH pharma-similarity index approach (PhSIA) using integrated molecular dynamics calculations, pharmacophore hypothesis, and comparative molecular similarity index analysis (CoMSIA) contour information techniques. The approach, for the discovery and design of novel inhibitors, was based on 25 diverse known hDHODH inhibitors. Three statistical methods were used to verify the performance of hDHODH PhSIA. Fischer’s cross-validation test provided a 98% confidence level and the goodness of hit (GH) test score was 0.61. The q2, r2, and predictive r2 values were 0.55, 0.97, and 0.92, respectively, for a partial least squares validation method. In our approach, each diverse inhibitor structure could easily be aligned with contour information, and common substructures were unnecessary. For our second aim, we used the proposed approach to design 13 novel hDHODH inhibitors using a scaffold-hopping strategy. Chemical features of the approach were divided into two groups, and the Vitas-M Laboratory fragment was used to create de novo inhibitors. This approach provides a useful tool for the discovery and design of potential inhibitors of hDHODH, and does not require docking analysis; thus, our method can assist medicinal chemists in their efforts to identify novel inhibitors.
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Affiliation(s)
- Kuei-Chung Shih
- Department of Computer Science, National Tsing Hua University, Hsinchu, Taiwan
- * E-mail: (KCS); (CYT)
| | - Chi-Ching Lee
- Bioinformatics Center, Chang Gung University, Taoyuan, Taiwan
| | - Chi-Neu Tsai
- Graduate Institute of Chang-Gung Medical Science, Chang-Gung University, Taoyuan, Taiwan
| | - Yu-Shan Lin
- Department of Computer Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Chuan-Yi Tang
- Department of Computer Science, National Tsing Hua University, Hsinchu, Taiwan
- Department of Computer Science and Information Engineering, Providence University, Taichung, Taiwan
- * E-mail: (KCS); (CYT)
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Papadopoulou A, Kappos L, Sprenger T. Teriflunomide for oral therapy in multiple sclerosis. Expert Rev Clin Pharmacol 2013; 5:617-28. [PMID: 23234322 DOI: 10.1586/ecp.12.56] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Teriflunomide, the active metabolite of an approved antirheumatic drug, is an emerging oral therapy for multiple sclerosis (MS). Next to the inhibition of pyrimidine biosynthesis and proliferation of activated lymphocytes, it seems to have multiple anti-inflammatory and immunomodulating effects. Phase II and III clinical trials in relapsing MS demonstrated favorable safety and tolerability of the drug, as well as clinical efficacy, with a significant reduction of relapse rate, comparable with those of the available injectable immunomodulatory agents. While multiple other studies with teriflunomide are currently ongoing, its exact place in future treatment algorithms for MS is difficult to predict. It may be a good alternative for patients wishing to have an oral treatment with relatively large data regarding long-term safety.
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Nguyen M, Kabir M, Ravaud P. Short-term efficacy and safety of leflunomide in the treatment of active rheumatoid arthritis in everyday clinical use : open-label, prospective study. Clin Drug Investig 2012; 24:103-12. [PMID: 17516696 DOI: 10.2165/00044011-200424020-00005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
OBJECTIVE To determine the efficacy and safety profile of 6-month treatment with leflunomide 20mg daily in patients with acute rheumatoid arthritis (RA) receiving treatment from 197 office-based rheumatologists in France. METHODS This open-label, prospective, multicentre study included 378 ambulatory RA patients who received leflunomide at a loading dose of 100mg daily on days 1-3, followed by 20mg daily for 6 months. The primary efficacy endpoint was a >/=20% response according to the American College of Rheumatology criteria (ACR 20) after 6 months. Secondary efficacy criteria were a >/=50% response (ACR 50) and a >/=70% response (ACR 70), as well as disease activity score (DAS28) responses. RESULTS Among the 407 selected patients, 378 patients were included in the study, all of whom were treated with leflunomide. Female patients made up 78.6% of the study population; the mean age was 57.7 +/- 12.0 years, and the mean disease duration was 9.7 +/- 8.5 years. At 6 months, the ACR 20 response rate was 48.2% (95% confidence interval [CI] 43-53%). ACR 50 and 70 response rates were 25.3% (95% CI 21.0-30.1) and 11.7% (95% CI 8.6-15.4%), respectively. According to the DAS28, 21.8% of patients had a good response, 39.9% a moderate response, and 38.2% were non-responders. The DAS28 response rate was thus 61.8% (95% CI 56.5-66.9%). Mean improvements in tender joint count were -5.6 +/- 7.4 (from baseline of 12.2 +/- 6.7), in swollen joint count were -4.2 +/- 5.7 (from baseline of 9.8 +/- 5.8), and in investigator's global assessment of RA disease activity were -20.2 +/- 25.1 (from baseline of 51.6 +/- 17.1). Treatment-related adverse events caused 15.9% of patients to discontinue the study prematurely. Serious adverse events possibly related to therapy were reported in 2.4% of patients. CONCLUSIONS This 6-month study carried out under daily routine practice conditions in a typical sample of RA patients showed a favourable efficacy and safety profile for leflunomide 20mg daily. The study confirms the findings of the earlier phase II and III study programme in more selected patient samples.
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Affiliation(s)
- Minh Nguyen
- René Descartes University, Institute of Rheumatology, Cochin Hospital, Paris, France
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Walse B, Dufe VT, Svensson B, Fritzson I, Dahlberg L, Khairoullina A, Wellmar U, Al-Karadaghi S. The structures of human dihydroorotate dehydrogenase with and without inhibitor reveal conformational flexibility in the inhibitor and substrate binding sites. Biochemistry 2008; 47:8929-36. [PMID: 18672895 DOI: 10.1021/bi8003318] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Inhibitors of dihydroorotate dehydrogenase (DHODH) have been suggested for the treatment of rheumatoid arthritis, psoriasis, autoimmune diseases, Plasmodium, and bacterial and fungal infections. Here we present the structures of N-terminally truncated (residues Met30-Arg396) DHODH in complex with two inhibitors: a brequinar analogue (6) and a novel inhibitor (a fenamic acid derivative) (7), as well as the first structure of the enzyme to be characterized without any bound inhibitor. It is shown that 7 uses the "standard" brequinar binding mode and, in addition, interacts with Tyr356, a residue conserved in most class 2 DHODH proteins. Compared to the inhibitor-free structure, some of the amino acid side chains in the tunnel in which brequinar binds and which was suggested to be the binding site of ubiquinone undergo changes in conformation upon inhibitor binding. Using our data, the loop regions of residues Leu68-Arg72 and Asn212-Leu224, which were disordered in previously studied human DHODH structures, could be built into the electron density. The first of these loops, which is located at the entrance to the inhibitor-binding pocket, shows different conformations in the three structures, suggesting that it may interfere with inhibitor/cofactor binding. The second loop has been suggested to control the access of dihydroorotate to the active site of the enzyme and may be an important player in the enzymatic reaction. These observations provide new insights into the dynamic features of the DHODH reaction and suggest new approaches to the design of inhibitors against DHODH.
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Affiliation(s)
- Björn Walse
- SARomics AB, P.O. Box 724, SE-220 07 Lund, Sweden.
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Leban J, Kralik M, Mies J, Baumgartner R, Gassen M, Tasler S. Biphenyl-4-ylcarbamoyl thiophene carboxylic acids as potent DHODH inhibitors. Bioorg Med Chem Lett 2006; 16:267-70. [PMID: 16246558 DOI: 10.1016/j.bmcl.2005.10.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2005] [Revised: 09/14/2005] [Accepted: 10/05/2005] [Indexed: 10/25/2022]
Abstract
A previously discovered DHODH inhibitor series was further improved by replacing the cyclopentene ring by aromatic heterocycles. Different isomers of these compounds were prepared by the directed ortho-metallation procedure. The compounds are more active than the corresponding cyclopentene analogs and show potent effects on PBMC's proliferation.
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Affiliation(s)
- Johann Leban
- 4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany.
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Hocevar A, Rozman B, Praprotnik S, Lestan B, Erzen D, Petric V, Tomsic M. Leflunomide-associated tuberculosis? Rheumatology (Oxford) 2005; 45:228-9. [PMID: 16319103 DOI: 10.1093/rheumatology/kei173] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Leban J, Kralik M, Mies J, Gassen M, Tentschert K, Baumgartner R. SAR, species specificity, and cellular activity of cyclopentene dicarboxylic acid amides as DHODH inhibitors. Bioorg Med Chem Lett 2005; 15:4854-7. [PMID: 16143532 DOI: 10.1016/j.bmcl.2005.07.053] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2005] [Revised: 07/05/2005] [Accepted: 07/07/2005] [Indexed: 11/22/2022]
Abstract
Novel DHODH inhibitors were developed based on a previously described series by introduction of heteroatoms into the cyclopentene ring and hydroxyl groups attached to it. Also, the hydrophobic biphenyl side chain was replaced with benzyloxy phenyl groups. Activities on human, rat, and mouse enzymes indicate a species specificity of these inhibitors.
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Affiliation(s)
- Johann Leban
- 4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany.
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Brown DS, Belfield AJ, Brown GR, Campbell D, Foubister A, Masters DJ, Pike KG, Snelson WL, Wells SL. A novel series of p38 MAP kinase inhibitors for the potential treatment of rheumatoid arthritis. Bioorg Med Chem Lett 2004; 14:5383-7. [PMID: 15454231 DOI: 10.1016/j.bmcl.2004.08.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2004] [Revised: 07/30/2004] [Accepted: 08/05/2004] [Indexed: 11/18/2022]
Abstract
A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide-induced tumour necrosis factor-alpha release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues.
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Affiliation(s)
- Dearg S Brown
- AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
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Poór G, Strand V. Efficacy and safety of leflunomide 10 mg versus 20 mg once daily in patients with active rheumatoid arthritis: multinational double-blind, randomized trial. Rheumatology (Oxford) 2004; 43:744-9. [PMID: 15026583 DOI: 10.1093/rheumatology/keh168] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVE To compare the efficacy and safety profile of two daily maintenance doses of leflunomide, 10 mg and 20 mg, for the treatment of active rheumatoid arthritis (RA). METHODS In this multinational, randomized, double-blind, parallel-group study, 402 RA patients were randomized equally to receive daily doses of 10 mg leflunomide (n = 202; loading dose on day 3, 100 mg) or 20 mg leflunomide (n = 200; loading dose on day 1-3, 100 mg) for 24 weeks. The study was designed to demonstrate non-inferiority of the efficacy of 10 mg compared with 20 mg by calculating 95% confidence intervals for differences in changes in tender joint count (TJC), swollen joint count (SJC) and Health Assessment Questionnaire Disability Index (HAQ DI), comparing these confidence intervals with predefined bounds. RESULTS In the intent-to-treat population, mean improvements at the end-point in the 10 and 20 mg groups respectively were: TJC, -7.57 and -8.89 (P = 0.061); SJC, -6.38 and -6.96 (P = 0.304); and HAQ DI, 0-0.37 and 0-0.49 (P = 0.095). By American College of Rheumatology (ACR) > or =20% criteria, response rates were 49.8 and 56.6% respectively (P = 0.1724). Adverse events (AEs) resulting in treatment withdrawal were higher in the 10 mg (15.3%) than in the 20 mg treatment group (12.0%), as were serious adverse events (SAEs): 12.9 vs 10.0%. CONCLUSIONS This study rejected the hypothesis of non-inferiority of 10 mg compared with 20 mg daily maintenance doses of leflunomide. More AEs resulting in treatment discontinuation and SAEs in patients receiving 10 mg leflunomide daily also support a better efficacy profile for the 20 mg daily dose.
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Affiliation(s)
- G Poór
- National Institute of Rheumatology and Physiotherapy, Budapest, Hungary.
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Leban J, Saeb W, Garcia G, Baumgartner R, Kramer B. Discovery of a novel series of DHODH inhibitors by a docking procedure and QSAR refinement. Bioorg Med Chem Lett 2004; 14:55-8. [PMID: 14684297 DOI: 10.1016/j.bmcl.2003.10.021] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
A novel series of DHODH inhibitors was developed based on a lead which was obtained by a docking procedure and a medicinal chemistry exploration. The activity of the initial lead was improved by a QSAR method to yield low nanomolar inhibitors.
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Affiliation(s)
- Johann Leban
- 4SC AG, Am Klopferspitz 19a, 82152 Martinsried, Germany.
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Abstract
AIM: To study the effect of leflunomide on immunological liver injury (ILI) in mice.
METHODS: ILI was induced by tail vein injection of 2.5 mg Bacillus Calmette-Guerin (BCG), and 10 d later with 10 mg lipopolysaccharide (LPS) in 0.2 mL saline (BCG + LPS). The alanine aminotransferase (ALT), aspartate aminotransferase (AST), nitric oxide (NO) level in plasma and molondiadehyde (MDA), glutathione peroxidase (GSHpx) in liver homogenate were assayed by spectroscopy. The serum content of tumor necrosis factors-α (TNF-α) was determined by ELISA. Interleukin-1 (IL-1), interleukin-2 (IL-2) and Concanavalin A (ConA)-induced splenocyte proliferation response were determined by methods of 3H-infiltrated cell proliferation.
RESULTS: Leflunomide (4, 12, 36 mg·kg-1) was found to significantly decrease the serum transaminase (ALT, AST) activity and MDA content in liver homogenate, and improve reduced GSHpx level of liver homogenate. Leflunomide (4, 12, 36 mg·kg-1) significantly lowered TNF-α and NO level in serum, and IL-1 produced by intraperitoneal macrophages (PMF). Moreover, the decreased IL-2 production and ConA-induced splenocyte proliferation response were further inhibited.
CONCLUSION: These findings suggested that leflunomide had significant protective action on ILI in mice.
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Affiliation(s)
- Hong-Wei Yao
- Institute of Clinical Pharmacology, Anhui Medical University, Heifei 230032, Anhui Province, China
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Faragher RJ, Motto JM, Kaminski MA, Schwan AL. A convenient synthesis of13C4-Leflunomide and its primary metabolite13C4-A77 1726. J Labelled Comp Radiopharm 2003. [DOI: 10.1002/jlcr.701] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Mimouni D, Nousari HC. Inhibitors of purine and pyrimidine synthesis: mycophenolate, azathioprine, and leflunomide. Dermatol Ther 2002. [DOI: 10.1046/j.1529-8019.2002.01539.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Saravanan V, Hamilton J. Advances in the treatment of rheumatoid arthritis: old versus new therapies. Expert Opin Pharmacother 2002; 3:845-56. [PMID: 12083985 DOI: 10.1517/14656566.3.7.845] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Rheumatoid arthritis (RA) is a common cause of disability in the western population, with an annual incidence of 0.05% and a prevalence of 1%. Although a small percentage of patients go into natural remission, the untreated disease progresses to cause disability, morbidity and early mortality. Unravelling of the cytokine network in the pathogenesis of RA has led to the development of drugs that target these cytokines and prevent joint damage. Three biological anticytokine agents, etanercept, infliximab and anakinra, are now available for use in RA. More experience will quantify their safety and benefits. The potency of the older disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, is also being realised, especially when used early in the disease process and in combination. Leflunomide is a new DMARD with efficacy similar to methotrexate and sulfasalazine. Symptomatic treatment of RA with nonsteroidal anti-inflammatory drugs has also undergone a revolution with the availability of a new class of COX-2-specific inhibitors. These drugs control inflammation and provide pain relief with less GI toxicity. Management of comorbid conditions associated with RA and its treatment (i.e., osteoporosis, cardiovascular and lung disease) has also become a priority for the rheumatologist. It is hoped that more aggressive use of conventional DMARDs and biological agents will result in less disability and a higher proportion of patients achieving remission.
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Affiliation(s)
- Vadivelu Saravanan
- Department of Rheumatology, James Cook University Hospital, Middlesbrough, UK
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