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Xue JY, Chen MT, Jian YH, Liang LL, Yang XR, Sun SH, Liu P, Liu QY, Jiang Y, Liu MN. The role of the TREM receptor family in cardiovascular diseases: Functions, mechanisms, and therapeutic target. Life Sci 2025; 369:123555. [PMID: 40068732 DOI: 10.1016/j.lfs.2025.123555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 03/03/2025] [Accepted: 03/08/2025] [Indexed: 03/15/2025]
Abstract
The Triggering Receptor Expressed in the Myeloid Cells (TREM) family represents an emerging subgroup within the immunoglobulin superfamily, which includes key members such as TREM-1, TREM-2, TREM-3, TREM-like transcript-1 (TLT-1), TLT-2, and TLT-4. TREM-1 serves as a potent amplifier of immune responses, exacerbating atherosclerosis and myocardial injury by enhancing inflammatory reactions. In contrast, TREM-2 exerts protective effects by regulating lipid metabolism, mitigating inflammation, and promoting phagocytic activity, thereby attenuating cardiovascular damage. Both soluble TLT-1 and TLT-4 have been identified as potential biomarkers for cardiovascular risk. In recent years, the roles of the TREM family in the pathogenesis of cardiovascular diseases (CVD) have garnered growing interest within the scientific community. This review aims to illuminate the functional roles, underlying mechanisms, and clinical relevance of TREM family members in the regulation of CVD, while exploring their potential applications in early diagnosis, disease monitoring, and the development of novel therapeutic targets for CVD, ultimately laying a foundation for their clinical translation and advancement in precision medicine.
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Affiliation(s)
- Jin-Yi Xue
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China
| | - Ming-Tai Chen
- Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, 518000, China
| | - Yu-Hong Jian
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China
| | - Ling-Ling Liang
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China
| | - Xin-Rui Yang
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China
| | - Shi-Han Sun
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China
| | - Ping Liu
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China
| | - Qiu-Yu Liu
- School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
| | - Yan Jiang
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China.
| | - Meng-Nan Liu
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, China.
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Feng Y, Chen C, Shao A, Wu L, Hu H, Zhang T. Emerging interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors or degraders as therapeutic agents for autoimmune diseases and cancer. Acta Pharm Sin B 2024; 14:5091-5105. [PMID: 39807338 PMCID: PMC11725142 DOI: 10.1016/j.apsb.2024.09.008] [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: 05/06/2024] [Revised: 06/20/2024] [Accepted: 07/26/2024] [Indexed: 01/16/2025] Open
Abstract
Interleukin-1 receptor-related kinase (IRAK4) is a widely expressed serine/threonine kinase involved in the regulation of innate immunity. IRAK4 plays a pivotal role as a key kinase within the downstream signaling pathway cascades of interleukin-1 receptors (IL-1R) and Toll-like receptors (TLRs). The signaling pathways orchestrated by IRAK4 are integral to inflammatory responses, and its overexpression is implicated in the pathogenesis of inflammatory diseases, autoimmune disorders, and cancer. Consequently, targeting IRAK4-mediated signaling pathways has emerged as a promising therapeutic strategy. Small molecule inhibitors and degraders designed to modulate IRAK4 have shown efficacy in mitigating related diseases. In this paper, we will provide a detailed description of the structure and function of IRAK4, the role of IRAK4 in related diseases, as well as the currently reported small molecule inhibitors and degraders of IRAK4. It is expected to provide new directions for enriching the clinical treatment of inflammation and related diseases.
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Affiliation(s)
- Yifan Feng
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Chengjuan Chen
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Anqi Shao
- Department of Dermatology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Lei Wu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Haiyu Hu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Tiantai Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
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Khalilian P, Eskandari N, Sharifi MJ, Soltani M, Nematollahi P. Toll-Like Receptor 4, 2, and Interleukin 1 Receptor Associated Kinase4: Possible Diagnostic Biomarkers in Myelodysplastic Syndrome Patients. Adv Biomed Res 2024; 13:17. [PMID: 38525404 PMCID: PMC10958736 DOI: 10.4103/abr.abr_67_23] [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: 02/21/2023] [Revised: 05/02/2023] [Accepted: 05/10/2023] [Indexed: 03/26/2024] Open
Abstract
Background Myelodysplastic syndrome (MDS) is a clonal hematologic disorder that requires the integration of morphologic, cytogenetic, hematologic, and clinical findings for a successful diagnosis. Trying to find ancillary tests such as biomarkers improve the diagnosis process. Several studies showed that a disordered immune system is associated with MDS. The chronic activated innate immune system, particularly the Toll-like receptors (TLRs) pathway could be involved in the induction of the inflammation. Materials and Methods In the present study, we investigated the expression of TLR2, TLR4, and IRAK4 in bone marrow (BM) of MDS patients, the leukemia group, and the healthy group. For this purpose, we assessed the expression of TLR2, TLR4, and IRAK4 by real time-PCR. Results In line with new findings, we demonstrated that the expression of TLR2, TLR4, and IRAK4 significantly increased in MDS BM compared with the healthy group. Moreover, IRAK4 expression raised significantly in MDS patients compared with other studied hematologic neoplasms. Also, the expression levels of TLR2 and TLR4 significantly increased in MDS in comparison to some studied non-MDS malignancies (P ˂ 0.05). Receiver operating characteristics (ROC) analysis and area under the curve (AUC) suggested that the expression of TLR2, TLR4, and IRAK4 (AUC = 0.702, AUC = 0.75, and AUC = 0.682, respectively) had acceptable diagnostic values to identify MDS from the other understudied leukemias. Conclusion Overall, the expression of TLR2, TLR4, and IRAK4 could be potential biomarkers for discriminating MDS from some hematologic disorders.
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Affiliation(s)
- Parvin Khalilian
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nahid Eskandari
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Applied Physiology Research Center, Isfahan Cardiovascular Research Institute, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Jafar Sharifi
- Department of Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Soltani
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Pardis Nematollahi
- Department of Pathology, School of Medicine, Cancer Prevention Research Center, Seyyed Al-Shohada Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
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Mekala S, Sukumar G, Chawla S, Geesala R, Prashanth J, Reddy BJM, Mainkar P, Das A. Therapeutic Potential of Benzimidazoisoquinoline Derivatives in Alleviating Murine Hepatic Fibrosis. Chem Biodivers 2024; 21:e202301429. [PMID: 38221801 DOI: 10.1002/cbdv.202301429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 01/09/2024] [Accepted: 01/09/2024] [Indexed: 01/16/2024]
Abstract
Short Title: Benzimidazoisoquinoline derivatives as potent antifibrotics Hepatic fibrosis is a pathological condition of liver disease with an increasing number of cases worldwide. Therapeutic strategies are warranted to target the activated hepatic stellate cells (HSCs), the collagen-producing cells, an effective strategy for controlling the disease progression. Benzimidazoisoquinoline derivatives were synthesized as hybrid molecules by the combination of benzimidazoles and isoquinolines to evaluate their anti-fibrotic potential using an in-vitro and in-vivo model of hepatic fibrosis. A small library of benzimidazoisoquinoline derivatives (1-17 and 18-21) was synthesized from 2-aryl benzimidazole and acetylene functionalities through C-H and N-H activation. Compounds (10 and its recently synthesized derivatives 18-21) depicted a significant decrease in PDGF-BB and/or TGFβ-induced proliferation (1.7-1.9 -fold), migration (3.5-5.0 -fold), and fibrosis-related gene expressions in HSCs. These compounds could revert the hepatic damage caused by chronic exposure to hepatotoxicants, ethanol, and/or carbon tetrachloride as evident from the histological, biochemical, and molecular analysis. Anti-fibrotic effect of the compounds was supported by the decrease in the malondialdehyde level, collagen deposition, and gene expression levels of fibrosis-related markers such as α-SMA, COL1α1, PDGFRβ, and TGFRIIβ in the preclinical models of hepatic fibrosis. In conclusion, the synthesized benzimidazoisoquinoline derivatives (compounds 18, 19, 20, and 21) possess anti-fibrotic therapeutic potential against liver fibrosis.
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Affiliation(s)
- Sowmya Mekala
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, TS-500 007, INDIA
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, INDIA
| | - Genji Sukumar
- Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, TS-500007, INDIA
- Department of Chemistry, Adikavi Nannaya University, Rajamahendravaram, AP-533 296, INDIA
| | - Shilpa Chawla
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, TS-500 007, INDIA
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, INDIA
| | - Ramasatyaveni Geesala
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, TS-500 007, INDIA
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, INDIA
| | - Jupally Prashanth
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, INDIA
- Centre for X-ray Crystallography, Department of Analytical & Structural Chemistry, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, TS-500 007, INDIA
| | - B Jagan Mohan Reddy
- Department of Chemistry, Adikavi Nannaya University, Rajamahendravaram, AP-533 296, INDIA
| | - Prathama Mainkar
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, INDIA
- Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, TS-500007, INDIA
| | - Amitava Das
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, TS-500 007, INDIA
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, INDIA
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Deng Y, Liao Y, Huang P, Yao Y, Liu W, Gu Y, Weng G. IRAK-M deficiency exacerbates dopaminergic neuronal damage in a mouse model of sub-acute Parkinson's disease. Neuroreport 2023; 34:463-470. [PMID: 37161987 DOI: 10.1097/wnr.0000000000001913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Emerging evidence has proved that inflammatory responses aggravate the pathological progression of Parkinson's disease. This study aimed to identify the role of Interleukin-1 receptor-associated kinase-M (IRAK-M) as an important negative regulator of innate immunity, in the pathological progression of Parkinson's disease. In the present study, a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection was administered to prepare the acute and sub-acute Parkinson's disease mouse models. Western blot analysis was utilized to examine the protein expressions of tyrosine hydroxylase and IRAK-M. The mRNA expression levels of IRAK-M, interleukin (IL)-6, IL-β, and cyclooxygenase-2 were evaluated via using reverse transcription quantitative PCR (RT-qPCR). The expression of tyrosine hydroxylase-positive neurons in corpus striatum and substantia nigra pars compacta (SNc) tissues was detected using immunohistochemistry. The results showed that the protein and mRNA levels of IRAK-M were considerably upregulated in corpus striatum and SNc tissues in the sub-acute Parkinson's disease model. Furthermore, IRAK-M knockout significantly enhanced the MPTP-induced loss of tyrosine hydroxylase-positive fibers in corpus striatum and tyrosine hydroxylase-positive neurons in SNc, and intensified the effect of MPTP on the activation of microglial cells and the expression of inflammatory cytokines. In addition, sub-acute Parkinson's disease mice with IRAK-M deletion exhibited worse motor abilities than those of wild-type littermates. Overall, the present study suggested that IRAK-M reduces dopaminergic neuron damage in sub-acute Parkinson's disease by suppressing inflammation, which may provide a new therapeutic target for Parkinson's disease treatment.
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Affiliation(s)
- Yidong Deng
- Neurointerventional Department, Hainan General Hospital, Haikou, Hainan
| | - Yuangao Liao
- Department of Neurology, Huanggang Central Hospital of Yangtze University, Huanggang, Hubei
| | | | - Yujian Yao
- Clinical Research Center, Hainan Provincial Hospital of Traditional Chinese Medicine
- Hainan Clinical Center for Encephalopathy of Chinese Medicine, Hainan Provincial Hospital of Traditional Chinese Medicine, Haikou, Hainan, PR China
| | - Weihua Liu
- Department of Encephalopathy, Hainan Provincial Hospital of Traditional Chinese Medicine
- Hainan Clinical Center for Encephalopathy of Chinese Medicine, Hainan Provincial Hospital of Traditional Chinese Medicine, Haikou, Hainan, PR China
| | - Yong Gu
- Clinical Research Center, Hainan Provincial Hospital of Traditional Chinese Medicine
- Department of Encephalopathy, Hainan Provincial Hospital of Traditional Chinese Medicine
- Hainan Clinical Center for Encephalopathy of Chinese Medicine, Hainan Provincial Hospital of Traditional Chinese Medicine, Haikou, Hainan, PR China
| | - Guohu Weng
- Department of Encephalopathy, Hainan Provincial Hospital of Traditional Chinese Medicine
- Hainan Clinical Center for Encephalopathy of Chinese Medicine, Hainan Provincial Hospital of Traditional Chinese Medicine, Haikou, Hainan, PR China
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Choudhary SA, Patra D, Sinha A, Mazumder S, Pant R, Chouhan R, Jha AN, Prusty BM, Manna D, Das SK, Tikoo K, Pal D, Dasgupta S. A small molecule potent IRAK4 inhibitor abrogates lipopolysaccharide-induced macrophage inflammation in-vitro and in-vivo. Eur J Pharmacol 2023; 944:175593. [PMID: 36804543 DOI: 10.1016/j.ejphar.2023.175593] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 02/03/2023] [Accepted: 02/15/2023] [Indexed: 02/19/2023]
Abstract
Increasing evidence supports vanillin and its analogs as potent toll-like receptor signaling inhibitors that strongly attenuate inflammation, though, the underlying molecular mechanism remains elusive. Here, we report that vanillin inhibits lipopolysaccharide (LPS)-induced toll-like receptor 4 activation in macrophages by targeting the myeloid differentiation primary-response gene 88 (MyD88)-dependent pathway through direct interaction and suppression of interleukin-1 receptor-associated kinase 4 (IRAK4) activity. Moreover, incubation of vanillin in cells expressing constitutively active forms of different toll-like receptor 4 signaling molecules revealed that vanillin could only able to block the ligand-independent constitutively activated IRAK4/1 or its upstream molecules-associated NF-κB activation and NF-κB transactivation along with the expression of various proinflammatory cytokines. A significant inhibition of LPS-induced IRAK4/MyD88, IRAK4/IRAK1, and IRAK1/TRAF6 association was evinced in response to vanillin treatment. Furthermore, mutations at Tyr262 and Asp329 residues in IRAK4 or modifications of 3-OMe and 4-OH side groups in vanillin, significantly reduced IRAK4 activity and vanillin function, respectively. Mice pretreated with vanillin followed by LPS challenge markedly impaired LPS-induced IRAK4 activation and inflammation in peritoneal macrophages. Thus, the present study posits vanillin as a novel and potent IRAK4 inhibitor and thus providing an opportunity for its therapeutic application in managing various inflammatory diseases.
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Affiliation(s)
- Saynaz A Choudhary
- Metabolic Disease Biology Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, 784028, Assam, India
| | - Debarun Patra
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, 140001, Punjab, India
| | - Archana Sinha
- Metabolic Disease Biology Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, 784028, Assam, India
| | - Sayani Mazumder
- Metabolic Disease Biology Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, 784028, Assam, India
| | - Rajat Pant
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India
| | - Raju Chouhan
- Department of Chemical Sciences, Tezpur University, Tezpur, 784028, Assam, India
| | - Anupam Nath Jha
- Computational Biophysics Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, 784028, Assam, India
| | - Biswa Mohan Prusty
- Department of Chemistry, Indian Institute of Technology Guwahati, Assam, 781039, India
| | - Debasis Manna
- Department of Chemistry, Indian Institute of Technology Guwahati, Assam, 781039, India
| | - Sajal K Das
- Department of Chemical Sciences, Tezpur University, Tezpur, 784028, Assam, India
| | - Kulbhushan Tikoo
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India
| | - Durba Pal
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, 140001, Punjab, India
| | - Suman Dasgupta
- Metabolic Disease Biology Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, 784028, Assam, India.
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Charan HV, Dwivedi DK, Khan S, Jena G. Mechanisms of NLRP3 inflammasome-mediated hepatic stellate cell activation: Therapeutic potential for liver fibrosis. Genes Dis 2023; 10:480-494. [PMID: 37223529 PMCID: PMC10201559 DOI: 10.1016/j.gendis.2021.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 11/09/2021] [Accepted: 12/01/2021] [Indexed: 01/18/2023] Open
Abstract
The liver injury leads to an inflammatory response, which causes the activation of hepatic stellate cells (HSCs) that further secrete ECM proteins and play an important role in liver fibrosis. Moreover, the inflammatory response is a driving force for fibrogenesis, which is triggered by many types of injuries. Exaggerated inflammatory immune responses are mediated by cytoplasmic protein complexes known as inflammasomes, which are involved in many chronic liver diseases. Inflammasomes are pattern recognition receptors (PRRs) that can sense any microbial motifs known as pathogen-associated molecular patterns (PAMPs), and host- or environmental-derived stress signals known as damage-associated molecular patterns (DAMPs). The inflammasomes cause caspase-mediated proteolytic cleavage of pro-IL-1β and pro-IL-18 into active IL-1β and IL-18. In this review, we provide a comprehensive summary of the important roles of NLRP3 inflammasome in the pathogenesis of liver fibrosis with an emphasis on several direct and indirect pathways responsible for the NLRP3 inflammasome-mediated HSCs activation and fibrogenesis. In addition, we discuss the general pharmacological and genetics strategies for the inhibition of NLRP3 inflammasome activation and its downstream signaling with examples of emerging pharmacotherapeutics, targeting the NLRP3 inflammasome signaling as well as a possible way to develop effective and safer NLRP3 inflammasome inhibitors.
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Affiliation(s)
- Harsh Vardhan Charan
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India
| | - Durgesh Kumar Dwivedi
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India
| | - Sabbir Khan
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Gopabandhu Jena
- Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India
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Wang W, Liu Y, Mao Y, Xu Y, Wang Z, Zhang R, Liu B, Xia K, Yang M, Yan J. Toll-interacting protein negatively regulated innate immune response via NF-κB signal pathway in blunt snout bream, Megalobrama amblycephala. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2023; 140:104595. [PMID: 36427557 DOI: 10.1016/j.dci.2022.104595] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 11/20/2022] [Accepted: 11/20/2022] [Indexed: 06/16/2023]
Abstract
Toll-interacting protein (Tollip) is an important negative regulator of Toll-like receptor-mediated innate immunity by preventing excessive proinflammatory responses. The structure and function of Tollip have been well identified in mammals, but the piscine Tollip remains poorly understood. In the present study, a homologue of Tollip was identified and characterized from blunt snout bream (named MaTollip), which was composed of an 831 bp open reading frame encoding a protein of 276 amino acids. Phylogenetic analysis indicated that MaTollip is a novel member of Tollip family and possessed the highest similarity to that of grass carp (99.28%). Multiple alignment of amino acid sequence showed that MaTOLLIP shared a high degree of structural conservation, including a TBD domain, a C2 domain and a CUE domain, with its counterparts from other vertebrates. With regard to tissue-specific expression without immune challenge, MaTollip was constitutively expressed in a wide range of normal tissues, with the highest in the head-kidney and the lowest in the intestine. MaTollip expression in the head-kidney was strongly upregulated upon LPS stimulation and A. hydrophila infection. Fluorescence microscopic analysis revealed that the green fluorescent protein-TOLLIP was localized predominantly in the cytoplasm of EPC cells in a dot-like state. When MaTollip was overexpressed in HEK-293T and EPC cells, it could significantly inhibit the activity of nuclear factor-κB (NF-κB) promoter in a dose dependent manner. MaTollip overexpression in MAF cells lowered drastically the transcriptional expression level of lipopolysaccharide-induced proinflammatory cytokines (IL-1β, IL-6 and IL-8), whereas they were dramatically promoted by MaTollip knock down with siRNA. Taken together, this study demonstrated that MaTollip played a pivotal role in mediating host innate immune response to pathogen invasion, and unveiled the involvement of MaTollip in NF-κB-mediated transcription of inflammation genes, which paved the way for further studies of immune negative regulation mechanisms mediated by Tollip in fish.
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Affiliation(s)
- Wenjun Wang
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, 410017, China
| | - Yang Liu
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, 410017, China
| | - Ying Mao
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, 410017, China
| | - Yandong Xu
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, 410017, China
| | - Zuzhen Wang
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, 410017, China
| | - Ru Zhang
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, 410017, China
| | - Bing Liu
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, 410017, China
| | - Kuanyu Xia
- Xiangya School of Medicine, Central South University, Changsha, 410017, China
| | - Moci Yang
- Xiangya School of Medicine, Central South University, Changsha, 410017, China
| | - Jinpeng Yan
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, 410017, China.
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Vargas-Cortez T, Jacobo-Velázquez DA, Benavides J. Therapeutic Plants with Immunoregulatory Activity and Their Applications: A Scientific Vision of Traditional Medicine in Times of COVID-19. J Med Food 2022; 25:1074-1085. [PMID: 36067145 DOI: 10.1089/jmf.2022.0038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The progression of SARS-CoV-2 (COVID-19) in humans heavily depends on the patient's overall health status, especially on its immunoregulatory capacity. Different plants and plant-derived preparations (infusions, encapsulated, etc.) have been used as immunoregulators, several of them with scientific support. Nevertheless, due to the composition complexity of such plant-derived preparations, the molecular and physiological mechanisms involved in their beneficial effects remain, in some cases, unclear. In this review article, the most reported plants used in traditional medicine to enhance immunoregulatory capacity are presented, and their effect on the innate immune response is discussed and correlated with their respective phytochemical profile. Understanding how the plant phytochemical profile relates to the observed impact on the innate and adaptative immune response is fundamental to designing plant-derived co-treatments to lessen the symptoms and favor the recovery of COVID-19 patients. In this regard, we propose a prospective guideline for using plants and plant-derived preparations as co-treatments for COVID-19 (and similar viral infections), which could be helpful in the context of the worldwide effort to end the current SARS-CoV-2 pandemic.
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Affiliation(s)
- Teresa Vargas-Cortez
- Tecnologico de Monterrey, The Institute for Obesity Research, Monterrey, México
- Tecnologico de Monterrey, School of Engineering and Sciences, Monterrey, México
| | - Daniel A Jacobo-Velázquez
- Tecnologico de Monterrey, The Institute for Obesity Research, Zapopan, México
- Tecnologico de Monterrey, School of Engineering and Sciences, Zapopan, México
| | - Jorge Benavides
- Tecnologico de Monterrey, The Institute for Obesity Research, Monterrey, México
- Tecnologico de Monterrey, School of Engineering and Sciences, Monterrey, México
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10
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Inflammasome Signaling in Atrial Fibrillation. J Am Coll Cardiol 2022; 79:2349-2366. [DOI: 10.1016/j.jacc.2022.03.379] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 12/26/2022]
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Li C, Lin H, He H, Ma M, Jiang W, Zhou R. Inhibition of the NLRP3 Inflammasome Activation by Manoalide Ameliorates Experimental Autoimmune Encephalomyelitis Pathogenesis. Front Cell Dev Biol 2022; 10:822236. [PMID: 35252186 PMCID: PMC8888861 DOI: 10.3389/fcell.2022.822236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/31/2022] [Indexed: 12/30/2022] Open
Abstract
The activation of NLRP3 inflammasome leads to cell pyroptosis and inflammatory cytokines secretion and gets involved in the development of many diseases, such as neuroinflammation and metabolic syndrome, but the drugs targeting NLRP3 are not clinically available for now. Through screening the small molecule library, we found that manoalide is a highly selective small molecule inhibitor of NLRP3. Mechanismly, manoalide inhibited the NLRP3 inflammasome activation by acting downstream of potassium efflux, chloride efflux and mitochondrial dysfunction. Moreover, manoalide blocked the interaction between NEK7 and NLRP3 by covalently binding to Lys 377 of the NLRP3 protein. Treatment of manoalide relieved the pathogenesis of experimental autoimmune encephalomyelitis (EAE) in mice. Thus, our results identify manoalide as a selective and covalent NLRP3 inhibitor and suggest it has the potential for the treatment of NLRP3-associated diseases.
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Affiliation(s)
- Cong Li
- Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, China.,CAS Centre for Excellence in Cell and Molecular Biology, University of Science and Technology of China, Hefei, China
| | - Hualong Lin
- Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, China.,CAS Centre for Excellence in Cell and Molecular Biology, University of Science and Technology of China, Hefei, China
| | - Hongbin He
- Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, China.,CAS Centre for Excellence in Cell and Molecular Biology, University of Science and Technology of China, Hefei, China
| | - Ming Ma
- Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, China.,CAS Centre for Excellence in Cell and Molecular Biology, University of Science and Technology of China, Hefei, China
| | - Wei Jiang
- Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, China.,CAS Centre for Excellence in Cell and Molecular Biology, University of Science and Technology of China, Hefei, China
| | - Rongbin Zhou
- Department of Geriatrics, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, University of Science and Technology of China, Hefei, China.,CAS Centre for Excellence in Cell and Molecular Biology, University of Science and Technology of China, Hefei, China
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12
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Torres S, Brol MJ, Magdaleno F, Schierwagen R, Uschner FE, Klein S, Ortiz C, Tyc O, Bachtler N, Stunden J, Bertheloot D, Kitanovic A, Sanchez B, Schrum J, Roush WR, Franchi L, Byth K, Latz E, Trebicka J. The Specific NLRP3 Antagonist IFM-514 Decreases Fibrosis and Inflammation in Experimental Murine Non-Alcoholic Steatohepatitis. Front Mol Biosci 2021; 8:715765. [PMID: 34513923 PMCID: PMC8425476 DOI: 10.3389/fmolb.2021.715765] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022] Open
Abstract
Background and Aims: Activation of the inflammasome NLRP3 (NOD-, LRR- and pyrin domain containing 3) contributes to the development of non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH). Therefore, this study explored the therapeutic effects of a novel and selective NLRP3 antagonist in a murine dietary model of NASH. Methods: Groups of 12-week-old ApoE-/- mice were fed ad lib for 7 weeks with a methionine/choline deficient (MCD) and western diet (WD). After 3 weeks of diet-induced injury, mice were injected i. p. with the NLRP3 antagonist IFM-514 (100 mg/kg body weight) or vehicle (0.5% carmellose) every day, 5 days/week for a further 4 weeks. Several markers of inflammation, fibrosis and steatosis were evaluated. Whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed. Results: IFM-514 inhibited IL-1β production in mice challenged with 20 mg/kg lipopolysaccharide, and in mouse and human inflammatory cells in vitro. IFM-514 inhibited hepatic inflammation in the in vivo non-alcoholic steatohepatitis model assessed by H&E staining and in the hepatic gene expression of inflammasome-related proinflammatory cytokines. This effect was associated with significant reduction in caspase-1 activation. Similarly, IFM-514 was efficacious in vivo in MDC-fed ApoE-/- mice, markedly reducing portal pressure, Sirius red staining and 4-hydroxyproline content compared to vehicle-treated mice. Moreover, IFM-514 significantly reduced hepatic steatosis in MCD-fed ApoE-/- mice, as evidenced by NAFLD scores, oil red O staining, hepatic triglycerides and gene expression. In WD treated animals, similar trends in inflammation and fibrosis were observed, although not sufficient IFM-514 levels were reached. Conclusion: Overall, IFM-514 reduced liver inflammation and fibrosis, with mild effects on liver steatosis in experimental murine NASH. Blocking of NLRP3 may be an attractive therapeutic approach for NASH patients.
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Affiliation(s)
- Sandra Torres
- Translational Hepatology, Department of Internal Medicine I, Universitätsklinikum/ Goethe-Universität, Frankfurt, Germany
| | - Maximilian J Brol
- Translational Hepatology, Department of Internal Medicine I, Universitätsklinikum/ Goethe-Universität, Frankfurt, Germany
| | - Fernando Magdaleno
- Department of Internal Medicine I, University Clinic Bonn, Bonn, Germany
| | - Robert Schierwagen
- Translational Hepatology, Department of Internal Medicine I, Universitätsklinikum/ Goethe-Universität, Frankfurt, Germany
| | - Frank E Uschner
- Translational Hepatology, Department of Internal Medicine I, Universitätsklinikum/ Goethe-Universität, Frankfurt, Germany
| | - Sabine Klein
- Translational Hepatology, Department of Internal Medicine I, Universitätsklinikum/ Goethe-Universität, Frankfurt, Germany
| | - Cristina Ortiz
- Translational Hepatology, Department of Internal Medicine I, Universitätsklinikum/ Goethe-Universität, Frankfurt, Germany
| | - Olaf Tyc
- Translational Hepatology, Department of Internal Medicine I, Universitätsklinikum/ Goethe-Universität, Frankfurt, Germany
| | - Nadine Bachtler
- Translational Hepatology, Department of Internal Medicine I, Universitätsklinikum/ Goethe-Universität, Frankfurt, Germany
| | | | - Damien Bertheloot
- IFM Therapeutics, Boston, MA, United States.,Institute of Innate Immunity, University Clinic Bonn, Bonn, Germany
| | | | | | | | | | | | - Kate Byth
- IFM Therapeutics, Boston, MA, United States
| | - Eicke Latz
- IFM Therapeutics, Boston, MA, United States.,Institute of Innate Immunity, University Clinic Bonn, Bonn, Germany
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Universitätsklinikum/ Goethe-Universität, Frankfurt, Germany.,European Foundation for the Study of Chronic Liver Failure - EF Clif, Barcelona, Spain
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13
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Khanfar MA. Structure-Based Pharmacophore Screening Coupled with QSAR Analysis Identified Potent Natural-Product-Derived IRAK-4 Inhibitors. Mol Inform 2021; 40:e2100025. [PMID: 34427398 DOI: 10.1002/minf.202100025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 08/13/2021] [Indexed: 11/10/2022]
Abstract
Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) has crucial functions in inflammation, innate immunity, and malignancy. Structure-based pharmacophore modeling integrated with validated QSAR analysis was implemented to discover structurally novel IRAK-4 inhibitors from natural products database. The QSAR model combined molecular descriptors with structure-based pharmacophore capable of explaining bioactivity variation of structurally diverse IRAK-4 inhibitors. Manually built pharmacophore model, validated with receiver operating characteristic curve, and selected using the statistically optimum QSAR equation, was applied as a 3D-search query to mine AnalytiCon Discovery database of natural products. Experimental in vitro testing of highest-ranked hits identified uvaretin, saucerneol, and salvianolic acid B as active IRAK-4 inhibitors with IC50 values in low micromolar range.
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Affiliation(s)
- Mohammad A Khanfar
- College of Pharmacy, Alfaisal University, Al Takhassusi Rd, P.O. Box 50927, Riyadh 1, 1533, Saudi Arabia.,Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, P.O Box 13140, Amman, 11942, Jordan
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14
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Kaplan MJ. Targeting the Myddosome in Systemic Autoimmunity: Ready for Prime Time? Arthritis Rheumatol 2021; 73:2163-2165. [PMID: 34424598 DOI: 10.1002/art.41951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 08/17/2021] [Indexed: 11/09/2022]
Affiliation(s)
- Mariana J Kaplan
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland
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15
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Stoy N. Involvement of Interleukin-1 Receptor-Associated Kinase 4 and Interferon Regulatory Factor 5 in the Immunopathogenesis of SARS-CoV-2 Infection: Implications for the Treatment of COVID-19. Front Immunol 2021; 12:638446. [PMID: 33936053 PMCID: PMC8085890 DOI: 10.3389/fimmu.2021.638446] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 02/24/2021] [Indexed: 12/15/2022] Open
Abstract
Interleukin-1 receptor-associated kinase 4 (IRAK4) and interferon regulatory factor 5 (IRF5) lie sequentially on a signaling pathway activated by ligands of the IL-1 receptor and/or multiple TLRs located either on plasma or endosomal membranes. Activated IRF5, in conjunction with other synergistic transcription factors, notably NF-κB, is crucially required for the production of proinflammatory cytokines in the innate immune response to microbial infection. The IRAK4-IRF5 axis could therefore have a major role in the induction of the signature cytokines and chemokines of the hyperinflammatory state associated with severe morbidity and mortality in COVID-19. Here a case is made for considering IRAK4 or IRF5 inhibitors as potential therapies for the "cytokine storm" of COVID-19.
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Affiliation(s)
- Nicholas Stoy
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
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16
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Hodl I, Bosch P, Dreo B, Stradner MH. Case Report: Extensive Phosphorylation of Interleukin-1 Receptor-Associated Kinase 4 in a Patient With Schnitzler Syndrome. Front Immunol 2020; 11:576200. [PMID: 33123160 PMCID: PMC7569524 DOI: 10.3389/fimmu.2020.576200] [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: 07/06/2020] [Accepted: 09/07/2020] [Indexed: 11/13/2022] Open
Abstract
Schnitzler syndrome (SchS) is a rare autoinflammatory disease, characterized by urticarial rash, recurrent fever, osteo-articular pain/arthritis with bone condensation, and monoclonal gammopathy. Diagnosis may be difficult due to overlapping signs with other diseases. Here, we describe the case of a 62-year-old man with SchS, who was initially misdiagnosed with multicentric Castleman disease (MCD). As excessive release of IL-6 is characteristic of MCD, in contrast to IL-1 in SchS, we measured the phosphorylation of intracellular signaling proteins of the respective pathways by flow cytometry. We found a distinct increase of phosphorylated IRAK-4 in our patient's B cells and monocytes while phosphorylation of STAT-3 was low, suggesting predominant IL-1 signaling. In accordance with these results and the classification criteria, we established the diagnosis of SchS instead of MCD and commenced therapy with the IL-1 receptor antagonist anakinra. We observed a rapid remission of signs accompanied by a reduction of phosphorylated IRAK-4 to normal levels. In conclusion, we propose phosphorylated IRAK-4 in B cells and monocytes as a potential marker for diagnosis of SchS and for treatment response to IL-1 blockade.
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Affiliation(s)
| | | | | | - Martin H. Stradner
- Division of Rheumatology and Immunology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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17
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Sharghi H, Razavi SF, Aberi M, Tavakoli F, Shekouhy M. The Co
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Complex of [7‐Hydroxy‐4‐methyl‐8‐coumarinyl]glycine as a Nanocatalyst for the Synthesis and Biological Evaluation of New Mannich Bases of Benzimidazoles and Benzothiazoles. ChemistrySelect 2020. [DOI: 10.1002/slct.201904700] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Hashem Sharghi
- Department of Chemistry, College of SciencesShiraz University Shiraz 71454 Iran
| | | | - Mahdi Aberi
- Department of Chemical and Materials Engineering, Faculty of Shahid Rajaee, Shiraz BranchTechnical and Vocational University (TVU), Shiraz Iran
| | - Fatemeh Tavakoli
- Department of Toxicology, Faculty of PharmacyShahid Sadoughi University of Medical Sciences, Yazd Iran
| | - Mohsen Shekouhy
- Department of Chemistry, College of SciencesShiraz University Shiraz 71454 Iran
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18
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IRAK family in inflammatory autoimmune diseases. Autoimmun Rev 2020; 19:102461. [DOI: 10.1016/j.autrev.2020.102461] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 08/29/2019] [Indexed: 12/22/2022]
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19
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Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 2020; 16:155-166. [PMID: 32034323 DOI: 10.1038/s41584-020-0372-x] [Citation(s) in RCA: 869] [Impact Index Per Article: 173.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/09/2020] [Indexed: 12/15/2022]
Abstract
Despite widespread clinical use of antimalarial drugs such as hydroxychloroquine and chloroquine in the treatment of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and other inflammatory rheumatic diseases, insights into the mechanism of action of these drugs are still emerging. Hydroxychloroquine and chloroquine are weak bases and have a characteristic 'deep' volume of distribution and a half-life of around 50 days. These drugs interfere with lysosomal activity and autophagy, interact with membrane stability and alter signalling pathways and transcriptional activity, which can result in inhibition of cytokine production and modulation of certain co-stimulatory molecules. These modes of action, together with the drug's chemical properties, might explain the clinical efficacy and well-known adverse effects (such as retinopathy) of these drugs. The unknown dose-response relationships of these drugs and the lack of definitions of the minimum dose needed for clinical efficacy and what doses are toxic pose challenges to clinical practice. Further challenges include patient non-adherence and possible context-dependent variations in blood drug levels. Available mechanistic data give insights into the immunomodulatory potency of hydroxychloroquine and provide the rationale to search for more potent and/or selective inhibitors.
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20
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Buchwald JE, Xu J, Bozorgzadeh A, Martins PN. Therapeutics administered during ex vivo liver machine perfusion: An overview. World J Transplant 2020; 10:1-14. [PMID: 32110510 PMCID: PMC7031625 DOI: 10.5500/wjt.v10.i1.1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/26/2019] [Accepted: 12/06/2019] [Indexed: 02/06/2023] Open
Abstract
Although the use of extended criteria donors has increased the pool of available livers for transplant, it has also introduced the need to develop improved methods of protection against ischemia-reperfusion injury (IRI), as these "marginal" organs are particularly vulnerable to IRI during the process of procurement, preservation, surgery, and post-transplantation. In this review, we explore the current basic science research investigating therapeutics administered during ex vivo liver machine perfusion aimed at mitigating the effects of IRI in the liver transplantation process. These various categories of therapeutics are utilized during the perfusion process and include invoking the RNA interference pathway, utilizing defatting cocktails, and administering classes of agents such as vasodilators, anti-inflammatory drugs, human liver stem cell-derived extracellular vesicles, and δ-opioid agonists in order to reduce the damage of IRI. Ex vivo machine perfusion is an attractive alternative to static cold storage due to its ability to continuously perfuse the organ, effectively deliver substrates and oxygen required for cellular metabolism, therapeutically administer pharmacological or cytoprotective agents, and continuously monitor organ viability during perfusion. The use of administered therapeutics during machine liver perfusion has demonstrated promising results in basic science studies. While novel therapeutic approaches to combat IRI are being developed through basic science research, their use in clinical medicine and treatment in patients for liver transplantation has yet to be explored.
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Affiliation(s)
- Julianna E Buchwald
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
| | - Jing Xu
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
| | - Adel Bozorgzadeh
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
| | - Paulo N Martins
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
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21
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Chang MC, Lin SI, Pan YH, Lin LD, Wang YL, Yeung SY, Chang HH, Jeng JH. IL-1β-induced ICAM-1 and IL-8 expression/secretion of dental pulp cells is differentially regulated by IRAK and p38. J Formos Med Assoc 2019; 118:1247-1254. [PMID: 30558829 DOI: 10.1016/j.jfma.2018.11.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/23/2018] [Accepted: 11/27/2018] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/PURPOSE Interleukin 1 beta (IL-1β) is a pro-inflammatory cytokine involved in the acute and chronic inflammatory processes of dental pulp. Intercellular adhesion molecule-1 (ICAM-1) and IL-8 are two major inflammatory mediators. However, the role of interleukin-1 receptor-associated kinases (IRAKs) signaling pathways in responsible for the inflammatory effects of IL-1β on dental pulp cells is not clear. METHODS Cultured human dental pulp cells were exposed to IL-1β with/without pretreatment and co-incubation with IRAK1/4 inhibitor or SB203580 (p38 inhibitor). IRAK-1 phosphorylation was evaluated by immunno fluorescent staining. The protein expression of ICAM-1 and IL-8 were tested by western blotting. The secretion of soluble ICAM-1 (sICAM-1) and IL-8 was measured by enzyme-linked immunosorbant assay (ELISA). RESULTS IL-1β stimulated IRAK-1 phosphorylation of pulp cells within 120 min of exposure. IRAK1/4 inhibitor attenuated the IL-1β-induced ICAM-1, but not IL-8 protein expression. IRAK1/4 inhibitor also prevented the IL-1β-induced sICAM-1, but not IL-8 secretion. SB203580 showed little effect on IL-1β-induced sICAM-1 secretion, but effectively inhibited its induction of IL-8 secretion in pulp cells. CONCLUSION The Results reveal the important role of IL-1β in pulpal inflammatory responses via stimulation of IL-8 and ICAM-1 expression and secretion. Moreover, IL-1β-induced effects on IL-8 and ICAM-1 are differentially regulated by IRAK1/4 and p38 signaling in dental pulp cells. Blocking of IRAKs and p38 signaling may have potential to control inflammation of dental pulp in the future.
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Affiliation(s)
- Mei-Chi Chang
- Chang Gung University of Science and Technology, Kwei-Shan, Taoyuan, Taiwan; Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Szu-I Lin
- Department of Dentistry, Tao-Yuan General Hospital, Ministry of Health and Welfare, Taoyuan City, Taiwan; Department of Dentistry and School of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taiwan
| | - Yu-Hwa Pan
- Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Li-Deh Lin
- Department of Dentistry and School of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taiwan
| | - Yin-Lin Wang
- Department of Dentistry and School of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taiwan
| | - Sin-Yuet Yeung
- Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Hsiao-Hua Chang
- Department of Dentistry and School of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taiwan.
| | - Jiiang-Huei Jeng
- Department of Dentistry and School of Dentistry, National Taiwan University Hospital and National Taiwan University Medical College, Taiwan.
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22
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Khanfar MA, Alqtaishat S. Discovery of potent IRAK-4 inhibitors as potential anti-inflammatory and anticancer agents using structure-based exploration of IRAK-4 pharmacophoric space coupled with QSAR analyses. Comput Biol Chem 2019; 79:147-154. [PMID: 30818109 DOI: 10.1016/j.compbiolchem.2019.02.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 02/18/2019] [Accepted: 02/19/2019] [Indexed: 11/17/2022]
Abstract
Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) has an important role in immunity, inflammation, and malignancy. The significant role of IRAK-4 makes it an interesting target for the discovery and development of potent small molecule inhibitors. In the current study, multiple linear regression -based QSAR analyses coupled with structure-based pharmacophoric exploration was applied to reveal the structural and physiochemical properties required for IRAK-4 inhibition. Manually built pharmacophoric models were initially validated with receiver operating characteristic curve, and best-ranked models were subsequently integrated in QSAR analysis along with other physiochemical descriptors. The pharmacophore model, selected using the statistically optimum QSAR equation, was implied as a 3D-search filter to mine the National Cancer Institute database for novel IRAK-4 inhibitors. Whereas the associated QSAR model prioritized the bioactivities of captured hits for in vitro evaluation. Experimental validation identified several potent IRAK-4 inhibitors of novel structural scaffolds. The most potent captured hit exhibited an IC50 value of 157 nM.
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Affiliation(s)
- Mohammad A Khanfar
- Heinrich Heine University Düsseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Düsseldorf, Germany; College of Pharmacy, Alfaisal University, Al Takhassusi Rd, Riyadh 11533, Saudi Arabia.
| | - Saja Alqtaishat
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, P.O Box 13140, Amman 11942, Jordan
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23
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Saad MA, El-Sahhar AE, Arab HH, Al-Shorbagy MY. Nicorandil abates arthritic perturbations induced by complete Freund's adjuvant in rats via conquering TLR4-MyD88-TRAF6 signaling pathway. Life Sci 2019; 218:284-291. [PMID: 30611783 DOI: 10.1016/j.lfs.2019.01.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 12/23/2018] [Accepted: 01/02/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND PURPOSE Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease which poses a need to explore effective yet safe pharmacotherapeutic options. The current work aimed to study the therapeutic role of nicorandil in controlling RA. EXPERIMENTAL APPROACH Complete Freund's adjuvant (CFA)-induced arthritis model was applied by injecting 400 μL of CFA in the right hind paw at day 0 and day 7. Four groups of rats were used as follows: normal-control (CTRL), CFA-induced arthritis (ART), CFA-induced arthritis treated with diclofenac (DIC) and CFA-induced arthritis treated with nicorandil (NIC). Both NIC and DIC were administered at day 14 for two weeks. Paw volume, knee joint diameter, pain behavior assessment as well as body weight were all periodically recorded throughout the experimental period. Following the sacrifice of animals at day 28, gene expressions of TLR-4, MyD88 and TRAF6 as well as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), nuclear factor Kappa B (NF-κB) were quantified in hind paws tissue. Finally, the serum levels of the inflammatory biomarkers (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) together with the histopathological examination of sections in the rat hind paw were recorded. RESULTS Both NIC and DIC proved promising anti-arthritic potential mediated, at least in part through switching off TLR4-MyD88-TRAF6 axis as well as downstream TRAF6 dependent activated MAP kinases and NF-κB. CONCLUSION AND IMPLICATIONS Nicorandil, via interfering with TLR4 signaling, sheds light on a potential clinical role of the drug in pursuit for safe and effective regimens for RA.
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Affiliation(s)
- Muhammed A Saad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El Aini st., 11562 Cairo, Egypt.
| | - Ayman E El-Sahhar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El Aini st., 11562 Cairo, Egypt.
| | - Hany H Arab
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Kasr El Aini st., 11562 Cairo, Egypt; Biochemistry Division and GTMR Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Taif University, Taif, Saudi Arabia.
| | - Muhammad Y Al-Shorbagy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El Aini st., 11562 Cairo, Egypt; School of Pharmacy, Newgiza University, Cairo, Egypt.
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24
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El Bakri Y, Lai CH, Sebhaoui J, Ali AB, Ramli Y, Essassi EM, Mague JT. Synthesis, crystal structure, Hirshfeld surface analysis, and DFT calculations of new 1-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-6-methoxy-1H-benzimidazol-2(3H)-one. ACTA ACUST UNITED AC 2018. [DOI: 10.1016/j.cdc.2018.11.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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25
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Abstract
Danger signals are a hallmark of many common inflammatory diseases, and these stimuli can function to activate the cytosolic innate immune signalling receptor NLRP3 (NOD-, LRR- and pyrin domain-containing 3). Once activated, NLRP3 nucleates the assembly of an inflammasome, leading to caspase 1-mediated proteolytic activation of the interleukin-1β (IL-1β) family of cytokines, and induces an inflammatory, pyroptotic cell death. Pharmacological inhibition of NLRP3 activation results in potent therapeutic effects in a wide variety of rodent models of inflammatory diseases, effects that are mirrored by genetic ablation of NLRP3. Although these findings highlight the potential of NLRP3 as a drug target, an understanding of NLRP3 structure and activation mechanisms is incomplete, which has hampered the discovery and development of novel therapeutics against this target. Here, we review recent advances in our understanding of NLRP3 activation and regulation, highlight the evolving landscape of NLRP3 modulators and discuss opportunities for pharmacologically targeting NLRP3 with novel small molecules.
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Li J, Saruta K, Dumouchel JP, Magat JM, Thomas JL, Ajami D, Rebek M, Rebek J, Bigby TD. Small Molecule Mimetics of α-Helical Domain of IRAK2 Attenuate the Proinflammatory Effects of IL-33 in Asthma-like Mouse Models. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2018; 200:4036-4043. [PMID: 29728508 PMCID: PMC5988972 DOI: 10.4049/jimmunol.1700693] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 04/10/2018] [Indexed: 01/04/2023]
Abstract
IL-33 and its receptor ST2 play important roles in airway inflammation and contribute to asthma onset and exacerbation. The IL-33/ST2 signaling pathway recruits adapter protein myeloid differentiation primary response 88 (MyD88) to transduce intracellular signaling. MyD88 forms a complex with IL-R-associated kinases (IRAKs), IRAK4 and IRAK2, called the Myddosome (MyD88-IRAK4-IRAK2). The myddosome subsequently activates downstream NF-κB and MAPKs p38 and JNK. We established an asthma-like mouse model by intratracheal administration of IL-33. The IL-33 model has a very similar phenotype compared with the OVA-induced mouse asthma model. The importance of MyD88 in the IL-33/ST2 signaling transduction was demonstrated by the MyD88 knockout mice, which were protected from the IL-33-induced asthma. We synthesized small molecule mimetics of the α-helical domain of IRAK2 with drug-like characteristics based on the recent advances in the designing of α-helix compounds. The mimetics can competitively interfere in the protein-protein interaction between IRAK2 and IRAK4, leading to disruption of Myddosome formation. A series of small molecules were screened using an NF-κB promoter assay in vitro. The lead compound, 7004, was further studied in the IL-33-induced and OVA-induced asthma mouse models in vivo. Compound 7004 can inhibit the IL-33-induced NF-κB activity, disrupt Myddosome formation, and attenuate the proinflammatory effects in asthma-like models. Our data indicate that the Myddosome may represent a novel intracellular therapeutic target for diseases in which IL-33/ST2 plays important roles, such as asthma and other inflammatory diseases.
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Affiliation(s)
- Jinghong Li
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093;
- Veterans Affairs San Diego Healthcare System, San Diego, CA 92161; and
| | - Kunio Saruta
- The Scripps Research Institute, La Jolla, CA 92037
| | - Justin P Dumouchel
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093
- Veterans Affairs San Diego Healthcare System, San Diego, CA 92161; and
| | - Jenna M Magat
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093
- Veterans Affairs San Diego Healthcare System, San Diego, CA 92161; and
| | - Joanna L Thomas
- Veterans Affairs San Diego Healthcare System, San Diego, CA 92161; and
| | | | - Mitra Rebek
- The Scripps Research Institute, La Jolla, CA 92037
| | - Julius Rebek
- The Scripps Research Institute, La Jolla, CA 92037
| | - Timothy D Bigby
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093
- Veterans Affairs San Diego Healthcare System, San Diego, CA 92161; and
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Naruishi K, Nagata T. Biological effects of interleukin‐6 on Gingival Fibroblasts: Cytokine regulation in periodontitis. J Cell Physiol 2018; 233:6393-6400. [DOI: 10.1002/jcp.26521] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 01/30/2018] [Indexed: 12/21/2022]
Affiliation(s)
- Koji Naruishi
- Department of Periodontology and Endodontology, Institute of Biomedical SciencesTokushima University Graduate SchoolKuramotoTokushimaJapan
| | - Toshihiko Nagata
- Department of Periodontology and Endodontology, Institute of Biomedical SciencesTokushima University Graduate SchoolKuramotoTokushimaJapan
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Song J, Han X, Yao YL, Li YM, Zhang J, Shao DY, Hou LS, Fan Y, Song SZ, Lian LH, Nan JX, Wu YL. Acanthoic acid suppresses lipin1/2 via TLR4 and IRAK4 signalling pathways in EtOH- and lipopolysaccharide-induced hepatic lipogenesis. J Pharm Pharmacol 2018; 70:393-403. [PMID: 29341132 DOI: 10.1111/jphp.12877] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 12/16/2017] [Indexed: 12/16/2022]
Abstract
Abstract
Objectives
In alcoholic liver disease, alcohol and lipopolysaccharide (LPS) are major stimulation factors of hepatic lipogenesis. Our objective was to determine the protective mechanism of acanthoic acid (AA) in EtOH- and LPS-induced hepatic lipogenesis.
Methods
HSC-T6 cells were treated with ethanol (200 mm) plus LPS (1 μg/ml) for 1 h, followed by AA (10 or 20 μm) for another 6 h. C57BL/6 mice were pretreated with of AA (20 and 40 mg/kg) or equal volume of saline and then exposed to three doses of ethanol (5 g/kg body weight) within 24 h. The mice were sacrificed at 6 h after the last ethanol dosing.
Key findings
Acanthoic acid significantly decreased the expressions of α-SMA, collagen-I, SREBP-1, and lipin1/2 induced, also decreased fat droplets caused by EtOH/LPS. AA treatment decreased the protein expressions of TLR4, CD14, IRAK4, TRAF3, p-TAK1 and NF-κB increased by EtOH/LPS on HSC cells. Results in vivo were consistent with results in vitro.
Conclusions
Our data demonstrated that AA might modulate hepatic fibrosis and lipid deposition in HSC-T6 cell stimulated with ethanol combined with LPS by decreasing lipin1/2 via TLR4 and IRAK4 signalling pathways, and AA might be considered as a potential therapeutic candidate for alcoholic liver disease.
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Affiliation(s)
- Jian Song
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Xin Han
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - You-Li Yao
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Ya-Mei Li
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Jing Zhang
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Dan-Yang Shao
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Li-Shuang Hou
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Ying Fan
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Shun-Zong Song
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Li-Hua Lian
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
| | - Ji-Xing Nan
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
- Clinical Research Center, Yanbian University Hospital, Yanji, China
| | - Yan-Ling Wu
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province, China
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Fechtner S, Fox DA, Ahmed S. Transforming growth factor β activated kinase 1: a potential therapeutic target for rheumatic diseases. Rheumatology (Oxford) 2017; 56:1060-1068. [PMID: 27550296 DOI: 10.1093/rheumatology/kew301] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Indexed: 12/13/2022] Open
Abstract
Pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α are central regulators of autoinflammatory diseases. While targeting these cytokines has proven to be a successful clinical strategy, the long-term challenges such as drug resistance, lack of efficacy and poor clinical outcomes in some patients are some of the limitations faced by these therapies. This has ignited strategies to reduce inflammation by potentially targeting a variety of molecules, including cell surface receptors, signalling proteins and/or transcription factors to minimize cytokine-induced inflammation and tissue injury. In this regard, transforming growth factor β activated kinase 1 (TAK1) is activated in the inflammatory signal transduction pathways in response to IL-1β, TNF-α or toll-like receptor stimulation. Because of its ideal position upstream of mitogen-activated protein kinases and the IκB kinase complex in signalling cascades, targeting TAK1 may be an attractive strategy for treating diseases characterized by chronic inflammation. Here, we discuss the emerging role of TAK1 in mediating the IL-1β, TNF-α and toll-like receptor mediated inflammatory responses in diseases such as RA, OA, gout and SS. We also review evidence suggesting that TAK1 inhibition may have potential therapeutic value. Finally, we focus on the current status of the development of TAK1 inhibitors and suggest further opportunities for testing TAK1 inhibitors in rheumatic diseases.
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Affiliation(s)
- Sabrina Fechtner
- Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA
| | - David A Fox
- Department of Internal Medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Salahuddin Ahmed
- Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, WA
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IRAK-4-shRNA Prevents Ischemia/Reperfusion Injury Via Different Perfusion Periods Through the Portal Vein After Liver Transplantation in Rat. Transplant Proc 2017; 48:2803-2808. [PMID: 27788821 DOI: 10.1016/j.transproceed.2016.06.058] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 06/22/2016] [Indexed: 12/21/2022]
Abstract
BACKGROUND This study analyzed the effects of short hairpin RNA targeting interleukin-1 receptor-associated kinase-4 (IRAK-4-shRNA) via portal vein perfusion during different periods on ischemia/reperfusion injury after liver transplantation. METHODS Rats were randomly divided into 3 groups: the cold ischemia transfection group (CIT group, n = 18), in which graft livers were perfused with the plasmid of pSIIRAK-4 expressing IRAK-4-shRNA for 4 minutes (0.5 mL/min) via the portal vein during the cold ischemia period; the in vivo transfection group (IVT group, n = 18), in which equivalent volumes (2 mL) of IRAK-4-ShRNA plasmid (pSIIRAK-4) were injected during the operation; and the control group (n = 18), in which the rats received equivalent volumes of blank plasmid. At 0, 60, and 180 minutes after portal vein reperfusion, blood and liver tissues were collected for examination. IRAK-4 expression, nuclear factor kB (NF-kB) activity, tumor necrosis factor α, interleukin (IL)-1β, and IL-6 serum levels, as well as histologic changes, were detected. RESULTS At 0 minutes after reperfusion, IRAK-4 expression, NF-κB activity, and serum levels of tumor necrosis factor α, IL-1β, and IL-6 showed no significant differences among the 3 groups (P > .05). At 60 and 180 minutes after reperfusion, all indices of the IVT and control groups were significantly higher than those of the CIT group (P < .01). Meanwhile, all indices of the CIT group showed no significant differences at various time points (P > .05). Liver function and histologic changes exhibited less liver injury in the CIT group than in the other groups. CONCLUSIONS IRAK-4 activity was suppressed by IRAK-4-shRNA through portal vein perfusion during the cold ischemia period, and IRAK-4-shRNA effectively prevented ischemia/reperfusion injury after liver transplantation.
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Della Mina E, Borghesi A, Zhou H, Bougarn S, Boughorbel S, Israel L, Meloni I, Chrabieh M, Ling Y, Itan Y, Renieri A, Mazzucchelli I, Basso S, Pavone P, Falsaperla R, Ciccone R, Cerbo RM, Stronati M, Picard C, Zuffardi O, Abel L, Chaussabel D, Marr N, Li X, Casanova JL, Puel A. Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts. Proc Natl Acad Sci U S A 2017; 114:E514-E523. [PMID: 28069966 PMCID: PMC5278481 DOI: 10.1073/pnas.1620139114] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1 Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4- or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient's fibroblasts, which responded very poorly to all TLR2/6 (PAM2CSK4, LTA, FSL-1), TLR1/2 (PAM3CSK4), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1β. By contrast, the patient's peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1β. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.
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Affiliation(s)
- Erika Della Mina
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France
- Imagine Institute, Paris Descartes University, 75015 Paris, France
| | - Alessandro Borghesi
- Neonatal Intensive Care Unit, Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Matteo Hospital Foundation, 27100 Pavia, Italy
- Laboratory of Neonatal Immunology, IRCCS San Matteo Hospital Foundation, 27100 Pavia, Italy
| | - Hao Zhou
- Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106
| | | | | | - Laura Israel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France
- Imagine Institute, Paris Descartes University, 75015 Paris, France
| | - Ilaria Meloni
- Medical Genetics, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
| | - Maya Chrabieh
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France
- Imagine Institute, Paris Descartes University, 75015 Paris, France
| | - Yun Ling
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France
- Imagine Institute, Paris Descartes University, 75015 Paris, France
| | - Yuval Itan
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065
| | - Alessandra Renieri
- Medical Genetics, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
- Medical Genetics, University Hospital of Siena, 53100 Siena, Italy
| | - Iolanda Mazzucchelli
- Laboratory of Neonatal Immunology, IRCCS San Matteo Hospital Foundation, 27100 Pavia, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Sabrina Basso
- Laboratory of Transplant Immunology/Cell Factory, IRCCS San Matteo Hospital Foundation, 27100 Pavia, Italy
| | - Piero Pavone
- General Paediatrics Operative Unit, Vittorio Emanuele University Hospital, University of Catania, 95100 Catania, Italy
| | - Raffaele Falsaperla
- General Paediatrics Operative Unit, Vittorio Emanuele University Hospital, University of Catania, 95100 Catania, Italy
| | - Roberto Ciccone
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Rosa Maria Cerbo
- Neonatal Intensive Care Unit, Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Matteo Hospital Foundation, 27100 Pavia, Italy
| | - Mauro Stronati
- Neonatal Intensive Care Unit, Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Matteo Hospital Foundation, 27100 Pavia, Italy
- Laboratory of Neonatal Immunology, IRCCS San Matteo Hospital Foundation, 27100 Pavia, Italy
| | - Capucine Picard
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France
- Imagine Institute, Paris Descartes University, 75015 Paris, France
- Pediatric Hematology-Immunology Unit, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, 75015 Paris, France
- Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, 75015 Paris, France
| | - Orsetta Zuffardi
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Laurent Abel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France
- Imagine Institute, Paris Descartes University, 75015 Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065
| | | | - Nico Marr
- Sidra Medical and Research Center, Doha, Qatar
| | - Xiaoxia Li
- Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106
| | - Jean-Laurent Casanova
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France;
- Imagine Institute, Paris Descartes University, 75015 Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065
- Pediatric Hematology-Immunology Unit, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, 75015 Paris, France
- Howard Hughes Medical Institute, New York, NY 10065
| | - Anne Puel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, 75015 Paris, France;
- Imagine Institute, Paris Descartes University, 75015 Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065
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Abstract
PURPOSE OF REVIEW Blockade of interleukin (IL)-1 signaling is one of the oldest biologic therapies, yet the use of these agents is on the rise as the role of IL-1 activation is being recognized in a wide spectrum of inflammatory disorders. This review will cover established and emerging uses of IL-1 antagonism in rheumatic diseases. RECENT FINDINGS Expanding off-label indications for IL-1 blockade include neutrophil-dominant skin diseases, including pyoderma gangrenosum, hidradenitis supperativa, and pustular psoriasis. There is also increasing evidence for the use of IL-1 blockade in heart failure associated with rheumatic diseases. Somatic mosaicism in NLRP3 may explain the onset of later-in-life presentations of periodic fevers which are responsive to IL-1 blockade. Of importance, clinical response to anti-IL-1 therapy does not always denote protection from autoinflammatory disease complications such as macrophage activation syndrome or amyloidosis. SUMMARY Indications for IL-1 blocking therapies will likely continue to broaden, but given the rarity of many rheumatic diseases which respond to such treatment, rigorous, large clinical trials for each indication are unlikely to occur. Thus, recommended use of these medications will often fall to the discretion of the astute physician. However, medication cost and hurdles of insurance approval, rather than drug efficacy, may be the primary limitation for more widespread use.
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Akhtar W, Khan MF, Verma G, Shaquiquzzaman M, Rizvi MA, Mehdi SH, Akhter M, Alam MM. Therapeutic evolution of benzimidazole derivatives in the last quinquennial period. Eur J Med Chem 2016; 126:705-753. [PMID: 27951484 DOI: 10.1016/j.ejmech.2016.12.010] [Citation(s) in RCA: 136] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/10/2016] [Accepted: 12/03/2016] [Indexed: 12/21/2022]
Abstract
Benzimidazole, a fused heterocycle bearing benzene and imidazole has gained considerable attention in the field of contemporary medicinal chemistry. The moiety is of substantial importance because of its wide array of pharmacological activities. This nitrogen containing heterocycle is a part of a number of therapeutically used agents. Moreover, a number of patents concerning this moiety in the last few years further highlight its worth. The present review covers the recent work published by scientists across the globe during last five years.
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Affiliation(s)
- Wasim Akhtar
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India
| | - Mohemmed Faraz Khan
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India
| | - Garima Verma
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India
| | - M Shaquiquzzaman
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India
| | - M A Rizvi
- Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Syed Hassan Mehdi
- Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Mymoona Akhter
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India
| | - M Mumtaz Alam
- Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India.
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Recent Progress in the Molecular Recognition and Therapeutic Importance of Interleukin-1 Receptor-Associated Kinase 4. Molecules 2016; 21:molecules21111529. [PMID: 27845762 PMCID: PMC6274160 DOI: 10.3390/molecules21111529] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 11/09/2016] [Indexed: 11/17/2022] Open
Abstract
Toll-like receptors (TLRs) are the most upstream pattern recognition receptors in the cell, which detect pathogen associated molecular patterns and initiate signal transduction, culminating in the transcription of pro-inflammatory cytokines and antiviral interferon. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key mediator in TLR (except for TLR3) and interleukin-1 receptor signaling pathways. The loss of kinase function of IRAK4 is associated with increased susceptibility to various pathogens, while its over-activation causes autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and cancer. The therapeutic importance of this master kinase has been advocated by a number of recent preclinical studies, where potent inhibitors have been administered to improve various TLR-mediated pathologies. Increasing studies of X-ray crystallographic structures with bound inhibitors have improved our knowledge on the molecular recognition of ligands by IRAK4, which will be crucial for the development of new inhibitors with improved potencies. In this review, we briefly discuss the structural aspect of ligand recognition by IRAK4 and highlight its therapeutic importance in the context of TLR-associated unmet medical needs.
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Abstract
The selective utilization of IRAK kinases, which are thought to be recruited to MyD88 to form the ‘Myddosome’, has been shown to differ substantially in mouse and human cells. This finding has important implications for the development of therapeutics for inflammatory and autoimmune disorders associated with Toll-like receptors.
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Singh AK, Umar S, Riegsecker S, Chourasia M, Ahmed S. Regulation of Transforming Growth Factor β-Activated Kinase Activation by Epigallocatechin-3-Gallate in Rheumatoid Arthritis Synovial Fibroblasts: Suppression of K(63) -Linked Autoubiquitination of Tumor Necrosis Factor Receptor-Associated Factor 6. Arthritis Rheumatol 2016; 68:347-58. [PMID: 26473505 DOI: 10.1002/art.39447] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 09/17/2015] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Transforming growth factor β-activated kinase 1 (TAK1) is a key MAPKKK family protein in interleukin-1β (IL-1β), tumor necrosis factor (TNF), and Toll-like receptor signaling. This study was undertaken to examine the posttranslational modification of TAK1 and its therapeutic regulation in rheumatoid arthritis (RA). METHODS The effect of TAK1, IL-1 receptor-associated kinase 1 (IRAK-1), and TNF receptor-associated factor 6 (TRAF6) inhibition was evaluated in IL-1β-stimulated human RA synovial fibroblasts (RASFs). Western blotting, immunoprecipitation, and 20S proteasome assay were used to study the ubiquitination process in RASFs. The efficacy of epigallocatechin-3-gallate (EGCG), a potent antiinflammatory molecule, in regulating these processes in RASFs was evaluated. Molecular docking was performed to examine the interaction of EGCG with human TAK1, IRAK-1, and TRAF6. These findings were confirmed using a rat model of adjuvant-induced arthritis (AIA). RESULTS Inhibition of TAK1, but not IRAK-1 or TRAF6, completely abrogated IL-1β-induced IL-6 and IL-8 synthesis in RASFs. EGCG inhibited TAK1 phosphorylation at Thr(184/187) and occupied the C(174) position, an ATP-binding site, to inhibit its kinase activity. EGCG pretreatment also inhibited K(63) -linked autoubiquitination of TRAF6, a posttranslational modification essential for TAK1 autophosphorylation, by forming a stable H bond at the K(124) position on TRAF6. Furthermore, EGCG enhanced proteasome-associated deubiquitinase expression to rescue proteins from proteasomal degradation. Western blot analyses of joint homogenates from rats with AIA showed a significant increase in K(48) -linked polyubiquitination, TAK1 phosphorylation, and TRAF6 expression when compared to naive rats. Administration of EGCG (50 mg/kg/day) for 10 days ameliorated AIA in rats by reducing TAK1 phosphorylation and K(48) -linked polyubiquitination. CONCLUSION Our findings provide a rationale for targeting TAK1 for the treatment of RA with EGCG.
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Affiliation(s)
- Anil K Singh
- Washington State University College of Pharmacy, Spokane
| | - Sadiq Umar
- Washington State University College of Pharmacy, Spokane
| | - Sharayah Riegsecker
- University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, Ohio
| | - Mukesh Chourasia
- National Institute of Pharmaceutical Education and Research, Hajipur, India
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Toll-like receptors and chronic inflammation in rheumatic diseases: new developments. Nat Rev Rheumatol 2016; 12:344-57. [PMID: 27170508 DOI: 10.1038/nrrheum.2016.61] [Citation(s) in RCA: 142] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
In the past few years, new developments have been reported on the role of Toll-like receptors (TLRs) in chronic inflammation in rheumatic diseases. The inhibitory function of TLR10 has been demonstrated. Receptors that enhance the function of TLRs, and several TLR inhibitors, have been identified. In addition, the role of the microbiome and TLRs in the onset of rheumatic diseases has been reported. We review novel insights on the role of TLRs in several inflammatory joint diseases, including rheumatoid arthritis, systemic lupus erythematosus, gout and Lyme arthritis, with a focus on the signalling mechanisms mediated by the Toll-IL-1 receptor (TIR) domain, the exogenous and endogenous ligands of TLRs, and the current and future therapeutic strategies to target TLR signalling in rheumatic diseases.
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Mapping the pulmonary environment of animals protected from virulent H1N1 influenza infection using the TLR-2 agonist Pam₂Cys. Immunol Cell Biol 2015; 94:169-76. [PMID: 26272554 DOI: 10.1038/icb.2015.81] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 07/22/2015] [Accepted: 07/22/2015] [Indexed: 01/30/2023]
Abstract
We have previously shown that intranasal administration of the Toll-like receptor-2 agonist, S-(2,3-bis(palmitoyloxy)propyl) cysteine (Pam2Cys), provides immediate and antigen independent protection against challenge with influenza virus. Here we characterize the cellular pulmonary environments of mice which had either been treated with Pam2Cys or placebo and then challenged with influenza virus. We show that Pam2Cys treatment results in the influx of innate immune cells into the lungs and that depletion of phagocytic cells from this influx using clodronate-loaded liposomes caused a reduction in the number of interstitial macrophages and monocytes. This resulted in abolition of the protective effect indicating the importance of this cellular subset in Pam2Cys-mediated protection.
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