|
1
|
Patalano SD, Fuxman Bass P, Fuxman Bass JI. Transcription factors in the development and treatment of immune disorders. Transcription 2025; 16:118-140. [PMID: 38100543 PMCID: PMC11970766 DOI: 10.1080/21541264.2023.2294623] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 12/05/2023] [Accepted: 12/08/2023] [Indexed: 12/17/2023] Open
Abstract
Immune function is highly controlled at the transcriptional level by the binding of transcription factors (TFs) to promoter and enhancer elements. Several TF families play major roles in immune gene expression, including NF-κB, STAT, IRF, AP-1, NRs, and NFAT, which trigger anti-pathogen responses, promote cell differentiation, and maintain immune system homeostasis. Aberrant expression, activation, or sequence of isoforms and variants of these TFs can result in autoimmune and inflammatory diseases as well as hematological and solid tumor cancers. For this reason, TFs have become attractive drug targets, even though most were previously deemed "undruggable" due to their lack of small molecule binding pockets and the presence of intrinsically disordered regions. However, several aspects of TF structure and function can be targeted for therapeutic intervention, such as ligand-binding domains, protein-protein interactions between TFs and with cofactors, TF-DNA binding, TF stability, upstream signaling pathways, and TF expression. In this review, we provide an overview of each of the important TF families, how they function in immunity, and some related diseases they are involved in. Additionally, we discuss the ways of targeting TFs with drugs along with recent research developments in these areas and their clinical applications, followed by the advantages and disadvantages of targeting TFs for the treatment of immune disorders.
Collapse
Affiliation(s)
- Samantha D. Patalano
- Biology Department, Boston University, Boston, MA, USA
- Molecular Biology, Cellular Biology and Biochemistry Program, Boston University, Boston, MA, USA
| | - Paula Fuxman Bass
- Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
| | - Juan I. Fuxman Bass
- Biology Department, Boston University, Boston, MA, USA
- Molecular Biology, Cellular Biology and Biochemistry Program, Boston University, Boston, MA, USA
- Bioinformatics Program, Boston University, Boston, MA, USA
| |
Collapse
|
|
2
|
Zhou Y, Li Z, Yu S, Wang X, Xie T, Zhang W. Iguratimod prevents renal fibrosis in unilateral ureteral obstruction model mice by suppressing M2 macrophage infiltration and macrophage-myofibroblast transition. Ren Fail 2024; 46:2327498. [PMID: 38666363 PMCID: PMC11057400 DOI: 10.1080/0886022x.2024.2327498] [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: 10/02/2023] [Accepted: 03/03/2024] [Indexed: 05/01/2024] Open
Abstract
Iguratimod is a novel synthetic, small-molecule immunosuppressive agent used to treat rheumatoid arthritis. Through ongoing exploration of its role and mechanisms of action, iguratimod has been observed to have antifibrotic effects in the lung and skin; however, its effect on renal fibrosis remains unknown. This study aimed to investigate whether iguratimod could affect renal fibrosis progression. Three different concentrations of iguratimod (30 mg/kg/day, 10 mg/kg/day, and 3 mg/kg/day) were used to intervene in unilateral ureteral obstruction (UUO) model mice. Iguratimod at 10 mg/kg/day was observed to be effective in slowing UUO-mediated renal fibrosis. In addition, stimulating bone marrow-derived macrophages with IL-4 and/or iguratimod, or with TGF-β and iguratimod or SRC inhibitors in vitro, suggested that iguratimod mitigates the progression of renal fibrosis in UUO mice, at least in part, by inhibiting the IL-4/STAT6 signaling pathway to attenuate renal M2 macrophage infiltration, as well as by impeding SRC activation to reduce macrophage-myofibroblast transition. These findings reveal the potential of iguratimod as a treatment for renal disease.
Collapse
Affiliation(s)
- Yueyuan Zhou
- Department of General Medicine, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhilan Li
- Department of General Medicine, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Shenyi Yu
- Department of Rheumatology and Immunology, Zhuzhou Hospital Affiliated to Xiangya Medical College, Central South University, Zhuzhou, China
| | - Xuan Wang
- Department of General Medicine, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Tingting Xie
- Department of General Medicine, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Weiru Zhang
- Department of General Medicine, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| |
Collapse
|
|
3
|
Chen X, Wang W, Xue J. Efficacy and safety of iguratimod combined with celecoxib in active axial spondyloarthritis: a randomized, double-blind, placebo-controlled study. Scand J Rheumatol 2024; 53:420-427. [PMID: 38832489 DOI: 10.1080/03009742.2024.2346411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 04/19/2024] [Indexed: 06/05/2024]
Abstract
OBJECTIVE To assess the efficacy and safety of iguratimod in adult patients with active axial spondyloarthritis (axSpA). METHOD This randomized, double-blind, placebo-controlled clinical trial lasted for 28 weeks. Patients with axSpA were randomized 1:1 to receive iguratimod 25 mg twice daily or a placebo. All patients also took celecoxib 200 mg twice daily for the first 4 weeks and on demand from 4 to 28 weeks. The primary endpoints were ASAS20 at 4 weeks and the non-steroidal anti-inflammatory drug (NSAID) index at 28 weeks. Other assessment variables included ASAS40, ASAS5/6 response rates, Spondyloarthritis Research Consortium of Canada (SPARCC) scores, and adverse events. RESULTS In total, 35 patients completed the study and were included for analyses. The median (interquartile range) NSAID index was 43.8 (34.9-51.8) in the iguratimod group, which is significantly lower than 68.9 (42.5-86.4) in the placebo group (p = 0.025). ASAS response rates and changes in disease activity scores were similar between the iguratimod and placebo groups. Patients in the iguratimod group had more improvement in median (interquartile range) SPARCC scores for sacroiliac joints than did those in the placebo group [71% (54-100%) vs 40% (0-52%), p = 0.006]. Iguratimod combined with celecoxib was not associated with a greater risk of adverse effects than was monotherapy with celecoxib. No severe adverse events occurred. CONCLUSIONS In the treatment of active axSpA, iguratimod has a potential NSAID-sparing effect, and may also reduce magnetic resonance imaging-assessed bone marrow oedema in sacroiliac joints. Iguratimod provides an additional treatment option for patients with active axSpA.Clinical trial registration numberChiCTR2000029112, Chinese Clinical Trial Registry (http://www.chictr.org.cn).
Collapse
Affiliation(s)
- X Chen
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, PR China
| | - W Wang
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, PR China
| | - J Xue
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, PR China
| |
Collapse
|
|
4
|
Yang YQ, Liu YJ, Qiao WX, Jin W, Zhu SW, Yan YX, Luo Q, Xu Q. Iguratimod suppresses plasma cell differentiation and ameliorates experimental Sjögren's syndrome in mice by promoting TEC kinase degradation. Acta Pharmacol Sin 2024; 45:1926-1936. [PMID: 38744938 PMCID: PMC11336088 DOI: 10.1038/s41401-024-01288-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 04/09/2024] [Indexed: 05/16/2024]
Abstract
Primary Sjögren's syndrome (pSS) is a chronic inflammatory autoimmune disease with an unclear pathogenesis, and there is currently no approved drug for the treatment of this disease. Iguratimod, as a novel clinical anti-rheumatic drug in China and Japan, has shown remarkable efficacy in improving the symptoms of patients with pSS in clinical studies. In this study we investigated the mechanisms underlying the therapeutic effect of iguratimod in the treatment of pSS. Experimental Sjögren's syndrome (ESS) model was established in female mice by immunizing with salivary gland protein. After immunization, ESS mice were orally treated with iguratimod (10, 30, 100 mg·kg-1·d-1) or hydroxychloroquine (50 mg·kg-1·d-1) for 70 days. We showed that iguratimod administration dose-dependently increased saliva secretion, and ameliorated ESS development by predominantly inhibiting B cells activation and plasma cell differentiation. Iguratimod (30 and 100 mg·kg-1·d-1) was more effective than hydroxychloroquine (50 mg·kg-1·d-1). When the potential target of iguratimod was searched, we found that iguratimod bound to TEC kinase and promoted its degradation through the autophagy-lysosome pathway in BAFF-activated B cells, thereby directly inhibiting TEC-regulated B cells function, suggesting that the action mode of iguratimod on TEC was different from that of conventional kinase inhibitors. In addition, we found a crucial role of TEC overexpression in plasma cells of patients with pSS. Together, we demonstrate that iguratimod effectively ameliorates ESS via its unique suppression of TEC function, which will be helpful for its clinical application. Targeting TEC kinase, a new regulatory factor for B cells, may be a promising therapeutic option.
Collapse
Affiliation(s)
- Ya-Qi Yang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Yi-Jun Liu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Wen-Xuan Qiao
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Wei Jin
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Shun-Wei Zhu
- Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, 210042, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, 210042, China
| | - Yu-Xi Yan
- Jiangsu Simcere Pharmaceutical Co., Ltd, Nanjing, 210042, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, 210042, China
| | - Qiong Luo
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
| | - Qiang Xu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| |
Collapse
|
|
5
|
Laha A, Nasra S, Bhatia D, Kumar A. Advancements in rheumatoid arthritis therapy: a journey from conventional therapy to precision medicine via nanoparticles targeting immune cells. NANOSCALE 2024; 16:14975-14993. [PMID: 39056352 DOI: 10.1039/d4nr02182g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Rheumatoid arthritis (RA) is a progressive autoimmune disease that mainly affects the inner lining of the synovial joints and leads to chronic inflammation. While RA is not known as lethal, recent research indicates that it may be a silent killer because of its strong association with an increased risk of chronic lung and heart diseases. Patients develop these systemic consequences due to the regular uptake of heavy drugs such as disease-modifying antirheumatic medications (DMARDs), glucocorticoids (GCs), nonsteroidal anti-inflammatory medicines (NSAIDs), etc. Nevertheless, a number of these medications have off-target effects, which might cause adverse toxicity, and have started to become resistant in patients as well. Therefore, alternative and promising therapeutic techniques must be explored and adopted, such as post-translational modification inhibitors (like protein arginine deiminase inhibitors), RNA interference by siRNA, epigenetic drugs, peptide therapy, etc., specifically in macrophages, neutrophils, Treg cells and dendritic cells (DCs). As the target cells are specific, ensuring targeted delivery is also equally important, which can be achieved with the advent of nanotechnology. Furthermore, these nanocarriers have fewer off-site side effects, enable drug combinations, and allow for lower drug dosages. Among the nanoparticles that can be used for targeting, there are both inorganic and organic nanomaterials such as solid-lipid nanoparticles, liposomes, hydrogels, dendrimers, and biomimetics that have been discussed. This review highlights contemporary therapy options targeting macrophages, neutrophils, Treg cells, and DCs and explores the application of diverse nanotechnological techniques to enhance precision RA therapies.
Collapse
Affiliation(s)
- Anwesha Laha
- Biological and Life Sciences, School of Arts & Sciences, Ahmedabad University, Central Campus, Navrangpura, Ahmedabad 380009, Gujarat, India.
| | - Simran Nasra
- Biological and Life Sciences, School of Arts & Sciences, Ahmedabad University, Central Campus, Navrangpura, Ahmedabad 380009, Gujarat, India.
| | - Dhiraj Bhatia
- Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar - 382055, Gujarat, India
| | - Ashutosh Kumar
- Biological and Life Sciences, School of Arts & Sciences, Ahmedabad University, Central Campus, Navrangpura, Ahmedabad 380009, Gujarat, India.
| |
Collapse
|
|
6
|
Lund SJ, Del Rosario PGB, Honda A, Caoili KJ, Hoeksema MA, Nizet V, Patras KA, Prince LS. Sialic Acid-Siglec-E Interactions Regulate the Response of Neonatal Macrophages to Group B Streptococcus. Immunohorizons 2024; 8:384-396. [PMID: 38809232 PMCID: PMC11150127 DOI: 10.4049/immunohorizons.2300076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 04/24/2024] [Indexed: 05/30/2024] Open
Abstract
The mammalian Siglec receptor sialoadhesin (Siglec1, CD169) confers innate immunity against the encapsulated pathogen group B Streptococcus (GBS). Newborn lung macrophages have lower expression levels of sialoadhesin at birth compared with the postnatal period, increasing their susceptibility to GBS infection. In this study, we investigate the mechanisms regulating sialoadhesin expression in the newborn mouse lung. In both neonatal and adult mice, GBS lung infection reduced Siglec1 expression, potentially delaying acquisition of immunity in neonates. Suppression of Siglec1 expression required interactions between sialic acid on the GBS capsule and the inhibitory host receptor Siglec-E. The Siglec1 gene contains multiple STAT binding motifs, which could regulate expression of sialoadhesin downstream of innate immune signals. Although GBS infection reduced STAT1 expression in the lungs of wild-type newborn mice, we observed increased numbers of STAT1+ cells in Siglece-/- lungs. To test if innate immune activation could increase sialoadhesin at birth, we first demonstrated that treatment of neonatal lung macrophages ex vivo with inflammatory activators increased sialoadhesin expression. However, overcoming the low sialoadhesin expression at birth using in vivo prenatal exposures or treatments with inflammatory stimuli were not successful. The suppression of sialoadhesin expression by GBS-Siglec-E engagement may therefore contribute to disease pathogenesis in newborns and represent a challenging but potentially appealing therapeutic opportunity to augment immunity at birth.
Collapse
MESH Headings
- Animals
- Mice
- Streptococcus agalactiae/immunology
- Animals, Newborn
- N-Acetylneuraminic Acid/metabolism
- Sialic Acid Binding Ig-like Lectin 1/metabolism
- Streptococcal Infections/immunology
- Streptococcal Infections/microbiology
- STAT1 Transcription Factor/metabolism
- STAT1 Transcription Factor/genetics
- Mice, Knockout
- Immunity, Innate
- Mice, Inbred C57BL
- Lung/immunology
- Lung/microbiology
- Lung/metabolism
- Macrophages, Alveolar/immunology
- Macrophages, Alveolar/metabolism
- Female
- Macrophages/immunology
- Macrophages/metabolism
- Lectins/metabolism
- Lectins/genetics
- Sialic Acid Binding Immunoglobulin-like Lectins/metabolism
- Sialic Acid Binding Immunoglobulin-like Lectins/genetics
- Antigens, CD/metabolism
- Antigens, CD/genetics
- Antigens, Differentiation, B-Lymphocyte
Collapse
Affiliation(s)
- Sean J. Lund
- Department of Pediatrics, University of California, San Diego, La Jolla, CA
| | - Pamela G. B. Del Rosario
- Department of Pediatrics, University of California, San Diego, La Jolla, CA
- Rady Children’s Hospital, San Diego, CA
| | - Asami Honda
- Department of Pediatrics, University of California, San Diego, La Jolla, CA
| | | | - Marten A. Hoeksema
- Department of Medical Biochemistry, Amsterdam University Medical Center, Amsterdam Zuidoost, the Netherlands
| | - Victor Nizet
- Department of Pediatrics, University of California, San Diego, La Jolla, CA
| | - Kathryn A. Patras
- Department of Molecular Virology and Microbiology, Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX
| | | |
Collapse
|
|
7
|
Yamasaki R. Connexins Control Glial Inflammation in Various Neurological Diseases. Int J Mol Sci 2023; 24:16879. [PMID: 38069203 PMCID: PMC10706219 DOI: 10.3390/ijms242316879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/25/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Connexins (Cxs) form gap junctions through homotypic/heterotypic oligomerization. Cxs are initially synthesized in the endoplasmic reticulum, then assembled as hexamers in the Golgi apparatus before being integrated into the cell membrane as hemichannels. These hemichannels remain closed until they combine to create gap junctions, directly connecting neighboring cells. Changes in the intracellular or extracellular environment are believed to trigger the opening of hemichannels, creating a passage between the inside and outside of the cell. The size of the channel pore depends on the Cx isoform and cellular context-specific effects such as posttranslational modifications. Hemichannels allow various bioactive molecules, under ~1 kDa, to move in and out of the host cell in the direction of the electrochemical gradient. In this review, we explore the fundamental roles of Cxs and their clinical implications in various neurological dysfunctions, including hereditary diseases, ischemic brain disorders, degenerative conditions, demyelinating disorders, and psychiatric illnesses. The influence of Cxs on the pathomechanisms of different neurological disorders varies depending on the circumstances. Hemichannels are hypothesized to contribute to proinflammatory effects by releasing ATP, adenosine, glutamate, and other bioactive molecules, leading to neuroglial inflammation. Modulating Cxs' hemichannels has emerged as a promising therapeutic approach.
Collapse
Affiliation(s)
- Ryo Yamasaki
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| |
Collapse
|
|
8
|
Wang Q, Yi J, Liu H, Luo M, Yin G, Huang Z. Iguratimod promotes functional recovery after SCI by repairing endothelial cell tight junctions. Exp Neurol 2023; 368:114503. [PMID: 37572946 DOI: 10.1016/j.expneurol.2023.114503] [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: 06/11/2023] [Revised: 07/31/2023] [Accepted: 08/09/2023] [Indexed: 08/14/2023]
Abstract
Destruction of the blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) is an important factor promoting the progression of the injury. This study addressed how to repair the BSCB in order to promote the repair of injured spinal cords. Iguratimod (IGU), an anti-rheumatic drug, has been approved for clinical use. A spinal cord injury mouse model and TNF-α-stimulated bEnd.3 cells were used to investigate the effect and mechanism of IGU on injured BSCB. An intracerebroventricular osmotic pump was used to administer drugs to the SCI mouse model. The results showed that the SCI mice in the treatment group had better recovery of neurological function than the control group. Examination of the tissue revealed better repair of the BSCB in injured spinal cords after medication. According to the results from the cell model, IGU promoted the expression of tight junction proteins and reduced cell permeability. Further research found that IGU repaired the barrier function by regulating glycolysis levels in the injured endothelial cells. In studying the mechanism, IGU was found to regulate HIF-1α expression through the NF-κB pathway, thereby regulating the expression of the glycolytic enzymes related to endothelial injury. In summary, IGU promoted functional recovery in vivo by repairing the BSCB. In vitro, IGU regulated the level of glycolysis in the damaged endothelium through the NF-κB pathway, thereby repairing the tight junctions between the endothelium. Therefore, IGU may become a potential drug for treating spinal cord injury.
Collapse
Affiliation(s)
- Qian Wang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jiang Yi
- Department of Orthopedics, Yancheng Third People's Hospital, Yancheng 224008, Jiangsu, China
| | - Hao Liu
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Mingran Luo
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Guoyong Yin
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
| | - Zhenfei Huang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
| |
Collapse
|
|
9
|
Long Z, Zeng L, He Q, Yang K, Xiang W, Ren X, Deng Y, Chen H. Research progress on the clinical application and mechanism of iguratimod in the treatment of autoimmune diseases and rheumatic diseases. Front Immunol 2023; 14:1150661. [PMID: 37809072 PMCID: PMC10552782 DOI: 10.3389/fimmu.2023.1150661] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 08/04/2023] [Indexed: 10/10/2023] Open
Abstract
Autoimmune diseases are affected by complex pathophysiology involving multiple cell types, cytokines, antibodies and mimicking factors. Different drugs are used to improve these autoimmune responses, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antibodies, and small molecule drugs (DMARDs), which are prevalent clinically in the treatment of rheumatoid arthritis (RA), etc. However, low cost-effectiveness, reduced efficacy, adverse effects, and patient non-response are unattractive factors driving the development of new drugs such as iguratimod. As a new disease-modifying antirheumatic drug, iguratimod has pharmacological activities such as regulating autoimmune disorders, inflammatory cytokines, regulating immune cell activation, differentiation and proliferation, improving bone metabolism, and inhibiting fibrosis. In recent years, clinical studies have found that iguratimod is effective in the treatment of RA, SLE, IGG4-RD, Sjogren 's syndrome, ankylosing spondylitis, interstitial lung disease, and other autoimmune diseases and rheumatic diseases. The amount of basic and clinical research on other autoimmune diseases is also increasing. Therefore, this review systematically reviews the latest relevant literature in recent years, reviews the research results in recent years, and summarizes the research progress of iguratimod in the treatment of related diseases. This review highlights the role of iguratimod in the protection of autoimmune and rheumatic bone and related immune diseases. It is believed that iguratimod's unique mode of action and its favorable patient response compared to other DMARDs make it a suitable antirheumatic and bone protective agent in the future.
Collapse
Affiliation(s)
- Zhiyong Long
- Department of Rehabilitation Medicine, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Liuting Zeng
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Graduate School of Peking Union Medical College, Nanjing, China
| | - Qi He
- People's Hospital of Ningxiang City, Ningxiang, China
| | - Kailin Yang
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Wang Xiang
- Department of Rheumatology, The First People's Hospital Changde City, Changde, Hunan, China
| | - Xiang Ren
- Department of Rheumatology, The First People's Hospital Changde City, Changde, Hunan, China
| | - Ying Deng
- People's Hospital of Ningxiang City, Ningxiang, China
| | - Hua Chen
- Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| |
Collapse
|
|
10
|
Nagata S, Yamasaki R, Takase EO, Iida K, Watanabe M, Masaki K, Wijering MHC, Yamaguchi H, Kira JI, Isobe N. Iguratimod Ameliorates the Severity of Secondary Progressive Multiple Sclerosis in Model Mice by Directly Inhibiting IL-6 Production and Th17 Cell Migration via Mitigation of Glial Inflammation. BIOLOGY 2023; 12:1217. [PMID: 37759616 PMCID: PMC10525689 DOI: 10.3390/biology12091217] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/30/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023]
Abstract
We previously reported a novel secondary progressive multiple sclerosis (SPMS) model, progressive experimental autoimmune encephalomyelitis (pEAE), in oligodendroglia-specific Cx47-inducible conditional knockout (Cx47 icKO) mice. Based on our prior study showing the efficacy of iguratimod (IGU), an antirheumatic drug, for acute EAE treatment, we aimed to elucidate the effect of IGU on the SPMS animal model. We induced pEAE by immunizing Cx47 icKO mice with myelin oligodendrocyte glycoprotein peptide 35-55. IGU was orally administered from 17 to 50 days post-immunization. We also prepared a primary mixed glial cell culture and measured cytokine levels in the culture supernatant after stimulation with designated cytokines (IL-1α, C1q, TNF-α) and lipopolysaccharide. A migration assay was performed to evaluate the effect of IGU on the migration ability of T cells toward mixed glial cell cultures. IGU treatment ameliorated the clinical signs of pEAE, decreased the demyelinated area, and attenuated glial inflammation on immunohistochemical analysis. Additionally, IGU decreased the intrathecal IL-6 level and infiltrating Th17 cells. The migration assay revealed reduced Th17 cell migration and IL-6 levels in the culture supernatant after IGU treatment. Collectively, IGU successfully mitigated the clinical signs of pEAE by suppressing Th17 migration through inhibition of IL-6 production by proinflammatory-activated glial cells.
Collapse
Affiliation(s)
- Satoshi Nagata
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Ryo Yamasaki
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Ezgi Ozdemir Takase
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kotaro Iida
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Mitsuru Watanabe
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Katsuhisa Masaki
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Marion Heleen Cathérine Wijering
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- Section Molecular Neurobiology, Department of Biomedical Sciences of Cells & Systems, University of Groningen, University Medical Center Groningen (UMCG), MS Center Noord Nederland, 9713 AV Groningen, The Netherlands
| | - Hiroo Yamaguchi
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- School of Physical Therapy, Faculty of Rehabilitation, Reiwa Health Sciences University, Fukuoka 811-0213, Japan
| | - Jun-ichi Kira
- Translational Neuroscience Center, Graduate School of Medicine, and School of Pharmacy at Fukuoka, International University of Health and Welfare, Fukuoka 831-8501, Japan
- Department of Neurology, Brain and Nerve Center, Fukuoka Central Hospital, Fukuoka 810-0022, Japan
| | - Noriko Isobe
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| |
Collapse
|
|
11
|
Yan Q, Zhang M, Du F, Kang Y, Ye P, Li Q, Liu B, Dai M, Bao C. Efficacy and safety of Iguratimod as an add-on therapy for refractory lupus nephritis: A preliminary investigational study. Front Immunol 2023; 14:1062919. [PMID: 36969217 PMCID: PMC10030952 DOI: 10.3389/fimmu.2023.1062919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 02/27/2023] [Indexed: 03/11/2023] Open
Abstract
ObjectivesIGU (IGU), a novel immunomodulatory agent for rheumatoid arthritis, has been shown to be effective and safe as monotherapy in a small population with refractory lupus nephritis (LN). The aim of this prospective study was to evaluate the efficacy and safety of IGU as an add-on therapy in patients with refractory LN in the context of clinical practice.MethodsThis is a single-arm observational study. We have enrolled LN patients since 2019 at Renji Hospital. All participants should have recurrent or refractory LN with at least one immunosuppressant (IS) and have a baseline urine protein/creatinine ratio (UPCR) >1.0. After enrollment, we added IGU (25 mg twice daily) to one of their previous immunosuppressants (IS) without increasing the dose of steroids. The primary outcome was the complete renal response (CRR) in the 6th month. UPCR decrease of over 50% was defined as partial response (PR). Extended follow-up was performed after the initial 6 months.ResultsWe enrolled 26 eligible participants. 11/26 patients had chronic kidney disease (CKD) stage 2/3 at the baseline. The IS combined with IGU included mycophenolate mofetil, tacrolimus, and cyclosporin A. No IS change was allowed. 80.7% of patients had baseline steroids less than 0.5mg/kg daily and there was no steroids escalation during the IGU treatment. The CRR rate was 42.3% (11/26) at month 6. With a median follow-up of 52 weeks (range: 23-116 weeks), the CRR rate at the last visit was 50% (13/26) and 73.1% (19/26) of patients had UPCR decrease of over 50%. Six patients withdrew, three for no response and three for renal flare after initial CRR. One patient had an estimated glomerular filtration rate worsening of over 20% and was classified as renal flare. Three mild to moderate adverse events were recorded.ConclusionsOur investigation merits further investigation in IGU as a potentially tolerable component of combination therapy for refractory LN.
Collapse
Affiliation(s)
- Qingran Yan
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Chunde Bao, ; Min Dai, ; Qingran Yan,
| | - Mei Zhang
- Department of Nephrology and Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Nephrology and Rheumatology, Anhui Public Health Clinical Center, Hefei, China
| | - Fang Du
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuening Kang
- The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, China
| | - Ping Ye
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qianqian Li
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bei Liu
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Dai
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Chunde Bao, ; Min Dai, ; Qingran Yan,
| | - Chunde Bao
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Chunde Bao, ; Min Dai, ; Qingran Yan,
| |
Collapse
|
|
12
|
Liu L, Du X, Yang Q, Li M, Ran Q, Liu Q, Yang L, Sun L, Guo Y, Li Y, Chen Y, Zhu X, Li Q. Ginsenoside Rg1 promotes remyelination and functional recovery in demyelinating disease by enhancing oligodendrocyte precursor cells-mediated myelin repair. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 106:154309. [PMID: 35994846 DOI: 10.1016/j.phymed.2022.154309] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 06/16/2022] [Accepted: 06/29/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Inefficient differentiation of oligodendrocyte precursor cells (OPCs) is one of the significant pathological obstacles of myelin repair and provides an essential therapeutic target against behavioral dysfunction in various neurodegenerative diseases, especially in secondary progressive multiple sclerosis (SPMS). Ginsenoside Rg1 (Rg1) has traditionally been recognized as a protector of neuronal damages, preventing its degeneration. PURPOSE We investigated the effects of Rg1 on myelin regeneration-mediated by OPCs and its therapeutic significance in SPMS. METHODS A cuprizone (CPZ) model was established and then administered with Rg1 specific for evaluations of functional recovery and remyelination. In vitro, the primary mouse OPCs were isolated and cultured for examining their ability of myelin repair. Furthermore, a chronic experimental autoimmune encephalomyelitis (EAE) model was utilized to assess the therapeutic value on SPMS. RESULTS We found that Rg1 promoted functional recovery of the demyelinated mice, including spatial memory, motor function, and anxiety-like behavior. Histologically, Rg1 enhanced myelin-genesis as proven by myelin staining and microstructures of myelin observed by transmission electron microscope. Furthermore, Rg1 significantly increased Olig2+ oligodendrocyte lineage cells in callosum, implying that the pro-remyelination effect of Rg1 was closely correlated to the enhanced differentiation of OPCs. We further demonstrated that Rg1 increased the survival and proliferation of OPCs as well as induced maturation in oligodendrocytes (OLs). Molecular analysis showed that Rg1 transduced the pro-differentiation signaling programmed by the GSK3β/β-Catenin pathway. Notably, relying on its pro-remyelination effects, Rg1 ameliorated severity and histopathology of EAE disease. CONCLUSION By paving the way for OPCs differentiation, Rg1 could maintain the integrity of myelin and is a promising candidate for functional recovery in demyelinating diseases.
Collapse
Affiliation(s)
- Li Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China; Postdoctoral Research Station, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Xinke Du
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Qing Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Manjing Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Qingsen Ran
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China; Postdoctoral Research Station, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Qingwu Liu
- Department of Dermatology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Lina Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Lisong Sun
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yuxuan Guo
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yujie Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Ying Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Xiaoxin Zhu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Qi Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| |
Collapse
|
|
13
|
Malange KF, Navia-Pelaez JM, Dias EV, Lemes JBP, Choi SH, Dos Santos GG, Yaksh TL, Corr M. Macrophages and glial cells: Innate immune drivers of inflammatory arthritic pain perception from peripheral joints to the central nervous system. FRONTIERS IN PAIN RESEARCH 2022; 3:1018800. [PMID: 36387416 PMCID: PMC9644179 DOI: 10.3389/fpain.2022.1018800] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 10/03/2022] [Indexed: 07/22/2023] Open
Abstract
Millions of people suffer from arthritis worldwide, consistently struggling with daily activities due to debilitating pain evoked by this disease. Perhaps the most intensively investigated type of inflammatory arthritis is rheumatoid arthritis (RA), where, despite considerable advances in research and clinical management, gaps regarding the neuroimmune interactions that guide inflammation and chronic pain in this disease remain to be clarified. The pain and inflammation associated with arthritis are not isolated to the joints, and inflammatory mechanisms induced by different immune and glial cells in other tissues may affect the development of chronic pain that results from the disease. This review aims to provide an overview of the state-of-the-art research on the roles that innate immune, and glial cells play in the onset and maintenance of arthritis-associated pain, reviewing nociceptive pathways from the joint through the dorsal root ganglion, spinal circuits, and different structures in the brain. We will focus on the cellular mechanisms related to neuroinflammation and pain, and treatments targeting these mechanisms from the periphery and the CNS. A comprehensive understanding of the role these cells play in peripheral inflammation and initiation of pain and the central pathways in the spinal cord and brain will facilitate identifying new targets and pathways to aide in developing therapeutic strategies to treat joint pain associated with RA.
Collapse
Affiliation(s)
- Kaue Franco Malange
- Department of Anesthesiology, University of California, San Diego, CA, United States
| | | | - Elayne Vieira Dias
- Department of Neurology, University of California, San Francisco, CA, United States
| | | | - Soo-Ho Choi
- Department of Medicine, University of California, San Diego, CA, United States
| | | | - Tony L. Yaksh
- Department of Anesthesiology, University of California, San Diego, CA, United States
| | - Maripat Corr
- Department of Medicine, University of California, San Diego, CA, United States
| |
Collapse
|
|
14
|
Al Mamun A, Suchi SA, Aziz MA, Zaeem M, Munir F, Wu Y, Xiao J. Pyroptosis in acute pancreatitis and its therapeutic regulation. Apoptosis 2022; 27:465-481. [PMID: 35687256 DOI: 10.1007/s10495-022-01729-w] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/18/2022] [Indexed: 12/20/2022]
Abstract
Pyroptosis defines a new type of GSDMs-mediated programmed cell death, distinguishes from the classical concepts of apoptosis and necrosis-mediated cell death and is prescribed by cell swelling and membrane denaturation, leading to the extensive secretion of cellular components and low-grade inflammatory response. However, NLRP3 inflammasome activation can trigger its downstream inflammatory cytokines, leading to the activation of pyroptosis-regulated cell death. Current studies reveal that activation of caspase-4/5/11-driven non-canonical inflammasome signaling pathways facilitates the pathogenesis and progression of acute pancreatitis (AP). In addition, a large number of studies have reported that NLRP3 inflammasome-dependent pyroptosis is a crucial player in driving the course of the pathogenesis of AP. Excessive uncontrolled GSDMD-mediated pyroptosis has been implicated in AP. Therefore, the pyroptosis-related molecule GSDMD may be an independent prognostic biomarker for AP. The present review paper summarizes the molecular mechanisms of pyroptotic signaling pathways and their pathophysiological impacts on the progress of AP. Moreover, we briefly present some experimental compounds targeting pyroptosis-regulated cell death for exploring novel therapeutic directions for the treatment and management of AP. Our review investigations strongly suggest that targeting pyroptosis could be an ideal therapeutic approach in AP.
Collapse
Affiliation(s)
- Abdullah Al Mamun
- Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Zhejiang Province, Wenzhou, 325035, China
| | - Suzia Aktar Suchi
- Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, 501759, South Korea
| | - Md Abdul Aziz
- Department of Pharmacy, Faculty of Pharmacy and Health Sciences, State University of Bangladesh, Dhaka, 1205, Bangladesh.,Laboratory of Pharmacogenomics and Molecular Biology, Department of Pharmacy, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh
| | - Muhammad Zaeem
- Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Zhejiang Province, Wenzhou, 325035, China
| | - Fahad Munir
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Province, Wenzhou, 325000, China
| | - Yanqing Wu
- Institute of Life Sciences, Wenzhou University, Zhejiang Province, Wenzhou, 325035, China
| | - Jian Xiao
- Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Zhejiang Province, Wenzhou, 325035, China. .,Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Province, Wenzhou, 325035, China.
| |
Collapse
|
|
15
|
Xue L, Xu J, Lu W, Fu J, Liu Z. Iguratimod alleviates tubulo-interstitial injury in mice with lupus. Ren Fail 2022; 44:636-647. [PMID: 35387545 PMCID: PMC9004506 DOI: 10.1080/0886022x.2022.2058962] [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] [Indexed: 10/28/2022] Open
Abstract
INTRODUCTION Tubulo-interstitial injury is a poor prognostic factor for lupus nephritis (LN). Here, we tested whether iguratimod could inhibit tubulo-interstitial injury in LN. METHODS MRL/lpr mice, an animal model of lupus, were treated with iguratimod or vehicle solution. Pathological changes of kidney were evaluated blindly by the same pathologist. Renal type I collagen (COL-I), IgG, E-cadherin, fibroblast-specific protein 1 (FSP-1) were detected by immunofluorescence, immunohistochemical staining or quantitative real-time PCR. After treated with transforming growth factor β1 (TGF-β1) and iguratimod, E-cadherin, fibronectin, Smad2/3, p38 MAPK, p-Smad2/3, and p-p38 MAPK, β-catenin and TGF-β type II receptor (TGFβRII) in HK2 cells were measured by western blotting, quantitative real-time PCR or immunofluorescence. RESULTS Iguratimod reduced immune deposition along the tubular basement membrane, inhibited the tubulo-interstitial infiltration of inflammatory cells, and alleviated tubular injury in MRL/lpr mice. Moreover, Iguratimod eased the tubulo-interstitial deposition of collagen fibers, which was confirmed by decreased expression of COL-I. Furthermore, iguratimod suppressed the expression of FSP-1 and increased that of E-cadherin in renal tubular epithelial cells. In HK2 cells cultured with TGF-β1, iguratimod treatment not only reversed cellular morphological changes, but also prevented E-cadherin downregulation and fibronectin upregulation. In addition, iguratimod inhibited phosphorylation of TGFβRII, Smad2/3 and p38 MAPK in HK2 cells treated with TGF-β1, and also blocked nuclear translocation of β-catenin. CONCLUSION Iguratimod eased tubulo-interstitial lesions in LN, especially tubulo-interstitial fibrosis, and might have potential as a drug for inhibiting the progression of tubulo-interstitial fibrosis in LN.
Collapse
Affiliation(s)
- Leixi Xue
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiajun Xu
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Wentian Lu
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jinxiang Fu
- Department of Hematology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhichun Liu
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| |
Collapse
|
|
16
|
Zhang M, Lei YS, Meng XW, Liu HY, Li LG, Zhang J, Zhang JX, Tao WH, Peng K, Lin J, Ji FH. Iguratimod Alleviates Myocardial Ischemia/Reperfusion Injury Through Inhibiting Inflammatory Response Induced by Cardiac Fibroblast Pyroptosis via COX2/NLRP3 Signaling Pathway. Front Cell Dev Biol 2021; 9:746317. [PMID: 34760889 PMCID: PMC8573346 DOI: 10.3389/fcell.2021.746317] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/27/2021] [Indexed: 12/31/2022] Open
Abstract
Background: NLRP3 inflammasome contributes a lot to sterile inflammatory response and pyroptosis in ischemia/reperfusion (I/R) injury. Cardiac fibroblasts (CFs) are regarded as semi-professional inflammatory cells and they exert an immunomodulatory role in heart. Iguratimod provides a protective role in several human diseases through exerting a powerful anti-inflammatory effect. However, it is still unclear whether iguratimod could alleviate myocardial I/R injury and whether inflammation triggered by NLRP3-related pyroptosis of CFs is involved in this process. Methods: Transcriptomics analysis for GSE160516 dataset was conducted to explore the biological function of differentially expressed genes during myocardial I/R. In vivo, mice underwent ligation of left anterior descending coronary artery for 30 min followed by 24 h reperfusion. In vitro, primary CFs were subjected to hypoxia for 1 h followed by reoxygenation for 3 h (H/R). Iguratimod was used prior to I/R or H/R. Myocardial infarct area, serum level of cardiac troponin I (cTnI), pathology of myocardial tissue, cell viability, lactate dehydrogenase (LDH) release, and the expression levels of mRNA and protein for pyroptosis-related molecules were measured. Immunofluorescence was applied to determine the cellular localization of NLRP3 protein in cardiac tissue. Results: During myocardial I/R, inflammatory response was found to be the most significantly enriched biological process, and nucleotide-binding oligomerization domain (NOD)-like receptor signaling was a crucial pathway in mediating cardiac inflammation. In our experiments, pretreatment with iguratimod significantly ameliorated I/R-induced myocardial injury and H/R-induced pyroptosis of CFs, as evidenced by reduced myocardial infarct area, serum cTnI level, and LDH release in supernatants, as well as improved pathology of cardiac tissue and cell viability. Immunofluorescence analysis showed that NLRP3 was mainly localized in CFs. Moreover, iguratimod inhibited the expression of pro-inflammatory cytokines and pyroptosis-related molecules, including NLRP3, cleaved caspase-1, and GSDMD-N. Conclusion: Our results suggested that inflammatory response mediated by NOD-like receptor signaling is of vital importance in myocardial I/R injury. Iguratimod protected cardiomyocytes through reducing the cascade of inflammation in heart by inhibiting cardiac fibroblast pyroptosis via the COX2/NLRP3 signaling pathway.
Collapse
Affiliation(s)
- Mian Zhang
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Anesthesiology, Soochow University, Suzhou, China
| | - Yi-Shan Lei
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Anesthesiology, Soochow University, Suzhou, China
| | - Xiao-Wen Meng
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Anesthesiology, Soochow University, Suzhou, China
| | - Hua-Yue Liu
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Anesthesiology, Soochow University, Suzhou, China
| | - Lin-Gui Li
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Anesthesiology, Soochow University, Suzhou, China
| | - Jun Zhang
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Anesthesiology, Soochow University, Suzhou, China
| | - Jia-Xin Zhang
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Anesthesiology, Soochow University, Suzhou, China
| | - Wen-Hui Tao
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Anesthesiology, Soochow University, Suzhou, China
| | - Ke Peng
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Anesthesiology, Soochow University, Suzhou, China
| | - Jun Lin
- Department of Orthopedics, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Fu-Hai Ji
- Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, China.,Institute of Anesthesiology, Soochow University, Suzhou, China
| |
Collapse
|
|
17
|
Litovchenko AV, Zabrodskaya YM, Sitovskaya DA, Khuzhakhmetova LK, Nezdorovina VG, Bazhanova ED. Markers of Neuroinflammation and Apoptosis in the Temporal Lobe of Patients with Drug-Resistant Epilepsy. J EVOL BIOCHEM PHYS+ 2021. [DOI: 10.1134/s0022093021050069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Abstract
Current antiepileptic strategies aim to normalize the interaction
of the excitatory and inhibitory systems, which is ineffective in
treating patients with drug-resistant epilepsy. Neuroinflammatory processes
in the epileptic focus and its perifocal area can trigger apoptosis
and also contribute to the development of drug resistance. The level
of pro- and anti-apoptotic proteins (p-NF-kB, TNF-α, p53, FAS, caspase-3,
caspase-9) was analyzed in intraoperative biopsies of the temporal
lobe gray and white matter in the brain of patients with drug-resistant
epilepsy. An increased level of pro-apoptotic proteins was revealed
in the cortex and perifocal area’s white matter against the background
of an imbalance of protective anti-apoptotic proteins. It appears
that the activation of the extrinsic pathway of apoptosis occurs
in the perifocal area, while in the epileptic focus, there are proteins
responsible for the activation of the anti-apoptotic survival pathways.
Active neuroinflammation in the epileptic focus and perifocal area
of the temporal lobe may contribute to the development of the resistance
to antiepileptic drugs and the progression of neurodegeneration in
such patients.
Collapse
|
|
18
|
Xiao Y, Wang X, Wang S, Li J, Xu X, Wang M, Li G, Shen W. Celastrol Attenuates Learning and Memory Deficits in an Alzheimer's Disease Rat Model. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5574207. [PMID: 34350293 PMCID: PMC8328733 DOI: 10.1155/2021/5574207] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/19/2021] [Accepted: 07/08/2021] [Indexed: 01/31/2023]
Abstract
Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder that is associated with learning, memory, and cognitive deficits. Neuroinflammation and synapse loss are involved in the pathology of AD. Diverse measures have been applied to treat AD, but currently, there is no effective treatment. Celastrol (CEL) is a pentacyclic triterpene isolated from Tripterygium wilfordii Hook F that has been shown to enhance cell viability and inhibit amyloid-β production induced by lipopolysaccharides in vitro. In the present study, the protective effect of CEL on Aβ 25-35-induced rat model of AD was assessed. Our results showed that CEL administration at a dose of 2 mg/kg/day improved spatial memory in the Morris water maze. Further biochemical analysis showed that CEL treatment of intrahippocampal Aβ 25-35-microinjected rats attenuated hippocampal NF-κB activity; inhibited proinflammatory markers, namely, IL-1β, IL-6, and TNF-α; and upregulated anti-inflammatory factors, such as IL-4 and IL-10. Furthermore, CEL upregulated hippocampal neurexin-1β, neuroligin-1, CA1, and PSD95 expression levels, which may improve synaptic function. Simultaneously, CEL also increased glucose metabolism in Aβ 25-35-microinjected rats. In conclusion, CEL could exert protective effects against learning and memory decline induced by intrahippocampal Aβ 25-35 through anti-inflammation, promote synaptic development, and maintain hippocampal energy metabolism.
Collapse
Affiliation(s)
- Yao Xiao
- Department of Neurology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xifeng Wang
- Department of Neurology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Siyi Wang
- Department of Neurology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Li
- Department of Neurology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xueyu Xu
- Department of Neurology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Wang
- Department of Neurology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gang Li
- Department of Neurology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Shen
- Department of Neurology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
19
|
Shao S, Qu Z, Liang Y, Xu Y, Zhou D, Li D, Zhang Y, Yin S. Iguratimod decreases bleomycin-induced pulmonary fibrosis in association with inhibition of TNF-α in mice. Int Immunopharmacol 2021; 99:107936. [PMID: 34284287 DOI: 10.1016/j.intimp.2021.107936] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/16/2021] [Accepted: 06/28/2021] [Indexed: 10/20/2022]
Abstract
Severe interstitial lung disease secondary to connective tissue diseases, characterized by pulmonary inflammation and fibrosis, often have very poor prognosis due to lack of effective treatments. Iguratimod (IGU) shows encouraging efficacy in treating connective tissue diseases, however, the underlying mechanism is still to be elucidated. In this study, we investigated the impact of IGU on bleomycin-induced interstitial lung disease and the related tumor necrosis factor-α (TNF-α) signaling pathway in mice and in the alveolar epithelial cell A549. We found IGU decreased pulmonary inflammation and fibrosis and expression of fibrosis-related genes such as Collagen I, α-smooth muscle actin (α-SMA) and matrix metalloproteinase-2 (MMP-2) induced by bleomycin. IGU inhibited epithelial-mesenchymal transition as evidenced by decreased E-cadherin expression but increased vimentin expression. IGU reduced TNF-α production in the pulmonary fibrosis murine model and in the in vitro cultured A549 cells. Furthermore, IGU ameliorated TNF-α-induced severe pulmonary fibrosis and inhibited TNF-α-induced activation of NF-κB. In addition, IGU decreased IL-6 production and phosphorylation of STAT3. In conclusion, the IGU-mediated anti-fibrogenesis effect was associated with the inhibition of TNF-α and NF-κB.
Collapse
Affiliation(s)
- Siqi Shao
- Department of Rheumatology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China; The First Clinical Medicine School, Xuzhou Medical University, Xuzhou 221002, China
| | - Ziye Qu
- Department of Rheumatology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China; The First Clinical Medicine School, Xuzhou Medical University, Xuzhou 221002, China
| | - Yiwen Liang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221002, China
| | - Yan Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou 221002, China
| | - Dongmei Zhou
- Department of Rheumatology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China; The First Clinical Medicine School, Xuzhou Medical University, Xuzhou 221002, China
| | - Danhua Li
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou 221004, China
| | - Ying Zhang
- Department of Pathology, Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou 221004, China.
| | - Songlou Yin
- Department of Rheumatology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China; The First Clinical Medicine School, Xuzhou Medical University, Xuzhou 221002, China.
| |
Collapse
|
|
20
|
Chen LJ, Zhou YJ, Wen ZH, Tian F, Li JY. Efficacy and safety of iguratimod combined with methotrexate vs. methotrexate alone in rheumatoid arthritis : A systematic review and meta-analysis of randomized controlled trials. Z Rheumatol 2021; 80:432-446. [PMID: 33346891 PMCID: PMC8189982 DOI: 10.1007/s00393-020-00944-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/27/2020] [Indexed: 01/21/2023]
Abstract
The current systematic review and meta-analysis aims to evaluate the efficacy and safety of iguratimod (IGU) combined with methotrexate (MTX) versus MTX alone in rheumatoid arthritis (RA). Two independent investigators searched for original randomized controlled trials (RCTs) related to the combination of IGU and MTX in RA published before November 1, 2019, in PubMed, Cochrane Library, Embase, the China National Knowledge Infrastructure (CNKI), the Chinese Biomedical Literature Database (CBM), and WanFang Data. Additionally, we searched clinical trial registry websites. We assessed the methodological quality of the included trials using the Cochrane Collaboration tool and the seven-point Jadad scale. Statistical analyses were performed using Review Manager (RevMan) 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Meta-regression and publication bias analyses were performed using Stata version 14 software (StataCorp., College Station, TX, USA). A total of 7 RCTs consisting of 665 participants, with 368 participants in the active arm and 297 in the placebo arm, were included in the meta-analysis. The American College of Rheumatology (ACR) value was better in the IGU + MTX group than in the MTX alone group, with a pooled relative risk (RR) for ACR20 (American College of Rheumatology 20% improvement criteria), ACR50, and ACR70 of 1.40 (95% CI, 1.13-1.74), 2.09 (95% CI, 1.67-2.61), and 2.24 (95% CI, 1.53-3.28), respectively. The results of the meta-analysis demonstrated that there was no statistical significance in adverse events (1.06 (95% CI, 0.92-1.23)). The combined treatment is an effective, safe, and economical treatment option for patients who do not respond well to methotrexate alone or for patients who cannot afford expensive biologics that have no confirmed efficacy.
Collapse
Affiliation(s)
- L-J Chen
- Department of Rheumatology and Immunology, The Affiliated ZhuZhou Hospital of XiangYa Medical College, Central South University, 116 South Changjiang Road, 412007, ZhuZhou, Hunan Province, China
| | - Y-J Zhou
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
| | - Z-H Wen
- Department of Rheumatology and Immunology, The Affiliated ZhuZhou Hospital of XiangYa Medical College, Central South University, 116 South Changjiang Road, 412007, ZhuZhou, Hunan Province, China
| | - F Tian
- Department of Rheumatology and Immunology, The Affiliated ZhuZhou Hospital of XiangYa Medical College, Central South University, 116 South Changjiang Road, 412007, ZhuZhou, Hunan Province, China
| | - J-Y Li
- Department of Rheumatology and Immunology, The Affiliated ZhuZhou Hospital of XiangYa Medical College, Central South University, 116 South Changjiang Road, 412007, ZhuZhou, Hunan Province, China.
| |
Collapse
|
|
21
|
Liu S, Song LP, Li RB, Feng LH, Zhu H. Iguratimod promotes transformation of mononuclear macrophages in elderly patients with rheumatoid arthritis by nuclear factor-κB pathway. World J Clin Cases 2021; 9:2181-2191. [PMID: 33869594 PMCID: PMC8026846 DOI: 10.12998/wjcc.v9.i10.2181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/13/2021] [Accepted: 02/11/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The role of macrophages in rheumatoid arthritis (RA) and its mechanism have attracted much attention in RA pathogenesis. Macrophages accumulate in the synoviums of RA, and the proportion of M1 type pro-inflammatory macrophages is higher than that of M2 type anti-inflammatory macrophages, leading to the secretion of inflammatory molecules and the aggravation of inflammatory reaction, which has made macrophages a potential target of RA drugs. Iguratimod is a kind of cyclo-oxygenase-2 inhibitor that affects macrophage polarity. It is speculated that its anti-inflammatory and anti-rheumatic effects may be related to the regulation of macrophage M1/M2 ratio.
AIM To investigate the effects of Iguratimod on the polarity of mononuclear macrophages in elderly patients with RA.
METHODS Elderly patients with RA and joint effusion were selected, including 10 men and 25 women, with an average age of 66.37 ± 4.42 years. Patients were treated with oral administration of 25 mg Iguratimod (Iremod, State Food and Drug Administration Approval No. H20110084) twice daily for 12 wk. Disease Activity Score 28 and Health Assessment Questionnaire score were collected according to the disease severity before and after treatment. Venous blood and joint effusion fluid were collected, mononuclear macrophages were extracted and expression of cell surface markers CD86, CD64, CD163, and CD206 was analyzed by flow cytometry. The concentration of inflammatory factors interleukin (IL)-6, IL-1β, transforming growth factor-β, and IL-4 in the joint effusion fluid was analyzed by enzyme-linked immunosorbent assay. Expression of mononuclear cells inhibitor of nuclear factor-κB (IκB) and phosphorylated IκB in peripheral blood was analyzed by western blotting.
RESULTS Disease Activity Score 28 score and Health Assessment Questionnaire score of patients treated with Iguratimod decreased significantly. The percentage of cell surface markers CD86 and CD64 decreased significantly, and the percentage of CD163 and CD206 increased significantly (P < 0.05). The inflammatory factors IL-6 and IL-1β decreased significantly, and transforming growth factor-β and IL-4 increased significantly. Western blot analysis showed that mononuclear cell inhibitor of nuclear factor-κB in peripheral blood was significantly increased after treatment, and its phosphorylation level was significantly decreased (P < 0.05).
CONCLUSION Iguratimod can promote the transformation of mononuclear macrophages from M1 to M2 in elderly patients with RA by inhibiting the nuclear factor-κB pathway, thus improving symptoms of RA.
Collapse
Affiliation(s)
- Sha Liu
- Department of Rheumatism, The First Hospital of Qiqihar, Affiliated Qiqihar Hospital of Southern Medical University, Qiqihar 161005, Heilongjiang Province, China
| | - Li-Ping Song
- Department of Rheumatism, The First Hospital of Qiqihar, Affiliated Qiqihar Hospital of Southern Medical University, Qiqihar 161005, Heilongjiang Province, China
| | - Rong-Bin Li
- Department of Rheumatism, The First Hospital of Qiqihar, Affiliated Qiqihar Hospital of Southern Medical University, Qiqihar 161005, Heilongjiang Province, China
| | - Le-Heng Feng
- Department of Rheumatism, The First Hospital of Qiqihar, Affiliated Qiqihar Hospital of Southern Medical University, Qiqihar 161005, Heilongjiang Province, China
| | - Hui Zhu
- Department of Rheumatism, The First Hospital of Qiqihar, Affiliated Qiqihar Hospital of Southern Medical University, Qiqihar 161005, Heilongjiang Province, China
| |
Collapse
|
|
22
|
Liu S, Cui Y, Zhang X. Molecular mechanisms and clinical studies of iguratimod for the treatment of ankylosing spondylitis. Clin Rheumatol 2021; 40:25-32. [PMID: 32506313 DOI: 10.1007/s10067-020-05207-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/19/2020] [Accepted: 05/28/2020] [Indexed: 02/05/2023]
Abstract
Iguratimod (IGU) is a novel small molecule anti-rheumatic drug with the effect of non-steroidal anti-inflammatory drug and disease-modifying anti-rheumatic drug. IGU has various mechanisms of action, including inhibition of prostaglandin E2, tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17) production, inhibition of macrophage migration inhibitory factor (MIF)-induced proinflammatory effects, inhibition of osteoclastogenesis, and promotion of osteoblastic differentiation. Ankylosing spondylitis (AS) is the major subtype of spondyloarthritis that affects the axial skeleton, causing inflammatory back pain, which can lead to impairments in structure and function and a decrease in quality of life. Theories on pathogenesis of AS include misfolding of human leukocyte antigen-B27 during its assembly leading to endoplasmic reticulum stress and unfolded protein response (UPR). Activation of UPR genes results in release of TNF-α and IL-17, which have been shown to be important in the development of AS. In addition, current evidence suggests the importance of cyclooxygenase-2/prostaglandin E2 pathway and MIF in the pathogenesis of AS. Current drugs for the treatment of AS are limited and exploration of effective drugs is needed. IGU may be effective for the treatment of AS given that its mechanisms of action are closely related to the pathogenesis of AS. In fact, several small-scale clinical trials have shown the efficacy of IGU for the treatment of AS. This article reviews the molecular mechanisms of IGU that are related to the pathogenesis of AS and clinical trials of IGU for the treatment of AS, providing a reference for future clinical application of IGU for AS.
Collapse
Affiliation(s)
- Suling Liu
- Shantou University Medical College, Shantou, Guangdong Province, China
- Department of Rheumatology and Immunology, Guangdong Provincial People's General Hospital, Guangdong Academy of Medical Sciences, No.106 2nd Zhongshan Road, Yuexiu district, Guangzhou, 510080, China
| | - Yang Cui
- Department of Rheumatology and Immunology, Guangdong Provincial People's General Hospital, Guangdong Academy of Medical Sciences, No.106 2nd Zhongshan Road, Yuexiu district, Guangzhou, 510080, China.
| | - Xiao Zhang
- Department of Rheumatology and Immunology, Guangdong Provincial People's General Hospital, Guangdong Academy of Medical Sciences, No.106 2nd Zhongshan Road, Yuexiu district, Guangzhou, 510080, China
| |
Collapse
|
|
23
|
Jiang S, Baba K, Okuno T, Kinoshita M, Choong CJ, Hayakawa H, Sakiyama H, Ikenaka K, Nagano S, Sasaki T, Shimamura M, Nagai Y, Hagihara K, Mochizuki H. Go-sha-jinki-Gan Alleviates Inflammation in Neurological Disorders via p38-TNF Signaling in the Central Nervous System. Neurotherapeutics 2021; 18:460-473. [PMID: 33083995 PMCID: PMC8116410 DOI: 10.1007/s13311-020-00948-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2020] [Indexed: 01/14/2023] Open
Abstract
Go-sha-jinki-Gan (GJG) is a traditional Japanese herbal medicine. In clinical practice, GJG is effective against neuropathic pain and hypersensitivity induced by chemotherapy or diabetes. In our previous study using a chronic constriction injury mouse model, we showed that GJG inhibited microglia activation by suppressing the expression of tumor necrosis factor-α (TNF-α) and p38 mitogen-activated protein kinase (p38 MAPK) in the peripheral nervous system. To investigate whether GJG can suppress inflammation in the central nervous system (CNS) in the context of neurological disorders, we examined the effect of GJG on the activation of resident glial cells and on p38-TNF signaling in two mouse models of neurological disorders: the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. GJG administration relieved the severity of clinical EAE symptoms and MPTP-induced inflammation by decreasing the number of microglia and the production of TNF-α in the spinal cord of EAE mice and the substantia nigra of MPTP-treated mice. Accordingly, GJG suppressed the phosphorylation of p38 in glial cells of these two mouse models. We conclude that GJG attenuates inflammation of the CNS by suppressing glial cell activation, followed by a decrease in the production of TNF-α via p38-TNF signaling.
Collapse
Affiliation(s)
- Shiying Jiang
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Kousuke Baba
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Tatsusada Okuno
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Makoto Kinoshita
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Chi-Jing Choong
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Hideki Hayakawa
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Hiroshi Sakiyama
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Kensuke Ikenaka
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Seiichi Nagano
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Tsutomu Sasaki
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Munehisa Shimamura
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
- Department of Health Development and Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Yoshitaka Nagai
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
- Department of Neurotherapeutics, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Keisuke Hagihara
- Department of Advanced Hybrid Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
| | - Hideki Mochizuki
- Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
| |
Collapse
|
|
24
|
Murugesh N, Karvembu R, Vedachalam S. A Convenient Synthesis of Iguratimod‐Amine Precursor via NHC‐Catalyzed Aldehyde‐Nitrile Cross Coupling Reaction. ChemistrySelect 2020. [DOI: 10.1002/slct.202003553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Affiliation(s)
- Nithya Murugesh
- Department of Chemistry National Institute of Technology Tiruchirappalli 620015 India
| | - Ramasamy Karvembu
- Department of Chemistry National Institute of Technology Tiruchirappalli 620015 India
| | - Seenuvasan Vedachalam
- Department of Chemistry National Institute of Technology Tiruchirappalli 620015 India
| |
Collapse
|
|
25
|
Luppi F, Sebastiani M, Sverzellati N, Cavazza A, Salvarani C, Manfredi A. Lung complications of Sjogren syndrome. Eur Respir Rev 2020; 29:29/157/200021. [PMID: 32817113 PMCID: PMC9489025 DOI: 10.1183/16000617.0021-2020] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 03/20/2020] [Indexed: 12/14/2022] Open
Abstract
Primary Sjogren syndrome (pSS) is a systemic autoimmune disease characterised by lymphocytic infiltration of exocrine glands and by a number of systemic manifestations, including those regarding the lung. Pulmonary involvement in pSS includes interstitial lung disease (ILD) and airway disease, together with lymphoproliferative disorders. Patients with pSS-ILD report impaired health-related quality of life and a higher risk of death, suggesting the importance of early diagnosis and treatment of this type of pulmonary involvement. In contrast, airway disease usually has little effect on respiratory function and is rarely the cause of death in these patients. More rare disorders can be also identified, such as pleural effusion, cysts or bullae. Up to date, available data do not allow us to establish an evidence-based treatment strategy in pSS-ILD. No data are available regarding which patients should be treated, the timing to start therapy and better therapeutic options. The lack of knowledge about the natural history and prognosis of pSS-ILD is the main limitation to the development of clinical trials or shared recommendations on this topic. However, a recent trial showed the efficacy of the antifibrotic drug nintedanib in slowing progression of various ILDs, including those in pSS patients. Primary Sjogren syndrome is a systemic autoimmune disease with a possible lung involvement, that it appears as polymorphic, including interstitial lung disease, airway disease and lymphoproliferative disorders with different degree of severityhttps://bit.ly/3akjk4b
Collapse
Affiliation(s)
- Fabrizio Luppi
- Dept of Medicine and Surgery, University of Milan Bicocca, Milan, Italy .,Respiratory Unit, San Gerardo Hospital, ASST Monza, Monza, Italy
| | - Marco Sebastiani
- Rheumatology Unit, University of Modena and Reggio Emilia, Azienda Ospedaliero- Universitaria Policlinico di Modena, Modena, Italy
| | - Nicola Sverzellati
- Section of Radiology, Unit of Surgical Sciences, Dept of Medicine and Surgery (DiMeC), University of Parma, Parma, Italy
| | - Alberto Cavazza
- Pathology Unit, AUSL/IRCCS of Reggio Emilia, Reggio Emilia, Italy
| | - Carlo Salvarani
- Rheumatology Unit, University of Modena and Reggio Emilia, Azienda Ospedaliero- Universitaria Policlinico di Modena, Modena, Italy
| | - Andreina Manfredi
- Rheumatology Unit, University of Modena and Reggio Emilia, Azienda Ospedaliero- Universitaria Policlinico di Modena, Modena, Italy
| |
Collapse
|
|
26
|
Ramadass V, Vaiyapuri T, Tergaonkar V. Small Molecule NF-κB Pathway Inhibitors in Clinic. Int J Mol Sci 2020; 21:E5164. [PMID: 32708302 PMCID: PMC7404026 DOI: 10.3390/ijms21145164] [Citation(s) in RCA: 139] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/07/2020] [Accepted: 07/14/2020] [Indexed: 12/18/2022] Open
Abstract
Nuclear factor kappa B (NF-κB) signaling is implicated in all major human chronic diseases, with its role in transcription of hundreds of gene well established in the literature. This has propelled research into targeting the NF-κB pathways for modulating expression of those genes and the diseases mediated by them. In-spite of the critical, but often promiscuous role played by this pathway and the inhibition causing adverse drug reaction, currently many biologics, macromolecules, and small molecules that modulate this pathway are in the market or in clinical trials. Furthermore, many marketed drugs that were later found to also have NF-κB targeting activity were repurposed for new therapeutic interventions. Despite the rising importance of biologics in drug discovery, small molecules got around 76% of US-FDA (Food and Drug Administration-US) approval in the last decade. This encouraged us to review information regarding clinically relevant small molecule inhibitors of the NF-κB pathway from cell surface receptor stimulation to nuclear signaling. We have also highlighted the underexplored targets in this pathway that have potential to succeed in clinic.
Collapse
Affiliation(s)
| | | | - Vinay Tergaonkar
- Institute of Molecular and Cell Biology (IMCB), Singapore 138673, Singapore;
- Department of Pathology, NUS, Singapore 117597, Singapore
| |
Collapse
|
|
27
|
Xie S, Li S, Tian J, Li F. Iguratimod as a New Drug for Rheumatoid Arthritis: Current Landscape. Front Pharmacol 2020; 11:73. [PMID: 32174824 PMCID: PMC7054862 DOI: 10.3389/fphar.2020.00073] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 01/24/2020] [Indexed: 12/20/2022] Open
Abstract
Iguratimod (IGU) is a novel synthetic small molecule disease modified anti-rheumatic drug approved only in Japan and China up to date. IGU plays an important immunomodulatory role in the synovial tissue of rheumatoid arthritis by inhibiting the production of immunoglobulins and cytokines and regulating T lymphocyte subsets. IGU also regulates bone metabolism by stimulating bone formation while inhibiting osteoclast differentiation, migration, and bone resorption. In clinical trials, IGU was shown to be superior to placebo and not inferior to salazosulfapyridine. Combined therapy of IGU with other disease-modifying anti-rheumatic drugs showed significant improvements for disease activity. IGU has good efficacy and tolerance as an additional treatment for rheumatoid arthritis patients with inadequate response to methotrexate and biological disease-modifying anti-rheumatic drugs. In this review, we summarize current landscape on the mechanism of action of IGU and its clinical effectiveness and safety. It is expected that further translational studies on IGU will pave the road for wider application of IGU in the treatment of autoimmune diseases other than rheumatoid arthritis.
Collapse
Affiliation(s)
- Sisi Xie
- Department of Internal Medicine, The 2nd Xiangya Hospital of Central South University, Changsha, China
| | - Shu Li
- Department of Internal Medicine, The 2nd Xiangya Hospital of Central South University, Changsha, China
| | - Jing Tian
- Department of Internal Medicine, The 2nd Xiangya Hospital of Central South University, Changsha, China
| | - Fen Li
- Department of Internal Medicine, The 2nd Xiangya Hospital of Central South University, Changsha, China
| |
Collapse
|
|
28
|
Liu Y, Zhang Y, Bian W, Fu J, Sun X, Chen D, Chen J, Zhao X, Li Y, Zhang W, Li Z. Efficacy and safety of iguratimod on patients with relapsed or refractory IgG4-related disease. Clin Rheumatol 2019; 39:491-497. [PMID: 31848912 DOI: 10.1007/s10067-019-04880-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 12/01/2019] [Accepted: 12/04/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To evaluate the therapeutic efficacy and safety of iguratimod on patients with relapsed or refractory IgG4-related disease (IgG4-RD). METHODS We conducted a retrospective single-center study in 17 IgG4-RD patients admitted to Peking University People's Hospital. Patients were given iguratimod, 25 mg, twice daily and clinical data were collected at 0, 12, and 24 weeks. The baseline treatments include prednisone, cyclophosphamide, leflunomide, mycophenolate mofetil, and methotrexate. Clinical manifestation, IgG4-RD responder index (IgG-RD RI), serological indexes, gland ultrasound findings, and adverse drug effect were recorded. IgG4-RD RI scores < 3 and declining ≥ 2 were recognized as complete response (CR); IgG4-RD RI scores declining ≥ 2 but remaining ≥ 3 were recognized as partial response (PR). If a patient's IgG4-RD RI score was 3 at the beginning, PR was considered as a 1-point decrease after the therapy. RESULTS Serum IgG4 decreased significantly from 708 (321-902) mg/dl at baseline to 446 (138-396) mg/dl at 24 weeks (P = 0.0016). IgG4-RD RI decreased significantly from 9.79 ± 3.07 at baseline to 3.57 ± 1.09 at 24 weeks (P < 0.0001). Overall, 2 (14.3%) patients achieved CR, 11 (78.6%) patients achieved PR, and 1 (7.14%) patient had no response to treatment at week 24. Serum IgG level and salivary glands major diameter also decreased significantly at week 12 and 24 after treatment. CONCLUSION Iguratimod can be a therapeutic strategy to achieve remission in relapsed or refractory IgG4-RD patients inadequately responding to corticosteroid treatment with or without other immunosuppressant treatment. Key messages • Iguratimod was effective for relapsed or refractory IgG4-RD patients. • Iguratimod can improve the clinical symptoms of patients, reduce the serum IgG and IgG4 levels, and can also reduce the volume of involved glands.
Collapse
Affiliation(s)
- Yanying Liu
- Department of Rheumatology and Immunology, Peking University People's Hospital, 11, Xizhimen South Street, Beijing, 100044, China
| | - Yuxin Zhang
- Department of Rheumatology and Immunology, Peking University People's Hospital, 11, Xizhimen South Street, Beijing, 100044, China
| | - Wenjie Bian
- Department of Rheumatology and Immunology, Peking University People's Hospital, 11, Xizhimen South Street, Beijing, 100044, China
| | - Jiangnan Fu
- Department of Rheumatology and Immunology, Peking University People's Hospital, 11, Xizhimen South Street, Beijing, 100044, China
| | - Xing Sun
- Department of Rheumatology and Immunology, Peking University People's Hospital, 11, Xizhimen South Street, Beijing, 100044, China
| | - Da Chen
- Department of Rheumatology and Immunology, Peking University People's Hospital, 11, Xizhimen South Street, Beijing, 100044, China
| | - Jiali Chen
- Department of Rheumatology and Immunology, Peking University People's Hospital, 11, Xizhimen South Street, Beijing, 100044, China
| | - Xiaozhen Zhao
- Department of Rheumatology and Immunology, Peking University People's Hospital, 11, Xizhimen South Street, Beijing, 100044, China
| | - Yingni Li
- Department of Rheumatology and Immunology, Peking University People's Hospital, 11, Xizhimen South Street, Beijing, 100044, China
| | - Wen Zhang
- Department of Rheumatology and Immunology, Peking Union Medical College Hospital, Beijing, 100005, China
| | - Zhanguo Li
- Department of Rheumatology and Immunology, Peking University People's Hospital, 11, Xizhimen South Street, Beijing, 100044, China.
| |
Collapse
|
|
29
|
Iguratimod: a valuable remedy from the Asia Pacific region for ameliorating autoimmune diseases and protecting bone physiology. Bone Res 2019; 7:27. [PMID: 31646017 PMCID: PMC6804744 DOI: 10.1038/s41413-019-0067-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 07/03/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023] Open
Abstract
Autoimmune diseases are affected by complex pathophysiology involving several cell types, cytokines, antibodies, and mimicking factors. Different drugs are used to ameliorate these autoimmune reactions, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antiantibodies, and small molecular drugs (DMARDs), and they are clinically in vogue for diseases such as rheumatoid arthritis (RA). Nevertheless, low cost-effectiveness, reduced efficacy, adverse effects, and patient nonresponse are unappealing factors driving the development of new drugs such as iguratimod. Iguratimod is primarily used to ameliorate RA in Japanese and Chinese clinics. However, its efficacy against other autoimmune ailments is also under intense investigation, and the number of investigations is becoming increasingly larger with each passing day. The articular structure comprises synovium, ligaments, and bone. The latter is more complex than the others since it regulates blood cells and autoimmunity in addition to providing skeletal support to the body. Therefore, its protection is also of prime importance in RA and other autoimmune diseases. Herein, we have highlighted the role of iguratimod in autoimmune diseases and bone protection. We suggest that iguratimod’s unique mode of action compared with that of other DMARDs and its good patient response makes it a suitable antirheumatic and bone-protecting drug.
Collapse
|
|
30
|
Zhang F, Zhang Y, Yang T, Ye ZQ, Tian J, Fang HR, Han JJ, Wang ZZ, Li X. Scopoletin Suppresses Activation of Dendritic Cells and Pathogenesis of Experimental Autoimmune Encephalomyelitis by Inhibiting NF-κB Signaling. Front Pharmacol 2019; 10:863. [PMID: 31427972 PMCID: PMC6688631 DOI: 10.3389/fphar.2019.00863] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 07/08/2019] [Indexed: 12/20/2022] Open
Abstract
Scopoletin, a phenolic coumarin derived from many medical or edible plants, is involved in various pharmacological functions. In the present study, we showed that Scopoletin effectively ameliorated experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), through novel regulatory mechanisms involving inhibition of NF-κB activity in dendritic cells (DCs). Scopoletin treatment significantly improved the severity of the disease and prominently decreased inflammation and demyelination of central nervous system (CNS) in EAE mice. Disease alleviation correlated with the downregulation of major histocompatibility complex (MHC) class II, CD80 and CD86, expressed on DCs of CNS or spleens, and the infiltration and polarization of encephalitogenic Th1/Th17 cells. Consistent with the in vivo data, Scopoletin-treated, bone marrow-derived dendritic cells (BM-DCs) exhibited reduced expression of MHC class II and costimulatory molecules (e.g., CD80 and CD86) and reduced NF-κB phosphorylation. These findings, for the first time, demonstrated the ability of Scopoletin to impair DC activation, downregulating pathogenic Th1/Th17 inflammatory cell responses and, eventually, reducing EAE severity. Our study demonstrates new evidence that natural products derived from medical or edible plants, such as Scopoletin, will be valuable in developing a novel therapeutic agent for MS in the future.
Collapse
Affiliation(s)
- Fei Zhang
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Yuan Zhang
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Ting Yang
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Ze-Qing Ye
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Jing Tian
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Hai-Rong Fang
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Juan-Juan Han
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Zhe-Zhi Wang
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Xing Li
- National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| |
Collapse
|
|
31
|
Guo S, Liu C, Yu J, Chai Z, Wang Q, Mi X, Song G, Li Y, Yang P, Feng L, Xiao B, Ma C. Nasal delivery of Fasudil-modified immune cells exhibits therapeutic potential in experimental autoimmune encephalomyelitis. CNS Neurosci Ther 2019; 25:783-795. [PMID: 30779332 PMCID: PMC6515703 DOI: 10.1111/cns.13111] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 01/21/2019] [Accepted: 01/27/2019] [Indexed: 12/12/2022] Open
Abstract
AIM Multiple sclerosis (MS) is a relapsing-remitting inflammatory demyelinating disease that requires long-term treatment. Although Rho kinase inhibitor Fasudil shows good therapeutic effect in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, certain side effects may limit its clinical use. This study aimed at observing the therapeutic potential of Fasudil-modified encephalitogenic mononuclear cells (MNCs) via nasal delivery in EAE and exploring possible mechanisms of action. METHODS Experimental autoimmune encephalomyelitis was induced with myelin oligodendrocyte glycoprotein 35-55 in C57BL/6 mice, and encephalitogenic MNCs were treated with Fasudil in vitro. Mice received 3 × 106 cells/10 μL per nasal cavity on day 3 and 11 postimmunization, respectively. RESULTS Fasudil-modified MNCs reduced clinical severity of EAE, improved demyelination, and decreased inflammatory cells in spinal cords. Immunohistochemical results indicated that CD4+ T cells and CD68+ macrophages were barely detected in Fasudil-MNCs group. Fasudil-modified MNCs decreased CD4+ IFN-γ+ and CD4+ IL-17+ T cells, increased CD4+ IL-10+ T cells, restrained M1 markers CD16/32, CCR7, IL-12, CD8a, enhanced M2 markers CD206, CD200, CD14 in spleen. Fasudil-modified MNCs inhibited the activation of inflammatory signaling p-NF-kB/P38, accompanied by the decrease of COX-2 and the increase of Arg-1 in spinal cord, as well as the reduction of IL-17, TNF-α, IL-6 and the elevation of IL-10 in cultured supernatant of splenocytes. Fasudil-modified MNCs enhanced the levels of neurotrophic factors BDNF and NT-3 in spinal cord. CONCLUSION Our results indicate that intranasal delivery of Fasudil-modified MNCs have therapeutic potential in EAE, providing a safe and effective cell therapeutic strategy to MS and/or other related disorders.
Collapse
MESH Headings
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology
- Administration, Intranasal
- Animals
- Cell- and Tissue-Based Therapy/methods
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Encephalomyelitis, Autoimmune, Experimental/therapy
- Female
- Leukocytes, Mononuclear/drug effects
- Leukocytes, Mononuclear/transplantation
- Mice, Inbred C57BL
- Myelin-Oligodendrocyte Glycoprotein
- Peptide Fragments
- Protein Kinase Inhibitors/pharmacology
- Spinal Cord/metabolism
- Spinal Cord/pathology
Collapse
Affiliation(s)
- Shang‐De Guo
- Department of Neurology, Institute of Brain Science, Medical SchoolShanxi Datong UniversityDatongChina
- Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Institute of Brain ScienceShanxi Datong UniversityDatongChina
| | - Chun‐Yun Liu
- Department of Neurology, Institute of Brain Science, Medical SchoolShanxi Datong UniversityDatongChina
- Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Institute of Brain ScienceShanxi Datong UniversityDatongChina
| | - Jing‐Wen Yu
- Department of Neurology, Institute of Brain Science, Medical SchoolShanxi Datong UniversityDatongChina
- Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Institute of Brain ScienceShanxi Datong UniversityDatongChina
| | - Zhi Chai
- Research Center of NeurobiologyShanxi University of Traditional Chinese MedicineTaiyuanChina
| | - Qing Wang
- Research Center of NeurobiologyShanxi University of Traditional Chinese MedicineTaiyuanChina
| | - Xi‐Ting Mi
- Department of Neurology, Institute of Brain Science, Medical SchoolShanxi Datong UniversityDatongChina
- Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Institute of Brain ScienceShanxi Datong UniversityDatongChina
| | - Guo‐Bin Song
- Department of Neurology, Institute of Brain Science, Medical SchoolShanxi Datong UniversityDatongChina
- Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Institute of Brain ScienceShanxi Datong UniversityDatongChina
| | - Yan‐Hua Li
- Department of Neurology, Institute of Brain Science, Medical SchoolShanxi Datong UniversityDatongChina
- Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Institute of Brain ScienceShanxi Datong UniversityDatongChina
| | - Peng‐Wei Yang
- Research Center of NeurobiologyShanxi University of Traditional Chinese MedicineTaiyuanChina
| | - Ling Feng
- Department of Neurology, Institute of Brain Science, Medical SchoolShanxi Datong UniversityDatongChina
- Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Institute of Brain ScienceShanxi Datong UniversityDatongChina
| | - Bao‐Guo Xiao
- Institute of NeurologyHuashan HospitalInstitutes of Brain Science and State Key Laboratory of Medical NeurobiologyFudan UniversityShanghaiChina
| | - Cun‐Gen Ma
- Department of Neurology, Institute of Brain Science, Medical SchoolShanxi Datong UniversityDatongChina
- Shanxi Key Laboratory of Inflammatory Neurodegenerative Diseases, Institute of Brain ScienceShanxi Datong UniversityDatongChina
- Research Center of NeurobiologyShanxi University of Traditional Chinese MedicineTaiyuanChina
| |
Collapse
|
|
32
|
Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disorder. Although all MS patients initially show a relapsing-remitting course, 20-50% subsequently enter a chronic progressive course at 10-20 years after onset that greatly influences their activities of daily living. There are 2.5 million MS patients worldwide with large regional and racial differences. In particular, there are many MS patients among Caucasians living in Europe, while the disease is relatively rare in Asians and Africans.Although MS is regarded as an autoimmune disease, many factors such as genetic background, environmental factors, and sex are involved in its pathogenesis. While the immunological mechanisms remain to be fully elucidated, invasion of autoreactive T cells into the central nervous system (CNS) tissue is considered the first step of the disease. These T cells react with myelin antigens and initiate demyelination of the CNS by activating cytotoxic T cells, macrophages, and B cells through the release of inflammatory cytokines. As a treatment option, disease-modifying therapies have recently been developed to prevent the recurrence of MS in addition to conventional treatment with corticosteroids for acute relapse. However, there are still few effective treatments for the chronic progressive phase, and it is thus imperative to decipher the mechanism for chronic progression.
Collapse
|
|
33
|
Fang M, Yamasaki R, Li G, Masaki K, Yamaguchi H, Fujita A, Isobe N, Kira JI. Connexin 30 Deficiency Attenuates Chronic but Not Acute Phases of Experimental Autoimmune Encephalomyelitis Through Induction of Neuroprotective Microglia. Front Immunol 2018; 9:2588. [PMID: 30464764 PMCID: PMC6234958 DOI: 10.3389/fimmu.2018.02588] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 10/19/2018] [Indexed: 01/25/2023] Open
Abstract
Glial connexins (Cxs) form gap junction channels through which a pan-glial network plays key roles in maintaining homeostasis of the central nervous system (CNS). In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), expression of astrocytic Cx43 is lost in acute lesions but upregulated in chronic plaques, while astrocytic Cx30 is very low in normal white matter and changes in its expression have not been convincingly shown. In Cx30 or Cx43 single knockout (KO) mice and even in Cx30/Cx43 double KO mice, acute EAE is unaltered. However, the effects of Cx30/Cx43 deficiency on chronic EAE remains to be elucidated. We aimed to clarify the roles of Cx30 in chronic neuroinflammation by studying EAE induced by myelin oligodendrocyte glycoprotein peptide 35–55 in Cx30 KO mice. We found that Cx30 deficiency improved the clinical symptoms and demyelination of chronic but not acute EAE without influencing CD3+ T cell infiltration. Furthermore, increased ramified microglia in the naïve state and induced earlier and stronger microglial activation in the acute and chronic phases of EAE was observed. These activated microglia had an anti-inflammatory phenotype, as shown by the upregulation of arginase-1 and brain-derived neurotrophic factor and the downregulation of nitric oxide synthase 2. In the naïve state, Cx30 deficiency induced modest enlargement of astrocytic processes in the spinal cord gray matter and a partial reduction of Cx43 expression in the spinal cord white matter. These astrocytes in Cx30 KO mice showed earlier and stronger activation during the acute phase of EAE, with upregulated A2 astrocyte markers and a significant decrease in Cx43 in the chronic phases. Spinal cord neurons and axons were more preserved in Cx30 KO mice than in littermates in the chronic phase of EAE. These findings suggest that Cx30 deficiency increased ramified microglia in the CNS in the naïve state and improved chronic EAE through redirecting microglia toward an anti-inflammatory phenotype, suggesting a hitherto unknown critical role of astrocytic Cx30 in regulating microglial number and functional state.
Collapse
Affiliation(s)
- Mei Fang
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryo Yamasaki
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Guangrui Li
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Katsuhisa Masaki
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroo Yamaguchi
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Atsushi Fujita
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Noriko Isobe
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun-Ichi Kira
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| |
Collapse
|