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Wang Q, Huang T, Zheng Z, Su Y, Wu Z, Zeng C, Yu G, Liu Y, Wang X, Li H, Chen X, Jiang Z, Zhang J, Zhuang Y, Tian Y, Yang Q, Verkhratsky A, Wan Y, Yi C, Niu J. Oligodendroglial precursor cells modulate immune response and early demyelination in a murine model of multiple sclerosis. Sci Transl Med 2025; 17:eadn9980. [PMID: 40173259 DOI: 10.1126/scitranslmed.adn9980] [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: 01/11/2024] [Revised: 06/23/2024] [Accepted: 03/12/2025] [Indexed: 04/04/2025]
Abstract
Reproducing the pathophysiology of human multiple sclerosis (MS) in animal models is critical to identifying mechanisms triggering demyelination and to developing early intervention strategies. Here, we aimed to model overactivated Wnt (wingless-related integration site) signaling previously shown in postmortem brain tissues of patients with MS by inducing experimental autoimmune encephalomyelitis (EAE) in PdgfraCreER;Apcfl/fl and Olig2Cre;Apcfl/fl mice. These mice have overactivated Wnt signaling in oligodendrocyte precursor cells (OPCs) because of a conditional knockout of the pathway repressor adenomatous polyposis coli (APC). PdgfraCreER;Apcfl/fl EAE mice exhibited increased expression of markers for Wnt activation such as Axis inhibition protein 2 (AXIN2) and Wnt inhibitory factor 1 (WIF1) in OPCs and showed exacerbated EAE progression in both the spinal cord and the brain. Genetic or antibody-mediated ablation of CC-chemokine ligand 4 (CCL4) prevented infiltration of CD4+ T cells and arrested disease progression in these mice. A characterization of CNS (central nervous system) immune cell clusters identified an augmented subpopulation of NK1.1+CD11b+Gr-1+ cytotoxic macrophages in PdgfraCreER;Apcfl/fl EAE mice. Microinjection of this subpopulation of macrophages into the brains of wild-type C57/B6J mice was sufficient to induce demyelination. Ablation of CD4+ T cells prevented the effects of Wnt overactivation on demyelination and immune cell infiltration. Antagonizing chemokine receptor 5 (CCR5) using a European Medicines Agency-approved drug, maraviroc, reduced immune cell infiltration, alleviated demyelination, and attenuated EAE progression. We found an OPC-orchestrated immune cellular network that instigates early demyelination, provides insight into MS pathophysiology, and suggests avenues for early interventions.
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Affiliation(s)
- Qi Wang
- Research Centre, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
- Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
- Biomedical Analysis Center, Third Military Medical University, Chongqing 400038, China
| | - Taida Huang
- Research Centre, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
| | - Zihan Zheng
- Biomedical Analysis Center, Third Military Medical University, Chongqing 400038, China
| | - Yixun Su
- Research Centre, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
- Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
| | - Zhonghao Wu
- Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
| | - Cong Zeng
- Biomedical Analysis Center, Third Military Medical University, Chongqing 400038, China
| | - Guangdan Yu
- China Astronaut Research and Training Center, Beijing 100094, China
| | - Yang Liu
- Biomedical Analysis Center, Third Military Medical University, Chongqing 400038, China
| | - Xiaorui Wang
- Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
| | - Hui Li
- Research Centre, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
- Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
| | - Xiaoying Chen
- Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
| | - Zhuoxu Jiang
- Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
| | - Jinyu Zhang
- National Engineering Research Center of Immunological Products, Third Military Medical University, Chongqing 400038, China
| | - Yuan Zhuang
- National Engineering Research Center of Immunological Products, Third Military Medical University, Chongqing 400038, China
| | - Yi Tian
- Institute of Immunology, Third Military Medical University, Chongqing 400038, China
| | - Qingwu Yang
- Department of Neurology, Second Affiliated Hospital, Third Military Medical University, Chongqing 400038, China
- Chongqing Institute for Brain and Intelligence, Chongqing 400037, China
| | - Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester M139PL, UK
- Department of Neurosciences, University of the Basque Country, Leioa 48940, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- International Joint Research Centre on Purinergic Signalling of Sichuan Province, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China
- Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang 110122, China
- Celica Biomedical, Technology Park 24, 1000 Ljubljana, Slovenia
| | - Ying Wan
- Biomedical Analysis Center, Third Military Medical University, Chongqing 400038, China
- Institute for Translational Immunology, Chongqing 400038, China
| | - Chenju Yi
- Research Centre, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, China
- Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research, Shenzhen 518107, China
| | - Jianqin Niu
- Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China
- Chongqing Key Laboratory of Neurobiology, Chongqing 400038, China
- State Key Laboratory of Trauma and Chemical Poisoning, Chongqing 400042, China
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Cao JF, Yang GJ, Zhang YA, Chen J. Contribution of interleukins in the regulation of teleost fish immunity: A review from the perspective of regulating macrophages. FISH & SHELLFISH IMMUNOLOGY 2025; 158:110173. [PMID: 39909123 DOI: 10.1016/j.fsi.2025.110173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/20/2025] [Accepted: 02/02/2025] [Indexed: 02/07/2025]
Abstract
Interleukins (ILs) are potent secreted regulators of a wide range of cell types and cellular activities, particularly in the immune system. They are able to participate in intercellular communication in homeostasis and disease, thereby exerting immune functions. Macrophages serve as the innate immune cells of vertebrates and play a pivotal role in defending against and eliminating external pathogens. In mammals, the immune response mounted by macrophages is intricately linked to ILs. Given the fact that teleost fish have evolved an innate immune system that closely resembles those of mammals, particularly in terms of the functionality of macrophages, raises the intriguing possibility that the regulatory function of ILs in macrophage-mediated immunity might be evolutionarily conserved across both mammal and teleost fish lineages. Consequently, from the perspective of interleukin regulation of macrophages, this review outlines the relationship between ILs and macrophages in teleost fish, and elucidates the regulatory role of ILs of immune cell function in teleost fish, thereby contributing to our understanding of the key role of these cytokines in the prevention and control of aquaculture diseases.
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Affiliation(s)
- Jia-Feng Cao
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315832, China; Key Laboratory of Aquacultural Biotechnology, Ministry of Education, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315832, China
| | - Guan-Jun Yang
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315832, China; Key Laboratory of Aquacultural Biotechnology, Ministry of Education, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315832, China
| | - Yong-An Zhang
- State Key Laboratory of Agricultural Microbiology, College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, China; Hubei Hongshan Laboratory, Huazhong Agricultural University, Wuhan, 430070, China.
| | - Jiong Chen
- State Key Laboratory for Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, China; Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo, 315832, China; Key Laboratory of Aquacultural Biotechnology, Ministry of Education, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, 315832, China.
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Wang YC, Zhu Y, Meng WT, Zheng Y, Guan XQ, Shao CL, Li XY, Hu D, Wang MZ, Guo HD. Dihydrotanshinone I improves cardiac function by promoting lymphangiogenesis after myocardial ischemia-reperfusion injury. Eur J Pharmacol 2025; 989:177245. [PMID: 39753160 DOI: 10.1016/j.ejphar.2024.177245] [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: 07/11/2024] [Revised: 12/26/2024] [Accepted: 12/30/2024] [Indexed: 01/11/2025]
Abstract
Dihydrotanshinone I (DHT) is an active ingredient derived from Salvia miltiorrhiza. Previous studies have demonstrated that DHT can improve cardiac function in rats with myocardial ischemia-reperfusion injury (IR). However, the mechanism by which DHT improves myocardial injury in rats still requires further research. Lymphangiogenesis can reduce myocardial edema, inflammation, and fibrosis after myocardial infarction in rats, and improve cardiac function. In this study, the changes in cardiac functions, collagen fiber deposition in the infarcted area and the level of relevant indicators of lymphangiogenesis were examined by echocardiography, Masson's trichrome staining, immunohistochemistry and Western blot, respectively. Human lymphatic endothelial cells (HLECs) were transfected with siVE-cadherin and siVEGFR-3, and the effects of DHT on HLEC cell viability, migration and tube formation were detected through CCK8, TUNEL, transwell, wound healing and tube formation assay. We found that in myocardial IR rats treated with DHT, the levels of LYVE-1, PROX1, VEGF-C, VEGFR-3, IGF-1, podoplanin and IGF-1R, which are associated with lymphangiogenesis, were increased, as well as the level of VE-cadherin, which maintains endothelial cell function. DHT reduced the levels of inflammatory factors and myocardial cell apoptosis, thereby improving cardiac function after I/R. To explore the mechanism of DHT promoting lymphangiogenesis, H2O2 and OGD/R injury models of HLECs were constructed to simulate the microenvironment of myocardial IR in vitro. The results proved that DHT could reduce the damage and apoptosis of HLECs. On the other hand, DHT enhanced the expression of VEGFR-3 and VE-cadherin in HLECs, promoted cell migration and tube formation. The effects of DHT on the tube formation and migration of HLECs were significantly decreased after knocking down VEGFR-3 or VE-cadherin. Our research proposed that DHT could improve the heart function after IR through the enhancement of lymphangiogenesis and contributed to the development of the treatment methods for myocardial IR.
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Affiliation(s)
- Ya-Chao Wang
- Academy of Integrated Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Zhu
- Department of Neurological Rehabilitation, The Second Rehabilitation Hospital of Shanghai, Shanghai, China
| | - Wan-Ting Meng
- Academy of Integrated Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Zheng
- Jiading Hospital of Traditional Chinese Medicine, Shanghai, China
| | - Xiao-Qi Guan
- Academy of Integrated Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chang-le Shao
- Academy of Integrated Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiu-Ya Li
- Academy of Integrated Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dan Hu
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China.
| | - Ming-Zhu Wang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
| | - Hai-Dong Guo
- Academy of Integrated Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Shan J, Ding J, Li DJ, Wang XQ. The double-edged role of IL-18 in reproductive endocrine and reproductive immune related disorders. Int Immunopharmacol 2025; 147:113859. [PMID: 39755106 DOI: 10.1016/j.intimp.2024.113859] [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: 07/22/2024] [Revised: 11/15/2024] [Accepted: 12/11/2024] [Indexed: 01/06/2025]
Abstract
Interleukin (IL)-18 is one of the members of IL-1 family cytokines, it was originally named as interferon gamma (IFN-γ) inducing factor. IL-18 is a pleiotropic immune regulator and has a bidirectional regulatory effect on immunity. It exerts a potent pro-inflammatory effect by inducing the expression of IFN-γ, also has an important anti-inflammatory role. In recent years, IL-18 has received widespread attention and become a research hotspot. Previous studies have described the roles of IL-18 in the pathogenesis of many diseases. However, the biologic activities of IL-18 and its role in the reproductive endocrine and reproductive immune related diseases are still not well understood, such as endometriosis (EMS), recurrent spontaneous abortion (RSA), polycystic ovary syndrome (PCOS), and infertility, which are closely related to inflammation and immunity. Here, we reviewed the research progress of IL-18 in these diseases in the past few years. This article provides an overview of the latest knowledge about the roles of IL-18 in these diseases, with a view to providing new possibilities for the diagnosis and treatment of reproductive endocrine and reproductive immune related disorders.
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Affiliation(s)
- Jing Shan
- Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Jie Ding
- Naval Medical University, Changhai Hospital, Department of Traditional Chinese Medicine, Shanghai, China
| | - Da-Jin Li
- Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
| | - Xiao-Qiu Wang
- Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, The Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
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Huard A, Fauteux-Daniel S, Goldstein J, Martin P, Jarlborg M, Andries J, Caruso A, Díaz-Barreiro A, Rodriguez E, Vaillant L, Savvides SN, Gabay C. Development of anti-murine IL-18 binding protein antibodies to stimulate IL-18 bioactivity. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025; 214:180-191. [PMID: 40018678 PMCID: PMC7617445 DOI: 10.1093/jimmun/vkae022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Interleukin (IL)-18 is an immunoregulatory cytokine that acts as a potent inducer of T helper 1 and cytotoxic responses. IL-18 activity is regulated by its decoy receptor IL-18 binding protein (IL-18BP) which forms a high affinity complex with IL-18 to block binding of the cognate receptors. A disbalance between IL-18 and IL-18BP associated with excessive IL-18 signaling can lead to systemic inflammation. Indeed, the severity of CpG-induced macrophage activation syndrome (MAS) is exacerbated in IL-18BP KO mice. On the contrary, targeting IL-18BP can have promising effects to enhance immune responses against pathogens and cancer. We generated monoclonal rabbit anti-mouse IL-18BP antibodies labeled from 441 to 450. All antibodies, except from antibody 443, captured mIL-18BP when used in a sandwich ELISA. Using an IL-18 bioassay, we showed that antibody 441 did not interfere with the regulatory effect of mIL-18BP, whereas all other antibodies displayed different levels of antagonism. Further experiments were performed using antibody 445 endowed with potent neutralizing activity and antibody 441. Despite binding to IL-18BP with the same affinity, antibody 445, but not antibody 441, was able to release IL-18 from preformed IL-18-IL-18BP complexes. Administration of antibody 445 significantly aggravated the severity of CpG-induced MAS as compared to antibody 441. Additional experiments using naïve WT, IL-18BP KO, and IL-18 KO mice confirmed the specificity of the neutralizing effect of antibody 445 towards IL-18BP. Our studies led to the development of a monoclonal anti-IL-18BP antibody with neutralizing activity that results in the promotion of IL-18 activities.
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Affiliation(s)
- Arnaud Huard
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Geneva, Switzerland
| | - Sébastien Fauteux-Daniel
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Geneva, Switzerland
| | - Jérémie Goldstein
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Geneva, Switzerland
| | - Praxedis Martin
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Geneva, Switzerland
| | - Matthias Jarlborg
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Geneva, Switzerland
| | - Julie Andries
- Department of Biochemistry and Microbiology, Ghent University, 9052, Ghent, Belgium
- Unit for Structural Biology, VIB-UGent Center for Inflammation Research, 9052, Ghent, Belgium
| | - Assunta Caruso
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Geneva, Switzerland
| | - Alejandro Díaz-Barreiro
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Geneva, Switzerland
| | - Emiliana Rodriguez
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Geneva, Switzerland
| | - Laurie Vaillant
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Geneva, Switzerland
| | - Savvas N. Savvides
- Department of Biochemistry and Microbiology, Ghent University, 9052, Ghent, Belgium
- Unit for Structural Biology, VIB-UGent Center for Inflammation Research, 9052, Ghent, Belgium
| | - Cem Gabay
- Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Geneva Centre for Inflammation Research, Geneva, Switzerland
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Stajer M, Horacek JM, Kupsa T, Zak P. The role of chemokines and interleukins in acute lymphoblastic leukemia: a systematic review. J Appl Biomed 2024; 22:165-184. [PMID: 40033805 DOI: 10.32725/jab.2024.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 11/15/2024] [Indexed: 03/05/2025] Open
Abstract
Acute lymphoblastic leukemia (ALL) is the most common childhood hematological malignancy, but it also affects adult patients with worse prognosis and outcomes. Leukemic cells benefit from protective mechanisms, which are mediated by intercellular signaling molecules - cytokines. Through these signals, cytokines modulate the biology of leukemic cells and their surroundings, enhancing the proliferation, survival, and chemoresistance of the disease. This ultimately leads to disease progression, refractoriness, and relapse, decreasing the chances of curability and overall survival of the patients. Targeting and modulating these pathological processes without affecting the healthy physiology is desirable, offering more possibilities for the treatment of ALL patients, which still remains unsatisfactory in certain cases. In this review, we comprehensively analyze the existing literature and ongoing trials regarding the role of chemokines and interleukins in the biology of ALL. Focusing on the functional pathways, genetic background, and critical checkpoints, we constructed a summary of molecules that are promising for prognostic stratification and mainly therapeutic use. Targeted therapy, including chemokine and interleukin pathways, is a new and promising approach to the treatment of cancer. With the expansion of our knowledge, we are able to uncover a spectrum of new potential checkpoints in order to modulate the disease biology. Several cytokine-related targets are advancing toward clinical application, offering the hope of higher disease response rates to treatment.
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Affiliation(s)
- Martin Stajer
- University of Defence, Military Faculty of Medicine, Department of Military Internal Medicine and Military Hygiene, Hradec Kralove, Czech Republic
- University Hospital Hradec Kralove and Charles University, Faculty of Medicine in Hradec Kralove, Department of Internal Medicine IV - Hematology, Hradec Kralove, Czech Republic
| | - Jan M Horacek
- University of Defence, Military Faculty of Medicine, Department of Military Internal Medicine and Military Hygiene, Hradec Kralove, Czech Republic
- University Hospital Hradec Kralove and Charles University, Faculty of Medicine in Hradec Kralove, Department of Internal Medicine IV - Hematology, Hradec Kralove, Czech Republic
| | - Tomas Kupsa
- University of Defence, Military Faculty of Medicine, Department of Military Internal Medicine and Military Hygiene, Hradec Kralove, Czech Republic
- University Hospital Hradec Kralove and Charles University, Faculty of Medicine in Hradec Kralove, Department of Internal Medicine IV - Hematology, Hradec Kralove, Czech Republic
| | - Pavel Zak
- University Hospital Hradec Kralove and Charles University, Faculty of Medicine in Hradec Kralove, Department of Internal Medicine IV - Hematology, Hradec Kralove, Czech Republic
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Gui R, Ren Y, Wang Z, Li Y, Wu C, Li X, Li M, Li Y, Qian L, Xiong Y. Deciphering interleukin-18 in diabetes and its complications: Biological features, mechanisms, and therapeutic perspectives. Obes Rev 2024; 25:e13818. [PMID: 39191434 DOI: 10.1111/obr.13818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 07/16/2024] [Accepted: 08/02/2024] [Indexed: 08/29/2024]
Abstract
Interleukin-18 (IL-18), a potent and multifunctional pro-inflammatory cytokine, plays a critical role in regulating β-cell failure, β-cell death, insulin resistance, and various complications of diabetes mellitus (DM). It exerts its effects by triggering various signaling pathways, enhancing the production of pro-inflammatory cytokines and nitric oxide (NO), as well as promoting immune cells infiltration and β-cells death. Abnormal alterations in IL-18 levels have been revealed to be strongly associated with the onset and development of DM and its complications. Targeting IL-18 may present a novel and promising approach for DM therapy. An increasing number of IL-18 inhibitors, including chemical and natural inhibitors, have been developed and have been shown to protect against DM and diabetic complications. This review provides a comprehensive understanding of the production, biological functions, action mode, and activated signaling pathways of IL-18. Next, we shed light on how IL-18 contributes to the pathogenesis of DM and its associated complications with links to its roles in the modulation of β-cell failure and death, insulin resistance in various tissues, and pancreatitis. Furthermore, the therapeutic potential of targeting IL-18 for the diagnosis and treatment of DM is also highlighted. We hope that this review will help us better understand the functions of IL-18 in the pathogenesis of DM and its complications, providing novel strategies for DM diagnosis and treatment.
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Affiliation(s)
- Runlin Gui
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
| | - Yuanyuan Ren
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Zhen Wang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Yang Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Chengsong Wu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Xiaofang Li
- Department of Gastroenterology, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
| | - Man Li
- Department of Endocrinology, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
| | - Yujia Li
- Department of Traditional Chinese Medicine, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
| | - Lu Qian
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
- Scientific Research Center, Xi'an Mental Health Center, Xi'an, Shaanxi, China
| | - Yuyan Xiong
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
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Bale R, Doshi G. Deciphering the role of siRNA in anxiety and depression. Eur J Pharmacol 2024; 981:176868. [PMID: 39128805 DOI: 10.1016/j.ejphar.2024.176868] [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: 01/04/2024] [Revised: 07/02/2024] [Accepted: 08/05/2024] [Indexed: 08/13/2024]
Abstract
Anxiety and depression are central nervous system illnesses that are among the most prevalent medical concerns of the twenty-first century. Patients with this condition and their families bear psychological, financial, and societal hardship. There are currently restrictions when utilizing the conventional course of treatment. RNA interference is expected to become an essential approach in anxiety and depression due to its potent and targeted gene silencing. Silencing of genes by post-transcriptional modification is the mechanism of action of small interfering RNA (siRNA). The suppression of genes linked to disease is typically accomplished by siRNA molecules in an efficient and targeted manner. Unfavourable immune responses, off-target effects, naked siRNA instability, nuclease vulnerability, and the requirement to create an appropriate delivery method are some of the challenges facing the clinical application of siRNA. This review focuses on the use of siRNA in the treatment of anxiety and depression.
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Affiliation(s)
- Rajeshwari Bale
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V L M Road, Vile Parle (w), Mumbai, 400056, India
| | - Gaurav Doshi
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V L M Road, Vile Parle (w), Mumbai, 400056, India.
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Zhao Q, Zhang R, Wang Y, Li T, Xue J, Chen Z. FOXQ1, deubiquitinated by USP10, alleviates sepsis-induced acute kidney injury by targeting the CREB5/NF-κB signaling axis. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167331. [PMID: 38960057 DOI: 10.1016/j.bbadis.2024.167331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 06/14/2024] [Accepted: 06/25/2024] [Indexed: 07/05/2024]
Abstract
Sepsis-induced acute kidney injury (S-AKI) is a severe and frequent complication that occurs during sepsis. This study aimed to understand the role of FOXQ1 in S-AKI and its potential upstream and downstream regulatory mechanisms. A cecal ligation and puncture induced S-AKI mouse model in vivo and an LPS-induced HK-2 cell model in vitro were used. FOXQ1 was significantly upregulated in CLP mice and downregulated in the LPS-induced HK-2 cells. Upregulation of FOXQ1 improved kidney injury and dysfunction in CLP mice. Overexpression of FOXQ1 remarkably suppressed the apoptosis and inflammatory response via down-regulating oxidative stress indicators and pro-inflammatory factors (IL-1β, IL-6, and TNF-α), both in vivo and in vitro. From online analysis, the CREB5/NF-κB axis was identified as the downstream target of FOXQ1. FOXQ1 transcriptionally activated CREB5, upregulating its expression. Overexpression of FOXQ1 suppressed the phosphorylation level and nucleus transport of p65. Rescue experiments showed that CREB5 mediates the protective role of FOXQ1 on S-AKI. Furthermore, FOXQ1 was identified as a substrate of USP10, a deubiquitinating enzyme. Ectopic expression of USP10 reduced the ubiquitination of FOXQ1, promoting its protein stability. USP10 upregulation alleviated LPS-induced cell apoptosis and inflammatory response, while suppression of FOXQ1 augmented these trends. Collectively, our results suggest that FOXQ1, deubiquitinated by USP10, plays a protective role in S-AKI induced inflammation and apoptosis by targeting CREB5/NF-κB axis.
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Affiliation(s)
- Qi Zhao
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ran Zhang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yu Wang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Tiegang Li
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Jinqi Xue
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Zhiguang Chen
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
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10
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Palanca A, Bartual-Rodrigo A, Cuenca C, Mayo-López OD, Ampudia-Blasco FJ, González-Navarro H, Ascaso JF, García-García AB, Chaves FJ, Real JT, Martínez-Hervás S. Association of carotid atheroma plaque with IL-18 levels and with polymorphisms in the IL-18 receptor gene in a Mediterranean population. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE ARTERIOSCLEROSIS 2024; 36:210-217. [PMID: 38216380 DOI: 10.1016/j.arteri.2023.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 12/14/2023] [Accepted: 12/15/2023] [Indexed: 01/14/2024]
Abstract
BACKGROUND Atherosclerosis is an inflammatory disease. Interleukin 18 (IL-18) is an inflammatory molecule that has been linked to the development of atherosclerosis and cardiovascular disease. OBJECTIVE To evaluate the possible relationship between plasma levels of IL-18 and the presence of atherosclerosis evaluated at the carotid level, as well as to analyze the possible modulation by different polymorphisms in a Mediterranean population. MATERIAL AND METHODS Seven hundred and forty-six individuals from the metropolitan area of Valencia were included, recruited over a period of 2 years. Hydrocarbon and lipid metabolism parameters were determined using standard methodology and IL-18 using ELISA. In addition, carotid ultrasound was performed and the genotype of four SNPs related to the IL-18 signaling pathway was analyzed. RESULTS Patients with higher plasma levels of IL-18 had other associated cardiovascular risk factors. Elevated IL-18 levels were significantly associated with higher carotid IMT and the presence of atheromatous plaques. The genotype with the A allele of the SNP rs2287037 was associated with a higher prevalence of carotid atheromatous plaque. On the contrary, the genotype with the C allele of the SNP rs2293224 was associated with a lower prevalence of atheromatous plaque. CONCLUSIONS High levels of IL-18 were significantly associated with a higher carotid IMT and the presence of atheromatous plaques, which appear to be influenced by genetic factors, as evidenced by associations between SNPs in the IL-18 receptor gene and the presence of atheroma plaque.
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Affiliation(s)
- Ana Palanca
- Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, Valencia, España; INCLIVA, Instituto de Investigación Sanitaria, Valencia, España
| | - Amparo Bartual-Rodrigo
- Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, Valencia, España
| | - Carolina Cuenca
- INCLIVA, Instituto de Investigación Sanitaria, Valencia, España
| | | | - Francisco Javier Ampudia-Blasco
- Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, Valencia, España; INCLIVA, Instituto de Investigación Sanitaria, Valencia, España; CIBER de Diabetes y Enfermedades Metabólicas asociadas, Instituto de Salud Carlos III, Madrid, España; Departament de Medicina, Universitat de València, Valencia, España
| | - Herminia González-Navarro
- INCLIVA, Instituto de Investigación Sanitaria, Valencia, España; Departamento de Bioquímica y Biología Molecular, Universitat de València, Valencia, España; CIBER de Diabetes y Enfermedades Metabólicas asociadas, Instituto de Salud Carlos III, Madrid, España
| | - Juan F Ascaso
- INCLIVA, Instituto de Investigación Sanitaria, Valencia, España; Departament de Medicina, Universitat de València, Valencia, España
| | - Ana Bárbara García-García
- INCLIVA, Instituto de Investigación Sanitaria, Valencia, España; CIBER de Diabetes y Enfermedades Metabólicas asociadas, Instituto de Salud Carlos III, Madrid, España; Unidad de Genómica y Diabetes, INCLIVA, Instituto de Investigación Sanitaria, Valencia, España
| | - Felipe Javier Chaves
- INCLIVA, Instituto de Investigación Sanitaria, Valencia, España; CIBER de Diabetes y Enfermedades Metabólicas asociadas, Instituto de Salud Carlos III, Madrid, España; Unidad de Genómica y Diabetes, INCLIVA, Instituto de Investigación Sanitaria, Valencia, España
| | - José T Real
- Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, Valencia, España; INCLIVA, Instituto de Investigación Sanitaria, Valencia, España; CIBER de Diabetes y Enfermedades Metabólicas asociadas, Instituto de Salud Carlos III, Madrid, España; Departament de Medicina, Universitat de València, Valencia, España
| | - Sergio Martínez-Hervás
- Servicio de Endocrinología y Nutrición, Hospital Clínico Universitario de Valencia, Valencia, España; INCLIVA, Instituto de Investigación Sanitaria, Valencia, España; CIBER de Diabetes y Enfermedades Metabólicas asociadas, Instituto de Salud Carlos III, Madrid, España; Departament de Medicina, Universitat de València, Valencia, España.
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11
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Švajger U, Kamenšek U. Interleukins and interferons in mesenchymal stromal stem cell-based gene therapy of cancer. Cytokine Growth Factor Rev 2024; 77:76-90. [PMID: 38508954 DOI: 10.1016/j.cytogfr.2024.03.002] [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: 02/05/2024] [Revised: 03/07/2024] [Accepted: 03/11/2024] [Indexed: 03/22/2024]
Abstract
The tumor microenvironment is importantly shaped by various cytokines, where interleukins (ILs) and interferons (IFNs) shape the balance of immune activity within tumor niche and associated lymphoid organs. Their importance in activation and tuning of both innate and adaptive immune responses prompted their use in several clinical trials, albeit with limited therapeutic efficacy and risk of toxicity due to systemic administration. Increasing preclinical evidence suggests that local delivery of ILs and IFNs could significantly increase their effectiveness, while simultaneously attenuate the known side effects and issues related to their biological activity. A prominent way to achieve this is to use cell-based delivery vehicles. For this purpose, mesenchymal stromal stem cells (MSCs) are considered an almost ideal candidate. Namely, MSCs can be obtained in large quantities and from obtainable sources (e.g. umbilical cord or adipose tissue), their ex vivo expansion is relatively straightforward compared to other cell types and they possess very low immunogenicity making them suitable for allogeneic use. Importantly, MSCs have shown an intrinsic capacity to respond to tumor-directed chemotaxis. This review provides a focused and detailed discussion on MSC-based gene therapy using ILs and IFNs, engineering techniques and insights on potential future advancements.
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Affiliation(s)
- Urban Švajger
- Slovenian Institute for Transfusion Medicine, Department for Therapeutic Services, Šlajmerjeva Ulica 6, Ljubljana SI-1000, Slovenia; Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, Ljubljana SI-1000, Slovenia.
| | - Urška Kamenšek
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloška Cesta 2, Ljubljana SI-1000, Slovenia; Biotechnical Faculty, University of Ljubljana, Jamnikarjeva Ulica 101, Ljubljana SI-1000, Slovenia
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12
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Xu Y, Sun X, Tong Y. Interleukin-12 in multimodal tumor therapies for induction of anti-tumor immunity. Discov Oncol 2024; 15:170. [PMID: 38753073 PMCID: PMC11098992 DOI: 10.1007/s12672-024-01011-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 05/03/2024] [Indexed: 05/19/2024] Open
Abstract
Interleukin-12 (IL-12) can be used as an immunomodulator in cancer immunotherapy. And it has demonstrated enormous potential in inhibiting tumor growth and improving the tumor microenvironment (TME) by several preclinical models. However, some disappointing results have showed in the early clinical trials when IL-12 used as a single agent for systemic cancer therapy. Combination therapy is an effective way to significantly fulfill the great potential of IL-12 as an immunomodulator. Here, we discuss the effects of IL-12 combined with traditional methods (chemotherapy, radiotherapy and surgery), targeted therapy or immunotherapy in the preclinical and clinical studies. Moreover, we summarized the potential mechanism underlying the anti-tumor effect of IL-12 in the combination strategies. And we also discussed the delivery methods and tumor-targeted modification of IL-12 and outlines future prospects for IL-12 as an immunomodulator.
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Affiliation(s)
- Yulian Xu
- College of Life Sciences, China Jiliang University, 168 Xueyuan Street, Hangzhou, Zhejiang, China
| | - Xueli Sun
- College of Life Sciences, China Jiliang University, 168 Xueyuan Street, Hangzhou, Zhejiang, China
| | - Yunguang Tong
- College of Life Sciences, China Jiliang University, 168 Xueyuan Street, Hangzhou, Zhejiang, China.
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- Omigen, Inc, Hangzhou, 310018, Zhejiang, China.
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13
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Tian J, Liu X, Liang H, Shen Y, Xiang X, Zhu F, Wang X, Liu C, Xu X, Zhang X, Xue Q, Gu Y. Expression of lymphocyte activation gene-3 on CD4 +T cells is regulated by cytokine interleukin-18 in myasthenia gravis. J Neuroimmunol 2024; 388:578308. [PMID: 38325197 DOI: 10.1016/j.jneuroim.2024.578308] [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: 10/01/2023] [Revised: 01/18/2024] [Accepted: 01/31/2024] [Indexed: 02/09/2024]
Abstract
Myasthenia gravis (MG) is a T cell-dependent, B cell-mediated, and complement-dependent autoimmune disease. Lymphocyte activation gene-3 (LAG-3; CD223) is an immune checkpoint protein that plays an important role in maintaining autoimmune tolerance and homeostasis. To investigate the cytokine-regulated expression pattern of LAG-3, CD4+T cells were sorted from the peripheral blood of healthy volunteers by density gradient centrifugation and stimulated with various cytokines in vitro. The expression of membrane LAG-3 (mLAG-3), membrane a disintegrin and metallopeptidase domain10 (mADAM10) and membrane ADAM17 (mADAM17) on CD4+T cells was detected by flow cytometry; the concentration of soluble LAG-3 (sLAG-3) was detected by ELISA; and the relative expression of genes at the transcriptional level was detected by fluorescence quantitative RT-PCR (qRT-PCR). sLAG-3 levels were significantly increased in the peripheral plasma of AChR Ab-positive patients with MG compared to healthy volunteers, while the percentage of mLAG-3 expression on CD4+T lymphocytes in the peripheral blood of patients with MG was significantly reduced. IL-18 inhibited mLAG-3 levels on CD4+T cells in a concentration-dependent manner. Additionally, the concentration of sLAG-3 in the supernatant increased. After PHA and IL-18 stimulation, ADAM10 and ADAM17 also increased compared to those in the PHA-active group. Moreover, there were significant differences in the expression of mADAM10 and mADAM17 in CD4+T lymphocytes between patients with MG and healthy volunteers. These results suggest that IL-18 may regulate the expression pattern of mLAG-3 in CD4+T cells and sLAG-3 via ADAM10- and ADAM17-mediated pathways, thus affecting the immune effects of CD4+T cells. This study provides a preliminary exploration of the upstream regulatory molecules of the LAG-3 and IL-18/LAG-3 signalling pathways for potential targeted therapy of autoimmune diseases in the future.
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Affiliation(s)
- Jingluan Tian
- Department of Neurology, First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Xuan Liu
- Department of Neurology, First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Hansi Liang
- Jiangsu Institute of Clinical Immunology, Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Yu Shen
- Jiangsu Institute of Clinical Immunology, Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Xuanyi Xiang
- Department of Neurology, First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Feng Zhu
- Department of Neurology, First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Xin Wang
- Department of Neurology, First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Cuiping Liu
- Jiangsu Institute of Clinical Immunology, Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Xingshun Xu
- Department of Neurology, First Affiliated Hospital of Soochow University, Suzhou 215006, China; Institute of Neuroscience, Soochow University, Suzhou 215031, China
| | - Xueguang Zhang
- Jiangsu Institute of Clinical Immunology, Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Qun Xue
- Department of Neurology, First Affiliated Hospital of Soochow University, Suzhou 215006, China; Jiangsu Institute of Clinical Immunology, Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, Suzhou 215006, China.
| | - Yanzheng Gu
- Jiangsu Institute of Clinical Immunology, Jiangsu Key Laboratory of Clinical Immunology, First Affiliated Hospital of Soochow University, Suzhou 215006, China.
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14
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Ju J, Li Z, Jia X, Peng X, Wang J, Gao F. Interleukin-18 in chronic pain: Focus on pathogenic mechanisms and potential therapeutic targets. Pharmacol Res 2024; 201:107089. [PMID: 38295914 DOI: 10.1016/j.phrs.2024.107089] [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: 10/18/2023] [Revised: 01/22/2024] [Accepted: 01/26/2024] [Indexed: 02/05/2024]
Abstract
Chronic pain has been proven to be an independent disease, other than an accompanying symptom of certain diseases. Interleukin-18 (IL-18), a pro-inflammatory cytokine with pleiotropic biological effects, participates in immune modulation, inflammatory response, tumor growth, as well as the process of chronic pain. Compelling evidence suggests that IL-18 is upregulated in the occurrence of chronic pain. Antagonism or inhibition of IL-18 expression can alleviate the occurrence and development of chronic pain. And IL-18 is located in microglia, while IL-18R is mostly located in astrocytes in the spinal cord. This indicates that the interaction between microglia and astrocytes mediated by the IL-18/IL-18R axis is involved in the occurrence of chronic pain. In this review, we described the role and mechanism of IL-18 in different types of chronic pain. This review provides strong evidence that IL-18 is a potential therapeutic target in pain management.
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Affiliation(s)
- Jie Ju
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zheng Li
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoqian Jia
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoling Peng
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jihong Wang
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Gao
- Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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15
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Haines NA, Fowler MG, Zeh BG, Kriete CB, Bai Q, Wakefield MR, Fang Y. Unlocking the 'ova'-coming power: immunotherapy's role in shaping the future of ovarian cancer treatment. Med Oncol 2024; 41:67. [PMID: 38286890 DOI: 10.1007/s12032-023-02281-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 12/06/2023] [Indexed: 01/31/2024]
Abstract
Ovarian cancer is a prominent cancer worldwide with a relatively low survival rate for women diagnosed. Many individuals are diagnosed in the late stage of the disease and are prescribed a wide variety of treatment options. Current treatment options are primarily a combination of surgery and chemotherapy as well as a new but promising treatment involving immunotherapy. Nevertheless, contemporary therapeutic modalities exhibit a discernible lag in advancement when compared with the strides achieved in recent years in the context of other malignancies. Moreover, many surgery and chemotherapy options have a high risk for recurrence due to the late-stage diagnosis. Therefore, there is a necessity to further treatment options. There have been many new advancements in the field of immunotherapy. Immunotherapy has been approved for 16 various types of cancers and has shown significant treatment potential in many other cancers as well. Researchers have also found many promising outlooks for immunotherapy as a treatment for ovarian cancer. This review summarizes many of the new advancements in immunotherapy treatment options and could potentially offer valuable insights to gynecologists aimed at enhancing the efficacy of their treatment approaches for patients diagnosed with ovarian cancer.
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Affiliation(s)
- Nathan A Haines
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, 8025, Grand Ave, West Des Moines, IA, 50266, USA
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Mia G Fowler
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Benjamin G Zeh
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, 8025, Grand Ave, West Des Moines, IA, 50266, USA
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Carter B Kriete
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Qian Bai
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Mark R Wakefield
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Yujiang Fang
- Department of Microbiology, Immunology & Pathology, Des Moines University College of Osteopathic Medicine, 8025, Grand Ave, West Des Moines, IA, 50266, USA.
- Department of Surgery, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
- Ellis Fischel Cancer Center, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
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16
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Yao XP, Hong JC, Jiang ZJ, Pan YY, Liu XF, Wang JM, Fan RJ, Yang BH, Zhang WQ, Fan QC, Li LX, Lin BW, Zhao M. Systemic and cerebrospinal fluid biomarkers for tuberculous meningitis identification and treatment monitoring. Microbiol Spectr 2024; 12:e0224623. [PMID: 38047697 PMCID: PMC10783035 DOI: 10.1128/spectrum.02246-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 10/31/2023] [Indexed: 12/05/2023] Open
Abstract
IMPORTANCE Tuberculous meningitis is a life-threatening infection with high mortality and disability rates. Current diagnostic methods using cerebrospinal fluid (CSF) samples have limited sensitivity and lack predictive biomarkers for evaluating prognosis. This study's findings reveal excessive activation of the immune response during tuberculous meningitis (TBM) infection. Notably, a strong negative correlation was observed between CSF levels of monokine induced by interferon-γ (MIG) and the CSF/blood glucose ratio in TBM patients. MIG also exhibited the highest area under the curve with high sensitivity and specificity. This study suggests that MIG may serve as a novel biomarker for differentiating TBM infection in CSF or serum, potentially leading to improved diagnostic accuracy and better patient outcomes.
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Affiliation(s)
- Xiang-Ping Yao
- Department of Neurology, Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
- Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jian-Chen Hong
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Zai-Jie Jiang
- Department of Neurology, Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
| | - Yu-Ying Pan
- Department of Neurology, Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
| | - Xiao-Feng Liu
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jun-Mei Wang
- Department of Neurology, Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
| | - Rui-Jie Fan
- Department of Neurology, Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
| | - Bi-Hui Yang
- Department of Neurology, Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
| | - Wei-Qing Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Qi-Chao Fan
- Department of Infectious Disease, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Li-Xiu Li
- Department of Oncology, Fuzhou Pulmonary Hospital of Fujian, Fuzhou, China
| | - Bi-Wei Lin
- Department of Neurology, Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
| | - Miao Zhao
- Department of Neurology, Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China
- Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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17
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Modi P, Shah BM, Patel S. Interleukin-1β converting enzyme (ICE): A comprehensive review on discovery and development of caspase-1 inhibitors. Eur J Med Chem 2023; 261:115861. [PMID: 37857145 DOI: 10.1016/j.ejmech.2023.115861] [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: 08/12/2023] [Revised: 10/05/2023] [Accepted: 10/05/2023] [Indexed: 10/21/2023]
Abstract
Caspase-1 is a critical mediator of the inflammatory process by activating various pro-inflammatory cytokines such as pro-IL-1β, IL-18 and IL-33. Uncontrolled activation of caspase-1 leads to various cytokines-mediated diseases. Thus, inhibition of Caspase-1 is considered therapeutically beneficial to halt the progression of such diseases. Currently, rilonacept, canakinumab and anakinra are in use for caspase-1-mediated autoinflammatory diseases. However, the poor pharmacokinetic profile of these peptides limits their use as therapeutic agents. Therefore, several peptidomimetic inhibitors have been developed, but only a few compounds (VX-740, VX-765) have advanced to clinical trials; because of their toxic profile. Several small molecule inhibitors have also been progressing based on the three-dimensional structure of caspase-1. However there is no successful candidate available clinically. In this perspective, we highlight the mechanism of caspase-1 activation, its therapeutic potential as a disease target and potential therapeutic strategies targeting caspase-1 with their limitations.
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Affiliation(s)
- Palmi Modi
- Department of Pharmaceutical Chemistry, L. J. Institute of Pharmacy, L J University Ahmedabad - 382 210, Gujarat, India
| | - Bhumi M Shah
- Department of Pharmaceutical Chemistry, L. J. Institute of Pharmacy, L J University Ahmedabad - 382 210, Gujarat, India
| | - Shivani Patel
- Division of Biological and Life Sciences, Ahmedabad University, Ahmedabad, 380009, Gujarat, India.
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18
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Pérez-Gómez JM, Montero-Hidalgo AJ, Fuentes-Fayos AC, Sarmento-Cabral A, Guzmán-Ruiz R, Malagón MM, Herrera-Martínez AD, Gahete MD, Luque RM. Exploring the role of the inflammasomes on prostate cancer: Interplay with obesity. Rev Endocr Metab Disord 2023; 24:1165-1187. [PMID: 37819510 PMCID: PMC10697898 DOI: 10.1007/s11154-023-09838-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/21/2023] [Indexed: 10/13/2023]
Abstract
Obesity is a weight-related disorder characterized by excessive adipose tissue growth and dysfunction which leads to the onset of a systemic chronic low-grade inflammatory state. Likewise, inflammation is considered a classic cancer hallmark affecting several steps of carcinogenesis and tumor progression. In this regard, novel molecular complexes termed inflammasomes have been identified which are able to react to a wide spectrum of insults, impacting several metabolic-related disorders, but their contribution to cancer biology remains unclear. In this context, prostate cancer (PCa) has a markedly inflammatory component, and patients frequently are elderly individuals who exhibit weight-related disorders, being obesity the most prevalent condition. Therefore, inflammation, and specifically, inflammasome complexes, could be crucial players in the interplay between PCa and metabolic disorders. In this review, we will: 1) discuss the potential role of each inflammasome component (sensor, molecular adaptor, and targets) in PCa pathophysiology, placing special emphasis on IL-1β/NF-kB pathway and ROS and hypoxia influence; 2) explore the association between inflammasomes and obesity, and how these molecular complexes could act as the cornerstone between the obesity and PCa; and, 3) compile current clinical trials regarding inflammasome targeting, providing some insights about their potential use in the clinical practice.
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Affiliation(s)
- Jesús M Pérez-Gómez
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), IMIBIC Building, Av. Menéndez Pidal s/n, 14004, Córdoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
| | - Antonio J Montero-Hidalgo
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), IMIBIC Building, Av. Menéndez Pidal s/n, 14004, Córdoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
| | - Antonio C Fuentes-Fayos
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), IMIBIC Building, Av. Menéndez Pidal s/n, 14004, Córdoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
| | - André Sarmento-Cabral
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), IMIBIC Building, Av. Menéndez Pidal s/n, 14004, Córdoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
| | - Rocio Guzmán-Ruiz
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), IMIBIC Building, Av. Menéndez Pidal s/n, 14004, Córdoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
| | - María M Malagón
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), IMIBIC Building, Av. Menéndez Pidal s/n, 14004, Córdoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
| | - Aura D Herrera-Martínez
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), IMIBIC Building, Av. Menéndez Pidal s/n, 14004, Córdoba, Spain
- Hospital Universitario Reina Sofía (HURS), Cordoba, Spain
- Endocrinology and Nutrition Service, HURS/IMIBIC, Córdoba, Spain
| | - Manuel D Gahete
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), IMIBIC Building, Av. Menéndez Pidal s/n, 14004, Córdoba, Spain
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
- Hospital Universitario Reina Sofía (HURS), Cordoba, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain
| | - Raúl M Luque
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), IMIBIC Building, Av. Menéndez Pidal s/n, 14004, Córdoba, Spain.
- Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain.
- Hospital Universitario Reina Sofía (HURS), Cordoba, Spain.
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain.
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Hidalgo-Gajardo A, Gutiérrez N, Lamazares E, Espinoza F, Escobar-Riquelme F, Leiva MJ, Villavicencio C, Mena-Ulecia K, Montesino R, Altamirano C, Sánchez O, Rivas CI, Ruíz Á, Toledo JR. Co-Formulation of Recombinant Porcine IL-18 Enhances the Onset of Immune Response in a New Lawsonia intracellularis Vaccine. Vaccines (Basel) 2023; 11:1788. [PMID: 38140192 PMCID: PMC10747595 DOI: 10.3390/vaccines11121788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/20/2023] [Accepted: 11/25/2023] [Indexed: 12/24/2023] Open
Abstract
Pig is one of the most consumed meats worldwide. One of the main conditions for pig production is Porcine Enteropathy caused by Lawsonia intracellularis. Among the effects of this disease is chronic mild diarrhea, which affects the weight gain of pigs, generating economic losses. Vaccines available to prevent this condition do not have the desired effect, but this limitation can be overcome using adjuvants. Pro-inflammatory cytokines, such as interleukin 18 (IL-18), can improve an immune response, reducing the immune window of protection. In this study, recombinant porcine IL-18 was produced and expressed in Escherichia coli and Pichia pastoris. The protein's biological activity was assessed in vitro and in vivo, and we determined that the P. pastoris protein had better immunostimulatory activity. A vaccine candidate against L. intracellularis, formulated with and without IL-18, was used to determine the pigs' cellular and humoral immune responses. Animals injected with the candidate vaccine co-formulated with IL-18 showed a significant increase of Th1 immune response markers and an earlier increase of antibodies than those vaccinated without the cytokine. This suggests that IL-18 acts as an immunostimulant and vaccine adjuvant to boost the immune response against the antigens, reducing the therapeutic window of recombinant protein-based vaccines.
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Affiliation(s)
- Angela Hidalgo-Gajardo
- Laboratorio de Biotecnología y Biofármacos, Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, VIII Región, Concepción 4070386, Chile; (A.H.-G.); (M.J.L.); (C.V.); (C.I.R.)
- Centro de Desarrollo e Innovación Biovacuvet SpA, VIII Región, Concepción 4090838, Chile
| | - Nicolás Gutiérrez
- Laboratorio de Biotecnología y Biofármacos, Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, VIII Región, Concepción 4070386, Chile; (A.H.-G.); (M.J.L.); (C.V.); (C.I.R.)
- Centro de Desarrollo e Innovación Biovacuvet SpA, VIII Región, Concepción 4090838, Chile
| | - Emilio Lamazares
- Laboratorio de Biotecnología y Biofármacos, Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, VIII Región, Concepción 4070386, Chile; (A.H.-G.); (M.J.L.); (C.V.); (C.I.R.)
| | - Felipe Espinoza
- Laboratorio de Biotecnología y Biofármacos, Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, VIII Región, Concepción 4070386, Chile; (A.H.-G.); (M.J.L.); (C.V.); (C.I.R.)
- Centro de Desarrollo e Innovación Biovacuvet SpA, VIII Región, Concepción 4090838, Chile
| | - Fernanda Escobar-Riquelme
- Laboratorio de Biotecnología y Biofármacos, Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, VIII Región, Concepción 4070386, Chile; (A.H.-G.); (M.J.L.); (C.V.); (C.I.R.)
| | - María J. Leiva
- Laboratorio de Biotecnología y Biofármacos, Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, VIII Región, Concepción 4070386, Chile; (A.H.-G.); (M.J.L.); (C.V.); (C.I.R.)
| | - Carla Villavicencio
- Laboratorio de Biotecnología y Biofármacos, Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, VIII Región, Concepción 4070386, Chile; (A.H.-G.); (M.J.L.); (C.V.); (C.I.R.)
| | - Karel Mena-Ulecia
- Departamento de Ciencias Biológicas y Químicas, Facultad de Recursos Naturales, Universidad Católica de Temuco, IX Región, Temuco 4813302, Chile;
| | - Raquel Montesino
- Laboratorio de Biotecnología y Biofármacos, Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, VIII Región, Concepción 4070386, Chile; (A.H.-G.); (M.J.L.); (C.V.); (C.I.R.)
| | - Claudia Altamirano
- Laboratorio de Cultivos Celulares, Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, V Región, Valparaíso 2362803, Chile;
| | - Oliberto Sánchez
- Laboratorio de Biotecnología y Biofármacos, Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, VIII Región, Concepción 4070386, Chile; (A.H.-G.); (M.J.L.); (C.V.); (C.I.R.)
| | - Coralia I. Rivas
- Laboratorio de Biotecnología y Biofármacos, Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, VIII Región, Concepción 4070386, Chile; (A.H.-G.); (M.J.L.); (C.V.); (C.I.R.)
| | - Álvaro Ruíz
- Departamento de Patología y Medicina Preventiva, Facultad de Ciencias Veterinarias, Universidad de Concepción, XVI Región, Chillán 3812120, Chile;
| | - Jorge R. Toledo
- Laboratorio de Biotecnología y Biofármacos, Departamento de Fisiopatología, Facultad de Ciencias Biológicas, Universidad de Concepción, VIII Región, Concepción 4070386, Chile; (A.H.-G.); (M.J.L.); (C.V.); (C.I.R.)
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Wu J, Zhang X, Wu D, Jin O, Gu J. Evaluation of causal associations between interleukin-18 levels and immune-mediated inflammatory diseases: a Mendelian randomization study. BMC Med Genomics 2023; 16:306. [PMID: 38031150 PMCID: PMC10685486 DOI: 10.1186/s12920-023-01744-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 11/19/2023] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND Altered interleukin (IL)-18 levels are associated with immune-mediated inflammatory diseases (IMIDs), but no studies have investigated their causal relationship. This study aimed to examine the causal associations between IL-18 and IMIDs. METHODS We performed a two-sample Mendelian randomization (MR) analysis. Genetic variants were selected from genome-wide association study datasets following stringent assessments. We then used these variants as instrumental variables to estimate the causal effects of IL-18 levels on the risk of developing five common IMIDs: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ankylosing spondylitis (AS), and psoriasis. We used the inverse variance-weighted (IVW) method as the primary analysis, with sensitivity analyses performed to avoid potential bias. Reverse-direction MR analyses were performed to rule out the possibility of reverse associations. RESULTS We found that genetically determined higher circulating IL-18 levels were causally associated with a higher risk for SLE (PIVW = 0.009; OR, 1.214; 95% CI, 1.049 - 1.404) and IBD (PIVW < 0.001; OR, 1.142; 95% CI, 1.062 - 1.228), but found no significant associations of IL-18 with RA (PIVW = 0.496; OR, 1.044; 95% CI, 0.923 - 1.180), AS (PIVW = 0.021; OR, 1.181; 95% CI, 1.025 - 1.361), or psoriasis (PIVW = 0.232; OR, 1.198; 95% CI, 0.891 - 1.611). In the reverse direction, no causal relationship existed between SLE or IBD and IL-18 levels. Globally, sensitivity studies using alternative MR methods supported the results that were robust and reliable. The Cochran's Q test, MR-Egger intercept, and MR-Pleiotropy RESidual Sum and Outlier excluded the influence of heterogeneity, horizontal pleiotropy, and outliers. CONCLUSIONS We have demonstrated that elevated IL-18 levels increase the risk of SLE and IBD but not RA, AS, or psoriasis. The results enhanced our understanding of IL-18 in the pathology of IMIDs.
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Affiliation(s)
- Jialing Wu
- Department of Rheumatology and Immunology, Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, 510630, China
| | - Xi Zhang
- Department of Rheumatology and Immunology, Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, 510630, China
| | - Dongze Wu
- Department of Rheumatology and Immunology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Ou Jin
- Department of Rheumatology and Immunology, Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, 510630, China.
| | - Jieruo Gu
- Department of Rheumatology and Immunology, Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, 510630, China.
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21
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Yang K, Zhang J, Zhao Y, Shao Y, Zhai M, Liu H, Zhang L. Whole Genome Resequencing Revealed the Genetic Relationship and Selected Regions among Baicheng-You, Beijing-You, and European-Origin Broilers. BIOLOGY 2023; 12:1397. [PMID: 37997996 PMCID: PMC10669838 DOI: 10.3390/biology12111397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 10/30/2023] [Accepted: 11/01/2023] [Indexed: 11/25/2023]
Abstract
As the only two You-chicken breeds in China, Baicheng-You (BCY) and Beijing-You (BJY) chickens are famous for their good meat quality. However, so far, the molecular basis of germplasm of the two You-chicken breeds is not yet clear. The genetic relationship among BCY, BJY, and European-origin broilers (BRs) was analyzed using whole genome resequencing data to contribute to this issue. A total of 18,852,372 single nucleotide polymorphisms (SNPs) were obtained in this study. After quality control, 8,207,242 SNPs were applied to subsequent analysis. The data indicated that BJY chickens possessed distant distance with BRs (genetic differentiation coefficient (FST) = 0.1681) and BCY (FST = 0.1231), respectively, while BCY and BRs had a closer relationship (FST = 0.0946). In addition, by using FST, cross-population extended haplotype homozygosity (XP-EHH), and cross-population composite likelihood ratio (XP-CLR) methods, we found 374 selected genes between BJY and BRs chickens and 279 selected genes between BCY and BJY chickens, respectively, which contained a number of important candidates or genetic variations associated with feather growth and fat deposition of BJY chickens and potential disease resistance of BCY chickens. Our study demonstrates a genome-wide view of genetic diversity and differentiation among BCY, BJY, and BRs. These results may provide useful information on a molecular basis related to the special characteristics of these broiler breeds, thus enabling us to better understand the formation mechanism of Chinese-You chickens.
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Affiliation(s)
- Kai Yang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (K.Y.); (Y.Z.)
| | - Jian Zhang
- Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China; (J.Z.); (H.L.)
| | - Yuelei Zhao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (K.Y.); (Y.Z.)
| | - Yonggang Shao
- College of Animal Science, Xinjiang Agricultural University, Urumqi 830052, China; (Y.S.); (M.Z.)
| | - Manjun Zhai
- College of Animal Science, Xinjiang Agricultural University, Urumqi 830052, China; (Y.S.); (M.Z.)
| | - Huagui Liu
- Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China; (J.Z.); (H.L.)
| | - Lifan Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; (K.Y.); (Y.Z.)
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22
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Promila L, Joshi A, Khan S, Aggarwal A, Lahiri A. Role of mitochondrial dysfunction in the pathogenesis of rheumatoid arthritis: Looking closely at fibroblast- like synoviocytes. Mitochondrion 2023; 73:62-71. [PMID: 38506094 DOI: 10.1016/j.mito.2023.10.004] [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: 04/27/2023] [Revised: 09/28/2023] [Accepted: 10/28/2023] [Indexed: 03/21/2024]
Abstract
Rheumatoid arthritis (RA) is a chronic, autoimmune, and inflammatory disease that primarily targets the joints, leading to cartilage and bone destruction.Fibroblast-like synoviocytes (FLS) are specialized cells of the synovial lining in the joint that plays a fundamental role in the development of RA. Particularly, FLS of RA patients (RA-FLS) in the joint exhibit specific characteristics like higher invading and immunogenic properties, hyperproliferation, and reduced apoptotic capacity, suggesting a dysfunctional mitochondrial pool in these cells. Mitochondria are emerging as a potential organelle that can decide cellular immunometabolism, invasion properties, and cell death. Accordingly, multiplestudies established that mitochondria are crucial in establishing RA. However, the underlying mechanism of impaired mitochondrial function in RA remains poorly understood. This review will provide an overview of the mitochondrial role in the progression of RA, specifically in the context of FLS biology. We will also outline how mitochondria-centric therapeutics can be achieved that would yield novel avenues of research in pathological mediation and prevention.
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Affiliation(s)
- Lakra Promila
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Anubha Joshi
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Shazia Khan
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Amita Aggarwal
- Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medicine, Lucknow, India
| | - Amit Lahiri
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Hartley B, Bassiouni W, Schulz R, Julien O. The roles of intracellular proteolysis in cardiac ischemia-reperfusion injury. Basic Res Cardiol 2023; 118:38. [PMID: 37768438 DOI: 10.1007/s00395-023-01007-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 08/29/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023]
Abstract
Ischemic heart disease remains a leading cause of human mortality worldwide. One form of ischemic heart disease is ischemia-reperfusion injury caused by the reintroduction of blood supply to ischemic cardiac muscle. The short and long-term damage that occurs due to ischemia-reperfusion injury is partly due to the proteolysis of diverse protein substrates inside and outside of cardiomyocytes. Ischemia-reperfusion activates several diverse intracellular proteases, including, but not limited to, matrix metalloproteinases, calpains, cathepsins, and caspases. This review will focus on the biological roles, intracellular localization, proteolytic targets, and inhibitors of these proteases in cardiomyocytes following ischemia-reperfusion injury. Recognition of the intracellular function of each of these proteases includes defining their activation, proteolytic targets, and their inhibitors during myocardial ischemia-reperfusion injury. This review is a step toward a better understanding of protease activation and involvement in ischemic heart disease and developing new therapeutic strategies for its treatment.
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Affiliation(s)
- Bridgette Hartley
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
| | - Wesam Bassiouni
- Department of Pharmacology, University of Alberta, Edmonton, AB, Canada
| | - Richard Schulz
- Department of Pharmacology, University of Alberta, Edmonton, AB, Canada.
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
- Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada.
- Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada.
| | - Olivier Julien
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
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Rybi Szumińska A, Wasilewska A, Kamianowska M. Protein Biomarkers in Chronic Kidney Disease in Children-What Do We Know So Far? J Clin Med 2023; 12:3934. [PMID: 37373629 DOI: 10.3390/jcm12123934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/26/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
Chronic kidney disease (CKD) in children is a major concern of medical care and public health as it is related to high morbidity and mortality due to progression to end-stage kidney disease (ESKD). It is essential to identify patients with a risk of developing CKD to implement therapeutic interventions. Unfortunately, conventional markers of CKD, such as serum creatinine, glomerular filtration rate (GFR) and proteinuria, have many limitations in serving as an early and specific diagnostic tool for this condition. Despite the above, they are still the most frequently utilized as we do not have better. Studies from the last decade identified multiple CKD blood and urine protein biomarkers but mostly assessed the adult population. This article outlines some recent achievements and new perspectives in finding a set of protein biomarkers that might improve our ability to prognose CKD progression in children, monitor the response to treatment, or even become a potential therapeutic target.
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Affiliation(s)
- Agnieszka Rybi Szumińska
- Department of Peadiatrics and Nephrology, Medical University of Bialystok, Waszyngtona 17, 15-297 Bialystok, Poland
| | - Anna Wasilewska
- Department of Peadiatrics and Nephrology, Medical University of Bialystok, Waszyngtona 17, 15-297 Bialystok, Poland
| | - Monika Kamianowska
- Department of Peadiatrics and Nephrology, Medical University of Bialystok, Waszyngtona 17, 15-297 Bialystok, Poland
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Shao C, Lu L. PAR2 Overexpression is Involved in the Occurrence of Hyperoxygen-Induced Bronchopulmonary Dysplasia in Rats. Fetal Pediatr Pathol 2023; 42:423-437. [PMID: 36657618 DOI: 10.1080/15513815.2023.2166799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND Bronchopulmonary dysplasia is a chronic lung disease commonly seen in preterm infants. It is characterized by delayed development of the alveoli and lung fibrosis. Protease-activated receptor 2 (PAR2) is an inflammatory driver that plays a proinflammatory role mainly through the P38 MAPK/NF-κB signaling pathway. METHODS Newborn rat pups were kept under air or oxygen at >60% concentration. Lung tissues were collected at postnatal days (P) 1, 4, 7, and 10 to observe pathological changes and take measurements. RESULTS In the hyperoxic group, P4 and P7 rats showed delayed alveolar development, septal thickening, and disturbances in alveolar structure.PAR2, P38 MAPK, NF-κB, and IL-18 expression at P4, P7, and P10 was significantly higher than in the air group. CONCLUSION PAR2 is involved in lung injury induced by persistent hyperoxia. Activated PAR2 promotes IL-18 overexpression through the P38 MAPK/NF-κB signaling pathway, which may be an important mechanism of PAR2-mediated lung injury in bronchopulmonary dysplasia.
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Affiliation(s)
- Chunyan Shao
- Department of Pediatrics, Chengdu Medical College, Chengdu, China
| | - Liqun Lu
- Department of Pediatrics, The First Affiliated Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, China
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Wang X, Wang L, Wen X, Zhang L, Jiang X, He G. Interleukin-18 and IL-18BP in inflammatory dermatological diseases. Front Immunol 2023; 14:955369. [PMID: 36742296 PMCID: PMC9889989 DOI: 10.3389/fimmu.2023.955369] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 01/02/2023] [Indexed: 01/19/2023] Open
Abstract
Interleukin (IL)-18, an interferon-γ inducer, belongs to the IL-1 family of pleiotropic pro-inflammatory factors, and IL-18 binding protein (IL-18BP) is a native antagonist of IL-18 in vivo, regulating its activity. Moreover, IL-18 exerts an influential function in host innate and adaptive immunity, and IL-18BP has elevated levels of interferon-γ in diverse cells, suggesting that IL-18BP is a negative feedback inhibitor of IL-18-mediated immunity. Similar to IL-1β, the IL-18 cytokine is produced as an indolent precursor that requires further processing into an active cytokine by caspase-1 and mediating downstream signaling pathways through MyD88. IL-18 has been implicated to play a role in psoriasis, atopic dermatitis, rosacea, and bullous pemphigoid in human inflammatory skin diseases. Currently, IL-18BP is less explored in treating inflammatory skin diseases, while IL-18BP is being tested in clinical trials for other diseases. Thereby, IL-18BP is a prospective therapeutic target.
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Affiliation(s)
- Xiaoyun Wang
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China,Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Lian Wang
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiang Wen
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Zhang
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
| | - Xian Jiang
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China,Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Xian Jiang, ; Gu He,
| | - Gu He
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China,Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Xian Jiang, ; Gu He,
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Sil S, Bertilla J, Rupachandra S. A comprehensive review on RNA interference-mediated targeting of interleukins and its potential therapeutic implications in colon cancer. 3 Biotech 2023; 13:18. [PMID: 36568500 PMCID: PMC9768089 DOI: 10.1007/s13205-022-03421-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
Colon cancer is the world's fourth leading cause of death. It is cancer of the latter part of the large intestine, i.e. the colon. Chronic inflammation over a long period also leads to the development of cancer. Cancer in the colon region is arduous to diagnose and is detected at a later stage when it metastasizes to other parts of the body like the liver, lungs, peritoneum, etc. Colon cancer is a great example of solid tumours associated with chronic inflammation. Although conventional therapies are effective, they lose their effectiveness beyond a certain point. Relapse of the disease occurs frequently. RNA interference (RNAi) is emerging as a great tool to specifically attack the cancer cells of a target site like the colon. RNAi deals with epigenetic changes made in the defective cells which ultimately leads to their death without harming the healthy cells. In this review, two types of epigenetic modulators have been considered, namely siRNA and miRNA, and their effect on interleukins. Interleukins, a class of cytokines, are major inflammatory responses of the body that are released by immune cells like leukocytes and macrophages. Some of these interleukins are pro-inflammatory, thereby promoting inflammation which eventually causes cancer. RNAi can prevent colon cancer by inhibiting pro-inflammatory interleukins.
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Affiliation(s)
- Sagari Sil
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu 603 203 India
| | - Janet Bertilla
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu 603 203 India
| | - S. Rupachandra
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu 603 203 India
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A Novel Pyroptosis-Related Gene Signature for Prediction of Disease-Free Survival in Papillary Thyroid Carcinoma. J Pers Med 2022; 13:jpm13010085. [PMID: 36675746 PMCID: PMC9863179 DOI: 10.3390/jpm13010085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 12/24/2022] [Accepted: 12/27/2022] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND The incidence and recurrence rate of papillary thyroid carcinoma (PTC) are high. Thus, it is critical to accurately identify patients at high risk of recurrence. Pyroptosis is a type of programmed cell death closely related to the progression and prognosis of cancer. However, the role of pyroptosis in PTC remains unclear. METHODS Transcriptome data for PTC patients were obtained from The Cancer Genome Atlas database. The expression level of pyroptosis-related genes (PRGs) in PTC and normal tissues was identified. Based on these differentially expressed genes, a risk score model of disease-free survival (DFS) was established using least absolute shrinkage and selection operator Cox regression. In-cluster and quantitative real-time PCR validations were carried out. A nomogram, in combination with clinical factors, was also established. In addition, its relationship with immune characteristics and tumor gene mutations is discussed. RESULTS A risk score model with four PRGs, including CASP6, CASP9, IL-18, and NOD1, was established. The samples were divided into high- and low-risk clusters, according to the risk score, revealing significant differences in DFS between the two clusters. A nomogram was established combining age, lymph node metastasis and extrathyroidal extension. The area under the curve (AUC) of predicting one-, five-, and 10-year DFS in PTC patients was 0.745, 0.801, and 0.803, respectively. The low-risk cluster showed higher levels of immune infiltration and immune checkpoint gene expression, while the high-risk cluster demonstrated a higher tumor mutation burden. CONCLUSION A predictive DFS model was established, based on PRGs, which may aid in identifying patients at high risk of recurrence. The present study helps to better understand the role of pyroptosis in the progression and prognosis of PTC.
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IL-18 deficiency ameliorates the progression from AKI to CKD. Cell Death Dis 2022; 13:957. [PMID: 36379914 PMCID: PMC9666542 DOI: 10.1038/s41419-022-05394-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 10/29/2022] [Accepted: 10/31/2022] [Indexed: 11/16/2022]
Abstract
Inflammation is an important factor in the progression from acute kidney injury (AKI) to chronic kidney disease (CKD). The role of interleukin (IL)-18 in this progression has not been examined. We aimed to clarify whether and how IL-18 limits this progression. In a folic acid induced renal injury mouse model, we studied the time course of kidney injury and renal IL-18 expression. In wild-type mice following injection, renal IL-18 expression increased. In parallel, we characterized other processes, including at day 2, renal tubular necroptosis assessed by receptor-interacting serine/threonine-protein kinase1 (RIPK1) and RIPK3; at day 14, transdifferentiation (assessed by transforming growth factor β1, vimentin and E-cadherin); and at day 30, fibrosis (assessed by collagen 1). In IL-18 knockout mice given folate, compared to wild-type mice, tubular damage and necroptosis, transdifferentiation, and renal fibrosis were attenuated. Importantly, IL-18 deletion decreased numbers of renal M1 macrophages and M1 macrophage cytokine levels at day 14, and reduced M2 macrophages numbers and macrophage cytokine expression at day 30. In HK-2 cells, IL-18 knockdown attenuated necroptosis, transdifferentiating and fibrosis.In patients with tubulointerstitial nephritis, IL-18 protein expression was increased on renal biopsies using immunohistochemistry. We conclude that genetic IL-18 deficiency ameliorates renal tubular damage, necroptosis, cell transdifferentiation, and fibrosis. The renoprotective role of IL-18 deletion in the progression from AKI to fibrosis may be mediated by reducing a switch in predominance from M1 to profibrotic M2 macrophages during the process of kidney repair.
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Huang CH, Fan JH, Jeng WJ, Chang ST, Yang CK, Teng W, Wu TH, Hsieh YC, Chen WT, Chen YC, Sheen IS, Lin YC, Lin CY. Innate-like bystander-activated CD38 + HLA-DR + CD8 + T cells play a pathogenic role in patients with chronic hepatitis C. Hepatology 2022; 76:803-818. [PMID: 35060158 DOI: 10.1002/hep.32349] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 01/07/2022] [Accepted: 01/12/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS HCV-specific T cells are few and exhausted in patients with chronic hepatitis C (CHC). Whether these T cells are responsible for the liver damage and fibrosis is still debated. However, cluster of differentiation 38-positive (CD38+ ) human leukocyte antigen DR-positive (HLA-DR+ ) CD8+ T cells are regarded as bystander CD8+ T cells that cause liver injury in acute hepatitis. We propose that these innate CD8+ T cells play a pathogenic role in CHC. METHODS Lymphocytes from peripheral blood were obtained from 108 patients with CHC and 43 healthy subjects. Immunophenotyping, functional assays, T-cell receptor (TCR) repertoire, and cytotoxic assay of CD38+ HLA-DR+ CD8+ T cells were studied. RESULTS The percentage of CD38+ HLA-DR+ CD8+ T cells increased significantly in patients with CHC. These cells expressed higher levels of effector memory and proinflammatory chemokine molecules and showed higher interferon-γ production than CD38- HLA-DR- CD8 T cells. They were largely composed of non-HCV-specific CD8+ T cells as assessed by HLA-A2-restricted pentamers and next-generation sequencing analysis of the TCR repertoire. In addition, these CD38+ HLA-DR+ CD8+ T cells had strong cytotoxicity, which could be inhibited by anti-DNAX accessory molecule 1, anti-NKG2 family member D, and anti-natural killer NKp30 antibodies. Lastly, the percentage of CD38+ HLA-DR+ CD8+ T cells was significantly associated with liver injury and fibrosis and decreased significantly along with serum alanine aminotransferase normalization after successful direct-acting antiviral treatment. CONCLUSIONS The TCR-independent, cytokine-responsive bystander CD38+ HLA-DR+ CD8+ T cells are strongly cytotoxic and play a pathogenic role in patients with CHC.
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Affiliation(s)
- Chien-Hao Huang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Jian-He Fan
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Shu-Ting Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Chan-Keng Yang
- Division of Medical Oncology/Hematology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wei Teng
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Tsung-Han Wu
- Division of General Surgery, Chang-Gung Memorial Hospital, Linkou Medical Center, Taiwan
| | - Yi-Chung Hsieh
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Wei-Ting Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Yi-Cheng Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - I-Shyan Sheen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
| | - Yung-Chang Lin
- Division of Medical Oncology/Hematology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chun-Yen Lin
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,College of Medicine, Chang-Gung University, Taoyuan, Taiwan
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Cincotta AH, Cersosimo E, Alatrach M, Ezrokhi M, Agyin C, Adams J, Chilton R, Triplitt C, Chamarthi B, Cominos N, DeFronzo RA. Bromocriptine-QR Therapy Reduces Sympathetic Tone and Ameliorates a Pro-Oxidative/Pro-Inflammatory Phenotype in Peripheral Blood Mononuclear Cells and Plasma of Type 2 Diabetes Subjects. Int J Mol Sci 2022; 23:ijms23168851. [PMID: 36012132 PMCID: PMC9407769 DOI: 10.3390/ijms23168851] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/01/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022] Open
Abstract
Bromocriptine-QR is a sympatholytic dopamine D2 agonist for the treatment of type 2 diabetes that has demonstrated rapid (within 1 year) substantial reductions in adverse cardiovascular events in this population by as yet incompletely delineated mechanisms. However, a chronic state of elevated sympathetic nervous system activity and central hypodopaminergic function has been demonstrated to potentiate an immune system pro-oxidative/pro-inflammatory condition and this immune phenotype is known to contribute significantly to the advancement of cardiovascular disease (CVD). Therefore, the possibility exists that bromocriptine-QR therapy may reduce adverse cardiovascular events in type 2 diabetes subjects via attenuation of this underlying chronic pro-oxidative/pro-inflammatory state. The present study was undertaken to assess the impact of bromocriptine-QR on a wide range of immune pro-oxidative/pro-inflammatory biochemical pathways and genes known to be operative in the genesis and progression of CVD. Inflammatory peripheral blood mononuclear cell biology is both a significant contributor to cardiovascular disease and also a marker of the body’s systemic pro-inflammatory status. Therefore, this study investigated the effects of 4-month circadian-timed (within 2 h of waking in the morning) bromocriptine-QR therapy (3.2 mg/day) in type 2 diabetes subjects whose glycemia was not optimally controlled on the glucagon-like peptide 1 receptor agonist on (i) gene expression status (via qPCR) of a wide array of mononuclear cell pro-oxidative/pro-inflammatory genes known to participate in the genesis and progression of CVD (OXR1, NRF2, NQO1, SOD1, SOD2, CAT, GSR, GPX1, GPX4, GCH1, HMOX1, BiP, EIF2α, ATF4, PERK, XBP1, ATF6, CHOP, GSK3β, NFkB, TXNIP, PIN1, BECN1, TLR2, TLR4, TLR10, MAPK8, NLRP3, CCR2, GCR, L-selectin, VCAM1, ICAM1) and (ii) humoral measures of sympathetic tone (norepinephrine and normetanephrine), whole-body oxidative stress (nitrotyrosine, TBARS), and pro-inflammatory factors (IL-1β, IL-6, IL-18, MCP-1, prolactin, C-reactive protein [CRP]). Relative to pre-treatment status, 4 months of bromocriptine-QR therapy resulted in significant reductions of mRNA levels in PBMC endoplasmic reticulum stress-unfolded protein response effectors [GRP78/BiP (34%), EIF2α (32%), ATF4 (29%), XBP1 (25%), PIN1 (14%), BECN1 (23%)], oxidative stress response proteins [OXR1 (31%), NRF2 (32%), NQO1 (39%), SOD1 (52%), CAT (26%), GPX1 (33%), GPX4 (31%), GCH1 (30%), HMOX1 (40%)], mRNA levels of TLR pro-inflammatory pathway proteins [TLR2 (46%), TLR4 (20%), GSK3β (19%), NFkB (33%), TXNIP (18%), NLRP3 (32%), CCR2 (24%), GCR (28%)], mRNA levels of pro-inflammatory cellular receptor proteins CCR2 and GCR by 24% and 28%, and adhesion molecule proteins L-selectin (35%) and VCAM1 (24%). Relative to baseline, bromocriptine-QR therapy also significantly reduced plasma levels of norepinephrine and normetanephrine by 33% and 22%, respectively, plasma pro-oxidative markers nitrotyrosine and TBARS by 13% and 10%, respectively, and pro-inflammatory factors IL-18, MCP1, IL-1β, prolactin, and CRP by 21%,13%, 12%, 42%, and 45%, respectively. These findings suggest a unique role for circadian-timed bromocriptine-QR sympatholytic dopamine agonist therapy in reducing systemic low-grade sterile inflammation to thereby reduce cardiovascular disease risk.
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Affiliation(s)
- Anthony H. Cincotta
- VeroScience LLC, Tiverton, RI 02878, USA
- Correspondence: ; Tel.: +1-401-816-0525
| | - Eugenio Cersosimo
- Texas Diabetes Institute, University Health System, San Antonio, TX 78207, USA
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Mariam Alatrach
- Texas Diabetes Institute, University Health System, San Antonio, TX 78207, USA
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | | | - Christina Agyin
- Texas Diabetes Institute, University Health System, San Antonio, TX 78207, USA
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - John Adams
- Texas Diabetes Institute, University Health System, San Antonio, TX 78207, USA
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Robert Chilton
- Texas Diabetes Institute, University Health System, San Antonio, TX 78207, USA
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Curtis Triplitt
- Texas Diabetes Institute, University Health System, San Antonio, TX 78207, USA
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | | | | | - Ralph A. DeFronzo
- Texas Diabetes Institute, University Health System, San Antonio, TX 78207, USA
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
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Comparative Evaluation of Gingival Crevicular Fluid Interleukin-17, 18 and 21 in Different Stages of Periodontal Health and Disease. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58081042. [PMID: 36013509 PMCID: PMC9415654 DOI: 10.3390/medicina58081042] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/24/2022] [Accepted: 07/25/2022] [Indexed: 11/17/2022]
Abstract
Background and Objectives: The elicitation of a host’s immune−inflammatory responses to overcome oral bacterial biofilm challenges is mediated by numerous cytokines. We explored the role of three such cytokines, viz. interleukin (IL)-17, 18 and 21, by measuring their levels in the gingival crevicular fluid (GCF) of Indian individuals with healthy gingiva, chronic gingivitis, or chronic periodontitis. Materials and Method: Ninety systemically healthy individuals were enrolled in the study on the basis of predefined criteria and were categorized into three groups of 30 participants each. Groups A, B and C were composed of a control group with healthy gingiva, subjects with chronic gingivitis and subjects with chronic periodontitis, respectively. The periodontal disease status was assessed on the basis of a subject’s gingival index, probing pocket depth, clinical attachment loss and radiographic evidence of bone loss. After the complete history-taking and identification of gingival sulcus/pocket depth areas for GCF collection, a sample was collected from each subject in all groups for an estimation of the cytokine levels using ELISA. Statistical analysis was performed using SPSS v 21.0. Intergroup comparisons were conducted using a post hoc Tukey’s test. A value of p < 0.05 was considered to be statistically significant. Results: The mean IL-17, 18 and 21 concentrations in pg/mL was the greatest for Group C (99.67 ± 18.85, 144.61 ± 20.83 and 69.67 ± 12.46, respectively), followed by Group B (19.27 ± 2.78, 22.27 ± 2.43 and 22.74 ± 1.43, respectively) and finally by Group A (healthy control; 11.56 ± 0.99, 17.94 ± 1.24 and 12.83 ± 1.21 respectively). A statistically significant difference in the mean concentrations of two interleukins (IL-17 and IL-18) was observed between Groups A and C and also between Groups B and C. A statistically significant difference in the mean concentrations of IL-21 was observed between Groups B and C. Conclusions: Within the limitations of the present study, the findings revealed that the GCF levels of IL-17, IL-18 and IL-21 rose and correlated well with the severity of the disease. Thus, these cytokines present in GCF have the potential to be considered as biomarkers for periodontal tissue destruction. IL-21 in particular appears to be a promising biomarker for differentiating between gingivitis and periodontitis.
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Liu YH, Chen YH, Ko CH, Kuo CW, Yen CC, Chen W, Chong KY, Chen CM. SOD3 and IL-18 Predict the First Kidney Disease-Related Hospitalization or Death during the One-Year Follow-Up Period in Patients with End-Stage Renal Disease. Antioxidants (Basel) 2022; 11:antiox11061198. [PMID: 35740095 PMCID: PMC9231321 DOI: 10.3390/antiox11061198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/14/2022] [Accepted: 06/16/2022] [Indexed: 01/27/2023] Open
Abstract
End-stage renal disease (ESRD) patients experience oxidative stress due to excess exogenous or endogenous oxidants and insufficient antioxidants. Hence, oxidative stress and inflammation cause endothelial damage, contributing to vascular dysfunction and atherosclerosis. Therefore, ESRD patients suffer more cardiovascular and hospitalization events than healthy people. This study aims to test the correlations between ROS, SOD3, IL-2, IL-6, and IL-18 and the first kidney disease-related hospitalization or death events in ESRD patients undergoing regular hemodialysis. A total of 212 participants was enrolled, including 45 normal healthy adults and 167 ESRD patients on regular dialysis. Blood samples from all participants were collected for ROS, SOD3, IL-2, IL-6, and IL-18 measurement at the beginning of the study, and every kidney disease-related admission or death was recorded for the next year. Multivariate analysis was conducted by fitting a linear regression model, logistic regression model, and Cox proportional hazards model to estimate the adjusted effects of risk factors, prognostic factors, or predictors on continuous, binary, and survival outcome data. The results showed that plasma SOD3 and serum IL-18 were two strong predictors of the first kidney disease-related hospitalization or death. In the Cox proportional hazards models (run in R), higher IL-18 concentration (>69.054 pg/mL) was associated with a hazard ratio of 3.376 for the first kidney disease-related hospitalization or death (95% CI: 1.2644 to 9.012), while log(SOD3) < 4.723 and dialysis clearance (Kt/V; 1.11 < value < 1.869) had a hazard ratio = 0.2730 (95% CI: 0.1133 to 0.6576) for reducing future kidney disease-related hospitalization or death. Other markers, including body mass index (BMI), transferrin saturation, total iron binding capacity, and sodium and alkaline phosphate, were also found to be significant in our study. These results reveal the new predictors SOD3 and IL-18 for the medical care of end-stage renal disease patients.
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Affiliation(s)
- Yu-Hsien Liu
- Department of Life Sciences, Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan; (Y.-H.L.); (Y.-H.C.); (C.-H.K.); (C.-W.K.)
- Department of Internal Medicine, Jen-Ai Hospital, Dali Branch, Taichung 402, Taiwan
| | - Yu-Hsuan Chen
- Department of Life Sciences, Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan; (Y.-H.L.); (Y.-H.C.); (C.-H.K.); (C.-W.K.)
| | - Chi-Hua Ko
- Department of Life Sciences, Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan; (Y.-H.L.); (Y.-H.C.); (C.-H.K.); (C.-W.K.)
- Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Yunlin 638, Taiwan
| | - Chia-Wen Kuo
- Department of Life Sciences, Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan; (Y.-H.L.); (Y.-H.C.); (C.-H.K.); (C.-W.K.)
- Department of Internal Medicine, Taichung Armed Forces General Hospital, Taichung 411, Taiwan
| | - Chih-Ching Yen
- Department of Internal Medicine, China Medical University Hospital, College of Health Care, China Medical University, Taichung 404, Taiwan;
| | - Wei Chen
- Division of Pulmonary and Critical Care Medicine, Chia-Yi Christian Hospital, Chiayi 600, Taiwan;
| | - Kowit-Yu Chong
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Hyperbaric Oxygen Medical Research Lab, Bone and Joint Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan
- Correspondence: (K.-Y.C.); (C.-M.C.); Tel.: +886-4-2285-6309 (K.-Y.C.); +886-2-2118393 (C.-M.C.)
| | - Chuan-Mu Chen
- Department of Life Sciences, Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan; (Y.-H.L.); (Y.-H.C.); (C.-H.K.); (C.-W.K.)
- The iEGG and Animal Biotechnology Center, The Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Correspondence: (K.-Y.C.); (C.-M.C.); Tel.: +886-4-2285-6309 (K.-Y.C.); +886-2-2118393 (C.-M.C.)
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Pro- and anti-inflammatory bioactive lipids imbalance contributes to the pathobiology of autoimmune diseases. Eur J Clin Nutr 2022:10.1038/s41430-022-01173-8. [PMID: 35701524 DOI: 10.1038/s41430-022-01173-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 04/22/2022] [Accepted: 05/26/2022] [Indexed: 12/27/2022]
Abstract
Autoimmune diseases are driven by TH17 cells that secrete pro-inflammatory cytokines, especially IL-17. Under normal physiological conditions, autoreactive T cells are suppressed by TGF-β and IL-10 secreted by microglia and dendritic cells. When this balance is upset due to injury, infection and other causes, leukocyte recruitment and macrophage activation occurs resulting in secretion of pro-inflammatory IL-6, TNF-α, IL-17 and PGE2, LTs (leukotrienes) accompanied by a deficiency of anti-inflammatory LXA4, resolvins, protecting, and maresins. PGE2 facilitates TH1 cell differentiation and promotes immune-mediated inflammation through TH17 expansion. There is evidence to suggest that autoimmune diseases can be suppressed by anti-inflammatory bioactive lipids LXA4, resolvins, protecting, and maresins. These results imply that systemic and/or local application of LXA4, resolvins, protecting, and maresins and administration of their precursors AA/EPA/DHA could form a potential therapeutic approach in the prevention and treatment of autoimmune diseases.
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Upamalika SWAM, Wannige CT, Vidanagamachchi SM, Gunasekara SC, Kolli RT, De Silva PMCS, Kulasiri D, Jayasundara N. A review of molecular mechanisms linked to potential renal injury agents in tropical rural farming communities. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2022; 92:103850. [PMID: 35301132 DOI: 10.1016/j.etap.2022.103850] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 03/09/2022] [Accepted: 03/11/2022] [Indexed: 06/14/2023]
Abstract
The chronic kidney disease of unknown etiology (CKDu) is a global health concern primarily impacting tropical farming communities. Although the precise etiology is debated, CKDu is associated with environmental exposures including heat stress and chemical contaminants such as fluoride, heavy metals, and herbicide glyphosate. However, a comprehensive synthesis is lacking on molecular networks underpinning renal damage induced by these factors. Addressing this gap, here we present key molecular events associated with heat and chemical exposures. We identified that caspase activation and lipid peroxidation are common endpoints of glyphosate exposure, while vasopressin and polyol pathways are associated with heat stress and dehydration. Heavy metal exposure is shown to induce lipid peroxidation and endoplasmic reticulum stress from ROS activated MAPK, NFĸB, and caspase. Collectively, we identify that environmental exposure induced increased cellular oxidative stress as a common mechanism mediating renal cell inflammation, apoptosis, and necrosis, likely contributing to CKDu initiation and progression.
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Affiliation(s)
| | | | | | | | - Ramya Tulasi Kolli
- Nicholas School of the Environment, Duke University, NC 27708, United States.
| | | | - Don Kulasiri
- Department of Molecular Biosciences, and Centre for Advanced Computational Solutions (C-fACS), Lincoln University, New Zealand.
| | - Nishad Jayasundara
- Nicholas School of the Environment, Duke University, NC 27708, United States.
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36
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Thomas JM, Huuskes BM, Sobey CG, Drummond GR, Vinh A. The IL-18/IL-18R1 signalling axis: Diagnostic and therapeutic potential in hypertension and chronic kidney disease. Pharmacol Ther 2022; 239:108191. [PMID: 35461924 DOI: 10.1016/j.pharmthera.2022.108191] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/13/2022] [Accepted: 04/14/2022] [Indexed: 02/06/2023]
Abstract
Chronic kidney disease (CKD) is inherently an inflammatory condition, which ultimately results in the development of end stage renal disease or cardiovascular events. Low-grade inflammatory diseases such as hypertension and diabetes are leading causes of CKD. Declines in renal function correlate with elevated circulating pro-inflammatory cytokines in patients with these conditions. The inflammasome is an important inflammatory signalling platform that has been associated with low-grade chronic inflammatory diseases. Notably, activation and assembly of the inflammasome causes the auto cleavage of pro-caspase-1 into its active form, which then processes the pro-inflammatory cytokines pro-interleukin (IL)-1β and pro-IL-18 into their active forms. Currently, the nod-like receptor protein 3 (NLRP3) inflammasome has been implicated in the development of CKD in pre-clinical and clinical settings, and the ablation or inhibition of inflammasome components have been shown to be reno-protective in models of CKD. While clinical trials have demonstrated that neutralisation of IL-1β signalling by the drug anakinra lowers inflammation markers in haemodialysis patients, ongoing preclinical studies are showing that this ability to attenuate disease is limited in progressive models of kidney disease. These results suggest a potential predominant role for IL-18 in the development of CKD. This review will discuss the role of the inflammasome and its pro-inflammatory product IL-18 in the development of renal fibrosis and inflammation that contribute to the pathophysiology of CKD. Furthermore, we will examine the potential of the IL-18 signalling axis as an anti-inflammatory target in CKD and its usefulness as diagnostic biomarker to predict acute kidney injury.
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Affiliation(s)
- Jordyn M Thomas
- Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Brooke M Huuskes
- Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology & Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, Australia
| | - Christopher G Sobey
- Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology & Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, Australia
| | - Grant R Drummond
- Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology & Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, Australia.
| | - Antony Vinh
- Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology & Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, Victoria, Australia
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37
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Mycobacterium bovis Wild-Type BCG or Recombinant BCG Secreting Murine IL-18 (rBCG/IL-18) Strains in Driving Immune Responses in Immunocompetent or Immunosuppressed Mice. Vaccines (Basel) 2022; 10:vaccines10040615. [PMID: 35455364 PMCID: PMC9030902 DOI: 10.3390/vaccines10040615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 04/10/2022] [Accepted: 04/12/2022] [Indexed: 12/04/2022] Open
Abstract
Mycobacterium tuberculosis infections remain a global health problem in immunosuppressed patients. The effectiveness of BCG (Bacillus Calmette−Guérin), an anti-tuberculosis vaccine, is unsatisfactory. Finding a new vaccine candidate is a priority. We compared numerous immune markers in BCG-susceptible C57BL/6 and BCG-resistant C3H mice who had been injected with 0.9% NaCl (control) or with wild-type BCG or recombinant BCG secreting interleukin (IL)-18 (rBCG/IL-18) and in immunized mice who were immunocompromised with cyclophosphamide (CTX). The inoculation of rBCG/IL-18 in immunocompetent mice increased the percentage of bone marrow myeloblasts and promyelocytes, which were further elevated in the rBCG/IL-18/CTX-treated mice: C57BL/6 mice—3.0% and 11.4% (control) vs. 18.6% and 42.4%, respectively; C3H mice—1.1% and 7.7% (control) vs. 18.4% and 44.9%, respectively, p < 0.05. The bone marrow cells showed an increased mean fluorescence index (MFI) in the CD34 adhesion molecules: C57BL/6 mice—4.0 × 103 (control) vs. 6.2 × 103; C3H mice—4.0 × 103 (control) vs. 8.0 × 103, p < 0.05. Even in the CTX-treated mice, the rBCG/IL-18 mobilized macrophages for phagocytosis, C57BL/6 mice—4% (control) vs. 8%; C3H mice—2% (control) vs. 6%, and in immunocompetent mice, C57BL/6 induced the spleen homing of effector memory CD4+ and CD8+ T cells (TEM), 15% (control) vs. 28% and 8% (control) vs. 22%, respectively, p < 0.05. In conclusion, rBCG/IL-18 effectively induced selected immune determinants that were maintained even in immunocompromised mice.
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38
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Mahamar A, Gonzales Hurtado PA, Morrison R, Boone R, Attaher O, Diarra BS, Gaoussou S, Issiaka D, Dicko A, Duffy PE, Fried M. Plasma biomarkers of hemoglobin loss in Plasmodium falciparum-infected children identified by quantitative proteomics. Blood 2022; 139:2361-2376. [PMID: 34871370 PMCID: PMC9012130 DOI: 10.1182/blood.2021014045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/23/2021] [Indexed: 11/20/2022] Open
Abstract
Anemia is common among young children infected with Plasmodium falciparum and severe malarial anemia (SMA) is a major cause of their mortality. Two major mechanisms cause malarial anemia: hemolysis of uninfected as well as infected erythrocytes and insufficient erythropoiesis. In a longitudinal birth cohort in Mali, we commonly observed marked hemoglobin reductions during P falciparum infections with a small proportion that progressed to SMA. We sought biomarkers of these processes using quantitative proteomic analysis on plasma samples from 9 P falciparum-infected children, comparing those with reduced hemoglobin (with or without SMA) vs those with stable hemoglobin. We identified higher plasma levels of circulating 20S proteasome and lower insulin-like growth factor-1 (IGF-1) levels in children with reduced hemoglobin. We confirmed these findings in independent enzyme-linked immunosorbent assay-based validation studies of subsets of children from the same cohort (20S proteasome, N = 71; IGF-1, N = 78). We speculate that circulating 20S proteasome plays a role in digesting erythrocyte membrane proteins modified by oxidative stress, resulting in hemolysis, whereas decreased IGF-1, a critical factor for erythroid maturation, might contribute to insufficient erythropoiesis. Quantitative plasma proteomics identified soluble mediators that may contribute to the major mechanisms underlying malarial anemia. This study was registered at www.clinicaltrials.gov as #NCT01168271.
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Affiliation(s)
- Almahamoudou Mahamar
- Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Dentistry, University of Sciences Techniques and Technologies of Bamako, Bamako, Mali; and
| | | | - Robert Morrison
- Pathogenesis and Immunity Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Rachel Boone
- Molecular Pathogenesis and Biomarkers Section and
| | - Oumar Attaher
- Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Dentistry, University of Sciences Techniques and Technologies of Bamako, Bamako, Mali; and
| | - Bacary S Diarra
- Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Dentistry, University of Sciences Techniques and Technologies of Bamako, Bamako, Mali; and
| | - Santara Gaoussou
- Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Dentistry, University of Sciences Techniques and Technologies of Bamako, Bamako, Mali; and
| | - Djibrilla Issiaka
- Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Dentistry, University of Sciences Techniques and Technologies of Bamako, Bamako, Mali; and
| | - Alassane Dicko
- Malaria Research and Training Center, Faculty of Medicine, Pharmacy and Dentistry, University of Sciences Techniques and Technologies of Bamako, Bamako, Mali; and
| | - Patrick E Duffy
- Pathogenesis and Immunity Section, Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Michal Fried
- Molecular Pathogenesis and Biomarkers Section and
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Breitinger U, Farag NS, Sticht H, Breitinger HG. Viroporins: Structure, function, and their role in the life cycle of SARS-CoV-2. Int J Biochem Cell Biol 2022; 145:106185. [PMID: 35219876 PMCID: PMC8868010 DOI: 10.1016/j.biocel.2022.106185] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/15/2022] [Accepted: 02/21/2022] [Indexed: 12/12/2022]
Abstract
Viroporins are indispensable for viral replication. As intracellular ion channels they disturb pH gradients of organelles and allow Ca2+ flux across ER membranes. Viroporins interact with numerous intracellular proteins and pathways and can trigger inflammatory responses. Thus, they are relevant targets in the search for antiviral drugs. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) underlies the world-wide pandemic of COVID-19, where an effective therapy is still lacking despite impressive progress in the development of vaccines and vaccination campaigns. Among the 29 proteins of SARS-CoV-2, the E- and ORF3a proteins have been identified as viroporins that contribute to the massive release of inflammatory cytokines observed in COVID-19. Here, we describe structure and function of viroporins and their role in inflammasome activation and cellular processes during the virus replication cycle. Techniques to study viroporin function are presented, with a focus on cellular and electrophysiological assays. Contributions of SARS-CoV-2 viroporins to the viral life cycle are discussed with respect to their structure, channel function, binding partners, and their role in viral infection and virus replication. Viroporin sequences of new variants of concern (α–ο) of SARS-CoV-2 are briefly reviewed as they harbour changes in E and 3a proteins that may affect their function.
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Affiliation(s)
- Ulrike Breitinger
- Department of Biochemistry, German University in Cairo, New Cairo, Egypt
| | - Noha S Farag
- Department of Microbiology and Immunology, German University in Cairo, New Cairo, Egypt
| | - Heinrich Sticht
- Division of Bioinformatics, Institute for Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
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40
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Zhai X, Lou H, Hu J. Five-gene signature predicts acute kidney injury in early kidney transplant patients. Aging (Albany NY) 2022; 14:2628-2644. [PMID: 35320116 PMCID: PMC9004575 DOI: 10.18632/aging.203962] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 09/18/2021] [Indexed: 12/04/2022]
Abstract
Patients with acute kidney injury (AKI) show high morbidity and mortality, and a lack of effective biomarkers increases difficulty in its early detection. Weighted gene co-expression network analysis (WGCNA) detected a total of 22 gene modules and 6 miRNA modules, of which 4 gene modules and 3 miRNA modules were phenotypically co-related. Functional analysis revealed that these modules were related to different molecular pathways, which mainly involved PI3K-Akt signaling pathway and ECM-receptor interaction. The brown modules related to transplantation mainly involved immune-related pathways. Finally, five genes with the highest AUC were used to establish a diagnosis and prediction model of AKI. The model showed a high area under curve (AUC) in the training set and validation set, and their prediction accuracy for AKI was as high as 100%. Similarly, the prediction accuracy of AKI after 24 h in the 0 h transplant sample was 100%. This study may provide new features for the diagnosis and prediction of AKI after kidney transplantation, and facilitate the diagnosis and drug development of AKI in kidney transplant patients.
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Affiliation(s)
- Xia Zhai
- Medical Molecular Biology Laboratory, School of Medicine, Jinhua Polytechnic, Jinhua 321000, China
| | - Hongqiang Lou
- Medical Molecular Biology Laboratory, School of Medicine, Jinhua Polytechnic, Jinhua 321000, China
| | - Jing Hu
- Medical Molecular Biology Laboratory, School of Medicine, Jinhua Polytechnic, Jinhua 321000, China
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41
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Cheng L, Rao Q, Zhang Q, Song W, Guan S, Jiang Z, Wu T, Zhao Z, Song W. The immunotoxicity of decabromodiphenyl ether (BDE-209) on broiler chicks by transcriptome profiling analysis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 232:113284. [PMID: 35149409 DOI: 10.1016/j.ecoenv.2022.113284] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 01/29/2022] [Accepted: 02/02/2022] [Indexed: 06/14/2023]
Abstract
Decabromodiphenyl ether (BDE-209) has drawn significant attention due to its suppression of immune functions in animals and even humans. In order to explore the mechanism through which BDE-209 affects the immune system, broiler chicks were fed a diet containing various concentrations of BDE-209 (0, 0.004, 0.04, 0.4, and 4 g/kg) for 42 days. Histopathological observations of immune organs found damaged and necrotic lymphocytes in the spleen and bursa, and losses of lymphoid cells in thymic gland. The activities of catalase, glutathione, glutathione peroxidase, and superoxide dismutase in both the spleen and serum were affected by BDE-209. Obvious bioaccumulation effect was found in spleen tissues (high to 1339 ± 181.9 μg/kg). Furthermore, transcriptome sequencing analyses of the spleen identified 424 upregulated and 301 downregulated DEGs, and the cytokine-cytokine receptor interaction signal pathway was most significantly enriched based on the Kyoto Encyclopedia of Genes and Genomes database. Quantitative real-time PCR affirmed the decreased expressions of interleukin IL18, IL18R1, IL18RAP, IL21, as well as interferon gamma IFNG and tumor necrosis factor superfamily members TNFSF8, indicating significant interference to immunomodulation function and possible disease progression in inflammatory effects resulting from BDE-209 exposure. The immunotoxicity of BDE-209 may cause the suppression of immune and physiological functions of spleen cells, leading to inflammation and apoptosis and ultimately spleen atrophy.
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Affiliation(s)
- Lin Cheng
- Institute for Agri-food Standards and Testing Technology, Shanghai Academy of Agricultural Science, Shanghai 201403, China
| | - Qinxiong Rao
- Institute for Agri-food Standards and Testing Technology, Shanghai Academy of Agricultural Science, Shanghai 201403, China
| | - Qicai Zhang
- Institute for Agri-food Standards and Testing Technology, Shanghai Academy of Agricultural Science, Shanghai 201403, China
| | - Wei Song
- Institute for Agri-food Standards and Testing Technology, Shanghai Academy of Agricultural Science, Shanghai 201403, China
| | - Shuhui Guan
- Institute for Agri-food Standards and Testing Technology, Shanghai Academy of Agricultural Science, Shanghai 201403, China
| | - Zhilin Jiang
- College of Agriculture and Forestry, Puer University, Yunnan 665000, China
| | - Tian Wu
- College of Agriculture and Forestry, Puer University, Yunnan 665000, China
| | - Zhihui Zhao
- Institute for Agri-food Standards and Testing Technology, Shanghai Academy of Agricultural Science, Shanghai 201403, China.
| | - Weiguo Song
- Institute for Agri-food Standards and Testing Technology, Shanghai Academy of Agricultural Science, Shanghai 201403, China.
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42
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Abdelrahman RS, Abdelsalam RA, Zaghloul MS. Beneficial effect of trimetazidine on folic acid-induced acute kidney injury in mice: Role of HIF-1α/HO-1. J Biochem Mol Toxicol 2022; 36:e23011. [PMID: 35191561 DOI: 10.1002/jbt.23011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 11/28/2021] [Accepted: 01/04/2022] [Indexed: 11/10/2022]
Abstract
Acute kidney injury (AKI) is a complex syndrome associated with a decrease in renal function and a significant impact on patient outcomes. Injection of folic acid (FA) in mice is used for studying the pathogenesis of AKI. This study investigated the impact of trimetazidine (a metabolic modulator-antianginal drug; TMZ), against FA-induced AKI. AKI was induced by FA (250 mg/kg, ip) in mice. Two doses of TMZ were administered orally for 10 days. Administration of TMZ at a high dose (20 mg/kg) exhibited significant decreases in the renal somatic index (RSI), serum levels of lactate dehydrogenase (LDH), creatinine (Cr), blood urea nitrogen (1), and proteins level in urine. Moreover, TMZ significantly increased creatinine clearance (CCr), serum albumin, urine creatinine, and urine urea levels. This improvement in markers of kidney damage was associated with marked renal antioxidant effects (↓NO and ↓lipid peroxidation, normalized reduced glutathione (GSH) level and superoxide dismutase (SOD) activity, and increased HIF-1α/HO-1 level). Furthermore, TMZ significantly decreased FA-induced expression of MPO and inflammatory cytokine IL-18, TNF-α, and NF-κB p65 subunit. Renal apoptosis, along with apoptotic markers, were enhanced by FA injection and suppressed by TMZ administration (↓Caspase-3, ↓Bax, and ↑Bcl2 expression). Finally, TMZ amended FA-induced histopathological changes in kidneys. By mitigating functional alteration, oxidative stress, and preventing the development of inflammatory and apoptosis signals, TMZ provides dose-dependent defense against FA-induced AKI mainly via stimulation of hypoxia-inducible factor-1 alpha (HIF-1α)/heme oxygenase-1 (HO-1) pathway.
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Affiliation(s)
- Rehab S Abdelrahman
- Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi Arabia.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Ramy A Abdelsalam
- Department of Pathology, Faculty of medicine, Mansoura University, Mansoura, Egypt
| | - Marwa S Zaghloul
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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Kim EG, Leem JS, Baek SM, Kim HR, Kim KW, Kim MN, Sohn MH. Interleukin-18 Receptor α Modulates the T Cell Response in Food Allergy. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2022; 14:424-438. [PMID: 35837825 PMCID: PMC9293601 DOI: 10.4168/aair.2022.14.4.424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/28/2022] [Accepted: 05/07/2022] [Indexed: 11/20/2022]
Abstract
Purpose Methods Results Conclusions
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Affiliation(s)
- Eun Gyul Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Su Leem
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Min Baek
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Rin Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung Won Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
| | - Mi Na Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
| | - Myung Hyun Sohn
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
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Zhang Y, Zhang K, Zhang Y, Zhou L, Huang H, Wang J. IL-18 Mediates Vascular Calcification Induced by High-Fat Diet in Rats With Chronic Renal Failure. Front Cardiovasc Med 2021; 8:724233. [PMID: 34901204 PMCID: PMC8655337 DOI: 10.3389/fcvm.2021.724233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 10/28/2021] [Indexed: 01/07/2023] Open
Abstract
Objective: Vascular calcification (VC) is an important predictor of cardiovascular morbidity and mortality in patients with chronic renal failure (CRF). It is well-known that obesity and metabolic syndrome (OB/MS) predicts poor prognosis of CRF patients. However, the influence of OB/MS on VC in CRF patients isn't clear. IL-18 mediates OB/MS-related inflammation, but whether IL-18 is involved in OB/MS -mediated VC in CRF patients hasn't been studied. In this study, it was explored that whether OB/MS caused by high-fat diet (HFD) can affect the level of serum IL-18 and aggravate the degree of VC in CRF rats. Furthermore, it was studied that whether IL-18 induces rat vascular smooth muscle cells (VSMCs) calcification by activating the MAPK pathways. Approach: The rats were randomly assigned to the sham-operated, CRF and CRF + HFD groups. CRF was induced by 5/6 nephrectomy. Serum IL-18 levels and aortic calcification indicators were compared in each group. Primary rat VSMCs calcification were induced by β-glycerophosphate and exposed to IL-18. VSMCs were also treated with MAPK inhibitors. Results: The weight, serum levels of hsCRP, TG and LDL-C in CRF + HFD group were significantly higher than those in sham-operated and CRF groups (p < 0.05). Compared with the sham-operated group, the calcium content and the expression of BMP-2 of aorta in CRF and CRF + HFD groups were significantly increased (p < 0.05). Moreover, the calcium content and the expression of BMP-2 of aorta in CRF + HFD group was significantly higher than those in CRF group (p < 0.05). And the serum IL-18 level was positively correlated with aortic calcium content. It was also found that p38 inhibitor SB203580 can suppress the VSMCs calcification and osteoblast phenotype differentiation induced by IL-18. But the JNK inhibitor SP600125 can't suppress the VSMCs calcification and osteoblast phenotype differentiation induced by IL-18. Conclusions: These findings suggest that obesity-related inflammation induced by high-fat diet could exacerbate VC in CRF rats. Furthermore, serum IL-18 level had a positive correlation with the degree of VC. It is also found that IL-18 promoted osteogenic differentiation and calcification of rat VSMCs via p38 pathway activation.
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Affiliation(s)
- Yinyin Zhang
- Cardiology, Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Kun Zhang
- Cardiology, Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Yuling Zhang
- Cardiology, Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Lingqu Zhou
- Cardiology, Sun Yat-sen Memorial Hospital, Guangzhou, China
| | - Hui Huang
- Cardiology, The Eighth Affilliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jingfeng Wang
- Cardiology, Sun Yat-sen Memorial Hospital, Guangzhou, China
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NLRP3 Inflammasome Expression in Gingival Crevicular Fluid of Patients with Periodontitis and Chronic Hepatitis C. Mediators Inflamm 2021; 2021:6917919. [PMID: 34840527 PMCID: PMC8626199 DOI: 10.1155/2021/6917919] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/01/2021] [Accepted: 11/10/2021] [Indexed: 12/13/2022] Open
Abstract
The study is aimed at assessing the impact that periodontal disease and chronic hepatitis C could have on gingival crevicular fluid levels of the NLRP3 inflammasome, caspase-1 (CASP-1), and interleukin-18 (IL-18) and at evaluating whether the increased local inflammatory reaction with clinical periodontal consequences is correlated to their upregulation. Patients were divided into four groups, according to their periodontal status and previously diagnosed hepatitis C, as follows: (i) CHC group, chronic hepatitis C patients; (ii) P group, periodontal disease patients, systemically healthy; (iii) CHC + P group, patients suffering from both conditions; and (iv) H group, systemically and periodontally healthy controls. Gingival crevicular samples were collected for quantitative analysis of the NLRP3 inflammasome, CASP-1, and IL-18. CHC + P patients expressed the worse periodontal status and the highest NLRP3, CASP-1, and IL-18 levels, the difference being statistically significant (p < 0.05). The P group patients also expressed significantly more elevated NLRP3, CASP-1, and IL-18 levels, as compared to nonperiodontal patients (CHC and H groups). Chronic hepatitis C and periodontal disease could have a significant influence on the upregulation of NLRP3 inflammasome and its components, possibly contributing to an increased local inflammatory reaction and clinical periodontal consequences.
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Behura A, Das M, Kumar A, Naik L, Mishra A, Manna D, Patel S, Mishra A, Singh R, Dhiman R. ESAT-6 impedes IL-18 mediated phagosome lysosome fusion via microRNA-30a upon Calcimycin treatment in mycobacteria infected macrophages. Int Immunopharmacol 2021; 101:108319. [PMID: 34740079 DOI: 10.1016/j.intimp.2021.108319] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/05/2021] [Accepted: 10/25/2021] [Indexed: 01/18/2023]
Abstract
The weaponry possessed by Mycobacterium tuberculosis (M. tb) in the form of immunodominant antigens hijack the host immune system to give a survival advantage to this intracellular fiend, but the mechanism of this control is not entirely known. Since we have previously reported the mechanism of autophagy inhibition by early secreted antigenic target 6 kDa (ESAT-6) through microRNA (miR)-30a-3p in Calcimycin treated differentiated THP-1 (dTHP-1) cells, the present study was undertaken to deduce the effect of miR-30a on the immunomodulatory profile of ESAT-6 treated cells and the mechanism involved thereof, if any. Initially, the effect of recombinant ESAT-6 (rESAT-6) on the immunomodulatory profile in Calcimycin-treated phorbol 12-myristate 13-acetate (PMA) dTHP-1 cells was checked. Later, transfection studies using miR-30a-3p inhibitor or -5p mimic highlighted the contrary roles of different arms of the same miRNA in regulating IL-18 response by ESAT-6 in dTHP-1 cells after Calcimycin treatment. By using either IL-18 neutralizing antibody or inhibitors of phosphoinositide 3-kinase (PI3K)/NF-κB/phagosome-lysosome fusion in the miRNA-30a transfected background, IL-18 mediated signaling and intracellular killing of mycobacteria was reversed in the presence of ESAT-6. Overall, the results of this study conclusively prove the contrary roles of miR-30a-3p and miR-30a-5p in regulating IL-18 signaling by ESAT-6 in dTHP-1 cells upon Calcimycin treatment that affected phagosome-lysosome fusion and intracellular survival of mycobacteria.
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Affiliation(s)
- Assirbad Behura
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Mousumi Das
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Ashish Kumar
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Lincoln Naik
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Abtar Mishra
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Debraj Manna
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Salina Patel
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Amit Mishra
- Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India
| | - Ramandeep Singh
- Tuberculosis Research Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurugram Expressway, PO Box # 4, Faridabad 121001, Haryana, India
| | - Rohan Dhiman
- Laboratory of Mycobacterial Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
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Fernandes SM, Watanabe M, Vattimo MDFF. Inflammation: improving understanding to prevent or ameliorate kidney diseases. J Venom Anim Toxins Incl Trop Dis 2021; 27:e20200162. [PMID: 34712277 PMCID: PMC8525891 DOI: 10.1590/1678-9199-jvatitd-2020-0162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 04/12/2021] [Indexed: 11/21/2022] Open
Abstract
Inflammatory processes are believed to play an important role in immune response to maintain tissue homeostasis by activating cellular signaling pathways and releasing inflammatory mediators in the injured tissue. Although acute inflammation can be considered protective, an uncontrolled inflammation may evolve to tissue damage, leading to chronic inflammatory diseases. Inflammation can be considered the major factor involved in the pathological progression of acute and chronic kidney diseases. Functional characteristics of this organ increase its vulnerability to developing various forms of injuries, including acute kidney injury (AKI) and chronic kidney disease (CKD). In view of translational research, several discoveries should be considered regarding the pathogenesis of the inflammatory process, which results in the validation of biomarkers for early detection of kidney diseases. Biomarkers enable the identification of proinflammatory mediators in kidney affections, based on laboratory research applied to clinical practice. Some inflammatory molecules can be useful biomarkers for the detection and diagnosis of kidney diseases, such as neutrophil gelatinase-associated lipocalin, kidney injury molecule-1 and interleukin 18.
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Affiliation(s)
- Sheila Marques Fernandes
- Animal Model Experimental Laboratory (LEMA), School of Nursing (EEUSP), University of São Paulo (USP), São Paulo, SP, Brazil
| | - Mirian Watanabe
- Animal Model Experimental Laboratory (LEMA), School of Nursing (EEUSP), University of São Paulo (USP), São Paulo, SP, Brazil.,Health Sciences and Wellbeing (CISBEM), University Center of United Metropolitan Colleges, São Paulo, SP, Brazil
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Expression Levels of Il-6 and Il-18 in Acute Myeloid Leukemia and Its Relation with Response to Therapy and Acute GvHD After Bone Marrow Transplantation. Indian J Surg Oncol 2021; 12:465-471. [PMID: 34658572 DOI: 10.1007/s13193-021-01358-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 05/26/2021] [Indexed: 12/17/2022] Open
Abstract
Cytokines seem to play a crucial role in physiological and pathological conditions of acute myeloid leukemia (AML). The aim of this study was to evaluate the expression levels of interleukins-6 (IL-6) and IL-18 in patients with AML and its correlation with response to therapy and graft versus host disease (GvHD) after bone marrow transplantation. The expression levels of IL-6 and IL-18 genes were done in all patients and compared with matched control. Complete remission (CR) was used for evaluation of the effects of these cytokines on response to treatment in patients group. The expression level of these cytokines was also evaluated in patients who underwent bone marrow transplantation and experienced acute GvHD in compare with patients without aGvHD. Il-6 gene expression level was significantly higher in these patients in comparison with control but Il-18 gene expression level was not statistically significant compared to control group. Il-6 and also Il-18 expression levels were significantly higher in patients without a response to treatment according to CR compared to patient's whit response to treatment as well as patients experienced aGvHD after bone marrow transplantation. IL-6 and Il-18 are important markers in the progression of the disease and could be considered as a prognostic marker in acute leukemia. It is recommended that more studies with larger study groups and more involved cytokines are needed for more evaluation of the cytokine roles in pathophysiology and progression of acute leukemia.
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Roßmann L, Bagola K, Stephen T, Gerards AL, Walber B, Ullrich A, Schülke S, Kamp C, Spreitzer I, Hasan M, David-Watine B, Shorte SL, Bastian M, van Zandbergen G. Distinct single-component adjuvants steer human DC-mediated T-cell polarization via Toll-like receptor signaling toward a potent antiviral immune response. Proc Natl Acad Sci U S A 2021; 118:e2103651118. [PMID: 34561306 PMCID: PMC8488681 DOI: 10.1073/pnas.2103651118] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2021] [Indexed: 02/08/2023] Open
Abstract
The COVID-19 pandemic highlights the importance of efficient and safe vaccine development. Vaccine adjuvants are essential to boost and tailor the immune response to the corresponding pathogen. To allow for an educated selection, we assessed the effect of different adjuvants on human monocyte-derived dendritic cells (DCs) and their ability to polarize innate and adaptive immune responses. In contrast to commonly used adjuvants, such as aluminum hydroxide, Toll-like receptor (TLR) agonists induced robust phenotypic and functional DC maturation. In a DC-lymphocyte coculture system, we investigated the ensuing immune reactions. While monophosphoryl lipid A synthetic, a TLR4 ligand, induced checkpoint inhibitors indicative for immune exhaustion, the TLR7/8 agonist Resiquimod (R848) induced prominent type-1 interferon and interleukin 6 responses and robust CTL, B-cell, and NK-cell proliferation, which is particularly suited for antiviral immune responses. The recently licensed COVID-19 vaccines, BNT162b and mRNA-1273, are both based on single-stranded RNA. Indeed, we could confirm that the cytokine profile induced by lipid-complexed RNA was almost identical to the pattern induced by R848. Although this awaits further investigation, our results suggest that their efficacy involves the highly efficient antiviral response pattern stimulated by the RNAs' TLR7/8 activation.
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Affiliation(s)
- Laura Roßmann
- Division of Immunology, Paul-Ehrlich-Institut, 63225 Langen, Germany
| | - Katrin Bagola
- Division of Immunology, Paul-Ehrlich-Institut, 63225 Langen, Germany
| | - Tharshana Stephen
- Cytometry and Biomarkers UTechS, Institut Pasteur, 75015 Paris, France
| | - Anna-Lisa Gerards
- Division of Immunology, Paul-Ehrlich-Institut, 63225 Langen, Germany
| | - Bianca Walber
- Division of Immunology, Paul-Ehrlich-Institut, 63225 Langen, Germany
| | - Anja Ullrich
- Division of Immunology, Paul-Ehrlich-Institut, 63225 Langen, Germany
- Leibniz Institute on Aging-Fritz Lipmann Institute, 07745 Jena, Germany
| | - Stefan Schülke
- Molecular Allergology, Paul-Ehrlich-Institut, 63225 Langen, Germany
| | - Christel Kamp
- Division of Microbiology, Paul-Ehrlich-Institut, 63225 Langen, Germany
| | - Ingo Spreitzer
- Division of Microbiology, Paul-Ehrlich-Institut, 63225 Langen, Germany
| | - Milena Hasan
- Cytometry and Biomarkers UTechS, Institut Pasteur, 75015 Paris, France
| | | | | | - Max Bastian
- Friedrich-Loeffler-Institut, 17493 Greifswald-Insel Riems, Germany
| | - Ger van Zandbergen
- Division of Immunology, Paul-Ehrlich-Institut, 63225 Langen, Germany;
- Institute of Immunology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
- Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
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50
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Karakaya D, Çakmak Genc G, Karakas Celik S, Aktas T, Bayraktaroglu T, Dursun A. Association between IL-18 gene polymorphisms and Hashimoto thyroiditis. Mol Biol Rep 2021; 48:6703-6708. [PMID: 34460061 DOI: 10.1007/s11033-021-06659-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 08/16/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Hashimoto's thyroiditis (HT), which is also called lymphocytic thyroiditis, is the most frequent autoimmune thyroid disease (AITD), in which T helper-1 lymphocytes mediate the disease. IL-18 is expressed in thyroid follicular cells (TFCs) during HT. The findings of studies aimed at investigating the relationship between IL-18 and HT are highly contradictory. In this study, we aimed to investigate the association between IL-18 gene polymorphisms and HT. METHODS AND RESULTS The study included 97 patients diagnosed with HT and 86 volunteers in the healthy control group. The IL18-607C/A (rs1946518) and -137G/C (rs187238) genotypes were determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. No significant difference in the mean age or sex was observed between the groups (p = 0.763 and p = 0.658, respectively). The -137 IL18 CG genotype was more frequent in HT patients than in controls. In HT patients, the risk of the IL-18 CG genotype was more than 2.237 times higher (OR 2.237%95 Cl 1.195-4.187, p = 0.039) than that of the G/G genotype. Additionally, the -607 AC genotype was more frequent in the control group than in the HT group (in individuals with the IL18 CG genotype). CONCLUSIONS According to our results, the CG genotype might be a risk factor for HT. Conversely, there is a possibility that the AC genotype plays a protective role against the condition. However, further studies will contribute to new solutions by revealing the molecular and cellular mechanisms of HT.
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Affiliation(s)
- Dilek Karakaya
- Department of Endocrinology and Metabolism, Gebze Medical Park Hospital, Kavak Street No:5, Gebze/Kocaeli, Turkey.
| | - Gunes Çakmak Genc
- Department of Genetics, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Sevim Karakas Celik
- Department of Genetics, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
| | - Tugba Aktas
- Department of Molecular Biology and Genetics, Faculty of Sciences and Arts, Bulent Ecevit University, Zonguldak, Turkey
| | - Taner Bayraktaroglu
- Department of Endocrinology and Metabolism, Faculty of Medicine, Zonguldak, Turkey
| | - Ahmet Dursun
- Department of Genetics, Faculty of Medicine, Bulent Ecevit University, Zonguldak, Turkey
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