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Liu L, Ma C, Ji J, Gao R, Li D. Role of antidiarrheal agents nifuroxazide in antitumor multi‑target anticancer, multi‑mechanism anticancer drug (Review). Oncol Lett 2025; 29:260. [PMID: 40230426 PMCID: PMC11995686 DOI: 10.3892/ol.2025.15006] [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: 10/04/2024] [Accepted: 01/07/2025] [Indexed: 04/16/2025] Open
Abstract
Nifuroxazide (NFZ) is an antimicrobial drug, which has been found to be a promising antitumor agent in recent years. In addition to being a classic STAT3 inhibitor, NFZ can also act on IL-6 and exert an anti-tumor role through inflammatory factor pathways. It can also bind to target proteins of aldehyde dehydrogenase 1, one of the families of E-twenty-six transcription factors and ubiquitin-specific protease 21 to play an anti-tumor role in different pathways. NFZ is able to act on the tumor cell microenvironment to inhibit tumor angiogenesis and tumor cell migration, enhance tumor immune cells, increase the cytotoxicity of tumor cells and enhance the anti-tumor effect of other drugs. Furthermore, it has high safety with few toxic side effects. The anti-tumor mechanisms of NFZ were described in the current review, aiming to provide insight and a reference for future studies promoting the implementation of NFZ as an anti-tumor drug in the clinic.
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Affiliation(s)
- Liping Liu
- Oncology Department, Qingdao Endocrine and Diabetes Hospital, Qingdao, Shandong 266000, P.R. China
| | - Chengshan Ma
- Department of Orthopedic Surgery, Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250000, P.R. China
| | - Jinfeng Ji
- Oncology Department, Qingdao Endocrine and Diabetes Hospital, Qingdao, Shandong 266000, P.R. China
| | - Rong Gao
- Oncology Department, Qingdao Endocrine and Diabetes Hospital, Qingdao, Shandong 266000, P.R. China
| | - Deliang Li
- Emergency Department, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266100, P.R. China
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Lee SY, Le DD, Bae CS, Park JW, Lee M, Cho SS, Park DH. Oleic acid attenuates asthma pathogenesis via Th1/Th2 immune cell modulation, TLR3/4-NF-κB-related inflammation suppression, and intrinsic apoptotic pathway induction. Front Immunol 2024; 15:1429591. [PMID: 39421735 PMCID: PMC11484255 DOI: 10.3389/fimmu.2024.1429591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 08/19/2024] [Indexed: 10/19/2024] Open
Abstract
WHO reported that asthma was responsible for 455,000 deaths in 2019 and asthma patients was evaluated 262 million in May 2023. The incidence is expected to increase as the average life expectancy increases, highlighting asthma as a significant health challenge in an aging society. The etiology of asthma is linked to an imbalance of Th1 and Th2 cells, respiratory inflammation, and pulmonary cell proliferation. The purpose of this study is to investigate the anti-asthmatic effect and potential mechanism of oleic acid. The anti-inflammatory effect of oleic acid was evaluated in an LPS-induced RAW 264.7 cell model, and immune modulation and the anti-apoptotic effect were measured in an ovalbumin-induced BALB/c mouse model. A variety of analytical procedures, such as MTT, qPCR, ELISA, Western blotting, immunofluorescence, gene transfection, immunohistochemistry, and several staining methods (Diff Quik, H&E, PAS), were used to evaluate the effectiveness and mechanisms of these methods. The results from in vitro experiments showed that oleic acid could reduce the levels of inflammatory cytokines (TNF-α, IL-6, and IL-1β), and molecular docking studies suggested that oleic acid could interact with TLR3 and TLR4 proteins to form ligand-protein complexes, showing good binding affinity. Additionally, oleic acid attenuated the expression of MAPK pathway components (JNK, p38 MAPK) and NF-κB pathway constituents (IκB, NF-κB, COX-2, PGE2). In vivo results indicated that oleic acid reduced the levels of inflammatory cells (WBCs and eosinophils) and IgE activity, reduced the expression of the Th2 cell transcription factor GATA-3, and decreased the levels of Th2/Th17-related cytokines (IL-4, TNF-α, and IL-6). Oleic acid also alleviated OVA-induced pathological changes in the lung, such as epithelial cell proliferation, inflammatory cell infiltration, and mucus hypersecretion. OVA restored apoptosis in lung epithelial cells by modulating the expression of Bcl-2 and Bax. In summary, oleic acid has potential as a novel candidate for asthma treatment through its ability to regulate immune cells, exert anti-inflammatory effects, and promote apoptosis, thereby ameliorating asthma manifestations.
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Affiliation(s)
- Soon-Young Lee
- College of Oriental Medicine, Dongshin University, Naju, Republic of Korea
| | - Duc Dat Le
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon, Republic of Korea
| | - Chun-Sik Bae
- College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea
| | - Jin Woo Park
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Muan, Republic of Korea
| | - Mina Lee
- College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon, Republic of Korea
| | - Seung-Sik Cho
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Muan, Republic of Korea
- Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan, Republic of Korea
| | - Dae-Hun Park
- College of Oriental Medicine, Dongshin University, Naju, Republic of Korea
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Liu W, Huang J, Hu J, Bu Z, Zhou Z, Yu J, Wang H, Wu X, Wu P. The dual role of CCND1 in heterotopic ossification: A Non-canonical Pathway for Celecoxib treatment. Heliyon 2024; 10:e34936. [PMID: 39157338 PMCID: PMC11327559 DOI: 10.1016/j.heliyon.2024.e34936] [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: 05/02/2024] [Revised: 07/11/2024] [Accepted: 07/18/2024] [Indexed: 08/20/2024] Open
Abstract
Objective To explore the effective targets of Celecoxib in the treatment of heterotopic ossification using network pharmacology methods. Methods Potential molecules related to heterotopic ossification were obtained by retrieving the GEO and CTD databases and intersecting them. Potential binding targets of Celecoxib were acquired from the STITCH database. A protein-protein interaction network was constructed between potential binding targets of Celecoxib and potential related molecules of heterotopic ossification using the STRING database. Molecules in the protein-protein interaction network were further analyzed using GO and KEGG enrichment analysis in R software, followed by enrichment analysis of active molecules in the Celecoxib-heterotopic ossification target dataset. Hub genes were selected based on the "degree" value and enrichment within the protein-protein interaction network. The binding affinity of hub genes to Celecoxib was observed using molecular docking techniques. Finally, in vitro experiments were conducted to validate the effectiveness of hub genes and explore their regulatory role in the progression of heterotopic ossification. Additionally, the therapeutic effect of Celecoxib, which modulates the expression of the hub genes, was investigated in the treatment of heterotopic ossification. Results 568 potential molecules related to heterotopic ossification and 76 potential binding targets of Celecoxib were identified. After intersection, 13 potential functional molecules in Celecoxib's treatment of heterotopic ossification were obtained. KEGG analysis suggested pathways such as Rheumatoid arthritis, NF-kappa B signaling pathway, Pathways in cancer, Antifolate resistance, MicroRNAs in cancer play a role in the treatment of heterotopic ossification by Celecoxib. Further enrichment analysis of the 13 potential functional molecules identified 5 hub genes: IL6, CCND1, PTGS2, IGFBP3, CDH1. Molecular docking results indicated that Celecoxib displayed excellent binding affinity with CCND1 among the 5 hub genes. Experimental validation found that CCND1 is highly expressed in the progression of heterotopic ossification, promoting heterotopic ossification in the early stages and inhibiting it in the later stages, with Celecoxib's treatment of heterotopic ossification depending on CCND1. Conclusion In the process of treating heterotopic ossification with Celecoxib, immune and inflammatory signaling pathways play a significant role. The therapeutic effect of Celecoxib on heterotopic ossification depends on the hub gene CCND1, which plays different roles at different stages of the progression of heterotopic ossification, ultimately inhibiting the occurrence of heterotopic ossification.
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Affiliation(s)
- Wei Liu
- Department of Orthopedics, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Junchao Huang
- Department of Orthopedics, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Jianhai Hu
- Department of Orthopedics, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Ziheng Bu
- Department of Orthopedics, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Zheng Zhou
- Department of Orthopedics, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Jianing Yu
- Department of Orthopedics, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Huajun Wang
- Department of Sports Medicine, The First Affiliated Hospital, Guangdong Provincial Key Laboratory of Speed Capability, The Guangzhou Key Laboratory of Precision Orthopedics and Regenerative Medicine, State Key Laboratory of Frigid Zone Cardiovascular Diseases, Jinan University, Guangzhou, 510630, China
| | - Xinbo Wu
- Department of Orthopedics, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Peng Wu
- Department of Orthopedics, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
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Zhao Z, Lin S, Liu T, Hu X, Qin S, Zhan F, Ma J, Huang C, Huang Z, Wang Y, Zheng K, Zhang W, Ren Z. Artemvulactone E isolated from Artemisia vulgaris L. ameliorates lipopolysaccharide-induced inflammation in both RAW264.7 and zebrafish model. Front Pharmacol 2024; 15:1415352. [PMID: 39092222 PMCID: PMC11291208 DOI: 10.3389/fphar.2024.1415352] [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: 05/07/2024] [Accepted: 07/04/2024] [Indexed: 08/04/2024] Open
Abstract
Introduction Natural plants are valuable resources for exploring new bioactive compounds. Artemisia vulgaris L. is a traditional Chinese medicinal herb that has been historically used for treating multiple diseases. Active compounds isolated and extracted from A. vulgaris L. typically possess immunomodulatory and anti-inflammatory properties. Artemvulactone E (AE) is a new sesquiterpene lactone isolated and extracted from A. vulgaris L. with unclear biological activities. Methods The immunoregulatory effects of AE on macrophages were assessed by ELISA, RT-qPCR, immunofluorescence, and western blot assay. The effect of AE on lipopolysaccharide (LPS) -relates signaling pathways was examined by western blot assay. In zebrafish models, the larvae were yolk-microinjected with LPS to establish inflammation model and the effect of AE was evaluated by determining the survival rate, heart rate, yolk sac edema size, neutrophils and macrophages infiltration of zebrafish. The interaction between AE and Toll-like receptor 4 (TLR4) was examined by molecular docking and dynamic stimulation. Results AE reduced the expression and secretion of pro-inflammatory cytokines (TNF-α and IL-6), inflammatory mediators iNOS and COX-2, as well as decreases the production of intracellular NO and ROS in LPS-stimulated macrophages. In addition, AE exerted its anti-inflammatory effect synergistically by inhibiting MAPK/JAK/STAT3-NF-κB signaling pathways. Furthermore, AE enhanced the survival rate and attenuated inflammatory response in zebrafish embryos treated with LPS. Finally, the molecular dynamics results indicate that AE forms stable complexes with LPS receptor TLR4 through the Ser127 residue, thus completely impairing the subsequent activation of MAPK-NF-κB signaling. Conclusion AE exhibits notable anti-inflammatory activity and represents as a potential agent for treating inflammation-associated diseases.
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Affiliation(s)
- Zibo Zhao
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Shimin Lin
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Tao Liu
- Guangdong Province Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, China
| | - Xiao Hu
- Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Jinan University, Guangzhou, China
| | - Shurong Qin
- National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China
| | - Fengyun Zhan
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Jiaqi Ma
- Key Laboratory of Innovative Technology Research on Natural Products and Cosmetics Raw Materials, Jinan University, Guangzhou, China
| | - Chen Huang
- Key Laboratory of Innovative Technology Research on Natural Products and Cosmetics Raw Materials, Jinan University, Guangzhou, China
| | - Zhibin Huang
- Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yifei Wang
- National Engineering Technology Research Center for Modernization of Traditional Chinese Medicine, Jinan University, Guangzhou, China
| | - Kai Zheng
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, China
| | - Wenqing Zhang
- Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, China
| | - Zhe Ren
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
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Diallo M, Pimenta C, Murtinheira F, Martins-Alves D, Pinto FR, da Costa AA, Letra-Vilela R, Martin V, Rodriguez C, Rodrigues MS, Herrera F. Asymmetric post-translational modifications regulate the nuclear translocation of STAT3 homodimers in response to leukemia inhibitory factor. Cell Oncol (Dordr) 2024; 47:1065-1070. [PMID: 38150153 PMCID: PMC11219437 DOI: 10.1007/s13402-023-00911-9] [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] [Accepted: 12/08/2023] [Indexed: 12/28/2023] Open
Abstract
STAT3 is a pleiotropic transcription factor overactivated in 70% of solid tumours. We have recently reported that inactivating mutations on residues susceptible to post-translational modifications (PTMs) in only one of the monomers (i.e. asymmetric) caused changes in the cellular distribution of STAT3 homodimers. Here, we used more controlled experimental conditions, i.e. without the interference of endogenous STAT3 (STAT3-/- HeLa cells) and in the presence of a defined cytokine stimulus (Leukemia Inhibitory Factor, LIF), to provide further evidence that asymmetric PTMs affect the nuclear translocation of STAT3 homodimers. Time-lapse microscopy for 20 min after LIF stimulation showed that S727 dephosphorylation (S727A) and K685 inactivation (K685R) slightly enhanced the nuclear translocation of STAT3 homodimers, while K49 inactivation (K49R) delayed STAT3 nuclear translocation. Our findings suggest that asymmetrically modified STAT3 homodimers could be a new level of STAT3 regulation and, therefore, a potential target for cancer therapy.
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Affiliation(s)
- Mickael Diallo
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
- MOSTMICRO Research Unit, Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
| | - Constança Pimenta
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
| | - Fernanda Murtinheira
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
- MOSTMICRO Research Unit, Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
| | - Daniela Martins-Alves
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
| | - Francisco R Pinto
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
| | - André Abrantes da Costa
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
| | - Ricardo Letra-Vilela
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
- MOSTMICRO Research Unit, Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
| | - Vanesa Martin
- Departamento de Morfología y Biología Celular, Facultad de Medicina, University of Oviedo, c/Julian Claveria, Oviedo, 33006, Spain
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Oviedo, Spain
| | - Carmen Rodriguez
- Departamento de Morfología y Biología Celular, Facultad de Medicina, University of Oviedo, c/Julian Claveria, Oviedo, 33006, Spain
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Oviedo, Spain
| | - Mário S Rodrigues
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal
| | - Federico Herrera
- BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências da Universidade de Lisboa, Lisbon, 1749-016, Portugal.
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Liu CR, Li YP, Wang YK, Zhang W, Hao M, Wang WJ, Li T, Dang SS. Peripheral blood T cell and cytokine levels in HBV-related liver disease patients. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2024; 32:293-301. [DOI: 10.11569/wcjd.v32.i4.293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/28/2024]
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Taneera J, Khalique A, Mohammed AK, Mussa BM, Sulaiman N, Abu-Gharbieh E, El-Huneidi W, Saber-Ayad MM. Investigating the Impact of IL6 on Insulin Secretion: Evidence from INS-1 Cells, Human Pancreatic Islets, and Serum Analysis. Cells 2024; 13:685. [PMID: 38667300 PMCID: PMC11049194 DOI: 10.3390/cells13080685] [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: 02/26/2024] [Revised: 04/11/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Interleukin-6 (IL6) is a pleiotropic cytokine implicated in metabolic disorders and inflammation, yet its precise influence on insulin secretion and glucose metabolism remains uncertain. This study examined IL6 expression in pancreatic islets from individuals with/without diabetes, alongside a series of functional experiments, including siRNA silencing; IL6 treatment; and assessments of glucose uptake, cell viability, apoptosis, and expression of key β-cell genes, which were conducted in both INS-1 cells and human islets to elucidate the effect of IL6 on insulin secretion. Serum levels of IL6 from Emirati patients with type 2 diabetes (T2D) were measured, and the effect of antidiabetic drugs on IL6 levels was studied. The results revealed that IL6 mRNA expression was higher in islets from diabetic and older donors compared to healthy or young donors. IL6 expression correlated negatively with PDX1, MAFB, and NEUROD1 and positively with SOX4, HES1, and FOXA1. Silencing IL6 in INS-1 cells reduced insulin secretion and glucose uptake independently of apoptosis or oxidative stress. Reduced expression of IL6 was associated with the downregulation of Ins, Pdx1, Neurod1, and Glut2 in INS-1 cells. In contrast, IL6 treatment enhanced insulin secretion in INS-1 cells and human islets and upregulated insulin expression. Serum IL6 levels were elevated in patients with T2D and associated with higher glucose, HbA1c, and triglycerides, regardless of glucose-lowering medications. This study provides a new understanding of the role of IL6 in β-cell function and the pathophysiology of T2D. Our data highlight differences in the response to IL6 between INS-1 cells and human islets, suggesting the presence of species-specific variations across different experimental models. Further research is warranted to unravel the precise mechanisms underlying the observed effects of IL-6 on insulin secretion.
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Affiliation(s)
- Jalal Taneera
- College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates; (B.M.M.); (N.S.); (E.A.-G.); (W.E.-H.); (M.M.S.-A.)
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates; (A.K.); (A.K.M.)
| | - Anila Khalique
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates; (A.K.); (A.K.M.)
| | - Abdul Khader Mohammed
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates; (A.K.); (A.K.M.)
| | - Bashair M. Mussa
- College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates; (B.M.M.); (N.S.); (E.A.-G.); (W.E.-H.); (M.M.S.-A.)
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates; (A.K.); (A.K.M.)
| | - Nabil Sulaiman
- College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates; (B.M.M.); (N.S.); (E.A.-G.); (W.E.-H.); (M.M.S.-A.)
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates; (A.K.); (A.K.M.)
| | - Eman Abu-Gharbieh
- College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates; (B.M.M.); (N.S.); (E.A.-G.); (W.E.-H.); (M.M.S.-A.)
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates; (A.K.); (A.K.M.)
- School of Pharmacy, The University of Jordan, Amman 11942, Jordan
| | - Waseem El-Huneidi
- College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates; (B.M.M.); (N.S.); (E.A.-G.); (W.E.-H.); (M.M.S.-A.)
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates; (A.K.); (A.K.M.)
| | - Maha M. Saber-Ayad
- College of Medicine, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates; (B.M.M.); (N.S.); (E.A.-G.); (W.E.-H.); (M.M.S.-A.)
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates; (A.K.); (A.K.M.)
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Alser M, Naja K, Elrayess MA. Mechanisms of body fat distribution and gluteal-femoral fat protection against metabolic disorders. Front Nutr 2024; 11:1368966. [PMID: 38590830 PMCID: PMC10999599 DOI: 10.3389/fnut.2024.1368966] [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: 01/11/2024] [Accepted: 03/07/2024] [Indexed: 04/10/2024] Open
Abstract
Obesity is a major health problem that affects millions of individuals, and it is associated with metabolic diseases including insulin resistance (IR), type 2 diabetes (T2D), and cardiovascular diseases (CVDs). However, Body fat distribution (BFD) rather than crude obesity is now considered as a more accurate factor associated with these diseases. The factors affecting BFD vary, from genetic background, epigenetic factors, ethnicity, aging, hormonal changes, to lifestyle and medication consumptions. The main goal of controlling BFD comes from the fact that fat accumulation in different depots has a different effect on the overall health and metabolic health of individuals. It is well established that fat storage in the abdominal visceral depot is associated with metabolic disorder occurrence, while gluteal-femoral subcutaneous fat depot seems to be protective against these diseases. In this paper, we will summarize the factors affecting fat distribution. Then, we will present evidence connecting gluteal-femoral fat depot with protection against metabolic disorders including IR, T2D, and CVDs. Finally, we will list the suggested mechanisms that lead to this protective effect. The abstract is visualized in Graphical Abstract.
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Affiliation(s)
- Maha Alser
- Biomedical Research Center, Qatar University, Doha, Qatar
| | - Khaled Naja
- Biomedical Research Center, Qatar University, Doha, Qatar
| | - Mohamed A. Elrayess
- Biomedical Research Center, Qatar University, Doha, Qatar
- QU Health, Qatar University, Doha, Qatar
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Tran AT, Truong AD, Nguyen DTK, Nguyen HT, Nguyen TT, Tran HTT, Dang HV. Biological properties and diverse cytokine profiles followed by in vitro and in vivo infections with LSDV strain isolated in first outbreaks in Vietnam. Vet Res Commun 2023; 47:2005-2016. [PMID: 37382734 DOI: 10.1007/s11259-023-10158-2] [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: 05/10/2023] [Accepted: 06/26/2023] [Indexed: 06/30/2023]
Abstract
Preliminary information about LSD virus isolated from the first outbreaks in Vietnam has been reported by our laboratory. In the current study, LSDV strain, LSDV/Vietnam/Langson/HL01(HL01) was further analyzed to provide a better understanding of this viral pathogen. HL01 LSDV strain was propagated at MOI 0.01 in MDBK cells and then given to cattle at dose of 106.5 TCID50/ml (2ml/animal). The production of proinflammatory (IFN-γ, IL-1α, and TNF-α) and anti-inflammatory (IL-6, IL-10, and TGF-ß1) cytokines were measured by real-time PCR, both In vitro and In vivo. The results demonstrated that HL01 strain caused the typical signs of LSD and LSDV In vitro and In vivo, respectively suggesting a virulent field LSDV strain. Additionally, different cytokine profiles were observed in these In vitro and In vivo studies. In MDBK cells, different cytokines profiles were observed in two phases: in the early phase, the expression levels of all examined cytokines were significantly increased at 6 h (p < 0.05). In the later phase, the peak levels of the cytokine secretion were recognized from 72 to 96 h, with the exception of IL-1α when compared to controls. In cattle, the expression levels of all six cytokines were significantly higher at day 7 following LSDV challenge (p < 0.05) when compared to controls, especially expression levels of TGF-β1 and IL-10. These findings suggest the important roles of these cytokines in protection against LSDV infections. Additionally, the data from diverse cytokine profiles followed by this LSDV strain challenge provides key understanding of the underlying cellular immune mechanisms in the host against LSDV infection In vitro and In vivo.
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Affiliation(s)
- Anh Tuan Tran
- Department of Biochemistry and Immunology, National Institute of Veterinary Research, 86 Truong Chinh, Dong Da, Hanoi, 100000, Vietnam
- Nghe An, Regional Animal Health Office (RAHO3), Vinh City, Vietnam
| | - Anh Duc Truong
- Department of Biochemistry and Immunology, National Institute of Veterinary Research, 86 Truong Chinh, Dong Da, Hanoi, 100000, Vietnam
| | - Dung Thi Kim Nguyen
- National Veterinary Joint Stock Company (VETVACO), Km 18, National Highway 32, Duc Thuong Commune, Hoai Duc District, Hanoi, 100000, Vietnam
| | - Hung Tuan Nguyen
- National Veterinary Joint Stock Company (VETVACO), Km 18, National Highway 32, Duc Thuong Commune, Hoai Duc District, Hanoi, 100000, Vietnam
| | - Thanh Thuy Nguyen
- Department of Electron Microscopy, National Institute of Hygiene and Epidemiology, Hanoi, 100000, Vietnam
| | - Ha Thi Thanh Tran
- Department of Biochemistry and Immunology, National Institute of Veterinary Research, 86 Truong Chinh, Dong Da, Hanoi, 100000, Vietnam.
| | - Hoang Vu Dang
- Department of Biochemistry and Immunology, National Institute of Veterinary Research, 86 Truong Chinh, Dong Da, Hanoi, 100000, Vietnam.
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Ciryam P, Gerzanich V, Simard JM. Interleukin-6 in Traumatic Brain Injury: A Janus-Faced Player in Damage and Repair. J Neurotrauma 2023; 40:2249-2269. [PMID: 37166354 PMCID: PMC10649197 DOI: 10.1089/neu.2023.0135] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2023] Open
Abstract
Traumatic brain injury (TBI) is a common and often devastating illness, with wide-ranging public health implications. In addition to the primary injury, victims of TBI are at risk for secondary neurological injury by numerous mechanisms. Current treatments are limited and do not target the profound immune response associated with injury. This immune response reflects a convergence of peripheral and central nervous system-resident immune cells whose interaction is mediated in part by a disruption in the blood-brain barrier (BBB). The diverse family of cytokines helps to govern this communication and among these, Interleukin (IL)-6 is a notable player in the immune response to acute neurological injury. It is also a well-established pharmacological target in a variety of other disease contexts. In TBI, elevated IL-6 levels are associated with worse outcomes, but the role of IL-6 in response to injury is double-edged. IL-6 promotes neurogenesis and wound healing in animal models of TBI, but it may also contribute to disruptions in the BBB and the progression of cerebral edema. Here, we review IL-6 biology in the context of TBI, with an eye to clarifying its controversial role and understanding its potential as a target for modulating the immune response in this disease.
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Affiliation(s)
- Prajwal Ciryam
- Shock Trauma Neurocritical Care, Program in Trauma, R Adams Cowley Shock Trauma Center, University of Maryland Medical System, Baltimore, Maryland, USA
- Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Volodymyr Gerzanich
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - J. Marc Simard
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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11
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Grebenciucova E, VanHaerents S. Interleukin 6: at the interface of human health and disease. Front Immunol 2023; 14:1255533. [PMID: 37841263 PMCID: PMC10569068 DOI: 10.3389/fimmu.2023.1255533] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 09/11/2023] [Indexed: 10/17/2023] Open
Abstract
Interleukin 6 (IL-6) is a pleiotropic cytokine executing a diverse number of functions, ranging from its effects on acute phase reactant pathways, B and T lymphocytes, blood brain barrier permeability, synovial inflammation, hematopoiesis, and embryonic development. This cytokine empowers the transition between innate and adaptive immune responses and helps recruit macrophages and lymphocytes to the sites of injury or infection. Given that IL-6 is involved both in the immune homeostasis and pathogenesis of several autoimmune diseases, research into therapeutic modulation of IL-6 axis resulted in the approval of a number of effective treatments for several autoimmune disorders like neuromyelitis optica spectrum disorder (NMOSD), rheumatoid arthritis, juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis (GCA), and cytokine release syndrome, associated with SARS-CoV2 pneumonia. This review discusses downstream inflammatory pathways of IL-6 expression and therapeutic applications of IL-6 blockade, currently investigated for the treatment of several other autoimmune conditions such as autoimmune encephalitis, autoimmune epilepsy, as well as myelin oligodendrocyte glycoprotein associated demyelination (MOGAD). This review further highlights the need for clinical trials to evaluate IL-6 blockade in disorders such neuropsychiatric lupus erythematosus (SLE), sarcoidosis and Behcet's.
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Affiliation(s)
- Elena Grebenciucova
- Feinberg School of Medicine, Department of Neurology, Northwestern University, Chicago, IL, United States
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Wei J, Guo F, Song Y, Xu K, Lin F, Li K, Li B, Qian Z, Wang X, Wang H, Xu T. Transcriptional analysis of human peripheral blood mononuclear cells stimulated by Mycobacterium tuberculosis antigen. Front Cell Infect Microbiol 2023; 13:1255905. [PMID: 37818041 PMCID: PMC10561294 DOI: 10.3389/fcimb.2023.1255905] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 09/04/2023] [Indexed: 10/12/2023] Open
Abstract
Background Mycobacterium tuberculosis antigen (Mtb-Ag) is a polypeptide component with a molecular weight of 10-14 kDa that is obtained from the supernatant of the H37Ra strain after heat treatment. It stimulates the activation and proliferation of γδT cells in the blood to produce an immune response against tuberculosis. Mtb-Ag is therefore crucial for classifying and detecting the central genes and key pathways involved in TB initiation and progression. Methods In this study, we performed high-throughput RNA sequencing of peripheral blood mononuclear cells (PBMC) from Mtb-Ag-stimulated and control samples to identify differentially expressed genes and used them for gene ontology (GO) and a Kyoto Encyclopedia of Genomes (KEGG) enrichment analysis. Meanwhile, we used PPI protein interaction network and Cytoscape analysis to identify key genes and qRT-PCR to verify differential gene expression. Single-gene enrichment analysis (GSEA) was used further to elucidate the potential biological functions of key genes. Analysis of immune cell infiltration and correlation of key genes with immune cells after Mtb-Ag-stimulated using R language. Results We identified 597 differentially expressed genes in Mtb-Ag stimulated PBMCs. KEGG and GSEA enrichment analyzed the cellular pathways related to immune function, and DEGs were found to be primarily involved in the TNF signaling pathway, the IL-17 signaling pathway, the JAK-STAT signaling pathway, cytokine-cytokine receptor interactions, and the NF-κB signaling pathway. Wayne analysis using GSEA, KEGG, and the protein-protein interaction (PPI) network showed that 34 genes, including PTGS2, IL-1β, IL-6, TNF and IFN-γ et al., were co-expressed in the five pathways and all were up-regulated by Mtb-Ag stimulation. Twenty-four DEGs were identified using qRT-PCR, including fourteen up-regulated genes (SERPINB7, IL20, IFNG, CSF2, PTGS2, TNF-α, IL36G, IL6, IL10, IL1A, CXCL1, CXCL8, IL4, and CXCL3) and ten down-regulated genes (RTN1, CSF1R CD14, C5AR1, CXCL16, PLXNB2, OLIG1, EEPD1, ENG, and CCR1). These findings were consistent with the RNA-Seq results. Conclusion The transcriptomic features associated with Mtb-Ag provide the scientific basis for exploring the intracellular immune mechanisms against Mtb. However, more studies on these DEGs in pathways associated with Mtb-Ag stimulation are needed to elucidate the underlying pathologic mechanisms of Mtb-Ag during Mtb infection.
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Affiliation(s)
- Jing Wei
- Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Fangzheng Guo
- Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Yamin Song
- Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Kun Xu
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Feiyang Lin
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Kangsheng Li
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
| | - Baiqing Li
- Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
- Department of Immunology, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
| | - Zhongqing Qian
- Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
- Department of Immunology, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
| | - Xiaojing Wang
- Anhui Province Key Laboratory of Clinical and Preclinical Research in Respiratory Disease, Bengbu Medical College, Bengbu, China
| | - Hongtao Wang
- Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
- Department of Immunology, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
| | - Tao Xu
- Laboratory Medicine Experimental Center, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
- Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical College, Bengbu, China
- Department of Clinical Laboratory and Diagnostics, Laboratory Medicine College, Bengbu Medical College, Bengbu, China
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Fialho MFP, Brum ES, Oliveira SM. Could the fibromyalgia syndrome be triggered or enhanced by COVID-19? Inflammopharmacology 2023; 31:633-651. [PMID: 36849853 PMCID: PMC9970139 DOI: 10.1007/s10787-023-01160-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 02/08/2023] [Indexed: 03/01/2023]
Abstract
Fibromyalgia (FM) is a complex disease with an uncertain aetiology and intricate pathophysiology. Although its genesis is not fully explained, potential environmental factors, such as viral infections might trigger FM or worsen patients' clinical outcomes. The SARS-CoV-2 virus may affect central and peripheral nervous systems, leading to musculoskeletal, neurological, and psychological disturbances. These symptoms might persist at least 12 months beyond the recovery, often referred to as post-COVID syndrome, which resembles FM syndrome. In this sense, we argued the potential consequences of COVID-19 exclusively on FM syndrome. First, we have described post-COVID syndrome and its painful symptoms. Afterwards, we argued whether FM syndrome could be triggered or enhanced by COVID-19 infection or by numerous and persistent stressors imposed daily by the pandemic setting (isolation, uncertainty, depression, mental stress, generalized anxiety, and fear of the virus). In addition, we have demonstrated similarities between pathophysiological mechanisms and cardinal symptoms of FM and COVID-19, speculating that SARS-CoV-2 might represent a critical mediator of FM or an exacerbator of its symptoms once both syndromes share similar mechanisms and complaints. Therefore, pharmacologic and non-pharmacological approaches commonly used to treat FM could serve as strategic therapies to attenuate painful and neurological manifestations of post-COVID syndrome. Although it is still theoretical, clinicians and researchers should be alert of patients who develop symptoms similar to FM or those who had their FM symptoms increased post-COVID to manage them better.
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Affiliation(s)
- Maria Fernanda Pessano Fialho
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Evelyne Silva Brum
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Sara Marchesan Oliveira
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil.
- Department of Biochemistry and Molecular Biology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil.
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Yang L, Guo P, Wang P, Wang W, Liu J. IL-6/ERK signaling pathway participates in type I IFN-programmed, unconventional M2-like macrophage polarization. Sci Rep 2023; 13:1827. [PMID: 36726024 PMCID: PMC9892596 DOI: 10.1038/s41598-022-23721-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 11/03/2022] [Indexed: 02/03/2023] Open
Abstract
Type I interferons (IFN-Is) have been harnessed for cancer therapies due to their immunostimulatory functions. However, certain tumor-tolerating activities by IFN-Is also exist, and may potentially thwart their therapeutic effects. In this respect, our previous studies have demonstrated a monocyte-orchestrated, IFN-I-to-IL-4 cytokine axis, which can subsequently drive M2-skewed pro-tumoral polarization of macrophages. Whether other IFN-dependent signals may also contribute to such an unconventional circumstance of M2-like macrophage skewing remain unexplored. Herein, we first unveil IL-6 as another ligand that participates in IFN-dependent induction of a typical M2 marker (ARG1) in transitional monocytes. Indeed, IL-6 significantly promotes IL-4-dependent induction of a major group of prominent M2 markers in mouse bone marrow-derived macrophages (BMDMs) and human peripheral blood-derived macrophages, while it alone does not engage marked increases of these markers. Such a pattern of regulation is confirmed globally by RNAseq analyses in BMDMs, which in turn suggests an association of IL-6-amplified subset of M2 genes with the ERK1/2 signaling pathway. Interestingly, pharmacological experiments establish the role of SHP2-ERK cascade in mediating IL-6's enhancement effect on these M2 targets. Similar approaches also validate the involvement of IL-6/ERK signaling in promoting the IFN-dependent, unconventional M2-skewing phenotype in transitional monocytes. Furthermore, an inhibitor of ERK signaling cooperates with an IFN-I inducer to enable a greater antitumor effect, which correlates with suppression of treatment-elicited ARG1. The present work establishes a role of IL-6/ERK signaling in promoting M2-like macrophage polarization, and suggests this axis as a potential therapeutic target for combination with IFN-I-based cancer treatments.
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Affiliation(s)
- Limin Yang
- State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center at Medical School of Nanjing University, Nanjing, 210061, China.,Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, Yancheng, 224006, China
| | - Panpan Guo
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Pei Wang
- State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center at Medical School of Nanjing University, Nanjing, 210061, China
| | - Wei Wang
- Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, Yancheng, 224006, China. .,The First People's Hospital of Yancheng, Yancheng, 224006, China.
| | - Jianghuai Liu
- State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center at Medical School of Nanjing University, Nanjing, 210061, China. .,Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, Yancheng, 224006, China. .,Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China.
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15
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Lv J, Cao CJ, Li W, Li SL, Zheng J, Yang XL. Tear inflammation related indexes after cataract surgery in elderly patients with type 2 diabetes mellitus. World J Clin Cases 2023; 11:385-393. [PMID: 36686353 PMCID: PMC9850981 DOI: 10.12998/wjcc.v11.i2.385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/15/2022] [Accepted: 12/21/2022] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Quantitative studies on the changes in inflammation-related content in tears, especially the effect of diabetes, are lacking. In this study, we measured the preoperative and postoperative tear inflammatory mediator levels in cataract patients, focusing on the expression of inflammatory factors in postoperative cataracts in the diabetic, and investigated the effect of drugs on the control of postoperative inflammation.
AIM To study the expression of inflammatory factors in elderly people with type 2 diabetes after cataract surgery.
METHODS Patients with a mean age of 70.3 ± 6.3 years were divided into group A (composed of elderly patients with cataracts and type 2 diabetes, n = 20 eyes) and group B (patients with age-related cataract, n = 20 eyes). Their tears were collected before each operation and on days 1 and 3, and weeks 1, 2, 3, and 4 post-surgery. Saline (150 μL) was dropped into the conjunctival sac of the surgical eye, followed by oculogyration in four directions. The fluid in the conjunctival sac was extracted using a sterile syringe and stored in Eppendorf tubes at -80 °C until measurement. The expression levels of matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), TIMP-2, interleukin-6 (IL-6), and IL-20 in tear fluid were measured using enzyme-linked immunosorbent assays.
RESULTS The postoperative expression levels of MMP-2, MMP-9, TIMP-2, IL-6, and IL-20 in group A were significantly higher than those in group B, whereas the concentration of TIMP-1 in group A remained lower than that in group B. The levels of MMP-2 and IL-6 in both groups continuously increased until the peak in the first postoperative week, and then gradually decreased over the next three weeks. Ultimately, MMP-2 declined to a lower level than that preoperatively at week 4, but IL-6 decreased to the same level as that preoperatively. The level of MMP-9 peaked in the first two weeks postoperative and then returned to the same level as 1-day post-operation. The concentration of TIMP-1 post-operation remained constant at a lower level than before surgery, and TIMP-2 Levels remained stable in both groups. IL-20 content started to increase in the third week after surgery.
CONCLUSION Inflammatory factor levels in tears fluctuated before and post-operation, which indicated more severe postoperative inflammation in the first two weeks.
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Affiliation(s)
- Jun Lv
- Department of Optometry, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Cheng-Jian Cao
- Zigong Academy of Medical Sciences, Zigong First People’s Hospital, Zigong 643000, Sichuan Province, China
| | - Wei Li
- FB Biologie, Philipps-Universitaet Marburg, Marburg 35043, Germany
| | - Shuang-Le Li
- Department of Ophthalmology, Zigong First People’s Hospital, Zigong 643000, Sichuan Province, China
| | - Jun Zheng
- Department of Optometry, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Xiu-Li Yang
- Department of Ophthalmology, Zigong First People’s Hospital, Zigong 643000, Sichuan Province, China
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16
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Nash D, Hughes MG, Butcher L, Aicheler R, Smith P, Cullen T, Webb R. IL-6 signaling in acute exercise and chronic training: Potential consequences for health and athletic performance. Scand J Med Sci Sports 2023; 33:4-19. [PMID: 36168944 PMCID: PMC10092579 DOI: 10.1111/sms.14241] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/25/2022] [Accepted: 09/20/2022] [Indexed: 12/13/2022]
Abstract
The cytokine interleukin-6 (IL-6) is involved in a diverse set of physiological processes. Traditionally, IL-6 has been thought of in terms of its inflammatory actions during the acute phase response and in chronic conditions such as rheumatoid arthritis and obesity. However, IL-6 is also an important signaling molecule during exercise, being acutely released from working muscle fibers with increased exercise duration, intensity, and muscle glycogen depletion. In this context, IL-6 enables muscle-organ crosstalk, facilitating a coordinated response to help maintain muscle energy homeostasis, while also having anti-inflammatory actions. The range of actions of IL-6 can be explained by its dichotomous signaling pathways. Classical signaling involves IL-6 binding to a cell-surface receptor (mbIL-6R; present on only a small number of cell types) and is the predominant signaling mechanism during exercise. Trans-signaling involves IL-6 binding to a soluble version of its receptor (sIL-6R), with the resulting complex having a much greater half-life and the ability to signal in all cell types. Trans-signaling drives the inflammatory actions of IL-6 and is the predominant pathway in disease. A single nucleotide polymorphism (rs2228145) on the IL-6R gene can modify the classical/trans-signaling balance through increasing the levels of sIL-6R. This SNP has clinical significance, having been linked to inflammatory conditions such as rheumatoid arthritis and type 1 diabetes, as well as to the severity of symptoms experienced with COVID-19. This review will describe how acute exercise, chronic training and the rs2228145 SNP can modify the IL-6 signaling pathway and the consequent implications for health and athletic performance.
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Affiliation(s)
- Dan Nash
- School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, UK
| | - Michael G Hughes
- School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, UK
| | - Lee Butcher
- School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, UK
| | - Rebecca Aicheler
- School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, UK
| | - Paul Smith
- School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, UK
| | - Tom Cullen
- Research Centre for Sport, Exercise and Life Sciences, Coventry University, Coventry, UK
| | - Richard Webb
- School of Sport and Health Sciences, Cardiff Metropolitan University, Cardiff, UK
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17
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Protective Effect of High-Intensity Interval Training (HIIT) and Moderate-Intensity Continuous Training (MICT) against Vascular Dysfunction in Hyperglycemic Rats. J Nutr Metab 2022; 2022:5631488. [PMID: 36510592 PMCID: PMC9741543 DOI: 10.1155/2022/5631488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 11/01/2022] [Accepted: 11/03/2022] [Indexed: 12/04/2022] Open
Abstract
Background Hyperglycemia is a major risk factor for endothelial dysfunction. Endothelial dysfunction is associated with the inability of endothelial cells to maintain homeostasis of the cardiovascular system. Regular exercise may be considered as an effective and low-cost nonpharmacological tool for improving vascular function, though there is no agreement on the best type of exercise. Objectives To determine how high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) may prevent endothelial dysfunction under hyperglycemic conditions, and to compare these two interventions. Method Twenty-four eight-week-old male Wistar rats were randomly assigned into four groups: healthy nonexercising control (C), hyperglycemic control (HG-C), hyperglycemic + HIIT (HG-IT), and hyperglycemic + MICT (HG-CT). Hyperglycemia was induced by a single injection of streptozotocin. Hyperglycemic animals were subjected to HIIT or MICT protocols six days a week for six weeks. Decapitation was performed the day after the exercise protocols were completed. The ascending aorta (until the abdominal artery) was examined. An enzyme-linked immunosorbent assay (ELISA) was used to measure the glucagon-likepeptide-1 (GLP-1), endothelial nitric oxide synthase (eNOS), and tumor necrosis factor-alpha (TNFα) levels. A colorimetric assay was used to measure superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels. Quantitative real-time polymerase chain reaction (PCR) was used to measure the expression of the receptor for advanced glycation end-products (RAGE) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Hematoxylin and eosin (H&E) staining was used to histologically analyze the aortas. Results There was a significantly higher level of GLP-1 and lower expression of RAGE, NF-κB, and TNFα in the HG-IT and HG-CT group compared to the HG-C group. Microscopic examination of aortic tissue showed a better tissue arrangement in both treatment groups than in the HG-C group. Except for the MDA level, there were no significant differences in any of the measured parameters between the HG-IT and HG-CT groups. Conclusion Under hyperglycemic conditions, both HIIT and MICT have a protective role against endothelial dysfunction.
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18
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Yüce M, Albayrak E. Hyperthermia-stimulated tonsil-mesenchymal stromal cells suppress hematological cancer cells through downregulation of IL-6. J Cell Biochem 2022; 123:1966-1979. [PMID: 36029519 DOI: 10.1002/jcb.30322] [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: 10/06/2021] [Revised: 08/01/2022] [Accepted: 08/16/2022] [Indexed: 12/24/2022]
Abstract
There are contradictory reports on the use of mesenchymal stromal cells (MSCs) in cancer therapy. Variable outcomes have been associated with several factors including cancer pathology, experimental procedure, MSC source tissue, and individual genetic differences. It is also known that MSCs exert their therapeutic effects with various paracrine factors released from these cells. The profiles of the factors released from MSCs are altered by heat shock, hypoxia, oxidative stress, starvation or various agents such as inflammatory cytokines, and their therapeutic potential is affected. In this study, the antitumor potential of conditioned media (CM), which contains paracrine factors, of mild hyperthermia-stimulated mesenchymal stromal cells derived from lymphoid organ tonsil tissue (T-MSC) was investigated in comparison with CM obtained from T-MSCs grew under normal culture conditions. CM was obtained from T-MSCs that were successfully isolated from palatine tonsil tissue and characterized. The cytotoxic effect of CM on the growth of hematological cancer cell lines at different concentrations (1:1 and 1:2) was demonstrated by methylthiazoldiphenyl-tetrazolium bromide analysis. In addition, the apoptotic effect of T-MSC-CM treatment was evaluated on the cancer cells using Annexin-V/PI detection method by flow cytometry. The pro/anti-apoptotic and cytokine-related gene expressions were also analyzed by real-time polymerase chain reaction post T-MSC-CM treatment. In conclusion, we demonstrated that the factors released from hyperthermia-stimulated T-MSCs induced apoptosis in hematological cancer cell lines in a dose-dependent manner. Importantly, our results at the transcriptional level support that the factors and cytokines released from hyperthermia-stimulated T-MSC may exert antitumoral effects in cancer cells by downregulation of IL-6 that promotes tumorigenesis. These findings reveal that T-MSC-CM can be a powerful cell-free therapeutical strategy for cancer therapy.
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Affiliation(s)
- Melek Yüce
- Stem Cell Research & Application Center, Ondokuz Mayıs University, Kurupelit Campus, Atakum/Samsun, Turkey
| | - Esra Albayrak
- Stem Cell Research & Application Center, Ondokuz Mayıs University, Kurupelit Campus, Atakum/Samsun, Turkey
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19
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Wu J, Luo FL, Xie Y, Xiong H, Gao Y, Liu G, Zhang XL. EST12 regulates Myc expression and enhances anti-mycobacterial inflammatory response via RACK1-JNK-AP1-Myc immune pathway. Front Immunol 2022; 13:943174. [PMID: 36003390 PMCID: PMC9393728 DOI: 10.3389/fimmu.2022.943174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/20/2022] [Indexed: 11/13/2022] Open
Abstract
c-Myc (Myc) is a well-known transcription factor that regulates many essential cellular processes. Myc has been implicated in regulating anti-mycobacterial responses. However, its precise mechanism in modulating mycobacterial immunity remains elusive. Here, we found that a secreted Rv1579c (early secreted target with molecular weight 12 kDa, named EST12) protein, encoded by virulent Mycobacterium tuberculosis (M.tb) H37Rv region of deletion (RD)3, induces early expression and late degradation of Myc protein. Interestingly, EST12-induced Myc was further processed by K48 ubiquitin proteasome degradation in E3 ubiquitin ligase FBW7 dependent manner. EST12 protein activates JNK-AP1-Myc signaling pathway, promotes Myc binding to the promoters of IL-6, TNF-α and iNOS, then induces the expression of pro-inflammatory cytokines (IL-6 and TNF-α)/inducible nitric oxide synthase (iNOS)/nitric oxide (NO) to increase mycobacterial clearance in a RACK1 dependent manner, and these effects are impaired by both Myc and JNK inhibitors. Macrophages infected with EST12-deficiency strain (H37RvΔEST12) displayed less production of iNOS, IL-6 and TNF-α. In conclusion, EST12 regulates Myc expression and enhances anti-mycobacterial inflammatory response via RACK1-JNK-AP1-Myc immune pathway. Our finding provides new insights into M.tb-induced immunity through Myc.
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Affiliation(s)
- Jian Wu
- Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Feng-Ling Luo
- Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Yan Xie
- Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Huan Xiong
- Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Yadong Gao
- Department of Allergy, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Guanghui Liu
- Department of Allergy, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xiao-Lian Zhang
- Hubei Province Key Laboratory of Allergy and Immunology and Department of Immunology, Wuhan University School of Basic Medical Sciences, Wuhan, China
- Department of Allergy, Zhongnan Hospital of Wuhan University, Wuhan, China
- State Key Laboratory of Virology, Frontier Science Center for Immunology and Metabolism and Medical Research Institute, Wuhan University, Wuhan, China
- Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China
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Jabbar F, Kim YS, Lee SH. Biological Influence of Pulmonary Disease Conditions Induced by Particulate Matter on Microfluidic Lung Chips. BIOCHIP JOURNAL 2022; 16:305-316. [PMID: 35822173 PMCID: PMC9263805 DOI: 10.1007/s13206-022-00068-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 05/04/2022] [Accepted: 06/15/2022] [Indexed: 11/26/2022]
Abstract
Particulate matter (PM10)-induced respiratory illnesses are difficult to investigate in trans-well culture systems. Microphysiological systems offer the capacity to mimic these phenomena to analyze any possible hazards that PM10 exposure poses to respiratory system of Humans. This study proposes an on-chip healthy human lung distal airway model that efficiently reconstitutes in vivo-like environmental conditions in a microfluidic device. The lung-on-chip model comprises a TEER sensor chip and portable microscope for continuous monitoring. To determine the efficacy of our model, we assessed the response to exposure to three PM environmental conditions (mild, average, and severe) and analyzed the relevant in vivo physiological and toxicological data using the airway model. Our results revealed significant increases in the levels of the IL-13, IL-6, and MUC5AC pathological biomarkers, which indicate increased incidences of on-chip asthma and chronic obstructive pulmonary disease conditions. Overall, we deduced that this model will facilitate the identification of potential therapeutics and the prevention of chronic life-threatening toxicities and pandemics such as COVID-19. The proposed system provides basic data for producing an improved in organ-on-chip technology.
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Affiliation(s)
- Faiza Jabbar
- Advanced Micro Mechatronics Lab, School of Engineering, Jeju National University, Jeju, Republic of Korea
| | | | - Sang Ho Lee
- College of Pharmacy, Jeju National University, Jeju, Republic of Korea
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21
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Jao J, Balmert LC, Sun S, Qiu Y, Kraus TA, Kirmse B, Sperling RS, Abrams EJ, Myer L, Arpadi S, Geffner ME, LeRoith D, Kurland IJ. Distinct cord blood C-peptide, adipokine, and lipidomic signatures by in utero HIV exposure. Pediatr Res 2022; 92:233-241. [PMID: 34446848 PMCID: PMC8881568 DOI: 10.1038/s41390-021-01705-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 07/14/2021] [Accepted: 08/08/2021] [Indexed: 01/02/2023]
Abstract
BACKGROUND Early-life metabolic derangements in HIV-exposed uninfected (HEU) infants have been reported. METHODS Pregnant women with HIV and HIV-uninfected pregnant women were enrolled with their newborns in a US cohort from 2011 to 2015. We measured cord insulin, C-peptide, and metabolic cytokines of HEU and HIV-unexposed uninfected (HUU) newborns using ELISA and metabolites, lipid subspecies, and eicosanoids via liquid chromatography/mass spectrometry. Linear regression was employed to assess the association of intrauterine HIV/ART with insulin and C-peptide. Graphical lasso regression was used to identify differences between metabolite/lipid subspecies networks associated with C-peptide. RESULTS Of 118 infants, 56 were HEU, ART exposed. In adjusted analyses, mean cord insulin (β = 0.295, p = 0.03) and C-peptide (β = 0.522, p < 0.01) were significantly higher in HEU vs. HUU newborns. HEU neonates exhibited primarily positive associations between complex lipids and C-peptide, indicative of fuel storage, and augmented associations between cord eicosanoids and cytokines. HUU neonates exhibited negative associations with lipids and C-peptide indicative of increased fuel utilization. CONCLUSION Higher cord insulin and C-peptide in HEU vs. HUU newborns as well as differences in cord metabolites, metabolic-related cytokines, and eicosanoids may reflect a propensity for fuel storage and an inflammatory milieu suggestive of fetal metabolic changes associated with in utero HIV/ART exposure. IMPACT There is a paucity of studies assessing cord blood and neonatal metabolic health in HIV-exposed uninfected (HEU) newborns, an increasing population worldwide. Compared to HIV-unexposed uninfected (HUU) newborns, HEU newborns exhibit alterations in fuel homeostasis and an inflammatory milieu associated with in utero HIV/antiretroviral therapy (ART) exposure. The long-term implications of these neonatal findings are as yet unknown, but merit continued evaluation as this important and growing population ages into adulthood.
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Affiliation(s)
- Jennifer Jao
- Department of Pediatrics, Division of Pediatric Infectious Diseases, Department of Medicine, Division of Adult Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| | - Lauren C. Balmert
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA, Department of Preventive Medicine, Division of Biostatistics
| | - Shan Sun
- Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA, Department of Pediatrics, Division of Pediatric Infectious Diseases
| | - Yunping Qiu
- Albert Einstein College of Medicine, Bronx, NY, USA, Department of Medicine, Division of Endocrinology, Fleischer Institute for Diabetes and Metabolism
| | - Thomas A. Kraus
- Icahn School of Medicine at Mount Sinai, New York, NY, USA, Center for Therapeutic Antibody Development
| | - Brian Kirmse
- University of Mississippi Medical Center, Jackson, MS, USA, Department of Medical Genetics
| | - Rhoda S. Sperling
- Icahn School of Medicine at Mount Sinai, New York, NY, USA, Department of Obstetrics, Gynecology, and Reproductive Health
| | - Elaine J. Abrams
- ICAP at Columbia, Mailman School of Public Health and Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA,Vagelos College of Physicians & Surgeons and Mailman School of Public Health, Columbia University, New York, NY, USA, G.H. Sergievsky Center, Department of Pediatrics, Department of Epidemiology
| | - Landon Myer
- University of Cape Town, Cape Town, South Africa, School of Public Health & Family Medicine, Faculty of Health Sciences, Division of Epidemiology & Biostatistics
| | - Stephen Arpadi
- University of Cape Town, Cape Town, South Africa, School of Public Health & Family Medicine, Faculty of Health Sciences, Division of Epidemiology & Biostatistics
| | - Mitchell E. Geffner
- Keck School of Medicine of USC, Los Angeles, CA, USA, The Saban Research Institute of Children’s Hospital Los Angeles
| | - Derek LeRoith
- Icahn School of Medicine at Mount Sinai, New York, NY, USA, Department of Medicine, Division of Endocrinology, Diabetes and Bone Diseases
| | - Irwin J. Kurland
- Albert Einstein College of Medicine, Bronx, NY, USA, Department of Medicine, Division of Endocrinology, Fleischer Institute for Diabetes and Metabolism
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22
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Liu L, Zhou W, Fan Y, Zhang L, Liu S, Song S, Li H. Effect of interleukin 6 on scleral fibroblast proliferation, differentiation, and apoptosis involved in myopic scleral remodeling. Ophthalmic Res 2022; 65:529-539. [DOI: 10.1159/000524502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 03/25/2022] [Indexed: 11/19/2022]
Abstract
Introduction: Scleral hypoxia (HO) is present in myopic eyes, and interleukin (IL)-6 is increased in the aqueous humor of patients with high myopia. The aim of this study was to investigate the effects of IL-6 on scleral fibroblast proliferation, differentiation, and apoptosis under conditions of HO and the possible role of IL-6 in myopic scleral remodeling. Methods: Primary human scleral fibroblasts (HSFs) were cultured using a tissue mass adherent method. First, cells were cultured under conditions of HO (2% O2) or normoxia (NO, 20% O2) for different times. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunofluorescence were used to detect the expression of IL-6 in HSFs. Next, cells were divided into five groups: NO, HO, HO plus IL-6, HO plus interleukin-6 receptor inhibitor (IL6RI), and HO plus IL-6 and IL6RI. The groups were treated separately for 72 h. A Cell Counting Kit-8 assay and flow cytometry were used to detect cell proliferation and apoptosis, respectively. Western blotting and qRT-PCR were used to detect the expression of various genes in the transforming growth factor-β1/Smad2/matrix metalloproteinase-2 pathway; these methods and immunofluorescence were also used to detect transdifferentiation of HSFs. Results: HO resulted in upregulation of IL-6 expression in HSFs. Compared with NO, HO resulted in diminished cell proliferation and increased apoptosis and differentiation in HSFs; the above trend was further enhanced by the addition of IL6RI. Compared with the HO group, the addition of IL-6 led to a decrease in cell proliferation and an increase in apoptosis and differentiation of HSFs; the above trends showed opposite changes after the addition of both IL-6 and IL6RI. Additionally, IL-6 and IL6RI exerted opposite regulatory effects on the transforming growth factor-β1/Smad2/matrix metalloproteinase-2 pathway under conditions of HO. Conclusion: HO caused HSFs to overexpress IL-6. IL-6 has a role in scleral remodeling in myopic eyes through affecting the proliferation, differentiation, and apoptosis of HSFs.
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23
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Chaoyi M, Shrestha B, Hui L, Qiujin D, Ping F. Tocilizumab therapy for persistent high-grade fever in systemic lupus erythematosus: two cases and a literature review. J Int Med Res 2022; 50:3000605221088558. [PMID: 35350923 PMCID: PMC8973080 DOI: 10.1177/03000605221088558] [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] [Indexed: 11/16/2022] Open
Abstract
Tocilizumab (TCZ) is a humanized immunoglobulin (Ig) G1 monoclonal antibody directed against the interleukin (IL)-6 receptor. We report on two patients with persistent high-grade fever and systemic lupus erythematosus (SLE) who were treated with TCZ. Two female Chinese patients presented with SLE and high-grade fever, with raised inflammatory markers including C-reactive protein, erythrocyte sedimentation rate, and IL-6, but no signs of opportunistic infections. Their fever and other symptoms responded poorly to broad-spectrum antibiotics, antifungals, antivirals, and glucocorticoids. They were both treated with TCZ. Their body temperatures returned to normal after treatment with TCZ, and other symptoms, including arthralgia, gradually improved. Both patients were followed-up and their conditions remained steady to date. TCZ may thus be an alternative treatment for patients with SLE and persistent high-grade fever who fail to respond to initial antibiotics and high-dose glucocorticoids.
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Affiliation(s)
- Ma Chaoyi
- Department of Rheumatology and Clinical Immunology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, P.R of China
| | - Bikash Shrestha
- Department of Internal Medicine, Grande International Hospital, Dhapasi, Kathmandu, Nepal
| | - Li Hui
- Department of Rheumatology and Clinical Immunology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, P.R of China
| | - Ding Qiujin
- Department of Rheumatology and Clinical Immunology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, P.R of China
| | - Fu Ping
- Department of Rheumatology and Clinical Immunology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, P.R of China
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24
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Docherty S, Harley R, McAuley JJ, Crowe LAN, Pedret C, Kirwan PD, Siebert S, Millar NL. The effect of exercise on cytokines: implications for musculoskeletal health: a narrative review. BMC Sports Sci Med Rehabil 2022; 14:5. [PMID: 34991697 PMCID: PMC8740100 DOI: 10.1186/s13102-022-00397-2] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 12/31/2021] [Indexed: 02/07/2023]
Abstract
The physiological effects of physical exercise are ubiquitously reported as beneficial to the cardiovascular and musculoskeletal systems. Exercise is widely promoted by medical professionals to aid both physical and emotional wellbeing; however, mechanisms through which this is achieved are less well understood. Despite numerous beneficial attributes, certain types of exercise can inflict significant significant physiological stress. Several studies document a key relationship between exercise and immune activation. Activation of the innate immune system occurs in response to exercise and it is proposed this is largely mediated by cytokine signalling. Cytokines are typically classified according to their inflammatory properties and evidence has shown that cytokines expressed in response to exercise are diverse and may act to propagate, modulate or mitigate inflammation in musculoskeletal health. The review summarizes the existing literature on the relationship between exercise and the immune system with emphasis on how exercise-induced cytokine expression modulates inflammation and the immune response.
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Affiliation(s)
- Sophie Docherty
- Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, 120 University Avenue, Glasgow, G12 8TA, Scotland, UK
| | - Rachael Harley
- Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, 120 University Avenue, Glasgow, G12 8TA, Scotland, UK
| | - Joseph J McAuley
- Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, 120 University Avenue, Glasgow, G12 8TA, Scotland, UK
| | - Lindsay A N Crowe
- Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, 120 University Avenue, Glasgow, G12 8TA, Scotland, UK
| | - Carles Pedret
- Sports Medicine and Imaging Department, Clinica Diagonal, C/Sant Mateu 24-26, 08950, Esplugues de Llobregat, Spain
| | - Paul D Kirwan
- School of Physiotherapy, Royal College of Surgeons in Ireland, Dublin, Ireland
- Physiotherapy Department, Connolly Hospital, Dublin, Ireland
| | - Stefan Siebert
- Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, 120 University Avenue, Glasgow, G12 8TA, Scotland, UK
| | - Neal L Millar
- Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, 120 University Avenue, Glasgow, G12 8TA, Scotland, UK.
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25
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Zouhal H, Zare-Kookandeh N, Haghighi MM, Daraei A, de Sousa M, Soltani M, Abderrahman AB, M Tijani J, Hackney AC, Laher I, Saeidi A. Physical activity and adipokine levels in individuals with type 2 diabetes: A literature review and practical applications. Rev Endocr Metab Disord 2021; 22:987-1011. [PMID: 33931803 DOI: 10.1007/s11154-021-09657-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/19/2021] [Indexed: 12/13/2022]
Abstract
We review the effects of acute and long-term physical activity on adipokine levels in individuals with type 2 diabetes (T2D). Three electronic databases were searched. Studies made in animal models were excluded, while studies based on participants with and without T2D, and also studies with type 1 diabetes were included. Of the 2,450 citations, 63 trials, including randomised control trials, cross-sectional and longitudinal studies, met our inclusion criteria. Seventy and five percent of studies reported the effects of physical activity on tumor necrosis factor-alpha (TNFα), interleukin 6 (IL-6), adiponectin, visfatin, omentin-1, and leptin levels. There are no robust results due to variations in exercise modality, intensity, duration, and also differences in cohort characteristics in the literature. Only four studies described the effects of an acute session of physical activity on adipokine levels. Overall, physical activity improves diabetes status by regulating adipokine levels. However, long-term aerobic + resistance training combined with dietary modifications is likely to be a more effective strategy for improving adipokines profiles in patients with type 2 diabetes.
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Affiliation(s)
- Hassane Zouhal
- M2S (Laboratoire Mouvement, University of Rennes, 1274, F-35000, Sport, Santé), France.
| | | | | | - Ali Daraei
- Department of Biological Sciences in Sport, Faculty of Sports Sciences and Health, Shahid Beheshti University, Tehran, Iran
| | | | - Mohammad Soltani
- Department of Biological Sciences in Sport, Faculty of Sports Sciences and Health, Shahid Beheshti University, Tehran, Iran
| | | | | | - Anthony C Hackney
- Department of Exercise & Sport Science, Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA
| | - Ismail Laher
- Faculty of Medicine, Department of Anesthesiology, The University of British Columbia, Pharmacology & Therapeutics, Vancouver, Canada
| | - Ayoub Saeidi
- Department of Physical Education and Sport Sciences, University of Kurdistan, Sanandaj, Iran.
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26
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Nicin L, Wagner JUG, Luxán G, Dimmeler S. Fibroblast-mediated intercellular crosstalk in the healthy and diseased heart. FEBS Lett 2021; 596:638-654. [PMID: 34787896 DOI: 10.1002/1873-3468.14234] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/28/2021] [Accepted: 11/04/2021] [Indexed: 01/07/2023]
Abstract
Cardiac fibroblasts constitute a major cell population in the heart. They secrete extracellular matrix components and various other factors shaping the microenvironment of the heart. In silico analysis of intercellular communication based on single-cell RNA sequencing revealed that fibroblasts are the source of the majority of outgoing signals to other cell types. This observation suggests that fibroblasts play key roles in orchestrating cellular interactions that maintain organ homeostasis but that can also contribute to disease states. Here, we will review the current knowledge of fibroblast interactions in the healthy, diseased, and aging heart. We focus on the interactions that fibroblasts establish with other cells of the heart, specifically cardiomyocytes, endothelial cells and immune cells, and particularly those relying on paracrine, electrical, and exosomal communication modes.
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Affiliation(s)
- Luka Nicin
- Institute for Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany.,German Center for Cardiovascular Research (DZHK), Frankfurt am Main, Germany.,Cardio-Pulmonary Institute (CPI), Frankfurt am Main, Germany
| | - Julian U G Wagner
- Institute for Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany.,German Center for Cardiovascular Research (DZHK), Frankfurt am Main, Germany.,Cardio-Pulmonary Institute (CPI), Frankfurt am Main, Germany
| | - Guillermo Luxán
- Institute for Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany.,German Center for Cardiovascular Research (DZHK), Frankfurt am Main, Germany.,Cardio-Pulmonary Institute (CPI), Frankfurt am Main, Germany
| | - Stefanie Dimmeler
- Institute for Cardiovascular Regeneration, Goethe University, Frankfurt am Main, Germany.,German Center for Cardiovascular Research (DZHK), Frankfurt am Main, Germany.,Cardio-Pulmonary Institute (CPI), Frankfurt am Main, Germany
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27
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Cicalău GIP, Babes PA, Calniceanu H, Popa A, Ciavoi G, Iova GM, Ganea M, Scrobotă I. Anti-Inflammatory and Antioxidant Properties of Carvacrol and Magnolol, in Periodontal Disease and Diabetes Mellitus. Molecules 2021; 26:6899. [PMID: 34833990 PMCID: PMC8623889 DOI: 10.3390/molecules26226899] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 11/03/2021] [Accepted: 11/13/2021] [Indexed: 12/15/2022] Open
Abstract
Periodontal disease and diabetes mellitus are two pathologies that are extremely widespread worldwide and share the feature of chronic inflammation. Carvacrol is a phenolic monoterpenoid, produced by a variety of herbs, the most well-known of which is Origanum vulgare. Magnolol is a traditional polyphenolic compound isolated from the stem bark of Magnolia officinalis, mainly used in Chinese medicine. The purpose of this paper is to review the therapeutic properties of these bioactive compounds, in the treatment of periodontitis and diabetes. Based on our search strategy we conducted a literature search in the PubMed and Google Scholar databases to identify studies. A total of one hundred eighty-four papers were included in the current review. The results show that carvacrol and magnolol have anti-inflammatory, antioxidant, antimicrobial, anti-osteoclastic, and anti-diabetic properties that benefit both pathologies. Knowledge of the multiple activities of carvacrol and magnolol can assist with the development of new treatment strategies, and the design of clinical animal and human trials will maximize the potential benefits of these extracts in subjects suffering from periodontitis or diabetes.
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Affiliation(s)
- Georgiana Ioana Potra Cicalău
- Doctoral School of Biomedical Science, University of Oradea, 1st University Street, 410087 Oradea, Romania;
- Department of Dental Medicine, Faculty of Medicine and Pharmacy, University of Oradea, 1st Decembrie Street, 410073 Oradea, Romania; (G.C.); (G.M.I.); (I.S.)
| | - Petru Aurel Babes
- Doctoral School of Biomedical Science, University of Oradea, 1st University Street, 410087 Oradea, Romania;
| | - Horia Calniceanu
- Department of Periodontology, Faculty of Dental Medicine, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Periodontal and Periimplant Diseases Research Center “Prof. Dr. Anton Sculean”, Faculty of Dental Medicine, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Adelina Popa
- Department of Orthodontics, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Orthodontic Research Center (ORTHO-CENTER), Faculty of Dental Medicine, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Gabriela Ciavoi
- Department of Dental Medicine, Faculty of Medicine and Pharmacy, University of Oradea, 1st Decembrie Street, 410073 Oradea, Romania; (G.C.); (G.M.I.); (I.S.)
| | - Gilda Mihaela Iova
- Department of Dental Medicine, Faculty of Medicine and Pharmacy, University of Oradea, 1st Decembrie Street, 410073 Oradea, Romania; (G.C.); (G.M.I.); (I.S.)
| | - Mariana Ganea
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 1st Decembrie Street, 410073 Oradea, Romania;
| | - Ioana Scrobotă
- Department of Dental Medicine, Faculty of Medicine and Pharmacy, University of Oradea, 1st Decembrie Street, 410073 Oradea, Romania; (G.C.); (G.M.I.); (I.S.)
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28
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HuR Plays a Positive Role to Strengthen the Signaling Pathways of CD4 + T Cell Activation and Th17 Cell Differentiation. J Immunol Res 2021; 2021:9937243. [PMID: 34395636 PMCID: PMC8357502 DOI: 10.1155/2021/9937243] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 06/14/2021] [Accepted: 07/11/2021] [Indexed: 01/09/2023] Open
Abstract
After antigen and/or different cytokine stimulation, CD4+ T cells activated and differentiated into distinct T helper (Th) cells via differential T cell signaling pathways. Transcriptional regulation of the activation and differentiation of naïve CD4+ T cells into distinct lineage Th cells such as Th17 cells has been fully studied. However, the role of RNA-binding protein HuR in the signaling pathways of their activation and differentiation has not been well characterized. Here, we used HuR conditional knockout (HuR KO) CD4+ T cells to study mechanisms underlying HuR regulation of T cell activation and differentiation through distinct signaling pathways. Our work showed that, mechanistically, HuR positively promoted CD3g expression by binding its mRNA and enhanced the expression of downstream adaptor Zap70 and Malt1 in activated CD4+ T cells. Compared to WT Th0 cells, HuR KO Th0 cells with reduced Bcl-2 expression are much more susceptible to apoptosis than WT Th0 cells. We also found that HuR stabilized IL-6Rα mRNA and promoted IL-6Rα protein expression, thereby upregulating its downstream phosphorylation of Jak1 and Stat3 and increased level of phosphorylation of IκBα to facilitate Th17 cell differentiation. However, knockout of HuR increased IL-22 production in Th17 cells, which was due to HuR deficiency in reducing IL-22 transcription repressor c-Maf expression. These results highlight the importance of HuR in TCR signaling and IL-6/IL-6R axis driving naïve CD4+ T cell activation and differentiation into Th17 cells.
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29
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Resveratrol protects human nucleus pulposus cells from degeneration by blocking IL-6/JAK/STAT3 pathway. Eur J Med Res 2021; 26:81. [PMID: 34321087 PMCID: PMC8320225 DOI: 10.1186/s40001-021-00555-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 07/19/2021] [Indexed: 12/12/2022] Open
Abstract
Background Nucleus pulposus cells’ (NPCs’) degeneration is mainly responsible for the intervertebral disc degeneration (IDD), which is closely related to inflammatory response. Among the major proinflammatory factors that are related to NPCs’ degeneration, interleukin-6 (IL-6) and its downstream JAK/STAT3 pathway have received recent attention. The goal of our study is to figure out whether or how resveratrol (RSV) can protect NPCs from degeneration by affecting IL6/JAK/STAT3 pathway. Methods Different concentrations of RSV were added to NPCs’ mediums. Cell viability was measured by MTT assay and crystal violet staining. Cell cycle and apoptosis were analyzed by flow cytometry. Protein expression level was determined by western blot. mRNA expression level was measured by qPCR. Results Our study showed that RSV improved NPCs’ cell viability. It also inhibited cell apoptosis and cell cycle arrest, which were accompanied by the increased expression level of heat shock protein 90 (HSP90) and N-Cadherin. What’ more, RSV also improved the NPCs’ degeneration which was reflected in the increase of extracellular matrix (collagen II, Aggrecan). Moreover, RSV significantly attenuated the level of IL-6 secretion, which was accompanied by less phosphorylation of the transcription factors Janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3). Conclusion RSV exerted its protective effect on HNPCs’ degeneration by improving cell survival and function. The possible mechanism may be associated with the suppression of JAK/STAT3 phosphorylation and the decreased IL-6 production, which could be explained by a blockage of the positive feedback control loop between IL-6 and JAK/STAT3 pathway.
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30
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Wróbel A, Zapała Ł, Kluz T, Rogowski A, Misiek M, Juszczak K, Sieńko J, Gold D, Stangel-Wójcikiewicz K, Poleszak E, Radziszewski P. The Potential of Asiatic Acid in the Reversion of Cyclophosphamide-Induced Hemorrhagic Cystitis in Rats. Int J Mol Sci 2021; 22:ijms22115853. [PMID: 34072606 PMCID: PMC8198845 DOI: 10.3390/ijms22115853] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/25/2021] [Accepted: 05/25/2021] [Indexed: 01/15/2023] Open
Abstract
The purpose of this study was to determine if asiatic acid may act efficiently in the model of cyclophosphamide (CYP)-induced cystitis in rats. We performed experiments after administration of CYP (single dose 200 mg/kg, intraperitoneally), asiatic acid (30 mg/kg/day for 14 consecutive days, by oral gavage), or CYP plus asiatic acid, during which conscious cystometry, measurements of urothelium thickness and bladder edema, as well as selected biomarkers analyses were conducted. In rats that received asiatic acid together with CYP, a drop in bladder basal pressure, detrusor overactivity index, non-voiding contraction amplitude, non-voiding contraction frequency, and the area under the pressure curve were observed, when compared to the CYP group. Furthermore, a significant increase in threshold pressure, voided volume, intercontraction interval, bladder compliance, and volume threshold to elicit NVC were found in that group accordingly. Administration of the asiatic acid successfully restored concentrations of biomarkers both in bladder urothelium (BDNF, CGRP, OCT-3, IL-1β, IL-6, NGF, nitrotyrosine, malondialdehyde, TNF-α, SV2A, SNAP23, SNAP25, PAC-1, ORM1, occludin, IGFBP-3, HB-EGF, T–H protein, Z01, and HPX) and detrusor muscle (Rho kinase and VAChT) in CYP-treated rats. Finally, asiatic acid significantly decreased urothelium thickness and bladder oedema. Asiatic acid proved to be a potent and effective drug in the rat model of CYP-induced cystitis.
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Affiliation(s)
- Andrzej Wróbel
- Second Department of Gynecology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland
- Correspondence: (A.W.); (Ł.Z.)
| | - Łukasz Zapała
- Clinic of General, Oncological and Functional Urology, Medical University of Warsaw, Lindleya 4, 02-005 Warsaw, Poland;
- Correspondence: (A.W.); (Ł.Z.)
| | - Tomasz Kluz
- Department of Gynecology and Obstetrics, Institute of Medical Sciences, Medical College of Rzeszow University, 35-310 Rzeszow, Poland;
| | - Artur Rogowski
- Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University in Warsaw, 01-938 Warsaw, Poland;
- Department of Obstetrics and Gynecology, Mother and Child Institute, 01-211 Warsaw, Poland
| | - Marcin Misiek
- Department of Gynecologic Oncology, Holy Cross Cancer Center, 25-377 Kielce, Poland;
| | - Kajetan Juszczak
- Chair of Urology and Andrology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Skłodowskiej-Curie 9, 85-094 Bydgoszcz, Poland;
| | - Jacek Sieńko
- Second Department of Obstetrics and Gynecology, Medical University of Warsaw, 02-091 Warszawa, Poland;
| | - Daniela Gold
- Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz, 8036 Graz, Austria;
| | | | - Ewa Poleszak
- Chair and Department of Applied and Social Pharmacy, Laboratory of Preclinical Testing, Medical University of Lublin, 1 Chodźki Street, 20-093 Lublin, Poland;
| | - Piotr Radziszewski
- Clinic of General, Oncological and Functional Urology, Medical University of Warsaw, Lindleya 4, 02-005 Warsaw, Poland;
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Potere N, Batticciotto A, Vecchié A, Porreca E, Cappelli A, Abbate A, Dentali F, Bonaventura A. The role of IL-6 and IL-6 blockade in COVID-19. Expert Rev Clin Immunol 2021; 17:601-618. [PMID: 33874829 DOI: 10.1080/1744666x.2021.1919086] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a dysregulated hyperinflammatory response. AREAS COVERED Authors review evidence on IL-6 and IL-6 blockade in coronavirus disease 2019 (COVID-19) and discuss the pathophysiological and prognostic roles of this cytokine and the clinical impact of pharmacological blockade of IL-6 . The material includes original articles and reviews published from March 2020 to March 2021 and searched on PubMed, medRxiv, and bioRxiv. EXPERT OPINION IL-6 is one of the most prominent pro-inflammatory cytokines. Increased levels are recorded in COVID-19 patients, especially those with severe-to-critical disease. Evidence is accumulating on the relevance of IL-6 as a prognostic marker in COVID-19. Since IL-6 is a druggable target for several inflammatory diseases, pharmacological blockers of the IL-6 signaling pathway were repurposed to blunt the abnormal SARS-CoV-2-induced cytokine release. Data are limited to few randomized controlled trials that reported encouraging, though not conclusive, results, indicating the usefulness of IL-6 blockade early in the course of the disease in patients with hyperinflammation and no or limited organ damage. Further research is warranted to explore the role of IL-6 in different COVID-19 phenotypes and identify subgroups of patients who may mostly benefit from IL-6 pathway inhibition.
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Affiliation(s)
- Nicola Potere
- Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Alberto Batticciotto
- Rheumatology Unit, Internal Medicine Department, ASST Sette Laghi, Ospedale Di Circolo - Fondazione Macchi, Varese, Italy
| | | | - Ettore Porreca
- Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Antonella Cappelli
- Rheumatology Unit, Internal Medicine Department, ASST Sette Laghi, Ospedale Di Circolo - Fondazione Macchi, Varese, Italy
| | - Antonio Abbate
- Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Francesco Dentali
- Department of Medicine and Surgery, Insubria University, Varese, Italy
| | - Aldo Bonaventura
- Department of Internal Medicine, ASST Sette Laghi, Varese, Italy.,First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
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Goswami S, Choudhuri S, Bhattacharya B, Bhattacharjee R, Roy A, Mukhopadhyay S, Ghosh S, Chowdhury S. Chronic inflammation in polycystic ovary syndrome: A case-control study using multiple markers. Int J Reprod Biomed 2021; 19:313-320. [PMID: 33997590 PMCID: PMC8106819 DOI: 10.18502/ijrm.v19i4.9057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 07/27/2020] [Accepted: 09/21/2020] [Indexed: 11/24/2022] Open
Abstract
Background Polycystic ovary syndrome (PCOS) is associated with insulin resistance and elevated risk of cardiovascular disease and diabetes. Chronic inflammation has been observed in PCOS in several studies but there is also opposing evidence and a dearth of research in Indians. Objective To estimate chronic inflammation in PCOS and find its relationship with appropriate anthropometric and biochemical parameters. Materials and Methods Chronic inflammation was assessed in 30 women with PCOS (Group A) and 30 healthy controls (Group B) with highly sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), tumour necrosis factor alpha (TNFα), and platelet microparticles (PMP). In group A, the relationship of chronic inflammation with insulin resistance, waist hip ratio (WHR) serum testosterone, and serum glutamate pyruvate transaminase (SGPT) were examined. Results In group A, the hsCRP, TNFα, and PMP were significantly elevated compared to group B. However, IL-6 level was similar between the groups. In group A, PMP showed a significant positive correlation with waist-hip ratio and serum testosterone. IL-6 showed a significant positive correlation with insulin sensitivity and significant negative correlation with insulin resistance and serum glutamate pyruvate transaminase. Conclusion PCOS is associated with chronic inflammation and PMP correlates positively with central adiposity and biochemical hyperandrogenism in women with PCOS.
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Affiliation(s)
- Soumik Goswami
- Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education & Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal, India
| | - Subhadip Choudhuri
- Department of Biochemistry, Institute of Postgraduate Medical Education & Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal, India
| | - Basudev Bhattacharya
- Department of Biochemistry, Institute of Postgraduate Medical Education & Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal, India
| | - Rana Bhattacharjee
- Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education & Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal, India
| | - Ajitesh Roy
- Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education & Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal, India
| | - Satinath Mukhopadhyay
- Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education & Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal, India
| | - Sujoy Ghosh
- Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education & Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal, India
| | - Subhankar Chowdhury
- Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education & Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal, India
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Bogdanet D, Reddin C, Murphy D, Doheny HC, Halperin JA, Dunne F, O’Shea PM. Emerging Protein Biomarkers for the Diagnosis or Prediction of Gestational Diabetes-A Scoping Review. J Clin Med 2021; 10:1533. [PMID: 33917484 PMCID: PMC8038821 DOI: 10.3390/jcm10071533] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/02/2021] [Accepted: 04/02/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction: Gestational diabetes (GDM), defined as hyperglycemia with onset or initial recognition during pregnancy, has a rising prevalence paralleling the rise in type 2 diabetes (T2DM) and obesity. GDM is associated with short-term and long-term consequences for both mother and child. Therefore, it is crucial we efficiently identify all cases and initiate early treatment, reducing fetal exposure to hyperglycemia and reducing GDM-related adverse pregnancy outcomes. For this reason, GDM screening is recommended as part of routine pregnancy care. The current screening method, the oral glucose tolerance test (OGTT), is a lengthy, cumbersome and inconvenient test with poor reproducibility. Newer biomarkers that do not necessitate a fasting sample are needed for the prompt diagnosis of GDM. The aim of this scoping review is to highlight and describe emerging protein biomarkers that fulfill these requirements for the diagnosis of GDM. Materials and Methods: This scoping review was conducted according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines for scoping reviews using Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing & Allied Health Literature (CINAHL), PubMed, Embase and Web of Science with a double screening and extraction process. The search included all articles published in the literature to July 2020. Results: Of the 3519 original database citations identified, 385 were eligible for full-text review. Of these, 332 (86.2%) were included in the scoping review providing a total of 589 biomarkers studied in relation to GDM diagnosis. Given the high number of biomarkers identified, three post hoc criteria were introduced to reduce the items set for discussion: we chose only protein biomarkers with at least five citations in the articles identified by our search and published in the years 2017-2020. When applied, these criteria identified a total of 15 biomarkers, which went forward for review and discussion. Conclusions: This review details protein biomarkers that have been studied to find a suitable test for GDM diagnosis with the potential to replace the OGTT used in current GDM screening protocols. Ongoing research efforts will continue to identify more accurate and practical biomarkers to take GDM screening and diagnosis into the 21st century.
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Affiliation(s)
- Delia Bogdanet
- College of Medicine Nursing and Health Sciences, National University of Ireland Galway, H91TK33 Galway, Ireland;
- Centre for Diabetes Endocrinology and Metabolism, Galway University Hospital, Newcastle Road, H91YR71 Galway, Ireland; (C.R.); (D.M.); (H.C.D.); (P.M.O.)
| | - Catriona Reddin
- Centre for Diabetes Endocrinology and Metabolism, Galway University Hospital, Newcastle Road, H91YR71 Galway, Ireland; (C.R.); (D.M.); (H.C.D.); (P.M.O.)
| | - Dearbhla Murphy
- Centre for Diabetes Endocrinology and Metabolism, Galway University Hospital, Newcastle Road, H91YR71 Galway, Ireland; (C.R.); (D.M.); (H.C.D.); (P.M.O.)
| | - Helen C. Doheny
- Centre for Diabetes Endocrinology and Metabolism, Galway University Hospital, Newcastle Road, H91YR71 Galway, Ireland; (C.R.); (D.M.); (H.C.D.); (P.M.O.)
| | - Jose A. Halperin
- Divisions of Haematology, Brigham & Women’s Hospital, Boston, MA 02115, USA;
| | - Fidelma Dunne
- College of Medicine Nursing and Health Sciences, National University of Ireland Galway, H91TK33 Galway, Ireland;
- Centre for Diabetes Endocrinology and Metabolism, Galway University Hospital, Newcastle Road, H91YR71 Galway, Ireland; (C.R.); (D.M.); (H.C.D.); (P.M.O.)
| | - Paula M. O’Shea
- Centre for Diabetes Endocrinology and Metabolism, Galway University Hospital, Newcastle Road, H91YR71 Galway, Ireland; (C.R.); (D.M.); (H.C.D.); (P.M.O.)
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Liu H, Lin W, Liu Z, Song Y, Cheng H, An H, Wang X. E3 ubiquitin ligase NEDD4L negatively regulates keratinocyte hyperplasia by promoting GP130 degradation. EMBO Rep 2021; 22:e52063. [PMID: 33769697 DOI: 10.15252/embr.202052063] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 02/23/2021] [Accepted: 03/02/2021] [Indexed: 12/17/2022] Open
Abstract
Psoriasis is mainly characterized by abnormal hyperplasia of keratinocytes and immune cells infiltrating into the dermis and epidermis. Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) is a highly conserved HECT type E3 ligase that plays an important role in regulating physiological and pathological processes. Here, we identify NEDD4L as a negative regulator of psoriasis. Nedd4l significantly inhibits imiquimod (IMQ)-induced skin hyperplasia, and this effect is attributed to the inhibitory effect of NEDD4L on IL-6/GP130 signaling in keratinocytes. Mechanistically, NEDD4L directly interacts with GP130 and mediates its Lys-27-linked ubiquitination and proteasomal degradation. Moreover, the expression of NEDD4L is downregulated in the epidermis from IMQ-treated mice and psoriasis patients and negatively correlates with the protein levels of GP130 and p-STAT3 in clinical samples. Collectively, we uncover an inhibitory role of NEDD4L in the pathogenesis of psoriasis and suggest a new therapeutic strategy for the treatment of psoriasis.
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Affiliation(s)
- Huan Liu
- Institute of Immunology and Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Wenlong Lin
- Institute of Immunology and Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Zhiyong Liu
- Institute of Immunology and Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Yinjing Song
- Department of Dermatology and Venereology, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Hao Cheng
- Department of Dermatology and Venereology, School of Medicine, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Huazhang An
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Xiaojian Wang
- Institute of Immunology and Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
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Abstract
IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is an NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6-STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6-STAT3 axis is a critical target for treating diseases.
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Affiliation(s)
- Toshio Hirano
- National Institutes for Quantum and Radiological Science and Technology, Anagawa, Inage-ku, Chiba, Japan
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Callaghan MA, Alatorre-Hinojosa S, Connors LT, Singh RD, Thompson JA. Plasticizers and Cardiovascular Health: Role of Adipose Tissue Dysfunction. Front Pharmacol 2021; 11:626448. [PMID: 33716730 PMCID: PMC7947604 DOI: 10.3389/fphar.2020.626448] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 12/22/2020] [Indexed: 12/12/2022] Open
Abstract
Since the 1950s, the production of plastics has increased 200-fold, reaching 360 million tonnes in 2019. Plasticizers, additives that modify the flexibility and rigidity of the product, are ingested as they migrate into food and beverages. Human exposure is continuous and widespread; between 75 and 97% of urine samples contain detectable levels of bisphenols and phthalates, the most common plasticizers. Concern over the toxicity of plasticizers arose in the late 1990s, largely focused around adverse developmental and reproductive effects. More recently, many studies have demonstrated that exposure to plasticizers increases the risk for obesity, type 2 diabetes, and cardiovascular disease (CVD). In the 2000s, many governments including Canada, the United States and European countries restricted the use of certain plasticizers in products targeted towards infants and children. Resultant consumer pressure motivated manufacturers to substitute plasticizers with analogues, which have been marketed as safe. However, data on the effects of these new substitutes are limited and data available to-date suggest that many exhibit similar properties to the chemicals they replaced. The adverse effects of plasticizers have largely been attributed to their endocrine disrupting properties, which modulate hormone signaling. Adipose tissue has been well-documented to be a target of the disrupting effects of both bisphenols and phthalates. Since adipose tissue function is a key determinant of cardiovascular health, adverse effects of plasticizers on adipocyte signaling and function may underlie their link to cardiovascular disease. Herein, we discuss the current evidence linking bisphenols and phthalates to obesity and CVD and consider how documented impacts of these plasticizers on adipocyte function may contribute to the development of CVD.
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Affiliation(s)
- Mikyla A Callaghan
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Libin Cardiovascular Institute, Calgary, AB, Canada
| | | | - Liam T Connors
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Libin Cardiovascular Institute, Calgary, AB, Canada
| | - Radha D Singh
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Libin Cardiovascular Institute, Calgary, AB, Canada
| | - Jennifer A Thompson
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Libin Cardiovascular Institute, Calgary, AB, Canada.,Alberta Children's Health Research Institute, Calgary, AB, Canada
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Gunjegaonkar SM, Wankhede SB, Shanmugarajan TS, Shinde SD. Bioactive role of plant stress hormone methyl jasmonate against lipopolysaccharide induced arthritis. Heliyon 2020; 6:e05432. [PMID: 33225090 PMCID: PMC7666351 DOI: 10.1016/j.heliyon.2020.e05432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/28/2020] [Accepted: 11/02/2020] [Indexed: 10/26/2022] Open
Abstract
The current investigation was carried out to screen antiarthritic potential of Methyl Jasmonate (MJ) against lipopolysaccharide (LPS) induced arthritis. Cartilage damage was induced in experimental animals by intraplantar administration of LPS (1 mg/kg) and antiarthritic effect of MJ was screened in two doses of MJ-1 (20 mg/kg), MJ-2 (40 mg/kg) by intraperitoneally administration. Indomethacin (30 mg/kg p.o.) was used as standard drug. The severity of arthritis was evaluated by assessing arthritis score, secondary lesions, motility test, stair climbing ability, and dorsal flexion pain score method. The estimation of blood cytokine tumor necrosis factor- aplha (TNF-α),interleukine (IL-2 and IL-6) and thymus/spleen index was carried out to access the severity of inflammation. Estimation of hepaticenzymatic antioxidant activity superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx)and radiological examination was carried out on 28th day. Results indicated that MJ showed significant reduction in severity of arthritis by decreasing arthritis score, secondary lesions where as significant increase in motility, climbing ability and flexion pain score was observed. Significant decreased in blood cytokine viz. TNF-α, IL-2, IL-6 andthymus/spleen index was observed in MJ treated animals in dose dependent manner. MJ treated animals showed significant increased and restoration of hepatic antioxidant enzymatic activityof SOD, CAT, GSH, GPx where asradiological examination indicates protective effect on joint structure as compared to LPS treated rats. These current studies conclude that MJ has protective role in arthritis.
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Affiliation(s)
- S M Gunjegaonkar
- JSPM's Charak College of Pharmacy and Research, Department of Pharmacology, Gate No. 720/1&2, Pune-Nagar Road, Wagholi, 412207, Pune, Maharashtra, India
| | - S B Wankhede
- JSPM's Charak College of Pharmacy and Research, Department of Pharmaceutical Chemistry, Gate No. 720/1&2, Pune-Nagar Road, Wagholi, 412207, Pune, Maharashtra, India
| | - T S Shanmugarajan
- Vels Institute of Science, Technology and Advanced Studies, School of Pharmaceutical Sciences, Department of Pharmaceutics, Velan Nagar, P. V. Vaithiyalingam Road, Pallavaram, Chennai, 600 117, Tamil Nadu, India
| | - S D Shinde
- Shri. R. D. Bhakt College of Pharmacy, Department of Pharmacology, Jalna 431203, Maharashtra, India
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Othman FA, Tan SC. Preconditioning Strategies to Enhance Neural Stem Cell-Based Therapy for Ischemic Stroke. Brain Sci 2020; 10:893. [PMID: 33238363 PMCID: PMC7700351 DOI: 10.3390/brainsci10110893] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 11/18/2020] [Indexed: 02/05/2023] Open
Abstract
Transplantation of neural stem cells (NSCs) has been proposed as an alternative novel therapy to replace damaged neural circuitry after ischemic stroke onset. Nonetheless, albeit the potential of these cells for stroke therapy, many critical challenges are yet to be overcome to reach clinical applications. The major limitation of the NSC-based therapy is its inability to retain most of the donor stem cells after grafting into an ischemic brain area which is lacking of essential oxygen and nutrients for the survival of transplanted cells. Low cell survival rate limits the capacity of NSCs to repair the injured area and this poses a much more difficult challenge to the NSC-based therapy for ischemic stroke. In order to enhance the survival of transplanted cells, several stem cell culture preconditioning strategies have been employed. For ischemic diseases, hypoxic preconditioning is the most commonly applied strategy since the last few decades. Now, the preconditioning strategies have been developed and expanded enormously throughout years of efforts. This review systematically presented studies searched from PubMed, ScienceDirect, Web of Science, Scopus and the Google Scholar database up to 31 March 2020 based on search words containing the following terms: "precondition" or "pretreatment" and "neural stem cell" and "ischemic stroke". The searched data comprehensively reported seven major NSC preconditioning strategies including hypoxic condition, small drug molecules such as minocycline, doxycycline, interleukin-6, adjudin, sodium butyrate and nicorandil, as well as electrical stimulation using conductive polymer for ischemic stroke treatment. We discussed therapeutic benefits gained from these preconditioned NSC for in vitro and in vivo stroke studies and the detailed insights of the mechanisms underlying these preconditioning approaches. Nonetheless, we noticed that there was a scarcity of evidence on the efficacy of these preconditioned NSCs in human clinical studies, therefore, it is still too early to draw a definitive conclusion on the efficacy and safety of this active compound for patient usage. Thus, we suggest for more in-depth clinical investigations of this cell-based therapy to develop into more conscientious and judicious evidence-based therapy for clinical application in the future.
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Affiliation(s)
| | - Suat Cheng Tan
- School of Health Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia;
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Chen HY, Hu Y, Lu NH, Zhu Y. Caudal type homeoboxes as a driving force in Helicobacter pylori infection-induced gastric intestinal metaplasia. Gut Microbes 2020; 12:1-12. [PMID: 33031021 PMCID: PMC7553748 DOI: 10.1080/19490976.2020.1809331] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
(H. pylori), a common pathogenic bacterium in the stomach, has been demonstrated to be a major cause of gastric cancer (GC). The typical pathological evolution of H. pylori infection-induced GC involves development from gastric atrophy, via intestinal metaplasia (IM) and dysplasia, to intestinal-type GC. During this process, IM is considered to be an "irreversible point" that significantly increases the risk for GC. Therefore, the elucidation of the mechanism underlying IM is of great significance for the prevention and treatment of gastric mucosal carcinogenesis associated with H. pylori infection. Caudal type homeoboxes (CDXs) are transcription factors involved in intestinal differentiation establishment and the maintenance of normal intestinal mucosa and IM. H. pylori infection increases the expression of CDXs through epigenetic regulation, the nuclear factor-kappaB signaling pathway and its downstream proinflammatory factors, and the transforming growth factor-beta signaling pathway, leading to the progression from normal gastric mucosa to IM. However, the precise mechanisms of gastric intestinal metaplasia have not yet been fully elucidated. In this review, we focus on research progress revealing the functions of CDXs in H. pylori infection-induced IM, as well as the regulators modulating this process.
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Affiliation(s)
- Hong-Yan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yi Hu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Nong-Hua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China,CONTACT Yin Zhu Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang330006, Jiangxi Province, China
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Masiá M, Fernández-González M, Padilla S, Ortega P, García JA, Agulló V, García-Abellán J, Telenti G, Guillén L, Gutiérrez F. Impact of interleukin-6 blockade with tocilizumab on SARS-CoV-2 viral kinetics and antibody responses in patients with COVID-19: A prospective cohort study. EBioMedicine 2020; 60:102999. [PMID: 32950003 PMCID: PMC7492814 DOI: 10.1016/j.ebiom.2020.102999] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 08/24/2020] [Accepted: 08/27/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The virological and immunological effects of the immunomodulatory drugs used for COVID-19 remain unknown. We evaluated the impact of interleukin (IL)-6 blockade with tocilizumab on SARS-CoV-2 viral kinetics and the antibody response in patients with COVID-19. METHODS Prospective cohort study in patients admitted with COVID-19. Serial nasopharyngeal and plasma samples were measured for SARS-CoV-2 RNA and S-IgG/N-IgG titers, respectively. FINDINGS 138 patients with confirmed infection were included; 76 (55%) underwent IL-6 blockade. Median initial SOFA (p = 0•016) and SARS-CoV-2 viral load (p<0•001, Mann-Whitney-Wilcoxon test) were significantly higher among anti-IL-6 users. Patients under IL-6 blockade showed delayed viral clearance in the Kaplan-Meier curves (HR 0•35 [95%CI] [0•15-0•81], log-rank p = 0•014), but an adjusted propensity score matching model did not demonstrate a significant relationship of IL-6 blockade with viral clearance (HR 1•63 [0•35-7•7]). Cox regression showed an inverse association between SARS-CoV-2 RNA clearance and the initial viral load (HR 0•35 [0•11-0•89]). Patients under the IL-6 blocker showed shorter median time to seropositivity, higher peak antibody titers, and higher cumulative proportion of seropositivity in the Kaplan Meier curves (HR 3•1 [1•9-5] for S-IgG; and HR 3•0 [1•9-4•9] for N-IgG; log-rank p<0•001 for both). However, no significant differences between groups were found in either S-IgG (HR 1•56 [0•41-6•0]) nor N-IgG (HR 0•96 [0•26-3•5]) responses in an adjusted propensity score analysis. INTERPRETATION Our results suggest that in patients infected with SARS-CoV-2, IL-6 blockade does not impair the viral specific antibody responses. Although a delayed viral clearance was observed, it was driven by a higher initial viral load. The study supports the safety of this therapy in patients with COVID-19. FUNDING Instituto de salud Carlos III (Spain).
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Affiliation(s)
- Mar Masiá
- Hospital General Universitario de Elche and Universidad Miguel Hernández, Camí de la Almazara 11, Elche, Alicante 03203, Spain.
| | | | - Sergio Padilla
- Hospital General Universitario de Elche, Camí de la Almazara 11, Elche, Alicante 03203, Spain
| | - Piedad Ortega
- Hospital General Universitario de Elche, Camí de la Almazara 11, Elche, Alicante 03203, Spain
| | - José A García
- Operational Research Center, Universidad Miguel Hernández, Elche, Alicante, Spain
| | - Vanesa Agulló
- Hospital General Universitario de Elche, Camí de la Almazara 11, Elche, Alicante 03203, Spain
| | - Javier García-Abellán
- Hospital General Universitario de Elche, Camí de la Almazara 11, Elche, Alicante 03203, Spain
| | - Guillermo Telenti
- Hospital General Universitario de Elche, Camí de la Almazara 11, Elche, Alicante 03203, Spain
| | - Lucía Guillén
- Hospital General Universitario de Elche, Camí de la Almazara 11, Elche, Alicante 03203, Spain
| | - Félix Gutiérrez
- Hospital General Universitario de Elche and Universidad Miguel Hernández, Camí de la Almazara 11, Elche, Alicante 03203, Spain.
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Eicosanoid production varies by sex in mesenteric ischemia reperfusion injury. Clin Immunol 2020; 220:108596. [PMID: 32961332 DOI: 10.1016/j.clim.2020.108596] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/13/2020] [Accepted: 09/16/2020] [Indexed: 01/18/2023]
Abstract
Intestinal ischemia/reperfusion (I/R)-induced injury is an inflammatory response with significant morbidity and mortality. The early inflammatory response includes neutrophil infiltration. However, the majority of rodent studies utilize male mice despite a sexual dimorphism in intestinal I/R-related diseases. We hypothesized that sex may alter inflammation by changing neutrophil infiltration and eicosanoid production. To test this hypothesis, male and female C57Bl/6 mice were subjected to sham treatment or 30 min intestinal ischemia followed by a time course of reperfusion. We demonstrate that compared to male mice, females sustain significantly less intestinal I/R-induced tissue damage and produced significant LTB4 concentrations. Male mice release PGE2. Finally, treatment with a COX-2 specific inhibitor, NS-398, attenuated I/R-induced injury, total peroxidase level, and PGE2 production in males, but not in similarly treated female mice. Thus, I/R-induced eicosanoid production and neutrophil infiltration varies between sexes suggesting that distinct therapeutic intervention may be needed in clinical ischemic diseases.
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Nitulescu GM, Paunescu H, Moschos SA, Petrakis D, Nitulescu G, Ion GND, Spandidos DA, Nikolouzakis TK, Drakoulis N, Tsatsakis A. Comprehensive analysis of drugs to treat SARS‑CoV‑2 infection: Mechanistic insights into current COVID‑19 therapies (Review). Int J Mol Med 2020; 46:467-488. [PMID: 32468014 PMCID: PMC7307820 DOI: 10.3892/ijmm.2020.4608] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 05/18/2020] [Indexed: 12/16/2022] Open
Abstract
The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID‑19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID‑19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.
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Affiliation(s)
| | - Horia Paunescu
- Faculty of Medicine, ′Carol Davila′ University of Medicine and Pharmacy, 020956 Bucharest, Romania
| | - Sterghios A. Moschos
- Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University
- PulmoBioMed Ltd., Newcastle-Upon-Tyne NE1 8ST, UK
| | | | | | | | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion
| | | | - Nikolaos Drakoulis
- Research Group of Clinical Pharmacology and Pharmacogenomics, Faculty of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15771 Athens, Greece
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43
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Cheema AK, Kaur P, Fadel A, Younes N, Zirie M, Rizk NM. Integrated Datasets of Proteomic and Metabolomic Biomarkers to Predict Its Impacts on Comorbidities of Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes 2020; 13:2409-2431. [PMID: 32753925 PMCID: PMC7354282 DOI: 10.2147/dmso.s244432] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 05/29/2020] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE The objective of the current study is to accomplish a relative exploration of the biological roles of differentially dysregulated genes (DRGs) in type 2 diabetes mellitus (T2DM). The study aimed to determine the impact of these DRGs on the biological pathways and networks that are related to the associated disorders and complications in T2DM and to predict its role as prospective biomarkers. METHODS Datasets obtained from metabolomic and proteomic profiling were used for investigation of the differential expression of the genes. A subset of DRGs was integrated into IPA software to explore its biological pathways, related diseases, and their regulation in T2DM. Upon entry into the IPA, only 94 of the DRGs were recognizable, mapped, and matched within the database. RESULTS The study identified networks that explore the dysregulation of several functions; cell components such as degranulation of cells; molecular transport process and metabolism of cellular proteins; and inflammatory responses. Top disorders associated with DRGs in T2DM are related to organ injuries such as renal damage, connective tissue disorders, and acute inflammatory disorders. Upstream regulator analysis predicted the role of several transcription factors of interest, such as STAT3 and HIF alpha, as well as many kinases such as JAK kinases, which affects the gene expression of the dataset in T2DM. Interleukin 6 (IL6) is the top regulator of the DRGs, followed by leptin (LEP). Monitoring the dysregulation of the coupled expression of the following biomarkers (TNF, IL6, LEP, AGT, APOE, F2, SPP1, and INS) highlights that they could be used as potential prognostic biomarkers. CONCLUSION The integration of data obtained by advanced metabolomic and proteomic technologies has made it probable to advantage in understanding the role of these biomarkers in the identification of significant biological processes, pathways, and regulators that are associated with T2DM and its comorbidities.
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Affiliation(s)
- Amrita K Cheema
- Department of Oncology, Lombardi Comprehensive Cancer Center at Georgetown University Medical Center, Washington, DC, USA
| | - Prabhjit Kaur
- Department of Oncology, Lombardi Comprehensive Cancer Center at Georgetown University Medical Center, Washington, DC, USA
| | - Amina Fadel
- Biomedical Sciences Department, College of Health Sciences and Biomedical Research Center, QU Health, Qatar University, Doha, Qatar
| | - Noura Younes
- Clinical Chemistry Lab, Hamad Medical Corporation, Doha, Qatar
| | - Mahmoud Zirie
- Endocrine Department, Hammad Medical Corporation, Doha, Qatar
| | - Nasser M Rizk
- Biomedical Sciences Department, College of Health Sciences and Biomedical Research Center, QU Health, Qatar University, Doha, Qatar
- Physiology Department, Mansoura Faculty of Medicine, Mansoura, Egypt
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Wójcik M, Herman AP, Zieba DA, Krawczyńska A. The Impact of Photoperiod on the Leptin Sensitivity and Course of Inflammation in the Anterior Pituitary. Int J Mol Sci 2020; 21:ijms21114153. [PMID: 32532062 PMCID: PMC7312887 DOI: 10.3390/ijms21114153] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/08/2020] [Accepted: 06/09/2020] [Indexed: 12/16/2022] Open
Abstract
Leptin has a modulatory impact on the course of inflammation, affecting the expression of proinflammatory cytokines and their receptors. Pathophysiological leptin resistance identified in humans occurs typically in sheep during the long-day photoperiod. This study aimed to determine the effect of the photoperiod with relation to the leptin-modulating action on the expression of the proinflammatory cytokines and their receptors in the anterior pituitary under physiological or acute inflammation. Two in vivo experiments were conducted on 24 blackface sheep per experiment in different photoperiods. The real-time PCR analysis for the expression of the genes IL1B, IL1R1, IL1R2, IL6, IL6R, IL6ST, TNF, TNFR1, and TNFR2 was performed. Expression of all examined genes, except IL1β and IL1R2, was higher during short days. The leptin injection increased the expression of all examined genes during short days. In short days the synergistic effect of lipopolysaccharide and leptin increased the expression of IL1B, IL1R1, IL1R2, IL6, TNF, and TNFR2, and decreased expression of IL6ST. This mechanism was inhibited during long days for the expression of IL1R1, IL6, IL6ST, and TNFR1. The obtained results suggest the occurrence of leptin resistance during long days and suggest that leptin modulates the course of inflammation in a photoperiod-dependent manner in the anterior pituitary.
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Affiliation(s)
- Maciej Wójcik
- The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, ul. Instytucka 3, 05-110 Jabłonna, Poland; (A.P.H.); (A.K.)
- Correspondence:
| | - Andrzej Przemysław Herman
- The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, ul. Instytucka 3, 05-110 Jabłonna, Poland; (A.P.H.); (A.K.)
| | - Dorota Anna Zieba
- Laboratory of Biotechnology and Genomics, Department of Nutrition, Animal Biotechnology and Fisheries, Agricultural University of Krakow, 30-248 Krakow, Poland;
| | - Agata Krawczyńska
- The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, ul. Instytucka 3, 05-110 Jabłonna, Poland; (A.P.H.); (A.K.)
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45
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Resveratrol Nanoparticles: A Promising Therapeutic Advancement over Native Resveratrol. Processes (Basel) 2020. [DOI: 10.3390/pr8040458] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The importance of fruit-derived resveratrol (RES) in the treatment of various diseases has been discussed in various research publications. Those research findings have indicated the ability of the molecule as therapeutic in the context of in vitro and in vivo conditions. Mostly, the application of RES in in vivo conditions, encapsulation processes have been carried out using various nanoparticles that are made of biocompatible biomaterials, which are easily digested or metabolized, and RES is absorbed effectively. These biomaterials are non-toxic and are safe to be used as components in the biotherapeutics. They are made from naturally available by-products of food materials like zein or corn or components of the physiological system as with lipids. The versatility of the RES nanoparticles in their different materials, working range sizes, specificity in their targeting in various human diseases, and the mechanisms associated with them are discussed in this review.
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Djourabchi Borojerdi AS, Welchowski T, Peng W, Buchen A, Novak N, Haidl G, Duan YG, Allam JP. Human spermatozoa of male patients with subfertility express the interleukin-6 receptor. Andrologia 2020; 52:e13511. [PMID: 32052474 DOI: 10.1111/and.13511] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 10/10/2019] [Accepted: 10/31/2019] [Indexed: 12/01/2022] Open
Abstract
Male subfertility has been associated with bacterial infections and chronic inflammation. In this context, several studies investigated cytokine levels in seminal plasma, whereas interleukin-6 (IL-6) appears to be crucial. However, little is known about its receptor, the IL-6R expression on human spermatozoa. Thus, the aim of the present study was to screen spermatozoa for IL-6R expression and to identify its localisation. Semen samples of 137 patients (median age 37.69, SD ± 7.82) with subfertility were analysed. Sperm analysis including determination of IL-6 was performed following the World Health Organization criteria. Also, flow cytometry was performed for sperm IL-6R expression. IL-6R+ cells were used for immunofluorescence staining to identify receptor localisation. The results showed positive staining for IL-6R in the midpiece of spermatozoa. Furthermore, a significant correlation between sperm IL-6R expression, seminal plasma IL-6 and total sperm count could be demonstrated, whereas a negative correlation was observed in sperm IL-6R expression and motility. However, no statistical significance could be observed between IL-6R expression, vitality and morphology. Moreover, incubation of spermatozoa with IL-6 led to a slight but significant decrease in motility after 24 hr. These data suggest that IL-6R expression may play a role in impaired sperm function during inflammation.
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Affiliation(s)
| | - Thomas Welchowski
- Department of Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Bonn, Germany
| | - Wenming Peng
- Department of Dermatology and Allergy, Andrology Unit, University Hospital Bonn, Bonn, Germany
| | - Alexa Buchen
- Department of Dermatology and Allergy, Andrology Unit, University Hospital Bonn, Bonn, Germany
| | - Natalija Novak
- Department of Dermatology and Allergy, Andrology Unit, University Hospital Bonn, Bonn, Germany
| | - Gerhard Haidl
- Department of Dermatology and Allergy, Andrology Unit, University Hospital Bonn, Bonn, Germany
| | - Yong-Gang Duan
- Center of Assisted Reproduction and Embryology (CARE), The University of Hong Kong-Shenzhen Hospital (HKU-SZH), Shenzhen, China
| | - Jean-Pierre Allam
- Department of Dermatology and Allergy, Andrology Unit, University Hospital Bonn, Bonn, Germany
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Giménez-Siurana A, Gómez García F, Pagan Bernabeu A, Lozano-Pérez AA, Aznar-Cervantes SD, Cenis JL, López-Jornet P. Chemoprevention of Experimental Periodontitis in Diabetic Rats with Silk Fibroin Nanoparticles Loaded with Resveratrol. Antioxidants (Basel) 2020; 9:antiox9010085. [PMID: 31963913 PMCID: PMC7022414 DOI: 10.3390/antiox9010085] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 01/15/2020] [Accepted: 01/16/2020] [Indexed: 12/16/2022] Open
Abstract
Objective: the objective of the present work is to study the effectiveness of treatment with silk fibroin nanoparticles loaded with resveratrol in experimental periodontitis in a diabetic rat model. Introduction: Periodontitis is an inflammatory pathology highly related to other diseases, such as type II diabetes. Both diseases have a specific inflammatory condition, with Interleukin (IL)-6, IL-1β and Transforming Grow Factor (TGF)-1β being the most relevant proinflammatory factors. Silk fibroin (SF) nanoparticles loaded with resveratrol (Res-SFN) are a new alternative as a treatment. Methods: 40 diabetic Sprague Dawley male rats were used and periodontitis was induced by ligation. The animals were divided into 5 treatment groups, and 1 mL of treatment was administered once a day for 4 weeks. The groups were: I: Carboxymethyl cellulose (CMC) 0.8%, II: CMC 0.8% + SF 1%, III: CMC 0.8% + RES-SFN 3 mg/mL, IV: CMC 0.8% + SF 1% + RES-SFN 3 mg/mL, V: Water. A peripheral blood sample was taken every week to quantify the inflammatory profile by ELISA (IL-6, IL-1β and TGF-1β). After 4 weeks the sacrifice was carried out and biopsies of the gum were taken. Results: Treatment with SF and RES-SFN reduced the amount of chemical inflammation mediators (with the exception of IL-1β in comparisons I-IV and II-IV (p > 0.05)), as well as the anatomopathological variables linked to it, in a significant way (p < 0.05). Conclusion: treatment with RES-SFN has reduced local inflammation in this experimental periodontitis model.
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Affiliation(s)
- Ana Giménez-Siurana
- Department of Bucal Medicine, Faculty of Medicine, University of Murcia, Av. Marqués de los Vélez, 2 Floor. 3008, Murcia, Spain; (A.G.-S.); (F.G.G.)
| | - Francisco Gómez García
- Department of Bucal Medicine, Faculty of Medicine, University of Murcia, Av. Marqués de los Vélez, 2 Floor. 3008, Murcia, Spain; (A.G.-S.); (F.G.G.)
| | - Ana Pagan Bernabeu
- Department of Biotechnology, Instituto Murciano de Investigación y Desarrollo Agrario y Alimentario (IMIDA), C/Mayor 30150 La Alberca, Murcia, Spain; (A.P.B.); (A.A.L.-P.); (S.D.A.-C.); (J.L.C.)
| | - Antonio Abel Lozano-Pérez
- Department of Biotechnology, Instituto Murciano de Investigación y Desarrollo Agrario y Alimentario (IMIDA), C/Mayor 30150 La Alberca, Murcia, Spain; (A.P.B.); (A.A.L.-P.); (S.D.A.-C.); (J.L.C.)
| | - Salvador D. Aznar-Cervantes
- Department of Biotechnology, Instituto Murciano de Investigación y Desarrollo Agrario y Alimentario (IMIDA), C/Mayor 30150 La Alberca, Murcia, Spain; (A.P.B.); (A.A.L.-P.); (S.D.A.-C.); (J.L.C.)
| | - José Luis Cenis
- Department of Biotechnology, Instituto Murciano de Investigación y Desarrollo Agrario y Alimentario (IMIDA), C/Mayor 30150 La Alberca, Murcia, Spain; (A.P.B.); (A.A.L.-P.); (S.D.A.-C.); (J.L.C.)
| | - Pía López-Jornet
- Department of Bucal Medicine, Faculty of Medicine, University of Murcia, Av. Marqués de los Vélez, 2 Floor. 3008, Murcia, Spain; (A.G.-S.); (F.G.G.)
- Correspondence:
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Sun S, Wang J, Wang J, Wang F, Yao S, Xia H. Maresin 1 Mitigates Sepsis-Associated Acute Kidney Injury in Mice via Inhibition of the NF-κB/STAT3/MAPK Pathways. Front Pharmacol 2019; 10:1323. [PMID: 31787899 PMCID: PMC6855000 DOI: 10.3389/fphar.2019.01323] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 10/15/2019] [Indexed: 12/31/2022] Open
Abstract
Acute kidney injury (AKI) is one of the most common and serious complications of sepsis in which the inflammatory cascade plays a crucial role. There is now increasing evidence that lipid mediators derived from the omega-3 fatty acid docosahexaenoic acid (DHA) have potent anti-inflammatory effects that promote the timely regression of acute inflammation. In this study, we investigated the protective effects and molecular mechanism of a novel DHA-derived lipid mediator Maresin 1 (MaR1) on AKI in septic mice. The cecal ligation and puncture (CLP) was used to establish a sepsis mice model. As a result, we found that MaR1 significantly increased the 7-day survival rate of septic mice and the anti-inflammatory factor IL-10 while reducing bacterial load and pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β). In addition, MaR1 dose dependently reduced renal injury scores and serum creatinine and urea nitrogen levels in septic mice while inhibiting renal neutrophil infiltration and myeloperoxidase (MPO) activity. In terms of signaling pathway, we found that MaR1 inhibits the expression of phosphorylated p65, Stat3, JNK, ERK, and p38 and significantly reduces nuclear translocation of p65. In conclusion, our results indicate that MaR1 is able to reduce neutrophil infiltration and inhibit nuclear factor-kappa B/signal transducer and activator of transcriptor 3/mitogen-activated protein kinase (NF-κB/STAT3/MAPK) activity and regulate inflammatory cytokine level to inhibit inflammatory response and thereby weaken sepsis-associated AKI in mice.
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Affiliation(s)
- ShuJun Sun
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - JiaMei Wang
- College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - JingXu Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - FuQuan Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - ShangLong Yao
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - HaiFa Xia
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Shi J, Fan J, Su Q, Yang Z. Cytokines and Abnormal Glucose and Lipid Metabolism. Front Endocrinol (Lausanne) 2019; 10:703. [PMID: 31736870 PMCID: PMC6833922 DOI: 10.3389/fendo.2019.00703] [Citation(s) in RCA: 150] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 09/30/2019] [Indexed: 12/20/2022] Open
Abstract
Clear evidence indicates that cytokines, for instance, adipokines, hepatokines, inflammatory cytokines, myokines, and osteokines, contribute substantially to the development of abnormal glucose and lipid metabolism. Some cytokines play a positive role in metabolism action, while others have a negative metabolic role linking to the induction of metabolic dysfunction. The mechanisms involved are not fully understood, but are associated with lipid accumulation in organs and tissues, especially in the adipose and liver tissue, changes in energy metabolism, and inflammatory signals derived from various cell types, including immune cells. In this review, we describe the roles of certain cytokines in the regulation of metabolism and inter-organ signaling in regard to the pathophysiological aspects. Given the disease-related changes in circulating levels of relevant cytokines, these factors may serve as biomarkers for the early detection of metabolic disorders. Moreover, based on preclinical studies, certain cytokines that can induce improvements in glucose and lipid metabolism and immune response may emerge as novel targets of broader and more efficacious treatments and prevention of metabolic disease.
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Affiliation(s)
- Jie Shi
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jiangao Fan
- Shanghai Key Laboratory of Children's Digestion and Nutrition, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qing Su
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhen Yang
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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50
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Bongartz H, Gille K, Hessenkemper W, Mandel K, Lewitzky M, Feller SM, Schaper F. The multi-site docking protein Grb2-associated binder 1 (Gab1) enhances interleukin-6-induced MAPK-pathway activation in an SHP2-, Grb2-, and time-dependent manner. Cell Commun Signal 2019; 17:135. [PMID: 31651330 PMCID: PMC6814103 DOI: 10.1186/s12964-019-0451-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 10/04/2019] [Indexed: 12/13/2022] Open
Abstract
Background Cytokine-dependent activation of signalling pathways is tightly orchestrated. The spatiotemporal activation of signalling pathways dictates the specific physiological responses to cytokines. Dysregulated signalling accounts for neoplastic, developmental, and inflammatory diseases. Grb2-associated binder (Gab) family proteins are multi-site docking proteins, which expand cytokine-induced signal transduction in a spatial- and time-dependent manner by coordinating the recruitment of proteins involved in mitogen activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) and phosphatidyl-inositol-3-kinase (PI3K) signalling. Interaction of Gab family proteins with these signalling proteins determines strength, duration and localization of active signalling cascades. However, the underlying molecular mechanisms of signal orchestration by Gab family proteins in IL-6-induced signalling are only scarcely understood. Methods We performed kinetic analyses of interleukin-6 (IL-6)-induced MAPK activation and analysed downstream responses. We compared signalling in wild-type cells, Gab1 knock-out cells, those reconstituted to express Gab1 mutants, and cells expressing gp130 receptors or receptor mutants. Results Interleukin-6-induced MAPK pathway activation can be sub-divided into an early Gab1-independent and a subsequent Gab1-dependent phase. Early Gab1-independent MAPK activation is critical for the subsequent initiation of Gab1-dependent amplification of MAPK pathway activation and requires binding of SH2 domain-containing phosphatase 2 (SHP2) to the interleukin-6 receptor complex. Subsequent and coordinated recruitment of Grb2 and SHP2 to Gab1 is essential for Gab1-dependent amplification of IL-6-induced late MAPK pathway activation and subsequent gene expression. Conclusions Overall, we elaborated the molecular requirements for Gab1-dependent, spatiotemporal orchestration of interleukin-6-dependent MAPK signalling. We discriminated IL-6-induced Gab1-independent, early activation of MAPK signalling and Gab1-dependent, sustained activation of MAPK signalling.
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Affiliation(s)
- Hannes Bongartz
- Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Universitätsplatz 2, Gebäude 28/Pfälzer Platz, 39106, Magdeburg, Germany
| | - Karen Gille
- Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Universitätsplatz 2, Gebäude 28/Pfälzer Platz, 39106, Magdeburg, Germany
| | - Wiebke Hessenkemper
- Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Universitätsplatz 2, Gebäude 28/Pfälzer Platz, 39106, Magdeburg, Germany
| | - Katharina Mandel
- Institute of Molecular Medicine, Charles Tanford Protein Research Center, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Straße 3a, 06120, Halle (Saale), Germany
| | - Marc Lewitzky
- Institute of Molecular Medicine, Charles Tanford Protein Research Center, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Straße 3a, 06120, Halle (Saale), Germany
| | - Stephan M Feller
- Institute of Molecular Medicine, Charles Tanford Protein Research Center, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Straße 3a, 06120, Halle (Saale), Germany
| | - Fred Schaper
- Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Universitätsplatz 2, Gebäude 28/Pfälzer Platz, 39106, Magdeburg, Germany.
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