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Nicchio IG, Cirelli T, Quil LCDC, Camilli AC, Scarel-Caminaga RM, Leite FRM. Understanding the peroxisome proliferator-activated receptor gamma (PPAR-γ) role in periodontitis and diabetes mellitus: A molecular perspective. Biochem Pharmacol 2025; 237:116908. [PMID: 40157459 DOI: 10.1016/j.bcp.2025.116908] [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: 12/12/2024] [Revised: 02/19/2025] [Accepted: 03/25/2025] [Indexed: 04/01/2025]
Abstract
Periodontitis and Type 2 Diabetes Mellitus (T2DM) are chronic conditions with dysregulated immune responses. Periodontitis involves immune dysfunction and dysbiotic biofilms, leading to tissue destruction. T2DM is marked by insulin resistance and systemic inflammation, driving metabolic and tissue damage. Both conditions share activation of key pathways, including Nuclear Factor Kappa B (NF-κB), Activator Protein-1 (AP-1), and Signal Transducer and Activator of Transcription (STAT) proteins, reinforcing an inflammatory feedback loop. This review highlights the role of Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ), a transcription factor central to lipid and glucose metabolism, adipogenesis, and immune regulation. PPAR-γ activation has been shown to suppress inflammatory mediators such as Tumor Necrosis Factor Alpha (TNF-α) and Interleukin 6 (IL-6) through the inhibition of NF-κB, AP-1, and STAT pathways, thereby potentially disrupting the inflammatory-metabolic cycle that drives both diseases. PPAR-γ agonists, including thiazolidinediones (TZDs) and endogenous ligands such as 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), show promise in reducing inflammation and improving insulin sensitivity, but they are limited by adverse effects. Therapies, including Selective Peroxisome Proliferator-Activated Receptor Modulators (SPPARMs), have been developed to offer a more targeted approach, allowing for selective modulation of PPAR-γ activity to retain its anti-inflammatory benefits while minimizing their side effects. By integrating insights into PPAR-γ's molecular mechanisms, this review underscores its therapeutic potential in mitigating inflammation and enhancing metabolic control.
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Affiliation(s)
- Ingra Gagno Nicchio
- Department of Diagnosis and Surgery, School of Dentistry at Araraquara, São Paulo State University-UNESP, Araraquara 14801-903, SP, Brazil; Department of Morphology, Genetics, Orthodontics and Pediatric Dentistry, School of Dentistry at Araraquara, São Paulo State University-UNESP, Araraquara 14801-903, SP, Brazil.
| | - Thamiris Cirelli
- Department of Dentistry, Centro Universitário das Faculdades Associadas, São João da Boa Vista 13870-377, SP, Brazil.
| | - Lucas César da Costa Quil
- Department of Diagnosis and Surgery, School of Dentistry at Araraquara, São Paulo State University-UNESP, Araraquara 14801-903, SP, Brazil; Department of Morphology, Genetics, Orthodontics and Pediatric Dentistry, School of Dentistry at Araraquara, São Paulo State University-UNESP, Araraquara 14801-903, SP, Brazil.
| | - Angelo Constantino Camilli
- Department of Diagnosis and Surgery, School of Dentistry at Araraquara, São Paulo State University-UNESP, Araraquara 14801-903, SP, Brazil.
| | - Raquel Mantuaneli Scarel-Caminaga
- Department of Morphology, Genetics, Orthodontics and Pediatric Dentistry, School of Dentistry at Araraquara, São Paulo State University-UNESP, Araraquara 14801-903, SP, Brazil.
| | - Fabio Renato Manzolli Leite
- National Dental Research Institute Singapore, National Dental Centre Singapore, 168938, Singapore; Oral Health Academic Clinical Programme, Duke-NUS Medical School, 169857, Singapore.
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Jiang Y, Chen J, Du Y, Fan M, Shen L. Immune modulation for the patterns of epithelial cell death in inflammatory bowel disease. Int Immunopharmacol 2025; 154:114462. [PMID: 40186907 DOI: 10.1016/j.intimp.2025.114462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 02/23/2025] [Accepted: 03/08/2025] [Indexed: 04/07/2025]
Abstract
Inflammatory bowel disease (IBD) is an inflammatory disease of the intestine whose primary pathological presentation is the destruction of the intestinal epithelium. The intestinal epithelium, located between the lumen and lamina propria, transmits luminal microbial signals to the immune cells in the lamina propria, which also modulate the intestinal epithelium. In IBD patients, intestinal epithelial cells (IECs) die dysfunction and the mucosal barrier is disrupted, leading to the recruitment of immune cells and the release of cytokines. In this review, we describe the structure and functions of the intestinal epithelium and mucosal barrier in the physiological state and under IBD conditions, as well as the patterns of epithelial cell death and how immune cells modulate the intestinal epithelium providing a reference for clinical research and drug development of IBD. In addition, according to the targeting of epithelial apoptosis and necroptotic pathways and the regulation of immune cells, we summarized some new methods for the treatment of IBD, such as necroptosis inhibitors, microbiome regulation, which provide potential ideas for the treatment of IBD. This review also describes the potential for integrating AI-driven approaches into innovation in IBD treatments.
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Affiliation(s)
- Yuting Jiang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China
| | - Jie Chen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China
| | - Yaoyao Du
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Center for Pharmaceutics Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China
| | - Minwei Fan
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Lan Shen
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Matos P, Jordan P. Alternative Splicing at the Crossroad of Inflammatory Bowel Diseases and Colitis-Associated Colon Cancer. Cancers (Basel) 2025; 17:219. [PMID: 39858001 PMCID: PMC11764256 DOI: 10.3390/cancers17020219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/06/2025] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
The risk of developing colorectal cancer (CRC) is increased in ulcerative colitis patients compared to the general population. This increased risk results from the state of chronic inflammation, a well-known tumour-promoting condition. This review explores the pathologic and molecular characteristics of colitis-associated colon cancer (CAC), emphasizing the distinct features from sporadic CRC. We focus on the key signalling pathways involved in the transition to CAC, highlighting the emerging role of alternative splicing in these processes, namely on how inflammation-induced alternative splicing can significantly contribute to the increased CRC risk observed among UC patients. This review calls for more transcriptomic studies to elucidate the molecular mechanisms through which inflammation-induced alternative splicing drives CAC pathogenesis. A better understanding of these splicing events is crucial as they may reveal novel biomarkers for disease progression and have the potential to target changes in alternative splicing as a therapeutic strategy.
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Affiliation(s)
- Paulo Matos
- Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal
- BioISI—Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal
| | - Peter Jordan
- Department of Human Genetics, National Institute of Health Dr. Ricardo Jorge, 1649-016 Lisbon, Portugal
- BioISI—Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal
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Chen A, Huang H, Fang S, Hang Q. ROS: A "booster" for chronic inflammation and tumor metastasis. Biochim Biophys Acta Rev Cancer 2024; 1879:189175. [PMID: 39218404 DOI: 10.1016/j.bbcan.2024.189175] [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: 05/09/2024] [Revised: 08/22/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
Reactive oxygen species (ROS) are a group of highly active molecules produced by normal cellular metabolism and play a crucial role in the human body. In recent years, researchers have increasingly discovered that ROS plays a vital role in the progression of chronic inflammation and tumor metastasis. The inflammatory tumor microenvironment established by chronic inflammation can induce ROS production through inflammatory cells. ROS can then directly damage DNA or indirectly activate cellular signaling pathways to promote tumor metastasis and development, including breast cancer, lung cancer, liver cancer, colorectal cancer, and so on. This review aims to elucidate the relationship between ROS, chronic inflammation, and tumor metastasis, explaining how chronic inflammation can induce tumor metastasis and how ROS can contribute to the evolution of chronic inflammation toward tumor metastasis. Interestingly, ROS can have a "double-edged sword" effect, promoting tumor metastasis in some cases and inhibiting it in others. This article also highlights the potential applications of ROS in inhibiting tumor metastasis and enhancing the precision of tumor-targeted therapy. Combining ROS with nanomaterials strategies may be a promising approach to enhance the efficacy of tumor treatment.
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Affiliation(s)
- Anqi Chen
- Medical College, Yangzhou University, Yangzhou 225009, China
| | - Haifeng Huang
- Department of Laboratory Medicine, The First People's Hospital of Yancheng, Yancheng 224006, China; Department of Laboratory Medicine, Yancheng Clinical Medical College of Jiangsu University, Yancheng 224006, China
| | - Sumeng Fang
- School of Mathematics, Tianjin University, Tianjin 300350, China
| | - Qinglei Hang
- Jiangsu Provincial Innovation and Practice Base for Postdoctors, Suining People's Hospital, Affiliated Hospital of Xuzhou Medical University, Suining 221200, China; Key Laboratory of Jiangsu Province University for Nucleic Acid & Cell Fate Manipulation, Yangzhou University, Yangzhou 225009, China; Department of Laboratory Medicine, Medical College, Yangzhou University, Yangzhou 225009, China.
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Toubasi AA, Eisma JJ, Wang J, Kazimuddin HF, Hernandez B, Vinarsky T, Gheen C, Rohm Z, Koch C, Clarke MA, Cheek R, Kramer J, Eaton J, Donahue MJ, Bagnato F. Chronic active lesions preferentially localize in watershed territories in multiple sclerosis. Ann Clin Transl Neurol 2024; 11:2912-2922. [PMID: 39447194 PMCID: PMC11572742 DOI: 10.1002/acn3.52202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 08/10/2024] [Indexed: 10/26/2024] Open
Abstract
OBJECTIVE Paramagnetic rim lesions (PRLs) are a biomarker of chronic active lesions (CALs), and an important driver of neurological disability in multiple sclerosis (MS). The reason subtending some acute lesions evolvement into CALs is not known. Here we ask whether a relatively lower oxygen content is linked to CALs. METHODS In this prospective cross-sectional study, 64 people with multiple sclerosis (PwMS), clinically isolated syndrome and radiologically isolated syndrome underwent a 7.0 Tesla (7 T) brain magnetic resonance imaging (MRI). The scanning protocol included a T2-w fluid-attenuated inversion recovery (FLAIR), and a single echo gradient echo from which susceptibility-weighted imaging (SWI) was derived. WM lesions were identified on the T2-w-FLAIR whilst PRLs were identified on the SWI sequence. T2-lesions were classified as PRLs and rimless lesions (PRLs-). We registered a universal vascular atlas to each subject's T2-w-FLAIR and classified each T2-lesions according to its location into watershed- (ws), non-watershed- (nws), and mixed-lesion (m). Ws-lesions were defined as lesions that were fully located in a region between the territories of two major arteries. RESULTS Out of 1,975 T2-lesions, 88 (4.5%) were PRLs. Ws-regions had a higher number (p = 0.005) and proportion (p < 0.001) of PRLs- compared to nws-regions. Ws-PRL- were larger compared to nws-ones (p = 0.009). The number (p = 0.043) and proportion (p < 0.001) of PRLs was higher in ws-regions compared to nws-ones. Ws-PRLs were not significantly larger than nws-ones (p = 0.195). INTERPRETATION We propose the novel concept of a link between arterial vascularization and chronic activity in MS by demonstrating a preferential localization of CALs in ws-territories.
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Affiliation(s)
- Ahmad A. Toubasi
- Neuroimaging Unit, Neuroimmunology Division, Department of NeurologyVanderbilt University Medical Center (VUMC)NashvilleTennesseeUSA
| | - Jarrod J. Eisma
- Cognitive Division, Department of NeurologyVUMCNashvilleTennesseeUSA
| | - Jiacheng Wang
- Neuroimaging Unit, Neuroimmunology Division, Department of NeurologyVanderbilt University Medical Center (VUMC)NashvilleTennesseeUSA
- Department of Computer ScienceSchool of Engineering, Vanderbilt UniversityNashvilleTennesseeUSA
| | - Habeeb F. Kazimuddin
- Neuroimaging Unit, Neuroimmunology Division, Department of NeurologyVanderbilt University Medical Center (VUMC)NashvilleTennesseeUSA
- National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Health (NIH)BethesdaMarylandUSA
| | - Bryan Hernandez
- Neuroimaging Unit, Neuroimmunology Division, Department of NeurologyVanderbilt University Medical Center (VUMC)NashvilleTennesseeUSA
- Medical Scientist ProgramVU School of MedicineNashvilleTennesseeUSA
- Department of Biological Sciences, College of ScienceUniversity of Texas at El PasoEl PasoTexasUSA
- Department of BiochemistryVU School of MedicineNashvilleTennesseeUSA
| | - Taegan Vinarsky
- Neuroimaging Unit, Neuroimmunology Division, Department of NeurologyVanderbilt University Medical Center (VUMC)NashvilleTennesseeUSA
| | - Caroline Gheen
- Neuroimaging Unit, Neuroimmunology Division, Department of NeurologyVanderbilt University Medical Center (VUMC)NashvilleTennesseeUSA
| | - Zachary Rohm
- Neuroimaging Unit, Neuroimmunology Division, Department of NeurologyVanderbilt University Medical Center (VUMC)NashvilleTennesseeUSA
| | - Carynn Koch
- Neuroimaging Unit, Neuroimmunology Division, Department of NeurologyVanderbilt University Medical Center (VUMC)NashvilleTennesseeUSA
| | - Margareta A. Clarke
- Neuroimaging Unit, Neuroimmunology Division, Department of NeurologyVanderbilt University Medical Center (VUMC)NashvilleTennesseeUSA
| | - Rachael Cheek
- Neuroimaging Unit, Neuroimmunology Division, Department of NeurologyVanderbilt University Medical Center (VUMC)NashvilleTennesseeUSA
- Meharry Medical CollegeSchool of MedicineNashvilleTennesseeUSA
| | - John Kramer
- Neuroimmunology Division, Department of NeurologyVUMCNashvilleTennesseeUSA
| | - James Eaton
- Cognitive Division, Department of NeurologyVUMCNashvilleTennesseeUSA
- Neuroimmunology Division, Department of NeurologyVUMCNashvilleTennesseeUSA
| | - Manus J. Donahue
- Cognitive Division, Department of NeurologyVUMCNashvilleTennesseeUSA
- Department of Psychiatry and Behavioral ScienceVUMCNashvilleTennesseeUSA
| | - Francesca Bagnato
- Neuroimaging Unit, Neuroimmunology Division, Department of NeurologyVanderbilt University Medical Center (VUMC)NashvilleTennesseeUSA
- Department of NeurologyVA Medical Center, TN Valley Healthcare SystemNashvilleTennesseeUSA
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Geister E, Ard D, Patel H, Findley A, DeSouza G, Martin L, Knox H, Gavara N, Lugea A, Sabbatini ME. The Role of Twist1 in Chronic Pancreatitis-Associated Pancreatic Stellate Cells. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:1879-1897. [PMID: 39032603 PMCID: PMC11423762 DOI: 10.1016/j.ajpath.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 06/18/2024] [Accepted: 06/28/2024] [Indexed: 07/23/2024]
Abstract
In healthy pancreas, pancreatic stellate cells (PaSCs) synthesize the basement membrane, which is mainly composed of type IV collagen and laminin. In chronic pancreatitis (CP), PaSCs are responsible for the production of a rigid extracellular matrix (ECM) that is mainly composed of fibronectin and type I/III collagen. Reactive oxygen species evoke the formation of the rigid ECM by PaSCs. One source of reactive oxygen species is NADPH oxidase (Nox) enzymes. Nox1 up-regulates the expression of Twist1 and matrix metalloproteinase-9 (MMP-9) in PaSCs from mice with CP. This study determined the functional relationship between Twist1 and MMP-9, and other PaSC-produced proteins, and the extent to which Twist1 regulates digestion of ECM proteins in CP. Twist1 induced the expression of MMP-9 in mouse PaSCs. The action of Twist1 was not selective to MMP-9 because Twist1 induced the expression of types I and IV collagen, fibronectin, transforming growth factor, and α-smooth muscle actin. Luciferase assay indicated that Twist1 in human primary PaSCs increased the expression of MMP-9 at the transcriptional level in an NF-κB dependent manner. The digestion of type I/III collagen by MMP-9 secreted by PaSCs from mice with CP depended on Twist1. Thus, Twist1 in PaSCs from mice with CP induced rigid ECM production and MMP-9 transcription in an NF-κB-dependent mechanism that selectively displayed proteolytic activity toward type I/III collagen.
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Affiliation(s)
- Emma Geister
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Dalton Ard
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Heer Patel
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Alyssa Findley
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Godfrey DeSouza
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Lyndsay Martin
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Henry Knox
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Natasha Gavara
- Department of Biological Sciences, Augusta University, Augusta, Georgia
| | - Aurelia Lugea
- Cedars-Sinai Medical Center, Los Angeles, California
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Zhu W, Qiong D, Changzhi X, Meiyu J, Hui L. Macrophage polarization regulation shed lights on immunotherapy for CaOx kidney stone disease. Biomed Pharmacother 2024; 179:117336. [PMID: 39180792 DOI: 10.1016/j.biopha.2024.117336] [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: 05/27/2024] [Revised: 08/09/2024] [Accepted: 08/21/2024] [Indexed: 08/27/2024] Open
Abstract
Kidney stone disease (KSD) is a major public health concern associated with high morbidity and recurrence, places a significant burden on the health care system worldwide. Calcium oxalate (CaOx) alone or a mixture of CaOx and calcium phosphate stones accounting for more than 80 % of cases. However, beyond surgical removal, the prevention and reduction of recurrence of CaOx kidney stones have always been a challenge. Given that macrophages are traditional innate immune cells that play critical roles in the clearance of pathogens and the maintenance of tissue homeostasis, which have gained more and more interests in nephrolithiasis. Several studies recently clearly demonstrated that M2-macrophage could reduce the renal calcium oxalate (CaOx) crystal acumination, and provide premise insights and therapeutic options for KSD by modulating the macrophage phenotypes. However, the mechanism of macrophage-polarization regulation and that effects on kidney stone prevention and treatments are far from clear. Here, we comprehensively reviewed the literatures related to cytokines, epigenetic modifications and metabolic reprograming of macrophage in CaOx kidney stone disease, aimed to provide better understandings on macrophage polarization regulation as well as its potential clinical applications in CaOx kidney stone disease treatments and prevention.
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Affiliation(s)
- Wang Zhu
- Department of Urology, The People's Hospital of Longhua, Shenzhen 518109, Guangdong, China.
| | - Deng Qiong
- Department of Urology, The People's Hospital of Longhua, Shenzhen 518109, Guangdong, China
| | - Xu Changzhi
- Department of Laboratory Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jin Meiyu
- Department of Urology, The People's Hospital of Longhua, Shenzhen 518109, Guangdong, China
| | - Liang Hui
- Department of Urology, The People's Hospital of Longhua, Shenzhen 518109, Guangdong, China.
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Li LH, Hsu DZ, Chandrasekaran VRM, Liu MY. Inhibiting CD44-ICD Attenuates LPS-Induced Initiation of Hepatic Inflammation in Septic Mice. Int J Mol Sci 2024; 25:8907. [PMID: 39201593 PMCID: PMC11354311 DOI: 10.3390/ijms25168907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 08/10/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024] Open
Abstract
Sepsis is a severe condition induced by microbial infection. It elicits a systemic inflammatory response, leading to multi-organ failure, and the liver, as a scavenger, plays a significant role in this process. Controlling hepatic inflammation and maintaining liver function is crucial in managing sepsis. CD44-ICD, as a CD44 signal transductor, is involved in multiple inflammatory responses. However, the role of CD44-ICD in lipopolysaccharide (LPS)-induced hepatic inflammation has not been investigated. Therefore, we aimed to examine whether CD44-ICD initiates hepatic inflammation in septic mice. We induced hepatic inflammation in mice by administering LPS. DAPT, a CD44-ICD inhibitor, was given to mice or Chang cells 30 min or 1 h before LPS administration (10 mg/kg, i.p., or 100 ng/mL, respectively). Inhibition of CD44-ICD decreased the level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), hepatic necrosis, inflammatory cell infiltration, interleukin (IL)-1β, inducible NO synthase (iNOS), nitric oxide (NO) production, nuclear factor (NF)κB signaling pathway proteins, and CD44 expression in mice. CD44-ICD inhibition also decreased IL-1β and CD44 expression levels in Chang cells. CD44-ICD may be a primary regulatory function in CD44-associated LPS-induced initiation of hepatic inflammation in mice.
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Affiliation(s)
| | | | - Victor Raj Mohan Chandrasekaran
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan
| | - Ming-Yie Liu
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan
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Xu R, Bi Y, He X, Zhang Y, Zhao X. Kidney-tonifying blood-activating decoction delays ventricular remodeling in rats with chronic heart failure by regulating gut microbiota and metabolites and p38 mitogen-activated protein kinase/p65 nuclear factor kappa-B/aquaporin-4 signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 330:118110. [PMID: 38580189 DOI: 10.1016/j.jep.2024.118110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2023] [Revised: 03/14/2024] [Accepted: 03/24/2024] [Indexed: 04/07/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Myocardial infarction has likely contributed to the increased prevalence of heart failure(HF).As a result of ventricular remodeling and reduced cardiac function, colonic blood flow decreases, causing mucosal ischemia and hypoxia of the villous structure of the intestinal wall.This damage in gut barrier function increases bowel wall permeability, leading to fluid metabolism disorder,gut microbial dysbiosis, increased gut bacteria translocation into the circulatory system and increased circulating endotoxins, thus promoting a typical inflammatory state.Traditional Chinese Medicine plays a key role in the prevention and treatment of HF.Kidney-tonifying Blood-activating(KTBA) decoction has been proved for clinical treatment of chronic HF.However,the mechanism of KTBA decoction on chronic HF is still unclear. AIMS OF THE STUDY The effect of KTBA decoction on gut microbiota and metabolites and p38MAPK/p65NF-κB/AQP4 signaling in rat colon was studied to investigate the mechanism that KTBA decoction delays ventricular remodeling and regulates water metabolism disorder in rats with HF after myocardial infarction based on the theory of "Kidney Storing Essence and Conducting Water". MATERIAL AND METHODS In vivo,a rat model of HF after myocardial infarction was prepared by ligating the left anterior descending coronary artery combined with exhaustive swimming and starvation.The successful modeling rats were randomly divided into five groups:model group, tolvaptan group(gavaged 1.35mg/(kg•D) tolvaptan),KTBA decoction group(gavaged 15.75g/(kg•D) of KTBA decoction),KTBA decoction combined with SB203580(p38MAPK inhibitor) group(gavaged 15.75g/(kg•D) of KTBA decoction and intraperitoneally injected 1.5mg/(kg•D) of SB203580),and KTBA decoction combined with PDTC(p65NF-kB inhibitor) group(gavaged 15.75g/(kg•D) of KTBA decoction and intraperitoneally injected 120mg/(kg•D) of PDTC).The sham-operation group and model group were gavaged equal volume of normal saline.After 4 weeks of intervention with KTBA decoction,the effect of KTBA decoction on the cardiac structure and function of chronic HF model rats was observed by ultrasonic cardiogram.General state and cardiac index in rats were evaluated.Enzyme linked immunosorbent assay(ELISA) was used to measure N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration in rat serum.Hematoxylin and eosin(H&E) staining,and transmission electron microscope(TEM) were used to observe the morphology and ultrastructure of myocardial and colonic tissue,and myocardial fibrosis was measured by Masson's staining.Cardiac E-cadherin level was detected by Western blot.The mRNA expression and protein expression levels of p38MAPK,I-κBα, p65NF-κB,AQP4,Occludin and ZO-1 in colonic tissue were detected by reverse transcription-quantitative real-time polymerase chain reaction(RT-qPCR) and immunohistochemistry. Protein expression of p38MAPK, p-p38MAPK,I-κBα,p-I-κBα,p65NF-κB, p-p65NF-κB,AQP4,Occludin and ZO-1 in rat colon was detected using Western blot.Colonic microbiota and serum metabolites were respectively analyzed by amplicon sequencing and liquid chromatography-mass spectrometry.In vitro, CCD-841CoN cell was placed in the ischemic solution under hypoxic conditions (94%N2,5%CO2,and 1%O2) in a 37 °C incubator to establish an ischemia and hypoxia model.The CCD-841CoN cells were divided into 7 groups, namely blank group and model group with normal rat serum plus control siRNA, tolvaptan group with rat serum containing tolvaptan plus control siRNA, KTBA group with rat serum containing KTBA plus control siRNA, KTBA plus p38MAPK siRNA group, KTBA plus p65NF-κB siRNA group,and KTBA plus AQP4siRNA group.After 24h and 48h of intervention with KTBA decoction,RT-qPCR,immunofluorescence and Western blot was used to detect the mRNA expression and protein expression levels of p38MAPK,I-κBα,p65NF-κB,AQP4, Occludin and ZO-1 in CCD-841CoN cells. RESULTS Compared with the model, KTBA decoction improved the general state, decraesed the serum NT-proBNP level,HW/BW ratio, LVIDd and LVIDs, increased E-cadherin level,EF and FS,reduced number of collagen fibers deposited in the myocardial interstitium,and recovered irregular arrangement of myofibril and swollen or vacuolated mitochondria with broken crista in myocardium.Moreover, KTBA decoction inhibited the expression of p38MAPK,I-κBα,and p65NF-κB and upregulated AQP4, Occludin and ZO-1 in colon tissues and CCD-841CoN cells.Additionally,p38siRNA or SB203580, p65siRNA or PDTC, and AQP4siRNA partially weakened the protective effects of KTBA in vitro and vivo.Notably,The LEfSe analysis results showed that there were six gut biomaker bacteria in model group, including Allobaculum, Bacillales,Turicibacter, Turicibacterales,Turicibacteraceae,and Bacilli. Besides, three gut biomaker bacteria containing Deltaproteobacteria, Desulfovibrionaceae,and Desulfovibrionales were enriched by KTBA treatment in chronic HF model.There were five differential metabolites, including L-Leucine,Pelargonic acid, Capsidiol,beta-Carotene,and L- Erythrulose, which can be regulated back in the same changed metabolic routes by the intervention of KTBA.L-Leucine had the positive correlation with Bacillales, Turicibacterales,Turicibacteraceae,and Turicibacter.L-Leucine significantly impacts Protein digestion and absorption, Mineral absorption,and Central carbon metabolism in cancer regulated by KTBA, which is involved in the expression of MAPK and tight junction in intestinal epithelial cells. CONCLUSIONS KTBA decoction manipulates the expression of several key proteins in the p38MAPK/p65NF-κB/AQP4 signaling pathway, modulates gut microbiota and metabolites toward a more favorable profile, improves gut barrier function, delays cardiomyocyte hypertrophy and fibrosis,and improves cardiac function.
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Affiliation(s)
- Rui Xu
- Liaoning University of Traditional Chinese Medicine,Shenyang,Liaoning 110847,China
| | - Yanping Bi
- Jilin Hospital of Integrated Traditional Chinese and Western Medicine,Jilin,Jilin 132000,China
| | - Xiaoteng He
- Liaoning University of Traditional Chinese Medicine,Shenyang,Liaoning 110847,China
| | - Yan Zhang
- The Affiliated Hospital, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110032, China.
| | - Xin Zhao
- The Second Hospital, Dalian Medical University, Dalian, Liaoning 116023, China.
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Zhang X, Zhou H, Liu H, Xu P. Role of Oxidative Stress in the Occurrence and Development of Cognitive Dysfunction in Patients with Obstructive Sleep Apnea Syndrome. Mol Neurobiol 2024; 61:5083-5101. [PMID: 38159196 DOI: 10.1007/s12035-023-03899-3] [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: 03/15/2023] [Accepted: 12/14/2023] [Indexed: 01/03/2024]
Abstract
Obstructive sleep apnea syndrome (OSAS) causes recurrent apnea and intermittent hypoxia at night, leading to several complications such as cognitive dysfunction. However, the molecular mechanisms underlying cognitive dysfunction in OSAS are unclear, and oxidative stress mediated by intermittent hypoxia is an important mechanism. In addition, the improvement of cognitive dysfunction in patients with OSAS varies by different treatment regimens; among them, continuous positive airway pressure therapy (CPAP) is mostly recognized for improving cognitive dysfunction. In this review, we discuss the potential mechanisms of oxidative stress in OSAS, the common factors of affecting oxidative stress and the Links between oxidative stress and inflammation in OSAS, focusing on the potential links between oxidative stress and cognitive dysfunction in OSAS and the potential therapies for neurocognitive dysfunction in patients with OSAS mediated by oxidative stress. Therefore, further analysis on the relationship between oxidative stress and cognitive dysfunction in patients with OSAS will help to clarify the etiology and discover new treatment options, which will be of great significance for early clinical intervention.
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Affiliation(s)
- XiaoPing Zhang
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Hongyan Zhou
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - HaiJun Liu
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Ping Xu
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
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11
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Zhu X, Hua E, Tu Q, Liu M, Xu L, Feng J. Foxq1 Promotes Alveolar Epithelial Cell Death through Tle1-mediated Inhibition of the NF-κB Signaling Pathway. Am J Respir Cell Mol Biol 2024; 71:53-65. [PMID: 38574238 DOI: 10.1165/rcmb.2023-0317oc] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 04/03/2024] [Indexed: 04/06/2024] Open
Abstract
Acute lung injury (ALI) is a common respiratory disease characterized by diffuse alveolar injury and interstitial edema, as well as a hyperinflammatory response, lung cell damage, and oxidative stress. Foxq1, a member of the FOX family of transcription factors, is expressed in various tissues, such as the lungs, liver, and kidneys, and contributes to various biological processes, such as stress, metabolism, cell cycle arrest, and aging-related apoptosis. However, the role of Foxq1 in ALI is unknown. We constructed ex vivo and in vivo ALI models by LPS tracheal perfusion of ICR mice and conditioned medium stimulation of injured MLE-12 cells. Foxq1 expression was increased, and its localization was altered, in our ALI model. In normal or injured MLE-12 cells, knockdown of Foxq1 promoted cell survival, and overexpression had the opposite effect. This regulatory effect was likely mediated by Tle1 and the NF-κB/Bcl2/Bax signaling pathway. These data suggest a potential link between Foxq1 and ALI, indicating that Foxq1 can be used as a biomarker for the diagnosis of ALI. Targeted inhibition of Foxq1 expression could promote alveolar epithelial cell survival and may provide a strategy for mitigating ALI.
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Affiliation(s)
- Xi Zhu
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital and Medical School of Nantong University, Nantong, China; and
| | - Ershi Hua
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital and Medical School of Nantong University, Nantong, China; and
| | - Qifeng Tu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Mei Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Liqin Xu
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital and Medical School of Nantong University, Nantong, China; and
| | - Jian Feng
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital and Medical School of Nantong University, Nantong, China; and
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12
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Song S, Li R, Wu C, Dong J, Wang P. EFFECTS OF HYPERBARIC OXYGEN THERAPY ON INTESTINAL ISCHEMIA-REPERFUSION AND ITS MECHANISM. Shock 2024; 61:650-659. [PMID: 38113056 DOI: 10.1097/shk.0000000000002287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2023]
Abstract
ABSTRACT Ischemia can cause reversible or irreversible cell or tissue damage, and reperfusion after ischemia not only has no therapeutic effect but also aggravates cell damage. Notably, gut tissue is highly susceptible to ischemia-reperfusion (IR) injury under many adverse health conditions. Intestinal IR (IIR) is an important pathophysiological process in critical clinical diseases. Therefore, it is necessary to identify better therapeutic methods for relieving intestinal ischemia and hypoxia. Hyperbaric oxygenation refers to the intermittent inhalation of 100% oxygen in an environment greater than 1 atm pressure, which can better increase the oxygen level in the tissue and change the inflammatory pathway. Currently, it can have a positive effect on hypoxia and ischemic diseases. Related studies have suggested that hyperbaric oxygen can significantly reduce ischemia-hypoxic injury to the brain, spinal cord, kidney, and myocardium. This article reviews the pathogenesis of IR and the current treatment measures, and further points out that hyperbaric oxygen has a better effect in IR. We found that not only improved hypoxia but also regulated IR induced injury in a certain way. From the perspective of clinical application, these changes and the application of hyperbaric oxygen therapy have important implications for treatment, especially IIR.
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Affiliation(s)
- Shurui Song
- Department of Emergency Surgery, The Affiliated Hospital of Qing Dao University, Qing Dao, PR China
| | - Ruojing Li
- Department of Emergency Surgery, The Affiliated Hospital of Qing Dao University, Qing Dao, PR China
| | - Changliang Wu
- Department of Emergency Surgery, The Affiliated Hospital of Qing Dao University, Qing Dao, PR China
| | | | - Peige Wang
- Department of Emergency Surgery, The Affiliated Hospital of Qing Dao University, Qing Dao, PR China
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13
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Rasouli M, Fattahi R, Nuoroozi G, Zarei-Behjani Z, Yaghoobi M, Hajmohammadi Z, Hosseinzadeh S. The role of oxygen tension in cell fate and regenerative medicine: implications of hypoxia/hyperoxia and free radicals. Cell Tissue Bank 2024; 25:195-215. [PMID: 37365484 DOI: 10.1007/s10561-023-10099-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 06/18/2023] [Indexed: 06/28/2023]
Abstract
Oxygen pressure plays an integral role in regulating various aspects of cellular biology. Cell metabolism, proliferation, morphology, senescence, metastasis, and angiogenesis are some instances that are affected by different tensions of oxygen. Hyperoxia or high oxygen concentration, enforces the production of reactive oxygen species (ROS) that disturbs physiological homeostasis, and consequently, in the absence of antioxidants, cells and tissues are directed to an undesired fate. On the other side, hypoxia or low oxygen concentration, impacts cell metabolism and fate strongly through inducing changes in the expression level of specific genes. Thus, understanding the precise mechanism and the extent of the implication of oxygen tension and ROS in biological events is crucial to maintaining the desired cell and tissue function for application in regenerative medicine strategies. Herein, a comprehensive literature review has been performed to find out the impacts of oxygen tensions on the various behaviors of cells or tissues.
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Affiliation(s)
- Mehdi Rasouli
- Student Research Committee, Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roya Fattahi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985717443, Iran
| | - Ghader Nuoroozi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985717443, Iran
| | - Zeinab Zarei-Behjani
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maliheh Yaghoobi
- Engineering Department, Faculty of Chemical Engineering, Zanjan University, Zanjan, Iran
| | - Zeinab Hajmohammadi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985717443, Iran
| | - Simzar Hosseinzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985717443, Iran.
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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14
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Feng Z, Wei Y, Zhang Z, Li M, Gu R, Lu L, Liu W, Qin H. Wheat peptides inhibit the activation of MAPK and NF-κB inflammatory pathways and maintain epithelial barrier integrity in NSAID-induced intestinal epithelial injury. Food Funct 2024; 15:823-837. [PMID: 38131381 DOI: 10.1039/d3fo03954d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Abstract
The use of non-steroidal anti-inflammatory drugs (NSAIDs) has negative effects on the gastrointestinal tract, but the proton pump inhibitors currently in use only protect against gastrointestinal disease and may even make NSAID-induced enteropathy worse. Therefore, new approaches to treating enteropathy are required. This study aimed to investigate the protective effect of wheat peptides (WPs) against NSAID-induced intestinal damage in mice and their mechanism. Here, an in vivo mouse model was built to investigate the protective and reparative effects of different concentrations of WPs on NSAID-induced intestinal injury. WPs ameliorated NSAID-induced weight loss and small intestinal tissue damage in mice. WP treatment inhibited NSAID-induced injury leading to increased levels of oxidative stress and expression levels of inflammatory factors. WPs protected and repaired the integrity and permeability injury of the intestinal tight junction induced by NSAIDs. An in vitro Caco-2 cell model was built with lipopolysaccharide (LPS). WP pretreatment inhibited LPS-induced changes in the Caco-2 cell permeability and elevated the levels of oxidative stress. WPs inhibited LPS-induced phosphorylation of NF-κB p65 and mitogen-activated protein kinase (MAPK) signaling pathways and reduced the expression of inflammatory factors. In addition, WPs increased tight junction protein expression, which contributed to improved intestinal epithelial dysfunction. Our results suggest that WPs can ameliorate NSAID-induced impairment of intestinal barrier functional integrity by improving intestinal oxidative stress levels and reducing inflammatory factor expression through inhibition of NF-κB p65 and MAPK signaling pathway activation. WPs can therefore be used as potential dietary supplements to reduce NSAID-induced injury of the intestine.
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Affiliation(s)
- Zhiyuan Feng
- Tianjin Key Laboratory of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin Economic and Technological Development Area, Tianjin, China.
- Beijing Engineering Research Center of Protein & Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing, 100015, China
| | - Ying Wei
- Department of Food Science and Engineering, Beijing University of Agriculture, Beijing, China.
| | - Zhuoran Zhang
- Beijing Engineering Research Center of Protein & Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing, 100015, China
| | - Mingliang Li
- Beijing Engineering Research Center of Protein & Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing, 100015, China
| | - Ruizeng Gu
- Beijing Engineering Research Center of Protein & Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing, 100015, China
| | - Lu Lu
- Beijing Engineering Research Center of Protein & Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing, 100015, China
| | - Wenying Liu
- Department of Food Science and Engineering, Beijing University of Agriculture, Beijing, China.
| | - Huimin Qin
- Tianjin Key Laboratory of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin Economic and Technological Development Area, Tianjin, China.
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15
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Xie Y, Zhao G, Lei X, Cui N, Wang H. Advances in the regulatory mechanisms of mTOR in necroptosis. Front Immunol 2023; 14:1297408. [PMID: 38164133 PMCID: PMC10757967 DOI: 10.3389/fimmu.2023.1297408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/01/2023] [Indexed: 01/03/2024] Open
Abstract
The mammalian target of rapamycin (mTOR), an evolutionarily highly conserved serine/threonine protein kinase, plays a prominent role in controlling gene expression, metabolism, and cell death. Programmed cell death (PCD) is indispensable for maintaining homeostasis by removing senescent, defective, or malignant cells. Necroptosis, a type of PCD, relies on the interplay between receptor-interacting serine-threonine kinases (RIPKs) and the membrane perforation by mixed lineage kinase domain-like protein (MLKL), which is distinguished from apoptosis. With the development of necroptosis-regulating mechanisms, the importance of mTOR in the complex network of intersecting signaling pathways that govern the process has become more evident. mTOR is directly responsible for the regulation of RIPKs. Autophagy is an indirect mechanism by which mTOR regulates the removal and interaction of RIPKs. Another necroptosis trigger is reactive oxygen species (ROS) produced by oxidative stress; mTOR regulates necroptosis by exploiting ROS. Considering the intricacy of the signal network, it is reasonable to assume that mTOR exerts a bifacial effect on necroptosis. However, additional research is necessary to elucidate the underlying mechanisms. In this review, we summarized the mechanisms underlying mTOR activation and necroptosis and highlighted the signaling pathway through which mTOR regulates necroptosis. The development of therapeutic targets for various diseases has been greatly advanced by the expanding knowledge of how mTOR regulates necroptosis.
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Affiliation(s)
- Yawen Xie
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Guoyu Zhao
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xianli Lei
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Na Cui
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Hao Wang
- Department of Critical Care Medicine, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
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16
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Leyderman M, Wilmore JR, Shope T, Cooney RN, Urao N. Impact of intestinal microenvironments in obesity and bariatric surgery on shaping macrophages. IMMUNOMETABOLISM (COBHAM, SURREY) 2023; 5:e00033. [PMID: 38037591 PMCID: PMC10683977 DOI: 10.1097/in9.0000000000000033] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 10/26/2023] [Indexed: 12/02/2023]
Abstract
Obesity is associated with alterations in tissue composition, systemic cellular metabolism, and low-grade chronic inflammation. Macrophages are heterogenous innate immune cells ubiquitously localized throughout the body and are key components of tissue homeostasis, inflammation, wound healing, and various disease states. Macrophages are highly plastic and can switch their phenotypic polarization and change function in response to their local environments. Here, we discuss how obesity alters the intestinal microenvironment and potential key factors that can influence intestinal macrophages as well as macrophages in other organs, including adipose tissue and hematopoietic organs. As bariatric surgery can induce metabolic adaptation systemically, we discuss the potential mechanisms through which bariatric surgery reshapes macrophages in obesity.
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Affiliation(s)
- Michael Leyderman
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, NY, USA
| | - Joel R. Wilmore
- Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY, USA
- Sepsis Interdisciplinary Research Center, State University of New York Upstate Medical University, Syracuse, NY, USA
| | - Timothy Shope
- Department of Surgery, State University of New York Upstate Medical University, Syracuse, NY, USA
| | - Robert N. Cooney
- Sepsis Interdisciplinary Research Center, State University of New York Upstate Medical University, Syracuse, NY, USA
- Department of Surgery, State University of New York Upstate Medical University, Syracuse, NY, USA
| | - Norifumi Urao
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, NY, USA
- Sepsis Interdisciplinary Research Center, State University of New York Upstate Medical University, Syracuse, NY, USA
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17
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Clària J, Arroyo V, Moreau R. Roles of systemic inflammatory and metabolic responses in the pathophysiology of acute-on-chronic liver failure. JHEP Rep 2023; 5:100807. [PMID: 37600957 PMCID: PMC10432809 DOI: 10.1016/j.jhepr.2023.100807] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/17/2023] [Accepted: 05/24/2023] [Indexed: 08/22/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) is the most severe form of acutely decompensated cirrhosis and is characterised by the presence of one or more organ failures, intense systemic inflammation, peripheral blood lymphopenia, and a high risk of death without liver transplantation within 28 days. Herein, we propose the hypothesis that intense systemic inflammation may lead to organ failures through five different non-mutually exclusive mechanisms. First, pathogen-associated molecular patterns and inflammatory mediators (i.e. cytokines and lipid mediators) stimulate the production of the vasorelaxant nitric oxide in the walls of splanchnic arterioles, leading to enhanced splanchnic and systemic vasodilation which, in turn, induces enhanced activity of endogenous vasoconstrictor systems causing renal vasoconstriction and acute kidney injury. Second, neutrophils that reach the systemic circulation are prone to adhere to the vascular endothelium. Cytokines and lipid mediators act on the endothelium in microvessels of vital organs, an effect that favours the migration of neutrophils (and probably other leukocytes) to surrounding tissues where neutrophils can cause tissue damage and thereby contribute to organ failure. Third, cytokines and lipid mediators promote the formation of microthrombi that impair microcirculation and tissue oxygenation. Fourth, acute inflammation stimulates intense peripheral catabolism of amino acids whose products may be metabotoxins that contribute to hepatic encephalopathy. Fifth, acute inflammatory responses, which include the production of a broad variety of biomolecules (proteins and lipids), and an increase in biomass (i.e., granulopoiesis requiring de novo nucleotide synthesis), among others, are energetically expensive processes that require large amounts of nutrients. Therefore, immunity competes with other maintenance programmes for energy. The brain stem integrates the energy demand of each organ system, with immunity considered a top priority. The brain stem may "decide" to make a trade-off which involves the induction of a dormancy programme that permits the shutdown of mitochondrial respiration and oxidative phosphorylation in peripheral organs. In the context of acutely decompensated cirrhosis, the consequence of a shutdown of mitochondrial respiration and ATP production would be a dramatic decrease in organ function.
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Affiliation(s)
- Joan Clària
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Grifols Chair, Barcelona, Spain
- Hospital Clínic-IDIBAPS, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Vicente Arroyo
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Grifols Chair, Barcelona, Spain
| | - Richard Moreau
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Grifols Chair, Barcelona, Spain
- INSERM, Université de Paris, Centre de Recherche sur l’Inflammation (CRI), Paris, France
- Assistance Publique – Hôpitaux de Paris (AP-HP), Hôpital Beaujon, Service d’Hépatologie, Clichy, France
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18
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Yu H, Deng W, Chen S, Qin B, Yao Y, Zhou C, Guo M. Strongylocentrotus nudus egg polysaccharide (SEP) suppresses HBV replication via activation of TLR4-induced immune pathway. Int J Biol Macromol 2023:125539. [PMID: 37355064 DOI: 10.1016/j.ijbiomac.2023.125539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 06/17/2023] [Accepted: 06/21/2023] [Indexed: 06/26/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is a worldwide public health problem that causes significant liver-related morbidity and mortality. In our previous study, Strongylocentrotus nudus eggs polysaccharide (SEP), extracted from sea urchins, had immunomodulatory and antitumor effects. Whether SEP has anti-HBV activity is still obscure. This study demonstrated that SEP decreased the secretion of hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), as well as the replication and transcription of HBV both in vitro and in vivo. Immunofluorescence and immunohistochemistry results showed that the level of HBV core antigen (HBcAg) was clearly reduced by SEP treatment. Mechanistically, RT-qPCR, western blot, and confocal microscopy analysis showed that SEP significantly increased the expression of toll-like receptor 4 (TLR4) and co-localization with TLR4. The downstream molecules of TLR4, including NF-κb and IRF3, were activated and the expression of IFN-β, TNF-α, IL-6, OAS, and MxA were also increased, which could suppress HBV replication. Moreover, SEP inhibited other genotypes of HBV and hepatitis C virus (HCV) replication in vitro. In summary, SEP could be investigated as a potential anti-HBV drug capable of modulating the innate immune.
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Affiliation(s)
- Haifei Yu
- State Key Laboratory of Natural Medicines, School of Life Science & Technolgy, China Pharmaceutical University, Nanjing 211198, Jiangsu province, China
| | - Wanyu Deng
- College of life science, Shangrao Normal University, Shangrao 334001, Jiangxi province, China
| | - Shuo Chen
- State Key Laboratory of Natural Medicines, School of Life Science & Technolgy, China Pharmaceutical University, Nanjing 211198, Jiangsu province, China
| | - Bo Qin
- Shaoxing Women and Children's Hospital, Shaoxing 312000, Zhejiang, China
| | - Yongxuan Yao
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children Medical Center, Guangzhou 510623, China.
| | - Changlin Zhou
- State Key Laboratory of Natural Medicines, School of Life Science & Technolgy, China Pharmaceutical University, Nanjing 211198, Jiangsu province, China.
| | - Min Guo
- State Key Laboratory of Natural Medicines, School of Life Science & Technolgy, China Pharmaceutical University, Nanjing 211198, Jiangsu province, China.
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19
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Leite CBG, Tavares LP, Leite MS, Demange MK. Revisiting the role of hyperbaric oxygen therapy in knee injuries: Potential benefits and mechanisms. J Cell Physiol 2023; 238:498-512. [PMID: 36649313 DOI: 10.1002/jcp.30947] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 12/07/2022] [Accepted: 01/03/2023] [Indexed: 01/18/2023]
Abstract
Knee injury negatively impacts routine activities and quality of life of millions of people every year. Disruption of tendons, ligaments, and articular cartilage are major causes of knee lesions, leading to social and economic losses. Besides the attempts for an optimal recovery of knee function after surgery, the joint healing process is not always adequate given the nature of intra-articular environment. Based on that, different therapeutic methods attempt to improve healing capacity. Hyperbaric oxygen therapy (HBOT) is an innovative biophysical approach that can be used as an adjuvant treatment post-knee surgery, to potentially prevent chronic disorders that commonly follows knee injuries. Given the well-recognized role of HBOT in improving wound healing, further research is necessary to clarify the benefits of HBOT in damaged musculoskeletal tissues, especially knee disorders. Here, we review important mechanisms of action for HBOT-induced healing including the induction of angiogenesis, modulation of inflammation and extracellular matrix components, and activation of parenchyma cells-key events to restore knee function after injury. This review discusses the basic science of the healing process in knee injuries, the role of oxygen during cicatrization, and shed light on the promising actions of HBOT in treating knee disorders, such as tendon, ligament, and cartilage injuries.
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Affiliation(s)
- Chilan B G Leite
- Instituto de Ortopedia e Traumatologia, Hospital das Clinicas, HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
- Department of Orthopedic Surgery, Center for Cartilage Repair and Sports Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Luciana P Tavares
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Magno S Leite
- Laboratório de Poluição Atmosférica Experimental LIM05, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil
| | - Marco K Demange
- Instituto de Ortopedia e Traumatologia, Hospital das Clinicas, HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
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20
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Salama AAA, Elgohary R, Fahmy MI. Protocatechuic acid ameliorates lipopolysaccharide-induced kidney damage in mice via downregulation of TLR-4-mediated IKBKB/NF-κB and MAPK/Erk signaling pathways. J Appl Toxicol 2023. [PMID: 36807594 DOI: 10.1002/jat.4447] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 01/31/2023] [Accepted: 02/14/2023] [Indexed: 02/19/2023]
Abstract
Acute kidney injury (AKI) is a very critical cause of death in the whole world. Lipopolysaccharide (LPS) induces kidney damage by activating various deleterious inflammatory and oxidative pathways. Protocatechuic acid, a natural phenolic compound, has shown to exert beneficial effects against oxidative and inflammatory responses. The study aimed to clarify the nephroprotective activity of protocatechuic acid in LPS-induced acute kidney damage in mice. Forty male Swiss mice were allocated in four groups as follows: normal control group; LPS (250 μg/kg, ip)-induced kidney injury group; LPS-injected mice treated with protocatechuic acid (15 mg/kg, po), and LPS-injected mice treated with protocatechuic acid (30 mg/kg, po). Significant toll-like receptor 4 (TLR-4)-mediated activation of IKBKB/NF-κB and MAPK/Erk/COX-2 inflammatory pathways has been observed in kidneys of mice treated with LPS. Oxidative stress was revealed by inhibition of total antioxidant capacity, catalase, nuclear factor erythroid 2-related factor 2 (Nrf2), and NAD(P)H quinone oxidoreductase (NQO1) enzyme along with increased nitric oxide level. In parallel, focal inflammatory effects were shown in between the tubules and glomeruli as well as in the perivascular dilated blood vessels at the cortex affecting the normal morphology of the kidney tissues of LPS-treated mice. However, treatment with protocatechuic acid reduced LPS-induced changes in the aforementioned parameters and restored normal histological features of the affected tissues. In conclusion, our study uncovered that protocatechuic acid has nephroprotective effects in mice with AKI through opposing different inflammatory and oxidative cascades.
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Affiliation(s)
| | - Rania Elgohary
- Narcotics, Ergogenics and Poisons Department, National Research Centre, Cairo, Egypt
| | - Mohamed Ibrahim Fahmy
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt
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21
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Carica Papaya Reduces High Fat Diet and Streptozotocin-Induced Development of Inflammation in Adipocyte via IL-1β/IL-6/TNF-α Mediated Signaling Mechanisms in Type-2 Diabetic Rats. Curr Issues Mol Biol 2023; 45:852-884. [PMID: 36826001 PMCID: PMC9956039 DOI: 10.3390/cimb45020056] [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: 12/02/2022] [Revised: 12/28/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
The prevalence of obesity in contemporary society has brought attention to how serious it is all around the world. Obesity, a proinflammatory condition defined by hypertrophied adipocytes and immune cells that reside in adipose tissue, is characterized by elevated circulating levels of proinflammatory cytokines. The pro-inflammatory mediators trigger a number of inflammatory pathways and affect the phosphorylation of a number of insulin-signaling pathways in peripheral tissues. In this work, we pointed the outcome of the leaves of Carica papaya (C. papaya) on the inflammatory molecules by in vivo and in silico analysis in order to prove its mechanisms of action. Adipocytokines, antioxidant enzymes, gene and protein expression of pro-inflammatory signaling molecules (mTOR, TNF-α, IL-1β, IL-6 and IKKβ) by q-RT-PCR and immunohistochemistry, as well as histopathological analysis, in adipose tissues were carried out. C. papaya reinstated the levels of adipocytokines, antioxidant enzymes and mRNA levels of mTOR, TNF-α, IL-1β, IL-6 and IKKβ in the adipose tissues of type 2 diabetic rats. Molecular docking and dynamics simulation studies revealed that caffeic acid, transferulic acid and quercetin had the top hit rates against IKKβ, TNF-α, IL-6, IL-1β, and mTOR. This study concludes that C. papaya put back the altered effects in fatty tissue of type 2 diabetic rats by restoring the adipocytokines and the gene expression.
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22
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Amruta N, Kandikattu HK, Intapad S. Cardiovascular Dysfunction in Intrauterine Growth Restriction. Curr Hypertens Rep 2022; 24:693-708. [PMID: 36322299 DOI: 10.1007/s11906-022-01228-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/09/2021] [Indexed: 11/30/2022]
Abstract
PURPOSE OF REVIEW We highlight important new findings on cardiovascular dysfunction in intrauterine growth restriction. RECENT FINDINGS Intrauterine growth restriction (IUGR) is a multifactorial condition which negatively impacts neonatal growth during pregnancy and is associated with health problems during the lifespan. It affects 5-15% of all pregnancies in the USA and Europe with varying percentages in developing countries. Epidemiological studies have reported that IUGR is associated with the pathogenesis of hypertension, activation of the renin-angiotensin system (RAS), disruption in placental-mTORC and TGFβ signaling cascades, and endothelial dysfunction in IUGR fetuses, children, adolescents, and adults resulting in the development of cardiovascular diseases (CVD). Experimental studies are needed to investigate therapeutic measures to treat increased blood pressure (BP) and long-term CVD problems in people affected by IUGR. We outline the mechanisms mediating fetal programming of hypertension in developing CVD. We have reviewed findings from different experimental models focusing on recent studies that demonstrate CVD in IUGR.
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Affiliation(s)
- Narayanappa Amruta
- Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, #8683, New Orleans, LA, 70112-2699, USA
| | - Hemanth Kumar Kandikattu
- Department of Medicine, Section of Pulmonary Diseases, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Suttira Intapad
- Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, #8683, New Orleans, LA, 70112-2699, USA.
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23
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Wu Q, Zou C. Microglial Dysfunction in Neurodegenerative Diseases via RIPK1 and ROS. Antioxidants (Basel) 2022; 11:antiox11112201. [PMID: 36358573 PMCID: PMC9686917 DOI: 10.3390/antiox11112201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/30/2022] [Accepted: 11/04/2022] [Indexed: 11/09/2022] Open
Abstract
Microglial dysfunction is a major contributor to the pathogenesis of multiple neurodegenerative diseases. The neurotoxicity of microglia associated with oxidative stress largely depends on NF-κB pathway activation, which promotes the production and release of microglial proinflammatory cytokines and chemokines. In this review, we discuss the current literature on the essential role of the NF-κB pathway on microglial activation that exacerbates neurodegeneration, with a particular focus on RIPK1 kinase activity-dependent microglial dysfunction. As upregulated RIPK1 kinase activity is associated with reactive oxygen species (ROS) accumulation in neurodegenerative diseases, we also discuss the current knowledge about the mechanistic links between RIPK1 activation and ROS generation. Given RIPK1 kinase activity and oxidative stress are closely regulated with each other in a vicious cycle, future studies are required to be conducted to fully understand how RIPK1 and ROS collude together to disturb microglial homeostasis that drives neurodegenerative pathogenesis.
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Affiliation(s)
- Qiaoyan Wu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd, Pudong District, Shanghai 201210, China
| | - Chengyu Zou
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 100 Haike Rd, Pudong District, Shanghai 201210, China
- Shanghai Key Laboratory of Aging Studies, 100 Haike Rd, Pudong District, Shanghai 201210, China
- Correspondence:
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24
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Fasudil, a ROCK inhibitor, preserves limb integrity in a mouse model of unilateral critical limb ischemia: Possible interplay of inflammatory and angiogenic signaling pathways. Life Sci 2022; 309:121019. [DOI: 10.1016/j.lfs.2022.121019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 09/17/2022] [Accepted: 09/27/2022] [Indexed: 11/20/2022]
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25
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Millar MW, Fazal F, Rahman A. Therapeutic Targeting of NF-κB in Acute Lung Injury: A Double-Edged Sword. Cells 2022; 11:3317. [PMID: 36291185 PMCID: PMC9601210 DOI: 10.3390/cells11203317] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/18/2022] [Accepted: 10/19/2022] [Indexed: 01/11/2023] Open
Abstract
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a devastating disease that can be caused by a variety of conditions including pneumonia, sepsis, trauma, and most recently, COVID-19. Although our understanding of the mechanisms of ALI/ARDS pathogenesis and resolution has considerably increased in recent years, the mortality rate remains unacceptably high (~40%), primarily due to the lack of effective therapies for ALI/ARDS. Dysregulated inflammation, as characterized by massive infiltration of polymorphonuclear leukocytes (PMNs) into the airspace and the associated damage of the capillary-alveolar barrier leading to pulmonary edema and hypoxemia, is a major hallmark of ALI/ARDS. Endothelial cells (ECs), the inner lining of blood vessels, are important cellular orchestrators of PMN infiltration in the lung. Nuclear factor-kappa B (NF-κB) plays an essential role in rendering the endothelium permissive for PMN adhesion and transmigration to reach the inflammatory site. Thus, targeting NF-κB in the endothelium provides an attractive approach to mitigate PMN-mediated vascular injury, not only in ALI/ARDS, but in other inflammatory diseases as well in which EC dysfunction is a major pathogenic mechanism. This review discusses the role and regulation of NF-κB in the context of EC inflammation and evaluates the potential and problems of targeting it as a therapy for ALI/ARDS.
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Affiliation(s)
| | | | - Arshad Rahman
- Department of Pediatrics (Neonatology), Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
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26
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Peres EC, Victorio JA, Nunes-Souza V, Breithaupt-Faloppa AC, Rabelo LA, Tavares-de-Lima W, Davel AP, Rossoni LV. Simvastatin protects against intestinal ischemia/reperfusion-induced pulmonary artery dysfunction. Life Sci 2022; 306:120851. [PMID: 35926590 DOI: 10.1016/j.lfs.2022.120851] [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: 05/30/2022] [Revised: 07/26/2022] [Accepted: 07/27/2022] [Indexed: 10/16/2022]
Abstract
AIMS The lung is an important target organ damage in intestinal ischemia/reperfusion (II/R), but mechanisms involved in II/R-induced pulmonary artery (PA) dysfunction, as well as its treatment, are not clear. The present study aimed to investigate the mechanisms involved in the II/R-induced PA dysfunction and a possible protective role of acute simvastatin pretreatment. MAIN METHODS Male Wistar rats were subjected to occlusion of the superior mesenteric artery for 45 min followed by 2 h reperfusion (II/R) or sham-operated surgery (sham). In some rats, simvastatin (20 mg/kg, oral gavage) was administrated 1 h before II/R. KEY FINDINGS II/R reduced acetylcholine-induced relaxation and phenylephrine-induced contraction of PA segments, which were prevented by acute simvastatin pretreatment in vivo or restored by inducible nitric oxide synthase (iNOS) inhibition in situ with 1400 W. Elevated reactive oxygen species (ROS) levels and higher nuclear translocation of nuclear factor kappa B (NFκB) subunit p65 were observed in PA of II/R rats and prevented by simvastatin. Moreover, simvastatin increased superoxide dismutase (SOD) activity and endothelial nitric oxide synthase (eNOS) expression in PA of the II/R group as well as prevented the increased levels of interleukin (IL)-1β and IL-6 in lung explants following II/R. SIGNIFICANCE The study suggests that pretreatment with a single dose of simvastatin prevents the II/R-induced increase of inflammatory factors and oxidative stress, as well as PA endothelial dysfunction and adrenergic hyporreactivity. Therefore, acute simvastatin administration could be therapeutic for pulmonary vascular disease in patients suffering from intestinal ischemic events.
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Affiliation(s)
- Emília C Peres
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Jamaira A Victorio
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Valéria Nunes-Souza
- Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife, Brazil
| | - Ana Cristina Breithaupt-Faloppa
- Laboratório de Cirurgia Cardiovascular e Fisiopatologia da Circulação (LIM-11), Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Luiza A Rabelo
- Laboratory of Cardiovascular Reactivity, Department of Physiology and Pharmacology, Institute of Biological Sciences, Federal University of Alagoas, Brazil
| | - Wothan Tavares-de-Lima
- Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Ana Paula Davel
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Luciana V Rossoni
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
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27
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Yang C, Zhou Y, Liu H, Xu P. The Role of Inflammation in Cognitive Impairment of Obstructive Sleep Apnea Syndrome. Brain Sci 2022; 12:brainsci12101303. [PMID: 36291237 PMCID: PMC9599901 DOI: 10.3390/brainsci12101303] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/14/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022] Open
Abstract
Obstructive sleep apnea syndrome (OSAS) has become a major worldwide public health concern, given its global prevalence. It has clear links with multiple comorbidities and mortality. Cognitive impairment is one related comorbidity causing great pressure on individuals and society. The clinical manifestations of cognitive impairment in OSAS include decline in attention/vigilance, verbal–visual memory loss, visuospatial/structural ability impairment, and executive dysfunction. It has been proven that chronic intermittent hypoxia (CIH) may be a main cause of cognitive impairment in OSAS. Inflammation plays important roles in CIH-induced cognitive dysfunction. Furthermore, the nuclear factor kappa B and hypoxia-inducible factor 1 alpha pathways play significant roles in this inflammatory mechanism. Continuous positive airway pressure is an effective therapy for OSAS; however, its effect on cognitive impairment is suboptimal. Therefore, in this review, we address the role inflammation plays in the development of neuro-impairment in OSAS and the association between OSAS and cognitive impairment to provide an overview of its pathophysiology. We believe that furthering the understanding of the inflammatory mechanisms involved in OSAS-associated cognitive impairment could lead to the development of appropriate and effective therapy.
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28
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Zhang G, Wang J, Zhao Z, Xin T, Fan X, Shen Q, Raheem A, Lee CR, Jiang H, Ding J. Regulated necrosis, a proinflammatory cell death, potentially counteracts pathogenic infections. Cell Death Dis 2022; 13:637. [PMID: 35869043 PMCID: PMC9307826 DOI: 10.1038/s41419-022-05066-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/29/2022] [Accepted: 07/04/2022] [Indexed: 02/07/2023]
Abstract
Since the discovery of cell apoptosis, other gene-regulated cell deaths are gradually appreciated, including pyroptosis, ferroptosis, and necroptosis. Necroptosis is, so far, one of the best-characterized regulated necrosis. In response to diverse stimuli (death receptor or toll-like receptor stimulation, pathogenic infection, or other factors), necroptosis is initiated and precisely regulated by the receptor-interacting protein kinase 3 (RIPK3) with the involvement of its partners (RIPK1, TRIF, DAI, or others), ultimately leading to the activation of its downstream substrate, mixed lineage kinase domain-like (MLKL). Necroptosis plays a significant role in the host's defense against pathogenic infections. Although much has been recognized regarding modulatory mechanisms of necroptosis during pathogenic infection, the exact role of necroptosis at different stages of infectious diseases is still being unveiled, e.g., how and when pathogens utilize or evade necroptosis to facilitate their invasion and how hosts manipulate necroptosis to counteract these detrimental effects brought by pathogenic infections and further eliminate the encroaching pathogens. In this review, we summarize and discuss the recent progress in the role of necroptosis during a series of viral, bacterial, and parasitic infections with zoonotic potentials, aiming to provide references and directions for the prevention and control of infectious diseases of both human and animals.
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Affiliation(s)
- Guangzhi Zhang
- grid.464332.4Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Jinyong Wang
- grid.508381.70000 0004 0647 272XShenzhen Bay Laboratory, Institute of Infectious Diseases, Shenzhen, 518000 China ,grid.258164.c0000 0004 1790 3548Institute of Respiratory Diseases, Shenzhen People’s Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, 518020 Guangdong China
| | - Zhanran Zhao
- grid.47840.3f0000 0001 2181 7878Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, CA 94720-3200 USA
| | - Ting Xin
- grid.464332.4Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Xuezheng Fan
- grid.464332.4Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Qingchun Shen
- grid.464332.4Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Abdul Raheem
- grid.464332.4Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, 100193 China ,grid.35155.370000 0004 1790 4137Present Address: Huazhong Agricultural University, Wuhan, China
| | - Chae Rhim Lee
- grid.47840.3f0000 0001 2181 7878Department of Molecular and Cell Biology and Cancer Research Laboratory, University of California, Berkeley, CA 94720-3200 USA ,grid.266093.80000 0001 0668 7243Present Address: University of California, Irvine, CA USA
| | - Hui Jiang
- grid.464332.4Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, 100193 China
| | - Jiabo Ding
- grid.464332.4Institute of Animal Sciences of Chinese Academy of Agricultural Sciences, Beijing, 100193 China
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29
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Ninnemann J, Winsauer C, Bondareva M, Kühl AA, Lozza L, Durek P, Lissner D, Siegmund B, Kaufmann SHE, Mashreghi MF, Nedospasov SA, Kruglov AA. TNF hampers intestinal tissue repair in colitis by restricting IL-22 bioavailability. Mucosal Immunol 2022; 15:698-716. [PMID: 35383266 PMCID: PMC9259490 DOI: 10.1038/s41385-022-00506-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/10/2022] [Indexed: 02/04/2023]
Abstract
Successful treatment of chronic inflammatory diseases integrates both the cessation of inflammation and the induction of adequate tissue repair processes. Strikingly, targeting a single proinflammatory cytokine, tumor necrosis factor (TNF), induces both processes in a relevant cohort of inflammatory bowel disease (IBD) patients. However, the molecular mechanisms underlying intestinal repair following TNF blockade during IBD remain elusive. Using a novel humanized model of experimental colitis, we demonstrate that TNF interfered with the tissue repair program via induction of a soluble natural antagonist of IL-22 (IL-22Ra2; IL-22BP) in the colon and abrogated IL-22/STAT3-mediated mucosal repair during colitis. Furthermore, membrane-bound TNF expressed by T cells perpetuated colonic inflammation, while soluble TNF produced by epithelial cells (IECs) induced IL-22BP expression in colonic dendritic cells (DCs) and dampened IL-22-driven restitution of colonic epithelial functions. Finally, TNF induced IL-22BP expression in human monocyte-derived DCs and levels of IL22-BP correlated with TNF in sera of IBD patients. Thus, our data can explain how anti-TNF therapy induces mucosal healing by increasing IL-22 availability and implicates new therapeutic opportunities for IBD.
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Affiliation(s)
- Justus Ninnemann
- German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany
| | - Caroline Winsauer
- German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany
| | - Marina Bondareva
- German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany
- Belozersky Institute of Physico-Chemical Biology and Faculty of Bioengineering and Bioinformatics, M.V. Lomonosov Moscow State University, Moscow, Russia
| | - Anja A Kühl
- iPATH.Berlin, Core Unit of Charité-Universitätsmedizin Berlin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Laura Lozza
- Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Pawel Durek
- German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany
| | - Donata Lissner
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Britta Siegmund
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Stefan H E Kaufmann
- Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany
| | | | - Sergei A Nedospasov
- Belozersky Institute of Physico-Chemical Biology and Faculty of Bioengineering and Bioinformatics, M.V. Lomonosov Moscow State University, Moscow, Russia
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
- Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Andrey A Kruglov
- German Rheumatism Research Center (DRFZ), a Leibniz Institute, Berlin, Germany.
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
- Belozersky Institute of Physico-Chemical Biology and Biological Faculty, M.V. Lomonosov Moscow State University, Moscow, Russia.
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Zhang T, Ding C, Chen H, Zhao J, Chen Z, Chen B, Mao K, Hao Y, Roulis M, Xu H, Kluger Y, Zou Q, Ye Y, Zhan M, Flavell RA, Li HB. m 6A mRNA modification maintains colonic epithelial cell homeostasis via NF-κB-mediated antiapoptotic pathway. SCIENCE ADVANCES 2022; 8:eabl5723. [PMID: 35333576 PMCID: PMC8956260 DOI: 10.1126/sciadv.abl5723] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 02/02/2022] [Indexed: 05/26/2023]
Abstract
Colonic mucosal barrier dysfunction is one of the major causes of inflammatory bowel disease (IBD). However, the mechanisms underlying mucosal barrier dysfunction are poorly understood. N6-methyladenosine (m6A) mRNA modification is an important modulator of epitranscriptional regulation of gene expression, participating in multiple physiological and pathological processes. However, the function of m6A modification in colonic epithelial cells and stem cells is unknown. Here, we show that m6A modification is essential for maintaining the homeostatic self-renewal in colonic stem cells. Specific deletion of the methyltransferase 14 (Mettl14) gene in mouse colon resulted in colonic stem cell apoptosis, causing mucosal barrier dysfunction and severe colitis. Mechanistically, we revealed that Mettl14 restricted colonic epithelial cell death by regulating the stability of Nfkbia mRNA and modulating the NF-κB pathway. Our results identified a previously unidentified role for m6A modification in colonic epithelial cells and stem cells, suggesting that m6A modification may be a potential therapeutic target for IBD.
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Affiliation(s)
- Ting Zhang
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai Jiao Tong University School of Medicine–Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Renji Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Chenbo Ding
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai Jiao Tong University School of Medicine–Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Huifang Chen
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai Jiao Tong University School of Medicine–Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jun Zhao
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8055, USA
| | - Zhejun Chen
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Baiwen Chen
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Kaiqiong Mao
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai Jiao Tong University School of Medicine–Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yajuan Hao
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai Jiao Tong University School of Medicine–Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Manolis Roulis
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520-8055, USA
| | - Hao Xu
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520-8055, USA
| | - Yuval Kluger
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8055, USA
| | - Qiang Zou
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Youqiong Ye
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Meixiao Zhan
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital of Jinan University, Zhuhai, Guangdong 519000, China
| | - Richard A. Flavell
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520-8055, USA
- Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520-8055, USA
| | - Hua-Bing Li
- Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Shanghai Jiao Tong University School of Medicine–Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520-8055, USA
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Soylu-Kucharz R, Khoshnan A, Petersén Å. IKKβ signaling mediates metabolic changes in the hypothalamus of a Huntington disease mouse model. iScience 2022; 25:103771. [PMID: 35146388 PMCID: PMC8819015 DOI: 10.1016/j.isci.2022.103771] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 11/16/2021] [Accepted: 01/11/2022] [Indexed: 01/13/2023] Open
Abstract
Huntington disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Metabolic changes are associated with HD progression, but underlying mechanisms are not fully known. As the IKKβ/NF-κB pathway is an essential regulator of metabolism, we investigated the involvement of IKKβ, the upstream activator of NF-κB in hypothalamus-specific HD metabolic changes. We expressed amyloidogenic N-terminal fragments of mutant HTT (mHTT) in the hypothalamus of mice with brain-specific ablation of IKKβ (Nestin/IKKβlox/lox) and control mice (IKKβlox/lox). We assessed effects on body weight, metabolic hormones, and hypothalamic neuropathology. Hypothalamic expression of mHTT led to an obese phenotype only in female mice. CNS-specific inactivation of IKKβ prohibited weight gain in females, which was independent of neuroprotection and microglial activation. Our study suggests that mHTT in the hypothalamus causes metabolic imbalance in a sex-specific fashion, and central inhibition of the IKKβ pathway attenuates the obese phenotype.
Mutant huntingtin in the hypothalamus causes sex-specific metabolic imbalance CNS-specific inactivation of the IKKβ pathway prevents the obese phenotype IKKβ inactivation leads to an increased number of mutant huntingtin inclusions IKKβ inactivation does not prevent orexin or A13 TH neuron loss
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Affiliation(s)
- Rana Soylu-Kucharz
- Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, BMC D11, 22184 Lund, Sweden
| | - Ali Khoshnan
- California Institute of Technology, Pasadena, CA 91125, USA
| | - Åsa Petersén
- Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, BMC D11, 22184 Lund, Sweden
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32
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Khan H, Sharma K, Kumar A, Kaur A, Singh TG. Therapeutic implications of cyclooxygenase (COX) inhibitors in ischemic injury. Inflamm Res 2022; 71:277-292. [PMID: 35175358 DOI: 10.1007/s00011-022-01546-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 01/19/2022] [Accepted: 01/22/2022] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Ischemia-reperfusion injury (IRI) is the inexplicable aggravation of cellular dysfunction that results in blood flow restoration to previously ischemic tissues. COX mediates the oxidative conversion of AA to various prostaglandins and thromboxanes, which are involved in various physiological and pathological processes. In the pathophysiology of I/R injuries, COX has been found to play an important role. I/R injuries affect most vital organs and are characterized by inflammation, oxidative stress, cell death, and apoptosis, leading to morbidity and mortality. MATERIALS AND METHODS A systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to understand the Nature and mechanistic interventions of the Cyclooxygenase modulations in ischemic injury. Here, we have discussed the COX Physiology and downstream signalling pathways modulated by COX, e.g., Camp Pathway, Peroxisome Proliferator-Activated Receptor Activity, NF-kB Signalling, PI3K/Akt Signalling in ischemic injury. CONCLUSION This review will discuss the various COX types, specifically COX-1 and COX-2, which are involved in developing I/R injury in organs such as the brain, spinal cord, heart, kidney, liver, and intestine.
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Affiliation(s)
- Heena Khan
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
| | - Kunal Sharma
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
| | - Amit Kumar
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
| | - Amarjot Kaur
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India.
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Brischetto C, Krieger K, Klotz C, Krahn I, Kunz S, Kolesnichenko M, Mucka P, Heuberger J, Scheidereit C, Schmidt-Ullrich R. NF-κB determines Paneth versus goblet cell fate decision in the small intestine. Development 2021; 148:273388. [PMID: 34751748 PMCID: PMC8627599 DOI: 10.1242/dev.199683] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 09/28/2021] [Indexed: 12/12/2022]
Abstract
Although the role of the transcription factor NF-κB in intestinal inflammation and tumor formation has been investigated extensively, a physiological function of NF-κB in sustaining intestinal epithelial homeostasis beyond inflammation has not been demonstrated. Using NF-κB reporter mice, we detected strong NF-κB activity in Paneth cells, in ‘+4/+5’ secretory progenitors and in scattered Lgr5+ crypt base columnar stem cells of small intestinal (SI) crypts. To examine NF–κB functions in SI epithelial self-renewal, mice or SI crypt organoids (‘mini-guts’) with ubiquitously suppressed NF-κB activity were used. We show that NF-κB activity is dispensable for maintaining SI epithelial proliferation, but is essential for ex vivo organoid growth. Furthermore, we demonstrate a dramatic reduction of Paneth cells in the absence of NF-κB activity, concomitant with a significant increase in goblet cells and immature intermediate cells. This indicates that NF-κB is required for proper Paneth versus goblet cell differentiation and for SI epithelial homeostasis, which occurs via regulation of Wnt signaling and Sox9 expression downstream of NF-κB. The current study thus presents evidence for an important role for NF-κB in intestinal epithelial self-renewal. Summary: The transcription factor NF-κB, together with downstream Wnt and Sox9, is required for Paneth and goblet cell fate decisions and for maintenance of the small intestinal stem cell niche.
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Affiliation(s)
- Cristina Brischetto
- Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany
| | - Karsten Krieger
- Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany
| | - Christian Klotz
- Unit for Mycotic and Parasitic Agents and Mycobacteria, Robert Koch-Institute (RKI), 13353 Berlin, Germany
| | - Inge Krahn
- Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany
| | - Séverine Kunz
- CF Electron Microscopy, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany
| | - Marina Kolesnichenko
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Patrick Mucka
- Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany
| | - Julian Heuberger
- Signal Transduction in Development and Cancer, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany.,Medical Department, Division of Gastroenterology and Hepatology, Charité University Medicine, 13353 Berlin, Germany
| | - Claus Scheidereit
- Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany
| | - Ruth Schmidt-Ullrich
- Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany
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Xu Y, Zhang S, Liao X, Li M, Chen S, Li X, Wu X, Yang M, Tang M, Hu Y, Li Z, Yu R, Huang M, Song L, Li J. Circular RNA circIKBKB promotes breast cancer bone metastasis through sustaining NF-κB/bone remodeling factors signaling. Mol Cancer 2021; 20:98. [PMID: 34325714 PMCID: PMC8320207 DOI: 10.1186/s12943-021-01394-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 07/17/2021] [Indexed: 12/28/2022] Open
Abstract
Background Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown. Methods Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-κB/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays. Results We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-κB pathway via promoting IKKβ-mediated IκBα phosphorylation, inhibiting IκBα feedback loop and facilitating NF-κB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively. Conclusion We revealed a plausible mechanism for circIKBKB-mediated NF-κB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-021-01394-8.
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Affiliation(s)
- Yingru Xu
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Shuxia Zhang
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xinyi Liao
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Man Li
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Suwen Chen
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xincheng Li
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xingui Wu
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Meisongzhu Yang
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Miaoling Tang
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Yameng Hu
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Ziwen Li
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Ruyuan Yu
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Mudan Huang
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China.,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Libing Song
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China.,State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510080, China
| | - Jun Li
- Program of Cancer Research, Key Laboratory of Protein Modification and Degradation and Guangzhou Institute of Oncology, Affiliated Guangzhou Women and Children's Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 510623, China. .,Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
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Lu C, Wang C, Xiao H, Chen M, Yang Z, Liang Z, Wang H, Liu Y, Yang Y, Wang Q. Ethyl pyruvate: A newly discovered compound against ischemia-reperfusion injury in multiple organs. Pharmacol Res 2021; 171:105757. [PMID: 34302979 DOI: 10.1016/j.phrs.2021.105757] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/21/2021] [Accepted: 07/02/2021] [Indexed: 12/23/2022]
Abstract
Ischemia-reperfusion injury (IRI) is a process whereby an initial ischemia injury and subsequent recovery of blood flow, which leads to the propagation of an innate immune response and the changes of structural and functional of multiple organs. Therefore, IRI is considered to be a great challenge in clinical treatment such as organ transplantation or coronary angioplasty. In recent years, ethyl pyruvate (EP), a derivative of pyruvate, has received great attention because of its stability and low toxicity. Previous studies have proved that EP has various pharmacological activities, including anti-inflammation, anti-oxidative stress, anti-apoptosis, and anti-fibrosis. Compelling evidence has indicated EP plays a beneficial role in a variety of acute injury models, such as brain IRI, myocardial IRI, renal IRI, and hepatic IRI. Moreover, EP can not only effectively inhibit multiple IRI-induced pathological processes, but also improve the structural and functional lesion of tissues and organs. In this study, we review the recent progress in the research on EP and discuss their implications for a better understanding of multiple organ IRI, and the prospects of targeting the EP for therapeutic intervention.
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Affiliation(s)
- Chenxi Lu
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Changyu Wang
- Department of Cardiology, Xi'an No.3 Hospital, School of Life Sciences and Medicine, Northwest University, 10 Fengcheng Three Road, Xi'an, China
| | - Haoxiang Xiao
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Mengfan Chen
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Zhi Yang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China
| | - Zhenxing Liang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East, Zhengzhou, China
| | - Haiying Wang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China
| | - Yonglin Liu
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China
| | - Yang Yang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, China.
| | - Qiang Wang
- Department of Paediatrics, Shenmu Hospital, School of Life Sciences and Medicine, Northwest University, Guangming Road, Shenmu, China.
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37
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Neuroinflammation: An Integrating Overview of Reactive-Neuroimmune Cell Interactions in Health and Disease. Mediators Inflamm 2021; 2021:9999146. [PMID: 34158806 PMCID: PMC8187052 DOI: 10.1155/2021/9999146] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 05/04/2021] [Indexed: 12/14/2022] Open
Abstract
The concept of central nervous system (CNS) inflammation has evolved over the last decades. Neuroinflammation is the response of reactive CNS components to altered homeostasis, regardless of the cause to be endogenous or exogenous. Neurological diseases, whether traumatic, neoplastic, ischemic, metabolic, toxic, infectious, autoimmune, developmental, or degenerative, involve direct and indirect immune-related neuroinflammation. Brain infiltrates of the innate and adaptive immune system cells appear in response to an infective or otherwise noxious agent and produce inflammatory mediators. Mediators of inflammation include local and recruited cells and signals. Processes derived from extrinsic and intrinsic CNS diseases also elicit the CNS inflammatory response. A deeper understanding of immune-related inflammation in health and disease is necessary to find potential therapeutic targets for preventing or reducing CNS damage. This review is aimed at discussing the innate and adaptive immune system functions and their roles in regulating brain cell responses in disease and homeostasis maintenance.
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McElrath C, Espinosa V, Lin JD, Peng J, Sridhar R, Dutta O, Tseng HC, Smirnov SV, Risman H, Sandoval MJ, Davra V, Chang YJ, Pollack BP, Birge RB, Galan M, Rivera A, Durbin JE, Kotenko SV. Critical role of interferons in gastrointestinal injury repair. Nat Commun 2021; 12:2624. [PMID: 33976143 PMCID: PMC8113246 DOI: 10.1038/s41467-021-22928-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 04/06/2021] [Indexed: 12/13/2022] Open
Abstract
The etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. Here we use IFN receptor-deficient mice in a dextran sulfate sodium (DSS) model of acute intestinal injury to study the contributions of type I and III interferons (IFN) to the initiation, progression and resolution of acute colitis. We find that mice lacking both types of IFN receptors exhibit enhanced barrier destruction, extensive loss of goblet cells and diminished proliferation of epithelial cells in the colon following DSS-induced damage. Impaired mucosal healing in double IFN receptor-deficient mice is driven by decreased amphiregulin expression, which IFN signaling can up-regulate in either the epithelial or hematopoietic compartment. Together, these data underscore the pleiotropic functions of IFNs and demonstrate that these critical antiviral cytokines also support epithelial regeneration following acute colonic injury.
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Affiliation(s)
- Constance McElrath
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Vanessa Espinosa
- Pediatrics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Jian-Da Lin
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Jianya Peng
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Department of Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Raghavendra Sridhar
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Orchi Dutta
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Pediatrics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Hsiang-Chi Tseng
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Sergey V Smirnov
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Heidi Risman
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Marvin J Sandoval
- Department of Pathology, New York University School of Medicine, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA
| | - Viralkumar Davra
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Yun-Juan Chang
- Office of Advance Research Computing, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Brian P Pollack
- Atlanta Veterans Affairs Medical Center, Atlanta, GA, USA
- Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Raymond B Birge
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Center for Cell Signaling, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Mark Galan
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Amariliz Rivera
- Pediatrics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Joan E Durbin
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Sergei V Kotenko
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA.
- Center for Cell Signaling, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA.
- Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, Newark, NJ, USA.
- Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA.
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Overexpression of TGR5 alleviates myocardial ischemia/reperfusion injury via AKT/GSK-3β mediated inflammation and mitochondrial pathway. Biosci Rep 2021; 40:221795. [PMID: 31909787 PMCID: PMC6981096 DOI: 10.1042/bsr20193482] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 12/26/2019] [Accepted: 12/28/2019] [Indexed: 12/31/2022] Open
Abstract
Ischemia/reperfusion (I/R) injury reduces cell proliferation, triggers inflammation, promotes cell apoptosis and necrosis, which are the leading reasons of morbidity and mortality in patients with cardiac disease. TGR5 is shown to express in hearts, but its functional role in I/R-induced myocardial injury is unclear. In the present study, we aimed to explore the underlying molecular mechanism of TGR5 in hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury in vitro. The results showed that TGR5 was significantly up-regulated in H9C2 (rat cardiomyocyte cells) and human cardiomyocytes (HCMs) after H/R. Overexpression of TGR5 significantly improved cell proliferation, alleviated apoptosis rate, the activities of caspase-3, cleaved caspases-3 and Bax protein expression levels, and increased Bcl-2 level. Overexpression of TGR5 significantly up-regulated ROS generation, stabilized the mitochondrial membrane potential (MMP), and reduced the concentration of intracellular Ca2+ as well as cytosolic translocation of mitochondrial cytochrome c (cyto-c). Meanwhile, overexpressed TGR5 also enhanced the mRNA and protein levels of interleukin (IL)-10, and decreased the mRNA and protein levels of IL-6 and tumor necrosis factor α (TNF-α). The shTGR5+H/R group followed opposite trends. In addition, overexpressed TGR5 induced an increase in the levels of p-AKT and p-GSK-3β. The protective effects of TGR5 were partially reversed by AKT inhibitor MK-2206. Taken together, these results suggest that TGR5 attenuates I/R-induced mitochondrial dysfunction and cell apoptosis as well as inflammation, and these protections may through AKT/GSK-3β pathway.
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Wang C, Wang C, Ren L, Chen S, Chen WH, Li Y. The protein kinase D1-mediated inflammatory pathway is involved in olanzapine-induced impairment of skeletal muscle insulin signaling in rats. Life Sci 2021; 270:119037. [PMID: 33497738 DOI: 10.1016/j.lfs.2021.119037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/07/2021] [Accepted: 01/07/2021] [Indexed: 11/18/2022]
Abstract
AIMS Skeletal muscle insulin resistance (SMIR) contributes to the metabolic syndrome. Mounting evidence has demonstrated that the second generation antipsychotic olanzapine causes SMIR. The present study sought to investigate the molecular mechanisms underlying olanzapine-induced SMIR. MAIN METHODS Male rats were given olanzapine (5 mg/kg, by a gavage method) for consecutive eight weeks. Plasma glucose and insulin concentrations were determined enzymatically or by ELISA. Gene/protein expression was analyzed by Real-Time PCR, Western blot and/or immunohistochemistry. KEY FINDINGS Olanzapine increased fasting plasma insulin concentration, and decreased glucose clearance during insulin tolerance test in rats. In skeletal muscle, it decreased protein expression of membrane glucose transporter (GLUT) 4, the ratio of membrane to total GLUT4, and total insulin receptor substrate 1 (IRS1). However, it increased protein phosphorylation of Ser307 in IRS1, Y607 in phosphoinositide 3-kinase p85α and Ser307 in AKT. These results indicate olanzapine-induced impairment of skeletal muscle insulin signaling. Mechanistically, olanzapine upregulated mRNA expression of TNFα, IL6 and IL1β, and protein phosphorylation of both IκB kinase (IKK)α/β and nuclear factor (NF)κB p65. Furthermore, it increased protein phosphorylation of Ser485/491 in AMPKα2, whereas it decreased AMPKα2 activity. More importantly, both Western blot and immunohistochemical analyses revealed that olanzapine increased protein phosphorylation of Ser744/748 in protein kinase D1 (PKD1). SIGNIFICANCE The present results suggest that the PKD1-mediated inflammatory pathway is involved in olanzapine-induced impairment of skeletal muscle insulin signaling in rats. Our findings may go new insight into the mechanisms underlying olanzapine-induced SMIR.
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Affiliation(s)
- Chunxia Wang
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Chengliang Wang
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Liying Ren
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Shankang Chen
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Wen-Hua Chen
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
| | - Yuhao Li
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, NSW 2000, Australia.
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41
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Li X, Berg NK, Mills T, Zhang K, Eltzschig HK, Yuan X. Adenosine at the Interphase of Hypoxia and Inflammation in Lung Injury. Front Immunol 2021; 11:604944. [PMID: 33519814 PMCID: PMC7840604 DOI: 10.3389/fimmu.2020.604944] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 11/25/2020] [Indexed: 12/19/2022] Open
Abstract
Hypoxia and inflammation often coincide in pathogenic conditions such as acute respiratory distress syndrome (ARDS) and chronic lung diseases, which are significant contributors to morbidity and mortality for the general population. For example, the recent global outbreak of Coronavirus disease 2019 (COVID-19) has placed viral infection-induced ARDS under the spotlight. Moreover, chronic lung disease ranks the third leading cause of death in the United States. Hypoxia signaling plays a diverse role in both acute and chronic lung inflammation, which could partially be explained by the divergent function of downstream target pathways such as adenosine signaling. Particularly, hypoxia signaling activates adenosine signaling to inhibit the inflammatory response in ARDS, while in chronic lung diseases, it promotes inflammation and tissue injury. In this review, we discuss the role of adenosine at the interphase of hypoxia and inflammation in ARDS and chronic lung diseases, as well as the current strategy for therapeutic targeting of the adenosine signaling pathway.
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Affiliation(s)
- Xiangyun Li
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
- Department of Anesthesiology, Tianjin Medical University NanKai Hospital, Tianjin, China
| | - Nathanial K. Berg
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Tingting Mills
- Department of Biochemistry, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Kaiying Zhang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Holger K. Eltzschig
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Xiaoyi Yuan
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
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42
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Guan Y, Yang YJ, Nagarajan P, Ge Y. Transcriptional and signalling regulation of skin epithelial stem cells in homeostasis, wounds and cancer. Exp Dermatol 2020; 30:529-545. [PMID: 33249665 DOI: 10.1111/exd.14247] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 10/10/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023]
Abstract
The epidermis and skin appendages are maintained by their resident epithelial stem cells, which undergo long-term self-renewal and multilineage differentiation. Upon injury, stem cells are activated to mediate re-epithelialization and restore tissue function. During this process, they often mount lineage plasticity and expand their fates in response to damage signals. Stem cell function is tightly controlled by transcription machineries and signalling transductions, many of which derail in degenerative, inflammatory and malignant dermatologic diseases. Here, by describing both well-characterized and newly emerged pathways, we discuss the transcriptional and signalling mechanisms governing skin epithelial homeostasis, wound repair and squamous cancer. Throughout, we highlight common themes underscoring epithelial stem cell plasticity and tissue-level crosstalk in the context of skin physiology and pathology.
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Affiliation(s)
- Yinglu Guan
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Youn Joo Yang
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Priyadharsini Nagarajan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yejing Ge
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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43
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Almoiliqy M, Wen J, Qaed E, Sun Y, Lian M, Mousa H, Al-Azab M, Zaky MY, Chen D, Wang L, AL-Sharabi A, Liu Z, Sun P, Lin Y. Protective Effects of Cinnamaldehyde against Mesenteric Ischemia-Reperfusion-Induced Lung and Liver Injuries in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:4196548. [PMID: 33381264 PMCID: PMC7748914 DOI: 10.1155/2020/4196548] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 11/17/2020] [Accepted: 11/25/2020] [Indexed: 12/23/2022]
Abstract
The aim of this study was to characterize and reveal the protective effects of cinnamaldehyde (CA) against mesenteric ischemia-reperfusion- (I/R-) induced lung and liver injuries and the related mechanisms. Sprague-Dawley (SPD) rats were pretreated for three days with 10 or 40 mg/kg/d, ig of CA, and then induced with mesenteric ischemia for 1 h and reperfusion for 2 h. The results indicated that pretreatment with 10 or 40 mg/kg of CA attenuated morphological damage in both lung and liver tissues of mesenteric I/R-injured rats. CA pretreatment significantly restored the levels of aspartate transaminase (AST) and alanine transaminase (ALT) in mesenteric I/R-injured liver tissues, indicating the improvement of hepatic function. CA also significantly attenuated the inflammation via reducing myeloperoxidase (MOP) activity and downregulating the expression of inflammation-related proteins, including interleukin-6 (IL-6), interleukin-1β (IL-1β), cyclooxygenase-2 (Cox-2), and tumor necrosis factor receptor type-2 (TNFR-2) in both lung and liver tissues of mesenteric I/R-injured rats. Pretreatment with CA significantly downregulated nuclear factor kappa B- (NF-κB-) related protein expressions (NF-κB p65, NF-κB p50, I kappa B alpha (IK-α), and inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ)) in both lung and liver tissues of mesenteric I/R-injured rats. CA also significantly downregulated the protein expression of p53 family members, including caspase-3, caspase-9, Bax, and p53, and restored Bcl-2 in both lung and liver tissues of mesenteric I/R-injured rats. CA pretreatment significantly reduced TUNEL-apoptotic cells and significantly inhibited p53 and NF-κB p65 nuclear translocation in both lung and liver tissues of mesenteric I/R-injured rats. CA neither induced pulmonary and hepatic histological alterations nor affected the parameters of inflammation and apoptosis in sham rats. We conclude that CA alleviated mesenteric I/R-induced pulmonary and hepatic injuries via attenuating apoptosis and inflammation through inhibition of NF-κB and p53 pathways in rats, suggesting the potential role of CA in remote organ ischemic injury protection.
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Affiliation(s)
- Marwan Almoiliqy
- Department of Pharmacology, Pharmaceutical College, Dalian Medical University, Dalian 116044, China
- Key Lab of Aromatic Plant Resources Exploitation and Utilization in Sichuan Higher Education, Yibin University, Yibin, 644000 Sichuan, China
| | - Jin Wen
- Department of Pharmacology, Pharmaceutical College, Dalian Medical University, Dalian 116044, China
| | - Eskandar Qaed
- Department of Pharmacology, Pharmaceutical College, Dalian Medical University, Dalian 116044, China
| | - Yuchao Sun
- Department of Pharmacology, Pharmaceutical College, Dalian Medical University, Dalian 116044, China
| | - Mengqiao Lian
- Department of Pharmacology, Pharmaceutical College, Dalian Medical University, Dalian 116044, China
| | - Haithm Mousa
- Department of Clinical Biochemistry, Dalian Medical University, Dalian 116044, China
| | - Mahmoud Al-Azab
- Department of Immunology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Mohamed Y. Zaky
- Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
- Molecular Physiology Division, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Dapeng Chen
- Laboratory Animal Center, Dalian Medical University, Dalian 116044, China
| | - Li Wang
- Department of Pharmacology, Pharmaceutical College, Dalian Medical University, Dalian 116044, China
| | - Abdulkarem AL-Sharabi
- Department of Pharmacology, Pharmaceutical College, Dalian Medical University, Dalian 116044, China
| | - Zhihao Liu
- Department of Pharmacology, Pharmaceutical College, Dalian Medical University, Dalian 116044, China
| | - Pengyuan Sun
- Department of Pharmacology, Pharmaceutical College, Dalian Medical University, Dalian 116044, China
| | - Yuan Lin
- Department of Pharmacology, Pharmaceutical College, Dalian Medical University, Dalian 116044, China
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44
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Akbari G. Emerging roles of microRNAs in intestinal ischemia/reperfusion-induced injury: a review. J Physiol Biochem 2020; 76:525-537. [PMID: 33140255 DOI: 10.1007/s13105-020-00772-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 10/06/2020] [Indexed: 02/06/2023]
Abstract
Intestinal ischemia/reperfusion (II/R) injury is a serious pathological phenomenon in underlying hemorrhagic shock, trauma, strangulated intestinal obstruction, and acute mesenteric ischemia which associated with high morbidity and mortality. MicroRNAs (miRNAs, miRs) are endogenous non-coding RNAs that regulate post-transcriptionally target mRNA translation via degrading it and/or suppressing protein synthesis. This review discusses on the role of some miRNAs in underlying II/R injury. Some of these miRNAs can have protective action through agomiR or specific antagomiR, and others can have destructive effects in the basal level of II/R insult. Based on these literature reviews, II/R injury affects several miRNAs and their specific target genes. Some miRNAs upregulate under condition of II/R injury, and multiple miRNAs downregulate following II/R damage. Data of this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, Web of Science, and Scientific Information Database from 2000 to 2020. It is shown a correlation between changes in the expression of miRNAs and autophagy, inflammation, oxidative stress, apoptosis, and epithelial barrier function. Taken together, agomiR or antagomiR of some miRNAs can be considered as one new target for the research and development of innovative drugs to the prevention or treatment of II/R damage.
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Affiliation(s)
- Ghaidafeh Akbari
- Medicinal Plants Research Center, Department of Physiology, School of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran.
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45
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Leslie J, Macia MG, Luli S, Worrell JC, Reilly WJ, Paish HL, Knox A, Barksby BS, Gee LM, Zaki MYW, Collins AL, Burgoyne RA, Cameron R, Bragg C, Xu X, Chung GW, Brown CDA, Blanchard AD, Nanthakumar CB, Karsdal M, Robinson SM, Manas DM, Sen G, French J, White SA, Murphy S, Trost M, Zakrzewski JL, Klein U, Schwabe RF, Mederacke I, Nixon C, Bird T, Teuwen LA, Schoonjans L, Carmeliet P, Mann J, Fisher AJ, Sheerin NS, Borthwick LA, Mann DA, Oakley F. c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis. Nat Metab 2020; 2:1350-1367. [PMID: 33168981 PMCID: PMC7116435 DOI: 10.1038/s42255-020-00306-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 09/30/2020] [Indexed: 02/07/2023]
Abstract
Fibrosis is a common pathological feature of chronic disease. Deletion of the NF-κB subunit c-Rel limits fibrosis in multiple organs, although the mechanistic nature of this protection is unresolved. Using cell-specific gene-targeting manipulations in mice undergoing liver damage, we elucidate a critical role for c-Rel in controlling metabolic changes required for inflammatory and fibrogenic activities of hepatocytes and macrophages and identify Pfkfb3 as the key downstream metabolic mediator of this response. Independent deletions of Rel in hepatocytes or macrophages suppressed liver fibrosis induced by carbon tetrachloride, while combined deletion had an additive anti-fibrogenic effect. In transforming growth factor-β1-induced hepatocytes, c-Rel regulates expression of a pro-fibrogenic secretome comprising inflammatory molecules and connective tissue growth factor, the latter promoting collagen secretion from HMs. Macrophages lacking c-Rel fail to polarize to M1 or M2 states, explaining reduced fibrosis in RelΔLysM mice. Pharmacological inhibition of c-Rel attenuated multi-organ fibrosis in both murine and human fibrosis. In conclusion, activation of c-Rel/Pfkfb3 in damaged tissue instigates a paracrine signalling network among epithelial, myeloid and mesenchymal cells to stimulate fibrogenesis. Targeting the c-Rel-Pfkfb3 axis has potential for therapeutic applications in fibrotic disease.
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Affiliation(s)
- Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
| | - Marina García Macia
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Saimir Luli
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Julie C Worrell
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - William J Reilly
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Hannah L Paish
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Amber Knox
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ben S Barksby
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Lucy M Gee
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Marco Y W Zaki
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Amy L Collins
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Rachel A Burgoyne
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Rainie Cameron
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Charlotte Bragg
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Xin Xu
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Git W Chung
- Newcells Biotech, The Biosphere, Newcastle Helix, Newcastle upon Tyne, UK
| | - Colin D A Brown
- Newcells Biotech, The Biosphere, Newcastle Helix, Newcastle upon Tyne, UK
| | - Andrew D Blanchard
- Fibrosis Discovery Performance Unit, Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, UK
| | - Carmel B Nanthakumar
- Fibrosis Discovery Performance Unit, Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, UK
| | - Morten Karsdal
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - Stuart M Robinson
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Derek M Manas
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Gourab Sen
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Jeremy French
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Steven A White
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Sandra Murphy
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Matthias Trost
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Johannes L Zakrzewski
- Center for Discovery and Innovation and John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA
| | - Ulf Klein
- Division of Haematology & Immunology, Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | | | - Ingmar Mederacke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Colin Nixon
- Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK
| | - Tom Bird
- Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
- MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Laure-Anne Teuwen
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Luc Schoonjans
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Jelena Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Andrew J Fisher
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Institute of Transplantation, The Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Neil S Sheerin
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Lee A Borthwick
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
- Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK.
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Cannon A, Clarke N, MacCarthy F, Dunne C, Kevans D, Mahmud N, Lysaght J, O'Sullivan J. Effect of cigarette smoke extract on the intestinal microenvironment of ulcerative colitis tissue. JGH OPEN 2020; 4:1191-1198. [PMID: 33319055 PMCID: PMC7731828 DOI: 10.1002/jgh3.12422] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 03/21/2020] [Accepted: 09/20/2020] [Indexed: 11/08/2022]
Abstract
Background and Aim Ulcerative colitis (UC) is an autoimmune disease characterized by inflammation in the gastrointestinal tract. The severity of UC is higher in nonsmokers than smokers; however, the biological mechanisms controlling this effect remain unknown. The aim of this study was to examine the effect of cigarette smoke extract (CSE) on inflamed and noninflamed colonic tissue from UC patients and to determine if inflammatory mediators, transcription factors, and T cell phenotypes are altered by CSE. Methods Blood and colonic biopsies were obtained from UC patients undergoing endoscopy. Biopsies were cultured in the presence or absence of CSE. Multiplex enzyme‐linked immunosorbent assay (ELISA) measured secreted levels of inflammatory mediators. Nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) and Hypoxia‐inducible factor 1‐alpha (HIF‐1α) expression were measured by DNA‐binding ELISA. T cell phenotypes were assessed by flow cytometry in matched blood and biopsies. Results Secreted levels of interleukin 2 (IL‐2), interleukin 6 (IL‐6), tumor necrosis factor ‐ alpha (TNF‐α), chemokine (C‐C motif) ligand 2 (CCL2), and interleukin 10 (IL‐10) were significantly (all P < 0.05) decreased following treatment with CSE. This effect was specific to inflamed tissue and was not observed in noninflamed tissue. CSE did not alter the expression of NF‐κB or HIF‐1α. Assessment of T cell phenotypes in blood and tissue revealed that there were significantly more activated and exhausted T cells in the colonic tissue compared to matched blood. These profiles were not altered following CSE treatment. Conclusion These data suggest that observed effects of CSE in reducing inflammatory mediators ex vivo are specific to inflamed colonic tissue but are not due to the activation of NF‐κB or HIF‐1α and are not caused by alterations in subpopulations of T cells in these UC tissues.
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Affiliation(s)
- Aoife Cannon
- Department of Surgery Trinity Translational Medicine Institute, Trinity College Dublin Dublin Ireland
| | - Niamh Clarke
- Department of Surgery Trinity Translational Medicine Institute, Trinity College Dublin Dublin Ireland
| | - Finbar MacCarthy
- Department of Clinical Medicine Trinity Translational Medicine Institute, St. James's Hospital Dublin Ireland.,Department of Gastroenterology SACC Directorate, St. James's Hospital Dublin Ireland
| | - Cara Dunne
- Department of Clinical Medicine Trinity Translational Medicine Institute, St. James's Hospital Dublin Ireland.,Department of Gastroenterology SACC Directorate, St. James's Hospital Dublin Ireland
| | - David Kevans
- Department of Clinical Medicine Trinity Translational Medicine Institute, St. James's Hospital Dublin Ireland.,Department of Gastroenterology SACC Directorate, St. James's Hospital Dublin Ireland
| | - Nasir Mahmud
- Department of Clinical Medicine Trinity Translational Medicine Institute, St. James's Hospital Dublin Ireland.,Department of Gastroenterology SACC Directorate, St. James's Hospital Dublin Ireland
| | - Joanne Lysaght
- Department of Surgery Trinity Translational Medicine Institute, Trinity College Dublin Dublin Ireland
| | - Jacintha O'Sullivan
- Department of Surgery Trinity Translational Medicine Institute, Trinity College Dublin Dublin Ireland
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Tan Y, Zuo W, Huang L, Zhou B, Liang H, Zheng S, Jia W, Chen S, Liu J, Yang X, Jiao Y. Nervilifordin F alleviates intestinal ischemia/reperfusion-induced acute lung injury via inhibiting inflammasome and mTOR pathway. Int Immunopharmacol 2020; 89:107014. [PMID: 33039959 DOI: 10.1016/j.intimp.2020.107014] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 09/13/2020] [Accepted: 09/13/2020] [Indexed: 02/07/2023]
Abstract
Acute lung injury (ALI) is a life-threatening disorder with high rates of morbidity and mortality. Up to now, there are still no effective drugs for its therapies due to the complexity of its etiology and pathogenesis. In this present study, we investigated the protective effect of Nervilifordin F (NF) on ALI induced by intestinal ischemia/reperfusion (II/R) and its related mechanism. Firstly, the ALI model rats were induced through II/R, and treated with NF. Then, the pathological and cytokine level changes in the lung tissue of ALI rats were evaluated by hematoxylin and eosin and enzyme-linked immunosorbent assay (ELISA). The related genes expression level of mammalian target of rapamycin (mTOR) pathway and inflammasome were measured by real-time quantitative polymerase chain reaction (RT-qPCR), western blot and immunohistochemistry. Finally, the NF-protein complexes were predicted by SYBYL-X 2.0. The results indicated that NF can significant reduces the levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 and IL-1β, and inhibits the expression of inflammasome related genes (such as toll-like receptor 4 (TLR4), p65, NOD-like receptor protein 3 (NLRP3) and Caspase 1), thereby reduce inflammation in II/R-induced ALI rats. Moreover, NF can activate the expression of FK506 binding protein 25 (FKBP25) and down-regulate the expression of mTOR and p70 ribosomal protein S6 kinase 1 (p70S6K). In addition, molecular docking results showed that NF can be combined well with p70S6K, TLR4, mTOR and NLRP3, which further verified the inhibitory effect of NF on ALI inflammation. Therefore, the findings indicate that NF can alleviates II/R-induced inflammation of ALI rats by inhibiting inflammasome related genes and mTOR pathway, which expected to use as a potential drug for the treatment of ALI.
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Affiliation(s)
- Yanjun Tan
- College of Pharmacy, Guangxi Medical University, Nanning, Guangxi, China
| | - Wenpu Zuo
- Life Science Institute, Guangxi Medical University, Nanning, Guangxi, China
| | - Lingling Huang
- College of Pharmacy, Guangxi Medical University, Nanning, Guangxi, China; The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; Langdong Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Bo Zhou
- Scientific Research Center, Guilin Medical University, Guilin, Guangxi, China
| | - Hui Liang
- College of Pharmacy, Guangxi Medical University, Nanning, Guangxi, China
| | - Shengfeng Zheng
- The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Wenxian Jia
- College of Pharmacy, Guangxi Medical University, Nanning, Guangxi, China
| | - Suixia Chen
- Department of Pathophysiology, Guangxi Medical University, Nanning, Guangxi, China
| | - Jiayi Liu
- The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xiaoli Yang
- College of Pharmacy, Guangxi Medical University, Nanning, Guangxi, China; Scientific Research Center, Guilin Medical University, Guilin, Guangxi, China.
| | - Yang Jiao
- College of Pharmacy, Guangxi Medical University, Nanning, Guangxi, China.
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48
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Ito H, Kimura H, Karasawa T, Hisata S, Sadatomo A, Inoue Y, Yamada N, Aizawa E, Hishida E, Kamata R, Komada T, Watanabe S, Kasahara T, Suzuki T, Horie H, Kitayama J, Sata N, Yamaji-Kegan K, Takahashi M. NLRP3 Inflammasome Activation in Lung Vascular Endothelial Cells Contributes to Intestinal Ischemia/Reperfusion-Induced Acute Lung Injury. THE JOURNAL OF IMMUNOLOGY 2020; 205:1393-1405. [PMID: 32727891 DOI: 10.4049/jimmunol.2000217] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 07/06/2020] [Indexed: 12/19/2022]
Abstract
Intestinal ischemia/reperfusion (I/R) injury is a life-threatening complication that leads to inflammation and remote organ damage. The NLRP3 inflammasome regulates the caspase-1-dependent release of IL-1β, an early mediator of inflammation after I/R injury. In this study, we investigated the role of the NLRP3 inflammasome in mice with intestinal I/R injury. Deficiency of NLRP3, ASC, caspase-1/11, or IL-1β prolonged survival after intestinal I/R injury, but neither NLRP3 nor caspase-1/11 deficiency affected intestinal inflammation. Intestinal I/R injury caused acute lung injury (ALI) characterized by inflammation, reactive oxygen species generation, and vascular permeability, which was markedly improved by NLRP3 deficiency. Bone marrow chimeric experiments showed that NLRP3 in non-bone marrow-derived cells was the main contributor to development of intestinal I/R-induced ALI. The NLRP3 inflammasome in lung vascular endothelial cells is thought to be important to lung vascular permeability. Using mass spectrometry, we identified intestinal I/R-derived lipid mediators that enhanced NLRP3 inflammasome activation in lung vascular endothelial cells. Finally, we confirmed that serum levels of these lipid mediators were elevated in patients with intestinal ischemia. To our knowledge, these findings provide new insights into the mechanism underlying intestinal I/R-induced ALI and suggest that endothelial NLRP3 inflammasome-driven IL-1β is a novel potential target for treating and preventing this disorder.
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Affiliation(s)
- Homare Ito
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.,Department of Surgery, Jichi Medical University, Tochigi 329-0498, Japan
| | - Hiroaki Kimura
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Tadayoshi Karasawa
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Shu Hisata
- Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan; and
| | - Ai Sadatomo
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.,Department of Surgery, Jichi Medical University, Tochigi 329-0498, Japan
| | - Yoshiyuki Inoue
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan.,Department of Surgery, Jichi Medical University, Tochigi 329-0498, Japan
| | - Naoya Yamada
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Emi Aizawa
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Erika Hishida
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Ryo Kamata
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Takanori Komada
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Sachiko Watanabe
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Tadashi Kasahara
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan
| | - Takuji Suzuki
- Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan; and
| | - Hisanaga Horie
- Department of Surgery, Jichi Medical University, Tochigi 329-0498, Japan
| | - Joji Kitayama
- Department of Surgery, Jichi Medical University, Tochigi 329-0498, Japan
| | - Naohiro Sata
- Department of Surgery, Jichi Medical University, Tochigi 329-0498, Japan
| | - Kazuyo Yamaji-Kegan
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201
| | - Masafumi Takahashi
- Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan;
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Guo M, Li M, Zhang C, Zhang X, Wu Y. Dietary Administration of the Bacillus subtilis Enhances Immune Responses and Disease Resistance in Chickens. Front Microbiol 2020; 11:1768. [PMID: 32849392 PMCID: PMC7396511 DOI: 10.3389/fmicb.2020.01768] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 07/06/2020] [Indexed: 12/25/2022] Open
Abstract
Bacillus subtilis (B. subtilis) has a variety of proposed beneficial effects for chickens, including growth promotion and disease prevention. In this study, chickens were fed a diet containing B. subtilis for 21 days and growth performance, intestinal morphology, intestinal microbiota, immune responses, and disease resistance were investigated. After 21 days of feeding, chickens fed a diet containing B. subtilis had higher body weights. The concentrations of serum immunoglobulins IgA and IgM were significantly increased by B. subtilis in the diet. Moreover, chickens fed with B. subtilis had greater villus height (VH), shallower crypt depth (CD), and a higher VH/CD ratio in the jejunum than chickens fed a standard control diet. Diet with B. subtilis can balance intestinal microbiota, facilitate an increase in beneficial bacteria, and inhibit the pathogenic bacteria after 21 days of feeding. After an Escherichia coli (E. coli) challenge, the survival rate of chickens fed with B. subtilis was 66.67%, which was significantly higher than the controls. The E. coli contents in spleens and lungs from chickens fed a diet with B. subtilis were lower than those in controls. In addition, B. subtilis can trigger the toll-like receptor 4 and cause induction of proinflammatory cytokine (Il1β, Il6, and Il8) production to develop innate immune responses in chickens. In conclusion, diets containing B. subtilis can improve growth performance, serum immunoglobulin levels, the intestinal villus-crypt system, intestinal homeostasis, immune responses, and disease resistance against E. coli in chickens.
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Affiliation(s)
- Mengjiao Guo
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Mingtao Li
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Chengcheng Zhang
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Xiaorong Zhang
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China
| | - Yantao Wu
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture & Agri-Product Safety (JIRLAAPS), Yangzhou University, Yangzhou, China
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50
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Guo CA, Ma L, Su XL, Wang YZ, Zhen LL, Zhang B, An H, Liu HB. Esmolol inhibits inflammation and apoptosis in the intestinal tissue via the overexpression of NF-κB-p65 in the early stage sepsis rats. TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 31:331-341. [PMID: 32412904 DOI: 10.5152/tjg.2020.19341] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND/AIMS Accumulating evidence reveals esmolol could protect the gut mucosa through the regulation of immune response and inflammation in patients with sepsis. However, its underlying mechanism is not fully understood. MATERIALS AND METHODS Diamine oxidase (DAO), intestinal fatty acid-binding protein (I-FABP), interleukin (IL)-6, and IL-10 in the plasma of rats were detected by ELISA assay. Western blotting was utilized to measure the expression levels of NF-kappa B-p65, Bcl-2, and cleaved caspase-3 in the intestinal tissues. The survival analysis was performed in each group. RESULTS The plasma levels of DAO and IL-10 levels were increased, whereas that of I-FABP and IL-6 were decreased in the sepsis rats after esmolol treatment, indicating that after the esmolol treatment, the intestinal inflammation and damages were remarkably reduced as compared to those in the normal saline treated sepsis rats. NF-κB-p65 and Bcl-2 were highly expressed, but cleaved caspase-3 showed lower expression in the esmolol treated groups. However, at the same time, we observed contrasting results in the normal saline treated group. Western blotting data indicated that the esmolol treatment inhibited the inflammation and apoptosis in the intestinal tissue due to the overexpression of NF-κB-p65 in the celiac sepsis rats. The survival analysis results indicate that the esmolol infusion should be used in the early stages sepsis rats. CONCLUSION Esmolol can suppress inflammation and apoptosis in the intestinal tissue via the overexpression of NF-kappa B-p65 in the early stage sepsis rats. kappa BEarly-stage use of esmolol might be an ideal treatment method for sepsis.
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Affiliation(s)
- Chang-An Guo
- Second Clinical Medical College, Lanzhou University, Gansu Province, China;First Aid Center, Lanzhou University Second Hospital, Gansu Province, China;Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, China
| | - Li Ma
- Intensive Care Unit, Lanzhou University Second Hospital, Gansu Province, China
| | - Xiao-Lu Su
- Department of Pathology, Lanzhou University Second Hospital, Gansu Province, China
| | - Ying-Zhen Wang
- Intensive Care Unit, Lanzhou University Second Hospital, Gansu Province, China
| | - Ling-Ling Zhen
- Intensive Care Unit, Lanzhou University Second Hospital, Gansu Province, China
| | - Bei Zhang
- Intensive Care Unit, Lanzhou University Second Hospital, Gansu Province, China
| | - Hong An
- Intensive Care Unit, Lanzhou University Second Hospital, Gansu Province, China
| | - Hong-Bin Liu
- Department of General Surgery, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, China
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