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Zhu D, Zhang J, Huang X, Wei N, Jiang J, Li J, Liu L, Liu Y, Zhou J, Jia J. Integrated network pharmacology and experimental validation to elucidate the mechanism of celastrol in mitigating sepsis-induced acute lung injury in mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156678. [PMID: 40133025 DOI: 10.1016/j.phymed.2025.156678] [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: 09/23/2024] [Revised: 01/13/2025] [Accepted: 03/20/2025] [Indexed: 03/27/2025]
Abstract
BACKGROUND Sepsis is an acute, life-threatening condition that precipitates multiple organ failure, including acute lung injury (ALI), characterized by a complex pathophysiological process and elevated mortality rates. Celastrol, a pentacyclic triterpenoid quinone derived from traditional Chinese medicine, exhibits diverse pharmacological properties, including immunomodulatory, anti-inflammatory, anticancer, and antifibrotic effects, and has demonstrated favorable safety profiles in vivo. However, the precise mechanism by which CSL contributes to sepsis-induced ALI remains to be elucidated. PURPOSE The study aimed to explore the mechanisms by which celastrol mitigates sepsis-induced ALI using network pharmacology, followed by experimental validation of its regulatory effects on sepsis-induced ALI. METHODS Utilizing a network pharmacology analysis, the potential targets and pathways of celastrol were identified. To explore celastrol's therapeutic effects on ALI, a rat model of sepsis was induced via cecal ligation and puncture, followed by assessment through hematoxylin-eosin staining, Real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting. Further investigation involved evaluating celastrol's influence on LPS-stimulated A549 and Raw264.7 cells, employing RT-qPCR, Western blotting, and immunofluorescence techniques. RESULTS Network pharmacological analysis identified 10 core targets and 31 pathways relevant to sepsis-induced ALI, with STAT3, TLR4, HIF-1α, and NF-κB1 emerging as central targets. Animal experiments demonstrated that celastrol treatment significantly reduced lung tissue inflammation, as evidenced by immunohistochemistry, Western blot, and RT-qPCR results, in comparison to the cecal ligation and puncture group. Notably, the levels of IL-1β, TNF-α, HIF-1α, STAT3, and NF-κB1 proteins and mRNA in the celastrol treatment group were significantly reduced compared to those in the cecal ligation and puncture (CLP) group and the LPS-treated group. Additionally, Western blot and immunofluorescence analyses confirmed the activation of the NF-κB pathway in vitro. CONCLUSION This study indicates that celastrol significantly suppresses the expression of inflammatory factors in sepsis-induced ALI by inhibiting the NF-κB/HIF-1α pathway in both in vivo and in vitro models, highlighting its therapeutic potential for modulating inflammation. These findings provide valuable evidence for future clinical research and drug development.
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Affiliation(s)
- Danli Zhu
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Jinghan Zhang
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Xiaochun Huang
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Na Wei
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Jinxiu Jiang
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Jiayao Li
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Li Liu
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Yulin Liu
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Jun Zhou
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China.
| | - Jing Jia
- Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China; Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan Province, China.
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Marshall T, Dysert K, Young M, DuMont T. Pathophysiology of Sepsis. Crit Care Nurs Q 2025; 48:88-92. [PMID: 40009855 DOI: 10.1097/cnq.0000000000000552] [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: 02/28/2025]
Abstract
Sepsis is a condition of life-threatening organ dysfunction caused by a dysregulated host response to infection. It is the result of a series of exaggerated physiologic responses that lead to simultaneous hyper- and hypoinflammatory states. In the hyperinflammatory phase, there is an exuberant release of cytokines, commonly referred to as a cytokine storm. The immune-suppressive phase is characterized by counterregulatory attempts to achieve homeostasis that sometimes "overshoot", leaving the host in a state of immunosuppression, thus predisposing to recurrent nosocomial and secondary infections. The aging population with comorbidities faces higher risks of immune dysfunction and inflammation. Thus, the number of sepsis survivors that develop subsequent infections is predicted to rise substantially in the next few decades. Understanding sepsis-induced immune dysregulation may enhance surveillance and outcomes. This review is intended to describe the pathophysiology of sepsis and its effects on the immune system.
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Affiliation(s)
- Tanya Marshall
- Pulmonary Critical Care Division, Allegheny General Hospital, Pittsburgh, Pennsylvania
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Nguyet Nguyen TM, Park H, Do TT, Kwak JY, Lee CK, Lee SH, Park JI, Yoon SY, Kim H, Park J, Park JT. CE9A215 (inotodiol), a lanostane-type oxysterol, mitigates LPS-induced sepsis through multifaceted mechanisms. Eur J Pharmacol 2024; 980:176836. [PMID: 39032762 DOI: 10.1016/j.ejphar.2024.176836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 07/05/2024] [Accepted: 07/18/2024] [Indexed: 07/23/2024]
Abstract
Dysregulated host response against infection triggers sepsis that leads to multiple organ dysfunction due to uncontrolled inflammatory responses. Despite marked progress in understanding of sepsis, numerous clinical trials for treatment of sepsis have proven daunting and a new therapeutic approach is highly needed. CE9A215 (inotodiol), a fungal secondary metabolite, has been researched for its pharmacological activities and has shown potent anti-allergic effects. In this study, we evaluated the anti-inflammatory activities of CE9A215 upon lipopolysaccharide (LPS) stimulation in vivo and in vitro for the first time. CE9A215 decreased the production of interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), and IL-1β in a concentration-dependent manner in LPS-stimulated RAW264.7 cells. Intriguingly, in human mast cell line LUVA, CE9A215 significantly lowered IL-4 and IL-10, and this effect could be beneficial for the clearance of bacterial infection. In addition, administration of CE9A215 improved the survival rate of LPS-stimulated mice and inhibited the pro-inflammatory cytokines, IL-6, TNF-α, and IL-1β in blood. Moreover, CE9A215 enhanced the expression levels of plasma phospholipid transfer protein (PLTP), apolipoprotein E (ApoE), and ATP-binding cassette transporter (ABCA1) in LPS-stimulated RAW246.7 cells. Liver PLTP level increased significantly in the CE9A215-administered group compared with the control group, which implies that CE9A215 promotes LPS clearance and neutralization by reverse transport of LPS by increasing the expressions of PLTP, ApoE, and ABCA1. Our results highlight CE9A215's potential as a novel therapeutic option for the treatment of sepsis.
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Affiliation(s)
- Thi Minh Nguyet Nguyen
- CARBOEXPERT Inc, Daejeon, 34134, Republic of Korea; Vinmec-VinUni Institute of Immunology, Vinmec Healthcare System, Hanoi, 100000, Viet Nam.
| | - Hyunah Park
- CARBOEXPERT Inc, Daejeon, 34134, Republic of Korea.
| | | | - Ji-Yun Kwak
- Department of Food Science and Technology, Chungnam National University, Daejeon, 34134, Republic of Korea.
| | | | - Seung Hoon Lee
- Department of Biochemistry, Research Institute for Medical Science, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea.
| | - Jong-Il Park
- Department of Biochemistry, Research Institute for Medical Science, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea.
| | - Sun-Young Yoon
- Department of Allergy and Pulmonology in Internal Medicine, Chungnam National University, Chungnam National University Sejong Hospital, Sejong, 30099, Republic of Korea.
| | - Hyunjung Kim
- Department of Dermatology, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
| | - Jihyun Park
- CARBOEXPERT Inc, Daejeon, 34134, Republic of Korea.
| | - Jong-Tae Park
- CARBOEXPERT Inc, Daejeon, 34134, Republic of Korea; Department of Food Science and Technology, Chungnam National University, Daejeon, 34134, Republic of Korea.
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Mun SJ, Cho E, Kim HK, Gil WJ, Yang CS. Enhancing acute inflammatory and sepsis treatment: superiority of membrane receptor blockade. Front Immunol 2024; 15:1424768. [PMID: 39081318 PMCID: PMC11286478 DOI: 10.3389/fimmu.2024.1424768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 07/03/2024] [Indexed: 08/02/2024] Open
Abstract
Conditions such as acute pancreatitis, ulcerative colitis, delayed graft function and infections caused by a variety of microorganisms, including gram-positive and gram-negative organisms, increase the risk of sepsis and therefore mortality. Immune dysfunction is a characterization of sepsis, so timely and effective treatment strategies are needed. The conventional approaches, such as antibiotic-based treatments, face challenges such as antibiotic resistance, and cytokine-based treatments have shown limited efficacy. To address these limitations, a novel approach focusing on membrane receptors, the initiators of the inflammatory cascade, is proposed. Membrane receptors such as Toll-like receptors, interleukin-1 receptor, endothelial protein C receptor, μ-opioid receptor, triggering receptor expressed on myeloid cells 1, and G-protein coupled receptors play pivotal roles in the inflammatory response, offering opportunities for rapid regulation. Various membrane receptor blockade strategies have demonstrated efficacy in both preclinical and clinical studies. These membrane receptor blockades act as early stage inflammation modulators, providing faster responses compared to conventional therapies. Importantly, these blockers exhibit immunomodulatory capabilities without inducing complete immunosuppression. Finally, this review underscores the critical need for early intervention in acute inflammatory and infectious diseases, particularly those posing a risk of progressing to sepsis. And, exploring membrane receptor blockade as an adjunctive treatment for acute inflammatory and infectious diseases presents a promising avenue. These novel approaches, when combined with antibiotics, have the potential to enhance patient outcomes, particularly in conditions prone to sepsis, while minimizing risks associated with antibiotic resistance and immune suppression.
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Affiliation(s)
- Seok-Jun Mun
- Department of Bionano Engineering, Hanyang University, Seoul, Republic of Korea
- Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Republic of Korea
| | - Euni Cho
- Department of Bionano Engineering, Hanyang University, Seoul, Republic of Korea
- Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Republic of Korea
| | - Hyo Keun Kim
- Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Republic of Korea
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Woo Jin Gil
- Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Republic of Korea
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Chul-Su Yang
- Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Republic of Korea
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
- Department of Medicinal and Life Science, Hanyang University, Ansan, Republic of Korea
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Li D, Wei R, Zhang X, Gong S, Wan M, Wang F, Li J, Chen M, Liu R, Wan Y, Hong Y, Zeng Z, Gu P, Wang Z, Selva Nandakumar K, Jiang Y, Zhou H, Chen P. Gut commensal metabolite rhamnose promotes macrophages phagocytosis by activating SLC12A4 and protects against sepsis in mice. Acta Pharm Sin B 2024; 14:3068-3085. [PMID: 39027244 PMCID: PMC11252530 DOI: 10.1016/j.apsb.2024.03.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 01/14/2024] [Accepted: 02/23/2024] [Indexed: 07/20/2024] Open
Abstract
Sepsis progression is significantly associated with the disruption of gut eubiosis. However, the modulatory mechanisms of gut microbiota operating during sepsis are still unclear. Herein, we investigated how gut commensals impact sepsis development in a pre-clinical model. Cecal ligation and puncture (CLP) surgery was used to establish polymicrobial sepsis in mice. Mice depleted of gut microbiota by an antibiotic cocktail (ABX) exhibited a significantly higher level of mortality than controls. As determined by metabolomics analysis, ABX treatment has depleted many metabolites, and subsequent supplementation with l-rhamnose (rhamnose, Rha), a bacterial carbohydrate metabolite, exerted profound immunomodulatory properties with a significant enhancement in macrophage phagocytosis, which in turn improved organ damage and mortality. Mechanistically, rhamnose binds directly to and activates the solute carrier family 12 (potassium-chloride symporter), member 4 (SLC12A4) in macrophages and promotes phagocytosis by activating the small G-proteins, Ras-related C3 botulinum toxin substrate1 (Rac1) and cell division control protein 42 homolog (Cdc42). Interestingly, rhamnose has enhanced the phagocytosis capacity of macrophages from sepsis patients. In conclusion, by identifying SLC12A4 as the host interacting protein, we disclosed that the gut commensal metabolite rhamnose is a functional molecular that could promote the phagocytosis capacity of macrophages and protect the host against sepsis.
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Affiliation(s)
- Dongping Li
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
| | - Rongjuan Wei
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
| | - Xianglong Zhang
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
| | - Shenhai Gong
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
| | - Meijuan Wan
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
| | - Fangzhao Wang
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
| | - Jiaxin Li
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510000, China
| | - Meiling Chen
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
| | - Ruofan Liu
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
| | - Yantong Wan
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
| | - Yinghao Hong
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
| | - Zhenhua Zeng
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510000, China
| | - Peng Gu
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen 518000, China
| | - Zhang Wang
- Institute of Ecological Sciences, School of Life Sciences, South China Normal University, Guangzhou 510000, China
| | - Kutty Selva Nandakumar
- Department of Environmental and Biosciences, School of Business, Innovation and Sustainability, Kristian IV's väg 3, Halmstad University, Halmstad 30004, Sweden
| | - Yong Jiang
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
| | - Hongwei Zhou
- Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510000, China
| | - Peng Chen
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, China
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Berber NK, Kurt O, Altıntop Geçkil A, Erdem M, Kıran TR, Otlu Ö, Ecin SM, İn E. Evaluation of Oxidative Stress and Endothelial Dysfunction in COVID-19 Patients. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1041. [PMID: 39064471 PMCID: PMC11279166 DOI: 10.3390/medicina60071041] [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: 05/09/2024] [Revised: 06/01/2024] [Accepted: 06/05/2024] [Indexed: 07/28/2024]
Abstract
Background and Objectives: Heat shock proteins (HSPs) are stress proteins. The endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethyl arginine (ADMA) is a mediator of endothelial dysfunction. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes endothelial dysfunction and coagulopathy through severe inflammation and oxidative stress. Using these markers, we analyzed the prognostic value of serum ADMA and HSP-90 levels for early prediction of severe coronavirus disease (COVID-19) patients. Materials and Methods: A total of 76 COVID-19 patients and 35 healthy control subjects were included in this case-control study. COVID-19 patients were divided into two groups: mild and severe. Results: Serum ADMA and HSP-90 levels were significantly higher in the COVID-19 patients compared to the control subjects (p < 0.001). Additionally, serum ADMA and HSP-90 levels were determined to be higher in a statistically significant way in severe COVID-19 compared to mild COVID-19 (p < 0.001). Univariable logistic regression analysis revealed that ADMA and HSP-90, respectively, were independent predictors of severe disease in COVID-19 patients (ADMA (OR = 1.099, 95% CI = 1.048-1.152, p < 0.001) and HSP-90 (OR = 5.296, 95% CI = 1.719-16.316, p = 0.004)). When the cut-off value for ADMA was determined as 208.94 for the prediction of the severity of COVID-19 patients, the sensitivity was 72.9% and the specificity was 100% (AUC = 0.938, 95%CI = 0.858-0.981, p < 0.001). When the cut-off value for HSP-90 was determined as 12.68 for the prediction of the severity of COVID-19 patients, the sensitivity was 88.1% and the specificity was 100% (AUC = 0.975, 95% CI= 0.910-0.997, p < 0.001). Conclusions: Increased levels of Heat shock proteins-90 (HSP-90) and ADMA were positively correlated with increased endothelial damage in COVID-19 patients, suggesting that treatments focused on preventing and improving endothelial dysfunction could significantly improve the outcomes and reduce the mortality rate of COVID-19. ADMA and HSP-90 might be simple, useful, and prognostic biomarkers that can be utilized to predict patients who are at high risk of severe disease due to COVID-19.
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Affiliation(s)
- Nurcan Kırıcı Berber
- Department of Chest Diseases, Malatya Turgut Özal University, Malatya 44210, Turkey;
| | - Osman Kurt
- Department of Public Health, Faculty of Medicine, Inonu University, Malatya 44210, Turkey;
| | | | - Mehmet Erdem
- Department of Medical Biochemistry, Malatya Turgut Özal University, Malatya 44210, Turkey; (M.E.); (T.R.K.); (Ö.O.)
| | - Tuğba Raika Kıran
- Department of Medical Biochemistry, Malatya Turgut Özal University, Malatya 44210, Turkey; (M.E.); (T.R.K.); (Ö.O.)
| | - Önder Otlu
- Department of Medical Biochemistry, Malatya Turgut Özal University, Malatya 44210, Turkey; (M.E.); (T.R.K.); (Ö.O.)
| | - Seval Müzeyyen Ecin
- Department of Occupational Medicine and Internal Medicine Clinic, Mersin City Training and Research Hospital, Mersin 33240, Turkey;
| | - Erdal İn
- Department of Pulmonary Diseases, Faculty of Medicine, İzmir University of Economics, İzmir 35330, Turkey;
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Zhang N, Huang D, Li X, Yan J, Yan Q, Ge W, Zhou J. Identification and validation of oxidative stress-related genes in sepsis-induced myopathy. Medicine (Baltimore) 2024; 103:e37933. [PMID: 38701300 PMCID: PMC11062695 DOI: 10.1097/md.0000000000037933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 03/28/2024] [Indexed: 05/05/2024] Open
Abstract
BACKGROUND Sepsis-induced myopathy (SIM) a complication of sepsis that results in prolonged mechanical ventilation, long-term functional disability, and increased patient mortality. This study was performed to identify potential key oxidative stress-related genes (OS-genes) as biomarkers for the diagnosis of SIM using bioinformatics. METHODS The GSE13205 was obtained from the Gene Expression Omnibus (GEO) database, including 13 SIM samples and 8 healthy samples, and the differentially expressed genes (DEGs) were identified by limma package in R language. Simultaneously, we searched for the genes related to oxidative stress in the Gene Ontology (GO) database. The intersection of the genes selected from the GO database and the genes from the GSE13205 was considered as OS-genes of SIM, where the differential genes were regarded as OS-DEGs. OS-DEGs were analyzed using GO enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and protein-protein interaction (PPI) networks. Hub genes in OS-DEGs were selected based on degree, and diagnostic genes were further screened by gene expression and receiver operating characteristic (ROC) curve. Finally, a miRNA-gene network of diagnostic genes was constructed. RESULTS A total of 1089 DEGs were screened from the GSE13205, and 453 OS-genes were identified from the GO database. The overlapping DEGs and OS-genes constituted 25 OS-DEGs, including 15 significantly upregulated and 10 significantly downregulated genes. The top 10 hub genes, including CD36, GPX3, NQO1, GSR, TP53, IDH1, BCL2, HMOX1, JAK2, and FOXO1, were screened. Furthermore, 5 diagnostic genes were identified: CD36, GPX3, NQO1, GSR, and TP53. The ROC analysis showed that the respective area under the curves (AUCs) of CD36, GPX3, NQO1, GSR, and TP53 were 0.990, 0.981, 0.971, 0.971, and 0.971, which meant these genes had very high diagnostic values of SIM. Finally, based on these 5 diagnostic genes, we found that miR-124-3p and miR-16-5p may be potential targets for the treatment of SIM. CONCLUSIONS The results of this study suggest that OS-genes might play an important role in SIM. CD36, GPX3, NQO1, GSR, and TP53 have potential as specific biomarkers for the diagnosis of SIM.
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Affiliation(s)
- Ning Zhang
- Intensive Care Unit, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
| | - Dan Huang
- Department of Ophthalmology, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Xiang Li
- Intensive Care Unit, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
| | - JinXia Yan
- Intensive Care Unit, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
| | - Qi Yan
- Department of Ophthalmology, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - WeiXing Ge
- Intensive Care Unit, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
| | - Jun Zhou
- Intensive Care Unit, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
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Valibouze C, Dubuquoy C, Chavatte P, Genin M, Maquet V, Modica S, Desreumaux P, Rousseaux C. Chitin-glucan improves important pathophysiological features of irritable bowel syndrome. World J Gastroenterol 2024; 30:2258-2271. [PMID: 38690023 PMCID: PMC11056916 DOI: 10.3748/wjg.v30.i16.2258] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/21/2024] [Accepted: 03/28/2024] [Indexed: 04/26/2024] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is one of the most frequent and debilitating conditions leading to gastroenterological referrals. However, recommended treatments remain limited, yielding only limited therapeutic gains. Chitin-glucan (CG) is a novel dietary prebiotic classically used in humans at a dosage of 1.5-3.0 g/d and is considered a safe food ingredient by the European Food Safety Authority. To provide an alternative approach to managing patients with IBS, we performed preclinical molecular, cellular, and animal studies to evaluate the role of chitin-glucan in the main pathophysiological mechanisms involved in IBS. AIM To evaluate the roles of CG in visceral analgesia, intestinal inflammation, barrier function, and to develop computational molecular models. METHODS Visceral pain was recorded through colorectal distension (CRD) in a model of long-lasting colon hypersensitivity induced by an intra-rectal administration of TNBS [15 milligrams (mg)/kilogram (kg)] in 33 Sprague-Dawley rats. Intracolonic pressure was regularly assessed during the 9 wk-experiment (weeks 0, 3, 5, and 7) in animals receiving CG (n = 14) at a human equivalent dose (HED) of 1.5 g/d or 3.0 g/d and compared to negative control (tap water, n = 11) and positive control (phloroglucinol at 1.5 g/d HED, n = 8) groups. The anti-inflammatory effect of CG was evaluated using clinical and histological scores in 30 C57bl6 male mice with colitis induced by dextran sodium sulfate (DSS) administered in their drinking water during 14 d. HT-29 cells under basal conditions and after stimulation with lipopolysaccharide (LPS) were treated with CG to evaluate changes in pathways related to analgesia (µ-opioid receptor (MOR), cannabinoid receptor 2 (CB2), peroxisome proliferator-activated receptor alpha, inflammation [interleukin (IL)-10, IL-1b, and IL-8] and barrier function [mucin 2-5AC, claudin-2, zonula occludens (ZO)-1, ZO-2] using the real-time PCR method. Molecular modelling of CG, LPS, lipoteichoic acid (LTA), and phospholipomannan (PLM) was developed, and the ability of CG to chelate microbial pathogenic lipids was evaluated by docking and molecular dynamics simulations. Data were expressed as the mean ± SEM. RESULTS Daily CG orally-administered to rats or mice was well tolerated without including diarrhea, visceral hypersensitivity, or inflammation, as evaluated at histological and molecular levels. In a model of CRD, CG at a dosage of 3 g/d HED significantly decreased visceral pain perception by 14% after 2 wk of administration (P < 0.01) and reduced inflammation intensity by 50%, resulting in complete regeneration of the colonic mucosa in mice with DSS-induced colitis. To better reproduce the characteristics of visceral pain in patients with IBS, we then measured the therapeutic impact of CG in rats with TNBS-induced inflammation to long-lasting visceral hypersensitivity. CG at a dosage of 1.5 g/d HED decreased visceral pain perception by 20% five weeks after colitis induction (P < 0.01). When the CG dosage was increased to 3.0 g/d HED, this analgesic effect surpassed that of the spasmolytic agent phloroglucinol, manifesting more rapidly within 3 wk and leading to a 50% inhibition of pain perception (P < 0.0001). The underlying molecular mechanisms contributing to these analgesic and anti-inflammatory effects of CG involved, at least in part, a significant induction of MOR, CB2 receptor, and IL-10, as well as a significant decrease in pro-inflammatory cytokines IL-1b and IL-8. CG also significantly upregulated barrier-related genes including muc5AC, claudin-2, and ZO-2. Molecular modelling of CG revealed a new property of the molecule as a chelator of microbial pathogenic lipids, sequestering gram-negative LPS and gram-positive LTA bacterial toxins, as well as PLM in fungi at the lowesr energy conformations. CONCLUSION CG decreased visceral perception and intestinal inflammation through master gene regulation and direct binding of microbial products, suggesting that CG may constitute a new therapeutic strategy for patients with IBS or IBS-like symptoms.
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Affiliation(s)
- Caroline Valibouze
- Department of Digestive Surgery and Transplantation, Lille University, Lille 59037, France
| | - Caroline Dubuquoy
- Intestinal Biotech Development, Faculté de Médicine, Lille 59045, France
| | - Philippe Chavatte
- U1286-INFINITE-Institute for Translational Research in Inflammation, Université de Lille, Lille 59000, France
| | - Michaël Genin
- ULR 2694-METRICS, Évaluation des Technologies de santé et des Pratiques Médicales, University of Lille, Lille 59000, France
| | - Veronique Maquet
- KitoZyme SA, Institution Société Anonyme, Zone 2, Parc des Hauts Sarts, Rue de Milmort, Herstal 4040, Belgium
| | - Salvatore Modica
- KitoZyme SA, Institution Société Anonyme, Zone 2, Parc des Hauts Sarts, Rue de Milmort, Herstal 4040, Belgium
| | - Pierre Desreumaux
- Hepato-Gastroenterology Department, Lille University Hospital, Lille 59037, France
| | - Christel Rousseaux
- Intestinal Biotech Development, Faculté de Médicine, Lille 59045, France
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Fujii K, Yamakawa K, Takeda Y, Okuda N, Takasu A, Ono F. Understanding the pathophysiology of acute critical illness: translational lessons from zebrafish models. Intensive Care Med Exp 2024; 12:8. [PMID: 38291192 PMCID: PMC10828313 DOI: 10.1186/s40635-024-00595-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 01/10/2024] [Indexed: 02/01/2024] Open
Abstract
The models used to investigate the pathophysiological mechanisms of acute critical illness are not limited to mammalian species. The zebrafish (Danio rerio) is a popular model organism for studying diseases due to its transparency and rapid development. The genes and signaling pathways involved in acute critical illness appear highly conserved among zebrafish and humans. Forward genetics such as random mutagenesis by a chemical mutagen or reverse genetics methods represented by CRISPR/Cas9 allowed researchers to reveal multiple novel aspects of pathological processes in areas including infection, immunity, and regeneration. As a model of sepsis, transgenic zebrafish allowed the visualization of lipopolysaccharide (LPS)-induced vascular leakage in vivo and the demonstration of changes in the expression of cellular junction proteins. Other transgenic zebrafish visualizing the extravascular migration of neutrophils and macrophages have demonstrated a decrease in neutrophil numbers and an increased expression of an inflammatory gene, which replicates a phenomenon observed in humans in clinically encountered sepsis. The regenerative potential and the visibility of zebrafish organs also enabled clarification of important mechanisms in wound healing, angiogenesis, and neurogenesis. After spinal cord injury (SCI), a marker gene expressed in glial bridging was discovered. Furthermore, localized epithelial-to-mesenchymal transition (EMT) and molecular mechanisms leading to spinal cord repair were revealed. These translational studies using zebrafish show the potential of the model system for the treatment of acute critical illnesses such as sepsis, organ failure, and trauma.
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Affiliation(s)
- Kensuke Fujii
- Department of Emergency and Critical Care Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
| | - Kazuma Yamakawa
- Department of Emergency and Critical Care Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan.
| | - Yuriko Takeda
- Department of Emergency and Critical Care Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
| | - Natsuko Okuda
- Department of Physiology, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
| | - Akira Takasu
- Department of Emergency and Critical Care Medicine, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
| | - Fumihito Ono
- Department of Physiology, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka, 569-8686, Japan
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10
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Kundu A, Ghosh P, Bishayi B. Vitexin along with verapamil downregulates efflux pump P-glycoprotein in macrophages and potentiate M1 to M2 switching via TLR4-NF-κB-TNFR2 pathway in lipopolysaccharide treated mice. Immunobiology 2024; 229:152767. [PMID: 38103391 DOI: 10.1016/j.imbio.2023.152767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/22/2023] [Accepted: 11/29/2023] [Indexed: 12/19/2023]
Abstract
The lipopolysaccharide, a microbial toxin, is one of the major causative agents of sepsis. P-gp expression and its functions are altered during inflammation. LPS has been known to impair the functions of P-gp, an efflux transporter. But the effect of LPS on P-gp expression in murine peritoneal macrophages is poorly understood. Molecular docking studies reveal that vitexin is a potent substrate and verapamil a potent inhibitor of P-gp. In the present experimental study, the curative potential of vitexin as a fruit component and verapamil treated as a control inhibitor of P-gp was examined in a murine LPS sepsis model. The effects of vitexin and verapamil on P-gp expression in macrophages correlating with changes in macrophage polarization and associated functional responses during LPS induced sepsis were studied. Peritoneal macrophages of LPS (10 mg/kg body weight) challenged mice exhibited elevated levels of H2O2, superoxide, and NO in parallel with lower antioxidant activity. LPS treatment increased P-gp expression through increased TLR4/expression. However, LPS challenged mice treated with vitexin (5 mg/kg body weight) + verapamil (5 mg/kg body weight) showed higher anti-oxidant enzyme activity (SOD, CAT and GRx) resulting in reduced oxidative stress. This combination treatment also elevated TNFR2, concomitant with down-regulation of TLR4, NF-κB and P-gp expression in murine peritoneal macrophages, resulting in a switch from M1 to M2 polarisation of macrophages and reduced inflammatory responses. In conclusion, combined vitexin and verapamil treatment could be used as a promising therapy to regulate P-gp expression and protection against LPS mediated sepsis and inflammatory damages.
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Affiliation(s)
- Ayantika Kundu
- Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India
| | - Pratiti Ghosh
- Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India.
| | - Biswadev Bishayi
- Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India.
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11
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Durak C, Guney Sahin E, Can YY, Varol F. Retrospective evaluation of therapeutic plasma exchange treatment in a pediatric intensive care unit: Single-center experience. Artif Organs 2023; 47:1464-1471. [PMID: 37150936 DOI: 10.1111/aor.14559] [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: 01/18/2023] [Revised: 04/13/2023] [Accepted: 04/28/2023] [Indexed: 05/09/2023]
Abstract
BACKGROUND The aim of this study is to characterize the clinical indications, outcomes, and complications of therapeutic plasma exchange (TPE) in pediatric intensive care unit. METHODS A retrospective study was conducted on critically ill patients who received TPE. A dataset of 672 treatments administered to 102 patients was analyzed. RESULTS The most common indication for TPE was COVID-19-related clinical conditions, followed by sepsis (24.5%), neurological diseases (9.8%) and renal diseases (6.9%). None of our patients died due to TPE-related complications, and the most common complication during and after the TPE was hypotension (21.7%). CONCLUSION Although TPE is riskier to provide to critically ill children, our experience indicates that it can be performed relatively safely in critically ill children with appropriate treatment indications. In particular, indications, onset time, number of sessions and other procedures should be standardized for the pediatric age group.
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Affiliation(s)
- Cansu Durak
- Department of Pediatric Intensive Care, University of Health Science Sancaktepe Sehit Prof. Dr. IlhanVarank Training and Research Hospital, Istanbul, Turkey
| | - Ebru Guney Sahin
- Department of Pediatric Intensive Care, University of Health Science Sancaktepe Sehit Prof. Dr. IlhanVarank Training and Research Hospital, Istanbul, Turkey
| | - Yasar Yusuf Can
- Department of Pediatric Intensive Care, University of Health Science Sancaktepe Sehit Prof. Dr. IlhanVarank Training and Research Hospital, Istanbul, Turkey
| | - Fatih Varol
- Department of Pediatric Intensive Care, University of Health Science Sancaktepe Sehit Prof. Dr. IlhanVarank Training and Research Hospital, Istanbul, Turkey
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12
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Mallick S, K.N. A, Sivaprasadan S, S. S. Immunosuppression in Liver Transplant Recipients in the Setting of Sepsis. J Clin Exp Hepatol 2023; 13:682-690. [PMID: 37440935 PMCID: PMC10333943 DOI: 10.1016/j.jceh.2022.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
Management of immunosuppression (IS) in liver transplant recipients in the setting of sepsis is an open stage for debate. The age-long practice of reduction or complete cessation of IS during sepsis has been followed by most centres across the world, although, their exact strategies are highly heterogeneous. On the other hand, the emergence of striking new evidence suggesting that there is, in fact, decreased mortality with the continuation of IS in sepsis, has raised doubts about our previously conceived intuitive notion that IS portends increased risk in sepsis. The theory postulated is that IS agents, perhaps reverse the state of dysregulated immune response in sepsis to that of an iatrogenically modulated immune response, thus dimming the inflammatory cascade and preventing its deleterious effects. Of note, none of these studies reported exaggerated rejection-related complications. These contrasting outlooks have made it rather onerous to formulate an evidence-based recommendation for liver transplant recipients afflicted with sepsis. Inclusion of transplanted patients in randomised controlled trials of sepsis-related interventions seems to be the need of the hour.
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Affiliation(s)
- Shweta Mallick
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, India
| | - Anila K.N.
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, India
| | - Saraswathy Sivaprasadan
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, India
| | - Sudhindran S.
- Department of Gastrointestinal Surgery and Solid Organ Transplantation, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, India
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13
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Stupak A, Kwaśniewski W. Evaluating Current Molecular Techniques and Evidence in Assessing Microbiome in Placenta-Related Health and Disorders in Pregnancy. Biomolecules 2023; 13:911. [PMID: 37371491 PMCID: PMC10296270 DOI: 10.3390/biom13060911] [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: 03/24/2023] [Revised: 05/25/2023] [Accepted: 05/28/2023] [Indexed: 06/29/2023] Open
Abstract
The microbiome is of great interest due to its potential influence on the occurrence and treatment of some human illnesses. It may be regarded as disruptions to the delicate equilibrium that humans ordinarily maintain with their microorganisms or the microbiota in their environment. The focus of this review is on the methodologies and current understanding of the functional microbiome in pregnancy outcomes. We present how novel techniques bring new insights to the contemporary field of maternal-fetal medicine with a critical analysis. The maternal microbiome in late pregnancy has been extensively studied, although data on maternal microbial changes during the first trimester are rare. Research has demonstrated that, in healthy pregnancies, the origin of the placental microbiota is oral (gut) rather than vaginal. Implantation, placental development, and maternal adaptation to pregnancy are complex processes in which fetal and maternal cells interact. Microbiome dysbiosis or microbial metabolites are rising as potential moderators of antenatal illnesses related to the placenta, such as fetal growth restriction, preeclampsia, and others, including gestational diabetes and preterm deliveries. However, because of the presence of antimicrobial components, it is likely that the bacteria identified in placental tissue are (fragments of) bacteria that have been destroyed by the placenta's immune cells. Using genomic techniques (metagenomics, metatranscriptomics, and metaproteomics), it may be possible to predict some properties of a microorganism's genome and the biochemical (epigenetic DNA modification) and physical components of the placenta as its environment. Despite the results described in this review, this subject needs further research on some major and crucial aspects. The phases of an in utero translocation of the maternal gut microbiota to the fetus should be explored. With a predictive knowledge of the impacts of the disturbance on microbial communities that influence human health and the environment, genomics may hold the answer to the development of novel therapies for the health of pregnant women.
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Affiliation(s)
- Aleksandra Stupak
- Department of Obstetrics and Pathology of Pregnancy, Medical University of Lublin, Staszica Str. 16, 20-081 Lublin, Poland
| | - Wojciech Kwaśniewski
- Department of Gynecological Oncology and Gynecology, Medical University of Lublin, 20-081 Lublin, Poland
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14
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Vajdi M, Karimi A, Karimi M, Abbasalizad Farhangi M, Askari G. Effects of luteolin on sepsis: A comprehensive systematic review. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 113:154734. [PMID: 36898254 DOI: 10.1016/j.phymed.2023.154734] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 02/16/2023] [Accepted: 02/22/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND Sepsis and septic shock are the main causes of mortality and complications in intensive care units all over the world. Luteolin is thought to have a significant role as a free radical scavenger, an anti-inflammatory agent, and an immune system modulator. The object of this review is to conduct a systematic review of the effects of luteolin and its mechanisms of action in the treatment of sepsis and its complications. METHOD The investigation was carried out in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines (PROSPERO: CRD42022321023). We searched Embase, Web of Science, Google Scholar, Science Direct, PubMed, ProQuest, and Scopus databases up to January 2023 by using the relevant keywords. RESULTS Out of 1,395 records screened, 33 articles met the study criteria. In the collected papers, the main reported findings are that luteolin can affect inflammation-initiating pathways such as toll-like receptors and high mobility group box-1 and reduces the expression of genes that produce inflammatory cytokines, such as the Nod receptor protein-3, and nuclear factor kappa-light chain-enhancer of activated B cells. Luteolin also reduces the overactivity of macrophages, neutrophil extracellular traps and lymphocytes by regulating the immune response. CONCLUSION Most studies revealed luteolin's positive benefits on sepsis through several pathways. Luteolin showed the capacity to reduce inflammation and oxidative stress, control immunological response, and prevent organ damage (in vivo studies) during sepsis. Large-scale in vivo experiments are necessary to elucidate its potential impacts on sepsis.
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Affiliation(s)
- Mahdi Vajdi
- Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Arash Karimi
- Nutrition Research Center, Department of Clinical Nutrition, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Mozhdeh Karimi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mahdieh Abbasalizad Farhangi
- Department of Community Nutrition, School of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gholamreza Askari
- Department of Community Nutrition, School of Nutrition and Food Science, Nutrition and Food Security Research Center, Isfahan University of Medical Science, Isfahan, Iran.
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Sorrells MG, Seo Y, Magnen M, Broussard B, Sheybani R, Shah AM, O’Neal HR, Tse HTK, Looney MR, Di Carlo D. Biophysical Changes of Leukocyte Activation (and NETosis) in the Cellular Host Response to Sepsis. Diagnostics (Basel) 2023; 13:1435. [PMID: 37189536 PMCID: PMC10138275 DOI: 10.3390/diagnostics13081435] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/03/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
Sepsis, the leading cause of mortality in hospitals, currently lacks effective early diagnostics. A new cellular host response test, the IntelliSep test, may provide an indicator of the immune dysregulation characterizing sepsis. The objective of this study was to examine the correlation between the measurements performed using this test and biological markers and processes associated with sepsis. Phorbol myristate acetate (PMA), an agonist of neutrophils known to induce neutrophil extracellular trap (NET) formation, was added to whole blood of healthy volunteers at concentrations of 0, 200, and 400 nM and then evaluated using the IntelliSep test. Separately, plasma from a cohort of subjects was segregated into Control and Diseased populations and tested for levels of NET components (citrullinated histone (cit-H3) DNA and neutrophil elastase (NE) DNA) using customized ELISA assays and correlated with ISI scores from the same patient samples. Significant increases in IntelliSep Index (ISI) scores were observed with increasing concentrations of PMA in healthy blood (0 and 200: p < 10-10; 0 and 400: p < 10-10). Linear correlation was observed between the ISI and quantities of NE DNA and Cit-H3 DNA in patient samples. Together these experiments demonstrate that the IntelliSep test is associated with the biological processes of leukocyte activation and NETosis and may indicate changes consistent with sepsis.
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Affiliation(s)
| | - Yurim Seo
- Departments of Medicine and Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA
| | - Melia Magnen
- Departments of Medicine and Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA
| | - Bliss Broussard
- Department of Biological Sciences, Nicholls State University, Thibodaux, LA 70310, USA
| | | | | | - Hollis R. O’Neal
- LSU Health Sciences Center/Our Lady of the Lake Regional Medical Center, Baton Rouge, LA 70808, USA
| | | | - Mark R. Looney
- Departments of Medicine and Laboratory Medicine, University of California San Francisco, San Francisco, CA 94143, USA
| | - Dino Di Carlo
- Departments of Bioengineering and Mechanical and Aerospace Engineering, University of California Los Angeles, Los Angeles, CA 90095, USA
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Çevlik T, Kaya Ö, Gül F, Turkal R, İnanç N, Direskeneli H, İlki A, Şirikçi Ö, Haklar G, Cinel İ. Evaluation of the Diagnostic Value of Cell Population Data in Sepsis in Comparison to Localized Infection, Chronic Inflammation, and Noninfectious Inflammation Cases. J Intensive Care Med 2023; 38:382-390. [PMID: 36147030 DOI: 10.1177/08850666221127185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Sepsis, defined as an increase of 2 points or more in the sequential organ failure assessment score, is a life-threatening organ dysfunction caused by the dysregulated host response to infection. Volume-conductivity-scatter (VCS) parameters of cell counters which are known as cell population data (CPD) have been suggested to be beneficial in diagnosing sepsis. We aimed to evaluate the diagnostic value of CPD parameters in sepsis in comparison to nonsystemic infection cases (NSI) and non-infectious acute and chronic inflammatory conditions. MATERIALS AND METHODS We prospectively included four groups of patients" data: sepsis (n = 66), localized infection (pneumonia, n = 59), chronic inflammation (rheumatoid arthritis, n = 92) and noninfectious inflammation (coronary artery bypass graft operation, n = 56) groups, according to their clinical status and laboratory results. Samples for cell counting and serum markers were collected on the same day of culture collection. VCS parameters were measured by Unicel DxH800 Coulter Cellular Analyzer (Beckman Coulter, USA). RESULTS Mean neutrophil volume (MN-V-NE), was highest in the sepsis group [155(149-168)] compared to the localized infection [148(140-158)], chronic inflammation [144.5(142-149)] and noninfectious inflammation [149(145.2-153.7)] (P = 0.001, P < 0.001, P < 0.001, respectively). Neutrophil volume SD (SD-V-NE) was higher in the sepsis [21(18.8-23.7)], significantly differentiating sepsis from other groups. The area under curves of procalcitonin and hs-C-reactive protein were 0.846 and 0.837, respectively, in the receiver-operating characteristic curves (ROC) . CPD combinations, (SD-V NE + SD-V LY + SD-V MO), (SD-V NE + SD-V MO), and (MN-V NE + SD-V NE + SD-C LY + SD-V MO) had greater AUC values than procalcitonin's. CONCLUSION VCS parameters might be promising for differentiating sepsis and non-sepsis cases. Additionally, obtaining these data routinely makes their prospects promising without any additional cost and time.
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Affiliation(s)
- Tülay Çevlik
- Biochemistry Laboratory, Marmara University Pendik E&R Hospital, Istanbul, Turkey
| | - Özlem Kaya
- Division of Critical Care Medicine, Dept. of Anesthesiology and Reanimation, School of Medicine, Marmara University, Istanbul, Turkey
| | - Fethi Gül
- Division of Critical Care Medicine, Dept. of Anesthesiology and Reanimation, School of Medicine, Marmara University, Istanbul, Turkey
| | - Rana Turkal
- Biochemistry Laboratory, Marmara University Pendik E&R Hospital, Istanbul, Turkey
| | - Nevsun İnanç
- Division of Rheumatology, Dept. of Internal Medicine, School of Medicine, Marmara University, Istanbul, Turkey
| | - Haner Direskeneli
- Division of Rheumatology, Dept. of Internal Medicine, School of Medicine, Marmara University, Istanbul, Turkey
| | - Arzu İlki
- Dept. of Microbiology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Önder Şirikçi
- Biochemistry Laboratory, Marmara University Pendik E&R Hospital, Istanbul, Turkey.,Dept. of Biochemistry, School of Medicine, Marmara University, Istanbul, Turkey
| | - Goncagül Haklar
- Biochemistry Laboratory, Marmara University Pendik E&R Hospital, Istanbul, Turkey.,Dept. of Biochemistry, School of Medicine, Marmara University, Istanbul, Turkey
| | - İsmail Cinel
- Division of Critical Care Medicine, Dept. of Anesthesiology and Reanimation, School of Medicine, Marmara University, Istanbul, Turkey
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Zhang J, Chen L, Yang Y, Liu X, Yuan Y, Song SR, Zhao Y, Mao J. Clinical and laboratory findings to differentiate late-onset sepsis caused by Gram-negative vs Gram-positive bacteria among perterm neonates: A retrospective cohort study. Int Immunopharmacol 2023; 116:109769. [PMID: 36716519 DOI: 10.1016/j.intimp.2023.109769] [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: 11/20/2022] [Revised: 01/16/2023] [Accepted: 01/20/2023] [Indexed: 01/29/2023]
Abstract
PURPOSE Late-onset sepsis (LOS) is a clinical condition that results in serious morbidity and mortality in preterm neonates. The aim of this study was to identify differences in clinical and laboratory findings of LOS caused by Gram-negative vs Gram-positive bacteria among perterm neonates and to evaluate the diagnostic accuracy of biomarkers. METHODS The retrospective cohort study included 649 preterm neonates with LOS assigned to either the Gram-positive group (n = 194, 29.89 %) or the Gram-negative group (n = 455, 70.11 %). Demographic data, serum levels of C-reactive protein (CRP), and complete blood counts at 0-24 h (T1), 24-48 h (T2), and 48-72 h (T3) were retrieved and compared. RESULTS At T1, T2, and T3, serum CRP levels were higher (p < 0.001), while platelet (PTL) counts were significantly lower (p < 0.001) in the Gram-negative group vs Gram-positive group. The area under the curve (AUC) of the PLT count was 0.688 (95 % confidence interval [CI] = 0.644-0.731) at T1, 0.795 (95 % CI = 0.743-0.848) at T2, and 0.785 (95 % CI = 0.739-0.831) at T3, indicating good discriminatory power, while the AUC of serum CRP was 0.654 (95 % CI = 0.61-0.697) at T1, 0.831 (95 % CI = 0.781-0.888) at T2, and 0.94 (95 % CI = 0.744-0.843) at T3. CONCLUSIONS Neonatal LOS caused by Gram-negative bacteria was associated with higher CRP and lower PLT levels. These results suggested that PLT and CRP values may be useful biomarkers to differentiate sepsis caused by Gram-negative vs Gram-positive bacteria among perterm neonates.
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Affiliation(s)
- Jing Zhang
- Department of Neonatology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China
| | - Ling Chen
- Department of Neonatology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China
| | - Yang Yang
- Department of Neonatology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China
| | - Xiao Liu
- Department of Neonatology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China
| | - Yuan Yuan
- Department of Neonatology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China
| | - Shi-Rong Song
- Department of Neonatology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China
| | - Yue Zhao
- Department of Neonatology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China
| | - Jian Mao
- Department of Neonatology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning 110004, China.
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18
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Banaszak M, Górna I, Woźniak D, Przysławski J, Drzymała-Czyż S. Association between Gut Dysbiosis and the Occurrence of SIBO, LIBO, SIFO and IMO. Microorganisms 2023; 11:573. [PMID: 36985147 PMCID: PMC10052891 DOI: 10.3390/microorganisms11030573] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/21/2023] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Abstract
Gut microbiota is the aggregate of all microorganisms in the human digestive system. There are 1014 CFU/mL of such microorganisms in the human body, including bacteria, viruses, fungi, archaea and protozoa. The Firmicutes and Bacteroidetes bacteria phyla comprise 90% of the human gut microbiota. The microbiota support the healthy functioning of the human body by helping with digestion (mainly via short-chain fatty acids and amino acids) and producing short-chain fatty acids. In addition, it exhibits many physiological functions, such as forming the intestinal epithelium, intestinal integrity maintenance, the production of vitamins, and protection against pathogens. An altered composition or the number of microorganisms, known as dysbiosis, disrupts the body's homeostasis and can lead to the development of inflammatory bowel disease, irritable bowel syndrome, and metabolic diseases such as diabetes, obesity and allergies. Several types of disruptions to the gut microbiota have been identified: SIBO (Small Intestinal Bacterial Overgrowth), LIBO (Large Intestinal Bacterial Overgrowth), SIFO (Small Intestinal Fungal Overgrowth), and IMO (Intestinal Methanogen Overgrowth). General gastrointestinal problems such as abdominal pain, bloating, gas, diarrhoea and constipation are the main symptoms of dysbiosis. They lead to malabsorption, nutrient deficiencies, anaemia and hypoproteinaemia. Increased lipopolysaccharide (LPS) permeability, stimulating the inflammatory response and resulting in chronic inflammation, has been identified as the leading cause of microbial overgrowth in the gut. The subject literature is extensive but of limited quality. Despite the recent interest in the gut microbiome and its disorders, more clinical research is needed to determine the pathophysiology, effective treatments, and prevention of small and large intestinal microbiota overgrowth. This review was designed to provide an overview of the available literature on intestinal microbial dysbiosis (SIBO, LIBO, SIFO and IMO) and to determine whether it represents a real threat to human health.
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Affiliation(s)
- Michalina Banaszak
- Department of Bromatology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
- Poznan University of Medical Sciences Doctoral School, Poznan University of Medical Sciences, Bukowska 70, 60-812 Poznan, Poland
| | - Ilona Górna
- Department of Bromatology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
| | - Dagmara Woźniak
- Department of Bromatology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
- Poznan University of Medical Sciences Doctoral School, Poznan University of Medical Sciences, Bukowska 70, 60-812 Poznan, Poland
| | - Juliusz Przysławski
- Department of Bromatology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
| | - Sławomira Drzymała-Czyż
- Department of Bromatology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
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19
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Gül F, Gonen ZB, Jones OY, Taşlı NP, Zararsız G, Ünal E, Özdarendeli A, Şahin F, Eken A, Yılmaz S, Karakukçu M, Kırbaş OK, Gökdemir NS, Bozkurt BT, Özkul Y, Oktay BD, Uygut MA, Cinel I, Çetin M. A pilot study for treatment of severe COVID-19 pneumonia by aerosolized formulation of convalescent human immune plasma exosomes (ChipEXO™). Front Immunol 2022; 13:963309. [PMID: 36439138 PMCID: PMC9682905 DOI: 10.3389/fimmu.2022.963309] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 09/20/2022] [Indexed: 07/22/2023] Open
Abstract
This is a single-center prospective, open-label, single arm interventional study to test the safety and efficacy of recently described ChipEXO™ for severe COVID-19 pneumonia. The ChipEXO™ is a natural product derived from convalescent human immune plasma of patients recovered from moderate COVID-19 infection. In September 2021, 13 patients with pending respiratory failure were treated with ChipEXO™ adapted for aerosolized formulation delivered via jet nebulizer. Patients received 1-5x1010 nano vesicle/5 mL in distilled water twice daily for five days as an add-on to ongoing conventional COVID-19 treatment. The primary endpoint was patient safety and survival over a 28-day follow-up. The secondary endpoint was longitudinal assessment of clinical parameters following ChipEXO™ to evaluate treatment response and gain insights into the pharmacodynamics. ChipEXO™ was tolerated well without any allergic reaction or acute toxicity. The survival rate was 84.6% and 11 out of 13 recovered without any sequel to lungs or other organs. ChipEXO™ treatment was effective immediately as shown in arterial blood gas analyses before and two hours after exosome inhalation. During the 5 days of treatment, there was a sustainable and gradual improvement on oxygenation parameters: i.e. respiratory rate (RR) [20.8% (P < 0.05)], oxygen saturation (SpO2) [6,7% (P < 0.05)] and partial pressure of oxygen to the fraction of inspired oxygen (PaO2/FiO2) [127.9% (P < 0.05)] that correlated with steep decrease in the disease activity scores and inflammatory markers, i.e. the sequential organ failure assessment (SOFA) score (75%, p < 0.05), C-reactive protein (46% p < 0.05), ferritin (58% p = 0.53), D-dimer (28% p=0.46). In conclusion, aerosolized ChipEXO™ showed promising safety and efficacy for life-threatening COVID-19 pneumonia. Further studies on larger patient populations are required to confirm our findings and understand the pathophysiology of improvement toward a new therapeutic agent for the treatment of severe COVID-19 pneumonia.
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Affiliation(s)
- Fethi Gül
- Department of Anesthesiology and Reanimation, Division of Critical Care Medicine, School of Medicine, Marmara University, Istanbul, Türkiye
| | | | - Olcay Y. Jones
- Division of Rheumatology, Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, United States
| | - Neslihan Pakize Taşlı
- Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, İstanbul, Türkiye
| | - Gökmen Zararsız
- Department of Biostatistics, Faculty of Medicine, Erciyes University, Kayseri, Türkiye
| | - Ekrem Ünal
- Department of Pediatrics, Division of Pediatric Hematology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye
| | - Aykut Özdarendeli
- Faculty of Medicine, Vaccine Research and Development Application and Research Center, Erciyes University, Kayseri, Türkiye
| | - Fikrettin Şahin
- Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, İstanbul, Türkiye
| | - Ahmet Eken
- Department of Biology, Faculty of Science, Erciyes University, Kayseri, Türkiye
| | - Semih Yılmaz
- Institute of Health Sciences, Department of Medical Biochemistry, Erciyes University, Kayseri, Türkiye
| | - Musa Karakukçu
- Department of Pediatrics, Division of Pediatric Hematology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye
| | - Oğuz Kaan Kırbaş
- Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, İstanbul, Türkiye
| | - Nur Seda Gökdemir
- Betül-Ziya Eren Genome and Stem Cell Center (GENKOK), Kayseri, Türkiye
| | - Batuhan Turhan Bozkurt
- Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, İstanbul, Türkiye
| | - Yusuf Özkul
- Faculty of Medicine, Erciyes University, Kayseri, Türkiye
| | - Burçin Doruk Oktay
- Department of Anesthesiology and Reanimation, Division of Critical Care Medicine, School of Medicine, Marmara University, İstanbul, Türkiye
| | - Muhammet Ali Uygut
- Vaccine Research and Development Application and Research Center, Erciyes University, Kayseri, Türkiye
| | - Ismail Cinel
- Department of Anesthesiology and Reanimation, Division of Critical Care Medicine, School of Medicine, Marmara University, İstanbul, Türkiye
| | - Mustafa Çetin
- Faculty of Medicine, Erciyes University, Kayseri, Türkiye
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20
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Gül F, Gonen ZB, Jones OY, Taşlı NP, Zararsız G, Ünal E, Özdarendeli A, Şahin F, Eken A, Yılmaz S, Karakukçu M, Kırbaş OK, Gökdemir NS, Bozkurt BT, Özkul Y, Oktay BD, Uygut MA, Cinel I, Çetin M. A pilot study for treatment of severe COVID-19 pneumonia by aerosolized formulation of convalescent human immune plasma exosomes (ChipEXO™). Front Immunol 2022. [DOI: https://doi.org/10.3389/fimmu.2022.963309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
This is a single-center prospective, open-label, single arm interventional study to test the safety and efficacy of recently described ChipEXO™ for severe COVID-19 pneumonia. The ChipEXO™ is a natural product derived from convalescent human immune plasma of patients recovered from moderate COVID-19 infection. In September 2021, 13 patients with pending respiratory failure were treated with ChipEXO™ adapted for aerosolized formulation delivered via jet nebulizer. Patients received 1-5x1010 nano vesicle/5 mL in distilled water twice daily for five days as an add-on to ongoing conventional COVID-19 treatment. The primary endpoint was patient safety and survival over a 28-day follow-up. The secondary endpoint was longitudinal assessment of clinical parameters following ChipEXO™ to evaluate treatment response and gain insights into the pharmacodynamics. ChipEXO™ was tolerated well without any allergic reaction or acute toxicity. The survival rate was 84.6% and 11 out of 13 recovered without any sequel to lungs or other organs. ChipEXO™ treatment was effective immediately as shown in arterial blood gas analyses before and two hours after exosome inhalation. During the 5 days of treatment, there was a sustainable and gradual improvement on oxygenation parameters: i.e. respiratory rate (RR) [20.8% (P < 0.05)], oxygen saturation (SpO2) [6,7% (P < 0.05)] and partial pressure of oxygen to the fraction of inspired oxygen (PaO2/FiO2) [127.9% (P < 0.05)] that correlated with steep decrease in the disease activity scores and inflammatory markers, i.e. the sequential organ failure assessment (SOFA) score (75%, p < 0.05), C-reactive protein (46% p < 0.05), ferritin (58% p = 0.53), D-dimer (28% p=0.46). In conclusion, aerosolized ChipEXO™ showed promising safety and efficacy for life-threatening COVID-19 pneumonia. Further studies on larger patient populations are required to confirm our findings and understand the pathophysiology of improvement toward a new therapeutic agent for the treatment of severe COVID-19 pneumonia.
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21
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Gül F, Gonen ZB, Jones OY, Taşlı NP, Zararsız G, Ünal E, Özdarendeli A, Şahin F, Eken A, Yılmaz S, Karakukçu M, Kırbaş OK, Gökdemir NS, Bozkurt BT, Özkul Y, Oktay BD, Uygut MA, Cinel I, Çetin M. A pilot study for treatment of severe COVID-19 pneumonia by aerosolized formulation of convalescent human immune plasma exosomes (ChipEXO™). Front Immunol 2022. [DOI: https:/doi.org/10.3389/fimmu.2022.963309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
This is a single-center prospective, open-label, single arm interventional study to test the safety and efficacy of recently described ChipEXO™ for severe COVID-19 pneumonia. The ChipEXO™ is a natural product derived from convalescent human immune plasma of patients recovered from moderate COVID-19 infection. In September 2021, 13 patients with pending respiratory failure were treated with ChipEXO™ adapted for aerosolized formulation delivered via jet nebulizer. Patients received 1-5x1010 nano vesicle/5 mL in distilled water twice daily for five days as an add-on to ongoing conventional COVID-19 treatment. The primary endpoint was patient safety and survival over a 28-day follow-up. The secondary endpoint was longitudinal assessment of clinical parameters following ChipEXO™ to evaluate treatment response and gain insights into the pharmacodynamics. ChipEXO™ was tolerated well without any allergic reaction or acute toxicity. The survival rate was 84.6% and 11 out of 13 recovered without any sequel to lungs or other organs. ChipEXO™ treatment was effective immediately as shown in arterial blood gas analyses before and two hours after exosome inhalation. During the 5 days of treatment, there was a sustainable and gradual improvement on oxygenation parameters: i.e. respiratory rate (RR) [20.8% (P < 0.05)], oxygen saturation (SpO2) [6,7% (P < 0.05)] and partial pressure of oxygen to the fraction of inspired oxygen (PaO2/FiO2) [127.9% (P < 0.05)] that correlated with steep decrease in the disease activity scores and inflammatory markers, i.e. the sequential organ failure assessment (SOFA) score (75%, p < 0.05), C-reactive protein (46% p < 0.05), ferritin (58% p = 0.53), D-dimer (28% p=0.46). In conclusion, aerosolized ChipEXO™ showed promising safety and efficacy for life-threatening COVID-19 pneumonia. Further studies on larger patient populations are required to confirm our findings and understand the pathophysiology of improvement toward a new therapeutic agent for the treatment of severe COVID-19 pneumonia.
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22
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Iba T, Levi M, Thachil J, Levy JH. Disseminated Intravascular Coagulation: The Past, Present, and Future Considerations. Semin Thromb Hemost 2022; 48:978-987. [PMID: 36100234 DOI: 10.1055/s-0042-1756300] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Disseminated intravascular coagulation (DIC) has been understood as a consumptive coagulopathy. However, impaired hemostasis is a component of DIC that occurs in a progressive manner. The critical concept of DIC is systemic activation of coagulation with vascular endothelial damage. DIC is the dynamic coagulation/fibrinolysis disorder that can proceed from compensated to decompensated phases, and is not simply impaired hemostasis, a misunderstanding that continues to evoke confusion among clinicians. DIC is a critical step of disease progression that is important to monitor over time. Impaired microcirculation and subsequent organ failure due to pathologic microthrombi formation are the pathophysiologies in sepsis-associated DIC. Impaired hemostasis due to coagulation factor depletion from hemodilution, shock, and hyperfibrinolysis occurs in trauma-associated DIC. Overt-DIC diagnostic criteria have been used clinically for more than 20 years but may not be adequate to detect the compensated phase of DIC, and due to different underlying causes, there is no "one-size-fits-all criteria." Individualized criteria for heterogeneous conditions continue to be proposed to facilitate the diagnosis. We believe that future research will provide therapeutics using new diagnostic criteria. Finally, DIC is also classified as either acute or chronic, and acute DIC results from progressive coagulation activation over a short time and requires urgent management. In this review, we examine the advances in research for DIC.
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Affiliation(s)
- Toshiaki Iba
- Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Marcel Levi
- Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands.,Department of Medicine, Cardiometabolic Programme-NIHR UCLH/UCL BRC, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Jecko Thachil
- Department of Haematology, Manchester Royal Infirmary, Manchester, United Kingdom
| | - Jerrold H Levy
- Department of Anesthesiology, Critical Care, and Surgery, Duke University School of Medicine, Durham, North Carolina
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23
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Li Z, He P, Xu Y, Deng Y, Gao Y, Chen SL. In vivo evaluation of a lipopolysaccharide-induced ear vascular leakage model in mice using photoacoustic microscopy. BIOMEDICAL OPTICS EXPRESS 2022; 13:4802-4816. [PMID: 36187238 PMCID: PMC9484413 DOI: 10.1364/boe.471079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/05/2022] [Accepted: 08/05/2022] [Indexed: 06/16/2023]
Abstract
Sepsis is caused by dysregulated host inflammatory response to infection. During sepsis, early identification and monitoring of vascular leakage are pivotal for improved diagnosis, treatment, and prognosis. However, there is a lack of research on noninvasive observation of inflammation-related vascular leakage. Here, we investigate the use of photoacoustic microscopy (PAM) for in vivo visualization of lipopolysaccharide (LPS)-induced ear vascular leakage in mice using Evans blue (EB) as an indicator. A model combining needle pricking on the mouse ear, topical smearing of LPS on the mouse ear, and intravenous tail injection of EB is developed. Topical application of LPS is expected to induce local vascular leakage in skin. Inflammatory response is first validated by ex vivo histology and enzyme-linked immunosorbent assay. Then, local ear vascular leakage is confirmed by ex vivo measurement of swelling, thickening, and EB leakage. Finally, PAM for in vivo identification and evaluation of early vascular leakage using the model is demonstrated. For PAM, common excitation wavelength of 532 nm is used, and an algorithm is developed to extract quantitative metrics for EB leakage. The results show potential of PAM for noninvasive longitudinal monitoring of peripheral skin vascular leakage, which holds promise for clinical sepsis diagnosis and management.
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Affiliation(s)
- Zhe Li
- Department of Critical Care Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
- These authors contributed equally to this work
| | - Pengbo He
- University of Michigan-Shanghai Jiao Tong University Joint Institute, Shanghai Jiao Tong University, Shanghai 200240, China
- These authors contributed equally to this work
| | - Yuqing Xu
- Department of Critical Care Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yuxiao Deng
- Department of Critical Care Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yuan Gao
- Department of Critical Care Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Sung-Liang Chen
- University of Michigan-Shanghai Jiao Tong University Joint Institute, Shanghai Jiao Tong University, Shanghai 200240, China
- Engineering Research Center of Digital Medicine and Clinical Translation, Ministry of Education, Shanghai 200030, China
- State Key Laboratory of Advanced Optical Communication Systems and Networks, Shanghai Jiao Tong University, Shanghai 200240, China
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24
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Horseman M, Panahi L, Udeani G, Tenpas AS, Verduzco Jr. R, Patel PH, Bazan DZ, Mora A, Samuel N, Mingle AC, Leon LR, Varon J, Surani S. Drug-Induced Hyperthermia Review. Cureus 2022; 14:e27278. [PMID: 36039261 PMCID: PMC9403255 DOI: 10.7759/cureus.27278] [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] [Accepted: 07/22/2022] [Indexed: 11/26/2022] Open
Abstract
Humans maintain core body temperature via a complicated system of physiologic mechanisms that counteract heat/cold fluctuations from metabolism, exertion, and the environment. Overextension of these mechanisms or disruption of body temperature homeostasis leads to bodily dysfunction, culminating in a syndrome analogous to exertional heat stroke (EHS). The inability of this thermoregulatory process to maintain the body temperature is caused by either thermal stress or certain drugs. EHS is a syndrome characterized by hyperthermia and the activation of systemic inflammation. Several drug-induced hyperthermic syndromes may resemble EHS and share common mechanisms. The purpose of this article is to review the current literature and compare exertional heat stroke (EHS) to three of the most widely studied drug-induced hyperthermic syndromes: malignant hyperthermia (MH), neuroleptic malignant syndrome (NMS), and serotonin syndrome (SS). Drugs and drug classes that have been implicated in these conditions include amphetamines, diuretics, cocaine, antipsychotics, metoclopramide, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and many more. Observations suggest that severe or fulminant cases of drug-induced hyperthermia may evolve into an inflammatory syndrome best described as heat stroke. Their underlying mechanisms, symptoms, and treatment approaches will be reviewed to assist in accurate diagnosis, which will impact the management of potentially life-threatening complications.
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25
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The role of nitric oxide in sepsis-associated kidney injury. Biosci Rep 2022; 42:231441. [PMID: 35722824 PMCID: PMC9274646 DOI: 10.1042/bsr20220093] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/07/2022] [Accepted: 06/17/2022] [Indexed: 01/09/2023] Open
Abstract
Sepsis is one of the leading causes of acute kidney injury (AKI), and several mechanisms including microcirculatory alterations, oxidative stress, and endothelial cell dysfunction are involved. Nitric oxide (NO) is one of the common elements to all these mechanisms. Although all three nitric oxide synthase (NOS) isoforms are constitutively expressed within the kidneys, they contribute in different ways to nitrergic signaling. While the endothelial (eNOS) and neuronal (nNOS) isoforms are likely to be the main sources of NO under basal conditions and participate in the regulation of renal hemodynamics, the inducible isoform (iNOS) is dramatically increased in conditions such as sepsis. The overexpression of iNOS in the renal cortex causes a shunting of blood to this region, with consequent medullary ischemia in sepsis. Differences in the vascular reactivity among different vascular beds may also help to explain renal failure in this condition. While most of the vessels present vasoplegia and do not respond to vasoconstrictors, renal microcirculation behaves differently from nonrenal vascular beds, displaying similar constrictor responses in control and septic conditions. The selective inhibition of iNOS, without affecting other isoforms, has been described as the ideal scenario. However, iNOS is also constitutively expressed in the kidneys and the NO produced by this isoform is important for immune defense. In this sense, instead of a direct iNOS inhibition, targeting the NO effectors such as guanylate cyclase, potassium channels, peroxynitrite, and S-nitrosothiols, may be a more interesting approach in sepsis-AKI and further investigation is warranted.
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26
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Wei CX, Wu JH, Huang YH, Wang XZ, Li JY. Lactobacillus plantarum improves LPS-induced Caco2 cell line intestinal barrier damage via cyclic AMP-PKA signaling. PLoS One 2022; 17:e0267831. [PMID: 35639684 PMCID: PMC9154120 DOI: 10.1371/journal.pone.0267831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 04/17/2022] [Indexed: 11/18/2022] Open
Abstract
Lactobacillus plantarum (LP) has been shown to exhibit protective effects on intestinal barrier function in septic rats, although the regulatory mechanism has not been established. We determined whether LP imparts such protective effects in a lipopolysaccharide (LPS)-induced Caco2 cell monolayer model and whether cAMP-PKA signaling is the underlying mechanism of action. The cyclic adenosine monophosphate (cAMP) agonist, forskolin (FSK), and the protein kinase A (PKA) inhibitor, HT89, were used to study the protective effect of LP on the destruction of the tight junction (TJ) structure of cells treated with LPS and the corresponding changes in cAMP-PKA signaling. Our experimental results demonstrated that LP promoted the expression of TJ proteins between Caco2 cells after LPS treatment, and increased the electrical barrier detection (TEER) between Caco2 cells. Moreover, transmission electron microscopy (TEM) revealed that the TJ structural integrity of cells treated with LPS + LP was improved compared to cells treated with LPS alone. In addition, our findings were consistent between the FSK and LP intervention group, while HT89 inhibited LP influence. Taken together, our results indicate that LP has an improved protective effect on LPS-induced damage to the monolayer membrane barrier function of Caco2 cells and is regulated by the cAMP-PKA pathway.
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Affiliation(s)
- Chen-Xiang Wei
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, P.R. China
| | - Ju-Hua Wu
- Digestive Endoscopy Center, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian Province, P.R. China
| | - Yue-Hong Huang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, P.R. China
| | - Xiao-Zhong Wang
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, P.R. China
- * E-mail: (XZW); (JYL)
| | - Jian-Ying Li
- Department of Gastroenterology and Fujian Institute of Digestive Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, P.R. China
- * E-mail: (XZW); (JYL)
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Immunomodulation via MyD88-NFκB Signaling Pathway from Human Umbilical Cord-Derived Mesenchymal Stem Cells in Acute Lung Injury. Int J Mol Sci 2022; 23:ijms23105295. [PMID: 35628107 PMCID: PMC9141460 DOI: 10.3390/ijms23105295] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/08/2022] [Accepted: 05/08/2022] [Indexed: 01/01/2023] Open
Abstract
Excess inflammatory processes play a key detrimental role in the pathophysiology of acute lung injury (ALI). Mesenchymal stem cells (MSCs) were reported to be beneficial to ALI, but the underlying mechanisms have not been completely understood. The present study aimed to examine the involvement of MyD88−NFκB signaling in the immunomodulation of MSCs in mice with lipopolysaccharides (LPS)-induced ALI. We found that serum concentrations of IL-6, TNF-α, MCP-1, IL-1β, and IL-8 were significantly decreased at 6 h after LPS-induced ALI in the MSC group (p < 0.05). For each of the five cytokines, the serum concentration of each individual mouse in either group declined to a similar level at 48 h. The intensity of lung injury lessened in the MSC group, as shown by histopathology and lung injury scores (p < 0.001). The expressions of MyD88 and phospho-NFκB in the lung tissue were significantly decreased in mice receiving MSCs as measured by Western blotting and immunohistochemistry. Our data demonstrated that human umbilical cord-derived MSCs could effectively alleviate the cytokine storm in mice after LPS-induced ALI and attenuated lung injury. Firstly, we documented the correlation between the down-regulation of MyD88−NFκB signaling and immunomodulatory effects of MSCs in the situation of ALI.
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Heithoff DM, Pimienta G, Mahan SP, Yang WH, Le DT, House JK, Marth JD, Smith JW, Mahan MJ. Coagulation factor protein abundance in the pre-septic state predicts coagulopathic activities that arise during late-stage murine sepsis. EBioMedicine 2022; 78:103965. [PMID: 35349828 PMCID: PMC8965145 DOI: 10.1016/j.ebiom.2022.103965] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/21/2022] [Accepted: 03/10/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Although sepsis accounts for 1 in 5 deaths globally, few molecular therapies exist for this condition. The development of effective biomarkers and treatments for sepsis requires a more complete understanding of host responses and pathogenic mechanisms at early stages of disease to minimize host-driven pathology. METHODS An alternative to the current symptom-based approach used to diagnose sepsis is a precise assessment of blood proteomic changes during the onset and progression of Salmonella Typhimurium (ST) murine sepsis. FINDINGS A distinct pattern of coagulation factor protein abundance was identified in the pre-septic state- prior to overt disease symptoms or bacteremia- that was predictive of the dysregulation of fibrinolytic and anti-coagulant activities and resultant consumptive coagulopathy during ST murine sepsis. Moreover, the changes in protein abundance observed generally have the same directionality (increased or decreased abundance) reported for human sepsis. Significant overlap of ST coagulopathic activities was observed in Gram-negative Escherichia coli- but not in Gram-positive staphylococcal or pneumococcal murine sepsis models. Treatment with matrix metalloprotease inhibitors prevented aberrant inflammatory and coagulopathic activities post-ST infection and increased survival. Antibiotic treatment regimens initiated after specific changes arise in the plasma proteome post-ST infection were predictive of an increase in disease relapse and death after cessation of antibiotic treatment. INTERPRETATION Altered blood proteomics provides a platform to develop rapid and easy-to-perform tests to predict sepsis for early intervention via biomarker incorporation into existing blood tests prompted by patient presentation with general malaise, and to stratify Gram-negative and Gram-positive infections for appropriate treatment. Antibiotics are less effective in microbial clearance when initiated after the onset of altered blood proteomics as evidenced by increased disease relapse and death after termination of antibiotic therapy. Treatment failure is potentially due to altered bacterial / host-responses and associated increased host-driven pathology, providing insight into why delays in antibiotic administration in human sepsis are associated with increased risk for death. Delayed treatment may thus require prolonged therapy for microbial clearance despite the prevailing notion of antibiotic de-escalation and shortened courses of antibiotics to improve drug stewardship. FUNDING National Institutes of Health, U.S. Army.
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Affiliation(s)
- Douglas M Heithoff
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara CA 93106, USA; Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA 93106, USA
| | - Genaro Pimienta
- Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Scott P Mahan
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara CA 93106, USA; Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA 93106, USA; Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis CA 95616, USA
| | - Won Ho Yang
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara CA 93106, USA; Glycosylation Network Research Center and Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; Infectious and Inflammatory Diseases Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Dzung T Le
- Department of Pathology, University of California, La Jolla, San Diego, CA 92093, USA
| | - John K House
- Faculty of Science, Sydney School of Veterinary Science, The University of Sydney, Camden, New South Wales 2570, Australia
| | - Jamey D Marth
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara CA 93106, USA; Infectious and Inflammatory Diseases Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Jeffrey W Smith
- Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Michael J Mahan
- Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara CA 93106, USA; Institute for Collaborative Biotechnologies, University of California, Santa Barbara, CA 93106, USA.
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Mul Fedele ML, Senna CA, Aiello I, Golombek DA, Paladino N. Circadian Rhythms in Bacterial Sepsis Pathology: What We Know and What We Should Know. Front Cell Infect Microbiol 2021; 11:773181. [PMID: 34956930 PMCID: PMC8696002 DOI: 10.3389/fcimb.2021.773181] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Sepsis is a syndrome caused by a deregulated host response to infection, representing the primary cause of death from infection. In animal models, the mortality rate is strongly dependent on the time of sepsis induction, suggesting a main role of the circadian system. In patients undergoing sepsis, deregulated circadian rhythms have also been reported. Here we review data related to the timing of sepsis induction to further understand the different outcomes observed both in patients and in animal models. The magnitude of immune activation as well as the hypothermic response correlated with the time of the worst prognosis. The different outcomes seem to be dependent on the expression of the clock gene Bmal1 in the liver and in myeloid immune cells. The understanding of the role of the circadian system in sepsis pathology could be an important tool to improve patient therapies.
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Affiliation(s)
- Malena Lis Mul Fedele
- Laboratorio de Cronofisiología, Instituto de Investigaciones Biomédicas/Pontificia Universidad Católica Argentina - Consejo Nacional de Investigaciones Científicas y Técnicas (UCA-CONICET), Buenos Aires, Argentina
| | - Camila Agustina Senna
- Laboratorio de Cronobiología, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes/Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Ignacio Aiello
- Laboratorio de Cronobiología, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes/Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Diego Andres Golombek
- Laboratorio de Cronobiología, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes/Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Natalia Paladino
- Laboratorio de Cronobiología, Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes/Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- *Correspondence: Natalia Paladino,
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Dellinger RP, Levy MM, Schorr CA, Townsend SR. 50 Years of Sepsis Investigation/Enlightenment Among Adults-The Long and Winding Road. Crit Care Med 2021; 49:1606-1625. [PMID: 34342304 DOI: 10.1097/ccm.0000000000005203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- R Phillip Dellinger
- Cooper Medical School of Rowan University and Cooper University Health, Camden, NJ
| | | | - Christa A Schorr
- Cooper Medical School of Rowan University and Cooper University Health, Camden, NJ
| | - Sean R Townsend
- University of California Pacific Medical Center, (Sutter Health), San Francisco, CA
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Miller MR, Koch SR, Choi H, Lamb FS, Stark RJ. Apoptosis signal-regulating kinase 1 (ASK1) inhibition reduces endothelial cytokine production without improving permeability after toll-like receptor 4 (TLR4) challenge. Transl Res 2021; 235:115-128. [PMID: 33857660 PMCID: PMC8328918 DOI: 10.1016/j.trsl.2021.04.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 04/05/2021] [Accepted: 04/08/2021] [Indexed: 12/12/2022]
Abstract
Sepsis represents a life-threatening event often mediated by the host's response to pathogens such as gram-negative organisms, which release the proinflammatory lipopolysaccharide (LPS). Within the endothelium, the mitogen-activated protein kinase (MAPK) pathway is an important driver of endothelial injury during sepsis, of which oxidant-sensitive apoptosis signal-regulating kinase 1 (ASK1) is postulated to be a critical upstream regulator. We hypothesized that ASK1 would play a key role in endothelial inflammation during bacterial challenge. Utilizing RNA sequencing data from patients and cultured human microvascular endothelial cells (HMVECs), ASK1 expression was increased in sepsis and after LPS challenge. Two ASK1 inhibitors, GS444217 and MSC2023964A, reduced cytokine production in HMVECs following LPS stimulation, but had no effect on permeability as measured by transendothelial electrical resistance and intercellular space. MAPKs are known to interact with endothelial nitric oxide synthase (eNOS) and ASK1 expression levels correlated with eNOS expression in patients with septic shock. In addition, eNOS physically interacted with ASK1, though this interaction was not altered by ASK1 inhibition, nor did inhibition alter MAPK p38 activity. Instead, among MAPKs, ASK1 inhibition only impaired LPS-induced JNK phosphorylation. The reduction in JNK activation caused by ASK1 inhibition impaired JNK-mediated cytokine production without affecting permeability. Thus, LPS triggers JNK-dependent cytokine production that requires ASK1 activation, but both its effects on permeability and activation of p38 are ASK1-independent. These data demonstrate how distinct MAPK signaling pathways regulate endothelial inflammatory outputs during acute infectious challenge.
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Affiliation(s)
- Michael R Miller
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Stephen R Koch
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Hyehun Choi
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Fred S Lamb
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Ryan J Stark
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
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Luo Q, Liu R, Qu K, Liu G, Hang M, Chen G, Xu L, Jin Q, Guo D, Kang Q. Cangrelor ameliorates CLP-induced pulmonary injury in sepsis by inhibiting GPR17. Eur J Med Res 2021; 26:70. [PMID: 34229761 PMCID: PMC8262027 DOI: 10.1186/s40001-021-00536-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 06/21/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Sepsis is a common complication of severe wound injury and infection, with a very high mortality rate. The P2Y12 receptor inhibitor, cangrelor, is an antagonist anti-platelet drug. METHODS In our study, we investigated the protective mechanisms of cangrelor in CLP-induced pulmonary injury in sepsis, using C57BL/6 mouse models. RESULTS TdT-mediated dUTP Nick-End Labeling (TUNEL) and Masson staining showed that apoptosis and fibrosis in lungs were alleviated by cangrelor treatment. Cangrelor significantly promoted surface expression of CD40L on platelets and inhibited CLP-induced neutrophils in Bronchoalveolar lavage fluid (BALF) (p < 0.001). We also found that cangrelor decreased the inflammatory response in the CLP mouse model and inhibited the expression of inflammatory cytokines, IL-1β (p < 0.01), IL-6 (p < 0.05), and TNF-α (p < 0.001). Western blotting and RT-PCR showed that cangrelor inhibited the increased levels of G-protein-coupled receptor 17 (GPR17) induced by CLP (p < 0.001). CONCLUSION Our study indicated that cangrelor repressed the levels of GPR17, followed by a decrease in the inflammatory response and a rise of neutrophils in BALF, potentially reversing CLP-mediated pulmonary injury during sepsis.
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Affiliation(s)
- Qiancheng Luo
- Department of Critical Care Medicine, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People's Republic of China
| | - Rui Liu
- Department of Endocrinology, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People's Republic of China
| | - Kaili Qu
- Postgraduate Training Base in Shanghai Gongli Hospital, Ningxia Medical University, Shanghai, 200135, People's Republic of China
| | - Guorong Liu
- Department of Critical Care Medicine, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People's Republic of China
| | - Min Hang
- Department of Critical Care Medicine, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People's Republic of China
| | - Guo Chen
- Department of Critical Care Medicine, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People's Republic of China
| | - Lei Xu
- Department of Critical Care Medicine, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People's Republic of China
| | - Qinqin Jin
- Department of Critical Care Medicine, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People's Republic of China
| | - Dongfeng Guo
- Department of Critical Care Medicine, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People's Republic of China.
| | - Qi Kang
- Department of Critical Care Medicine, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai, 200135, People's Republic of China.
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Lung Transplantation, Pulmonary Endothelial Inflammation, and Ex-Situ Lung Perfusion: A Review. Cells 2021; 10:cells10061417. [PMID: 34200413 PMCID: PMC8229792 DOI: 10.3390/cells10061417] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/01/2021] [Accepted: 06/02/2021] [Indexed: 12/31/2022] Open
Abstract
Lung transplantation (LTx) is the gold standard treatment for end-stage lung disease; however, waitlist mortality remains high due to a shortage of suitable donor lungs. Organ quality can be compromised by lung ischemic reperfusion injury (LIRI). LIRI causes pulmonary endothelial inflammation and may lead to primary graft dysfunction (PGD). PGD is a significant cause of morbidity and mortality post-LTx. Research into preservation strategies that decrease the risk of LIRI and PGD is needed, and ex-situ lung perfusion (ESLP) is the foremost technological advancement in this field. This review addresses three major topics in the field of LTx: first, we review the clinical manifestation of LIRI post-LTx; second, we discuss the pathophysiology of LIRI that leads to pulmonary endothelial inflammation and PGD; and third, we present the role of ESLP as a therapeutic vehicle to mitigate this physiologic insult, increase the rates of donor organ utilization, and improve patient outcomes.
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Hon KL, Leung KKY, Oberender F, Leung AK. Paediatrics: how to manage septic shock. Drugs Context 2021; 10:dic-2021-1-5. [PMID: 34122587 PMCID: PMC8177956 DOI: 10.7573/dic.2021-1-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 03/22/2021] [Indexed: 02/07/2023] Open
Abstract
Background Septic shock is a common critical illness associated with high morbidity and mortality in children. This article provides an updated narrative review on the management of septic shock in paediatric practice. Methods A PubMed search was performed using the following Medical Subject Headings: "sepsis", "septic shock" and "systemic inflammatory response syndrome". The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies and reviews. The search was limited to the English literature and specific to children. Results Septic shock is associated with high mortality and morbidity. The outcome can be improved if the diagnosis is made promptly and treatment initiated without delay. Early treatment with antimicrobial therapy, fluid therapy and vasoactive medications, and rapid recognition of the source of sepsis and control are the key recommendations from paediatric sepsis management guidelines. Conclusion Most of the current paediatric sepsis guideline recommendations are based on the adult population; therefore, the research gaps in paediatric sepsis management should be addressed.
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Affiliation(s)
- Kam Lun Hon
- Paediatric Intensive Care Unit, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong
| | - Karen Ka Yan Leung
- Paediatric Intensive Care Unit, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong
| | - Felix Oberender
- Paediatric Intensive Care Unit, Monash Children's Hospital, Melbourne, Australia.,Monash University, School of Clinical Sciences, Department of Paediatrics, Melbourne, Australia
| | - Alexander Kc Leung
- Department of Pediatrics, University of Calgary and Alberta Children's Hospital, Calgary, Alberta, Canada
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The protective role of fosfomycin in lung injury due to oxidative stress and inflammation caused by sepsis. Life Sci 2021; 279:119662. [PMID: 34081989 DOI: 10.1016/j.lfs.2021.119662] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 05/02/2021] [Accepted: 05/24/2021] [Indexed: 11/22/2022]
Abstract
AIM Early and prompt treatment of sepsis by effective antibiotics against susceptible organisms may be lifesaving. However, increased antibiotic resistance and side effects of chemotherapeutic agents limiting their tolerability result in a restricted use of medications. This has led to an increased search for solution oriented novel treatments and therapeutic targets, as well as investigations on the pathogenesis and physiology of sepsis. In this study, we aimed to examine the antioxidant and anti-inflammatory effects of fosfomycin in sepsis resulting from other causes. MAIN METHODS Sprague Dawley rats were assigned into three groups. Randomly selected control rats received intraperitoneal saline solution only. Only caecal puncture and ligation were carried out in the caecal ligation and puncture (CLP) group, while in the CLP + fosfomycin group (CLP + FOS), together with sepsis due to caecal puncture and ligation, 500 mg/kg of FOS was administered intraperitoneally (i.p.). KEY FINDINGS As compared to the control group, elevated TBARS and TNF-α levels as well as increased expression of NF-kB/p65 and TLR-4 and reduced -SH levels were found in the lung tissue of CLP rats. On the other hand, TBARS and TNF-α levels were reduced and NF-kB/p65 and TLR-4 expressions were decreased together with increase in total -SH levels among CLP + FOS (500 mg/kg i.p.) rats. SIGNIFICANCE FOS treatment may represent a promising agent in terms of reducing the sepsis-related lung injury due to its antimicrobial effects as well as its antioxidant and anti-inflammatory properties.
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Li C, Wang P, Li M, Zheng R, Chen S, Liu S, Feng Z, Yao Y, Shang H. The current evidence for the treatment of sepsis with Xuebijing injection: Bioactive constituents, findings of clinical studies and potential mechanisms. JOURNAL OF ETHNOPHARMACOLOGY 2021; 265:113301. [PMID: 32860891 DOI: 10.1016/j.jep.2020.113301] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 11/16/2019] [Accepted: 08/08/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Xuebijing (XBJ) injection is a Chinese medicine containing extracts from Carthamus tinctorius L. (Carthami Flos, hong hua, Asteraceae), Paeonia lactiflora Pall. (Paeoniae radix rubra, chi shao, Ranunculaceae), Ligusticum chuanxiong Hort. (Chuanxiong Rhizoma, chuan xiong, Umbelliferae), Salvia miltiorrhiza Bge. (Salviae miltiorrhizae Radix Et Rhizoma, dan shen, Labiatae) and Angelica sinensis (Oliv.) Diels (Angelicae sinensis Radix, dang gui, Umbelliferae). It has been approved for the treatment of sepsis in China since 2004 and has been widely used as an add-on treatment for sepsis or septic shock with few side effects. AIM OF THE STUDY The aim of the present review was to analyse up-to-date information related to the treatment of sepsis with XBJ, including the bioactive constituents, clinical studies and potential mechanisms, and to discuss possible scientific gaps, to provide a reliable reference for future studies. MATERIALS AND METHODS Scientific resources concentrating on treating sepsis with XBJ were searched through PubMed, the Chinese National Knowledge Infrastructure (CNKI) and WanFang databases from inception to November 2018. Dissertations were also searched, and eligible dissertations were selected. Studies related to the identification of constituents, bioactive components and their targets of action or pathways, clinical trials, and animal or cellular experiments that explored pharmacological mechanisms were manually selected. The quality of reporting and methodology of the included pharmacological experiments were assessed using the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines and the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE)'s risk of bias tool. RESULTS A total of 108 relative studies were eventually included, containing 12 bioactivity research studies, 10 systematic reviews on clinical trials and 86 animal or cellular experiments. We noted that as identification methods progressed, further constituents could be detected in XBJ. XBJ was also found to have "multi-ingredient, multi-target and multi-pathway" effects. The systematic review revealed that XBJ could improve the 28-day mortality and other indexes, such as the APACHE II score, body temperature, and white blood cell (WBC) count, to some extent. A major organ protection effect was demonstrated in septic rats. Pharmacological investigations suggested that XBJ acts in both the early and late stages of sepsis by anti-inflammatory, anti-coagulation, immune regulation, vascular endothelial protection, anti-oxidative stress and other mechanisms. However, most of the included studies were poorly reported, and the risk of bias was unclear. CONCLUSIONS With respect to the multiple therapeutic mechanisms contributing to both the early and late stages of sepsis, the multiple effective constituents detected and randomized controlled trials (RCTs) performed to prove its efficacy, XBJ is a promising therapy for the treatment of sepsis. However, although XBJ has shown some efficacy for the treatment of sepsis, there are currently some scientific gaps. More studies concerning the pharmacokinetics, interactions with antibiotics, real-world efficacy and safety, pharmacological mechanisms of the bioactive components and large-scale clinical trials should be conducted in the future.
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Affiliation(s)
- Chengyu Li
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing, 100700, China.
| | - Ping Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Sunny South Street, Fangshan District, Beijing, 102488, China.
| | - Min Li
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing, 100700, China.
| | - Rui Zheng
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing, 100700, China.
| | - Shiqi Chen
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing, 100700, China.
| | - Si Liu
- Tianjin Chase Sun Pharmaceutical Co. LTD, 20 Quanfa Road, Tianjin Wuqing Development Area, Tianjin, 300170, China.
| | - Zhiqiao Feng
- Tianjin Chase Sun Pharmaceutical Co. LTD, 20 Quanfa Road, Tianjin Wuqing Development Area, Tianjin, 300170, China.
| | - Yongming Yao
- First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, 51 Bucheng Road, Haidian District, Beijing, 100048, China.
| | - Hongcai Shang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Haiyuncang Lane, Dongcheng District, Beijing, 100700, China.
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Park JW, Lee SJ, Kim JE, Kang MJ, Bae SJ, Choi YJ, Gong JE, Kim KS, Jung YS, Cho JY, Choi YS, Hwang DY, Song HK. Comparison of response to LPS-induced sepsis in three DBA/2 stocks derived from different sources. Lab Anim Res 2021; 37:2. [PMID: 33407886 PMCID: PMC7788770 DOI: 10.1186/s42826-020-00079-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/27/2020] [Indexed: 12/26/2022] Open
Abstract
Sepsis, one of the most fatal diseases in the world, is known to culminate in multiple organ failure due to an uncontrolled inflammatory response. Hence, the use of animal models in sepsis research is very important to study complex immune responses. The current study was undertaken to compare commercial stocks with KFDA stocks of DBA/2 mice as an animal model for sepsis study. To compare responses of DBA/2 mice to lipopolysaccharides (LPS)-induced sepsis, we measured altered characteristics of various factors associated with sepsis, including survival curves, organ failure and inflammatory response, in DBA/2Korl stock and two commercial stocks (DBA/2A and DBA/2B). Survival rates after LPS exposure were similar for DBA/2Korl and DBA/2B; however, for times over 20 h, survival rates were reduced and concentration dependent in DBA/2A. In order to evaluate multiple organ failure caused by sepsis, H&E stains were evaluated for liver and spleen tissues obtained in the early (2 h) and later (20 h) stages after exposure to LPS; no significant differences were observed between the three stocks. mRNA and protein levels of proinflammatory cytokines were assessed for evaluating inflammatory reactions, and were found to increase in a dose-dependent manner in most DBA/2 mice after LPS treatment. However, no changes were observed in the mRNA levels of proinflammatory cytokines at 20 h after LPS exposure in the DBA/2A stock. The induction of inflammation-mediated factors by LPS exposure did not induce alterations in the mRNA levels of COX-2 and iNOS in all three DBA/2 stocks. Our results indicate that response of DBA/2Korl to LPS-induced sepsis is similar to the two commercial DBA/2 stocks, thus representing its potential as a useful biological resource established in Korea.
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Affiliation(s)
- Ji Won Park
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute/Laboratory Animals Resources Center, Pusan National University, Miryang, South Korea
| | - Su Jin Lee
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute/Laboratory Animals Resources Center, Pusan National University, Miryang, South Korea
| | - Ji Eun Kim
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute/Laboratory Animals Resources Center, Pusan National University, Miryang, South Korea
| | - Mi Ju Kang
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute/Laboratory Animals Resources Center, Pusan National University, Miryang, South Korea
| | - Su Ji Bae
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute/Laboratory Animals Resources Center, Pusan National University, Miryang, South Korea
| | - Yun Ju Choi
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute/Laboratory Animals Resources Center, Pusan National University, Miryang, South Korea
| | - Jeong Eun Gong
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute/Laboratory Animals Resources Center, Pusan National University, Miryang, South Korea
| | - Kil Soo Kim
- College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea
| | - Young-Suk Jung
- College of Pharmacy, Pusan National University, Busan, South Korea
| | - Joon-Yong Cho
- Exercise Biochemistry Laboratory, Korea National Sport University, Seoul, South Korea
| | - Yeon Shik Choi
- Department of Biomedical Analysis, Korea Bio Polytechnic College, Nonsan, South Korea
| | - Dae Youn Hwang
- Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute/Laboratory Animals Resources Center, Pusan National University, Miryang, South Korea.
| | - Hyun Keun Song
- Central Research Institute, Kinesiences Co., Seoul, South Korea.
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C7ORF41 Regulates Inflammation by Inhibiting NF- κB Signaling Pathway. BIOMED RESEARCH INTERNATIONAL 2021; 2021:7413605. [PMID: 33506033 PMCID: PMC7806384 DOI: 10.1155/2021/7413605] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 12/02/2020] [Accepted: 12/18/2020] [Indexed: 11/18/2022]
Abstract
Inflammation is an important biological process for eliciting immune responses against physiological and pathological stimuli. Inflammation must be efficiently regulated to ensure homeostasis in the body. Nuclear factor-kappa B (NF-κB) signaling is crucial for inflammatory and immune responses. Aberrant activation of NF-κB signaling leads to development of numerous human diseases. In this study, we investigated the function of chromosome 7 open reading frame 41 (C7ORF41) in NF-κB signaling during inflammation. C7ORF41 was upregulated in cells stimulated with tumor necrosis factor-alpha or lipopolysaccharide. Moreover, overexpression of C7ORF41 inhibited the activation of NF-κB and decreased the expression of its downstream target genes. Notably, small hairpin RNA-mediated depletion of C7ORF41 increased the levels of downstream genes and enabled the activation of NF-κB. In conclusion, C7ORF41 negatively regulated inflammation via NF-κB signaling and p65 phosphorylation in vitro. These findings may help to diagnose and prognosticate inflammatory conditions and may help develop new strategies for the management of inflammation-related diseases.
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Sherlock LG, Sjostrom K, Sian L, Delaney C, Tipple TE, Krebs NF, Nozik-Grayck E, Wright CJ. Hepatic-Specific Decrease in the Expression of Selenoenzymes and Factors Essential for Selenium Processing After Endotoxemia. Front Immunol 2020; 11:595282. [PMID: 33224150 PMCID: PMC7674557 DOI: 10.3389/fimmu.2020.595282] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 10/14/2020] [Indexed: 01/05/2023] Open
Abstract
Background Selenium (Se) levels decrease in the circulation during acute inflammatory states and sepsis, and are inversely associated with morbidity and mortality. A more specific understanding of where selenoproteins and Se processing are compromised during insult is needed. We investigated the acute signaling response in selenoenzymes and Se processing machinery in multiple organs after innate immune activation in response to systemic lipopolysaccharide (LPS). Methods Wild type (WT) adult male C57/B6 mice were exposed to LPS (5 mg/kg, intraperitoneal). Blood, liver, lung, kidney and spleen were collected from control mice as well as 2, 4, 8, and 24 h after LPS. Plasma Se concentration was determined by ICP-MS. Liver, lung, kidney and spleen were evaluated for mRNA and protein content of selenoenzymes and proteins required to process Se. Results After 8 h of endotoxemia, plasma levels of Se and the Se transporter protein, SELENOP were significantly decreased. Consistent with this timing, the transcription and protein content of several hepatic selenoenzymes, including SELENOP, glutathione peroxidase 1 and 4 were significantly decreased. Furthermore, hepatic transcription and protein content of factors required for the Se processing, including selenophosphate synthetase 2 (Sps2), phosphoseryl tRNA kinase (Pstk), selenocysteine synthase (SepsecS), and selenocysteine lyase (Scly) were significantly decreased. Significant LPS-induced downregulation of these key selenium processing enzymes was observed in isolated hepatocytes. In contrast to the acute and dynamic changes observed in the liver, selenoenzymes did not decrease in the lung, kidney or spleen. Conclusion Hepatic selenoenzyme production and Se processing factors decreased after endotoxemia. This was temporally associated with decreased circulating Se. In contrast to these active changes in the regulation of Se processing in the liver, selenoenzymes did not decrease in the lung, kidney or spleen. These findings highlight the need to further study the impact of innate immune challenges on Se processing in the liver and the impact of targeted therapeutic Se replacement strategies during innate immune challenge.
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Affiliation(s)
- Laura G Sherlock
- Perinatal Research Center, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Kara Sjostrom
- Perinatal Research Center, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Lei Sian
- Perinatal Nutrition Laboratory, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Cassidy Delaney
- Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Trent E Tipple
- Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK, United States
| | - Nancy F Krebs
- Perinatal Nutrition Laboratory, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Eva Nozik-Grayck
- Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Clyde J Wright
- Perinatal Research Center, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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Chavant A, Gautier-Veyret E, Chhun S, Guilhaumou R, Stanke-Labesque F. [Pharmacokinetic changes related to acute infection. Examples from the SARS-CoV-2 pandemic]. Therapie 2020; 76:319-333. [PMID: 33129512 PMCID: PMC7833468 DOI: 10.1016/j.therap.2020.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/18/2020] [Accepted: 10/12/2020] [Indexed: 01/08/2023]
Abstract
The knowledge of factors of pharmacokinetic variability is important in order to personalize pharmacological treatment, particularly for drugs with a narrow therapeutic range for which pharmacological therapeutic monitoring is recommended. Inflammation is a protective response against acute infections and injuries that contributes to intra- and inter-individual variability in drug exposure by modulating the activity of enzymes involved in drug metabolism, and by altering the binding of drugs to plasma proteins. The understanding of the impact of inflammation on drug metabolism and the related clinical consequences allow to better take into consideration the effect of inflammation on the variability of drug exposure. We first summarized the molecular mechanisms by which inflammation contributes to the inhibition of drug metabolism enzymes. We then presented an updated overview of the consequences of the outcome of acute infectious event on pharmacokinetic exposure of drugs with a narrow therapeutic range and that are substrates of cytochrome P450, and the related clinical consequences. Finally, in the context of the COVID-19 pandemic, we reported examples of drug overexposures in COVID- 19 infected patients.
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Affiliation(s)
- Anaëlle Chavant
- Laboratoire de pharmacologie-pharmacogénétique-toxicologie, pôle de biologie et pathologie, CHU Grenoble Alpes, 38700 La Tronche, France
| | - Elodie Gautier-Veyret
- Laboratoire de pharmacologie-pharmacogénétique-toxicologie, pôle de biologie et pathologie, CHU Grenoble Alpes, 38700 La Tronche, France; University Grenoble Alpes, Inserm, CHU Grenoble Alpes, HP2, 38043 Grenoble, France
| | - Stéphanie Chhun
- UFR de médecine Paris centre, 75015 Paris, France; Institut Necker-Enfants Malades (INEM), Inserm U1151-CNRS UMR 8253, 75015 Paris, France; Laboratoire d'immunologie biologique, département médico universitaire BioPhyGen, hôpital universitaire Necker-enfants malades, AP-HP, 75015 Paris, France
| | - Romain Guilhaumou
- Unité de pharmacologie clinique et pharmacovigilance AP-HM, 13354 Marseille, France; Aix Marseille Univ, Inserm, INS Inst Neurosci Syst, 13354 Marseille, France
| | - Françoise Stanke-Labesque
- Laboratoire de pharmacologie-pharmacogénétique-toxicologie, pôle de biologie et pathologie, CHU Grenoble Alpes, 38700 La Tronche, France; University Grenoble Alpes, Inserm, CHU Grenoble Alpes, HP2, 38043 Grenoble, France.
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You N, Chu S, Cai B, Gao Y, Hui M, Zhu J, Wang M. Bioactive hyaluronic acid fragments inhibit lipopolysaccharide-induced inflammatory responses via the Toll-like receptor 4 signaling pathway. Front Med 2020; 15:292-301. [PMID: 32946028 DOI: 10.1007/s11684-020-0806-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 05/29/2020] [Indexed: 12/16/2022]
Abstract
The high- and the low-molecular weight hyaluronic acids (HMW-HA and LMW-HA, respectively) showed different biological activities in inflammation. However, the role of LMW-HA in inflammatory response is controversial. In this study, we aimed to investigate the effect of bioactive hyaluronan (B-HA) on lipopolysaccharide (LPS)-induced inflammatory responses in human macrophages and mice. B-HA was produced from HA treated with glycosylated recombinant human hyaluronidase PH20. Human THP-1 cells were induced to differentiate into macrophages. THP-1-derived macrophages were treated with B-HA, LPS, or B-HA + LPS. The mRNA expression and the production of inflammatory cytokines were determined using quantitative real-time PCR and enzyme-linked immunosorbent assay. The phosphorylation levels of proteins in the nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and IRF-3 signaling pathways were measured using Western blot. The in vivo efficacy of B-HA was assessed in a mouse model of LPS-induced inflammation. Results showed that B-HA inhibited the expression of TNF-α, IL-6, IL-1, and IFN-β, and enhanced the expression of the antiinflammatory cytokine IL-10 in LPS-induced inflammatory responses in THP-1-derived macrophages and in vivo. B-HA significantly suppressed the phosphorylation of the TLR4 signaling pathway proteins p65, IKKα/β, IκBα, JNK1/2, ERK1/2, p38, and IRF-3. In conclusion, our results demonstrated that the B-HA attenuated the LPS-stimulated inflammatory response by inhibiting the activation of the TLR4 signaling pathway. B-HA could be a potential anti-inflammatory drug in the treatment of inflammatory disease.
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Affiliation(s)
- Na You
- Department of Infectious Disease, The People's Hospital of Bozhou, Bozhou, 236800, China
| | - Sasa Chu
- Department of Infectious Disease, The People's Hospital of Linyi, Linyi, 276000, China
| | - Binggang Cai
- Department of Infectious Disease, The People's Hospital of Yancheng, Yancheng, 224000, China
| | - Youfang Gao
- Department of Infectious Disease, The People's Hospital of Bozhou, Bozhou, 236800, China
| | - Mizhou Hui
- AnRuipu Biological Products Research Co., Ltd., Hangzhou, 310019, China
| | - Jin Zhu
- Huadong Medical Institute of Biotechniques, Nanjing, 210002, China.
| | - Maorong Wang
- Institute of Liver Disease, Jinling Hospital, Nanjing, 210002, China.
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Splichal I, Rychlik I, Splichalova I, Karasova D, Splichalova A. Toll-Like Receptor 4 Signaling in the Ileum and Colon of Gnotobiotic Piglets Infected with Salmonella Typhimurium or Its Isogenic ∆ rfa Mutants. Toxins (Basel) 2020; 12:toxins12090545. [PMID: 32842482 PMCID: PMC7551901 DOI: 10.3390/toxins12090545] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/16/2020] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
Salmonella Typhimurium is a Gram-negative bacterium that causes enterocolitis in humans and pigs. Lipopolysaccharide (LPS) is a component of the outer leaflet of Gram-negative bacteria that provokes endotoxin shock. LPS can be synthesized completely or incompletely and creates S (smooth) or R (rough) chemotypes. Toll-like receptors (TLR) 2, 4, and 9 initiate an inflammatory reaction to combat bacterial infections. We associated/challenged one-week-old gnotobiotic piglets with wild-type S. Typhimurium with S chemotype or its isogenic ∆rfa mutants with R chemotype LPS. The wild-type S. Typhimurium induced TLR2 and TLR4 mRNA expression but not TLR9 mRNA expression in the ileum and colon of one-week-old gnotobiotic piglets 24 h after challenge. The TLR2 and TLR4 stimulatory effects of the S. Typhimurium ∆rfa mutants were related to the completeness of their LPS chain. The transcription of IL-12/23 p40, IFN-γ, and IL-6 in the intestine and the intestinal and plasmatic levels of IL-12/23 p40 and IL-6 but not IFN-γ were related to the activation of TLR2 and TLR4 signaling pathways. The avirulent S. Typhimurium ∆rfa mutants are potentially useful for modulation of the TLR2 and TLR4 signaling pathways to protect the immunocompromised gnotobiotic piglets against subsequent infection with the virulent S. Typhimurium.
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Affiliation(s)
- Igor Splichal
- Laboratory of Gnotobiology, Institute of Microbiology, Czech Academy of Sciences, 549 22 Novy Hradek, Czech Republic;
| | - Ivan Rychlik
- Department of Immunology, Veterinary Research Institute, 621 00 Brno, Czech Republic; (I.R.); (D.K.)
| | - Iva Splichalova
- Laboratory of Immunobiology, Institute of Molecular Genetics, Czech Academy of Sciences, 142 20 Prague 4-Krc, Czech Republic;
| | - Daniela Karasova
- Department of Immunology, Veterinary Research Institute, 621 00 Brno, Czech Republic; (I.R.); (D.K.)
| | - Alla Splichalova
- Laboratory of Gnotobiology, Institute of Microbiology, Czech Academy of Sciences, 549 22 Novy Hradek, Czech Republic;
- Correspondence: ; Tel.: +420-491-418-539
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Therapeutic Potential of Cathelicidin Peptide LL-37, an Antimicrobial Agent, in a Murine Sepsis Model. Int J Mol Sci 2020; 21:ijms21175973. [PMID: 32825174 PMCID: PMC7503894 DOI: 10.3390/ijms21175973] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/24/2020] [Accepted: 08/10/2020] [Indexed: 12/12/2022] Open
Abstract
Among the mechanisms put-up by the host to defend against invading microorganisms, antimicrobial peptides represent the first line. In different species of mammals, the cathelicidin family of antimicrobial peptides AMPs has been identified, and in humans, LL-37 is the only type of cathelicidin identified. LL-37 has many different biological activities, such as regulation of responses to inflammation, besides its lipopolysaccharide (LPS)-neutralizing and antimicrobial and activities. Recently, employing a murine septic model that involves cecal ligation and puncture (CLP), we examined the effect of LL-37. The results indicated that LL-37 exhibits multiple protective actions on septic mice; firstly, the survival of CLP mice was found to be improved by LL-37 by the suppression of the macrophage pyroptosis that induces the release of pro-inflammatory cytokines (such as IL-1β) and augments inflammatory reactions in sepsis; secondly, the release of neutrophil extracellular traps (NETs), which have potent bactericidal activity, is enhanced by LL-37, and protects mice from CLP-induced sepsis; thirdly, LL-37 stimulates neutrophils to release antimicrobial microvesicles (ectosomes), which improve the pathological condition of sepsis. These findings indicate that LL-37 protects CLP septic mice through at least three mechanisms, i.e., the suppression of pro-inflammatory macrophage pyroptosis and the release of antimicrobial NETs (induction of NETosis) and ectosomes from neutrophils. Thus, LL-37 can be a potential therapeutic candidate for sepsis due to its multiple properties, including the modulation of cell death (pyroptosis and NETosis) and the release of antimicrobial NETs and ectosomes as well as its own bactericidal and LPS-neutralizing activities.
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Jarczak D, Kluge S, Nierhaus A. Use of Intravenous Immunoglobulins in Sepsis Therapy-A Clinical View. Int J Mol Sci 2020; 21:E5543. [PMID: 32756325 PMCID: PMC7432410 DOI: 10.3390/ijms21155543] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 07/29/2020] [Accepted: 07/30/2020] [Indexed: 12/29/2022] Open
Abstract
Sepsis is a life-threatening organ dysfunction, defined by a dysregulated host immune response to infection. During sepsis, the finely tuned system of immunity, inflammation and anti-inflammation is disturbed in a variety of ways. Both pro-inflammatory and anti-inflammatory pathways are upregulated, activation of the coagulation cascade and complement and sepsis-induced lymphopenia occur. Due to the manifold interactions in this network, the use of IgM-enriched intravenous immunoglobulins seems to be a promising therapeutic approach. Unfortunately, there is still a lack of evidence-based data to answer the important questions of appropriate patient populations, optimal timing and dosage of intravenous immunoglobulins. With this review, we aim to provide an overview of the role of immunoglobulins, with emphasis on IgM-enriched formulations, in the therapy of adult patients with sepsis and septic shock.
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Affiliation(s)
| | | | - Axel Nierhaus
- Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (D.J.); (S.K.)
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45
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Lin HY. The severe COVID-19: A sepsis induced by viral infection? And its immunomodulatory therapy. Chin J Traumatol 2020; 23:190-195. [PMID: 32690231 PMCID: PMC7451584 DOI: 10.1016/j.cjtee.2020.06.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/24/2020] [Accepted: 05/30/2020] [Indexed: 02/06/2023] Open
Abstract
COVID-19 is known for its magical infectivity, fast transmission and high death toll based on the large number of infected people. From the perspective of the clinical manifestation, autopsy examination and pathophysiology, the essence of COVID-19 should be viewed as a sepsis induced by viral infection, and has the essential characteristics as sepsis induced by other pathogens. Therefore, in addition to etiological and supportive treatment, immunomodulatory therapy is also appropriate to severe COVID-19. Although there is still a lack of consensus on immunotherapy for sepsis so far, relatively rich experiences have been accumulated in the past decades, which will help us in the treatment of severe COVID-19. This article will elaborate immunotherapy of sepsis, though it may not be consistent.
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Affiliation(s)
- Hong-Yuan Lin
- Forth Medical Center, General Hospital of PLA, Beijing, China.
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Consideration of Severe Coronavirus Disease 2019 As Viral Sepsis and Potential Use of Immune Checkpoint Inhibitors. Crit Care Explor 2020; 2:e0141. [PMID: 32696004 PMCID: PMC7314326 DOI: 10.1097/cce.0000000000000141] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Taking into consideration the multisystemic clinical and autopsy findings in “severe” coronavirus disease 2019 patients, viral sepsis would be a more accurate term to describe the whole clinical picture. The most significant pathophysiological components of this picture are intense cytokine release, prolonged inflammation, immunosuppression with T cell exhaustion, and the development of organ dysfunctions. Currently, the optimal treatment for severe coronavirus disease 2019 is uncertain. Supportive treatment and immunomodulators have a critical place in the treatment of severe patients until effective antivirals are developed. Interleukin-6 antagonists, one of the immunomodulating agents, appears to be effective in the treatment of cytokine storm, but some patients continue to have severe lymphopenia and immunosuppression. We believe it can be useful as immunomodulator therapy in critical coronavirus disease 2019 patients because of the benefits of immune checkpoint inhibitors in cancer and sepsis patients.
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Nicolai O, Pötschke C, Schmoeckel K, Darisipudi MN, van der Linde J, Raafat D, Bröker BM. Antibody Production in Murine Polymicrobial Sepsis-Kinetics and Key Players. Front Immunol 2020; 11:828. [PMID: 32425951 PMCID: PMC7205023 DOI: 10.3389/fimmu.2020.00828] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 04/14/2020] [Indexed: 12/16/2022] Open
Abstract
Although antigen-specific priming of antibody responses is impaired during sepsis, there is nevertheless a strong increase in IgM and IgG serum concentrations. Using colon ascendens stent peritonitis (CASP), a mouse model of polymicrobial abdominal sepsis, we observed substantial increases in IgM as well as IgG of all subclasses, starting at day 3 and peaking 2 weeks after sepsis induction. The dominant source of antibody-secreting cells was by far the spleen, with a minor contribution of the mesenteric lymph nodes. Remarkably, sepsis induction in splenectomized mice did not change the dynamics of the serum IgM/IgG reaction, indicating that the marginal zone B cells, which almost exclusively reside in the spleen, are dispensable in such a setting. Hence, in systemic bacterial infection, the function of the spleen as dominant niche of antibody-producing cells can be compensated by extra-splenic B cell populations as well as other lymphoid organs. Depletion of CD4+ T cells did not affect the IgM response, while it impaired IgG generation of all subclasses with the exception of IgG3. Taken together, our data demonstrate that the robust class-switched antibody response in sepsis encompasses both T cell-dependent and -independent components.
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Affiliation(s)
- Oliver Nicolai
- Immunology Department, Institute of Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Christian Pötschke
- Immunology Department, Institute of Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Katrin Schmoeckel
- Immunology Department, Institute of Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Murthy N Darisipudi
- Immunology Department, Institute of Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Julia van der Linde
- Department of General Surgery, Visceral, Thoracic and Vascular Surgery, University Medicine Greifswald, Greifswald, Germany
| | - Dina Raafat
- Immunology Department, Institute of Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.,Department of Microbiology and Immunology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Barbara M Bröker
- Immunology Department, Institute of Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany
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Shi CX, Wang Y, Chen Q, Jiao FZ, Pei MH, Gong ZJ. Extracellular Histone H3 Induces Pyroptosis During Sepsis and May Act Through NOD2 and VSIG4/NLRP3 Pathways. Front Cell Infect Microbiol 2020; 10:196. [PMID: 32432055 PMCID: PMC7216582 DOI: 10.3389/fcimb.2020.00196] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 04/14/2020] [Indexed: 12/17/2022] Open
Abstract
Background: Histones could be released from the nucleus when stimulated. Increasing evidence has shown that extracellular histones are associated with a variety of inflammation and diseases. Nucleotide binding oligomerzation domain 2 (NOD2) belongs to the NOD like receptor (NLR) family and is reported to promote apoptosis and aggravate inflammatory response. And V-set and immunoglobulin domain containing 4 (VSIG4), a B7 family-related protein, has been confirmed to mediate transcriptional inhibition of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3). However, little is known about the impact of extracellular histones on NOD2 or VSIG4 signal transduction. In this study, we aim to explore the effect and mechanism of extracellular histone H3 on pyroptosis. Aim: The purpose of this work was to investigate the mechanism of extracellular histone H3 on pyroptosis in sepsis. Methods: Lipopolysaccharide (LPS) and histone H3 were used to induce sepsis mice model and damage in ANA-1 macrophages. H3 antibody was applied to antagonize the effect of histone H3. NOD2 inhibitor NOD-IN-1 and VSIG4-siRNA were used to investigate the mechanism of histone H3 on pyroptosis. Enzyme linked immune sorbent assay (ELISA) was applied to detect the level of extracellular histone H3. Real-time PCR and Western blotting were employed to detect the key mRNA and protein levels. The pathology of tissues was detected. Results: The level of extracellular histone H3 was increased after LPS stimulation. The mRNA and protein levels of NLRP3, caspase-1, gasdermin D (GSDMD), interleukin (IL)-1β, IL-18 were increased in LPS group, but suppressed by H3 antibody. And the expression of NOD2, receptor-interacting protein 2 (RIP2) was elevated compared with control group. The expression of VSIG4 was inhibited by LPS and suppression of H3 promoted the protein level of VSIG4. H3 antibody alleviated pathological damages in tissues. Furthermore, the mRNA and protein levels of NOD2 in H3 group was higher compared with control group. The mRNA and protein levels of VSIG4 in H3 group was decreased compared with control group, but up-regulated by NOD-IN-1. Besides, the mRNA and protein levels of VSIG4 in NOD-IN-1 + VSIG4-siRNA group was elevated compared with VSIG4-siRNA group. Conclusions: Extracellular histone H3 induced by LPS could cause pyroptosis during sepsis via NOD2 and VSIG4/NLRP3 pathway.
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Affiliation(s)
- Chun-Xia Shi
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yao Wang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qian Chen
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fang-Zhou Jiao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Mao-Hua Pei
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zuo-Jiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
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Li L, He X, Wang X, Sun Y, Wu G, Fang H, Wang C, Luo P, Xia Z. Ruxolitinib protects lipopolysaccharide (LPS)-induced sepsis through inhibition of nitric oxide production in mice. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:546. [PMID: 32411769 PMCID: PMC7214887 DOI: 10.21037/atm-20-2972] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Background Ruxolitinib is an inhibitor of Janus kinases (JAK) 1/2. It was authorised recently by the U.S. Food and Drug Administration (FDA) as a new Myelofibrosis treatment. In this study, we identified ruxolitinib as a new inhibitor of nitric oxide (NO) production in response to lipopolysaccharide (LPS)stimulation of RAW 264.7 cells. Methods In vitro direct effects of ruxolitinib were determined through NO production on RAW 264.7 cells. Also the expression level of iNOS, TNF-α and IL-6 were detected by Western Blotting and qRT-PCR. In vivo therapeutic effects of ruxolitinib on sepsis were evaluated by an endotoxemia model with C57 mice. The survival was calculated and histopathological damage of organs was observed by HE. Cytokines in serum were detected by Mouse Cytokine Array Panel. Results Ruxolitinib was found to significantly reduce NO production, inducible nitric oxide synthase (iNOS), TNF-α, and IL-6 expression, suggesting that ruxolitinib blocks LPS signaling that leads to pro-inflammatory factor expression. Furthermore, the inhibitory effects of ruxolitinib contributed to the survival of septic mice by 70% and pro-inflammatory cytokines in serum declined apparently. The results taken together indicate that ruxolitinib can significantly suppress LPS-stimulated NO production and improve the survival of septic mice, perhaps by interfering with the NF-κB pathway. Conclusions These findings suggest ruxolitinib might be a possible therapeutic candidate for sepsis therapy.
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Affiliation(s)
- Li Li
- Department of Burn Surgery, Affiliated Changhai Hospital of the Navy Medical University, Shanghai 200433, China
| | - Xingfeng He
- Department of Burn Surgery, Affiliated Changhai Hospital of the Navy Medical University, Shanghai 200433, China.,Department of Burns and Plastic Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Xingtong Wang
- Department of Burns and Plastic Surgery, The Sixth Medical Center of General Hospital, The People's Liberation Army, Beijing 100046, China
| | - Yu Sun
- Department of Burn Surgery, Affiliated Changhai Hospital of the Navy Medical University, Shanghai 200433, China
| | - Guosheng Wu
- Department of Burn Surgery, Affiliated Changhai Hospital of the Navy Medical University, Shanghai 200433, China
| | - He Fang
- Department of Burn Surgery, Affiliated Changhai Hospital of the Navy Medical University, Shanghai 200433, China
| | - Chen Wang
- Department of Burn Surgery, Affiliated Changhai Hospital of the Navy Medical University, Shanghai 200433, China
| | - Pengfei Luo
- Department of Burn Surgery, Affiliated Changhai Hospital of the Navy Medical University, Shanghai 200433, China
| | - Zhaofan Xia
- Department of Burn Surgery, Affiliated Changhai Hospital of the Navy Medical University, Shanghai 200433, China.,Department of Burns and Plastic Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China
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Postovalova EA, Makarova OV, Kosyreva AM, Dzhalilova DS. Hypoxia is a key mechanism for regulating inflammation in ulcerative colitis. RUSSIAN OPEN MEDICAL JOURNAL 2020. [DOI: 10.15275/rusomj.2020.0101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Intestinal bowel diseases (IBD), including ulcerative colitis (UC), is the group of difficult to diagnose widespread among the population diseases. Pathogenesis of the disease is associated with a complex interaction of the genetic factors, the environment, the microbiome and the unpredicted reaction of the immune system, and the existing treatment methods are not effective enough. It is known, that hypoxia plays a key role in both system and local inflammatory reactions, mainly due to microcirculatory disorders and disseminated intravascular coagulation. Therefore a lot of studies have demonstrated that severity of any inflammatory diseases, including Crohn's disease (CD) and UC depends on hypoxia resistance. In this review we discussed microcirculation of blood and physiological hypoxia in the intestine, the role of hypoxia-inducible factors in the development of IBD and UC, as well as their influence on the severity of the inflammatory process. Authors described the protective effect of various PHD inhibitors and its benefits and disadvantages, so as new approaches of searching of very specific low molecular weight substanses as drugs for the control of IBD and UC.
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