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Zhao R, Li H, Xu B, Cao J. CXCL5 as a biomarker for early diagnosis and prognosis of sepsis: A comprehensive clinical evaluation. Clin Biochem 2025; 136:110878. [PMID: 39788476 DOI: 10.1016/j.clinbiochem.2025.110878] [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: 08/25/2024] [Revised: 01/04/2025] [Accepted: 01/06/2025] [Indexed: 01/12/2025]
Abstract
OBJECTIVES Sepsis, a critical condition caused by a dysregulated host response to infection, has high morbidity and mortality rates. Timely diagnosis and treatment are vital for improving patient outcomes. This study explores the potential role of CXCL5 in the diagnosis, severity assessment, and prognosis of sepsis. DESIGN AND METHODS We included 147 sepsis patients, 50 patients with systemic inflammatory response syndrome (SIRS) and 120 healthy controls. Serum CXCL5 levels, inflammation scores (APACHE II, SOFA), and other laboratory indicators were recorded. Univariate and multivariate logistic regression analyses were conducted to assess the relationship between CXCL5 and sepsis diagnosis, severity, and prognosis. A prognostic nomogram was constructed and evaluated using receiver operator characteristic curves, calibration curves, and clinical decision curves. RESULTS Serum CXCL5 levels in sepsis patients were significantly higher than those in patients with SIRS and healthy controls. CXCL5 was identified as a risk factor for sepsis diagnosis. CXCL5 levels were significantly elevated in patients with septic shock (P = 0.04) and in deceased patients compared to survivors (P < 0.001). The prognostic model, incorporating CXCL5, lactate, APACHE II scores, C-reactive protein levels, and respiratory rate, demonstrated high predictive accuracy with an area under the curve of 0.873. Calibration and decision curve analyses demonstrated the model's good predictive performance and potential clinical value. CONCLUSIONS Serum CXCL5 concentration is a promising biomarker for enhancing the diagnostic accuracy and prognostic evaluation of sepsis. The constructed multivariate prediction model offers new insights into sepsis prognosis, but its direct application in clinical practice requires further validation.
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Affiliation(s)
- Rui Zhao
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - HangBo Li
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Banglao Xu
- Department of Laboratory Medicine, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China.
| | - Ju Cao
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Hsieh MS, Wu PH, Chiu KC, Liao SH, Chen CS, Hsiao TH, Chen YM, Hu SY, How CK, Chattopadhyay A, Lu TP. Population-specific genetic-risk scores enable improved prediction of mortality within 28 days of sepsis onset: a retrospective Taiwanese cohort study. J Intensive Care 2025; 13:11. [PMID: 40011956 DOI: 10.1186/s40560-025-00783-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 02/13/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND Sepsis is characterized by organ dysfunction as a response to infection and is one of the leading causes of mortality and loss of health. The heterogeneous nature of sepsis, along with ethnic differences in susceptibility, challenges a thorough understanding of its etiology. This study aimed to propose prediction models by leveraging genetic-risk scores and clinical variables that can assist in risk stratification of patients. METHODS A total of 1,403 patients from Taiwan, diagnosed with sepsis, were utilized. Genome-wide survival analysis was conducted, with death within 28 days from sepsis onset, as the primary event to report significantly associated SNPs. A polygenic risk score (PRS-sepsis) was constructed via clumping and thresholding method which was added to clinical-only models to generate better performing prognostic models for identifying high-risk patients. Kaplan-Meier analysis was conducted using PRS-sepsis. RESULTS A total of five single-nucleotide-polymorphisms (SNPs) reached genome-wide significance (p < 5e-8), and 86 SNPs reached suggestive significance (p < 1e-5). The prognostic model using PRS-sepsis showed significantly improved performance with c-index [confidence interval (CI)] of 0.79 [0.62-0.96] and area under receiver operating characteristic curve (AUROC) [CI] of 0.78 [0.75-0.80], in comparison to clinical-only prognostic models (c-index [CI] = 0.63 [0.45- 0.81], AUROC [CI] = 0.61 [0.58-0.64]). The ethnic specificity was established for our proposed models by comparing it with models generated using significant SNPs from prior European studies (c-index [CI] = 0.63 [0.42-0.85], AUROC [CI] = 0.60 [0.58-0.63]). Kaplan-Meier plots showed that patient groups with higher PRSs have inferior survival probability compared to those with lower PRSs. CONCLUSIONS This study proposed genetic-risk models specific for Taiwanese populations that outperformed clinical-only models. Also it established a strong racial-effect on the underlying genetics of sepsis-related mortality. The model can potentially be used in real clinical setting for deciding precise treatment courses for patients at high-risk thereby reducing the possibility of worse outcomes.
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Affiliation(s)
- Ming-Shun Hsieh
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taoyuan Branch, Taoyuan, 330, Taiwan
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, 11217, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
- Department of Emergency Medicine, Taichung Veterans General Hospital, Taichung, 40705, Taiwan
| | - Pei-Hsuan Wu
- Institute of Epidemiology and Preventive Medicine, Department of Public Health, National Taiwan University, Taipei, 100, Taiwan
| | - Kuan-Chih Chiu
- Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, 100, Taiwan
| | - Shu-Hui Liao
- Department of Pathology and Laboratory, Taipei Veterans General Hospital, Taoyuan Branch, Taoyuan, 330, Taiwan
| | - Che-Shao Chen
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taoyuan Branch, Taoyuan, 330, Taiwan
| | - Tzu-Hung Hsiao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan
- Research Center for Biomedical Science and Engineering, National Tsing Hua University, Hsinchu, Taiwan
- Department of Public Health, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Yi-Ming Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, National Chung Hsing University, Taichung, Taiwan
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Sung-Yuan Hu
- Department of Emergency Medicine, Taichung Veterans General Hospital, Taichung, 40705, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, 402, Taiwan
| | - Chorng-Kuang How
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, 11217, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
| | - Amrita Chattopadhyay
- Institute of Epidemiology and Preventive Medicine, Department of Public Health, National Taiwan University, Taipei, 100, Taiwan.
| | - Tzu-Pin Lu
- Institute of Health Data Analytics and Statistics, Department of Public Health, National Taiwan University, Taipei, 100, Taiwan.
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Bällgren F, Bergfast T, Ginosyan A, Mahajan J, Lipcsey M, Hammarlund-Udenaes M, Syvänen S, Loryan I. Active CNS delivery of oxycodone in healthy and endotoxemic pigs. Fluids Barriers CNS 2024; 21:86. [PMID: 39443944 PMCID: PMC11515623 DOI: 10.1186/s12987-024-00583-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 10/04/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND The primary objective of this study was to advance our understanding of active drug uptake at brain barriers in higher species than rodents, by examining oxycodone brain concentrations in pigs. METHODS This was investigated by a microdialysis study in healthy and endotoxemic conditions to increase the understanding of inter-species translation of putative proton-coupled organic cation (H+/OC) antiporter-mediated central nervous system (CNS) drug delivery in health and pathology, and facilitate the extrapolation to humans for improved CNS drug treatment in patients. Additionally, we sought to evaluate the efficacy of lumbar cerebrospinal fluid (CSF) exposure readout as a proxy for brain unbound interstitial fluid (ISF) concentrations. By simultaneously monitoring unbound concentrations in blood, the frontal cortical area, the lateral ventricle (LV), and the lumbar intrathecal space in healthy and lipopolysaccharide (LPS)-induced inflammation states within the same animal, we achieved exceptional spatiotemporal resolution in mapping oxycodone transport across CNS barriers. RESULTS Our findings provide novel evidence of higher unbound oxycodone concentrations in brain ISF compared to blood, yielding an unbound brain-to-plasma concentration ratio (Kp,uu,brain) of 2.5. This supports the hypothesis of the presence of the H+/OC antiporter system at the blood-brain barrier (BBB) in pigs. Despite significant physiological changes, reflected in pig Sequential Organ Failure Assessment, pSOFA scores, oxycodone blood concentrations and its active net uptake across the BBB remained nearly unchanged during three hours of i.v. infusion of 4 µg/kg/h LPS from Escherichia coli (O111:B4). Mean Kp,uu,LV values indicated active uptake also at the blood-CSF barrier in healthy and endotoxemic pigs. Lumbar CSF concentrations showed minimal inter-individual variability during the experiment, with a mean Kp,uu,lumbarCSF of 1.5. LPS challenge caused a slight decrease in Kp,uu,LV, while Kp,uu,lumbarCSF remained unaffected. CONCLUSIONS This study enhances our understanding of oxycodone pharmacokinetics and CNS drug delivery in both healthy and inflamed conditions, providing crucial insights for translating these findings to clinical settings.
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Affiliation(s)
- Frida Bällgren
- Translational Pharmacokinetics/Pharmacodynamics Group (tPKPD), Department of Pharmacy, Uppsala University, Husargatan 3, 752 37, Uppsala, Sweden.
| | - Tilda Bergfast
- Translational Pharmacokinetics/Pharmacodynamics Group (tPKPD), Department of Pharmacy, Uppsala University, Husargatan 3, 752 37, Uppsala, Sweden
| | - Aghavni Ginosyan
- Translational Pharmacokinetics/Pharmacodynamics Group (tPKPD), Department of Pharmacy, Uppsala University, Husargatan 3, 752 37, Uppsala, Sweden
| | - Jessica Mahajan
- Translational Pharmacokinetics/Pharmacodynamics Group (tPKPD), Department of Pharmacy, Uppsala University, Husargatan 3, 752 37, Uppsala, Sweden
- School of Applied Sciences, Abertay University, Bell Street, Dundee, DD1 1HG, Scotland, UK
| | - Miklós Lipcsey
- Hedenstierna Laboratory, Department of Surgical Sciences, Uppsala University, Akademiska Sjukhuset, 751 85, Uppsala, Sweden
| | - Margareta Hammarlund-Udenaes
- Translational Pharmacokinetics/Pharmacodynamics Group (tPKPD), Department of Pharmacy, Uppsala University, Husargatan 3, 752 37, Uppsala, Sweden
| | - Stina Syvänen
- Molecular Geriatrics, Department of Public Health and Caring Sciences, Uppsala University, Rudbecklaboratoriet, Dag Hammarskjölds Väg 20, 751 85, Uppsala, Sweden
| | - Irena Loryan
- Translational Pharmacokinetics/Pharmacodynamics Group (tPKPD), Department of Pharmacy, Uppsala University, Husargatan 3, 752 37, Uppsala, Sweden.
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Bendas G, Gobec M, Schlesinger M. Modulating Immune Responses: The Double-Edged Sword of Platelet CD40L. Semin Thromb Hemost 2024. [PMID: 39379039 DOI: 10.1055/s-0044-1791512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2024]
Abstract
The CD40-CD40L receptor ligand pair plays a fundamental role in the modulation of the innate as well as the adaptive immune response, regulating monocyte, T and B cell activation, and antibody isotype switching. Although the expression and function of the CD40-CD40L dyad is mainly attributed to the classical immune cells, the majority of CD40L is expressed by activated platelets, either in a membrane-bound form or shed as soluble molecules in the circulation. Platelet-derived CD40L is involved in the communication with different immune cell subpopulations and regulates their functions effectively. Thus, platelet CD40L contributes to the containment and clearance of bacterial and viral infections, and additionally guides leukocytes to sites of infection. However, platelet CD40L promotes inflammatory cellular responses also in a pathophysiological context. For example, in HIV infections, platelet CD40L is supportive of neuronal inflammation, damage, and finally HIV-related dementia. In sepsis, platelet CD40L can induce extensive endothelial and epithelial damage resulting in barrier dysfunction of the gut, whereby the translocation of microbiota into the circulation further aggravates the uncontrolled systemic inflammation. Nevertheless, a distinct platelet subpopulation expressing CD40L under septic conditions can attenuate systemic inflammation and reduce mortality in mice. This review focuses on recent findings in the field of platelet CD40L biology and its physiological and pathophysiological implications, and thereby highlights platelets as vital immune cells that are essential for a proper immune surveillance. In this context, platelet CD40L proves to be an interesting target for various inflammatory diseases. However, either an agonism or a blockade of CD40L needs to be well balanced since both the approaches can cause severe adverse events, ranging from hyperinflammation to immune deficiency. Thus, an interference in CD40L activities should be likely done in a context-dependent and timely restricted manner.
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Affiliation(s)
- Gerd Bendas
- Department of Pharmacy, University of Bonn, Bonn, Germany
| | - Martina Gobec
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Martin Schlesinger
- Department of Pharmacy, University of Bonn, Bonn, Germany
- Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany
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Yang Y, Luo K, Xu G. Acute kidney injury following chimeric antigen receptor T-cell therapy: Epidemiology, mechanism and prognosis. Clin Immunol 2024; 266:110311. [PMID: 38996858 DOI: 10.1016/j.clim.2024.110311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 05/03/2024] [Accepted: 07/09/2024] [Indexed: 07/14/2024]
Abstract
Chimeric antigen receptor T cell (CAR-T) therapy is a promising treatment for hematologic tumors, and adverse events of acute kidney injury (AKI) have been reported. However, its incidence, clinical characteristics, and prognosis remained unclear. We searched PubMed, EMBASE, and Web of Science for study about AKI after CAR-T therapy, a total of 15 studies, comprising 694 patients, were included. Among the 694 patients, 154 (22%) developed AKI, of which 89 (57.8%) were in stage 1, 59 (38.3%) were in stage 2 or 3, and 6 (3.9%) were not reported. Cytokine release syndrome is considered to be the most common cause of AKI. Of the 154 AKI patients, only 16 (10.4%) received renal replacement therapy, most AKI recovered renal function after symptomatic treatment. Although the occurrence of AKI after CAR-T therapy is rare and mostly mild, active knowledge of its pathogenesis, timely diagnosis and treatment are necessary for clinicians.
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Affiliation(s)
- Yang Yang
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, PR China; Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, PR China
| | - Kaiping Luo
- Department of Nephrology, Ganzhou People's Hospital, Ganzhou, PR China.
| | - Gaosi Xu
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, PR China.
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Xu W, Wu Y, Wang S, Hu S, Wang Y, Zhou W, Chen Y, Li Q, Zhu L, Yang H, Lv X. Melatonin alleviates septic ARDS by inhibiting NCOA4-mediated ferritinophagy in alveolar macrophages. Cell Death Discov 2024; 10:253. [PMID: 38789436 PMCID: PMC11126704 DOI: 10.1038/s41420-024-01991-8] [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: 09/02/2023] [Revised: 04/15/2024] [Accepted: 04/25/2024] [Indexed: 05/26/2024] Open
Abstract
Ferroptosis is a novel form of programmed cell death which can exacerbate lung injury in septic acute respiratory distress syndrome (ARDS). Alveolar macrophages, crucial innate immune cells, play a pivotal role in the pathogenesis of ARDS. Ferritinophagy is a process of ferritin degradation mediated by nuclear receptor coactivator 4 (NCOA4) which releases large amounts of iron ions thus promoting ferroptosis. Recent evidence revealed that inhibiting macrophage ferroptosis can effectively attenuate pulmonary inflammatory injury. Melatonin (MT), an endogenous neurohormone, has antioxidant and anti-inflammatory effects and can reduce septic ARDS. However, it is not clear whether MT's pulmonary protective effect is related to the inhibition of macrophage ferritinophagy. Our in vitro experiments demonstrated that MT decreased intracellular malondialdehyde (MDA), Fe2+, and lipid peroxidation levels, increased glutathione (GSH) levels and cell proliferation, and upregulated glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) protein levels in LPS-treated macrophages. Mechanistically, the antiferroptotic effect of MT on LPS-treated macrophages was significantly compromised by the overexpression of NCOA4. Our in vivo experiments revealed that MT alleviated the protein expression of NCOA4 and FTH1 in the alveolar macrophages of septic mice. Furthermore, MT improved lipid peroxidation and mitigated damage in alveolar macrophages and lung tissue, ultimately increasing the survival rates of septic mice. These findings indicate that MT can inhibit ferroptosis in an NCOA4-mediated ferritinophagy manner, thereby ameliorating septic ARDS.
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Affiliation(s)
- Wenting Xu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
- Anhui Medical University, Hefei, Anhui, 236000, People's Republic of China
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, People's Republic of China
| | - Yutong Wu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Sheng Wang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Song Hu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Yu Wang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Wenyu Zhou
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Yuanli Chen
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Quanfu Li
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Lina Zhu
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China
| | - Hao Yang
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China.
| | - Xin Lv
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People's Republic of China.
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Lai K, Lin G, Chen C, Xu Y. Development and Validation of a Predictive Model for Acute Kidney Injury in Sepsis Patients Based on Recursive Partition Analysis. J Intensive Care Med 2024; 39:465-476. [PMID: 37964547 DOI: 10.1177/08850666231214243] [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] [Indexed: 11/16/2023]
Abstract
BACKGROUND Sepsis-associated acute kidney injury (SA-AKI) is a critical condition with significant clinical implications, yet there is a need for a predictive model that can reliably assess the risk of its development. This study is undertaken to bridge a gap in healthcare by creating a predictive model for SA-AKI with the goal of empowering healthcare providers with a tool that can revolutionize patient care and ultimately lead to improved outcomes. METHODS A cohort of 615 patients afflicted with sepsis, who were admitted to the intensive care unit, underwent random stratification into 2 groups: a training set (n = 435) and a validation set (n = 180). Subsequently, a multivariate logistic regression model, imbued with nonzero coefficients via LASSO regression, was meticulously devised for the prognostication of SA-AKI. This model was thoughtfully rendered in the form of a nomogram. The salience of individual risk factors was assessed and ranked employing Shapley Additive Interpretation (SHAP). Recursive partition analysis was performed to stratify the risk of patients with sepsis. RESULTS Among the panoply of clinical variables examined, hypertension, diabetes mellitus, C-reactive protein, procalcitonin (PCT), activated partial thromboplastin time, and platelet count emerged as robust and independent determinants of SA-AKI. The receiver operating characteristic curve analysis for SA-AKI risk discrimination in both the training set and validation set yielded an area under the curve estimates of 0.843 (95% CI: 0.805 to 0.882) and 0.834 (95% CI: 0.775 to 0.893), respectively. Notably, PCT exhibited the most conspicuous influence on the model's predictive capacity. Furthermore, statistically significant disparities were observed in the incidence of SA-AKI and the 28-day survival rate across high-risk, medium-risk, and low-risk cohorts (P < .05). CONCLUSION The composite predictive model, amalgamating the quintet of SA-AKI predictors, holds significant promise in facilitating the identification of high-risk patient subsets.
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Affiliation(s)
- Kunmei Lai
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Guo Lin
- Department of Intensive Care Unit, The First Affifiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Caiming Chen
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yanfang Xu
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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Zhu X, Pan Y, Xu X, Xu J. Kaempferitrin alleviates LPS-induced septic acute lung injury in mice through downregulating NF-κB pathway. Allergol Immunopathol (Madr) 2023; 51:1-7. [PMID: 37937489 DOI: 10.15586/aei.v51i6.838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 02/27/2023] [Indexed: 11/09/2023]
Abstract
BACKGROUND Acute lung injury (ALI) causes severe and uncontrolled pulmonary inflammation and has high morbidity in dying patients. OBJECTIVE This study aimed to evaluate the potential function of Kaempferitrin (Kae) and uncover its mechanisms in ALI. MATERIAL AND METHODS We evaluated the role of Kae in ALI through the lipopolysaccharide (LPS)-induced histopathological changes, lung wet/dry (W/D) ratio, total bronchoalveolar lavage fluid (BALF) cells count, pulmonary inflammation, and the levels of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-1β. The effect of Kae on NF-κB signaling pathway was discovered through the protein expression levels of transcription factors p65, p-p65, IκBα, and p-IκBα by Western blot analysis. RESULTS The results showed that Kae could improve lung injury by reducing apoptosis, histopathological changes, and lung W/D ratio; more importantly, Kae enhanced the survival of ALI mice. Moreover, Kae relieved inflammation, as it reduced total BALF cells count, and deceased the levels of TNF-α, IL-6, and IL-1β in serum. In addition, Western blot analysis data suggested that Kae could decrease the protein expression levels of transcription factors p65, p-p65, IκB-α, and p-IκB-α, which were promoted by LPS. CONCLUSION The results of this study suggested that Kae could relieve LPS-induced ALI in mice and reduce inflammation and apoptosis through NF-κB pathway.
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Affiliation(s)
- Xiaoli Zhu
- Critical Care Medicine, Zhejiang Youth Hospital, Hangzhou, Zhejiang Province, China;
| | - Yongyue Pan
- Critical Care Medicine, Zhejiang Youth Hospital, Hangzhou, Zhejiang Province, China
| | - Xin Xu
- Critical Care Medicine, Zhejiang Chinese Medicine University, Hangzhou, Zhejiang Province, China
| | - Jing Xu
- Critical Care Medicine, Zhejiang Youth Hospital, Hangzhou, Zhejiang Province, China
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Konstantis G, Tsaousi G, Pourzitaki C, Kitsikidou E, Magouliotis DE, Wiener S, Zeller AC, Willuweit K, Schmidt HH, Rashidi-Alavijeh J. Efficacy of Granulocyte Colony-Stimulating Factor in Acute on Chronic Liver Failure: A Systematic Review and Survival Meta-Analysis. J Clin Med 2023; 12:6541. [PMID: 37892679 PMCID: PMC10607065 DOI: 10.3390/jcm12206541] [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: 09/04/2023] [Revised: 10/02/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Acute-on-chronic liver failure (ACLF) mostly occurs when there is an acute insult to the liver in patients with pre-existing liver disease, and it is characterized by a high mortality rate. Various therapeutic approaches have been used thus far, with orthotopic liver transplantation being the only definitive cure. Clinical trials and meta-analyses have investigated the use of granulocyte colony-stimulating factor (G-CSF) to mobilize bone marrow-derived stem cells. Some studies have suggested that G-CSF may have a significant role in the management and survival of patients with ACLF. However, the results are conflicting, and the efficacy of G-CSF still needs to be confirmed. AIM The aim was to assess the efficacy of G-CSF in patients with ACLF. METHODS Electronic databases were searched until May 2023 for randomized controlled trials investigating the use of G-CSF in adult patients with ACLF. Outcome measures were the effects of G-CSF on overall survival, changes in liver disease severity scores, complications of cirrhosis, other G-CSF-related adverse effects, and all-cause mortality. The study's protocol has been registered with Prospero (CRD42023420273). RESULTS Five double-blind randomized controlled trials involving a total of 421 participants met the inclusion criteria. The use of G-CSF demonstrated a significant effect on overall survival (HR 0.63, 95% CI 0.41 to 0.95, and I2 48%), leading to a decreased mortality (LogOR-0.97, 95% CI -1.57 to -0.37, and I2 37.6%) and improved Model for End-Stage Liver Disease (MELD) scores (SMD -0.87, 95% CI -1.62 to -0.13, and I2 87.3%). There was no correlation between the improvement of the Child-Pugh score and the use of G-CSF(SMD -2.47, 95% CI -5.78 to 0.83, and I2 98.1%). The incidence of complications of cirrhosis did not decrease significantly with G-CSF treatment (rate ratio 0.51, 95% CI 0.26 to 1.01, and I2 90%). A qualitative synthesis showed that the use of G-CSF is safe. CONCLUSIONS The administration of G-CSF has demonstrated a positive impact on overall survival, liver function, and the MELD score. The presence of heterogeneity in the included studies prohibits conclusive recommendations.
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Affiliation(s)
- Georgios Konstantis
- Clinical Pharmacology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Georgia Tsaousi
- Department of Anesthesiology and ICU, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Chryssa Pourzitaki
- Clinical Pharmacology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Elisavet Kitsikidou
- Department of Internal Medicine, Evangelical Hospital Dusseldorf, 40217 Dusseldorf, Germany;
| | | | - Sebastian Wiener
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Amos Cornelius Zeller
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Katharina Willuweit
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Hartmut H. Schmidt
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Jassin Rashidi-Alavijeh
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
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10
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He S, Han Q, Wang X, Zhang X, Li N, Liu Z. Aspartate aminotransferase to platelet ratio at admission can predict the prognosis of patients with hemorrhagic fever with renal syndrome. J Med Virol 2023; 95:e29126. [PMID: 37786231 DOI: 10.1002/jmv.29126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/30/2023] [Accepted: 09/05/2023] [Indexed: 10/04/2023]
Abstract
Early indicators are needed to predict the prognosis of patients with hemorrhagic fever with renal syndrome (HFRS). Aspartate aminotransferase to platelet ratio index (APRI) has been shown to be related to mortality risk of patients with various diseases. This study evaluated the prognostic value of APRI and other inflammatory scores in HFRS patients. Data of hospitalized HFRS patients from a tertiary hospital in northwest China were collected and the inflammatory scores such as APRI and neutrophil to lymphocyte count ratio (NLR) were calculated at the day of patient admission. Independent factors related to the survival of patients were determined by multivariate logistic regression. Receiver operating characteristic curve was used to analyze the predictive value, and area under the curve (AUC) and 95% confidence interval (CI) were calculated for quantification. Of the 317 HFRS patients included in study, 15 patients died. Age (OR: 1.10, 95% CI: 1.04-1.16, p = 0.001), NLR (OR: 1.11, 95% CI: 1.02-1.19, p = 0.01), and APRI (OR: 1.06, 95% CI: 1.03-1.10, p = 0.001) were quantitative objective factors independently associated with the survival of patients. APRI had an AUC of 0.95 (95% CI: 0.91-1.00, p < 0.001) for predicting the prognosis of patients, with a sensitivity of 93.3% and a specificity of 86.8%. The performance of APRI was better than that of age or NLR. Patients with an APRI ≥ 6.15 had significantly decreased survival compared with those with an APRI < 6.15. In conclusion, this simple index APRI calculated at admission can serve as a biomarker to identify HFRS patients at risk of poor prognosis.
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Affiliation(s)
- Shan He
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Postgraduate Department, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Qunying Han
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaoyun Wang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xiaoge Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Na Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Zhengwen Liu
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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11
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Balkrishna A, Sinha S, Kumar A, Arya V, Gautam AK, Valis M, Kuca K, Kumar D, Amarowicz R. Sepsis-mediated renal dysfunction: Pathophysiology, biomarkers and role of phytoconstituents in its management. Biomed Pharmacother 2023; 165:115183. [PMID: 37487442 DOI: 10.1016/j.biopha.2023.115183] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 07/08/2023] [Accepted: 07/18/2023] [Indexed: 07/26/2023] Open
Abstract
Sepsis has evolved as an enormous health issue amongst critically ill patients. It is a major risk factor that results in multiple organ failure and shock. Acute kidney injury (AKI) is one of the most frequent complications underlying sepsis, which portends a heavy burden of mortality and morbidity. Thus, the present review is aimed to provide an insight into the recent progression in the molecular mechanisms targeting dysregulated immune response and cellular dysfunction involved in the development of sepsis-associated AKI, accentuating the phytoconstituents as eligible candidates for attenuating the onset and progression of sepsis-associated AKI. The pathogenesis of sepsis-mediated AKI entails a complicated mechanism and is likely to involve a distinct constellation of hemodynamic, inflammatory, and immune mechanisms. Novel biomarkers like neutrophil gelatinase-associated lipocalin, soluble triggering receptor expressed on myeloid cells 1, procalcitonin, alpha-1-microglobulin, and presepsin can help in a more sensitive diagnosis of sepsis-associated AKI. Many bioactive compounds like curcumin, resveratrol, baicalin, quercetin, and polydatin are reported to play an important role in the prevention and management of sepsis-associated AKI by decreasing serum creatinine, blood urea nitrogen, cystatin C, lipid peroxidation, oxidative stress, IL-1β, TNF-α, NF-κB, and increasing the activity of antioxidant enzymes and level of PPARγ. The plant bioactive compounds could be developed into a drug-developing candidate in managing sepsis-mediated acute kidney injury after detailed follow-up studies. Lastly, the gut-kidney axis may be a more promising therapeutic target against the onset of septic AKI, but a deeper understanding of the molecular pathways is still required.
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Affiliation(s)
- Acharya Balkrishna
- Patanjali Herbal Research Department, Patanjali Research Institute, Haridwar, India
| | - Sugandh Sinha
- Patanjali Herbal Research Department, Patanjali Research Institute, Haridwar, India
| | - Ashwani Kumar
- Patanjali Herbal Research Department, Patanjali Research Institute, Haridwar, India.
| | - Vedpriya Arya
- Patanjali Herbal Research Department, Patanjali Research Institute, Haridwar, India
| | - Ajay Kumar Gautam
- Patanjali Herbal Research Department, Patanjali Research Institute, Haridwar, India
| | - Martin Valis
- Department of Neurology, Charles University in Prague, Faculty of Medicine in Hradec Králové and University Hospital, Hradec Králové, Czech Republic
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic; Biomedical Research Center, University Hospital in Hradec Kralove, Sokolska 581, Hradec Kralove, Czech Republic.
| | - Dinesh Kumar
- School of Bioengineering and Food Technology, Shoolini University of Biotechnology and Management Sciences, Solan, India
| | - Ryszard Amarowicz
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland
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12
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Li JC, Wang LJ, Feng F, Chen TT, Shi WG, Liu LP. Role of heparanase in sepsis‑related acute kidney injury (Review). Exp Ther Med 2023; 26:379. [PMID: 37456170 PMCID: PMC10347300 DOI: 10.3892/etm.2023.12078] [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: 01/04/2023] [Accepted: 06/08/2023] [Indexed: 07/18/2023] Open
Abstract
Sepsis-related acute kidney injury (S-AKI) is a common and significant complication of sepsis in critically ill patients, which can often only be treated with antibiotics and medications that reduce S-AKI symptoms. The precise mechanism underlying the onset of S-AKI is still unclear, thus hindering the development of new strategies for its treatment. Therefore, it is necessary to explore the pathogenesis of S-AKI to identify biomarkers and therapeutic targets for its early diagnosis and treatment. Heparanase (HPA), the only known enzyme that cleaves the side chain of heparan sulfate, has been widely studied in relation to tumor metabolism, procoagulant activity, angiogenesis, inflammation and sepsis. It has been reported that HPA plays an important role in the progression of S-AKI. The aim of the present review was to provide an overview of the function of HPA in S-AKI and to summarize its underlying molecular mechanisms, including mediating inflammatory response, immune response, autophagy and exosome biogenesis. It is anticipated that emerging discoveries about HPA in S-AKI will support HPA as a potential biomarker and therapeutic target to combat S-AKI.
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Affiliation(s)
- Jian-Chun Li
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Lin-Jun Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Fei Feng
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Ting-Ting Chen
- The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Wen-Gui Shi
- Cuiying Biomedical Research Center, The Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Li-Ping Liu
- Department of Emergency, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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13
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Abstract
The field of hepatology has made impressive progress over its ~75 years of existence. Advances in understanding liver function and its dysregulation in disease, genetic determinants of disease, antiviral therapy, and transplantation have transformed the lives of patients. However, there are still significant challenges that require ongoing creativity and discipline, particularly with the emergence of fatty liver diseases, as well as managing autoimmune disease, cancer, and liver disease in children. Diagnostic advances are urgently needed to accelerate risk stratification and efficient testing of new agents with greater precision in enriched populations. Integrated, holistic care models should be extended beyond liver cancer to diseases like NAFLD with systemic manifestations or extrahepatic comorbidities such as cardiovascular disease, diabetes, addiction, and depressive disorders. To meet the growing burden of asymptomatic liver disease, the workforce will need to be expanded by incorporating more advanced practice providers and educating other specialists. The training of future hepatologists will benefit from incorporating emerging skills in data management, artificial intelligence, and precision medicine. Continued investment in basic and translational science is crucial for further progress. The challenges ahead are significant, but with collective effort, the field of hepatology will continue to make progress and overcome obstacles.
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Affiliation(s)
- Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
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14
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Zhang J, Zhang M, Huo XK, Ning J, Yu ZL, Morisseau C, Sun CP, Hammock BD, Ma XC. Macrophage Inactivation by Small Molecule Wedelolactone via Targeting sEH for the Treatment of LPS-Induced Acute Lung Injury. ACS CENTRAL SCIENCE 2023; 9:440-456. [PMID: 36968547 PMCID: PMC10037491 DOI: 10.1021/acscentsci.2c01424] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Indexed: 05/03/2023]
Abstract
Soluble epoxide hydrolase (sEH) plays a critical role in inflammation by modulating levels of epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFAs). Here, we investigate the possible role of sEH in lipopolysaccharide (LPS)-mediated macrophage activation and acute lung injury (ALI). In this study, we found that a small molecule, wedelolactone (WED), targeted sEH and led to macrophage inactivation. Through the molecular interaction with amino acids Phe362 and Gln384, WED suppressed sEH activity to enhance levels of EETs, thus attenuating inflammation and oxidative stress by regulating glycogen synthase kinase 3beta (GSK3β)-mediated nuclear factor-kappa B (NF-κB) and nuclear factor E2-related factor 2 (Nrf2) pathways in vitro. In an LPS-stimulated ALI animal model, pharmacological sEH inhibition by WED or sEH knockout (KO) alleviated pulmonary damage, such as the increase in the alveolar wall thickness and collapse. Additionally, WED or sEH genetic KO both suppressed macrophage activation and attenuated inflammation and oxidative stress in vivo. These findings provided the broader prospects for ALI treatment by targeting sEH to alleviate inflammation and oxidative stress and suggested WED as a natural lead candidate for the development of novel synthetic sEH inhibitors.
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Affiliation(s)
- Juan Zhang
- College
of Pharmacy, Dalian Medical University, Dalian 116044, China
- Second
Affiliated Hospital, Dalian Medical University, Dalian 116023, China
- School
of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518061, China
| | - Min Zhang
- College
of Pharmacy, Dalian Medical University, Dalian 116044, China
- School
of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518061, China
| | - Xiao-Kui Huo
- Second
Affiliated Hospital, Dalian Medical University, Dalian 116023, China
| | - Jing Ning
- College
of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Zhen-Long Yu
- College
of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Christophe Morisseau
- Department
of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, California 95616, United States
| | - Cheng-Peng Sun
- College
of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Bruce D. Hammock
- Department
of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, California 95616, United States
| | - Xiao-Chi Ma
- Second
Affiliated Hospital, Dalian Medical University, Dalian 116023, China
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15
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Zhang J, Sun Y, Sun C, Shang D. The antimicrobial peptide LK2(6)A(L) exhibits anti-inflammatory activity by binding to the myeloid differentiation 2 domain and protects against LPS-induced acute lung injury in mice. Bioorg Chem 2023; 132:106376. [PMID: 36706531 DOI: 10.1016/j.bioorg.2023.106376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 01/07/2023] [Accepted: 01/12/2023] [Indexed: 01/19/2023]
Abstract
Acute lung injury (ALI) is a life-threatening disease that is generally attributable to an uncontrolled inflammatory response in the lung, but there is a lack of effective treatments. At present, regulating the inflammatory response has become an important strategy for treating ALI. In the present study, LK2(6)A(L), a peptide derived from the natural antimicrobial peptide temporin-1CEa, inhibited lipopolysaccharide (LPS)-induced expression of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and NO in RAW264.7 cells. Herein, the anti-inflammatory mechanism of LK2(6)A(L) was investigated. The RNA-sequencing (RNA-seq) results showed that LK2(6)A(L) significantly inhibited the TLR4-mediated NF-κB and MAPK signaling pathways in LPS-induced RAW264.7 cells. The results of co-immunoprecipitation (Co-IP), pull-down experiment, confocal laser scanning microscopy, and surface plasmon resonance (SPR) suggested that MD2 was the direct target of LK2(6)A(L). Chemical inhibition of MD2 and its knockdown abolished the anti-inflammatory effect of LK2(6)A(L). Molecular dynamic simulation indicated that LK2(6)A(L) could bind to the active domain of the MD2 hydrophobic pocket via six hydrogen bonds. The truncated peptides were designed based on analysis of the molecular docking of LK2(6)A(L) to MD2. The truncated peptide IS-7 showed strong affinity to MD2 and a remarkable inhibitory effect on pro-inflammatory factors that was comparable to the effect of LK2(6)A(L). Finally, LK2(6)A(L) and IS-7 relieved inflammatory symptoms and lung tissue destruction in the ALI mouse model. Overall, our study suggested that LK2(6)A(L) showed promising anti-inflammatory activity by targeting MD2, and the amino acid domain 7-13 was an important area that binds with MD2 and also an anti-inflammatory active region. LK2(6)A(L) and IS-7 may be potential new treatments for ALI and other acute inflammatory diseases.
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Affiliation(s)
- Juan Zhang
- School of Life Science, Liaoning Normal University, Dalian 116081, China
| | - Yue Sun
- School of Life Science, Liaoning Normal University, Dalian 116081, China; Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116081, China
| | - Chengpeng Sun
- College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Dejing Shang
- School of Life Science, Liaoning Normal University, Dalian 116081, China; Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116081, China.
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16
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Zhang M, Zhang J, Zhu QM, Zhao WY, Lv X, Yi J, Huo XK, Wang MJ, Sun CP. Inula japonica ameliorated the inflammation and oxidative stress in LPS-induced acute lung injury through the MAPK/NF-κB and Keap1/Nrf2 signalling pathways. J Pharm Pharmacol 2023; 75:287-299. [PMID: 36617177 DOI: 10.1093/jpp/rgac084] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 10/15/2022] [Indexed: 01/09/2023]
Abstract
OBJECTIVES To investigate the protective effect and underlying mechanism of Inula japonica (TEIJ) in the treatment of acute lung injury (ALI). METHODS Protective effects of TEIJ in the inflammation and oxidative stress were studied in lipopolysaccharide (LPS)-induced ALI mice. Meanwhile, Western blot and real-time qPCR were carried out to investigate the underlying mechanism of TEIJ for ALI as well as immunohistochemistry. KEY FINDINGS TEIJ significantly alleviated the course of ALI via suppressing the interstitial infiltrated inflammatory cells, the increase of inflammatory factors and the decrease of anti-oxidative factors. TEIJ inactivated the MAPK/NF-κB signalling pathway to suppress the transcription of its downstream target genes, such as TNF-α, IL-6, etc. Meanwhile, TEIJ activated the Keap1/Nrf2 signalling pathway to regulate expression levels of Nrf2 and its target proteins. The results of LC-QTOF-MS/MS indicated potential active constituents of I. japonica, terpenoids and flavonoids. Additionally, terpenoids and flavonoids synergistically alleviated LPS-induced ALI depending on MAPK/NF-κB and Keap1/Nrf2 signalling pathways. CONCLUSION I. japonica could be considered a potential agent to treat ALI via regulating the MAPK/NF-κB and Keap1/Nrf2 signalling pathways.
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Affiliation(s)
- Min Zhang
- College of Pharmacy, College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China.,Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Juan Zhang
- College of Pharmacy, College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China.,School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China
| | - Qi-Meng Zhu
- College of Pharmacy, College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Wen-Yu Zhao
- College of Pharmacy, College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Xia Lv
- College of Pharmacy, College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Jing Yi
- College of Pharmacy, College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Xiao-Kui Huo
- College of Pharmacy, College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Mi-Jia Wang
- Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Cheng-Peng Sun
- College of Pharmacy, College (Institute) of Integrative Medicine, Dalian Medical University, Dalian, China
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17
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Infante B, Conserva F, Pontrelli P, Leo S, Stasi A, Fiorentino M, Troise D, dello Strologo A, Alfieri C, Gesualdo L, Castellano G, Stallone G. Recent advances in molecular mechanisms of acute kidney injury in patients with diabetes mellitus. Front Endocrinol (Lausanne) 2023; 13:903970. [PMID: 36686462 PMCID: PMC9849571 DOI: 10.3389/fendo.2022.903970] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 12/14/2022] [Indexed: 01/06/2023] Open
Abstract
Several insults can lead to acute kidney injury (AKI) in native kidney and transplant patients, with diabetes critically contributing as pivotal risk factor. High glucose per se can disrupt several signaling pathways within the kidney that, if not restored, can favor the instauration of mechanisms of maladaptive repair, altering kidney homeostasis and proper function. Diabetic kidneys frequently show reduced oxygenation, vascular damage and enhanced inflammatory response, features that increase the kidney vulnerability to hypoxia. Importantly, epidemiologic data shows that previous episodes of AKI increase susceptibility to diabetic kidney disease (DKD), and that patients with DKD and history of AKI have a generally worse prognosis compared to DKD patients without AKI; it is therefore crucial to monitor diabetic patients for AKI. In the present review, we will describe the causes that contribute to increased susceptibility to AKI in diabetes, with focus on the molecular mechanisms that occur during hyperglycemia and how these mechanisms expose the different types of resident renal cells to be more vulnerable to maladaptive repair during AKI (contrast- and drug-induced AKI). Finally, we will review the list of the existing candidate biomarkers of diagnosis and prognosis of AKI in patients with diabetes.
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Affiliation(s)
- Barbara Infante
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Francesca Conserva
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Paola Pontrelli
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Serena Leo
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Alessandra Stasi
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Marco Fiorentino
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Dario Troise
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | | | - Carlo Alfieri
- Nephrology, Dialysis and Renal Transplant Unit, Department of Clinical Sciences and Community Health, University of Milan, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Renal Transplant Unit, Department of Clinical Sciences and Community Health, University of Milan, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giovanni Stallone
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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18
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Muacevic A, Adler JR, Horinishi Y, Sano C, Ohta R. A Case of Capillary Leak Syndrome and Intestinal Ischemia Caused by Rheumatoid Vasculitis. Cureus 2023; 15:e33404. [PMID: 36751197 PMCID: PMC9899103 DOI: 10.7759/cureus.33404] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/05/2023] [Indexed: 01/07/2023] Open
Abstract
Rheumatoid vasculitis (RV) is a rare disease associated with rheumatoid arthritis (RA). The incidence of RV has decreased with the development of treatment for RA. However, some patients still develop RV in rural areas, where medical care for autoimmune diseases is inadequate. In this report, we describe a case of RV complicated by an acute exacerbation of generalized ulcerative lesions and capillary leak syndrome in an 86-year-old woman with a severe joint deformity due to RA. RV is a systemic vasculitis characterized by various symptoms. When a patient with RA is diagnosed with poorly controlled joint deformities, general physicians should consider the possibility of RV. Urgent investigation and intensive treatment should be initiated for vasculitis to support the lives of older patients with advanced RA.
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19
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Le Guern F, Gaucher A, Cosentino G, Lagune M, Haagsman HP, Roux AL, Prim D, Rottman M. Labeled TEMPO-Oxidized Mannan Differentiates Binding Profiles within the Collectin Families. Int J Mol Sci 2022; 23:16067. [PMID: 36555720 PMCID: PMC9786299 DOI: 10.3390/ijms232416067] [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: 11/03/2022] [Revised: 12/05/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Establishing the rapid and accurate diagnosis of sepsis is a key component to the improvement of clinical outcomes. The ability of analytical platforms to rapidly detect pathogen-associated molecular patterns (PAMP) in blood could provide a powerful host-independent biomarker of sepsis. A novel concept was investigated based on the idea that a pre-bound and fluorescent ligand could be released from lectins in contact with high-affinity ligands (such as PAMPs). To create fluorescent ligands with precise avidity, the kinetically followed TEMPO oxidation of yeast mannan and carbodiimide coupling were used. The chemical modifications led to decreases in avidity between mannan and human collectins, such as the mannan-binding lectin (MBL) and human surfactant protein D (SP-D), but not in porcine SP-D. Despite this effect, these fluorescent derivatives were captured by human lectins using highly concentrated solutions. The resulting fluorescent beads were exposed to different solutions, and the results showed that displacements occur in contact with higher affinity ligands, proving that two-stage competition processes can occur in collectin carbohydrate recognition mechanisms. Moreover, the fluorescence loss depends on the discrepancy between the respective avidities of the recognized ligand and the fluorescent mannan. Chemically modulated fluorescent ligands associated with a diversity of collectins may lead to the creation of diagnostic tools suitable for multiplex array assays and the identification of high-avidity ligands.
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Affiliation(s)
- Florent Le Guern
- Institut Lavoisier de Versailles, CNRS, UVSQ, Université Paris-Saclay, 78035 Versailles, France
- Faculté de Médecine Simone Veil, Université de Versailles St Quentin, INSERM UMR U1173, 2 Avenue de la Source de la Bièvre, 78180 Montigny le Bretonneux, France
| | - Anne Gaucher
- Institut Lavoisier de Versailles, CNRS, UVSQ, Université Paris-Saclay, 78035 Versailles, France
| | - Gina Cosentino
- Faculté de Médecine Simone Veil, Université de Versailles St Quentin, INSERM UMR U1173, 2 Avenue de la Source de la Bièvre, 78180 Montigny le Bretonneux, France
| | - Marion Lagune
- Faculté de Médecine Simone Veil, Université de Versailles St Quentin, INSERM UMR U1173, 2 Avenue de la Source de la Bièvre, 78180 Montigny le Bretonneux, France
| | - Henk P. Haagsman
- Section Molecular Host Defence, Division Infectious Diseases & Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CS Utrecht, The Netherlands
| | - Anne-Laure Roux
- Hôpital Raymond Poincaré, AP-HP, GHU Paris Saclay, 104 Bd Poincaré, 92380 Garches, France
- Plateforme des Biomarqueurs Innovants, 104 Bd Poincaré, 92380 Garches, France
| | - Damien Prim
- Institut Lavoisier de Versailles, CNRS, UVSQ, Université Paris-Saclay, 78035 Versailles, France
| | - Martin Rottman
- Faculté de Médecine Simone Veil, Université de Versailles St Quentin, INSERM UMR U1173, 2 Avenue de la Source de la Bièvre, 78180 Montigny le Bretonneux, France
- Hôpital Raymond Poincaré, AP-HP, GHU Paris Saclay, 104 Bd Poincaré, 92380 Garches, France
- Plateforme des Biomarqueurs Innovants, 104 Bd Poincaré, 92380 Garches, France
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20
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Zhang J, Zhang M, Zhang WH, Zhu QM, Ning J, Huo XK, Xiao HT, Sun CP. Total terpenoids of Inula japonica activated the Nrf2 receptor to alleviate the inflammation and oxidative stress in LPS-induced acute lung injury. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 107:154377. [PMID: 36116200 DOI: 10.1016/j.phymed.2022.154377] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/15/2022] [Accepted: 08/01/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Acute lung injury (ALI) is a life-threatening lung disease and characterized by pulmonary edema and atelectasis. Inula japonica Thunb. is a commonly used traditional Chinese medicine for the treatment of lung diseases. However, the potential effect and mechanism of total terpenoids of I. japonica (TTIJ) on ALI remain obscure. PURPOSE This study focused on the protective effect of TTIJ on lipopolysaccharide (LPS)-induced ALI in mice and its potential mechanism. STUDY DESIGN AND METHODS A mouse model of ALI was established by intratracheal instillation of LPS to investigate the protective effect of TTIJ. RNA-seq and bioinformatics were then performed to reveal the underlying mechanism. Finally, western blot and real-time qPCR were used to verify the effects of TTIJ on the inflammation and oxidative stress. RESULTS TTIJ notably attenuated LPS-induced histopathological changes of lung. The RNA-seq result suggested that the protective effect of TTIJ on LPS-induced ALI were associated with the Toll-like receptor 4 (TLR4) and nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathways. Pretreatment with TTIJ significantly reduced the inflammation and oxidative stress via regulating levels of pro-inflammatory and anti-oxidative cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD), and glutathione (GSH), in LPS-induced ALI mice. TTIJ treatment could suppress the cyclooxygenase-2 (COX-2) expression level and the phosphorylation of p65, p38, ERK, and JNK through the inactivation of the MAPK/NF-κB signaling pathway in a TLR4-independent manner. Meanwhile, TTIJ treatment upregulated expression levels of proteins involved in the Nrf2 signaling pathway, such as heme oxygenase-1 (HO-1), NAD(P)H: quinoneoxidoreductase-1 (NQO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and glutamate-cysteine ligase modifier subunit (GCLM), via activating the Nrf2 receptor, which was confirmed by the luciferase assay. CONCLUSION TTIJ could activate the Nrf2 receptor to alleviate the inflammatory response and oxidative stress in LPS-induced ALI mice, which suggested that TTIJ could serve as the potential agent in the treatment of ALI.
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Affiliation(s)
- Juan Zhang
- College of Civil and Transportation Engineering, Shenzhen University, Shenzhen, China; School of pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China; Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Min Zhang
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Wen-Hao Zhang
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Qi-Meng Zhu
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Jing Ning
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Xiao-Kui Huo
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China.
| | - Hai-Tao Xiao
- School of pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China.
| | - Cheng-Peng Sun
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China.
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Zhang J, Zhang M, Zhang WH, Zhu QM, Huo XK, Sun CP, Ma XC, Xiao HT. Total flavonoids of Inula japonica alleviated the inflammatory response and oxidative stress in LPS-induced acute lung injury via inhibiting the sEH activity: Insights from lipid metabolomics. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 107:154380. [PMID: 36150346 DOI: 10.1016/j.phymed.2022.154380] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/04/2022] [Accepted: 08/02/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Acute lung injury (ALI) is a severe respiratory disease characterized by diffuse lung interstitial and respiratory distress and pulmonary edema with a mortality rate of 35%-40%. Inula japonica Thunb., known as "Xuan Fu Hua" in Chinese, is a traditional Chinese medicine Inulae Flos to use for relieving cough, eliminating expectorant, and preventing bacterial infections in the clinic, and possesses an anti-pulmonary fibrosis effect. However, the effect and action mechanism of I. japonica on ALI is still unclear. PURPOSE This study aimed to investigate the protective effect and underlying mechanism of total flavonoids of I. japonica (TFIJ) in the treatment of ALI. STUDY DESIGN AND METHODS A mouse ALI model was established through administration of LPS by the intratracheal instillation. Protective effects of TFIJ in the inflammation and oxidative stress were studied in LPS-induced ALI mice based on inflammatory and oxidative stress factors, including MDA, MPO, SOD, and TNF-α. Lipid metabolomics, bioinformatics, Western blot, quantitative real-time PCR, and immunohistochemistry were performed to reveal the potential mechanism of TFIJ in the treatment of ALI. RESULTS TFIJ significantly alleviated the interstitial infiltration of inflammatory cells and the collapse of the alveoli in LPS-induced ALI mice. Lipid metabolomics demonstrated that TFIJ could significantly affect the CYP2J/sEH-mediated arachidonic acid metabolism, such as 11,12-EET, 14,15-EET, 8,9-DHET, 11,12-DHET, and 14,15-DHET, revealing that sEH was the potential target of TFIJ, which was further supported by the recombinant sEH-mediated the substrate hydrolysis in vitro (IC50 = 1.18 μg/ml). Inhibition of sEH by TFIJ alleviated the inflammatory response and oxidative stress via the MAPK, NF-κB, and Nrf2 signaling pathways. CONCLUSION These results demonstrated that TFIJ could suppress the sEH activity to stabilize the level of EETs, allowing the alleviation of the pathological course of lung injury in LPS-treated mice, which suggested that TFIJ could serve as the potential agents in the treatment of ALI.
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Affiliation(s)
- Juan Zhang
- School of pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China; Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Min Zhang
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Wen-Hao Zhang
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Qi-Meng Zhu
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Xiao-Kui Huo
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Cheng-Peng Sun
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China.
| | - Xiao-Chi Ma
- Second Affiliated Hospital, College of Pharmacy, Dalian Medical University, Dalian, China.
| | - Hai-Tao Xiao
- School of pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China.
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22
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Yadav S, Priya A, Borade DR, Agrawal-Rajput R. Macrophage subsets and their role: co-relation with colony-stimulating factor-1 receptor and clinical relevance. Immunol Res 2022; 71:130-152. [PMID: 36266603 PMCID: PMC9589538 DOI: 10.1007/s12026-022-09330-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 10/14/2022] [Indexed: 01/10/2023]
Abstract
Macrophages are one of the first innate immune cells to reach the site of infection or injury. Diverse functions from the uptake of pathogen or antigen, its killing, and presentation, the release of pro- or anti-inflammatory cytokines, activation of adaptive immune cells, clearing off tissue debris, tissue repair, and maintenance of tissue homeostasis have been attributed to macrophages. Besides tissue-resident macrophages, the circulating macrophages are recruited to different tissues to get activated. These are highly plastic cells, showing a spectrum of phenotypes depending on the stimulus received from their immediate environment. The macrophage differentiation requires colony-stimulating factor-1 (CSF-1) or macrophage colony-stimulating factor (M-CSF), colony-stimulating factor-2 (CSF-2), or granulocyte–macrophage colony-stimulating factor (GM-CSF) and different stimuli activate them to different phenotypes. The richness of tissue macrophages is precisely controlled via the CSF-1 and CSF-1R axis. In this review, we have given an overview of macrophage origin via hematopoiesis/myelopoiesis, different phenotypes associated with macrophages, their clinical significance, and how they are altered in various diseases. We have specifically focused on the function of CSF-1/CSF-1R signaling in deciding macrophage fate and the outcome of aberrant CSF-1R signaling in relation to macrophage phenotype in different diseases. We further extend the review to briefly discuss the possible strategies to manipulate CSF-1R and its signaling with the recent updates.
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Affiliation(s)
- Shivani Yadav
- Immunology Lab, Indian Institute of Advanced Research, Gandhinagar, 382426, Gujarat, India
| | - Astik Priya
- Immunology Lab, Indian Institute of Advanced Research, Gandhinagar, 382426, Gujarat, India
| | - Diksha R Borade
- Immunology Lab, Indian Institute of Advanced Research, Gandhinagar, 382426, Gujarat, India
| | - Reena Agrawal-Rajput
- Immunology Lab, Indian Institute of Advanced Research, Gandhinagar, 382426, Gujarat, India.
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23
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Comparison of Short- and Long-Term Mortality in Patients with or without Cancer Admitted to the ICU for Septic Shock: A Retrospective Observational Study. Cancers (Basel) 2022; 14:cancers14133196. [PMID: 35804966 PMCID: PMC9264783 DOI: 10.3390/cancers14133196] [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: 06/10/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 12/10/2022] Open
Abstract
Introduction: Cancer patients are at high risk of developing septic shock (SSh) and are increasingly admitted to ICU given their improved long-term prognosis. We, therefore, compared the prognosis of cancer and non-cancer patients with SSh. Methods: We conducted a monocentric, retrospective cohort study (2013−2019) on patients admitted to ICU for SSh. We compared the clinical characteristics and management and studied short- and long-term mortality with ICU and in-hospital mortality and 1-year survival according to cancer status. Results: We analyzed 239 ICU stays in 210 patients, 59.5% of whom were men (n = 125), with a median age of 66.5 (IQR 56.3−77.0). Of the 121 cancer patients (57.6% of all patients), 70 had solid tumors (33.3%), and 51 had hematological malignancies (24.3%). When comparing ICU stays of patients with versus without cancer (n = 148 vs. n = 91 stays, respectively), mortality reached 30.4% (n = 45) vs. 30.0% (n = 27) in the ICU (p = 0.95), and 41.6% (n = 59) vs. 35.6% (n = 32) in hospital (p = 0.36), respectively. ICU length of stay (LOS) was 5.0 (2.0−11.3) vs. 6.0 (3.0−15.0) days (p = 0.27), whereas in-hospital LOS was 25.5 (13.8−42.0) vs. 19.5 (10.8−41.0) days (p = 0.33). Upon multivariate analysis, renal replacement therapy (OR = 2.29, CI95%: 1.06−4.93, p = 0.03), disseminated intravascular coagulation (OR = 5.89, CI95%: 2.49−13.92, p < 0.01), and mechanical ventilation (OR = 7.85, CI95%: 2.90−21.20, p < 0.01) were associated with ICU mortality, whereas malignancy, hematological, or solid tumors were not (OR = 1.41, CI95%: 0.65−3.04; p = 0.38). Similarly, overall cancer status was not associated with in-hospital mortality (OR = 1.99, CI95%: 0.98−4.03, p = 0.06); however, solid cancers were associated with increased in-hospital mortality (OR = 2.52, CI95%: 1.12−5.67, p = 0.03). Lastly, mortality was not significantly different at 365-day follow-up between patients with and without cancer. Conclusions: In-hospital and ICU mortality, as well as LOS, were not different in SSh patients with and without cancer, suggesting that malignancies should no longer be considered a barrier to ICU admission.
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Anter A, Ahmed ASF, Hammad ASA, Almalki WH, Abdel Hafez SMN, Kasem AW, El-Moselhy MA, Alrabia MW, Ibrahim ARN, El-Daly M. The Severity of Acute Kidney and Lung Injuries Induced by Cecal Ligation and Puncture Is Attenuated by Menthol: Role of Proliferating Cell Nuclear Antigen and Apoptotic Markers. Front Med (Lausanne) 2022; 9:904286. [PMID: 35814769 PMCID: PMC9260148 DOI: 10.3389/fmed.2022.904286] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 05/16/2022] [Indexed: 11/24/2022] Open
Abstract
Objective Sepsis-induced acute lung injury (ALI) and acute kidney injury (AKI) are major causes of mortality. Menthol is a natural compound that has anti-inflammatory and antioxidative actions. Since exaggerated inflammatory and oxidative stress are characteristics of sepsis, the aim of this study was to evaluate the effect of menthol against sepsis-induced mortality, ALI, and AKI. Methods The cecal ligation and puncture (CLP) procedure was employed as a model of sepsis. Rats were grouped into sham, sham-Menthol, CLP, and CLP-Menthol (100 mg/kg, p.o). Key Findings A survival study showed that menthol enhanced the survival after sepsis from 0% in septic group to 30%. Septic rats developed histological evidence of ALI and AKI. Menthol markedly suppressed sepsis induced elevation of tissue TNF-a, ameliorated sepsis-induced cleavage of caspase-3 and restored the antiapoptotic marker Bcl2. Significance We introduced a role of the proliferating cell nuclear antigen (PCNA) in these tissues with a possible link to the damage induced by sepsis. PCNA level was markedly reduced in septic animals and menthol ameliorated this effect. Our data provide novel evidence that menthol protects against organ damage and decreases mortality in experimental sepsis.
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Affiliation(s)
- Aliaa Anter
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
| | - Al-Shaimaa F. Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
- *Correspondence: Al-Shaimaa F. Ahmed,
| | - Asmaa S. A. Hammad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
| | - Waleed Hassan Almalki
- Department of Pharmacology and Toxicology, Umm Al-Qura University, Makkah, Saudi Arabia
| | | | - AlShaimaa W. Kasem
- Department of Pathology, Faculty of Medicine, Minia University, Minya, Egypt
| | - Mohamed A. El-Moselhy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
- Department of Clinical Pharmacy and Pharmacology, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia
| | - Mohammad W. Alrabia
- Department of Microbiology and Medical Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ahmed R. N. Ibrahim
- Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minya, Egypt
| | - Mahmoud El-Daly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
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Clinical Value of Prognostic Nutritional Index and Neutrophil-to-Lymphocyte Ratio in Prediction of the Development of Sepsis-Induced Kidney Injury. DISEASE MARKERS 2022; 2022:1449758. [PMID: 35711566 PMCID: PMC9197608 DOI: 10.1155/2022/1449758] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/17/2022] [Accepted: 05/25/2022] [Indexed: 11/27/2022]
Abstract
Background Sepsis-related acute kidney injury (S-AKI) is a frequent complication of hospitalized patients and is linked to increased morbidity and mortality. Early prediction and detection remain conducive to optimizing treatment strategies and limiting further insults. This study was aimed at evaluating the potential predictive value of the combined prognostic nutrition index (PNI) and neutrophil-to-lymphocyte ratio (NLR) to predict the risk of AKI in septic patients. Methods In this retrospective study, 1238 adult patients with sepsis who were admitted to the First Affiliated Hospital of Xi'an Jiaotong University from January 2015 to June 2021 were enrolled. Patients were divided into two groups: the non-AKI group (n = 731) and the S-AKI group (n = 507). Univariate and multivariate logistic regression analyses were performed to screen the independent predictive factors of S-AKI. A receiver operating characteristic (ROC) curve was used to evaluate the predictive value of PNI and NLR. Results Multivariate logistic regression analysis indicated that age, chronic liver disease, cardiovascular disease, respiratory rate (RR), white blood cells (WBC), blood urea nitrogen (BUN), creatinine (CRE), international normalized ratio (INR), neutrophil-to-lymphocyte ratio (NLR), and prognostic nutrition index (PNI) were independent prognostic factors of S-AKI. In the three models, the adjusted OR of PNI for S-AKI was 0.802 (0.776-0.829), 0.801 (0.775-0.829), and 0.717 (0.666-0.772), while that of NLR was 1.094 (1.078-1.111), 1.097 (1.080-1.114), and 1.044 (1.016-1.072), respectively. In addition, the area under the ROC curve of the PNI plus NLR group was significantly greater than that of the CRE plus BUN group (0.801, 95% CI: 0.775-0.827 vs. 0.750, 95% CI: 0.722-0.778, respectively; P < 0.001). Conclusions PNI and NLR have been identified as readily available and independent predictors in septic patients with S-AKI. PNI, in combination with NLR, is of vital significance for early warning and efficient intervention of S-AKI and is superior to combined BUN and CRE.
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Yang K, Holt M, Fan M, Lam V, Yang Y, Ha T, Williams DL, Li C, Wang X. Cardiovascular Dysfunction in COVID-19: Association Between Endothelial Cell Injury and Lactate. Front Immunol 2022; 13:868679. [PMID: 35401579 PMCID: PMC8984030 DOI: 10.3389/fimmu.2022.868679] [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: 02/03/2022] [Accepted: 03/01/2022] [Indexed: 12/27/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), an infectious respiratory disease propagated by a new virus known as Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has resulted in global healthcare crises. Emerging evidence from patients with COVID-19 suggests that endothelial cell damage plays a central role in COVID-19 pathogenesis and could be a major contributor to the severity and mortality of COVID-19. Like other infectious diseases, the pathogenesis of COVID-19 is closely associated with metabolic processes. Lactate, a potential biomarker in COVID-19, has recently been shown to mediate endothelial barrier dysfunction. In this review, we provide an overview of cardiovascular injuries and metabolic alterations caused by SARS-CoV-2 infection. We also propose that lactate plays a potential role in COVID-19-driven endothelial cell injury.
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Affiliation(s)
- Kun Yang
- Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Matthew Holt
- James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Min Fan
- Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Victor Lam
- College of Arts and Science, New York University, New York City, NY, United States
| | - Yong Yang
- James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Tuanzhu Ha
- Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - David L. Williams
- Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Chuanfu Li
- Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Xiaohui Wang
- Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
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Haertel F, Reisberg D, Peters M, Nuding S, Schulze PC, Werdan K, Ebelt H. Predicting the Need for Renal Replacement Therapy Using a Vascular Occlusion Test and Tissue Oxygen Saturation in Patients in the Early Phase of Multiorgan Dysfunction Syndrome. J Clin Med 2022; 11:jcm11051420. [PMID: 35268511 PMCID: PMC8911273 DOI: 10.3390/jcm11051420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/19/2022] [Accepted: 03/02/2022] [Indexed: 11/25/2022] Open
Abstract
Background: Acute kidney injury (AKI) is associated with an increased mortality in critically ill patients, especially in patients with multiorgan dysfunction syndrome (MODS). In daily clinical practice, the grading of AKI follows the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. In most cases, a relevant delay occurs frequently between the onset of AKI and detectable changes in creatinine levels as well as clinical symptoms. The aim of the present study was to examine whether a near infrared spectroscopy (NIRS)-based, non-invasive ischemia–reperfusion test (vascular occlusion test (VOT)) together with unprovoked (under resting conditions) tissue oxygen saturation (StO2) measurements, contain prognostic information in the early stage of MODS regarding the developing need for renal replacement therapy (RRT). Methods: Within a period of 18 months, patients at the medical intensive care unit of a tertiary university hospital with newly developed MODS (≤24 h after diagnosis, APACHE II score ≥20) were included in our study. The VOT occlusion slope (OS) and recovery slope (RS) were recorded in addition to unprovoked StO2. StO2 was determined non-invasively in the area of the thenar muscles using a bedside NIRS device. The VOT was carried out by inflating a blood pressure cuff on the upper arm. AKI stages were determined by the changes in creatinine levels, urinary output, and/or the need for RRT according to KDIGO. Results: 56 patients with MODS were included in the study (aged 62.5 ± 14.4 years, 40 men and 16 women, APACHE II score 34.5 ± 6.4). Incidences of the different AKI stages were: no AKI, 16.1% (n = 9); AKI stage I, 19.6% (n = 11); AKI stage II, 25% (n = 14); AKI stage III, 39.3% (n = 22). Thus, 39.3% of the patients (n = 22) developed the need for renal replacement therapy (AKI stage III). These patients had a significantly higher mortality over 28 days (RRT, 72% (n = 16/22) vs. no RRT, 44% (n = 15/34); p = 0.03). The mean unprovoked StO2 of all patients at baseline was 81.7 ± 11.1%, and did not differ between patients with or without the need for RRT. Patients with RRT showed significantly weaker negative values of the OS (−9.1 ± 3.7 vs. −11.7 ± 4.1%/min, p = 0.01) and lower values for the RS (1.7 ± 0.9 vs. 2.3 ± 1.6%/s, p = 0.02) compared to non-dialysis patients. Consistent with these results, weaker negative values of the OS were found in higher AKI stages (no AKI, −12.7 ± 4.1%/min; AKI stage I, −11.5 ± 3.0%/min; AKI stage II, −11.1 ± 3.3%/min; AKI stage III, −9.1 ± 3.7%/min; p = 0.021). Unprovoked StO2 did not contain prognostic information regarding the AKI stages. Conclusions: The weaker negative values of the VOT parameter OS are associated with an increased risk of developing AKI and RRT, and increased mortality in the early phase of MODS, while unprovoked StO2 does not contain prognostic information in that regard.
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Affiliation(s)
- Franz Haertel
- Klinik für Innere Medizin I, Universitaetsklinikum Jena, Am Klinikum 1, 07747 Jena, Germany;
- Klinik für Innere Medizin III, Universitaetsklinikum Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany; (D.R.); (M.P.); (S.N.); (K.W.); (H.E.)
- Correspondence: ; Tel.: +49-3641-9324-554
| | - Diana Reisberg
- Klinik für Innere Medizin III, Universitaetsklinikum Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany; (D.R.); (M.P.); (S.N.); (K.W.); (H.E.)
- Klinik für Pädiatrie, Ameos Klinikum Aschersleben, Eislebener Str. 7A, 06449 Aschersleben, Germany
| | - Martin Peters
- Klinik für Innere Medizin III, Universitaetsklinikum Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany; (D.R.); (M.P.); (S.N.); (K.W.); (H.E.)
- Klinik für Innere Medizin, Helios Klinikum Jerichower Land, August-Bebel-Str. 55a, 39288 Burg, Germany
| | - Sebastian Nuding
- Klinik für Innere Medizin III, Universitaetsklinikum Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany; (D.R.); (M.P.); (S.N.); (K.W.); (H.E.)
- Klinik für Innere Medizin II, Krankenhaus “St. Elisabeth”, Mauerstr. 5, 06110 Halle (Saale), Germany
| | - P. Christian Schulze
- Klinik für Innere Medizin I, Universitaetsklinikum Jena, Am Klinikum 1, 07747 Jena, Germany;
| | - Karl Werdan
- Klinik für Innere Medizin III, Universitaetsklinikum Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany; (D.R.); (M.P.); (S.N.); (K.W.); (H.E.)
| | - Henning Ebelt
- Klinik für Innere Medizin III, Universitaetsklinikum Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany; (D.R.); (M.P.); (S.N.); (K.W.); (H.E.)
- Klinik für Innere Medizin II, Katholisches Krankenhaus “St. Johann Nepomuk”, Haarbergstr. 72, 99097 Erfurt, Germany
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Ohta R, Ikeda H, Kubota S, Sano C. Acute Cholecystitis in an Elderly Patient With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Case Report. Cureus 2022; 14:e21877. [PMID: 35265413 PMCID: PMC8898073 DOI: 10.7759/cureus.21877] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/03/2022] [Indexed: 11/25/2022] Open
Abstract
A diagnosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is difficult to establish in elderly patients. Herein, we report a case of acute cholecystitis mimicking sepsis in an elderly patient with ANCA-associated vasculitis. A 99-year-old woman was transferred to a rural community hospital on account of anorexia and hypotension; there, she was initially diagnosed with sepsis and treated accordingly. However, she developed new-onset right upper quadrant tenderness on indirect fist percussion of the liver, and Murphy’s sign was positive. While imaging did not reveal any findings suggestive of cholecystitis, the high index of suspicion for cholecystitis prompted an exploratory laparoscopy. Intraoperatively, the gallbladder wall was found to be inflamed, necessitating laparoscopic cholecystectomy. Histopathologic examination of the resected gallbladder showed neutrophilic infiltration and fibrinoid necrosis of the arterial walls. Perinuclear ANCA titers were elevated. These findings were consistent with a diagnosis of ANCA-associated vasculitis, and treatment with prednisolone markedly improved her condition. This case shows the difficulty encountered in differentiating between sepsis and ANCA-related vasculitis based on clinical features and relatively non-invasive diagnostic strategies alone. This study highlights the utility of invasive diagnostic procedures (e.g., biopsy) in elderly patients in whom a diagnosis of ANCA-associated vasculitis is difficult to establish.
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Zou R, Tao J, Qiu J, Lu H, Wu J, Zhu H, Li R, Mui D, Toan S, Chang X, Zhou H, Fan X. DNA-PKcs promotes sepsis-induced multiple organ failure by triggering mitochondrial dysfunction. J Adv Res 2022; 41:39-48. [PMID: 36328752 PMCID: PMC9637726 DOI: 10.1016/j.jare.2022.01.014] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 01/24/2022] [Accepted: 01/27/2022] [Indexed: 11/29/2022] Open
Abstract
DNA-PKcs inhibition attenuates sepsis-related MODS by preserving mitochondrial function and homeostasis. Organ-specific deletion of DNA-PKcs sustained myocardial contraction, liver function, and kidney performance in LPS-challenged mice. DNA-PKcs deficiency supported cardiomyocyte function through improving mitochondrial respiration. DNA-PKcs deficiency alleviated liver dysfunction by inhibiting LPS-induced mitochondrial oxidative stress and apoptosis. DNA-PKcs deficiency attenuated kidney dysfunction by normalizing mitochondrial dynamics and biogenesis, as well as mitophagy. Introduction Multiple organ failure is the commonest cause of death in septic patients. Objectives This study was undertaken in an attempt to elucidate the functional importance of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) on mitochondrial dysfunction associated with the development and progression of sepsis-related multiple organ dysfunction syndrome (MODS). Methods Cardiomyocyte-specific DNA-PKcs knockout (DNA-PKcsCKO) mice, liver-specific DNA-PKcs knockout (DNA-PKcsLKO) mice, and kidney tubular cell-specific DNA-PKcs knockout (DNA-PKcsTKO) mice were used to generate an LPS-induced sepsis model. Echocardiography, serum biochemistry, and tissue microscopy were used to analyze organ damage and morphological changes induced by sepsis. Mitochondrial function and dynamics were determined by qPCR, western blotting, ELISA, and mt-Keima and immunofluorescence assays following siRNA-mediated DNA-PKCs knockdown in cardiomyocytes, hepatocytes, and kidney tubular cells. Results DNA-PKcs deletion attenuated sepsis-mediated myocardial damage through improving mitochondrial metabolism. Loss of DNA-PKcs protected the liver against sepsis through inhibition of mitochondrial oxidative damage and apoptosis. DNA-PKcs deficiency sustained kidney function upon LPS stress through normalization of mitochondrial fission/fusion events, mitophagy, and biogenesis. Conclusion We conclude that strategies targeting DNA-PKcs expression or activity may be valuable therapeutic options to prevent or reduce mitochondrial dysfunction and organ damage associated with sepsis-induced MODS.
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Xu Z, Lin X, Zhu J, Zhu Z. Long noncoding RNAs Colorectal Neoplasia Differentially Expressed and taurine-upregulated gene 1 are downregulated in sepsis and positively regulate each other to suppress the apoptosis of cardiomyocytes. Bioengineered 2021; 12:11369-11375. [PMID: 34872438 PMCID: PMC8810183 DOI: 10.1080/21655979.2021.2008658] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) Colorectal Neoplasia Differentially Expressed (CRNDE) and taurine-upregulated gene 1 (TUG1) play similar roles in sepsis, indicating the existence of the crosstalk between them. Sepsis is a major cause of injuries in heart, which are related to high mortality rates. This study was therefore carried out to analyze the potential crosstalk between CRNDE and TUG1 in sepsis, with a focus on sepsis-induced cell apoptosis in heart. Expression of CRNDE and TUG1 was analyzed with RT-qPCR. Correlations between them were analyzed by Pearson’s correlation coefficient. CRNDE and TUG1 were overexpressed in cardiomyocytes to determine the relationship between them. The roles of CRNDE and TUG1 in regulating the apoptosis of cardiomyocytes were explored by cell apoptosis assay. We found that both CRNDE and TUG1 were downregulated in sepsis. In cardiomyocytes, LPS treatment resulted in the downregulation of CRNDE and TUG1. Overexpression of CRNDE and TUG1 in cardiomyocytes increased the expression levels of each other. Under lipopolysaccharide (LPS) treatment, decreased apoptosis rates of cardiomyocytes were observed after CRNDE and TUG1 overexpression. CRNDE and TUG1 co-overexpression showed a stronger effect. In conclusion, CRNDE and TUG1 are downregulated in sepsis and they positively regulate each other to suppress the apoptosis of cardiomyocytes.
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Affiliation(s)
- Zhenwei Xu
- Department of Emergency, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou City, Fujian Province, PR. China
| | - Xingyu Lin
- Department of Emergency, Fujian Medical University Union Hospital, Fuzhou City, Fujian Province, PR China
| | - Jingfa Zhu
- Department of Emergency, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou City, Fujian Province, PR. China
| | - Zhixia Zhu
- Department of Emergency, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou City, Fujian Province, PR. China
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Lin HC, Chiang HP, Jiang WP, Lan YH, Huang GJ, Hsieh MT, Kuo SC, Lo CL, Chiang YT. Exploitation of a rod-shaped, acid-labile curcumin-loaded polymeric nanogel system in the treatment of systemic inflammation. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 133:112597. [DOI: 10.1016/j.msec.2021.112597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 12/02/2021] [Accepted: 12/03/2021] [Indexed: 10/19/2022]
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Abstract
Liver failure in the context of acute (ALF) and acute on chronic liver failure (ACLF) is associated with high mortality in the absence of a liver transplant. For decades, therapeutic plasma exchange (TPE) is performed for the management of immune-mediated diseases. TPE has emerged as an attractive extracorporeal blood purification technique in patients with ALF and ACLF. The basic premise of using TPE is to remove the toxic substances which would allow recovery of native liver functions by facilitating liver regeneration. In recent years, encouraging data have emerged, suggesting the benefits of TPE in patients with liver failure. TPE has emerged as an attractive liver support device for the failing liver until liver transplantation or clinical recovery. The data in patients with ALF suggest routine use of high-volume TPE, while the data for such a strategy are less robust for patients with ACLF.
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Affiliation(s)
- Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Chen L, Han Z, Shi Z, Liu C, Lu Q. Melatonin Alleviates Renal Injury in Mouse Model of Sepsis. Front Pharmacol 2021; 12:697643. [PMID: 34539395 PMCID: PMC8443790 DOI: 10.3389/fphar.2021.697643] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 08/05/2021] [Indexed: 11/16/2022] Open
Abstract
Melatonin (N-acetyl-5-methoxytryptamine; MLT) has been shown to have a renal-protective effect against kidney injury. However, the mechanisms underlying the protective role of MLT in sepsis-induced renal injury are yet to be revealed. In this study, MLT alleviated renal dysfunction with the increase of BUN (blood urea nitrogen) and SCR (serum creatinine) and reduction of fibrosis in the CLP (cecal ligation puncture) model. RNA-seq analysis showed that MLT repressed the oxidant stress in response to kidney injury. Our in vitro study showed that MLT suppresses LPS-induced accumulation of ROS (reactive oxygen species) production via SOD2 downregulation and Nox4 upregulation in HK-2 cells. Furthermore, we found that MLT alleviated the inflammatory response, with the mRNA-level reduction of Il-1α, Il-1β, Mcp-1, and Tgf-β1. Taken together, in evaluating the therapeutic effect of MLT on sepsis-induced acute kidney injury, the results showed that MLT alleviated renal damage by regulating the production of ROS.
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Affiliation(s)
- Liyang Chen
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Zhijian Han
- The Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, China
| | - Zhiguang Shi
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Chao Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning, China
| | - Qiulun Lu
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China
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Lee J, Son W, Hong J, Song Y, Yang CS, Kim YH. Down-regulation of TNF-α via macrophage-targeted RNAi system for the treatment of acute inflammatory sepsis. J Control Release 2021; 336:344-353. [PMID: 34147573 DOI: 10.1016/j.jconrel.2021.06.022] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023]
Abstract
Sepsis is a systemic inflammatory response syndrome caused by bacterial infection. The sepsis therapy has involved prescription of adequate antibiotics, requiring several days to determine the proper type without reducing the inflammatory response. Thus, it is necessary to rapidly decrease fundamental inflammation, which can induce serious organ damage. In the inflammatory mechanism, tumor necrosis factor-alpha (TNF-α) produced by macrophages has an important role in infiltration of macrophages into infected sites and as a trigger for secretion of pro-inflammatory cytokines. However, commercialized TNF-α antibody medicines have limits such as fibrosis, cytokine storms, and high production costs. There is a growing need for anti-inflammatory sepsis treatment free from side effects. For this reason, TNF-α converting enzyme (TACE) could be an innovative target to break the positive feedback loop of inflammatory mediators (TNF-α) since it converts the inactive TNF-α membrane bound form to the activated soluble form in macrophages. A non-viral gene delivery system was developed in this study to deliver siRNA into inflammation-mediated macrophages without toxicity. The peptide-based gene carrier created by conjugating positively-charged nine arginine (9R) and the TKPR (Thr-Lys-Pro-Arg) sequence from the Fc region of Immunoglobulin G (IgG) specifically binds to the neuropilin-1 (NRP-1) receptor on the macrophage surface. Our results demonstrated that siTACE/TKPR-9R complexes were internalized in macrophages and successfully down-regulated TACE mRNA level. Finally, RNA interference with cell-targeted peptide carriers indicates a fundamental therapy for acute inflammatory sepsis free of off-target effects.
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Affiliation(s)
- Jieun Lee
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, Republic of Korea
| | - Wooic Son
- Department of Molecular and Life Science, Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Republic of Korea
| | - Juhyeong Hong
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, Republic of Korea
| | - Yoonsung Song
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, Republic of Korea
| | - Chul-Su Yang
- Department of Molecular and Life Science, Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Republic of Korea.
| | - Yong-Hee Kim
- Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, Republic of Korea.
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Ge Z, Huang J, Liu Y, Xiang J, Gao Y, Walline JH, Lu X, Yu S, Zhao L, Li Y. Thiamine combined with vitamin C in sepsis or septic shock: a systematic review and meta-analysis. Eur J Emerg Med 2021; 28:189-195. [PMID: 33709993 DOI: 10.1097/mej.0000000000000812] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Thiamine and vitamin C have been increasingly used in patients with sepsis or septic shock because of their potential for improving metabolism and reducing mortality. OBJECTIVE We aim to determine if thiamine combined vitamin C can reduce mortality in patients with sepsis or septic shock. EVIDENCE SOURCES AND STUDY SELECTION We comprehensively searched the PubMed, Embase, Cochrane Library, and Web of Science databases from their inception dates through 1 January 2021. Literature works evaluating the efficacy of thiamine combined vitamin C in patients with sepsis or septic shock were considered. DATA EXTRACTION AND OUTCOME MEASUREMENTS Two reviewers extracted data and assessed study quality. A meta-analysis was performed to calculate an odds ratio (OR), 95% confidence intervals (CIs), and P values for in-hospital mortality (primary outcome). Secondary outcomes included duration of ICU stay, duration of hospital stay, duration of vasopressor use, and change in sequential organ failure assessment (SOFA) scores. RESULTS Seven randomized controlled trials were identified, encompassing a total of 868 patients. There was no statistical difference between groups for in-hospital mortality (OR: 1.11; 95% CI [0.79-1.56]; P = 0.55). Other than improving SOFA score during the first 72 h after enrollment and duration of vasopressor use, we found no other significant associations. CONCLUSIONS Despite widespread enthusiasm for thiamine combined with vitamin C for sepsis and septic shock, we only found an association with reduced SOFA score and time of vasopressor use. There was no association with in-hospital mortality.
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Affiliation(s)
- Zengzheng Ge
- Emergency Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing
| | - Jiewu Huang
- Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou
| | - Yawei Liu
- Health Service Department of the Guard Bureau of the Joint Staff Department
| | - Jun Xiang
- General Medicine Department of Jingnan Medical Center, General Hospital of PLA, Beijing
| | - Yanxia Gao
- Department of Emergency, the First Affiliated Hospital of Zhengzhou University, Zhengzhou
| | - Joseph Harold Walline
- Accident and Emergency Medicine Academic Unit, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Xin Lu
- Emergency Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing
| | - Shiyuan Yu
- Emergency Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing
| | - Lina Zhao
- Emergency Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing
| | - Yi Li
- Emergency Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing
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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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Chen D, Hou Y, Cai X. MiR-210-3p Enhances Cardiomyocyte Apoptosis and Mitochondrial Dysfunction by Targeting the NDUFA4 Gene in Sepsis-Induced Myocardial Dysfunction. Int Heart J 2021; 62:636-646. [PMID: 33994501 DOI: 10.1536/ihj.20-512] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Sepsis-induced myocardial dysfunction (SIMD) is a common complication with high incidence rates in sepsis patients. This study aimed to investigate the roles of miR-210-3p in regulating cardiomyocyte apoptosis and mitochondrial dysfunction associated with SIMD pathogenesis.A rat sepsis model was established by cecal ligation and puncture. Serum inflammatory factors, myocardial tissue apoptosis, and expression of miR-210-3p were evaluated. In vitro, miR-210-3p expression in H9C2 cells was altered by transfection with its mimics or inhibitors. H9C2 viability was assessed via CCK-8 assay, and reactive oxygen species (ROS) production and apoptosis were detected through flow cytometry. The targeting regulatory relations between miR-210-3p and NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4 (NDUFA4) were validated by dual luciferase reporter assay.The rat sepsis model showed increased serum TNF-α and IL-6 levels, significant myocardial tissue injuries and apoptosis with decreased Bcl-2 and increased Caspase-1 protein levels. In vitro, septic rat serum suppressed viability, promoted ROS production and apoptosis, impaired COX IV activities and increased cytochrome release in H9C2 cells. The expression of miR-210-3p was greatly increased in myocardial tissues of septic rats and septic serum-treated H9C2 cells. miR-210-3p directly binds to the 3' UTR of the NDUFA4 gene. Septic rat serum suppressed NDUFA4 and Iron-Sulfur Cluster Assembly Protein U gene expressions in H9C2 cells. The above cellular and molecular alterations in H9C2 cells induced by septic serum were enhanced by miR-210-3p mimics and abrogated by miR-210-3p inhibitors.miR-210-3p promoted SIMD pathogenesis by targeting NDUFA4 to enhance cardiomyocyte apoptosis and impair mitochondrial function.
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Affiliation(s)
- Dandan Chen
- Department of Critical Care Medicine, Affiliated Haikou Hospital of Xiangya Medical College, Central South University
| | - Yu Hou
- Department of Critical Care Medicine, Affiliated Haikou Hospital of Xiangya Medical College, Central South University
| | - Xingjun Cai
- Department of Pulmonary and Critical Care Medicine, Hainan General Hospital
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The Use of Central Venous to Arterial Carbon Dioxide Tension Gap for Outcome Prediction in Critically Ill Patients: A Systematic Review and Meta-Analysis. Crit Care Med 2021; 48:1855-1861. [PMID: 33003080 DOI: 10.1097/ccm.0000000000004578] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVES In this systematic review and meta-analysis, we assessed whether a high CO2 gap predicts mortality in adult critically ill patients with circulatory shock. DATA SOURCES A systematic search of MEDLINE and EMBASE electronic databases from inception to October 2019. STUDY SELECTION Studies from adult (age ≥ 18 yr) ICU patients with shock reporting CO2 gap and outcomes of interest. Case reports and conference abstracts were excluded. DATA EXTRACTION Data extraction and study quality assessment were performed independently in duplicate. DATA SYNTHESIS We used the Newcastle-Ottawa Scale to assess methodological study quality. Effect sizes were pooled using a random-effects model. The primary outcome was mortality (28 d and hospital). Secondary outcomes were ICU length of stay, hospital length of stay, duration of mechanical ventilation, use of renal replacement therapy, use of vasopressors and inotropes, and association with cardiac index, lactate, and central venous oxygen saturation. CONCLUSIONS We included 21 studies (n = 2,155 patients) from medical (n = 925), cardiovascular (n = 685), surgical (n = 483), and mixed (n = 62) ICUs. A high CO2 gap was associated with increased mortality (odds ratio, 2.22; 95% CI, 1.30-3.82; p = 0.004) in patients with shock, but only those from medical and surgical ICUs. A high CO2 gap was associated with higher lactate levels (mean difference 0.44 mmol/L; 95% CI, 0.20-0.68 mmol/L; p = 0.0004), lower cardiac index (mean difference, -0.76 L/min/m; 95% CI, -1.04 to -0.49 L/min/m; p = 0.00001), and central venous oxygen saturation (mean difference, -5.07; 95% CI, -7.78 to -2.37; p = 0.0002). A high CO2 gap was not associated with longer ICU or hospital length of stays, requirement for renal replacement therapy, longer duration of mechanical ventilation, or higher vasopressors and inotropes use. Future studies should evaluate whether resuscitation aimed at closing the CO2 gap improves mortality in shock.
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Causes of Death and Survival in Alcoholic Cirrhosis Patients Undergoing Liver Transplantation: Influence of the Patient's Clinical Variables and Transplant Outcome Complications. Diagnostics (Basel) 2021; 11:diagnostics11060968. [PMID: 34072173 PMCID: PMC8227029 DOI: 10.3390/diagnostics11060968] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/20/2021] [Accepted: 05/24/2021] [Indexed: 11/17/2022] Open
Abstract
Background. Clinical and molecular mechanisms involved in the cause and time of death of alcoholic cirrhosis (AC) patients undergoing liver transplantation (LT) are not entirely understood. In sudden death cases, judicial autopsy practice is mandatory for determining the cause and circumstances of death. The medico-legal autopsy data are essential for helping health authorities to guide future public health activities, assess the effectiveness of health systems, and adopt the necessary preventive measures to improve and adapt the treatments in order to increase these patients’ survival. Objective. Our study aimed to determine the different clinical and sociodemographic causes that influence the different causes of death and the short- and long-term survival of AC patients undergoing liver transplantation. Methods. A total of 122 deceased AC patients undergoing LT were analyzed at different times post-transplantation. The main pre- and post-transplant complications were analyzed in relation to the cause of death and the patient’s survival, as well as the causes and time at which the patient’s death occurred. Results. A total of 53.3% of non-sudden death was observed. A large number of the deaths of AC patients undergoing transplantation were due to non-sudden death, sepsis, and graft failure (GF), the main causes of death in the sample being similar in both sexes. In non-sudden deaths, there were no significant differences between the death rates either related or not related to the liver transplant. Sepsis was the main cause, with the highest percentage (21.3%) of mortality, followed by GF (18.9%) and multiorgan failure (15.6%) at ten years. Furthermore, our results showed how pre-transplant clinical complications, such as viral infections and encephalopathy, influence the age at which multiorgan failure occurs in the transplanted patient. Conclusion. Multiorgan failure is the leading cause of sudden death, with higher mortality during the first year after transplantation, followed by sepsis and GF. Our results show the vulnerability of AC patients, both in the hospital period after the transplant and outside.
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Bayer J, Vaghela R, Drechsler S, Osuchowski MF, Erben RG, Andrukhova O. The bone is the major source of high circulating intact fibroblast growth factor-23 in acute murine polymicrobial sepsis induced by cecum ligation puncture. PLoS One 2021; 16:e0251317. [PMID: 33989306 PMCID: PMC8121358 DOI: 10.1371/journal.pone.0251317] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 04/23/2021] [Indexed: 12/20/2022] Open
Abstract
Fibroblast growth factor-23 (FGF23), a bone-produced hormone, plays a critical role in mineral homeostasis. Human diseases associated with excessive intact circulating FGF23 (iFGF23) result in hypophosphatemia and low vitamin D hormone in patients with normal kidney function. In addition, there is accumulating evidence linking FGF23 with inflammation. Based on these studies and the frequent observation of hypophosphatemia among septic patients, we sought to elucidate further the relationship between FGF23 and mineral homeostasis in a clinically relevant murine polymicrobial sepsis model. Medium-severity sepsis was induced by cecum ligation puncture (CLP) in adult CD-1 mice of both sexes. Healthy CD-1 mice (without CLP) were used as controls. Forty-eight hours post-CLP, spontaneous urine was collected, and serum, organs and bones were sampled at necropsy. Serum iFGF23 increased ~20-fold in CLP compared to control mice. FGF23 protein concentration was increased in the bones, but not in spleen or liver of CLP mice. Despite the ~20-fold iFGF23 increase, we did not observe any significant changes in mineral homeostasis or parathyroid hormone levels in the blood of CLP animals. Urinary excretion of phosphate, calcium, and sodium remained unchanged in male CLP mice, whereas female CLP mice exhibited lower urinary calcium excretion, relative to healthy controls. In line with renal FGF23 resistance, expression of phosphate-, calcium- and sodium-transporting proteins did not show consistent changes in the kidneys of male and female CLP mice. Renal expression of the co-receptor αKlotho was downregulated in female, but not in male CLP mice. In conclusion, our data demonstrate that the dramatic, sex-independent rise in serum iFGF23 post-CLP was mainly caused by an upregulation of FGF23 secretion in the bone. Surprisingly, the upsurge in circulating iFGF23 did not alter humoral mineral homeostasis in the acutely septic mice. Hence, the biological function of elevated FGF23 in sepsis remains unclear and warrants further studies.
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Affiliation(s)
- Jessica Bayer
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Ravikumar Vaghela
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Susanne Drechsler
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria
| | - Marcin F. Osuchowski
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria
| | - Reinhold G. Erben
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Olena Andrukhova
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria
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Gadhiya KP, Hansrivijit P, Gangireddy M, Goldman JD. Clinical characteristics of hospitalised patients with COVID-19 and the impact on mortality: a single-network, retrospective cohort study from Pennsylvania state. BMJ Open 2021; 11:e042549. [PMID: 37579258 PMCID: PMC8039219 DOI: 10.1136/bmjopen-2020-042549] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 10/07/2020] [Accepted: 03/18/2021] [Indexed: 01/08/2023] Open
Abstract
Objective COVID-19 is a respiratory disease caused by SARS-CoV-2 with the highest burden in the USA. Data on clinical characteristics of patients with COVID-19 in US population are limited. Thus, we aim to determine the clinical characteristics and risk factors for in-hospital mortality from COVID-19. Design Retrospective observational study. Setting Single-network hospitals in Pennsylvania state. Participants Patients with confirmed SARS-CoV-2 infection who were hospitalised from 1 March to 31 May 2020. Primary and secondary outcome measures Primary outcome was in-hospital mortality. Secondary outcomes were complications, such as acute kidney injury (AKI) and acute respiratory distress syndrome (ARDS). Results Of 283 patients, 19.4% were non-survivors. The mean age of all patients was 64.1±15.9 years. 56.2% were male and 50.2% were white. Several factors were identified from our adjusted multivariate analyses to be associated with in-hospital mortality: increasing age (per 1-year increment; OR 1.07 (1.045 to 1.105)), hypoxia (oxygen saturation <95%; OR 4.630 (1.934 to 1.111)), opacity/infiltrate on imaging (OR 3.077 (1.276 to 7.407)), leucocytosis (white blood cell >10 109/µL; OR 2.732 (1.412 to 5.263)), ferritin >336 ng/mL (OR 4.016 (1.195 to 13.514)), lactate dehydrogenase >200 U/L (OR 7.752 (1.639 to 37.037)), procalcitonin >0.25 ng/mL (OR 2.404 (1.011 to 5.714)), troponin I >0.03 ng/mL (OR 2.242 (1.080 to 4.673)), need for advanced oxygen support other than simple nasal cannula (OR 4.608-13.889 (2.053 to 31.250)), intensive care unit admission/transfer (OR 13.699 (6.135 to 30.303)), renal replacement therapy (OR 21.277 (5.025 to 90.909)), need for vasopressor (OR 22.222 (9.434 to 52.632)), ARDS (OR 23.810 (10.204 to 55.556)), respiratory acidosis (OR 7.042 (2.915 to 16.949)), and AKI (OR 3.571 (1.715 to 7.407)). When critically ill patients were analysed independently, increasing Sequential Organ Failure Assessment score (OR 1.544 (1.168 to 2.039)), AKI (OR 2.128 (1.111 to 6.667)) and ARDS (OR 6.410 (2.237 to 18.182)) were predictive of in-hospital mortality. Conclusion We reported the characteristics of ethnically diverse, hospitalised patients with COVID-19 from Pennsylvania state.
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Affiliation(s)
- Kinjal P Gadhiya
- Department of Internal Medicine, UPMC Pinnacle, Harrisburg, Pennsylvania, USA
| | | | - Mounika Gangireddy
- Department of Internal Medicine, UPMC Pinnacle, Harrisburg, Pennsylvania, USA
| | - John D Goldman
- Department of Infectious Diseases, UPMC Pinnacle, Harrisburg, Pennsylvania, USA
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Rueschenbaum S, Ciesek S, Queck A, Widera M, Schwarzkopf K, Brüne B, Welsch C, Wedemeyer H, Zeuzem S, Weigert A, Lange CM. Dysregulated Adaptive Immunity Is an Early Event in Liver Cirrhosis Preceding Acute-on-Chronic Liver Failure. Front Immunol 2021; 11:534731. [PMID: 33574809 PMCID: PMC7870861 DOI: 10.3389/fimmu.2020.534731] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022] Open
Abstract
Introduction Acute-on-chronic liver failure (ACLF) is characterized by high levels of systemic inflammation and parallel suppression of innate immunity, whereas little is known about adaptive immune immunity in ACLF. We therefore aimed to characterize the development of the adaptive immune system during the progression of liver cirrhosis to ACLF. Patients with compensated/stable decompensated liver cirrhosis, acute decompensation of liver cirrhosis, or ACLF were recruited from a prospective cohort study. Comprehensive immunophenotyping was performed using high dimensional flow cytometry. Replication of Torque teno (TT) virus was quantified as a marker of immunosuppression. High frequencies of detectable TT virus were observed already in patients with compensated/stable decompensated liver cirrhosis compared to healthy controls (>50% vs. 19%), suggesting relatively early occurrence of immunosuppression in cirrhosis. In line, profoundly reduced numbers of distinct innate and adaptive immune cell populations were observed before ACLF development. These changes were accompanied by parallel upregulation of co-stimulatory (e.g. CD40L, OX40, CD69, GITR, TIM-1) and inhibitory immune checkpoints (e.g. PDPN, PROCR, 2B4, TIGIT) on CD4+ and CD8+ T cells, which again preceded the development of ACLF. On a functional basis, the capacity of CD4+ and CD8+ T cells to produce pro-inflammatory cytokines upon stimulation was strongly diminished in patients with acute decompensation of liver cirrhosis and ACLF. Conclusion Impaired innate and—in particular—adaptive cellular immunity occurs relatively early in the pathogenesis of liver cirrhosis and precedes ACLF. This may contribute to the development of ACLF by increasing the risk of infections in patients with liver cirrhosis.
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Affiliation(s)
- Sabrina Rueschenbaum
- Department of Gastroenterology and Hepatology, University Hospital and University of Duisburg-Essen, Essen, Germany.,Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Sandra Ciesek
- Institute of Virology, University Hospital Essen, Essen, Germany
| | - Alexander Queck
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Marek Widera
- Institute of Virology, University Hospital Essen, Essen, Germany
| | - Katharina Schwarzkopf
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Bernhard Brüne
- Faculty of Medicine, Institute of Biochemistry 1, Goethe-University Frankfurt, Frankfurt, Germany
| | - Christoph Welsch
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, University Hospital and University of Duisburg-Essen, Essen, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Andreas Weigert
- Faculty of Medicine, Institute of Biochemistry 1, Goethe-University Frankfurt, Frankfurt, Germany
| | - Christian M Lange
- Department of Gastroenterology and Hepatology, University Hospital and University of Duisburg-Essen, Essen, Germany.,Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
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Longhitano Y, Zanza C, Thangathurai D, Taurone S, Kozel D, Racca F, Audo A, Ravera E, Migneco A, Piccioni A, Franceschi F. Gut Alterations in Septic Patients: A Biochemical Literature Review. Rev Recent Clin Trials 2021; 15:289-297. [PMID: 32781963 DOI: 10.2174/1574887115666200811105251] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 06/04/2020] [Accepted: 06/19/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Sepsis is a life-threatening organ dysfunction with high mortality and morbidity rate and with the disease progression many alterations are observed in different organs. The gastrointestinal tract is often damaged during sepsis and septic shock and main symptoms are related to increased permeability, bacterial translocation and malabsorption. These intestinal alterations can be both cause and effect of sepsis. OBJECTIVE The aim of this review is to analyze different pathways that lead to intestinal alteration in sepsis and to explore the most common methods for intestinal permeability measurement and, at the same time to evaluate if their use permit to identify patients at high risk of sepsis and eventually to estimate the prognosis. MATERIAL AND METHODS The peer-reviewed articles analyzed were selected from PubMed databases using the keywords "sepsis" "gut alteration", "bowel permeability", "gut alteration", "bacterial translocation", "gut permeability tests", "gut inflammation". Among the 321 papers identified, 190 articles were selected, after title - abstract examination and removing the duplicates and studies on pediatric population,only 105 articles relating to sepsis and gut alterations were analyzed. RESULTS Integrity of the intestinal barrier plays a key role in the preventing of bacterial translocation and gut alteration related to sepsis. It is obvious that this dysfunction of the small intestine can have serious consequences and the early identification of patients at risk - to develop malabsorption or already malnourished - is very recommended to increase the survivor rate. Until now, in critical patients, the dosage of citrullinemia is easily applied test in clinical setting, in fact, it is relatively easy to administer and allows to accurately assess the functionality of enterocytes. CONCLUSION The sepsis can have an important impact on the gastrointestinal function. In addition, the alteration of the permeability can become a source of systemic infection. At the moment, biological damage markers are not specific, but the dosage of LPS, citrulline, lactulose/mannitol test, FABP and fecal calprotectin are becoming an excellent alternative with high specificity and sensitivity.
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Affiliation(s)
- Yaroslava Longhitano
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio and Cesare Arrigo Hospital, Alessandria, Italy
| | - Christian Zanza
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio and Cesare Arrigo Hospital, Alessandria, Italy
| | - Duraiyah Thangathurai
- Department of Anesthesiology, Keck Medical School of University of Southern California, Los Angeles, United States
| | - Samanta Taurone
- Department of Sensory Organs, Sapienza University of Rome, Rome, Italy
| | - Daniela Kozel
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio and Cesare Arrigo Hospital, Alessandria, Italy
| | - Fabrizio Racca
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio and Cesare Arrigo Hospital, Alessandria, Italy
| | - Andrea Audo
- Department of Anesthesia and Critical Care Medicine, St. Antonio and Biagio and Cesare Arrigo Hospital, Alessandria, Italy
| | - Enrico Ravera
- Department of Emergency, Anesthesia and Critical Care, Michele and Pietro Ferrero Hospital, Verduno, Italy
| | - Alessio Migneco
- Department of Anesthesiology and Emergency Sciences,, Policlinico Gemelli/IRCCS - Catholic University of Sacred Heart, Rome, Italy
| | - Andrea Piccioni
- Department of Anesthesiology and Emergency Sciences,, Policlinico Gemelli/IRCCS - Catholic University of Sacred Heart, Rome, Italy
| | - Francesco Franceschi
- Department of Anesthesiology and Emergency Sciences,, Policlinico Gemelli/IRCCS - Catholic University of Sacred Heart, Rome, Italy
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Amiri P, Abbasi H, Derakhshan A, Gharib B, Nooralishahi B, Mirzaaghayan M. Potential Prognostic Markers in the Heart Rate Variability Features for Early Diagnosis of Sepsis in the Pediatric Intensive Care Unit using Convolutional Neural Network Classifiers. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2020; 2020:5627-5630. [PMID: 33019253 DOI: 10.1109/embc44109.2020.9175481] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Blood infection due to different circumstances could immediately develop to an extreme body reaction that leads to a serious life-threatening condition, called Sepsis. Currently, therapeutic protocols through timely antibiotic resuscitation strategies play an important role to fight against the adverse conditions and improve survival. Therefore, timing, and more specifically early diagnosis of the illness, is crucially important for an effective treatment. Studies have indicated that vital signals such as heart rate variability (HRV) could provide potential prognostic biological markers that can help with early detection of sepsis before it is clinically diagnosed through its actual symptoms. Therefore, this study employs neonatal and pediatric electrocardiogram (ECG) to extract 52 hourly sets of linear and non-linear features from the HRV, starting from 24 hours prior to the clinical diagnosis of sepsis in patients with positive blood cultures (n=14). Similar sets of features were also obtained from a non-sepsis control group to create an evaluation benchmark (n=14).In particular, this study initially demonstrates how the variations within the 24 hours values of specific HRV featuresets could effectively reveal prognostic information about the evolution of sepsis, prior to the actual clinical diagnosis. Moreover, this study demonstrates that differences in the values of a particular set of features at 22 hours before the actual clinical diagnosis/symptoms can be reliably used to train a convolutional neural network for automatic classification between the individuals in the sepsis and non-sepsis groups with 88.89±7.86% accuracy.Clinical relevance- Results suggest potential early diagnosis of sepsis through real-time automatic classification of HRV features as prognostic indicators in clinical ECG recordings.
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Amiri P, Abbasi H, Derakhshan A, Gharib B, Nooralishahi B, Mirzaaghayan M. Potential Prognostic Markers in the Heart Rate Variability Features for Early Diagnosis of Sepsis in the Pediatric Intensive Care Unit using Convolutional Neural Network Classifiers. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2020; 2020:1031-1034. [PMID: 33018161 DOI: 10.1109/embc44109.2020.9176395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Blood infection due to different circumstances could immediately develop to an extreme body reaction that leads to a serious life-threatening condition, called Sepsis. Currently, therapeutic protocols through timely antibiotic resuscitation strategies play an important role to fight against the adverse conditions and improve survival. Therefore, timing, and more specifically early diagnosis of the illness, is crucially important for an effective treatment. Studies have indicated that vital signals such as heart rate variability (HRV) could provide potential prognostic biological markers that can help with early detection of sepsis before it is clinically diagnosed through its actual symptoms. Therefore, this study employs neonatal and pediatric electrocardiogram (ECG) to extract 52 hourly sets of linear and non-linear features from the HRV, starting from 24 hours prior to the clinical diagnosis of sepsis in patients with positive blood cultures (n=14). Similar sets of features were also obtained from a non-sepsis control group to create an evaluation benchmark (n=14).In particular, this study initially demonstrates how the variations within the 24 hours values of specific HRV feature-sets could effectively reveal prognostic information about the evolution of sepsis, prior to the actual clinical diagnosis. Moreover, this study demonstrates that differences in the values of a particular set of features at 22 hours before the actual clinical diagnosis/symptoms can be reliably used to train a convolutional neural network for automatic classification between the individuals in the sepsis and non-sepsis groups with 88.89±7.86% accuracy.
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Chang CY, Hsu HJ, Foo J, Shih HJ, Huang CJ. Peptide-Based TNF-α-Binding Decoy Therapy Mitigates Lipopolysaccharide-Induced Liver Injury in Mice. Pharmaceuticals (Basel) 2020; 13:ph13100280. [PMID: 33003495 PMCID: PMC7600127 DOI: 10.3390/ph13100280] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 09/22/2020] [Accepted: 09/28/2020] [Indexed: 12/14/2022] Open
Abstract
A peptide named SEM18, possessing structural similarity to the binding site of tumor necrosis factor (TNF)-α to TNF receptor 1 (TNFR1), was designed. We investigated whether the SEM18 peptide can mitigate lipopolysaccharide (LPS)-induced liver injury in mice. Adult male Balb/cJ mice received LPS (15 mg/kg; LPS group) or LPS plus SEM18 (LSEM group). Control groups were run simultaneously. At 2 h after LPS, the first dose of SEM18 (0.3 mg/kg) was administered, followed by three supplemental doses of SEM18 (0.15 mg/kg, every 2 h). At 24 h after LPS, surviving mice were euthanized for analyses. Compared with the LPS group, binding of TNF-α to TNFR1 in liver tissues was significantly lower in the LSEM group (p < 0.001). Plasma concentrations of aspartate transaminase and alanine transaminase, as well as Suzuki’s scores (liver damage assessment), wet/dry weight ratios, levels of polymorphonuclear neutrophil infiltration, and levels of mitochondrial injury in liver tissues, of the LSEM group were significantly lower than in the LPS group (all p < 0.05). Levels of necroptosis, pyroptosis, apoptosis, and autophagy upregulation in liver tissues in the LSEM group were also significantly lower than in the LPS group (all p < 0.05). Notably, exogenous TNF-α counteracted these effects of SEM18. SEM18 peptide mitigates LPS-induced liver injury in mice.
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Affiliation(s)
- Chao-Yuan Chang
- Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (C.-Y.C.); (J.F.)
- Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Hao-Jen Hsu
- Department of Life Sciences, College of Medicine, Tzu Chi University, Hualien 970, Taiwan;
| | - Jossen Foo
- Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (C.-Y.C.); (J.F.)
- Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
| | - Hung-Jen Shih
- Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: (H.-J.S.); (C.-J.H.)
| | - Chun-Jen Huang
- Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan; (C.-Y.C.); (J.F.)
- Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Correspondence: (H.-J.S.); (C.-J.H.)
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Yang JJ, Wu BB, Han F, Chen JH, Yang Y. Gene expression profiling of sepsis-associated acute kidney injury. Exp Ther Med 2020; 20:34. [PMID: 32952625 PMCID: PMC7485311 DOI: 10.3892/etm.2020.9161] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 06/19/2020] [Indexed: 12/29/2022] Open
Abstract
Sepsis accounts for more than 50% of all acute kidney injury (AKI) cases, and the combination of sepsis and AKI increases the risk of mortality from sepsis alone. However, to the best of our knowledge, the specific mechanism by which sepsis causes AKI has not yet been fully elucidated, and there is no targeted therapy for sepsis-associated AKI (SA-AKI). The present study investigated gene expression profiles using RNA sequencing (RNA-Seq) and bioinformatics analyses to assess the function of differentially expressed genes (DEGs) and the molecular mechanisms relevant to the prognosis of SA-AKI. From the bioinformatics analysis, 2,256 downregulated and 3,146 upregulated genes were identified (false discovery rate <0.1 and fold-change >2). Gene Ontology analysis revealed that the genes were enriched in cellular metabolic processes, cell death and apoptosis. The enriched transcription factors were v-rel reticuloendotheliosis viral oncogene homolog A and signaling transducer and activator of transcription 3. The enriched microRNAs (miRNAs or miRs) among the DEGs were miR-30e, miR-181a, miR-340, miR-466d and miR-466l. Furthermore, the enriched pathways included toll-like receptor signaling, nod-like receptor signaling and the Janus kinase/STAT signaling pathway. In conclusion, the present study identified certain prognosis-related genes, transcription factors, miRNAs and pathways by analyzing gene expression profiles of SA-AKI using RNA-Seq, which provides some basis for future experimental studies.
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Affiliation(s)
- Jing-Juan Yang
- Department of Nephrology, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu, Zhejiang 322000, P.R. China
| | - Bin-Bin Wu
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| | - Fei Han
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| | - Jiang-Hua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| | - Yi Yang
- Department of Nephrology, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu, Zhejiang 322000, P.R. China.,Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
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Levinson T, Tamir N, Shenhar-Tsarfaty S, Paran Y, Zeltzer D, Shapira I, Halpern P, Meilik A, Raykhshtat E, Goldiner I, Adler A, Berliner S, Rogowski O, Wasserman A. The potential benefit of a second C-reactive protein measurement in patients with gram-negative bacteraemia presenting to the emergency medicine department. Biomarkers 2020; 25:533-538. [PMID: 32715769 DOI: 10.1080/1354750x.2020.1797878] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
BACKGROUND Low C-reactive protein in acute bacterial infections could convey the erroneous impression of a mild infection. We focussed on gram-negative bacteraemia, a phenomenon frequently seen at the emergency room. METHODS Of 2200 patients with gram-negative bacteraemia, 460 patients with first C-reactive protein <30 mg/L and 460 patients with C-reactive protein >187 mg/L were reviewed. Following exclusions, we finally investigated 229 and 289 patients with low and high C-reactive protein concentrations, respectively. RESULTS The cohort was divided into low and high C-reactive protein groups. Median first C-reactive protein was 13.6 and 219.9 mg/L, respectively (interquartile range 6.4-21.6 and 195-270.1). Compared to patients with first high C-reactive protein, patients with first low C-reactive protein concentrations had a significant five-fold higher C-reactive protein level with their second test. CONCLUSIONS Patients with gram-negative bacteraemia can present with C-reactive protein within the range of apparently healthy individuals. A second C-reactive protein might help to avoid an erroneous decision regarding the severity of the infection.
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Affiliation(s)
- Tal Levinson
- Department of Internal Medicine C, D and E, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Infectious Diseases Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Natalie Tamir
- Department of Internal Medicine C, D and E, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shani Shenhar-Tsarfaty
- Department of Internal Medicine C, D and E, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yael Paran
- Infectious Diseases Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - David Zeltzer
- Department of Internal Medicine C, D and E, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Itzhak Shapira
- Department of Internal Medicine C, D and E, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Pinchas Halpern
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Emergency Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Ahuva Meilik
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Data Science and Quality Division, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Eli Raykhshtat
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Data Science and Quality Division, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Ilana Goldiner
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Clinical Laboratory Services, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Amos Adler
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Clinical Microbiology Laboratory, The Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Shlomo Berliner
- Department of Internal Medicine C, D and E, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ori Rogowski
- Department of Internal Medicine C, D and E, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Asaf Wasserman
- Department of Internal Medicine C, D and E, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Infectious Diseases Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Challenges in developing a consensus definition of neonatal sepsis. Pediatr Res 2020; 88:14-26. [PMID: 32126571 DOI: 10.1038/s41390-020-0785-x] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/24/2019] [Accepted: 01/13/2020] [Indexed: 01/03/2023]
Abstract
Sepsis remains a leading cause of morbidity and mortality in the neonatal population, and at present, there is no unified definition of neonatal sepsis. Existing consensus sepsis definitions within paediatrics are not suited for use in the NICU and do not address sepsis in the premature population. Many neonatal research and surveillance networks have criteria for the definition of sepsis within their publications though these vary greatly and there is typically a heavy emphasis on microbiological culture. The concept of organ dysfunction as a diagnostic criterion for sepsis is rarely considered in neonatal literature, and it remains unclear how to most accurately screen neonates for organ dysfunction. Accurately defining and screening for sepsis is important for clinical management, health service design and future research. The progress made by the Sepsis-3 group provides a roadmap of how definitions and screening criteria may be developed. Similar initiatives in neonatology are likely to be more challenging and would need to account for the unique presentation of sepsis in term and premature neonates. The outputs of similar consensus work within neonatology should be twofold: a validated definition of neonatal sepsis and screening criteria to identify at-risk patients earlier in their clinical course. IMPACT: There is currently no consensus definition of neonatal sepsis and the definitions that are currently in use are varied.A consensus definition of neonatal sepsis would benefit clinicians, patients and researchers.Recent progress in adults with publication of Sepsis-3 provides guidance on how a consensus definition and screening criteria for sepsis could be produced in neonatology.We discuss common themes and potential shortcomings in sepsis definitions within neonatology.We highlight the need for a consensus definition of neonatal sepsis and the challenges that this task poses.
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Prognostic Value of Tissue Oxygen Saturation Using a Vascular Occlusion Test in Patients in the Early Phase of Multiorgan Dysfunction Syndrome. Shock 2020; 51:706-712. [PMID: 30052575 DOI: 10.1097/shk.0000000000001225] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Multiple organ dysfunction syndrome (MODS) is a common disease pattern in intensive care units which is associated with an increased mortality. The aim of this study was to investigate whether a near-infrared spectroscopy (NIRS)-based noninvasive ischemia-reperfusion test (vascular occlusion test) using the parameter of tissue oxygen saturation (StO2) contains prognostic information for patients in the early phase of MODS. METHODS Within a period of 18 months between 2010 and 2012, 56 patients who newly developed MODS (≤24 h after diagnosis, Acute Physiology and Chronic Health Evaluation [APACHE] II score ≥20, subgroups: cardiogenic MODS [cMODS] and septic MODS [sMODS]) were included into the study. The StO2 was determined non-invasively in the area of the thenar muscles using a bedside NIRS device, InSpectra Tissue Spectrometer Model 650 (Hutchinson Technology Inc., Hutchinson, MN). The VOT was carried out by inflating a blood pressure cuff on the upper arm 30 mmHg above systolic blood pressure for 5 min. The parameters occlusion slope (OS) and recovery slope (RS) were recorded. RESULTS Fifteen patients with cMODS and 41 patients with sMODS were included in the study (age: 62.5 ± 14.4 years, 40 men and 16 women, APACHE II score: 34.6 ± 6.4). Twenty-eight-day-mortality was 55.4% (cMODS: 7 out of 15 patients, sMODS: 24 out of 41 patients). The measurement of StO2 while applying the VOT at baseline showed an OS of -11.7 ± 3.7%/min and an RS of 2.2 ± 1.5%/s. Survivors had significantly better values compared with non-survivors at baseline regarding OS (-12.8 ± 3.5%/min vs. -9.8 ± 3.4%/min; P = 0.016) and RS (2.6 ± 1.7%/s vs. 1.6 ± 1.0%/s; P = 0.022). Receiver-operating characteristic (ROC) curves show that the area under the curve (AUC) for OS was found to be significantly related to 28-day mortality (AUC: 0.7; 95% confidence interval [CI]: 0.56-0.85; P = 0.01). However, using both univariate and multivariate binary logistic regression models, RS was significantly associated with increased 28-day mortality (OR [univariate model]: 1.21 [95% CI: 1.1-1.8]; OR [multivariate model]: 1.23 [95% CI: 1.1-1.3]). CONCLUSIONS Impaired values of the VOT-parameters OS and RS are associated with an increased 28-day mortality in patients in the early phase of MODS.
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