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Kolahi A, Gholizadeh M, Shab-Bidar S. Adipokines in critically ill patients: A systematic review and meta-analysis of observational studies. Clin Nutr ESPEN 2025; 68:216-227. [PMID: 40274050 DOI: 10.1016/j.clnesp.2025.03.176] [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: 08/29/2024] [Revised: 02/01/2025] [Accepted: 03/31/2025] [Indexed: 04/26/2025]
Abstract
BACKGROUND Critical illness is a hypermetabolic state with high mortality rates. Adipokines, including leptin, adiponectin, and resistin, regulate energy balance, inflammation, and metabolism and may influence outcomes in critically ill patients. This study evaluated changes in adipokine levels in ICU patients compared to healthy controls and explored their associations with clinical outcomes. METHODS A systematic review and meta-analysis of 34 case-control studies involving 3365 participants were conducted. Pooled weighted mean difference (WMD) of adipokine levels between critically ill patients and controls were calculated using random-effects models. Subgroup analyses were performed based on ICU type (Medical, Surgical, Mixed), septic status (septic or non-septic), and injury phase (ebb or flow). Publication bias and sensitivity analyses were also conducted. RESULTS Leptin (WMD: 3.22 ng/mL; 95 % CI: 0.91 to 5.53) and resistin (WMD: 19.86 ng/mL; 95 % CI: 14.78 to 24.95) levels were significantly elevated in critically ill patients, while adiponectin levels showed no significant difference (WMD: 0.37 μg/dL; 95 % CI: -1.81 to 2.55). Subgroup analyses revealed higher leptin and resistin levels in mixed-ICU and septic patients. Leptin also increased during the ebb phase, but heterogeneity remained high (I2 > 97 %). CONCLUSIONS Leptin and resistin levels are elevated in critical illness, potentially serving as biomarkers for disease severity. However, high heterogeneity limits generalizability. Future research should standardize protocols and investigate adipokines' prognostic and therapeutic roles in critical care.
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Affiliation(s)
- Ahmadreza Kolahi
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Gholizadeh
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sakineh Shab-Bidar
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
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Geng H, Qi L, You L, Feng W, Yang X, Lei M. miR-361-3p overexpression promotes apoptosis and inflammation by regulating the USP49/IκBα/NF-κB pathway to aggravate sepsis-induced myocardial injury. Toxicol Res (Camb) 2024; 13:tfae190. [PMID: 39568464 PMCID: PMC11574052 DOI: 10.1093/toxres/tfae190] [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: 07/15/2024] [Revised: 10/27/2024] [Accepted: 11/06/2024] [Indexed: 11/22/2024] Open
Abstract
Background Sepsis is a major cause of in-hospital death, particularly in the intensive care unit. A huge amount of effort has been put into identifying reliable biomarkers to improve the prognosis of patients with sepsis. Among the numerous candidates, microRNAs have attracted attention because of their promising prognostic value. Multiple miRNAs have been suggested to play vital roles in manipulating the nuclear factor-kappa B (NF-κB) pathway, a key factor involved in sepsis. In this study, we attempted to elucidate the potential functions of miR-361-3p in sepsis-induced myocardial injury in vivo and in vitro. Methods A sepsis model was established by cecal ligation and puncture (CLP) in rats and by lipopolysaccharide (LPS) in H9c2 cells. The functions of miR-361-3p were revealed by assessing the level of biomarkers of myocardial injury and inflammation by Enzyme-linked immunosorbent assay, as well as the apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and flow cytometry. Binding of miR-361-3p and the 3' untranslated region of ubiquitin-specific peptidase 49 (Usp49) was revealed by Dual luciferase reporter gene assay. The interaction of USP49 and its downstream target NF-κB inhibitor alpha (IκBα) was revealed by Co-immunoprecipitation and western blot analysis. Results miR-361-3p antagomir inhibited myocardial injury and inflammation in CLP-induced rats, as evidenced by a decrease in the serum levels of cardiac troponin I, creatine kinase-MB, interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha and cell apoptosis. However, miR-361-3p agomir aggravated sepsis-induced myocardial injury. Moreover, miR-361-3p inhibition induced the inhibition of LPS-induced apoptosis and inflammation in H9c2 cells. miR-361-3p could inhibit the expression of Usp49 by binding to its 3' untranslated region. Furthermore, we demonstrated that Usp49 binds to IκBα and mediates its deubiquitination, leading to the stabilization of IκBα, which results in the cytoplasmic accumulation of NF-κB and eventually the suppression of NF-κB activity. Conclusion Taken together, our data demonstrate that miR-361-3p overexpression promotes apoptosis and inflammation by regulating the USP49/IκBα/NF-κB pathway to aggravate sepsis-induced myocardial injury.
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Affiliation(s)
- Huan Geng
- Trauma emergency center, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong new district, Shanghai 200137, China
| | - Luyao Qi
- Trauma emergency center, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong new district, Shanghai 200137, China
| | - Lijiao You
- Trauma emergency center, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong new district, Shanghai 200137, China
| | - Wentao Feng
- Trauma emergency center, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong new district, Shanghai 200137, China
| | - Xiaofang Yang
- Trauma emergency center, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong new district, Shanghai 200137, China
| | - Ming Lei
- Trauma emergency center, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong new district, Shanghai 200137, China
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El-Naggar AE, Helmy MM, El-Gowilly SM, El-Mas MM. Suppression by central adenosine A3 receptors of the cholinergic defense against cardiovascular aberrations of sepsis: role of PI3K/MAPKs/NFκB signaling. Front Pharmacol 2024; 15:1418981. [PMID: 38966542 PMCID: PMC11222418 DOI: 10.3389/fphar.2024.1418981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 06/06/2024] [Indexed: 07/06/2024] Open
Abstract
Introduction: Despite the established role of peripheral adenosine receptors in sepsis-induced organ dysfunction, little or no data is available on the interaction of central adenosine receptors with sepsis. The current study tested the hypothesis that central adenosine A3 receptors (A3ARs) modulate the cardiovascular aberrations and neuroinflammation triggered by sepsis and their counteraction by the cholinergic antiinflammatory pathway. Methods: Sepsis was induced by cecal ligation and puncture (CLP) in rats pre-instrumented with femoral and intracisternal (i.c.) catheters for hemodynamic monitoring and central drug administration, respectively. Results: The CLP-induced hypotension, reduction in overall heart rate variability (HRV) and sympathovagal imbalance towards parasympathetic predominance were abolished by i.v. nicotine (100 μg/kg) or i.c. VUF5574 (A3AR antagonist, 2 µg/rat). In addition, the selective A3AR agonist, 3-iodobenzyl-5'-N-methylcarboxamidoadenosine IB-MECA, 4 µg/rat, i.c.) exaggerated the hypotension and cardiac autonomic dysfunction induced by sepsis and opposed the favorable nicotine actions against these septic manifestations. Immunohistochemically, IB-MECA abolished the nicotine-mediated downregulation of NFκB and NOX2 expression in rostral ventrolateral medullary areas (RVLM) of brainstem of septic rats. The inhibitory actions of IB-MECA on nicotine responses disappeared after i.c. administration of PD98059 (MAPK-ERK inhibitor), SP600125 (MAPK-JNK inhibitor) or wortmannin (PI3K inhibitor). Moreover, infliximab (TNFα inhibitor) eliminated the IB-MECA-induced rises in RVLM-NFκB expression and falls in HRV, but not blood pressure. Conclusion: Central PI3K/MAPKs pathway mediates the A3AR counteraction of cholinergic defenses against cardiovascular and neuroinflammatory aberrations in sepsis.
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Affiliation(s)
- Amany E. El-Naggar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Mai M. Helmy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Sahar M. El-Gowilly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Mahmoud M. El-Mas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
- Department of Pharmacology and Toxicology, College of Medicine, Kuwait University, Kuwait City, Kuwait
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McMullan RR, McAuley DF, O'Kane CM, Silversides JA. Vascular leak in sepsis: physiological basis and potential therapeutic advances. Crit Care 2024; 28:97. [PMID: 38521954 PMCID: PMC10961003 DOI: 10.1186/s13054-024-04875-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 03/14/2024] [Indexed: 03/25/2024] Open
Abstract
Sepsis is a life-threatening condition characterised by endothelial barrier dysfunction and impairment of normal microcirculatory function, resulting in a state of hypoperfusion and tissue oedema. No specific pharmacological therapies are currently used to attenuate microvascular injury. Given the prominent role of endothelial breakdown and microcirculatory dysfunction in sepsis, there is a need for effective strategies to protect the endothelium. In this review we will discuss key mechanisms and putative therapeutic agents relevant to endothelial barrier function.
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Affiliation(s)
- Ross R McMullan
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University of Belfast, Lisburn Road, Belfast, BT9 7BL, UK.
| | - Daniel F McAuley
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University of Belfast, Lisburn Road, Belfast, BT9 7BL, UK
- Department of Critical Care, Belfast Health and Social Care Trust, Belfast, UK
| | - Cecilia M O'Kane
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University of Belfast, Lisburn Road, Belfast, BT9 7BL, UK
| | - Jonathan A Silversides
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University of Belfast, Lisburn Road, Belfast, BT9 7BL, UK
- Department of Critical Care, Belfast Health and Social Care Trust, Belfast, UK
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Mihaljevic O, Zivancevic-Simonovic S, Jovanovic D, Drakulic SM, Vukajlovic JT, Markovic A, Pirkovic MS, Srejovic I, Jakovljevic V, Milosevic-Djordjevic O. Oxidative stress and DNA damage in critically ill patients with sepsis. MUTATION RESEARCH. GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2023; 889:503655. [PMID: 37491118 DOI: 10.1016/j.mrgentox.2023.503655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 06/02/2023] [Accepted: 06/29/2023] [Indexed: 07/27/2023]
Abstract
The aim of our study was to assess the oxidative stress and inflammatory status in critically ill patients with sepsis as well as their relationship with the level of DNA damage. The study also evaluated the influence of all analyzed parameters on the outcome of the patients. The study included 27 critically ill patients with sepsis and 20 healthy subjects. Comet Assay was used for the measurement of the level of DNA damage, expressed as genetic damage index (GDI). Both oxidative stress parameters and the antioxidant parameters were obtained spectrophotometrically. The standard laboratory methods and the appropriate autoanalyzers were performed for determination the parameters of inflammation. A higher level of oxidative stress and more pronounced inflammation were found in the patients with sepsis compared to healthy subjects. The activity of the antioxidant enzymes was statistically declined in patients with sepsis, so that the most notable differences between two groups of participants were found for the activity of superoxide dismutase (SOD) (p = 0.004). Comet assay indicated that patients with sepsis had significantly higher GDI compared to healthy subjects (p < 0.001), which positively correlated with the concentration of superoxide anion radical (О2-) (r = 0.497, p = 0.010), and nitrites (NО2-) (r = 0.473, p = 0.015), as well with the concentration of C reactive protein (CRP) (r = 0.460, p = 0.041). Regression analysis confirmed that patients' age (p = 0.033), the level of О2- (p = 0.007), CRP concentration (p = 0.029) and GDI (p = 0.001) increased the risk of lethal outcome in critically ill patients with sepsis. In conclusion, critically ill patients with sepsis have a higher degree of oxidative stress and inflammation which contribute to a higher level of DNA damage. Consequently, above mentioned parameters, including patients' age, adversely affect the outcome of critically ill patients with sepsis.
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Affiliation(s)
- Olgica Mihaljevic
- University of Kragujevac, Faculty of Medical Sciences, Department of Pathophysiology, Serbia.
| | | | - Danijela Jovanovic
- University of Kragujevac, Faculty of Medical Sciences, Department of Surgery, Serbia; University Clinical Center Kragujevac, Serbia
| | - Svetlana Miletic Drakulic
- University Clinical Center Kragujevac, Serbia; University of Kragujevac, Faculty of Medical Sciences, Department of Neurology, Serbia
| | | | - Aleksandra Markovic
- University of Kragujevac, Faculty of Sciences, Department of Biology, Serbia
| | - Marijana Stanojevic Pirkovic
- University Clinical Center Kragujevac, Serbia; University of Kragujevac, Faculty of Medical Sciences, Department of Biochemistry, Serbia
| | - Ivan Srejovic
- University of Kragujevac, Faculty of Medical Sciences, Department of Physiology, Serbia
| | - Vladimir Jakovljevic
- University of Kragujevac, Faculty of Medical Sciences, Department of Physiology, Serbia
| | - Olivera Milosevic-Djordjevic
- University of Kragujevac, Faculty of Sciences, Department of Biology, Serbia; University of Kragujevac, Faculty of Medical Sciences, Department of Genetics, Serbia
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Elloumi N, Bahloul M, Benabdallah E, Kharrat S, Fakhfakh R, Bouchaala K, Abida O, Chtara K, Masmoudi H, Bouaziz M. Genes regulating oxidative-inflammatory response in circulating monocytes and neutrophils in septic syndrome. Biol Futur 2023; 74:199-207. [PMID: 37291472 DOI: 10.1007/s42977-023-00168-1] [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: 08/05/2022] [Accepted: 05/13/2023] [Indexed: 06/10/2023]
Abstract
Despite significant progress in the past decades, sepsis still lacks a specific treatment. Under normal conditions, leucocytes play a critical role in controlling infection and it is suggested that their activity is impaired during sepsis which contribute to the dysregulation of immune reactions. Indeed, in response to infection, several intracellular pathways are affected mainly those regulating the oxidative- inflammatory axis. Herein, we focused on the contribution of NF-kB, iNOS, Nrf2, HO-1 and MPO genes in the pathophysiology of septic syndrome, by analyzing the differential expression of their transcripts in circulating monocytes and neutrophils, and monitoring the nitrosative/oxidative status in septic syndrome patients. Circulating neutrophils of septic patients displayed a significant overexpression of NF-kB compared to other groups. In monocytes, patients with septic shock expressed the highest levels of iNOS and NF-kB mRNA. However, genes involved in cytoprotective response had increased expression in patients with sepsis, in particular, the Nrf2 and its target gene HO-1. Moreover, patient monitoring indicates that the iNOS enzyme expression and NO plasma levels may play a role in assessing the severity of septic conditions. Overall, in either monocytes or neutrophils, we pointed out the major role of NF-κB and Nrf2 in the pathophysiological process. Therefore, therapies targeted to redox abnormalities may be useful for better management of septic patients.
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Affiliation(s)
- Nesrine Elloumi
- Research Laboratory LR18/SP12 Auto-Immunity, Cancer and Immunogenetics, Immunology Department, Habib Bourguiba University Hospital, University of Sfax, 3029, Sfax, Tunisia.
| | - Mabrouk Bahloul
- Department of Intensive Care, Habib Bourguiba University Hospital, Sfax, Tunisia
| | - Emna Benabdallah
- Research Laboratory LR18/SP12 Auto-Immunity, Cancer and Immunogenetics, Immunology Department, Habib Bourguiba University Hospital, University of Sfax, 3029, Sfax, Tunisia
| | - Sana Kharrat
- Department of Intensive Care, Habib Bourguiba University Hospital, Sfax, Tunisia
| | - Raouia Fakhfakh
- Research Laboratory LR18/SP12 Auto-Immunity, Cancer and Immunogenetics, Immunology Department, Habib Bourguiba University Hospital, University of Sfax, 3029, Sfax, Tunisia
| | - Karama Bouchaala
- Department of Intensive Care, Habib Bourguiba University Hospital, Sfax, Tunisia
| | - Olfa Abida
- Research Laboratory LR18/SP12 Auto-Immunity, Cancer and Immunogenetics, Immunology Department, Habib Bourguiba University Hospital, University of Sfax, 3029, Sfax, Tunisia
| | - Kamilia Chtara
- Department of Intensive Care, Habib Bourguiba University Hospital, Sfax, Tunisia
| | - Hatem Masmoudi
- Research Laboratory LR18/SP12 Auto-Immunity, Cancer and Immunogenetics, Immunology Department, Habib Bourguiba University Hospital, University of Sfax, 3029, Sfax, Tunisia
| | - Mounir Bouaziz
- Department of Intensive Care, Habib Bourguiba University Hospital, Sfax, Tunisia
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Shi B, Chen M, Xia Z, Tang W, Li Y, Qin C, Ahmadi A, Huang C, Xu H. Genistein attenuates neuroinflammation and oxidative stress and improves cognitive impairment in a rat model of sepsis-associated encephalopathy: potential role of the Nrf2 signaling pathway. Metab Brain Dis 2023; 38:339-347. [PMID: 36301457 DOI: 10.1007/s11011-022-01076-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 08/30/2022] [Indexed: 02/03/2023]
Abstract
Oxidative stress and inflammation seem to be the main factors responsible for cognitive impairment in sepsis. Genistein (GEN) is claimed to exert many beneficial effects on health, however, its possible effects on brain sepsis remains unclear. Here, we assess the influence and underling mechanisms of GEN on cognitive impairments in cecal ligation and puncture (CLP)-induced septic model. Rats were randomly divided into Sham, Sham + GEN, CLP, CLP + GEN gropus. Rats were treated with GEN (15 mg/kg at 0 and 12 h after CLP, i.p). Twenty-four hours after CLP, protein levels of cytokines, NF-kB and Nrf2, myeloperoxidase (MPO) activity, oxidative damage to lipids and proteins, the activities of antioxidant enzymes and the expression of Nrf2-target genes were evaluated in the hippocampus. At 10 days after sepsis induction, behavioral tests were conducted to evaluate cognitive impairment. The results indicate that GEN can enhance survival percentage and improve cognitive function. Genistein administration significantly reduced TNF-α and IL-1β levels, MPO activity and protein level of NF-kB in the hippocampus of septic rats. Genistein also decreased the levels of oxidative stress parameters (MDA and protein carbonyls) and elevated the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in septic rats. Furthermore, nuclear Nrf2 and the expression of HO-1 and NQO-1 were also elevated by GEN treatment. These findings suggest that GEN improves cognition impairment in septic rats via decreasing inflammatory responses and oxidative stress, and activation of the Nrf2 pathway.
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Affiliation(s)
- Buyun Shi
- Department of Pediatric Intensive Care Unit (PICU), Maternal and Child Health Hospital of Hubei Province (Women and Children's Hospital of Hubei Province), NO.745 Wuluo Road, Hongshan District, 430070, Wuhan City, Hubei Province, China
| | - Ming Chen
- Department of Dermatology, Maternal and Child Health Hospital of Hubei Province (Women and Children's Hospital of Hubei Province), NO.745 Wuluo Road, Hongshan District, Wuhan City, China
| | - Zhi Xia
- Department of Pediatric Intensive Care Unit (PICU), Maternal and Child Health Hospital of Hubei Province (Women and Children's Hospital of Hubei Province), NO.745 Wuluo Road, Hongshan District, 430070, Wuhan City, Hubei Province, China
| | - Wen Tang
- Department of Pediatric Intensive Care Unit (PICU), Maternal and Child Health Hospital of Hubei Province (Women and Children's Hospital of Hubei Province), NO.745 Wuluo Road, Hongshan District, 430070, Wuhan City, Hubei Province, China
| | - Yong Li
- Department of Pediatric Intensive Care Unit (PICU), Maternal and Child Health Hospital of Hubei Province (Women and Children's Hospital of Hubei Province), NO.745 Wuluo Road, Hongshan District, 430070, Wuhan City, Hubei Province, China
| | - Chenguang Qin
- Department of Pediatric Intensive Care Unit (PICU), Maternal and Child Health Hospital of Hubei Province (Women and Children's Hospital of Hubei Province), NO.745 Wuluo Road, Hongshan District, 430070, Wuhan City, Hubei Province, China
| | - Amir Ahmadi
- Department of Pharmacy and Molecular Sciences, Faculty of Sciences, University of Shiraz, Shiraz, Iran
| | - Chengjiao Huang
- Department of Pediatric Intensive Care Unit (PICU), Maternal and Child Health Hospital of Hubei Province (Women and Children's Hospital of Hubei Province), NO.745 Wuluo Road, Hongshan District, 430070, Wuhan City, Hubei Province, China
| | - Hui Xu
- Department of Pediatric Intensive Care Unit (PICU), Maternal and Child Health Hospital of Hubei Province (Women and Children's Hospital of Hubei Province), NO.745 Wuluo Road, Hongshan District, 430070, Wuhan City, Hubei Province, China.
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Zhen D, Liu C, Huang T, Fu D, Bai X, Ma Q, Jiang M, Gong G. Ethanol extracts of Rhaponticum uniflorum (L.) DC inflorescence ameliorate LPS-mediated acute lung injury by alleviating inflammatory responses via the Nrf2/HO-1 signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2022; 296:115497. [PMID: 35738472 DOI: 10.1016/j.jep.2022.115497] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 06/07/2022] [Accepted: 06/17/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Rhaponticum uniflorum (L.) DC is a member of the Compositae family. Loulu flowers (LLF) is the inflorescence of this plant, which is a commonly used Mongolian medicine for the treatment of inflammatory diseases due to its heat-clearing and detoxifying properties. It is used caused by. However, its anti-inflammatory mechanisms are not clear. AIM OF THIS STUDY We investigated whether ethanol extracts of LLF can alleviate LPS-induced acute lung injury and explored the mechanism involved. MATERIAL AND METHODS BALB/C mice were intragastrically administered with sodium carboxymethyl cellulose (0.5%, 1 mL/100 g) or ethanol extracts of LLF at a dose of 100, 200, and 400 mg/kg, once daily, for 3 days. Subsequently, mice models of acute lung injury were established by LPS and used for the determination of anti-inflammatory effects of LLF. After 6 h of treatment, mice were sacrificed to collect lung tissues and bronchoalveolar lavage fluid (BALF). H&E staining assay was performed on the tissues for pathological analysis. The ELISA test was conducted to measure NO, IL-6, TNF-α, MPO, SOD, CAT, MDA and GSH-PX levels. The expression level of proteins associated with the Nrf2/HO-1 and MAPK/NF-κB signaling pathways were determined using Western blot analysis. Levels of F4/80 and Nrf2 in lungs were quantified using immunohistochemistry. RESULTS Oral administration of LLF extracts alleviated LPS-induced pathological alterations, reduced lung W/D weight ratio, decreased levels of TP, pro-inflammatory factors (TNF-α and IL-6), and NO in BALF. Pretreatment with LLF extract downregulated F4/80 expression in lung tissue and suppressed LPS-induced elevations in BALF and lung tissue levels of MPO. Moreover, treatment with LLF extract reduced the expression level of proteins associated with the MAPK signaling pathway (p-p38, p-JNK, p-ERK) and TLR4/NF-κB signaling pathways (TLR4, Myd88, p-IκB, p-p65). Moreover, LLF extract upregulated Nrf2, HO-1 and NQO1 protein levels, downregulated Keap1 protein level. Immunohistochemical analysis revealed that LLF reduced the LPS-induced increase in Nfr2 expression in lung tissues. CONCLUSION Ethanol extracts of LLF ameliorated LPS-induced acute lung injury by suppressing inflammatory response and enhancing antioxidation capacity, which correlated with the MAPK/NF-κB and Nfr2/HO-1 signaling pathways.
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Affiliation(s)
- Dong Zhen
- Institute of Pharmaceutical Chemistry and Pharmacology, Inner Mongolia Minzu University, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China.
| | - Chunyan Liu
- Institute of Pharmaceutical Chemistry and Pharmacology, Inner Mongolia Minzu University, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China.
| | - Tianpeng Huang
- Institute of Pharmaceutical Chemistry and Pharmacology, Inner Mongolia Minzu University, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China.
| | - Danni Fu
- Institute of Pharmaceutical Chemistry and Pharmacology, Inner Mongolia Minzu University, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China.
| | - Xue Bai
- Institute of Pharmaceutical Chemistry and Pharmacology, Inner Mongolia Minzu University, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China.
| | - Qianqian Ma
- Institute of Pharmaceutical Chemistry and Pharmacology, Inner Mongolia Minzu University, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China; Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China.
| | - Mingyang Jiang
- Collage of Computer Science and Technology, Inner Mongolia Minzu University, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China.
| | - Guohua Gong
- Inner Mongolia Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China; Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, 028000, Inner Mongolia Autonomous Region, PR China.
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The Interplay of Oxidative Stress and ROS Scavenging: Antioxidants as a Therapeutic Potential in Sepsis. Vaccines (Basel) 2022; 10:vaccines10101575. [PMID: 36298439 PMCID: PMC9609850 DOI: 10.3390/vaccines10101575] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 09/09/2022] [Accepted: 09/13/2022] [Indexed: 12/05/2022] Open
Abstract
Oxidative stress resulting from the disproportion of oxidants and antioxidants contributes to both physiological and pathological conditions in sepsis. To combat this, the antioxidant defense system comes into the picture, which contributes to limiting the amount of reactive oxygen species (ROS) leading to the reduction of oxidative stress. However, a strong relationship has been found between scavengers of ROS and antioxidants in preclinical in vitro and in vivo models. ROS is widely believed to cause human pathology most specifically in sepsis, where a small increase in ROS levels activates signaling pathways to initiate biological processes. An inclusive understanding of the effects of ROS scavenging in cellular antioxidant signaling is essentially lacking in sepsis. This review compiles the mechanisms of ROS scavenging as well as oxidative damage in sepsis, as well as antioxidants as a potent therapeutic. Direct interaction between ROS and cellular pathways greatly affects sepsis, but such interaction does not provide the explanation behind diverse biological outcomes. Animal models of sepsis and a number of clinical trials with septic patients exploring the efficiency of antioxidants in sepsis are reviewed. In line with this, both enzymatic and non-enzymatic antioxidants were effective, and results from recent studies are promising. The usage of these potent antioxidants in sepsis patients would greatly impact the field of medicine.
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Ding N, Xu X, Wang Y, Li H, Cao Y, Zheng L. Contribution of prognostic ferroptosis-related subtypes classification and hub genes of sepsis. Transpl Immunol 2022; 74:101660. [PMID: 35787932 DOI: 10.1016/j.trim.2022.101660] [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: 02/28/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND Sepsis in patients is a great threat to human health due to its high incidence rate, its rapid and unpredictable progression, as well as it is difficult to treat, and it has poor prognosis. Ferroptosis is a newly discovered type of cell death characterized by the iron-dependent peroxide aggregation. Furthermore, ferroptosis is different from other forms of cell death, namely apoptosis, necrosis, pyroptosis and autophagy. Our study investigated the role of ferroptosis-related genes in sepsis. METHODS The GSE65682 dataset from the Gene Expression Omnibus (GEO) database was used to screen ferroptosis-related genes associated with sepsis, and the GSE134347 dataset for the external validation of selected hub genes. The univariate Cox regression analysis, Kaplan-Meier (K-M) survival analysis and weighted gene co-expression network analysis (WGCNA) were used to identify hub genes. Evaluation of the immune cell infiltration in sepsis was used to explain the immune heterogeneity among the cell subtypes. Gene set variation analysis (GSVA) and transcriptional regulatory analysis of selected hub genes further elucidated the probable mechanism of ferroptosis-related genes associated with prognosis in sepsis. Finally, we constructed a competing endogenous RNA (ceRNA) network model. RESULTS A total of 479 RNA-seq data points were used for analysis, including 365 samples from patients who survived sepsis and 114 samples from patients who succumbed to sepsis from the available GSE65682 dataset. Consequently, the univariate Cox regression analysis and consensus clustering analysis divide all 479 sepsis samples into two clusters of "survivals" vs. "non-survivals". Following complex analysis were identified as the most important ferroptosis-related genes. Indeed, the WGCNA and K-M analyses associated the expression patterns of NEDD4L and SIAH2 hub genes as the best prognosis for the survival of sepsis (p < 0.05). The expression trend was also consistent with the survival trend of the NEDD4L and SIAH2 hub genes by the external validation of GSE134347 (p < 0.05). Immune cell infiltration analysis indicated that the types and numbers of different immune cells vary among different subtypes and NEDD4L and SIAH2 hub genes. For example, NEDD4L and SIAH2 gene expression had a positive correlation with M0 macrophages and a negative correlation with neutrophils (p > 0.05). Finally, analysis of two hub genes and transcription factors (TFs) showed that 71 TFs were predicted to be related to NEDD4L while 64 TFs to SIAH2 by the Cistrome DB online database. CONCLUSION We suggest that NEDD4L and SIAH2 hub genes are involved in the ferroptosis-associated sepsis. The pattern of NEDD4L and SIAH2 expression in patients undergoing sepsis may have prognostic potential for the severity of sepsis and eventually for patients' survival.
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Affiliation(s)
- Ni Ding
- Department of Anesthesiology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518071, Guangdong, China
| | - Xiangzhao Xu
- Department of Anesthesiology, The Fifth People's Hospital of Ningxia, Shizuishan 753000, Ningxia, China
| | - Yuting Wang
- Department of Anesthesiology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518071, Guangdong, China
| | - Huiting Li
- Department of Anesthesiology, Sun Yat-Sen University Cancer Center, Guangzhou 753000, Guangdong, China
| | - Yuling Cao
- Department of Anesthesiology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518071, Guangdong, China
| | - Lei Zheng
- Department of Anesthesiology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518071, Guangdong, China.
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Statins Inhibit the Gliosis of MIO-M1, a Müller Glial Cell Line Induced by TRPV4 Activation. Int J Mol Sci 2022; 23:ijms23095190. [PMID: 35563594 PMCID: PMC9100994 DOI: 10.3390/ijms23095190] [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: 04/19/2022] [Revised: 05/03/2022] [Accepted: 05/04/2022] [Indexed: 11/17/2022] Open
Abstract
We characterized Müller cell gliosis induced by the activation of transient receptor potential vanilloid-type 4 (TRPV4) and assessed whether statins could modulate the gliosis. The human Müller cell line, MIO-M1, was used to analyze the gliosis caused by glaucomatous stimulation. To induce Müller gliosis in MIO-M1 cells, GSK101 was used to activate TRPV4, and Müller gliosis was evaluated by analyzing vimentin, nestin, and glial fibrillary acidic protein (GFAP) expression. The expression level of TNF-α was determined by ELISA. To evaluate the GSK101 activation of the NF-κB pathway, p65 phosphorylation was measured by Western blotting, and the nuclear translocation of p65 and IκBα phosphorylation were assessed by immunostaining. To assess the effect of statins on MIO-M1 gliosis, cells were pretreated for 24 h with statins before GSK101 treatment. Vimentin, nestin, and GFAP expression were upregulated by GSK101, while statins effectively inhibited them. The expression of TNF-α was increased by GSK101. The phosphorylation and nuclear translocation of p65 and IκBα phosphorylation, which occurs prior to p65 activation, were induced. Statins suppressed the GSK101-mediated phosphorylation of IκBα and p65 translocation. Statins can mitigate gliosis in the human Müller cell line. Because TRPV4 activation in Müller cells reflects glaucoma pathophysiology, statins may have the potential to prevent RGC death.
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Un H, Ugan RA, Kose D, Yayla M, Tastan TB, Bayir Y, Halici Z. A new approach to sepsis treatment by rasagiline: a molecular, biochemical and histopathological study. Mol Biol Rep 2022; 49:3875-3883. [PMID: 35301652 DOI: 10.1007/s11033-022-07235-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 01/05/2022] [Accepted: 02/07/2022] [Indexed: 11/25/2022]
Abstract
AIM We aimed to investigate the effects of rasagiline on acute lung injury that develops in the sepsis model induced with the cecal ligation and puncture in rats. MAIN METHODS The rats were separated into the following six groups, Group 1: Sham, Group 2: Sham + Rasagiline 4 mg/kg, Group 3: Sepsis, Group 4: Sepsis + Rasagiline 1 mg/kg, Group 5: Sepsis + Rasagiline 2 mg/kg, Group 6: Sepsis + Rasagiline 4 mg/kg. A total of four holes were opened with a 16-gauge needle through the cecum distal to the point of ligation. KEY FINDINGS Rasagiline treatment increased glutathione level and superoxide dismutase activity while decreased the malondialdehyde level after the sepsis. There was a statistically significant improvement in the doses of 2 mg/kg and 4 mg/kg. Rasagiline also increased Tnf-α, IL1β, IL6, NF-κβand HMGB1 gene expressions in dose-dependent at 2 mg/kg and 4 mg/kg doses. In increased doses, rasagiline prevent the development of edema, the formation of inflammation, and hemorrhage. SIGNIFICANCE Rasagiline exerts both antioxidant and anti-inflammatory effects on the cecal ligation and puncture induced acute lung injury in rats.
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Affiliation(s)
- Harun Un
- Faculty of Pharmacy, Department of Biochemistry, Agri Ibrahim Cecen University, Agri, Turkey.
| | - Rustem Anil Ugan
- Faculty of Pharmacy, Department of Pharmacology, Ataturk University, Erzurum, Turkey
| | - Duygu Kose
- Faculty of Medicine, Department of Pharmacology, Ataturk University, Erzurum, Turkey
- Clinical Research, Development and Design Application and Research Center, Ataturk University, Erzurum, Turkey
| | - Muhammed Yayla
- Faculty of Medicine, Department of Pharmacology, Kafkas University, Kars, Turkey
| | - Tugba Bal Tastan
- Faculty of Medicine, Department of Histology and Embryology, Erzincan Binali Yıldırım University, Erzincan, Turkey
| | - Yasin Bayir
- Faculty of Pharmacy, Department of Biochemistry, Ataturk University, Erzurum, Turkey
| | - Zekai Halici
- Faculty of Medicine, Department of Pharmacology, Ataturk University, Erzurum, Turkey
- Clinical Research, Development and Design Application and Research Center, Ataturk University, Erzurum, Turkey
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13
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Arancibia-Hernández YL, Aranda-Rivera AK, Cruz-Gregorio A, Pedraza-Chaverri J. Antioxidant/anti-inflammatory effect of Mg 2+ in coronavirus disease 2019 (COVID-19). Rev Med Virol 2022; 32:e2348. [PMID: 35357063 PMCID: PMC9111052 DOI: 10.1002/rmv.2348] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/09/2022] [Accepted: 03/17/2022] [Indexed: 12/26/2022]
Abstract
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), characterised by high levels of inflammation and oxidative stress (OS). Oxidative stress induces oxidative damage to lipids, proteins, and DNA, causing tissue damage. Both inflammation and OS contribute to multi-organ failure in severe cases. Magnesium (Mg2+ ) regulates many processes, including antioxidant and anti-inflammatory responses, as well as the proper functioning of other micronutrients such as vitamin D. In addition, Mg2+ participates as a second signalling messenger in the activation of T cells. Therefore, Mg2+ deficiency can cause immunodeficiency, exaggerated acute inflammatory response, decreased antioxidant response, and OS. Supplementation with Mg2+ has an anti-inflammatory response by reducing the levels of nuclear factor kappa B (NF-κB), interleukin (IL) -6, and tumor necrosis factor alpha. Furthermore, Mg2+ supplementation improves mitochondrial function and increases the antioxidant glutathione (GSH) content, reducing OS. Therefore, Mg2+ supplementation is a potential way to reduce inflammation and OS, strengthening the immune system to manage COVID-19. This narrative review will address Mg2+ deficiency associated with a worse disease prognosis, Mg2+ supplementation as a potent antioxidant and anti-inflammatory therapy during and after COVID-19 disease, and suggest that randomised controlled trials are indicated.
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Affiliation(s)
| | - Ana Karina Aranda-Rivera
- Facultad de Química, Departamento de Biología, Laboratorio F-315, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Alfredo Cruz-Gregorio
- Facultad de Química, Departamento de Biología, Laboratorio F-315, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - José Pedraza-Chaverri
- Facultad de Química, Departamento de Biología, Laboratorio F-315, Universidad Nacional Autónoma de México, Mexico City, Mexico
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Chang CC, Peng SY, Tsao HH, Huang HT, Lai XY, Hsu HJ, Jiang SJ. A Multitarget Therapeutic Peptide Derived From Cytokine Receptors Based on in Silico Analysis Alleviates Cytokine-Stimulated Inflammation. Front Pharmacol 2022; 13:853818. [PMID: 35370629 PMCID: PMC8965626 DOI: 10.3389/fphar.2022.853818] [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: 01/13/2022] [Accepted: 02/18/2022] [Indexed: 11/13/2022] Open
Abstract
Septicemia is a severe inflammatory response caused by the invasion of foreign pathogens. Severe sepsis-induced shock and multiple organ failure are the two main causes of patient death. The overexpression of many proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, is closely related to severe sepsis. Although the treatment of sepsis has been subject to many major breakthroughs of late, the treatment of patients with septic shock is still accompanied by a high mortality rate. In our previous research, we used computer simulations to design the multifunctional peptide KCF18 that can bind to TNF-α, IL-1β, and IL-6 based on the binding regions of receptors and proinflammatory cytokines. In this study, proinflammatory cytokines were used to stimulate human monocytes to trigger an inflammatory response, and the anti-inflammatory ability of the multifunctional KCF18 peptide was further investigated. Cell experiments demonstrated that KCF18 significantly reduced the binding of proinflammatory cytokines to their cognate receptors and inhibited the mRNA and protein expressions of TNF-α, IL-1β, and IL-6. It could also reduce the expression of reactive oxygen species induced by cytokines in human monocytes. KCF18 could effectively decrease the p65 nucleus translocation induced by cytokines, and a mice endotoxemia experiment demonstrated that KCF18 could reduce the expression of IL-6 and the increase of white blood cells in the blood stimulated by lipopolysaccharides. According to our study of tissue sections, KCF18 alleviated liver inflammation. By reducing the release of cytokines in plasma and directly affecting vascular cells, KCF18 is believed to significantly reduce the risk of vascular inflammation.
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Affiliation(s)
- Chun-Chun Chang
- Department of Laboratory Medicine, Hualien Tzu Chi Hospital, Hualien, Taiwan
- Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Shih-Yi Peng
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Hao-Hsiang Tsao
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Hsin-Ting Huang
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Xing-Yan Lai
- Department of Life Sciences, College of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Hao-Jen Hsu
- Department of Life Sciences, College of Medicine, Tzu Chi University, Hualien, Taiwan
- *Correspondence: Hao-Jen Hsu, ; Shinn-Jong Jiang,
| | - Shinn-Jong Jiang
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan
- *Correspondence: Hao-Jen Hsu, ; Shinn-Jong Jiang,
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Gandhirajan A, Roychowdhury S, Vachharajani V. Sirtuins and Sepsis: Cross Talk between Redox and Epigenetic Pathways. Antioxidants (Basel) 2021; 11:antiox11010003. [PMID: 35052507 PMCID: PMC8772830 DOI: 10.3390/antiox11010003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/09/2021] [Accepted: 12/11/2021] [Indexed: 12/19/2022] Open
Abstract
Sepsis and septic shock are the leading causes of death among hospitalized patients in the US. The immune response in sepsis transitions from a pro-inflammatory and pro-oxidant hyper-inflammation to an anti-inflammatory and cytoprotective hypo-inflammatory phase. While 1/3rd sepsis-related deaths occur during hyper-, a vast majority of sepsis-mortality occurs during the hypo-inflammation. Hyper-inflammation is cytotoxic for the immune cells and cannot be sustained. As a compensatory mechanism, the immune cells transition from cytotoxic hyper-inflammation to a cytoprotective hypo-inflammation with anti-inflammatory/immunosuppressive phase. However, the hypo-inflammation is associated with an inability to clear invading pathogens, leaving the host susceptible to secondary infections. Thus, the maladaptive immune response leads to a marked departure from homeostasis during sepsis-phases. The transition from hyper- to hypo-inflammation occurs via epigenetic programming. Sirtuins, a highly conserved family of histone deacetylators and guardians of homeostasis, are integral to the epigenetic programming in sepsis. Through their anti-inflammatory and anti-oxidant properties, the sirtuins modulate the immune response in sepsis. We review the role of sirtuins in orchestrating the interplay between the oxidative stress and epigenetic programming during sepsis.
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Affiliation(s)
- Anugraha Gandhirajan
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (A.G.); (S.R.)
| | - Sanjoy Roychowdhury
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (A.G.); (S.R.)
| | - Vidula Vachharajani
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (A.G.); (S.R.)
- Department of Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Correspondence:
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16
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Protective Effect of Topiroxostat on Myocardial Injury Induced by Lipopolysaccharide. J Surg Res 2021; 271:171-179. [PMID: 34815074 DOI: 10.1016/j.jss.2021.08.047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 08/05/2021] [Accepted: 08/26/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND Myocardial injury induced by sepsis is the most common cause of death. Topiroxostat has been found to have organ protective effects, but its role in septic shock-related cardiomyocyte damage is still unclear and needs further study. MATERIAL AND METHODS An endotoxemic shock model in rats was constructed. After topiroxostat treatment, hemodynamic parameters, myocardial injury marker enzymes, oxidative stress, myocardial injury, and apoptosis were measured by polyphysiograph, enzyme-linked immunosorbent assay, hematoxylin and eosin staining, TUNEL staining, and western blot. During in vitro experiments, the effect of topiroxostat on cell vitality, oxidative stress, inflammatory factors, apoptosis-related markers, phosphorylated-p65 (p-p65) and p65 expressions were measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and western blot. RESULTS Topiroxostat improved myocardial dysfunction and superoxide dismutase activity while suppressing levels of creatine kinase, lactate dehydrogenase and malondialdehyde in serum of endotoxemic shock rats. Additionally, topiroxostat augmented dry-wet weight ratios of the hearts in rats. Meanwhile, topiroxostat was proved to alleviate interstitial edema and apoptosis in myocardial tissues of endotoxemic shock rats. During in vitro experiments, topiroxostat pretreatment elevated lipopolysaccharide (LPS)-induced H9c2 cell vitality, and alleviated oxidative stress and inflammation. Moreover, topiroxostat pretreatment downregulated apoptosis-related markers, p-p65, and p-p65/p65 levels in LPS-induced H9c2 cells. CONCLUSIONS Topiroxostat attenuated LPS-induced myocardial injury via repressing apoptosis and oxidative stress.
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17
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Haas AN, Furlaneto F, Gaio EJ, Gomes SC, Palioto DB, Castilho RM, Sanz M, Messora MR. New tendencies in non-surgical periodontal therapy. Braz Oral Res 2021; 35:e095. [PMID: 34586209 DOI: 10.1590/1807-3107bor-2021.vol35.0095] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 03/31/2021] [Indexed: 12/11/2022] Open
Abstract
The aim of this review was to update the evidence of new approaches to non-surgical therapy (NSPT) in the treatment of periodontitis. Preclinical and clinical studies addressing the benefits of adjunctive antimicrobial photodynamic therapy, probiotics, prebiotics/synbiotics, statins, pro-resolving mediators, omega-6 and -3, ozone, and epigenetic therapy were scrutinized and discussed. Currently, the outcomes of these nine new approaches, when compared with subgingival debridement alone, did not demonstrate a significant added clinical benefit. However, some of these new alternative interventions may have the potential to improve the outcomes of NSPT alone. Future evidence based on randomized controlled clinical trials would help clinicians and patients in the selection of different adjunctive therapies.
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Affiliation(s)
- Alex Nogueira Haas
- Universidade Federal do Rio Grande do Sul - UFRGS, School of Dentistry, Department of Periodontology, Porto Alegre, RS, Brazil
| | - Flavia Furlaneto
- Universidade de São Paulo - USP, School of Dentistry of Ribeirão Preto, Department of Oral Surgery and Periodontology, Ribeirão Preto, SP, Brazil
| | - Eduardo José Gaio
- Universidade Federal do Rio Grande do Sul - UFRGS, School of Dentistry, Department of Periodontology, Porto Alegre, RS, Brazil
| | - Sabrina Carvalho Gomes
- Universidade Federal do Rio Grande do Sul - UFRGS, School of Dentistry, Department of Periodontology, Porto Alegre, RS, Brazil
| | - Daniela Bazan Palioto
- Universidade de São Paulo - USP, School of Dentistry of Ribeirão Preto, Department of Oral Surgery and Periodontology, Ribeirão Preto, SP, Brazil
| | - Rogerio Moraes Castilho
- Michigan University, School of Dentistry, Department of Periodontics and Oral Medicine, Ann Arbor, MI, USA
| | - Mariano Sanz
- Complutense University of Madrid, Etiology and Therapy of Periodontal and Peri-implant Diseases Research Group, Madrid, Spain
| | - Michel Reis Messora
- Universidade de São Paulo - USP, School of Dentistry of Ribeirão Preto, Department of Oral Surgery and Periodontology, Ribeirão Preto, SP, Brazil
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Esculetin protects against early sepsis via attenuating inflammation by inhibiting NF-κB and STAT1/STAT3 signaling. Chin J Nat Med 2021; 19:432-441. [PMID: 34092294 DOI: 10.1016/s1875-5364(21)60042-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Indexed: 01/14/2023]
Abstract
Esculetin, a natural derivative from the traditional and widely-used Chinese medicinal herb Cortex Fraxini, has a variety of pharmacological effects, especially in anti-inflammation. However, it is not clear whether esculetin has a therapeutic effect on sepsis. This study aimed to investigate the anti-inflammatory and protective effects of esculetin on early sepsis. The results showed that the lung injury was significantly relieved with the treatment of esculetin, accompanied with the restrained production of inflammatory factors including IL-1β, IL-6, TNF-α, CCL2 and iNOS during the early phase of E.coli-induced sepsis. Of note, activation of NF-κB and STAT1/STAT3 signals, the main upstream signals of many inflammatory factors, were attenuated by esculetin in both lung tissues from septic mice and LPS-stimulated macrophage. These findings suggested that the protection of esculetin against early sepsis should be related to its anti-inflammatory effect, which was at least partly due to its inhibition on NF-κB and STAT1/STAT3 signaling pathway in macrophage. Thus, esculetin could serve as a potential therapeutic agent by rebalancing innate immune response in macrophage for the treatment of early sepsis.
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Samad N, Sodunke TE, Abubakar AR, Jahan I, Sharma P, Islam S, Dutta S, Haque M. The Implications of Zinc Therapy in Combating the COVID-19 Global Pandemic. J Inflamm Res 2021; 14:527-550. [PMID: 33679136 PMCID: PMC7930604 DOI: 10.2147/jir.s295377] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 01/27/2021] [Indexed: 12/15/2022] Open
Abstract
The global pandemic from COVID-19 infection has generated significant public health concerns, both health-wise and economically. There is no specific pharmacological antiviral therapeutic option to date available for COVID-19 management. Also, there is an urgent need to discover effective medicines, prevention, and control methods because of the harsh death toll from this novel coronavirus infection. Acute respiratory tract infections, significantly lower respiratory tract infections, and pneumonia are the primary cause of millions of deaths worldwide. The role of micronutrients, including trace elements, boosted the human immune system and was well established. Several vitamins such as vitamin A, B6, B12, C, D, E, and folate; microelement including zinc, iron, selenium, magnesium, and copper; omega-3 fatty acids as eicosapentaenoic acid and docosahexaenoic acid plays essential physiological roles in promoting the immune system. Furthermore, zinc is an indispensable microelement essential for a thorough enzymatic physiological process. It also helps regulate gene-transcription such as DNA replication, RNA transcription, cell division, and cell activation in the human biological system. Subsequently, zinc, together with natural scavenger cells and neutrophils, are also involved in developing cells responsible for regulating nonspecific immunity. The modern food habit often promotes zinc deficiency; as such, quite a few COVID-19 patients presented to hospitals were frequently diagnosed as zinc deficient. Earlier studies documented that zinc deficiency predisposes patients to a viral infection such as herpes simplex, common cold, hepatitis C, severe acute respiratory syndrome coronavirus (SARS-CoV-1), the human immunodeficiency virus (HIV) because of reducing antiviral immunity. This manuscript aimed to discuss the various roles played by zinc in the management of COVID-19 infection.
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Affiliation(s)
- Nandeeta Samad
- Department of Public Health, North South University, Dhaka, 1229, Bangladesh
| | | | - Abdullahi Rabiu Abubakar
- Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Bayero University, Kano, 700233, Nigeria
| | - Iffat Jahan
- Department of Physiology, Eastern Medical College, Cumilla, Bangladesh
| | - Paras Sharma
- Department of Pharmacognosy, BVM College of Pharmacy, Gwalior, India
| | - Salequl Islam
- Department of Microbiology, Jahangirnagar University, Dhaka, 1342, Bangladesh
| | - Siddhartha Dutta
- Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Mainul Haque
- The Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kuala Lumpur, Malaysia
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20
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Noori MS, Courreges MC, Bergmeier SC, McCall KD, Goetz DJ. Modulation of LPS-induced inflammatory cytokine production by a novel glycogen synthase kinase-3 inhibitor. Eur J Pharmacol 2020; 883:173340. [PMID: 32634441 PMCID: PMC7334664 DOI: 10.1016/j.ejphar.2020.173340] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/28/2020] [Accepted: 06/29/2020] [Indexed: 12/21/2022]
Abstract
Sepsis is a serious condition that can lead to long-term organ damage and death. At the molecular level, the hallmark of sepsis is the elevated expression of a multitude of potent cytokines, i.e. a cytokine storm. For sepsis involving gram-negative bacteria, macrophages recognize lipopolysaccharide (LPS) shed from the bacteria, activating Toll-like-receptor 4 (TLR4), and triggering a cytokine storm. Glycogen synthase kinase-3 (GSK-3) is a highly active kinase that has been implicated in LPS-induced cytokine production. Thus, compounds that inhibit GSK-3 could be potential therapeutics for sepsis. Our group has recently described a novel and highly selective inhibitor of GSK-3 termed COB-187. In the present study, using THP-1 macrophages, we evaluated the ability of COB-187 to attenuate LPS-induced cytokine production. We found that COB-187 significantly reduced, at the protein and mRNA levels, cytokines induced by LPS (e.g. IL-6, TNF-α, IL-1β, CXCL10, and IFN-β). Further, the data suggest that the inhibition could be due, at least in part, to COB-187 reducing NF-κB (p65/p50) DNA binding activity as well as reducing IRF-3 phosphorylation at Serine 396. Thus, COB-187 appears to be a potent inhibitor of the cytokine storm induced by LPS.
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Affiliation(s)
- Mahboubeh S Noori
- Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH, 45701, USA.
| | - Maria C Courreges
- Department of Specialty Medicine, Ohio University, Athens, OH, 45701, USA
| | - Stephen C Bergmeier
- Biomedical Engineering Program, Ohio University, Athens, OH, 45701, USA; Department of Chemistry and Biochemistry, Ohio University, Athens, OH, 45701, USA
| | - Kelly D McCall
- Department of Specialty Medicine, Ohio University, Athens, OH, 45701, USA; Biomedical Engineering Program, Ohio University, Athens, OH, 45701, USA; The Diabetes Institute, Ohio University, Athens, OH, 45701, USA; Molecular and Cellular Biology Program, Ohio University, Athens, OH, 45701, USA; Translational Biomedical Science Program, Ohio University, Athens, OH, 45701, USA
| | - Douglas J Goetz
- Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH, 45701, USA; Biomedical Engineering Program, Ohio University, Athens, OH, 45701, USA.
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Fan Y, Wang J, Feng Z, Cao K, Xu H, Liu J. Pinitol attenuates LPS-induced pneumonia in experimental animals: Possible role via inhibition of the TLR-4 and NF-κB/IκBα signaling cascade pathway. J Biochem Mol Toxicol 2020; 35:e22622. [PMID: 32926510 DOI: 10.1002/jbt.22622] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/12/2020] [Accepted: 08/25/2020] [Indexed: 11/07/2022]
Abstract
Pneumonia is a chronic disorder of the respiratory system associated with worsening quality of life and a significant economic burden. Pinitol, a plant cyclic polyol, has been documented for immune-inflammatory potential. The aim of present investigation was to evaluate the potential and possible mechanism of action of pinitol against lipopolysaccharide (LPS)-induced pneumonia in the experimental animal model. Pneumonia was induced in Sprague-Dawley rats by intratracheal administration of LPS (2 mg/kg). Animals were treated with either vehicle or dexamethasone or pinitol (5 or 10 or 20 mg/kg). Potential of pinitol against LPS-induced pulmonary insult was assessed based on behavioral, biochemical, molecular, and ultrastructural studies. Intratracheal instillation of LPS induced significant (P < .05) inflammatory infiltration in bronchoalveolar lavage fluid (BALF) and lung tissue reflected by elevated pleural effusion volume, lung edema, BALF polymorphonuclear leukocytes count and lung myeloperoxidase levels, which was attenuated by pinitol (10 and 20 mg/kg) administration. Pinitol also markedly (P < .05) inhibited LPS-induced alterations in electrocardiographic, hemodynamic changes, right ventricular, and lung function tests. The LPS-induced downregulated nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1), whereas upregulated transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), and inducible nitric oxide synthase (iNOs) lung messenger RNA expressions were significantly (P < .05) inhibited by pinitol. Western blot analysis suggested pinitol markedly (P < .05) decreased nuclear factor-κB (NF-κB), inhibitor of nuclear factor κB (IkBα), toll-like receptor 4 (TLR-4), and cyclooxygenase-II (COX-II) protein expressions in the lung. These findings were further supported by histological and ultrastructural analyses of lung tissue that show pinitol significantly (P < .05) ameliorates LPS-induced aberrations in lung tissue. In conclusion, pinitol attenuated LPS-induced pneumonia via inhibition of TLR-4 to downregulate the NF-κB/IκBα signaling cascade and thus ameliorated the production of proinflammatory cytokines (TNF-α, ILs, NLRP3, and TGF-β), inflammatory mediators (COX-II and iNOs) and elevated oxidative stress (Nrf-2 and HO-1).
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Affiliation(s)
- Yingying Fan
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Center for Mitochondrial Biology and Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jian Wang
- Department of Otolaryngology-Head and Neck Surgery, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Zhihui Feng
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Center for Mitochondrial Biology and Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Ke Cao
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Center for Mitochondrial Biology and Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Hao Xu
- Basic of Medical Science, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Jiankang Liu
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Center for Mitochondrial Biology and Medicine, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Xiao LX, Qi L, Zhang XL, Zhou YQ, Yue HL, Yu ED, Li QY. Liver injury in septic mice were suppressed by a camptothecin-bile acid conjugate via inhibiting NF-κB signaling pathway. Life Sci 2020; 257:118130. [DOI: 10.1016/j.lfs.2020.118130] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 07/17/2020] [Accepted: 07/19/2020] [Indexed: 12/19/2022]
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Abstract
The role of dietary fiber in chronic inflammatory disorders has been explored, but very little is known about its benefits in acute inflammation. Previously, we have demonstrated that dietary cellulose supplementation confers protection in a murine model of sepsis by promoting the growth of the gut microbiota that are linked to metabolic health. The survival benefit is associated with a decrease in serum concentration of proinflammatory cytokines, reduced neutrophil infiltration in the lungs, and diminished hepatic inflammation. Here, we aim to understand if the benefit of manipulating the gut microbiome exerts a broader "systemic" influence on the immune system in a lethal murine endotoxemia model. We hypothesize that mice-fed high-fiber cellulose (HF) diet will demonstrate a reduction in activated macrophages and dendritic cells (DCs) and a concomitant increase in the suppressive capacity of T-regulatory cells (Tregs) toward T cells responsiveness. We characterized the immunological profile and activation status of macrophages, DCs, and T cells in mice on HF diet that were then subjected to endotoxemia. Supplementation with HF diet decreased the number and activation of splenic macrophages and DCs in mice after LPS administration. Similarly, HF diet amplified the suppressive function of Tregs and induced anergy in T cells as compared with mice on a regular diet. Our data suggest that the use of HF diet can be a simple, yet effective tool that decreases the hepatic DNA-binding activity of NF-κB leading to a reduction in proinflammatory cytokine response in a murine endotoxemia model.
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24
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Meduri GU, Chrousos GP. General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections. Front Endocrinol (Lausanne) 2020; 11:161. [PMID: 32390938 PMCID: PMC7189617 DOI: 10.3389/fendo.2020.00161] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 03/09/2020] [Indexed: 12/20/2022] Open
Abstract
In critical illness, homeostatic corrections representing the culmination of hundreds of millions of years of evolution, are modulated by the activated glucocorticoid receptor alpha (GRα) and are associated with an enormous bioenergetic and metabolic cost. Appreciation of how homeostatic corrections work and how they evolved provides a conceptual framework to understand the complex pathobiology of critical illness. Emerging literature place the activated GRα at the center of all phases of disease development and resolution, including activation and re-enforcement of innate immunity, downregulation of pro-inflammatory transcription factors, and restoration of anatomy and function. By the time critically ill patients necessitate vital organ support for survival, they have reached near exhaustion or exhaustion of neuroendocrine homeostatic compensation, cell bio-energetic and adaptation functions, and reserves of vital micronutrients. We review how critical illness-related corticosteroid insufficiency, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection. Importantly, the allostatic overload imposed by these homeostatic corrections impacts negatively on both acute and long-term morbidity and mortality. Since the bioenergetic and metabolic reserves to support homeostatic corrections are time-limited, early interventions should be directed at increasing GRα and mitochondria number and function. Present understanding of the activated GC-GRα's role in immunomodulation and disease resolution should be taken into account when re-evaluating how to administer glucocorticoid treatment and co-interventions to improve cellular responsiveness. The activated GRα interdependence with functional mitochondria and three vitamin reserves (B1, C, and D) provides a rationale for co-interventions that include prolonged glucocorticoid treatment in association with rapid correction of hypovitaminosis.
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Affiliation(s)
- Gianfranco Umberto Meduri
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
- Memphis Veterans Affairs Medical Center, Memphis, TN, United States
| | - George P. Chrousos
- University Research Institute of Maternal and Child Health and Precision Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
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25
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Wang Y, Xu Z, Yue D, Zeng Z, Yuan W, Xu K. Linkage of lncRNA CRNDE sponging miR-181a-5p with aggravated inflammation underlying sepsis. Innate Immun 2019; 26:152-161. [PMID: 31604377 PMCID: PMC7016407 DOI: 10.1177/1753425919880946] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
This investigation was performed to verify whether lncRNA CRNDE sponging miR-181a-5p was involved with sepsis-relevant inflammatory dysfunctions. Aggregately 136 sepsis patients and 151 healthy people were recruited, and their fasting peripheral blood was gathered to detect expressions of CRNDE and miR-181a-5p. In addition, THP-1 cells were transfected with si-CRNDE, miR-181a-5p mimic, pcDNA3.1-TLR4 and si-TLR4, and then sepsis-specific inflammatory cytokines within the cells were quantified. The sponging relationships between CRNDE and miR-181a-5p, as well as between miR-181a-5p and TLR4, were ascertained by means of luciferase reporter gene assay. The experimental results revealed that over-expressed CRNDE and under-expressed miR-181a-5p were associated with shortened lifespan of sepsis patients. Mechanically, si-CRNDE-1 and miR-181a-5p mimic were able to reverse the promoting effects of LPS on production of NF-kB, TNF-α, IL-1β and IL-6 by THP-1 cells. Moreover, the expressional change of miR-181a-5p in THP-1 cells was in part owing to its being sponged by CRNDE. Lastly, TLR4, subjected to targeted modification of miR-181a-5p, was capable of disturbing the contribution of CRNDE and miR-181a-5p to THP-1 cells’ release of NF-kB, TNF-α, IL-1β and IL-6. Collectively, the CRNDE/miR-181a-5p/TLR4 axis seemed to have potential in modifying sepsis-related inflammatory pathogenesis, which offered a direction for sepsis diagnosis and treatment.
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Affiliation(s)
- Yijun Wang
- Department of Emergency Medicine, Chenzhou NO.1 People's Hospital, Chenzhou, Hunan Province, P. R. China
| | - Ziqiang Xu
- Department of Emergency Medicine, Chenzhou NO.1 People's Hospital, Chenzhou, Hunan Province, P. R. China
| | - Dongyou Yue
- Department of Emergency Medicine, Chenzhou NO.1 People's Hospital, Chenzhou, Hunan Province, P. R. China
| | - Zhenhua Zeng
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, P. R. China
| | - Weijie Yuan
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, P. R. China
| | - Ke Xu
- Department of Critical Care Medicine, Chenzhou NO.1 People's Hospital, Chenzhou, Hunan Province, P. R. China
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Skibsted S, Bhasin MK, Henning DJ, Jaminet SC, Lewandowski J, Kirkegaard H, Aird WC, Shapiro NI. Leukocyte Transcriptional Response in Sepsis. Shock 2019; 52:166-173. [PMID: 30211758 PMCID: PMC10608800 DOI: 10.1097/shk.0000000000001258] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND The complex host response to sepsis is incompletely understood. The aim of this investigation is to use leukocyte RNA sequencing to characterize biological functions, cellular pathways, and key regulatory molecules driving sepsis pathophysiology. METHODS This was a prospective, observational study of emergency department patients with sepsis, at an urban, academic, tertiary care center. In the derivation cohort, we collected blood at enrollment and 90 days after hospital discharge allowing each patient to serve as an internal control. We performed RNA sequencing to quantify transcriptional expression changes during sepsis and non-sepsis states. We then performed unsupervised and supervised analyses, as well as functional and pathway analyses. We selected the top down and upregulated genes and key regulatory molecules for validation. Validation occurred in a cohort of septic and non-septic using real-time PCR. RESULTS The derivation cohort included 5 patients, and RNA sequencing revealed 916 unique mRNA transcripts differentially expressed during sepsis. Among these, 673 (73%) genes were upregulated, and 243 (27%) were downregulated. Functional enrichment analysis revealed a highly dynamic downstream effect of the transcriptional activity during sepsis. Of the 43 functional cellular pathways activated during sepsis, the top pathways were closely associated with inflammation and response to infection. Validation occurred in 18 septic and 25 non-septic control patients, with 34/45 (76%) of identified genes validated. The regulatory analysis identified several key regulators of sepsis. CONCLUSIONS Highly dynamic transcriptional activity occurs in leukocytes during sepsis, activating key cellular pathways and master regulatory molecules that drive the sepsis process.
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Affiliation(s)
- Simon Skibsted
- Department of Emergency Medicine, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA, USA
- Center for Emergency Medicine Research, Aarhus University Hospital & Aarhus University, Aarhus, Denmark
| | - Manoj K. Bhasin
- Center for Genomics, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA, USA
| | - Daniel J. Henning
- Division of Emergency Medicine, University of Washington, Seattle, WA, USA
| | - Shou Ching Jaminet
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA, USA
- Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA, USA
| | - Jeffrey Lewandowski
- Department of Emergency Medicine, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA, USA
| | - Hans Kirkegaard
- Center for Emergency Medicine Research, Aarhus University Hospital & Aarhus University, Aarhus, Denmark
| | - William C. Aird
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA, USA
| | - Nathan I. Shapiro
- Department of Emergency Medicine, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA, USA
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, MA, USA
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27
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Wang L, Cao Y, Gorshkov B, Zhou Y, Yang Q, Xu J, Ma Q, Zhang X, Wang J, Mao X, Zeng X, Su Y, Verin AD, Hong M, Liu Z, Huo Y. Ablation of endothelial Pfkfb3 protects mice from acute lung injury in LPS-induced endotoxemia. Pharmacol Res 2019; 146:104292. [PMID: 31167111 DOI: 10.1016/j.phrs.2019.104292] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/15/2019] [Accepted: 05/30/2019] [Indexed: 12/29/2022]
Abstract
Acute lung injury (ALI) is one of the leading causes of death in sepsis. Endothelial inflammation and dysfunction play a prominent role in development of ALI. Glycolysis is the predominant bioenergetic pathway for endothelial cells (ECs). However, the role of EC glycolysis in ALI of sepsis remains unclear. Here we show that both the expression and activity of PFKFB3, a key glycolytic activator, were markedly increased in lipopolysaccharide (LPS)-treated human pulmonary arterial ECs (HPAECs) in vitro and in lung ECs of mice challenged with LPS in vivo. PFKFB3 knockdown significantly reduced LPS-enhanced glycolysis in HPAECs. Compared with LPS-challenged wild-type mice, endothelial-specific Pfkfb3 knockout (Pfkfb3ΔVEC) mice exhibited reduced endothelium permeability, lower pulmonary edema, and higher survival rate. This was accompanied by decreased expression of intracellular adhesion molecule-1 (Icam-1) and vascular cell adhesion molecule 1 (Vcam-1), as well as decreased neutrophil and macrophage infiltration to the lung. Consistently, PFKFB3 silencing or PFKFB3 inhibition in HPAECs and human pulmonary microvascular ECs (HPMVECs) significantly downregulated LPS-induced expression of ICAM-1 and VCAM-1, and monocyte adhesion to human pulmonary ECs. In contrast, adenovirus-mediated PFKFB3 overexpression upregulated ICAM-1 and VCAM-1 expression in HPAECs. Mechanistically, PFKFB3 silencing suppressed LPS-induced nuclear translocation of nuclear factor κB (NF-κB)-p65, and NF-κB inhibitors abrogated PFKFB3-induced expression of ICAM-1 and VCAM-1. Finally, administration of the PFKFB3 inhibitor 3PO also reduced the inflammatory response of vascular endothelium and protected mice from LPS-induced ALI. Overall, these findings suggest that targeting PFKFB3-mediated EC glycolysis is an efficient therapeutic strategy for ALI in sepsis.
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Affiliation(s)
- Lina Wang
- Drug Discovery Center, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China; Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Yapeng Cao
- Drug Discovery Center, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China; Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - B Gorshkov
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Yaqi Zhou
- Drug Discovery Center, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China
| | - Qiuhua Yang
- Drug Discovery Center, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China; Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Jiean Xu
- Drug Discovery Center, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China; Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Qian Ma
- Drug Discovery Center, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China; Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Xiaoyu Zhang
- Drug Discovery Center, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China; Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Jingjing Wang
- Drug Discovery Center, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China
| | - Xiaoxiao Mao
- Drug Discovery Center, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China
| | - Xianqiu Zeng
- Drug Discovery Center, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China
| | - Yunchao Su
- Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - A D Verin
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Mei Hong
- Drug Discovery Center, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China
| | - Zhiping Liu
- Drug Discovery Center, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China; Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
| | - Yuqing Huo
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
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Lei X, Zhao Y. Neovascular glaucoma regulation by arylsulfonyl indoline-benzamide (ASIB) through targeting NF-kB signalling pathway. 3 Biotech 2019; 9:211. [PMID: 31093481 DOI: 10.1007/s13205-019-1730-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 04/24/2019] [Indexed: 12/18/2022] Open
Abstract
The present study investigated the effect of arylsulfonyl indoline-benzamide (ASIB) on neovascular glaucoma in the mice model in vivo. In the mice model of glaucoma, ASIB treatment significantly (P < 0.05) increased PDGF-B-positive cell count in the corneal tissues. ASIB treatment at 5, 10, 15 and 20 mg/kg doses raised the level of PDGF-B mRNA in the mice cornea by 2.3-, 3.8-, 5.4- and 5.5-fold, respectively. Pre-treatment of the glaucoma mice with ASIB leads to inhibition of TNF-α and IL-6 production. In the glaucoma mice, treatment with ASIB leads to a marked decrease in the level of NOD2 mRNA and protein. ASIB treatment caused a significant decrease in the glaucoma-induced up-regulation of NF-κB p65 activation. The phosphorylation of NF-κB p65 was almost completely inhibited in the glaucoma mice on treatment with 15 mg/kg dose of ASIB. ASIB exhibited inhibitory effect on glaucoma-induced inflammatory cytokine and oxidative factor damage in the mice. It caused up-regulation of PDGF expression and down-regulated NF-κB activation. Therefore, ASIB can be of therapeutic significance for neovascular glaucoma treatment. However, more studies need to be performed to fully understand the molecular mechanism of ASIB in glaucoma treatment.
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Affiliation(s)
- Xiaojun Lei
- Opthalmology Department, Friendship Hospital of Da Lian, Da Lian, 116000 Liaoning Province China
| | - Yongxia Zhao
- Opthalmology Department, The Third People's Hospital of Da Lian, Da Lian, 116033 Liaoning Province China
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Intravenous Lipid Emulsions to Deliver Bioactive Omega-3 Fatty Acids for Improved Patient Outcomes. Mar Drugs 2019; 17:md17050274. [PMID: 31072006 PMCID: PMC6563008 DOI: 10.3390/md17050274] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 04/23/2019] [Accepted: 05/06/2019] [Indexed: 12/26/2022] Open
Abstract
Lipids used in intravenous nutrition support (i.e., parenteral nutrition) provide energy, building blocks, and essential fatty acids. These lipids are included as emulsions since they need to be soluble in an aqueous environment. Fish oil is a source of bioactive omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid). Lipid emulsions, including fish oil, have been used for parenteral nutrition for adult patients post-surgery (mainly gastrointestinal). This has been associated with alterations in biomarkers of inflammation and immune defense, and in some studies, a reduction in length of intensive care unit and hospital stay. These benefits, along with a reduction in infections, are emphasized through recent meta-analyses. Perioperative administration of fish oil may be superior to postoperative administration, but this requires further exploration. Parenteral fish oil has been used in critically ill adult patients. Here, the influence on inflammatory processes, immune function, and clinical endpoints is less clear. However, some studies found reduced inflammation, improved gas exchange, and shorter length of hospital stay in critically ill patients if they received fish oil. Meta-analyses do not present a consistent picture but are limited by the small number and size of studies. More and better trials are needed in patient groups in which parenteral nutrition is used and where fish oil, as a source of bioactive omega-3 fatty acids, may offer benefits.
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Johnsen N, Hamilton ADM, Greve AS, Christensen MG, Therkildsen JR, Wehmöller J, Skals M, Praetorius HA. α-Haemolysin production, as a single factor, causes fulminant sepsis in a model of Escherichia coli-induced bacteraemia. Cell Microbiol 2019; 21:e13017. [PMID: 30761726 DOI: 10.1111/cmi.13017] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 02/08/2019] [Accepted: 02/10/2019] [Indexed: 12/14/2022]
Abstract
α-Haemolysin (HlyA) from uropathogenic Escherichia coli has been demonstrated to be a significant virulence factor for ascending urinary tract infections. Once the E. coli reach the well-vascularised kidneys, there is a high risk of bacteraemia and a subsequent septic host response. Despite this, HlyA has the potential to accelerate the host response both directly and via its ability to facilitate adenosine triphosphate release from cells. It has not been settled whether HlyA aggravates bacteraemia into a septic state. To address this, we used an E. coli strain in a model of acute urosepsis that was either transfected with a plasmid containing the full HlyA operon or one with deletion in the HlyA gene. Here, we show that HlyA accelerates the host response to E. coli in the circulation. Mice exposed to HlyA-producing E. coli showed massively increased proinflammatory cytokines, a substantial fall in circulating thrombocytes, extensive haematuria, and intravascular haemolysis. This was not seen in mice exposed to either E. coli that do not secrete HlyA or vehicle controls. Consistent with the massive host response to the bacteria, the mice exposed to HlyA-producing E. coli died exceedingly early, whereas mice exposed to E. coli without HlyA production and vehicle controls survived the entire observation period. These data allow us to conclude that HlyA is a virulence factor that accelerates a state of bacteraemia into fulminant sepsis in a mouse model.
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Affiliation(s)
- Nanna Johnsen
- Department of Biomedicine, Aarhus University, Aarhus C, Denmark
| | | | | | | | | | - Julia Wehmöller
- Department of Biomedicine, Aarhus University, Aarhus C, Denmark
| | - Marianne Skals
- Department of Biomedicine, Aarhus University, Aarhus C, Denmark
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Jin J, Xu W, Wan B, Wang X, Zhou Z, Miao Y, Lv T, Song Y. Topotecan Alleviates Lipopolysaccharide-Mediated Acute Lung Injury Via the NF-κB Signaling Pathway. J Surg Res 2019; 235:83-92. [DOI: 10.1016/j.jss.2018.08.057] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 07/30/2018] [Accepted: 08/24/2018] [Indexed: 12/14/2022]
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Chia WT, Tseng FJ, Lin GJ, Chen YW, Lee HS, Sytwu HK. Knee joint injection resveratrol amelioration inflammation in collagen antibody induced arthritis. JOURNAL OF MEDICAL SCIENCES 2019. [DOI: 10.4103/jmedsci.jmedsci_8_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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33
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Hickey C, Schaible B, Nguyen S, Hurley D, Srikumar S, Fanning S, Brown E, Crifo B, Matallanas D, McClean S, Taylor CT, Schaffer K. Increased Virulence of Bloodstream Over Peripheral Isolates of P. aeruginosa Identified Through Post-transcriptional Regulation of Virulence Factors. Front Cell Infect Microbiol 2018; 8:357. [PMID: 30416988 PMCID: PMC6212473 DOI: 10.3389/fcimb.2018.00357] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Accepted: 09/18/2018] [Indexed: 11/13/2022] Open
Abstract
The factors influencing the virulence of P. aeruginosa in the development of invasive infection remain poorly understood. Here, we investigated the role of the host microenvironment in shaping pathogen virulence and investigated the mechanisms involved. Comparing seven paired genetically indistinguishable clinical bloodstream and peripheral isolates of P. aeruginosa, we demonstrate that isolates derived from bloodstream infections are more virulent than their peripheral counterparts (p = 0.025). Bloodstream and peripheral isolates elicited similar NF-kB responses in a THP-1 monocyte NF-kappaB reporter cell line implicating similar immunogenicity. Proteomic analysis by mass spectrometry identified multiple virulence and virulence-related factors including LecA and RpoN in significantly greater abundance in the bacterial supernatant from the bloodstream isolate in comparison to that from the corresponding peripheral isolate. Investigation by qPCR revealed that control of expression of these virulence factors was not due to altered levels of transcription. Based on these data, we hypothesize a post-transcriptional mechanism of virulence regulation in P. aeruginosa bloodstream infections influenced by surrounding microenvironmental conditions.
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Affiliation(s)
| | | | - Scott Nguyen
- School of Public Health, Physiotherapy & Sports Science, University College Dublin, Dublin, Ireland
| | - Daniel Hurley
- School of Public Health, Physiotherapy & Sports Science, University College Dublin, Dublin, Ireland
| | - Shabarinath Srikumar
- School of Public Health, Physiotherapy & Sports Science, University College Dublin, Dublin, Ireland
| | - Séamus Fanning
- School of Public Health, Physiotherapy & Sports Science, University College Dublin, Dublin, Ireland
| | - Eric Brown
- Conway Institute, University College Dublin, Dublin, Ireland
| | - Bianca Crifo
- Conway Institute, University College Dublin, Dublin, Ireland
| | - David Matallanas
- Systems Biology Ireland, University College Dublin, Dublin, Ireland.,School of Medicine, University College Dublin, Dublin, Ireland
| | - Siobhán McClean
- Biomedical and Biomolecular Science, University College Dublin, Dublin, Ireland
| | - Cormac T Taylor
- Conway Institute, University College Dublin, Dublin, Ireland.,Systems Biology Ireland, University College Dublin, Dublin, Ireland.,School of Medicine, University College Dublin, Dublin, Ireland
| | - Kirsten Schaffer
- School of Medicine, University College Dublin, Dublin, Ireland.,Department of Clinical Microbiology, St. Vincent's University Hospital, Dublin, Ireland
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Intke C, Korpelainen S, Hämäläinen S, Vänskä M, Koivula I, Jantunen E, Pulkki K, Juutilainen A. Interleukin-1 receptor antagonist as a biomarker of sepsis in neutropenic haematological patients. Eur J Haematol 2018; 101:691-698. [PMID: 30099772 DOI: 10.1111/ejh.13161] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 08/04/2018] [Accepted: 08/06/2018] [Indexed: 12/26/2022]
Abstract
OBJECTIVE The study aim was to compare the performance of interleukin-1 receptor antagonist (IL-1Ra) to C-reactive protein (CRP) and procalcitonin (PCT) in early prediction of the clinical course of febrile neutropenia. METHODS The study population consisted of 86 consecutive patients with febrile neutropenia who received intensive chemotherapy for haematological malignancy between November 2009 and November 2012 at the adult haematology ward of Kuopio University Hospital. Twenty-three (27%) patients had acute myeloid leukaemia and 63 (73%) patients were autologous stem cell transplant recipients. IL-1Ra, CRP and procalcitonin were measured at the onset of fever (d0), on day 1 (d1) and on day 2 (d2). RESULTS Eight patients developed severe sepsis, including three patients with septic shock. Eighteen patients had bacteraemia. After the onset of febrile neutropenia Youden´s indices (with their 95% confidence intervals) to identify severe sepsis were for IL-1Ra on d0 0.57 (0.20-0.71) and on d1 0.65 (0.28-0.78), for CRP on d0 0.41 (0.04-0.61) and on d1 0.47 (0.11-0.67) and for PCT on d0 0.39 (0.05-0.66) and on d1 0.52 (0.18-0.76). CONCLUSIONS In haematological patients, IL-1Ra has a comparable capacity with CRP and PCT to predict severe sepsis at the early stages of febrile neutropenia.
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Affiliation(s)
- Carina Intke
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Sini Korpelainen
- Institute of Clinical Medicine/Internal Medicine, University of Eastern Finland, Kuopio, Finland
| | - Sari Hämäläinen
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Matti Vänskä
- Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Irma Koivula
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Esa Jantunen
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
- Institute of Clinical Medicine/Internal Medicine, University of Eastern Finland, Kuopio, Finland
- Siun Sote - Hospital District of North Carelia, Joensuu, Finland
| | - Kari Pulkki
- Eastern Finland Laboratory Centre, Kuopio, Finland
- Laboratory Division, Turku University Central Hospital and Department of Clinical Chemistry, Faculty of Medicine, University of Turku, Turku, Finland
| | - Auni Juutilainen
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
- Institute of Clinical Medicine/Internal Medicine, University of Eastern Finland, Kuopio, Finland
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35
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Hattori Y, Hattori K, Suzuki T, Palikhe S, Matsuda N. Nucleic-acid based gene therapy approaches for sepsis. Eur J Pharmacol 2018; 833:403-410. [PMID: 29935173 DOI: 10.1016/j.ejphar.2018.06.031] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 06/06/2018] [Accepted: 06/19/2018] [Indexed: 12/15/2022]
Abstract
Despite advances in overall medical care, sepsis and its sequelae continue to be an embarrassing clinical entity with an unacceptably high mortality rate. The central reason for high morbidity and high mortality of sepsis and its sequelae is the lack of an effective treatment. Previous clinical trials have largely failed to identify an effective therapeutic target to improve clinical outcomes in sepsis. Thus, the key goal favoring the outcome of septic patients is to devise innovative and evolutionary therapeutic strategies. Gene therapy can be considered as one of the most promising novel therapeutic approaches for nasty disorders. Since a number of transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), play a pivotal role in the pathophysiology of sepsis that can be characterized by the induction of multiple genes and their products, sepsis may be regarded as a gene-related disorder and gene therapy may be considered a promising novel therapeutic approach for treatment of sepsis. In this review article, we provide an up-to-date summary of the gene-targeting approaches, which have been developed in animal models of sepsis. Our review sheds light on the molecular basis of sepsis pathology for the development of novel gene therapy approaches and leads to the conclusion that future research efforts may fully take into account gene therapy for the treatment of sepsis.
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Affiliation(s)
- Yuichi Hattori
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
| | - Kohshi Hattori
- Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Tokiko Suzuki
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
| | - Sailesh Palikhe
- Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
| | - Naoyuki Matsuda
- Department of Emergency and Critical Care Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
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da Silva KLC, Camacho AP, Mittestainer FC, Carvalho BM, Santos A, Guadagnini D, Oliveira AG, Saad MJA. Atorvastatin and diacerein reduce insulin resistance and increase disease tolerance in rats with sepsis. JOURNAL OF INFLAMMATION-LONDON 2018; 15:8. [PMID: 29760586 PMCID: PMC5944072 DOI: 10.1186/s12950-018-0184-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 04/30/2018] [Indexed: 12/30/2022]
Abstract
Background Sepsis is one of the leading causes of death among hospitalized patients. At the onset of this condition, there is an over-production of pro-inflammatory mediators that contribute to organ failure and death. The excess production of pro-inflammatory mediators also impairs insulin signaling, which may be a pathophysiological tissue marker of proinflammatory cytokine action before organ failure. Statins and diacerein have pleiotropic effects, such as the blockage of inflammatory signaling pathways, suggesting that these drugs may be an attractive therapeutic or prophylactic strategy against sepsis. The aim of the present study was to investigate whether a statin or diacerein can improve insulin signaling, disease tolerance and survival in sepsis by inhibiting inflammatory pathways. Methods We investigated the effect of these drugs on survival, tissue insulin signaling and inflammatory pathways in the liver and muscle of rats with sepsis induced by cecal ligation and puncture (CLP). Results The results showed that administration of medications, with anti-inflammatory ability, to septic animals increased survival and improved disease tolerance and insulin resistance in the liver and muscle. The treatment also attenuated ER stress, NF-κB, JNK activation and restored glucose-6-phosphatase (G6Pase) levels in the liver. Conclusions Our results indicate that atorvastatin and diacerein treatment can modulate inflammatory pathways and, in parallel, attenuate insulin resistance in sepsis. Since these two drugs have safety profiles and minimal side effects, we suggest that these drugs may be alternative therapies for the prevention or therapies for the treatment of insulin resistance in sepsis, which could potentially reduce mortality in patients with sepsis. Electronic supplementary material The online version of this article (10.1186/s12950-018-0184-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- K L C da Silva
- 1Department of Internal Medicine, State University of Campinas, Campinas, SP Brazil
| | - A P Camacho
- 1Department of Internal Medicine, State University of Campinas, Campinas, SP Brazil
| | - F C Mittestainer
- 1Department of Internal Medicine, State University of Campinas, Campinas, SP Brazil
| | - B M Carvalho
- 2Department of Biology Science, Federal University of Pernambuco, Recife, PE Brazil
| | - A Santos
- 1Department of Internal Medicine, State University of Campinas, Campinas, SP Brazil.,Departamento de Clínica Médica, FCM-UNICAMP, Cidade Universitária Zeferino Vaz, Campinas, SP 13083-887 Brazil
| | - D Guadagnini
- 1Department of Internal Medicine, State University of Campinas, Campinas, SP Brazil
| | - A G Oliveira
- 3Department of Physical Education, São Paulo State University (UNESP), Bioscience Institute, Rio Claro, SP Brazil
| | - M J A Saad
- 1Department of Internal Medicine, State University of Campinas, Campinas, SP Brazil.,Departamento de Clínica Médica, FCM-UNICAMP, Cidade Universitária Zeferino Vaz, Campinas, SP 13083-887 Brazil
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37
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Ubale RV, Shastri PN, Oettinger C, D’Souza MJ. Pulmonary Administration of Microparticulate Antisense Oligonucleotide (ASO) for the Treatment of Lung Inflammation. AAPS PharmSciTech 2018; 19:1908-1919. [PMID: 29663290 DOI: 10.1208/s12249-018-1002-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 03/19/2018] [Indexed: 01/01/2023] Open
Abstract
Targeted delivery to the lung for controlling lung inflammation is an area that we have explored in this study. The purpose was to use microparticles containing an antisense oligonucleotide (ASO) to NF-κB to inhibit the production of proinflammatory cytokines. Microparticles were prepared using the B-290 Buchi Spray Dryer using albumin as the microparticle matrix. Physicochemical characterization of the microparticles showed the size ranged from 2 to 5 μm, the charge was - 38.4 mV, and they had a sustained release profile over 72 h. Uptake of FITC-labeled ASO-loaded microparticles versus FITC-labeled ASO solution by RAW264.7 murine macrophage cells was 5-10-fold higher. After pulmonary delivery of microparticles to Sprague-Dawley rats, the microparticles were uniformly distributed throughout the lung and were retained in the lungs until 48 h. Serum cytokine (TNF-α and IL-1β) levels of rats after induction of lung inflammation by lipopolysaccharide were measured until 72 h. Animals receiving ASO-loaded microparticles were successful in significantly controlling lung inflammation during this period as compared to animals receiving no treatment. This study was successful in proving that microparticulate ASO therapy was capable of controlling lung inflammation.
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38
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Han T, Ren X, Jiang D, Zheng S, Chen Y, Qiu H, Hou PC, Liu W, Hu Y. Pathophysiological changes after lipopolysaccharide-induced acute inflammation in a type 2 diabetic rat model versus normal controls. Diabetes Res Clin Pract 2018; 138:99-105. [PMID: 29444446 DOI: 10.1016/j.diabres.2018.02.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 08/04/2017] [Accepted: 02/06/2018] [Indexed: 10/18/2022]
Abstract
AIMS The present study aimed to explore the mechanism of a potential beneficial effect of pre-existing diabetes in acute hyperglycemia during critical illness. METHODS Pathophysiological changes including blood glucose variability, changes of inflammatory and oxidative stress responses after lipopolysaccharide (LPS)-induced acute infection were compared between type 2 diabetic rat model (GK rats) and normal controls (Wistar rats). RESULTS After LPS injection, Wistar rats showed serious infective symptoms while GK rats did not. Blood glucose (BG) levels were significantly elevated in both GK and Wistar rats; however, compared to Wistar rats, GK rats had lower BG variability, smaller increases in the serum tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels, a larger increase in the serum IL-10 level, and a smaller decrease in the IκB-α protein level of lung tissue. Serum malondialdehyde (MDA) levels increased and serum total antioxidant capacity (T-AOC) levels decreased for both GK and Wistar rats. CONCLUSIONS We found diabetes was associated with adaptive changes at the cellular level that might actually be protective in acute hyperglycemia-mediated damage during sepsis. Chronic exposure to hyperglycemia potentially reduced the acute deleterious effects of acute hyperglycemia on septic mortality by decreasing BG variability, blunting the pro-inflammatory response and elevating the anti-inflammatory response.
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Affiliation(s)
- Tingting Han
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
| | - Xingxing Ren
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
| | - Dongdong Jiang
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
| | - Shuang Zheng
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
| | - Yawen Chen
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
| | - Huiying Qiu
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
| | - Peter C Hou
- Division of Emergency Critical Care Medicine, Department of Emergency Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard University, Boston 02115, USA.
| | - Wei Liu
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
| | - Yaomin Hu
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China.
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39
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Mechanistic insights into the protective impact of zinc on sepsis. Cytokine Growth Factor Rev 2017; 39:92-101. [PMID: 29279185 DOI: 10.1016/j.cytogfr.2017.12.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 12/19/2017] [Indexed: 12/11/2022]
Abstract
Sepsis, a systemic inflammation as a response to a bacterial infection, is a huge unmet medical need. Data accumulated over the last decade suggest that the nutritional status of patients as well as composition of their gut microbiome, are strongly linked with the risk to develop sepsis, the severity of the disease and prognosis. In particular, the essential micronutrient zinc is essential in the resistance against sepsis and has shown to be protective in animal models as well as in human patients. The potential mechanisms by which zinc protects in sepsis are discussed in this review paper: we will focus on the inflammatory response, chemotaxis, phagocytosis, immune response, oxidative stress and modulation of the microbiome. A full understanding of the mechanism of action of zinc may open new preventive and therapeutic interventions in sepsis.
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40
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RETRACTED: LncRNA MALAT1 regulates sepsis-induced cardiac inflammation and dysfunction via interaction with miR-125b and p38 MAPK/NFκB. Int Immunopharmacol 2017; 55:69-76. [PMID: 29227823 DOI: 10.1016/j.intimp.2017.11.038] [Citation(s) in RCA: 135] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 11/18/2017] [Accepted: 11/27/2017] [Indexed: 12/31/2022]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).
This article has been retracted at the request of the Editor-in-Chief as there are concerns about the reliability of the results included in the article. The journal was initially contacted by the corresponding author to request the retraction of the article.
Given the comments of Dr Elisabeth Bik regarding this article “This paper belongs to a set of over 400 papers (as per February 2020) that share very similar Western blots with tadpole-like shaped bands, the same background pattern …”, the journal requested the author to provide the raw data. However, the author was not able to fulfil this request.
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Critical Illness-Related Corticosteroid Insufficiency (CIRCI): A Narrative Review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Crit Care Med 2017; 45:2089-2098. [PMID: 28938251 DOI: 10.1097/ccm.0000000000002724] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI). PARTICIPANTS A multi-specialty task force of international experts in critical care medicine and endocrinology and members of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. DATA SOURCES Medline, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews. RESULTS Three major pathophysiologic events were considered to constitute CIRCI: dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids. The dysregulation of the HPA axis is complex, involving multidirectional crosstalk between the CRH/ACTH pathways, autonomic nervous system, vasopressinergic system, and immune system. Recent studies have demonstrated that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the primary cortisol-metabolizing enzymes in the liver and kidney. Despite the elevated cortisol levels during critical illness, tissue resistance to glucocorticoids is believed to occur due to insufficient glucocorticoid alpha-mediated anti-inflammatory activity. CONCLUSIONS Novel insights into the pathophysiology of CIRCI add to the limitations of the current diagnostic tools to identify at-risk patients and may also impact how corticosteroids are used in patients with CIRCI.
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Kuuliala K, Penttilä AK, Kaukonen KM, Mustonen H, Kuuliala A, Oiva J, Hämäläinen M, Moilanen E, Pettilä V, Puolakkainen P, Kylänpää L, Repo H. Signalling Profiles of Blood Leucocytes in Sepsis and in Acute Pancreatitis in Relation to Disease Severity. Scand J Immunol 2017; 87:88-98. [DOI: 10.1111/sji.12630] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 11/03/2017] [Indexed: 12/14/2022]
Affiliation(s)
- K. Kuuliala
- Department of Bacteriology and Immunology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - A. K. Penttilä
- Department of GI surgery; Abdominal Centre; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - K.-M. Kaukonen
- Department of Anesthesiology, Intensive Care and Pain Medicine; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - H. Mustonen
- Department of GI surgery; Abdominal Centre; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - A. Kuuliala
- Department of Bacteriology and Immunology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - J. Oiva
- Department of Surgery; Kuopio University Hospital; Kuopio Finland
| | - M. Hämäläinen
- The Immunopharmacology Research Group; Faculty of Medicine and Life Sciences; University of Tampere and Tampere University Hospital; Tampere Finland
| | - E. Moilanen
- The Immunopharmacology Research Group; Faculty of Medicine and Life Sciences; University of Tampere and Tampere University Hospital; Tampere Finland
| | - V. Pettilä
- Department of Anesthesiology, Intensive Care and Pain Medicine; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - P. Puolakkainen
- Department of GI surgery; Abdominal Centre; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - L. Kylänpää
- Department of GI surgery; Abdominal Centre; University of Helsinki and Helsinki University Hospital; Helsinki Finland
| | - H. Repo
- Department of Bacteriology and Immunology; University of Helsinki and Helsinki University Hospital; Helsinki Finland
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Chung M, Lee Y, Shen H, Cheng P, Huang Y, Lin Y, Huang Y, Lam K. Activation of autophagy is involved in the protective effect of 17β-oestradiol on endotoxaemia-induced multiple organ dysfunction in ovariectomized rats. J Cell Mol Med 2017; 21:3705-3717. [PMID: 28714586 PMCID: PMC5706505 DOI: 10.1111/jcmm.13280] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 05/23/2017] [Indexed: 01/01/2023] Open
Abstract
Oestrogens have been reported to attenuate acute inflammation in sepsis. In this study, the effects of long-term oestrogen replacement with 17β-oestradiol (E2 ) on endotoxaemia-induced circulatory dysfunction and multiple organ dysfunction syndrome were evaluated in ovariectomized (Ovx) rats. E2 (50 μg/kg, s.c., 3 times/week) was administered for 8 weeks, followed by the induction of endotoxaemia by intravenous infusion of lipopolysaccharides (LPS; 30 mg/kg/4 hrs). Oestrogen deficiency induced by ovariectomy for 9 weeks augmented the LPS-induced damage, including endotoxic shock, myocardial contractile dysfunction, renal dysfunction and rhabdomyolysis. Cardiac levels of NF-κB p65, iNOS and oxidized glutathione, free radical production in skeletal muscles, myoglobin deposition in renal tubules, and plasma levels of plasminogen activator inhibitor-1, TNF-α, and IL-6 were more pronounced in the Ovx + LPS group than in the Sham + LPS group. Long-term treatment of E2 prevented this amplified damage in Ovx rats. Six hours after LPS initiation, activation of the autophagic process, demonstrated by increases in Atg12 and LC3B-II/LC3B-I ratios, and induction of haem oxygenase (HO)-1 and heat-shock protein (HSP) 70 protein expression in myocardium were increased significantly in the Ovx + E2 + LPS group. These results suggest that activation of autophagy and induction of HO-1 and HSP70 contribute to the protective effect of long-term E2 replacement on multiple organ dysfunction syndrome in endotoxaemia.
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Affiliation(s)
- Ming‐Tzeung Chung
- Department of Obstetrics and GynecologyTri‐Service General Hospital Songshan BranchNational Defense Medical CenterTaipeiTaiwan, ROC
- Department of Gynecology and ObstetricsTaipei City Hospital Ren‐Ai BranchTaipeiTaiwan, ROC
| | - Yen‐Mei Lee
- Department of PharmacologyNational Defense Medical CenterTaipeiTaiwan, ROC
| | - Hsin‐Hsueh Shen
- Department of PharmacologyNational Defense Medical CenterTaipeiTaiwan, ROC
| | - Pao‐Yun Cheng
- Department of Physiology and BiophysicsNational Defense Medical CenterTaipeiTaiwan, ROC
| | - Yu‐Chen Huang
- Department of PharmacologyNational Defense Medical CenterTaipeiTaiwan, ROC
| | - Yu‐Ju Lin
- Department of PharmacologyNational Defense Medical CenterTaipeiTaiwan, ROC
| | - Yu‐Yang Huang
- Department of PharmacologyNational Defense Medical CenterTaipeiTaiwan, ROC
| | - Kwok‐Keung Lam
- Department of PharmacologyTaipei Medical UniversityTaipeiTaiwan, ROC
- Department of AnesthesiologyCatholic Mercy HospitalHsinchuTaiwan, ROC
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Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Intensive Care Med 2017; 43:1781-1792. [DOI: 10.1007/s00134-017-4914-x] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 08/16/2017] [Indexed: 01/02/2023]
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45
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Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem Soc Trans 2017; 45:1105-1115. [DOI: 10.1042/bst20160474] [Citation(s) in RCA: 530] [Impact Index Per Article: 66.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 08/07/2017] [Accepted: 08/09/2017] [Indexed: 12/21/2022]
Abstract
Inappropriate, excessive or uncontrolled inflammation contributes to a range of human diseases. Inflammation involves a multitude of cell types, chemical mediators and interactions. The present article will describe nutritional and metabolic aspects of omega-6 (n-6) and omega-3 (n-3) fatty acids and explain the roles of bioactive members of those fatty acid families in inflammatory processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are capable of partly inhibiting many aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte–endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid and production of pro-inflammatory cytokines. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid, and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of EPA and DHA include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor κB so reducing expression of inflammatory genes and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor γ. Animal experiments demonstrate benefit from EPA and DHA in a range of models of inflammatory conditions. Human trials demonstrate benefit of oral n-3 fatty acids in rheumatoid arthritis and in stabilizing advanced atherosclerotic plaques. Intravenous n-3 fatty acids may have benefits in critically ill patients through reduced inflammation. The anti-inflammatory and inflammation resolving actions of EPA, DHA and their derivatives are of clinical relevance.
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Lasky-Su J, Dahlin A, Litonjua AA, Rogers AJ, McGeachie MJ, Baron RM, Gazourian L, Barragan-Bradford D, Fredenburgh LE, Choi AMK, Mogensen KM, Quraishi SA, Amrein K, Christopher KB. Metabolome alterations in severe critical illness and vitamin D status. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2017; 21:193. [PMID: 28750641 PMCID: PMC5532782 DOI: 10.1186/s13054-017-1794-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 07/12/2017] [Indexed: 11/10/2022]
Abstract
BACKGROUND Metabolic homeostasis is substantially disrupted in critical illness. Given the pleiotropic effects of vitamin D, we hypothesized that metabolic profiles differ between critically ill patients relative to their vitamin D status. METHODS We performed a metabolomics study on biorepository samples collected from a single academic medical center on 65 adults with systemic inflammatory response syndrome or sepsis treated in a 20-bed medical ICU between 2008 and 2010. To identify key metabolites and metabolic pathways related to vitamin D status in critical illness, we first generated metabolomic data using gas and liquid chromatography mass spectroscopy. We followed this by partial least squares-discriminant analysis to identify individual metabolites that were significant. We then interrogated the entire metabolomics profile using metabolite set enrichment analysis to identify groups of metabolites and pathways that were differentiates of vitamin D status. Finally we performed logistic regression to construct a network model of chemical-protein target interactions important in vitamin D status. RESULTS Metabolomic profiles significantly differed in critically ill patients with 25(OH)D ≤ 15 ng/ml relative to those with levels >15 ng/ml. In particular, increased 1,5-anhydroglucitol, tryptophan betaine, and 3-hydroxyoctanoate as well as decreased 2-arachidonoyl-glycerophosphocholine and N-6-trimethyllysine were strong predictors of 25(OH)D >15 ng/ml. The combination of these five metabolites led to an area under the curve for discrimination for 25(OH)D > 15 ng/ml of 0.82 (95% CI 0.71-0.93). The metabolite pathways related to glutathione metabolism and glutamate metabolism are significantly enriched with regard to vitamin D status. CONCLUSION Vitamin D status is associated with differential metabolic profiles during critical illness. Glutathione and glutamate pathway metabolism, which play principal roles in redox regulation and immunomodulation, respectively, were significantly altered with vitamin D status.
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Affiliation(s)
- Jessica Lasky-Su
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Amber Dahlin
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Augusto A Litonjua
- Pulmonary and Critical Care Division, Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Angela J Rogers
- Pulmonary & Critical Care Medicine, Stanford University Medical Center, Stanford, CA, USA
| | - Michael J McGeachie
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Rebecca M Baron
- Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Lee Gazourian
- Pulmonary and Critical Care Medicine, Lahey Hospital & Medical Center, Burlington, MA, USA
| | - Diana Barragan-Bradford
- Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Laura E Fredenburgh
- Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Augustine M K Choi
- Department of Medicine, New York-Presbyterian Hospital, New York, NY, USA
| | - Kris M Mogensen
- Department of Nutrition, Brigham and Women's Hospital, Boston, MA, USA
| | - Sadeq A Quraishi
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Karin Amrein
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Kenneth B Christopher
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. .,Renal Division, Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, MRB 418, Boston, MA, 02115, USA.
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Sepsis Patients Display a Reduced Capacity to Activate Nuclear Factor-κB in Multiple Cell Types. Crit Care Med 2017; 45:e524-e531. [PMID: 28240686 DOI: 10.1097/ccm.0000000000002294] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVES Sepsis is a complex clinical condition associated with high morbidity and mortality. A distinctive feature of sepsis is the reduced capacity of leukocytes to release proinflammatory cytokines in response to ex vivo stimulation. Cellular signaling events leading to immunosuppression in sepsis are not well defined. We investigated cell-specific signaling events underlying the immunosuppressed phenotype in sepsis. DESIGN Ex vivo study. SETTING ICU of an academic hospital. PATIENTS Nineteen patients with sepsis and 19 age-matched healthy controls. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The phosphorylation state of p38 mitogen activated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B cells were determined in ex vivo stimulated CD4 T cells, CD8 T cells, B cells, monocytes, and neutrophils. Messenger RNA expression levels of p38 mitogen activated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B cells and negative regulators tumor necrosis factor-α-induced protein 3 (A20) and mitogen activated protein kinase phosphatase-1 were determined in neutrophils and peripheral blood mononuclear cells. Upon ex vivo stimulation, monocytes of sepsis patients were less capable in phosphorylating nuclear factor kappa-light-chain-enhancer of activated B cells. Sepsis was also associated with reduced phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells in stimulated B cells, CD4 and CD8 T cells. Messenger RNA expression levels of nuclear factor kappa-light-chain-enhancer of activated B cells and A20 were diminished in peripheral blood mononuclear cells of sepsis patients, whereas p38 mitogen activated protein kinase messenger RNA was up-regulated. In neutrophils of sepsis patients, mitogen activated protein kinase phosphatase-1 messenger RNA levels were down-regulated. CONCLUSIONS Sepsis-induced immunosuppression associates with a defect in the capacity to phosphorylate nuclear factor kappa-light-chain-enhancer of activated B cells in lymphoid cells and monocytes.
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Xu D, Lv Y, Wang J, Yang M, Kong L. Deciphering the mechanism of Huang-Lian-Jie-Du-Decoction on the treatment of sepsis by formula decomposition and metabolomics: Enhancement of cholinergic pathways and inhibition of HMGB-1/TLR4/NF-κB signaling. Pharmacol Res 2017; 121:94-113. [PMID: 28434923 DOI: 10.1016/j.phrs.2017.04.016] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 03/18/2017] [Accepted: 04/13/2017] [Indexed: 02/07/2023]
Abstract
Sepsis is the major cause of morbidity and mortality in surgical patients. Huang-Lian-Jie-Du-Decoction (HLJDD), a well-known Chinese herb formula, has long been used for the treatment of sepsis. In this investigation, by leaving one herb out each time, the four component herbs of HLJDD were reformulated to four HLJDD variants Form1-4, corresponding to the removal of Phellodendri Chinensis Cortex, Scutellariae Radix, Gardeniae Fructu and Coptidis Rhizoma, respectively. Metabolomics approach combined with histological inspection, biochemical measurement and molecular biology was used to investigate the treatment effects of HLJDD and its four variants on cecal ligation and puncture (CLP) model of sepsis, which were compared to decipher the formulating principles of HLJDD. Our results showed that HLJDD exhibit the strongest therapeutic effects in the CLP models as compared with the four variants, which could be ascribed to its most significant enhancement of cholinergic anti-inflammatory pathway and inhibition of HMGB-1/TLR4/NF-κB signaling pathway. Most of all, metabolites changed specifically between groups of HLJDD and its four variants were related with the exceptional treatment effects of HLJDD.
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Affiliation(s)
- Dingqiao Xu
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China
| | - Yan Lv
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China
| | - Junsong Wang
- Center for Molecular Metabolism, School of Environmental and Biological Engineering, Nanjing University of Science and Technology, 200 Xiao Ling Wei, Nanjing, 210014, People's Republic of China.
| | - Minghua Yang
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China
| | - Lingyi Kong
- Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
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49
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Wang L, Wu J, Guo X, Huang X, Huang Q. RAGE Plays a Role in LPS-Induced NF-κB Activation and Endothelial Hyperpermeability. SENSORS 2017; 17:s17040722. [PMID: 28358333 PMCID: PMC5421682 DOI: 10.3390/s17040722] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Revised: 03/20/2017] [Accepted: 03/28/2017] [Indexed: 02/06/2023]
Abstract
Endothelial functional dysregulation and barrier disruption contribute to the initiation and development of sepsis. The receptor for advanced glycation end products (RAGE) has been demonstrated to be involved in the pathogenesis of sepsis. The present study aimed to investigate the role of RAGE in lipopolysaccharide (LPS)-induced nuclear factor-κB (NF-κB) activation in endothelial cells and the consequent endothelial hyperpermeability. LPS-induced upregulation of RAGE protein expression in human umbilical vein endothelial cells (HUVECs) was detected by western blotting. Activation of NF-κB was revealed using western blotting and immunofluorescent staining. LPS-elicited endothelial hyperpermeability was explored by transendothelial electrical resistance (TER) assay and endothelial monolayer permeability assay. The blocking antibody specific to RAGE was used to confirm the role of RAGE in LPS-mediated NF-κB activation and endothelial barrier disruption. We found that LPS upregulated the protein expression of RAGE in a dose- and time-dependent manner in HUVECs. Moreover, LPS triggered a significant phosphorylation and degradation of IκBα, as well as NF-κB p65 nuclear translocation. Moreover, we observed a significant increase in endothelial permeability after LPS treatment. However, the RAGE blocking antibody attenuated LPS-evoked NF-κB activation and endothelial hyperpermeability. Our results suggest that RAGE plays an important role in LPS-induced NF-κB activation and endothelial barrier dysfunction.
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Affiliation(s)
- Liqun Wang
- Drug Discovery Research Center, Southwest Medical University, 319 Zhongshan Road, Luzhou 646000, China.
| | - Jie Wu
- First Clinical College of Medicine, Southern Medical University, Guangzhou 510515, China.
| | - Xiaohua Guo
- Department of Pathophysiology, Key Lab for Shock and Microcirculation Research, Southern Medical University, Guangzhou 510515, China.
| | - Xuliang Huang
- Department of Pathophysiology, Key Lab for Shock and Microcirculation Research, Southern Medical University, Guangzhou 510515, China.
| | - Qiaobing Huang
- Department of Pathophysiology, Key Lab for Shock and Microcirculation Research, Southern Medical University, Guangzhou 510515, China.
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50
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Vanoni S, Tsai YT, Waddell A, Waggoner L, Klarquist J, Divanovic S, Hoebe K, Steinbrecher KA, Hogan SP. Myeloid-derived NF-κB negative regulation of PU.1 and c/EBP-β-driven pro-inflammatory cytokine production restrains LPS-induced shock. Innate Immun 2017; 23:175-187. [PMID: 27932520 PMCID: PMC5563821 DOI: 10.1177/1753425916681444] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Sepsis is a life-threatening event predominantly caused by Gram-negative bacteria. Bacterial infection causes a pronounced macrophage (MΦ) and dendritic cell activation that leads to excessive pro-inflammatory cytokine IL-1β, IL-6 and TNF-α production (cytokine storm), resulting in endotoxic shock. Previous experimental studies have revealed that inhibiting NF-κB signaling ameliorates disease symptoms; however, the contribution of myeloid p65 in endotoxic shock remains elusive. In this study, we demonstrate increased mortality in mice lacking p65 in the myeloid lineage (p65Δmye) compared with wild type mice upon ultra-pure LPS challenge. We show that increased susceptibility to LPS-induced shock was associated with elevated serum level of IL-1β and IL-6. Mechanistic analyses revealed that LPS-induced pro-inflammatory cytokine production was ameliorated in p65-deficient bone marrow-derived MΦs; however, p65-deficient 'activated' peritoneal MΦs exhibited elevated IL-1β and IL-6. We show that the elevated pro-inflammatory cytokine secretion was due, in part, to increased accumulation of IL-1β mRNA and protein in activated inflammatory MΦs. The increased IL-1β was linked with heightened binding of PU.1 and CCAAT/enhancer binding protein-β to Il1b and Il6 promoters in activated inflammatory MΦs. Our data provide insight into a role for NF-κB in the negative regulation of pro-inflammatory cytokines in myeloid cells.
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Affiliation(s)
- Simone Vanoni
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Yi Ting Tsai
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Amanda Waddell
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Lisa Waggoner
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Jared Klarquist
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Senad Divanovic
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Kasper Hoebe
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Kris A. Steinbrecher
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
| | - Simon P. Hogan
- Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229
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