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Alzokaky AA, Saber SK, Zaki MO. The reno-protective effect of Empagliflozin against carbon tetrachloride (CCl4)-induced nephrotoxicity in mice halting JNK/MKK4/NRF2/NF-KB pathway. Food Chem Toxicol 2025; 201:115439. [PMID: 40204264 DOI: 10.1016/j.fct.2025.115439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 03/12/2025] [Accepted: 04/07/2025] [Indexed: 04/11/2025]
Abstract
AIM This study designed to evaluate the reno-protective effects of Empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, against carbon tetrachloride (CCl4)-induced nephrotoxicity in mice targeting JNK/MKK4/NRF2/NF-KB pathway. METHODS Male albino mice were given EMPA (10 mg/kg, orally) for 4 weeks prior to a single i.p. injection of 10 % CCl4 (20 ml/kg). Mice were sacrificed 48 h post CCl4 injection. KEY FINDINGS EMPA attenuated CCl4-induced renal injury, as reflected by a decrease in serum urea and creatinine levels, also preserved the histological integrity of kidney tissue. Theses reno-protective effects of EMPA can be mainly due to its 1. Antioxidant, (↑CAT, ↑SOD, ↑Nrf-2 and ↑ARE), 2. Anti-inflammatory (↓NF-κB and ↓TNF-α) and 3. Anti-apoptotic (↓Caspase-3) proprieties. EMPA also inhibited JNK/MKK4 signaling pathway, which plays a critical role in kidney damage. CONCLUSION These finding confirm the reno-protective effect of EMPA with a modulatory impact on JNK/MKK4/Nrf2/NF-κB signaling network; suggesting its therapeutic utility to minimize acute kidney injury (AKI) in clinical setting in the future.
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Affiliation(s)
- Amany A Alzokaky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11651, Egypt; Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt
| | - Shimaa K Saber
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
| | - Mennatallah O Zaki
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta, 34518, Egypt
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Ye S, Ma L, Chi Y, Liu N, Liu Y, Wei W, Niu Y, Zheng P, Yu J, Hai D. Targeting neutrophil dysfunction in acute lung injury: Insights from active components of Chinese medicine. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156664. [PMID: 40121883 DOI: 10.1016/j.phymed.2025.156664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 03/06/2025] [Accepted: 03/17/2025] [Indexed: 03/25/2025]
Abstract
BACKGROUNDS Acute lung injury (ALI) is a lethal condition characterized by uncontrolled pulmonary inflammatory responses, with high morbidity and mortality rates that pose a significant threat to patient health. The persistent retention of neutrophils in lung tissue and subsequent inflammatory damage represents a primary mechanism underlying the early onset of ALI disorders. In recent years, pharmaceutical research targeting these pathological processes has garnered considerable attention. Traditional Chinese medicines (TCM) and their active ingredients, known for their safety and stability, show promising potential in treating ALI through their ability to modulate neutrophil function via multiple pathways. PURPOSE This review examines the mechanisms of neutrophil involvement in the pathogenesis of ALI, investigates potential therapeutic targets and pathways through which Chinese medicines and their active ingredients regulate neutrophil function, and provides a theoretical foundation for developing novel clinical treatment strategies. METHODS A comprehensive literature search was conducted using multiple databases, including Science Direct, PubMed, Google Scholar, and Web of Science. Search terms included 'lung injury,' 'acute lung injury,' 'inflammatory lung injury,' 'inflammation,' 'active ingredient,' 'herbal,' 'traditional Chinese medicine,' 'mechanism,' 'drug,' and 'neutrophils.' The selected literature was systematically categorized and analyzed. RESULTS Our review reveals that TCM and active ingredients influence neutrophil function through four primary mechanisms to impede ALI progression: 1) reduction of neutrophil-mediated uncontrolled inflammatory responses by suppressing neutrophil hyperactivation and inhibiting neutrophil migration and infiltration; 2) attenuation of lung tissue inflammatory damage by inhibiting neutrophil-produced cytotoxic substances, including elastase granules, neutrophil extracellular traps (NETs), and reactive oxygen species (ROS); 3) suppression of inflammatory responses by decreasing the secretion of neutrophil-derived cytokines, such as interleukin (IL) -1β, IL-6 and tumor necrosis factor-alpha (TNF-α); and 4) enhancement of neutrophil phagocytosis and accelerate the removal of apoptotic neutrophils to eliminate harmful pathogens and promote late-stage tissue repair. These findings demonstrate that Chinese medicines and their active ingredients exhibit significant therapeutic potential in ALI disorders through the modulation of neutrophil function, providing a robust theoretical framework for their clinical applications. CONCLUSION Traditional Chinese medicines and their active ingredients demonstrate significant anti-inflammatory efficacy through multiple mechanisms of neutrophil function regulation, showing considerable promise for the treatment of ALI with broad clinical applications.
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Affiliation(s)
- Saiya Ye
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
| | - Lin Ma
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Yinchuan 750004, China; Colaborative Innovation Center for Ningxia Characteristic Traditional Chinese Medicine by Ningxia Hui Autonomous Region & Education Ministry of P.R. China, Yinchuan 750004, China; Ningxia Characteristic Traditional Chinese Medicine Moder Engineering and Technique Research Center, Yinchuan 750004, China
| | - Yannan Chi
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China
| | - Ning Liu
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Yinchuan 750004, China; Colaborative Innovation Center for Ningxia Characteristic Traditional Chinese Medicine by Ningxia Hui Autonomous Region & Education Ministry of P.R. China, Yinchuan 750004, China; Ningxia Characteristic Traditional Chinese Medicine Moder Engineering and Technique Research Center, Yinchuan 750004, China; Ningxia Key Laboratory of Drug Development and Generic Drug Research, Yinchuan 750004, China
| | - Yue Liu
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Yinchuan 750004, China; Colaborative Innovation Center for Ningxia Characteristic Traditional Chinese Medicine by Ningxia Hui Autonomous Region & Education Ministry of P.R. China, Yinchuan 750004, China; Ningxia Characteristic Traditional Chinese Medicine Moder Engineering and Technique Research Center, Yinchuan 750004, China
| | - Wei Wei
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Yinchuan 750004, China; Colaborative Innovation Center for Ningxia Characteristic Traditional Chinese Medicine by Ningxia Hui Autonomous Region & Education Ministry of P.R. China, Yinchuan 750004, China; Ningxia Characteristic Traditional Chinese Medicine Moder Engineering and Technique Research Center, Yinchuan 750004, China
| | - Yang Niu
- Key Laboratory of Ningxia Ethnomedicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan 750004, China
| | - Ping Zheng
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Yinchuan 750004, China.
| | - Jianqiang Yu
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Yinchuan 750004, China; Colaborative Innovation Center for Ningxia Characteristic Traditional Chinese Medicine by Ningxia Hui Autonomous Region & Education Ministry of P.R. China, Yinchuan 750004, China; Ningxia Characteristic Traditional Chinese Medicine Moder Engineering and Technique Research Center, Yinchuan 750004, China; Ningxia Key Laboratory of Drug Development and Generic Drug Research, Yinchuan 750004, China.
| | - Dongmei Hai
- School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China; Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Yinchuan 750004, China; Colaborative Innovation Center for Ningxia Characteristic Traditional Chinese Medicine by Ningxia Hui Autonomous Region & Education Ministry of P.R. China, Yinchuan 750004, China; Ningxia Characteristic Traditional Chinese Medicine Moder Engineering and Technique Research Center, Yinchuan 750004, China.
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Zhang L, Xu F, Hou L. IL-6 and diabetic kidney disease. Front Immunol 2024; 15:1465625. [PMID: 39749325 PMCID: PMC11693507 DOI: 10.3389/fimmu.2024.1465625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 12/03/2024] [Indexed: 01/04/2025] Open
Abstract
Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes associated with high mortality and disability rates. Inflammation has emerged as a key pathological mechanism in DKD, prompting interest in novel therapeutic approaches targeting inflammatory pathways. Interleukin-6 (IL-6), a well-established inflammatory cytokine known for mediating various inflammatory responses, has attracted great attention in the DKD field. Although multiple in vivo and in vitro studies highlight the potential of targeting IL-6 in DKD treatment, its exact roles in the disease remains unclear. This review presents the roles of IL-6 in the pathogenesis of DKD, including immunoinflammation, metabolism, hemodynamics, and ferroptosis. In addition, we summarize the current status of IL-6 inhibitors in DKD-related clinical trials and discuss the potential of targeting IL-6 for treating DKD in the clinic.
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Affiliation(s)
- Lei Zhang
- Pharmacy Department, Weihai Central Hospital Affiliated to Qingdao University, Weihai, China
| | - Futian Xu
- Logistics Management Department, Weihai Central Hospital Affiliated to Qingdao University, Weihai, China
| | - Liyan Hou
- Pharmacy Department, Weihai Central Hospital Affiliated to Qingdao University, Weihai, China
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Millar JE, Reddy K, Bos LDJ. Future Directions in Therapies for Acute Respiratory Distress Syndrome. Clin Chest Med 2024; 45:943-951. [PMID: 39443010 DOI: 10.1016/j.ccm.2024.08.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Acute respiratory distress syndrome (ARDS) is caused by a complex interplay among hyperinflammation, endothelial dysfunction, and alveolar epithelial injury. Targeted treatments toward the underlying pathways have been unsuccessful in unselected patient populations. The first reliable biological subphenotypes reflective of these biological disease states have been identified in the past decade. Subphenotype targeted intervention studies are needed to advance the pharmacologic treatment of ARDS.
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Affiliation(s)
- Jonathan E Millar
- Baillie-Gifford Pandemic Science Hub, Centre for Inflammation Research, Institute for Repair and Regeneration, University of Edinburgh, The Roslin Institute, Easter Bush Campus, Midlothian, Edinburgh EH25 9RG, UK; Department of Critical Care, Queen Elizabeth University Hospital, Glasgow, UK
| | - Kiran Reddy
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, University Road, Belfast BT7 1NN, UK
| | - Lieuwe D J Bos
- Intensive Care Department, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands.
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Zhao Q, Zhang R, Wang Y, Li T, Xue J, Chen Z. FOXQ1, deubiquitinated by USP10, alleviates sepsis-induced acute kidney injury by targeting the CREB5/NF-κB signaling axis. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167331. [PMID: 38960057 DOI: 10.1016/j.bbadis.2024.167331] [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: 11/22/2023] [Revised: 06/14/2024] [Accepted: 06/25/2024] [Indexed: 07/05/2024]
Abstract
Sepsis-induced acute kidney injury (S-AKI) is a severe and frequent complication that occurs during sepsis. This study aimed to understand the role of FOXQ1 in S-AKI and its potential upstream and downstream regulatory mechanisms. A cecal ligation and puncture induced S-AKI mouse model in vivo and an LPS-induced HK-2 cell model in vitro were used. FOXQ1 was significantly upregulated in CLP mice and downregulated in the LPS-induced HK-2 cells. Upregulation of FOXQ1 improved kidney injury and dysfunction in CLP mice. Overexpression of FOXQ1 remarkably suppressed the apoptosis and inflammatory response via down-regulating oxidative stress indicators and pro-inflammatory factors (IL-1β, IL-6, and TNF-α), both in vivo and in vitro. From online analysis, the CREB5/NF-κB axis was identified as the downstream target of FOXQ1. FOXQ1 transcriptionally activated CREB5, upregulating its expression. Overexpression of FOXQ1 suppressed the phosphorylation level and nucleus transport of p65. Rescue experiments showed that CREB5 mediates the protective role of FOXQ1 on S-AKI. Furthermore, FOXQ1 was identified as a substrate of USP10, a deubiquitinating enzyme. Ectopic expression of USP10 reduced the ubiquitination of FOXQ1, promoting its protein stability. USP10 upregulation alleviated LPS-induced cell apoptosis and inflammatory response, while suppression of FOXQ1 augmented these trends. Collectively, our results suggest that FOXQ1, deubiquitinated by USP10, plays a protective role in S-AKI induced inflammation and apoptosis by targeting CREB5/NF-κB axis.
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Affiliation(s)
- Qi Zhao
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ran Zhang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yu Wang
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Tiegang Li
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Jinqi Xue
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Zhiguang Chen
- Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
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Wu Y, Wang L, Li Y, Cao Y, Wang M, Deng Z, Kang H. Immunotherapy in the context of sepsis-induced immunological dysregulation. Front Immunol 2024; 15:1391395. [PMID: 38835773 PMCID: PMC11148279 DOI: 10.3389/fimmu.2024.1391395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 05/06/2024] [Indexed: 06/06/2024] Open
Abstract
Sepsis is a clinical syndrome caused by uncontrollable immune dysregulation triggered by pathogen infection, characterized by high incidence, mortality rates, and disease burden. Current treatments primarily focus on symptomatic relief, lacking specific therapeutic interventions. The core mechanism of sepsis is believed to be an imbalance in the host's immune response, characterized by early excessive inflammation followed by late immune suppression, triggered by pathogen invasion. This suggests that we can develop immunotherapeutic treatment strategies by targeting and modulating the components and immunological functions of the host's innate and adaptive immune systems. Therefore, this paper reviews the mechanisms of immune dysregulation in sepsis and, based on this foundation, discusses the current state of immunotherapy applications in sepsis animal models and clinical trials.
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Affiliation(s)
- Yiqi Wu
- Department of Critical Care Medicine, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Graduate School of The People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Lu Wang
- Department of Critical Care Medicine, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Graduate School of The People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Yun Li
- Department of Critical Care Medicine, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Graduate School of The People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Yuan Cao
- Department of Emergency Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Min Wang
- Department of Critical Care Medicine, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- Graduate School of The People’s Liberation Army (PLA) General Hospital, Beijing, China
| | - Zihui Deng
- Department of Basic Medicine, Graduate School, Chinese PLA General Hospital, Beijing, China
| | - Hongjun Kang
- Department of Critical Care Medicine, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing, China
- National Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing, China
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Shchulkin AV, Abalenikhina YV, Kosmachevskaya OV, Topunov AF, Yakusheva EN. Regulation of P-Glycoprotein during Oxidative Stress. Antioxidants (Basel) 2024; 13:215. [PMID: 38397813 PMCID: PMC10885963 DOI: 10.3390/antiox13020215] [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: 12/22/2023] [Revised: 02/02/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
P-glycoprotein (Pgp, ABCB1, MDR1) is an efflux transporter protein that removes molecules from the cells (outflow) into the extracellular space. Pgp plays an important role in pharmacokinetics, ensuring the absorption, distribution, and excretion of drugs and its substrates, as well as in the transport of endogenous molecules (steroid and thyroid hormones). It also contributes to tumor cell resistance to chemotherapy. In this review, we summarize the mechanisms of Pgp regulation during oxidative stress. The currently available data suggest that Pgp has a complex variety of regulatory mechanisms under oxidative stress, involving many transcription factors, the main ones being Nrf2 and Nf-kB. These factors often overlap, and some can be activated under certain conditions, such as the deposition of oxidation products, depending on the severity of oxidative stress. In most cases, the expression of Pgp increases due to increased transcription and translation, but under severe oxidative stress, it can also decrease due to the oxidation of amino acids in its molecule. At the same time, Pgp acts as a protector against oxidative stress, eliminating the causative factors and removing its by-products, as well as participating in signaling pathways.
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Affiliation(s)
- Aleksey V. Shchulkin
- Pharmacology Department, Ryazan State Medical University, 390026 Ryazan, Russia; (Y.V.A.); (E.N.Y.)
| | - Yulia V. Abalenikhina
- Pharmacology Department, Ryazan State Medical University, 390026 Ryazan, Russia; (Y.V.A.); (E.N.Y.)
| | - Olga V. Kosmachevskaya
- Bach Institute of Biochemistry, Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia; (O.V.K.); (A.F.T.)
| | - Alexey F. Topunov
- Bach Institute of Biochemistry, Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia; (O.V.K.); (A.F.T.)
| | - Elena N. Yakusheva
- Pharmacology Department, Ryazan State Medical University, 390026 Ryazan, Russia; (Y.V.A.); (E.N.Y.)
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Abdelnaser M, Alaaeldin R, Attya ME, Fathy M. Modulating Nrf-2/HO-1, apoptosis and oxidative stress signaling pathways by gabapentin ameliorates sepsis-induced acute kidney injury. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:947-958. [PMID: 37548662 PMCID: PMC10791735 DOI: 10.1007/s00210-023-02650-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 07/28/2023] [Indexed: 08/08/2023]
Abstract
PURPOSE Globally, sepsis, which is a major health issue resulting from severe infection-induced inflammation, is the fifth biggest cause of death. This research aimed to evaluate, for the first time, the molecular effects of gabapentin's possible nephroprotective potential on septic rats by cecal ligation and puncture (CLP). METHODS Sepsis was produced by CLP in male Wistar rats. Evaluations of histopathology and renal function were conducted. MDA, SOD, GSH, TNF-α, IL-1β, and IL-6 levels were measured. qRT-PCR was utilized to determine the expression of Bax, Bcl-2, and NF-kB genes. The expression of Nrf-2 and HO-1 proteins was examined by western blotting. RESULTS CLP caused acute renal damage, elevated the blood levels of creatinine, BUN, TNF-α, IL-1β, and IL-6, reduced the expression of Nrf-2 and HO-1 proteins and the Bcl-2 gene expression, and upregulated NF-kB and Bax genes. Nevertheless, gabapentin dramatically diminished the degree of the biochemical, molecular, and histopathological alterations generated by CLP. Gabapentin reduced the levels of proinflammatory mediators and MDA, improved renal content of GSH and SOD, raised the expression of Nrf-2 and HO-1 proteins and Bcl-2 gene, and reduced the renal expression of NF-kB and Bax genes. CONCLUSION Gabapentin mitigated the CLP-induced sepsis-related acute kidney injury through up-regulating Nrf-2/HO-1 pathway, repressing apoptosis, and attenuating the oxidative stress status by reducing the levels of the proinflammatory mediators and enhancing the antioxidant status.
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Affiliation(s)
- Mahmoud Abdelnaser
- Department of Biochemistry, Faculty of Pharmacy, Deraya University, Minia, 61111, Egypt
| | - Rania Alaaeldin
- Department of Biochemistry, Faculty of Pharmacy, Deraya University, Minia, 61111, Egypt
| | - Mina Ezzat Attya
- Department of Pathology, Faculty of Medicine, Minia University, Minia, 61519, Egypt
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt.
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Shan RR, Yu JT, Zhang SF, Xie MM, Hou R, Xie CY, Dong ZH, Yang Q, Hu XW, Dong YH, Zhang Y, Luo XF, Cui ZY, Liu XY, Xie YC, Wen JG, Liu MM, Jin J, Chen Q, Meng XM. Madecassoside alleviates acute kidney injury by regulating JNK-mediated oxidative stress and programmed cell death. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 123:155252. [PMID: 38056145 DOI: 10.1016/j.phymed.2023.155252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 11/12/2023] [Accepted: 11/27/2023] [Indexed: 12/08/2023]
Abstract
BACKGROUND Acute kidney injury (AKI) has high morbidity and mortality, which is manifested by inflammation and apoptosis. Effective treatment methods for AKI are currently lacking. OBJECTIVE This study demonstrated the protecting effects of Madecassoside (MA) in the cisplatin- and hypoxia-reoxygenation-induced renal tubular epithelial cells in vitro and AKI mice in vivo. METHODS In vivo AKI mouse models were established by inducing them with cisplatin and renal ischemia-reperfusion. In vitro injury models of mouse renal tubular epithelial cells were established by inducing them with cisplatin and hypoxia and reoxygenation, respectively. The mechanism of MA effects was further explored using molecular docking and RNA-sequencing. RESULTS MA could significantly reduce kidney injury in the cisplatin-and renal ischemia-reperfusion (IRI)-induced AKI. Further validation in the two cellular models also showed that MA had protect effects. MA can alleviate AKI in vitro and in vivo by inhibiting inflammation, cell apoptosis, and oxidative stress. MA exhibited high permeability across the Caco-2 cell, can enter cells directly. Through RNA-seq and molecular docking analysis, this study further demonstrated that MA inhibits its activity by directly binding to JNK kinase, thereby inhibiting c-JUN mediated cell apoptosis and improving AKI. In addition, MA has better renal protective effects compared to curcumin and JNK inhibitor SP600125. CONCLUSION The results demonstrate that MA might be a potential drug for the treatment of AKI and act through the JNK/c-JUN signaling pathway.
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Affiliation(s)
- Run-Run Shan
- School of Life Sciences, Anhui Medical University, Hefei, 230032, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Ju-Tao Yu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Shao-Fei Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Man-Man Xie
- School of Life Sciences, Anhui Medical University, Hefei, 230032, China
| | - Rui Hou
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Chun-Ya Xie
- School of Life Sciences, Anhui Medical University, Hefei, 230032, China
| | - Ze-Hui Dong
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Qin Yang
- Department of Clinical Pharmacology, Second Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, Anhui, China
| | - Xiao-Wei Hu
- Department of Clinical Pharmacy, Anhui provincial Children's Hospital, Hefei, 230051, China
| | - Yu-Hang Dong
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yao Zhang
- Anqing First People's Hospital of Anhui Medical University, Anqing, 246000, China
| | - Xiu-Feng Luo
- School of Life Sciences, Anhui Medical University, Hefei, 230032, China
| | - Zong-Yu Cui
- Second Clinical Medical College, Anhui Medical University, Hefei, 230032, China
| | - Xiao-Ying Liu
- School of Life Sciences, Anhui Medical University, Hefei, 230032, China; Translational Research Institute of Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Molecular Pathology Centre, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450053, China
| | - Yun-Chang Xie
- Key Laboratory of Functional Small Organic Molecule Ministry of Education and Jiangxi's Key Laboratory of Green Chemistry, Key Laboratory of Protection and Utilization of Subtropic Plant Resources of Jiangxi Province, School of Life Sciences, Jiangxi Normal University, Nanchang, 330022, China
| | - Jia-Gen Wen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Ming-Ming Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Juan Jin
- Department of Pharmacology, School of Basic Medical Sciences, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, China
| | - Qi Chen
- School of Life Sciences, Anhui Medical University, Hefei, 230032, China.
| | - Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
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10
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Liu M, Wang Q, Xu W, Wu J, Xu X, Yang H, Li X. Natural products for treating cytokine storm-related diseases: Therapeutic effects and mechanisms. Biomed Pharmacother 2023; 167:115555. [PMID: 37776639 DOI: 10.1016/j.biopha.2023.115555] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/18/2023] [Accepted: 09/18/2023] [Indexed: 10/02/2023] Open
Abstract
BACKGROUND A cytokine storm (CS) is a rapidly occurring, complex, and highly lethal systemic acute inflammatory response induced by pathogens and other factors. Currently, no clinical therapeutic drugs are available with a significant effect and minimal side effects. Given the pathogenesis of CS, natural products have become important resources for bioactive agents in the discovery of anti-CS drugs. PURPOSE This study aimed to provide guidance for preventing and treating CS-related diseases by reviewing the natural products identified to inhibit CS in recent years. METHODS A comprehensive literature review was conducted on CS and natural products, utilizing databases such as PubMed and Web of Science. The quality of the studies was evaluated and summarized for further analysis. RESULTS This study summarized more than 30 types of natural products, including 9 classes of flavonoids, phenols, and terpenoids, among others. In vivo and in vitro experiments demonstrated that these natural products could effectively inhibit CS via nuclear factor kappa-B, mitogen-activated protein kinase, and Mammalian target of rapamycin (mTOR) signaling pathways. Moreover, the enzyme inhibition assays revealed that more than 20 chemical components had the potential to inhibit ACE2, 3CL-protease, and papain-like protease activity. The experimental results were obtained using advanced technologies such as biochips and omics. CONCLUSIONS Various natural compounds in traditional Chinese medicine (TCM) extracts could directly or indirectly inhibit CS occurrence, potentially serving as effective drugs for treating CS-related diseases. This study may guide further exploration of the therapeutic effects and biochemical mechanisms of natural products on CS.
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Affiliation(s)
- Mei Liu
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Qing Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Wanai Xu
- School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, China
| | - Jingyu Wu
- School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, China
| | - Xingyue Xu
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China; China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Hongjun Yang
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China; China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Xianyu Li
- Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China; China Academy of Chinese Medical Sciences, Beijing 100700, China.
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11
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Aljuhani O, Al Sulaiman K, B Korayem G, Alharbi A, Altebainawi AF, Aldkheel SA, Alotaibi SG, Vishwakarma R, Alshareef H, Alsohimi S, AlFaifi M, Al Shaya A, Alhaidal HA, Alsubaie RM, Alrashidi H, Albarqi KJ, Alangari DT, Alanazi RM, Altaher NM, Al-Dorzi HM. The use of Tocilizumab in COVID-19 critically ill patients with renal impairment: a multicenter, cohort study. Ren Fail 2023; 45:2268213. [PMID: 37870869 PMCID: PMC11001317 DOI: 10.1080/0886022x.2023.2268213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 10/03/2023] [Indexed: 10/24/2023] Open
Abstract
Tocilizumab (TCZ) is recommended in patients with COVID-19 who require oxygen therapy or ventilatory support. Despite the wide use of TCZ, little is known about its safety and effectiveness in patients with COVID-19 and renal impairment. Therefore, this study evaluated the safety and effectiveness of TCZ in critically ill patients with COVID-19 and renal impairment. A multicenter retrospective cohort study included all adult COVID-19 patients with renal impairment (eGFR˂60 mL/min) admitted to the ICUs between March 2020 and July 2021. Patients were categorized into two groups based on TCZ use (Control vs. TCZ). The primary endpoint was the development of acute kidney injury (AKI) during ICU stay. We screened 1599 patients for eligibility; 394 patients were eligible, and 225 patients were included after PS matching (1:2 ratio); there were 75 TCZ-treated subjects and 150 controls. The rate of AKI was higher in the TCZ group compared with the control group (72.2% versus 57.4%; p = 0.03; OR: 1.83; 95% CI: 1.01, 3.34; p = 0.04). Additionally, the ICU length of stay was significantly longer in patients who received TCZ (17.5 days versus 12.5 days; p = 0.006, Beta coefficient: 0.30 days, 95% CI: 0.09, 0.50; p = 0.005). On the other hand, the 30-day and in-hospital mortality were lower in patients who received TCZ compared to the control group (HR: 0.45, 95% CI: 0.27, 0.73; p = 0.01 and HR: 0.63, 95% CI: 0.41, 0.96; p = 0.03, respectively). The use of TCZ in this population was associated with a statistically significantly higher rate of AKI while improving the overall survival on the other hand. Further research is needed to assess the risks and benefits of TCZ treatment in critically ill COVID-19 patients with renal impairment.
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Affiliation(s)
- Ohoud Aljuhani
- Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Khalid Al Sulaiman
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- Saudi Critical Care Pharmacy Research (SCAPE) Platform, Riyadh, Saudi Arabia
| | - Ghazwa B Korayem
- Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Aisha Alharbi
- Pharmaceutical Care Department, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Ali F. Altebainawi
- Pharmaceutical Care Services, King Salman Specialist Hospital, Hail Health Cluster, Ministry of Health, Hail, Saudi Arabia
- Department of Clinical Pharmacy, College of Pharmacy, University of Hail, Hail, Saudi Arabia
| | - Shatha A. Aldkheel
- Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Sarah G. Alotaibi
- Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | | | - Hanan Alshareef
- Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Samiah Alsohimi
- Pharmaceutical Care Services, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia
- Pharmaceutical Care Services, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
| | - Mashael AlFaifi
- Pharmaceutical Care Department, King Saud Medical City, Riyadh, Saudi Arabia
| | - Abdulrahman Al Shaya
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Haifa A. Alhaidal
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Raghad M. Alsubaie
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Hessah Alrashidi
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Khalid J. Albarqi
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Dalal T. Alangari
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Reem M. Alanazi
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Noora M. Altaher
- College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Hasan M. Al-Dorzi
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- Intensive Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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12
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Tang W, Xia Y, Deng J, Xu H, Tang Y, Xiao X, Wu L, Song G, Qin J, Wang Y. Anti-inflammatory Effect of Low-Intensity Ultrasound in Septic Rats. ULTRASOUND IN MEDICINE & BIOLOGY 2023; 49:1602-1610. [PMID: 37105771 DOI: 10.1016/j.ultrasmedbio.2023.03.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 02/17/2023] [Accepted: 03/07/2023] [Indexed: 05/17/2023]
Abstract
OBJECTIVE Sepsis is a severe systemic inflammatory response caused by infection. Here, the spleen region of Sprague-Dawley (SD) rats with sepsis was irradiated with low-intensity ultrasound (LIUS) to explore the regulation of inflammation and its mechanism by LIUS. METHODS In this study, 30 rats used for survival analysis were randomly divided into the sham-operated group (Sham, n = 10), the group in which sepsis was induced by cecal ligation and puncture (CLP, n = 10) and the group treated with LIUS immediately after CLP (LIUS, n = 10). The other 120 rats were randomly divided into the aforementioned three groups for detection at each time point. The parameters used in the LIUS group were 200 mW/cm2, 0.37 MHz, 20% duty cycle and 20 min, and no ultrasonic energy was produced in the Sham and CLP groups. Seven-day survival rate, histopathology and expression of inflammatory factors and proteins were evaluated in the three groups. RESULTS LIUS was able to improve the survival rate of septic SD rats (p < 0.05), significantly inhibit the expression of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6) and nuclear factor-κB p65 (NF-κB p65) (p < 0.05) and restore the ultrastructure of the spleen. CONCLUSION Our study determined that LIUS can relieve spleen damage and alleviate severe cytokine storm to improve survival outcomes in septic SD rats, and its mechanism may be related to the inhibition of the NF-κB signaling pathway by downregulation of IL-1β.
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Affiliation(s)
- Wentao Tang
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Yi Xia
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Juan Deng
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Haopeng Xu
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Yilin Tang
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Xinfang Xiao
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Liu Wu
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Guolin Song
- Department of Emergency, Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guizhou, China.
| | - Juan Qin
- Department of Obstetrics and Gynecology, Guiyang Maternal and Child Health Care Hospital, Guizhou Medical University, Guizhou, China.
| | - Yan Wang
- State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, China.
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13
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Koo JH, Yu HC, Nam S, Kim DC, Lee JH. Casein Kinase 2 Alpha Inhibition Protects against Sepsis-Induced Acute Kidney Injury. Int J Mol Sci 2023; 24:9783. [PMID: 37372931 PMCID: PMC10298465 DOI: 10.3390/ijms24129783] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 05/27/2023] [Accepted: 06/01/2023] [Indexed: 06/29/2023] Open
Abstract
Sepsis-induced acute kidney injury (AKI) is a common complication in critically ill patients, often resulting in high rates of morbidity and mortality. Previous studies have demonstrated the effectiveness of casein kinase 2 alpha (CK2α) inhibition in ameliorating ischemia-reperfusion-induced AKI. In this study, our aim was to investigate the potential of the selective CK2α inhibitor, 4,5,6,7-tetrabromobenzotriazole (TBBt), in the context of sepsis-induced AKI. To assess this, we initially confirmed an upregulation of CK2α expression following a cecum ligation and puncture (CLP) procedure in mice. Subsequently, TBBt was administered to a group of mice prior to CLP, and their outcomes were compared to those of sham mice. The results revealed that, following CLP, the mice exhibited typical sepsis-associated patterns of AKI, characterized by reduced renal function (evidenced by elevated blood urea nitrogen and creatinine levels), renal damage, and inflammation (indicated by increased tubular injury score, pro-inflammatory cytokine levels, and apoptosis index). However, mice treated with TBBt demonstrated fewer of these changes, and their renal function and architecture remained comparable to that of the sham mice. The anti-inflammatory and anti-apoptotic properties of TBBt are believed to be associated with the inactivation of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways. In conclusion, these findings suggest that inhibiting CK2α could be a promising therapeutic strategy for treating sepsis-induced AKI.
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Affiliation(s)
- Jeung-Hyun Koo
- Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea; (J.-H.K.); (H.C.Y.)
| | - Hwang Chan Yu
- Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea; (J.-H.K.); (H.C.Y.)
| | - Seonhwa Nam
- Department of Anesthesiology and Pain Medicine, Jeonbuk National University Medical School and Hospital, Jeonju 54896, Republic of Korea; (S.N.); (D.-C.K.)
| | - Dong-Chan Kim
- Department of Anesthesiology and Pain Medicine, Jeonbuk National University Medical School and Hospital, Jeonju 54896, Republic of Korea; (S.N.); (D.-C.K.)
| | - Jun Ho Lee
- Department of Anesthesiology and Pain Medicine, Jeonbuk National University Medical School and Hospital, Jeonju 54896, Republic of Korea; (S.N.); (D.-C.K.)
- Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54896, Republic of Korea
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14
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Fadanni GP, Calixto JB. Recent progress and prospects for anti-cytokine therapy in preclinical and clinical acute lung injury. Cytokine Growth Factor Rev 2023; 71-72:13-25. [PMID: 37481378 DOI: 10.1016/j.cytogfr.2023.07.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 07/10/2023] [Indexed: 07/24/2023]
Abstract
Acute respiratory distress syndrome (ARDS) is a heterogeneous cause of respiratory failure that has a rapid onset, a high mortality rate, and for which there is no effective pharmacological treatment. Current evidence supports a critical role of excessive inflammation in ARDS, resulting in several cytokines, cytokine receptors, and proteins within their downstream signalling pathways being putative therapeutic targets. However, unsuccessful trials of anti-inflammatory drugs have thus far hindered progress in the field. In recent years, the prospects of precision medicine and therapeutic targeting of cytokines coevolving into effective treatments have gained notoriety. There is an optimistic and growing understanding of ARDS subphenotypes as well as advances in treatment strategies and clinical trial design. Furthermore, large trials of anti-cytokine drugs in patients with COVID-19 have provided an unprecedented amount of information that could pave the way for therapeutic breakthroughs. While current clinical and nonclinical ARDS research suggest relatively limited potential in monotherapy with anti-cytokine drugs, combination therapy has emerged as an appealing strategy and may provide new perspectives on finding safe and effective treatments. Accurate evaluation of these drugs, however, also relies on well-founded experimental research and the implementation of biomarker-guided stratification in future trials. In this review, we provide an overview of anti-cytokine therapy for acute lung injury and ARDS, highlighting the current preclinical and clinical evidence for targeting the main cytokines individually and the therapeutic prospects for combination therapy.
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Affiliation(s)
- Guilherme Pasetto Fadanni
- Centre of Innovation and Preclinical Studies (CIEnP), Florianópolis, Santa Catarina, Brazil; Department of Pharmacology, Centre of Biological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil.
| | - João Batista Calixto
- Centre of Innovation and Preclinical Studies (CIEnP), Florianópolis, Santa Catarina, Brazil; Department of Pharmacology, Centre of Biological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil.
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15
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Wang Y, Deng F, Zhong X, Du Y, Fan X, Su H, Pan T. Dulaglutide provides protection against sepsis-induced lung injury in mice by inhibiting inflammation and apoptosis. Eur J Pharmacol 2023; 949:175730. [PMID: 37062504 DOI: 10.1016/j.ejphar.2023.175730] [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: 12/30/2022] [Revised: 04/04/2023] [Accepted: 04/14/2023] [Indexed: 04/18/2023]
Abstract
Sepsis is a dangerous condition with a high mortality rate. In addition to promoting insulin secretion in a glucose-dependent manner, glucagon-like peptide-1 (GLP-1) also exhibits anti-inflammatory properties. Dulaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA). In this study, we investigated the effects and mechanism of action of dulaglutide (Dul) in lipopolysaccharide (LPS) induced lung injury in mice with sepsis. In mice with LPS (15 mg/kg, ip, qd)-induced acute lung injury, the administration of dulaglutide (0.6 mg/kg, ip, qd) improved weight loss, reduced lung injury, reversed the increase in IL-1β, TNF-α, IL-6, CXCL1, CCL2 and CXCL2 expression in the lung, and reduced the infiltration of neutrophils and macrophages in the lung tissues. The decline in caspase-3, cleaved caspase-3, caspase-8, and Bcl-2/Bax expression and the increase in the number of TUNEL positive cells in the lung were reversed, suggesting that GLP-1RA could play a protective role in the lung by inhibiting inflammation and apoptosis. In addition, GLP-1RA could reduce the expression of P-STAT3 and NLRP3, suggesting that P-STAT3 and NLRP3 may be potential targets against lung injury in sepsis. Collectively, our data demonstrated that GLP-1RA exerts a protective effect against sepsis-induced lung injury through mechanisms related to the inhibition of inflammation, apoptosis, and STAT3 signaling.
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Affiliation(s)
- Yue Wang
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, 230061, Anhui Province, China; Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei 230061, Hefei, 230061, Anhui Province, China
| | - Fengyi Deng
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, 230061, Anhui Province, China; Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei 230061, Hefei, 230061, Anhui Province, China
| | - Xing Zhong
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, 230061, Anhui Province, China; Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei 230061, Hefei, 230061, Anhui Province, China
| | - Yijun Du
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, 230061, Anhui Province, China; Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei 230061, Hefei, 230061, Anhui Province, China
| | - Xingyu Fan
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, 230061, Anhui Province, China; Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei 230061, Hefei, 230061, Anhui Province, China
| | - Hong Su
- Department of Epidemiology and Health Statistics, School of Public Health, Anhui Medical University, No. 81 Meishan Road, Shushan District, Hefei, 230031, Anhui Province, China
| | - Tianrong Pan
- Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei, 230061, Anhui Province, China; Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei 230061, Hefei, 230061, Anhui Province, China.
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16
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Wang B, Wang Q, Liang Z, Yin Y, Wang L, Wang Q, Li Y, Ou J, Ren H, Dong Y. Tocilizumab, an IL6-receptor antibody, proved effective as adjuvant therapy for cytokine storm induced by severe infection in patients with hematologic malignancy. Ann Hematol 2023; 102:961-966. [PMID: 36864209 PMCID: PMC9981444 DOI: 10.1007/s00277-023-05146-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 02/21/2023] [Indexed: 03/04/2023]
Abstract
Patients with hematological malignancies who experience severe infections are at risk of developing dangerous complications due to excessive inflammatory cytokines. To improve the prognosis, it is crucial to identify better ways to manage the systemic inflammatory storm after infection. In this study, we evaluated four patients with hematological malignancies who developed severe bloodstream infections during the agranulocytosis phase. Despite receiving antibiotics, all four patients presented elevated serum IL-6 levels as well as persistent hypotension or organ injury. Adjuvant therapy with tocilizumab, an IL-6-receptor antibody, was administered, and three of the four patients showed significant improvement. Unfortunately, the fourth patient died due to multiple organ failure caused by antibiotic resistance. Our preliminary experience suggests that tocilizumab, as an adjuvant therapy, may help alleviate systemic inflammation and reduce risk of organ injury in patients with elevated IL-6 levels and severe infection. Further randomized controlled trials are needed to confirm the effectiveness of this IL-6 targeting approach.
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Affiliation(s)
- Bingjie Wang
- Department of Hematology, Peking University First Hospital, Beijing, 100034, China
| | - Qian Wang
- Department of Hematology, Peking University First Hospital, Beijing, 100034, China
| | - Zeyin Liang
- Department of Hematology, Peking University First Hospital, Beijing, 100034, China
| | - Yue Yin
- Department of Hematology, Peking University First Hospital, Beijing, 100034, China
| | - Lihong Wang
- Department of Hematology, Peking University First Hospital, Beijing, 100034, China
| | - Qingya Wang
- Department of Hematology, Peking University First Hospital, Beijing, 100034, China
| | - Yuan Li
- Department of Hematology, Peking University First Hospital, Beijing, 100034, China
| | - Jinping Ou
- Department of Hematology, Peking University First Hospital, Beijing, 100034, China
| | - Hanyun Ren
- Department of Hematology, Peking University First Hospital, Beijing, 100034, China.
| | - Yujun Dong
- Department of Hematology, Peking University First Hospital, Beijing, 100034, China.
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17
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Gandini L, Fior G, Schibler A, Obonyo NG, Li Bassi G, Suen JY, Fraser JF. Interleukin-6 inhibitors in non-COVID-19 ARDS: analyzing the past to step into the post-COVID-19 era. Crit Care 2023; 27:124. [PMID: 36966340 PMCID: PMC10039681 DOI: 10.1186/s13054-023-04394-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 03/04/2023] [Indexed: 03/27/2023] Open
Affiliation(s)
- Lucia Gandini
- Critical Care Research Group, The Prince Charles Hospital, University of Queensland, Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Gabriele Fior
- Critical Care Research Group, The Prince Charles Hospital, University of Queensland, Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Intensive Care Unit, St. Andrews War Memorial Hospital, Brisbane, QLD, Australia
| | - Andreas Schibler
- Critical Care Research Group, The Prince Charles Hospital, University of Queensland, Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Intensive Care Unit, St. Andrews War Memorial Hospital, Brisbane, QLD, Australia
| | - Nchafatso G Obonyo
- Critical Care Research Group, The Prince Charles Hospital, University of Queensland, Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Wellcome Trust Centre for Global Health Research, Imperial College London, London, UK
- Initiative to Develop African Research Leaders (IDeAL)/KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya
| | - Gianluigi Li Bassi
- Critical Care Research Group, The Prince Charles Hospital, University of Queensland, Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Intensive Care Unit, St. Andrews War Memorial Hospital, Brisbane, QLD, Australia
| | - Jacky Y Suen
- Critical Care Research Group, The Prince Charles Hospital, University of Queensland, Brisbane, QLD, Australia.
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
| | - John F Fraser
- Critical Care Research Group, The Prince Charles Hospital, University of Queensland, Brisbane, QLD, Australia.
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
- Intensive Care Unit, St. Andrews War Memorial Hospital, Brisbane, QLD, Australia.
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18
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Lee CY, Nguyen AT, Doan LH, Chu LW, Chang CH, Liu HK, Lee IL, Wang TH, Lai JM, Tsao SM, Liao HJ, Ping YH, Huang CYF. Repurposing Astragalus Polysaccharide PG2 for Inhibiting ACE2 and SARS-CoV-2 Spike Syncytial Formation and Anti-Inflammatory Effects. Viruses 2023; 15:641. [PMID: 36992350 PMCID: PMC10054482 DOI: 10.3390/v15030641] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/05/2023] [Accepted: 02/23/2023] [Indexed: 03/04/2023] Open
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to global public health. In an effort to develop novel anti-coronavirus therapeutics and achieve prophylactics, we used gene set enrichment analysis (GSEA) for drug screening and identified that Astragalus polysaccharide (PG2), a mixture of polysaccharides purified from Astragalus membranaceus, could effectively reverse COVID-19 signature genes. Further biological assays revealed that PG2 could prevent the fusion of BHK21-expressing wild-type (WT) viral spike (S) protein and Calu-3-expressing ACE2. Additionally, it specifically prevents the binding of recombinant viral S of WT, alpha, and beta strains to ACE2 receptor in our non-cell-based system. In addition, PG2 enhances let-7a, miR-146a, and miR-148b expression levels in the lung epithelial cells. These findings speculate that PG2 has the potential to reduce viral replication in lung and cytokine storm via these PG2-induced miRNAs. Furthermore, macrophage activation is one of the primary issues leading to the complicated condition of COVID-19 patients, and our results revealed that PG2 could regulate the activation of macrophages by promoting the polarization of THP-1-derived macrophages into an anti-inflammatory phenotype. In this study, PG2 stimulated M2 macrophage activation and increased the expression levels of anti-inflammatory cytokines IL-10 and IL-1RN. Additionally, PG2 was recently used to treat patients with severe COVID-19 symptoms by reducing the neutrophil-to-lymphocyte ratio (NLR). Therefore, our data suggest that PG2, a repurposed drug, possesses the potential to prevent WT SARS-CoV-2 S-mediated syncytia formation with the host cells; it also inhibits the binding of S proteins of WT, alpha, and beta strains to the recombinant ACE2 and halts severe COVID-19 development by regulating the polarization of macrophages to M2 cells.
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Affiliation(s)
- Chia-Yin Lee
- Taiwan National Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 112304, Taiwan
| | - Anh Thuc Nguyen
- Taiwan National Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 112304, Taiwan
| | - Ly Hien Doan
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Li-Wei Chu
- Department and Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Chih-Hung Chang
- Department of Orthopedic Surgery, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan
| | - Hui-Kang Liu
- Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine (NRICM), Ministry of Health and Welfare, Taipei 112304, Taiwan
| | - I-Lin Lee
- PhytoHeath Corporation, Taipei 105403, Taiwan
| | | | - Jin-Mei Lai
- Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242062, Taiwan
| | - Shih-Ming Tsao
- Division of Pulmonary Medicine, School of Medicine, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung 402306, Taiwan
| | - Hsiu-Jung Liao
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan
| | - Yueh-Hsin Ping
- Department and Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Chi-Ying F. Huang
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
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An AY, Baghela A, Zhang P, Falsafi R, Lee AH, Trahtemberg U, Baker AJ, dos Santos CC, Hancock REW. Severe COVID-19 and non-COVID-19 severe sepsis converge transcriptionally after a week in the intensive care unit, indicating common disease mechanisms. Front Immunol 2023; 14:1167917. [PMID: 37090709 PMCID: PMC10115984 DOI: 10.3389/fimmu.2023.1167917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 03/20/2023] [Indexed: 04/25/2023] Open
Abstract
Introduction Severe COVID-19 and non-COVID-19 pulmonary sepsis share pathophysiological, immunological, and clinical features. To what extent they share mechanistically-based gene expression trajectories throughout hospitalization was unknown. Our objective was to compare gene expression trajectories between severe COVID-19 patients and contemporaneous non-COVID-19 severe sepsis patients in the intensive care unit (ICU). Methods In this prospective single-center observational cohort study, whole blood was drawn from 20 COVID-19 patients and 22 non-COVID-19 adult sepsis patients at two timepoints: ICU admission and approximately a week later. RNA-Seq was performed on whole blood to identify differentially expressed genes and significantly enriched pathways. Results At ICU admission, despite COVID-19 patients being almost clinically indistinguishable from non-COVID-19 sepsis patients, COVID-19 patients had 1,215 differentially expressed genes compared to non-COVID-19 sepsis patients. After one week in the ICU, the number of differentially expressed genes dropped to just 9 genes. This drop coincided with decreased expression of antiviral genes and relatively increased expression of heme metabolism genes over time in COVID-19 patients, eventually reaching expression levels seen in non-COVID-19 sepsis patients. Both groups also had similar underlying immune dysfunction, with upregulation of immune processes such as "Interleukin-1 signaling" and "Interleukin-6/JAK/STAT3 signaling" throughout disease compared to healthy controls. Discussion Early on, COVID-19 patients had elevated antiviral responses and suppressed heme metabolism processes compared to non-COVID-19 severe sepsis patients, although both had similar underlying immune dysfunction. However, after one week in the ICU, these diseases became indistinguishable on a gene expression level. These findings highlight the importance of early antiviral treatment for COVID-19, the potential for heme-related therapeutics, and consideration of immunomodulatory therapies for both diseases to treat shared immune dysfunction.
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Affiliation(s)
- Andy Y. An
- Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
| | - Arjun Baghela
- Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
| | - Peter Zhang
- Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
| | - Reza Falsafi
- Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
| | - Amy H. Lee
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
| | - Uriel Trahtemberg
- The Department of Critical Care, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada
- Department of Critical Care, Galilee Medical Center, Nahariya, Israel
| | - Andrew J. Baker
- The Department of Critical Care, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada
| | - Claudia C. dos Santos
- The Department of Critical Care, Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada
| | - Robert E. W. Hancock
- Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- *Correspondence: Robert E. W. Hancock,
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20
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Uzel K, Lakhno I, Turkler C, Kuzucu M, Yazici GN, Mammadov R, Suleyman B, Kale A, Suleyman H. Tocilizumab is effective in preventing ovarian injury induced by ischemia- reperfusion in rats. AN ACAD BRAS CIENC 2023; 95:e20220442. [PMID: 37194914 DOI: 10.1590/0001-3765202320220442] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/01/2022] [Indexed: 05/18/2023] Open
Abstract
Ovarian torsion can be defined as the bending of the ovaries on the supporting ligament, disrupting both venous and arterial blood circulation. Insufficient blood flow causes ovarian tissue hypoxia and leads to ischemia. This study aimed to investigate whether tocilizumab has a protective effect on ischemia-reperfusion injury due to ovarian torsion in rats. Eighteen female Wistar albino rats were divided into three equal groups (Sham (SG), ischemia-reperfusion (OIR), and ischemia-reperfusion+tocilizumab (OIRT)). Degeneration, necrosis, vascular dilatation/congestion, interstitial edema, hemorrhage, and polymorphonuclear lymphocyte (PMNL) infiltration scores were significantly different between the groups (p=0.001 for all parameters). Moreover, the OIRT group had a significant improvement in these criteria compared to the OIR group (p<0.05). Additionally, there was a considerable difference between OIRT and OIR groups in the number of primordial, developing, and atretic follicles groups (p<0.05), while there was no difference in the number of corpus luteum (p=0.052). Stress markers or cytokines, such as MDA, tGSH, NF-κB, TNF-α, IL-1β, and IL-6, were significantly different between groups (p<0.05). Furthermore, a significant improvement was found in the measured variables when the OIRT group was compared with the OIR group (p<0.05). Tocilizumab may be an alternative option for treating ischemia-reperfusion injury due to ovarian torsion.
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Affiliation(s)
- Kemine Uzel
- Erzincan Binali Yıldırım University Mengucek Gazi Training and Research Hospital, Department of Obstetrics and Gynecology, Basbaglar District, Haci Ali Akin Street, 32, 24100, Center, Erzincan, Turkey
| | - Igor Lakhno
- Kharkiv Medical Academy of Postgraduate Education, Department of Obstetrics and Gynecology, 58, Amosova str, 61176, Kharkiv, Ukraine
| | - Can Turkler
- Erzincan Binali Yıldırım University Mengucek Gazi Training and Research Hospital, Department of Obstetrics and Gynecology, Basbaglar District, Haci Ali Akin Street, 32, 24100, Center, Erzincan, Turkey
| | - Mehmet Kuzucu
- Erzincan Binali Yildirim University, Department of Molecular Biology, Faculty of Medicine, Basbaglar District, Haci Ali Akin Street, 32, 24100, Center, Erzincan, Turkey
| | - Gulce Naz Yazici
- Erzincan Binali Yildirim University, Department of Histology and Embryology, Faculty of Medicine, Basbaglar District, Haci Ali Akin Street, 32, 24100, Center, Erzincan, Turkey
| | - Renad Mammadov
- Erzincan Binali Yildirim University, Department of Pharmacology, Faculty of Medicine, Basbaglar District, Haci Ali Akin Street, 32, 24100, Center, Erzincan, Turkey
| | - Bahadir Suleyman
- Erzincan Binali Yildirim University, Department of Pharmacology, Faculty of Medicine, Basbaglar District, Haci Ali Akin Street, 32, 24100, Center, Erzincan, Turkey
| | - Ahmet Kale
- University of Health Science Kartal Dr. Lutfi Kirdar City Hospital, Department of Obstetrics and Gynecology, D-100 North Sideway N:47 Cevizli, 34865, Kartal, Istanbul, Turkey
| | - Halis Suleyman
- Erzincan Binali Yildirim University, Department of Pharmacology, Faculty of Medicine, Basbaglar District, Haci Ali Akin Street, 32, 24100, Center, Erzincan, Turkey
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21
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Wang X, Tang G, Liu Y, Zhang L, Chen B, Han Y, Fu Z, Wang L, Hu G, Ma Q, Sheng S, Wang J, Hu X, Shao S. The role of IL-6 in coronavirus, especially in COVID-19. Front Pharmacol 2022; 13:1033674. [PMID: 36506506 PMCID: PMC9727200 DOI: 10.3389/fphar.2022.1033674] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/02/2022] [Indexed: 11/25/2022] Open
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infects both people and animals and may cause significant respiratory problems, including lung illness: Corona Virus Disease 2019 (COVID-19). Swabs taken from the throat and nose of people who have the illness or are suspected of having it have shown this pathogenic virus. When SARS-CoV-2 infects the upper and lower respiratory tracts, it may induce moderate to severe respiratory symptoms, as well as the release of pro-inflammatory cytokines including interleukin 6 (IL-6). COVID-19-induced reduction of IL-6 in an inflammatory state may have a hitherto undiscovered therapeutic impact. Many inflammatory disorders, including viral infections, has been found to be regulated by IL-6. In individuals with COVID-19, one of the primary inflammatory agents that causes inflammatory storm is IL-6. It promotes the inflammatory response of virus infection, including the virus infection caused by SARS-CoV-2, and provides a new diagnostic and therapeutic strategy. In this review article, we highlighted the functions of IL-6 in the coronavirus, especially in COVID-19, showing that IL-6 activation plays an important function in the progression of coronavirus and is a rational therapeutic goal for inflammation aimed at coronavirus.
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Affiliation(s)
- Xinyi Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Guozheng Tang
- Department of Orthopaedics, Lu’an Hospital of Anhui Medical University, Lu’an, Anhui, China
| | - Yuchen Liu
- Department of Otolaryngology, Head and Neck Surgery, The First Affifiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Lizhi Zhang
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Bangjie Chen
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yanxun Han
- Department of Otolaryngology, Head and Neck Surgery, The First Affifiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Ziyue Fu
- Second Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Liuning Wang
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Guangzhi Hu
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Qing Ma
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Shuyan Sheng
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Jianpeng Wang
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Xinyang Hu
- First Clinical Medical College, Anhui Medical University, Hefei, Anhui, China
| | - Song Shao
- Department of Orthopaedics, Lu’an Hospital of Anhui Medical University, Lu’an, Anhui, China,*Correspondence: Song Shao,
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22
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Wang X, Zhang X, Sun L, Gao G, Li Y. Protective effect of Secukinumab on severe sepsis model rats by neutralizing IL-17A to inhibit IKBα/NFκB inflammatory signal pathway. Eur J Med Res 2022; 27:206. [PMID: 36253831 PMCID: PMC9578221 DOI: 10.1186/s40001-022-00845-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 10/09/2022] [Indexed: 11/10/2022] Open
Abstract
Secukinumab is a specific neutralizing antibody for IL-17A. At present, numerous studies have confirmed the important role of IL-17A in sepsis, but the role of secukinumab in sepsis has not been studied. The present study explored the protective effect and underlying mechanism of secukinumab in severe sepsis model rats. We established a severe sepsis rat model using cecal ligation and puncture (CLP). The optimal dose of secukinumab was determined by observing the 7-day survival rate of severe sepsis model rats. The expression levels of TNF-α, IL-6, and IL-17A in plasma and lung tissue were determined by enzyme-linked immunosorbent assay. The degree of pathological damage to lung tissue was evaluated by hematoxylin–eosin (H–E) staining and pathological damage scale. The expressions of IKBα/NFκB pathway proteins and downstream-related inflammatory factors were detected by western blotting and real-time quantitative polymerase chain reaction (RT-qPCR). Our results show that high-dose secukinumab can inhibit the activation of the IKBα/NFκB inflammatory pathway by neutralizing IL-17A and reducing the gene expression of pathway-related inflammatory cytokines, thereby reducing the levels of inflammatory cytokines in lung tissue and plasma, thereby reducing the damage of lung tissue in severe sepsis model rats and improving the systemic inflammatory response.
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Affiliation(s)
- Xingsheng Wang
- Intensive Care Unit, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.,Intensive Care Unit, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xinxin Zhang
- Department of Emergency Medicine, Fuyang People's Hospital, Fuyang, Anhui, China
| | - Li Sun
- Intensive Care Unit, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.,Intensive Care Unit, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Guangsheng Gao
- Intensive Care Unit, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China. .,Intensive Care Unit, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. .,Central Hospital Affiliated to Shandong First Medical University, NO. 105 Jiefang Road, Jinan, 250000, Shandong, China.
| | - Yun Li
- Intensive Care Unit, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China. .,Intensive Care Unit, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. .,Central Hospital Affiliated to Shandong First Medical University, NO. 105 Jiefang Road, Jinan, 250000, Shandong, China.
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23
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XueFu ZhuYu Decoction Alleviates Cardiopulmonary Bypass-Induced NLRP3 Inflammasome-Dependent Pyroptosis by Inhibiting IkB-α/NF-κB Pathway in Acute Lung Injury Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:6248870. [PMID: 36124015 PMCID: PMC9482486 DOI: 10.1155/2022/6248870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/05/2022] [Accepted: 07/23/2022] [Indexed: 11/30/2022]
Abstract
XueFu ZhuYu Decoction (XFZYD) is an effective prescription that is widely used to improve blood circulation by removing blood stasis. This study aimed to investigate the effects and the underlying molecular mechanisms of XFZYD on lung pyroptosis in cardiopulmonary bypass- (CPB-) induced acute lung injury (ALI) rats. A rat model of ALI was induced by CPB treatment after XFZYD, Ac-YVAD-CMK, and Bay-11-7082 administration. The respiratory index (RI) and oxygenation index (OI) were determined at each time point. The levels of interleukin (IL)-1β, IL-6, IL-18, and TNF-α in serum and lung were measured by enzyme-linked immunosorbent assays (ELISA). Moreover, the protein levels, neutrophil counts, and total cell of bronchoalveolar lavage fluid (BALF) were detected. Additionally, Myeloperoxidase (MPO) expression was detected by immunohistochemical assay. Lung injury was evaluated with the wet/dry (W/D) ratio and pathologic changes, respectively. Besides, the expression of NLRP3 inflammasome and IkB-α/NF-κB pathway proteins was estimated by immunofluorescence, quantitative real-time PCR (qRT-PCR), and Western blotting assays, respectively. XFZYD pretreatment significantly ameliorated pulmonary ventilation function and reduced the CPB-induced lung histopathological injury, inflammatory cell infiltration in BALF and lung, and the apoptosis of lung cells. Interestingly, XFZYD decreased the CPB-induced NLRP3, ASC, Caspase-1 p20, Pro-GSDMD, GSDMD p30, IL-18, IL-1β p-P65, and p-IKBα mRNA or protein levels in lung tissues in ALI model rats. In summary, these findings suggest that XFZYD effectively mitigates NLRP3 inflammasome-dependent pyroptosis in CPB-induced ALI model rats, possibly by inhibiting the IkB-α/NF-κB pathway in the lung.
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24
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Senousy SR, Ahmed ASF, Abdelhafeez DA, Khalifa MMA, Abourehab MAS, El-Daly M. Alpha-Chymotrypsin Protects Against Acute Lung, Kidney, and Liver Injuries and Increases Survival in CLP-Induced Sepsis in Rats Through Inhibition of TLR4/NF-κB Pathway. Drug Des Devel Ther 2022; 16:3023-3039. [PMID: 36105322 PMCID: PMC9467300 DOI: 10.2147/dddt.s370460] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 08/11/2022] [Indexed: 11/23/2022] Open
Abstract
Abstract Inflammation and oxidative stress play a major role in the development of sepsis and its associated complications, leading to multiple organ failure and death. The lungs, liver, and kidneys are among the early affected organs correlated with mortality in sepsis. Alpha-chymotrypsin (α-ch) is a serine protease that exerts anti-inflammatory, anti-edematous, and anti-oxidant properties. Purpose This study was undertaken to elucidate if the anti-inflammatory and anti-oxidant effects of α-ch observed in previous studies can alleviate lung, liver, and kidney injuries in a cecal ligation and puncture (CLP)-induced sepsis model, and thus decrease mortality. Materials and Methods Septic animals were given α-ch 2 h post CLP procedure. Sepsis outcomes were assessed in the lungs, liver, and kidneys. Separate animal groups were investigated for a survival study. Results CLP resulted in 0% survival, while α-chymotrypsin post-treatment led to 50% survival at the end of the study. Administration of α-chymotrypsin resulted in a significant attenuation of sepsis-induced elevated malonaldehyde (MDA) and total nitrite/nitrate (NOx) levels. In addition, there was a significant increase in reduced glutathione (GSH) content and superoxide dismutase (SOD) activity in the lungs, liver, and kidneys. Administration of α-ch reduced elevated tissue expression of toll-like receptor-4 (TLR4), nuclear factor kappa-B (NF-κB), myeloperoxidase (MPO), and inducible nitric oxide synthase (iNOS). Alpha-chymotrypsin resulted in a significant reduction in serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). Alpha-chymotrypsin attenuated the rise in serum creatinine, cystatin C, blood urea nitrogen (BUN), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels that was observed in the septic group. In addition, α-ch significantly reduced the lung wet/dry weight ratio, total protein content, and leukocytic counts in bronchoalveolar lavage fluid (BALF). Histopathological examination of the lungs, liver, and kidneys confirmed the protective effects of α-ch on those organs. Conclusion α-ch has protective potential against sepsis through lowering tissue expression of TLR4, NF-κB, MPO, and iNOS leading to decreased oxidative stress and inflammatory signals induced by sepsis. This effect appeared to alleviate the damage to the lungs, liver, and kidneys and increase survival in rats subjected to sepsis.
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Affiliation(s)
- Shaymaa Ramzy Senousy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt
| | - Al-Shaimaa F Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt
- Correspondence: Al-Shaimaa F Ahmed, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt, Tel +20 1020018842, Email
| | - Dalia A Abdelhafeez
- Department of Pathology, Faculty of Medicine, Minia University, Minia, Egypt
| | | | - Mohammed A S Abourehab
- Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah, 21955, Saudi Arabia
| | - Mahmoud El-Daly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt
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25
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Matouk AI, El-Daly M, Habib HA, Senousy S, Naguib Abdel Hafez SM, Kasem AW, Almalki WH, Alzahrani A, Alshehri A, Ahmed ASF. Protective effects of menthol against sepsis-induced hepatic injury: Role of mediators of hepatic inflammation, apoptosis, and regeneration. Front Pharmacol 2022; 13:952337. [PMID: 36120368 PMCID: PMC9476320 DOI: 10.3389/fphar.2022.952337] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 08/01/2022] [Indexed: 11/22/2022] Open
Abstract
Liver dysfunction in sepsis is a major complication that amplifies multiple organ failure and increases the risk of death. Inflammation and oxidative stress are the main mediators in the pathophysiology of sepsis. Therefore, we investigated the role of menthol, a natural antioxidant, against sepsis-induced liver injury in female Wistar rats. Sepsis was induced by cecal ligation and puncture (CLP). Menthol (100 mg/kg) was given intragastric 2 h after CLP. Blood samples and liver tissues were collected 24 h after surgery. Menthol significantly (p < 0.05) attenuated the sepsis-induced elevation in serum liver enzymes and improved the hepatic histopathological changes. Menthol treatment significantly (p < 0.05) decreased hepatic levels of tumor necrosis factor-alpha, malondialdehyde, total nitrite, and cleaved caspase-3. It restored the hepatic levels of superoxide dismutase and reduced glutathione. Additionally, menthol significantly (p < 0.05) increased hepatic levels of B-cell lymphoma 2 (Bcl-2); an anti-apoptotic factor, and proliferating cell nuclear antigen (PCNA), a biomarker of regeneration and survival. Our results showed the therapeutic potential of menthol against liver injury induced by sepsis.
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Affiliation(s)
- Asmaa I. Matouk
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
| | - Mahmoud El-Daly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
| | - Heba A. Habib
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
| | - Shaymaa Senousy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
| | | | - AlShaimaa W. Kasem
- Department of Histology and Cell Biology, Faculty of Medicine, Minia University, Minya, Egypt
| | - Waleed Hassan Almalki
- Department of Pharmacology and Toxicology, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Abdulaziz Alzahrani
- Department of Pharmacology and Toxicology, College of Clinical Pharmacy, AlBaha University, Al Bahah, Saudi Arabia
| | - Ahmed Alshehri
- Department of Pharmacology and Toxicology, College of Clinical Pharmacy, AlBaha University, Al Bahah, Saudi Arabia
| | - Al-Shaimaa F. Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minya, Egypt
- *Correspondence: Al-Shaimaa F. Ahmed,
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26
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Senousy SR, El-Daly M, Ibrahim ARN, Khalifa MMA, Ahmed ASF. Effect of Celecoxib and Infliximab against Multiple Organ Damage Induced by Sepsis in Rats: A Comparative Study. Biomedicines 2022; 10:biomedicines10071613. [PMID: 35884918 PMCID: PMC9312943 DOI: 10.3390/biomedicines10071613] [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: 05/25/2022] [Revised: 06/22/2022] [Accepted: 06/29/2022] [Indexed: 12/30/2022] Open
Abstract
In cases of sepsis, the immune system responds with an uncontrolled release of proinflammatory cytokines and reactive oxygen species. The lungs, kidneys, and liver are among the early impacted organs during sepsis and are a direct cause of mortality. The aim of this study was to compare the effects of infliximab (IFX) and celecoxib (CLX) on septic rats that went through a cecal ligation and puncture (CLP) surgery to induce sepsis. This study included four groups: sham, CLP (untreated), and CLP-treated with CLX or IFX. The administration of “low dose” CLX or IFX was performed after 2 h following the induction of sepsis. Twenty-four hours following the induction of sepsis, the rats were sacrificed and blood samples were collected to evaluate kidney, liver, and lung injuries. MDA and NOx content, in addition to SOD activity and GSH levels, were evaluated in the tissue homogenates of each group. Tissue samples were also investigated histopathologically. In a separate experiment, the same groups were employed to evaluate the survival of septic rats in a 7-day observation period. The results of this study showed that treatment with either CLX or IFX ameliorated the three organs’ damage compared to septic-untreated rats, decreased oxidative stress, enhanced the antioxidant defense, and reduced serum cytokines. As a result, a higher survival rate resulted: 62.5% and 37.5% after the administration of CLX and IFX, respectively, compared to 0% in the CLP group after 7 days. No significant differences were observed between the two agents in all measured parameters. Histopathological examination confirmed the observed results. In conclusion, CLX and IFX ameliorated lung, kidney, and liver injuries associated with sepsis through anti-inflammatory and antioxidant actions, which correlated to the increase in survival observed with both of them.
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Affiliation(s)
- Shaymaa Ramzy Senousy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia 61511, Egypt; (S.R.S.); (M.E.-D.); (M.M.A.K.); (A.-S.F.A.)
| | - Mahmoud El-Daly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia 61511, Egypt; (S.R.S.); (M.E.-D.); (M.M.A.K.); (A.-S.F.A.)
| | - Ahmed R. N. Ibrahim
- Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61511, Egypt
- Correspondence: ; Tel.: +96-65-5408-8979
| | - Mohamed Montaser A. Khalifa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia 61511, Egypt; (S.R.S.); (M.E.-D.); (M.M.A.K.); (A.-S.F.A.)
| | - Al-Shaimaa F. Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia 61511, Egypt; (S.R.S.); (M.E.-D.); (M.M.A.K.); (A.-S.F.A.)
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Cabrera-Rivera GL, Madera-Sandoval RL, León-Pedroza JI, Ferat-Osorio E, Salazar-Rios E, Hernández-Aceves JA, Guadarrama-Aranda U, López-Macías C, Wong-Baeza I, Arriaga-Pizano LA. Increased Tnf- Production In Response To Il-6 In Patients With Systemic Inflammation Without Infection. Clin Exp Immunol 2022; 209:225-235. [PMID: 35647912 DOI: 10.1093/cei/uxac055] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 03/28/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Acute systemic inflammation can lead to life-threatening organ dysfunction. In patients with sepsis, systemic inflammation is triggered in response to infection, but in other patients, a systemic inflammatory response syndrome (SIRS) is triggered by non-infectious events. IL-6 is a major mediator of inflammation, including systemic inflammatory responses. In homeostatic conditions, when IL-6 engages its membrane-bound receptor on myeloid cells, it promotes pro-inflammatory cytokine production, phagocytosis and cell migration. However, under non-physiologic conditions, such as SIRS and sepsis, leucocyte dysfunction could modify the response of these cells to IL-6. So, our aim was to evaluate the response to IL-6 of monocytes from patients diagnosed with SIRS or sepsis. We observed that monocytes from patients with SIRS, but not from patients with sepsis, produced significantly more TNF-α than monocytes from healthy volunteers, after stimulation with IL-6. Monocytes from SIRS patients had a significantly increased baseline phosphorylation of the p65 subunit of NF-κB, with no differences in STAT3 phosphorylation or SOCS3 levels, compared to monocytes from septic patients, and this increased phosphorylation was maintained during the IL-6 activation. We found no significant differences in the expression levels of the membrane-bound IL-6 receptor, or the serum levels of IL-6, soluble IL-6 receptor, or soluble gp130, between patients with SIRS and patients with sepsis. Our results suggest that, during systemic inflammation in the absence of infection, IL-6 promotes TNF-α production by activating NF-κB, and not the canonical STAT3 pathway.
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Affiliation(s)
- Graciela L Cabrera-Rivera
- Unidad de Investigación Médica en Inmunoquímica. Centro Medico Nacional "Siglo XXI". Instituto Mexicano del Seguro Social. Mexico City, Mexico.,Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Ruth L Madera-Sandoval
- Unidad de Investigación Médica en Inmunoquímica. Centro Medico Nacional "Siglo XXI". Instituto Mexicano del Seguro Social. Mexico City, Mexico
| | - José Israel León-Pedroza
- Coordinación de Investigación, Unidad 401-C, Urgencias Médicas, Hospital General de México "Dr. Eduardo Liceaga". Mexico City, Mexico.,Coordinación de Ciclos Básicos, Universidad Anáhuac, Mexico City, Mexico
| | - Eduardo Ferat-Osorio
- Unidad de Investigación Médica en Inmunoquímica. Centro Medico Nacional "Siglo XXI". Instituto Mexicano del Seguro Social. Mexico City, Mexico.,División de Investigación en Salud, UMAE Hospital de Especialidades "Dr. Bernardo Sepúlveda Gutiérrez", Centro Médico Nacional "Siglo XXI", Instituto Mexicano del Seguro Social. Mexico City, Mexico
| | - Enrique Salazar-Rios
- Unidad de Investigación Médica en Inmunoquímica. Centro Medico Nacional "Siglo XXI". Instituto Mexicano del Seguro Social. Mexico City, Mexico.,Facultad de Medicina, Universidad Autónoma del Estado de Morelos. Mexico City, Mexico
| | - Juan A Hernández-Aceves
- Unidad de Investigación Médica en Inmunoquímica. Centro Medico Nacional "Siglo XXI". Instituto Mexicano del Seguro Social. Mexico City, Mexico.,Facultad de Química, Universidad Nacional Autónoma de México. Mexico City, Mexico
| | - Uriel Guadarrama-Aranda
- Unidad de Investigación Médica en Inmunoquímica. Centro Medico Nacional "Siglo XXI". Instituto Mexicano del Seguro Social. Mexico City, Mexico.,Facultad de Medicina, Universidad Nacional Autónoma de México. Mexico City, Mexico
| | - Constantino López-Macías
- Unidad de Investigación Médica en Inmunoquímica. Centro Medico Nacional "Siglo XXI". Instituto Mexicano del Seguro Social. Mexico City, Mexico.,Visiting Professor of Immunology. Nuffield Department of Medicine. University of Oxford, UK
| | - Isabel Wong-Baeza
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Lourdes A Arriaga-Pizano
- Unidad de Investigación Médica en Inmunoquímica. Centro Medico Nacional "Siglo XXI". Instituto Mexicano del Seguro Social. Mexico City, Mexico
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28
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Dai J, Zhang X, Zhang J, Yang W, Yang X, Bian H, Chen Z. Blockade of mIL‐6R alleviated lipopolysaccharide‐induced systemic inflammatory response syndrome by suppressing NF‐κB‐mediated Ccl2 expression and inflammasome activation. MedComm (Beijing) 2022; 3:e132. [PMID: 35548710 PMCID: PMC9075038 DOI: 10.1002/mco2.132] [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: 12/30/2021] [Revised: 03/16/2022] [Accepted: 03/18/2022] [Indexed: 12/04/2022] Open
Abstract
Systemic inflammatory response syndrome (SIRS) is characterized by dysregulated cytokine release, immune responses and is associated with organ dysfunction. IL‐6R blockade indicates promising therapeutic effects in cytokine release storm but still remains unknown in SIRS. To address the issue, we generated the human il‐6r knock‐in mice and a defined epitope murine anti‐human membrane‐bound IL‐6R (mIL‐6R) mAb named h‐mIL‐6R mAb. We found that the h‐mIL‐6R and the commercial IL‐6R mAb Tocilizumab significantly improved the survival rate, reduced the levels of TNF‐α, IL‐6, IL‐1β, IFN‐γ, transaminases and blood urea nitrogen of LPS‐induced SIRS mice. Besides, the h‐mIL‐6R mAb could also dramatically reduce the levels of inflammatory cytokines in LPS‐treated THP‐1 cells in vitro. RNA‐seq analysis indicated that the h‐mIL‐6R mAb could regulate LPS‐induced activation of NF‐κB/Ccl2 and NOD‐like receptor signaling pathways. Furthermore, we found that the h‐mIL‐6R mAb could forwardly inhibit Ccl2 expression and NLRP3‐mediated pyroptosis by suppressing NF‐κB in combination with the NF‐κB inhibitor. Collectively, mIL‐6R mAbs suppressed NF‐κB/Ccl2 signaling and inflammasome activation. IL‐6R mAbs are potential alternative therapeutics for suppressing excessive cytokine release, over‐activated inflammatory responses and alleviating organ injuries in SIRS.
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Affiliation(s)
- Ji‐Min Dai
- National Translational Science Center for Molecular Medicine&Department of Cell Biology State Key Laboratory of Cancer Biology the Fourth Military Medical University Xi'an P.R. China
- Faculty of Hepato‐Biliary‐Pancreatic Surgery The First Medical Center of Chinese People's Liberation Army (PLA) General Hospital Beijing P.R. China
| | - Xue‐Qin Zhang
- National Translational Science Center for Molecular Medicine&Department of Cell Biology State Key Laboratory of Cancer Biology the Fourth Military Medical University Xi'an P.R. China
| | - Jia‐Jia Zhang
- National Translational Science Center for Molecular Medicine&Department of Cell Biology State Key Laboratory of Cancer Biology the Fourth Military Medical University Xi'an P.R. China
| | - Wei‐Jie Yang
- National Translational Science Center for Molecular Medicine&Department of Cell Biology State Key Laboratory of Cancer Biology the Fourth Military Medical University Xi'an P.R. China
| | - Xiang‐Min Yang
- National Translational Science Center for Molecular Medicine&Department of Cell Biology State Key Laboratory of Cancer Biology the Fourth Military Medical University Xi'an P.R. China
| | - Huijie Bian
- National Translational Science Center for Molecular Medicine&Department of Cell Biology State Key Laboratory of Cancer Biology the Fourth Military Medical University Xi'an P.R. China
| | - Zhi‐Nan Chen
- National Translational Science Center for Molecular Medicine&Department of Cell Biology State Key Laboratory of Cancer Biology the Fourth Military Medical University Xi'an P.R. China
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29
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Hasselbach L, Weidner J, Elsässer A, Theilmeier G. Heart Failure Relapses in Response to Acute Stresses - Role of Immunological and Inflammatory Pathways. Front Cardiovasc Med 2022; 9:809935. [PMID: 35548445 PMCID: PMC9081344 DOI: 10.3389/fcvm.2022.809935] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 03/23/2022] [Indexed: 12/15/2022] Open
Abstract
Cardiovascular diseases continue to be the most imminent health care problems in the western world, accounting for numerous deaths per year. Heart failure (HF), namely the reduction of left ventricular function, is one of the major cardiovascular disease entities. It is chronically progressing with relapsing acute decompensations and an overall grave prognosis that is little different if not worse than most malignant diseases. Interestingly acute metabolically and/or immunologically challenging events like infections or major surgical procedures will cause relapses in the course of preexisting chronic heart failure, decrease the patients wellbeing and worsen myocardial function. HF itself and or its progression has been demonstrated to be driven at least in part by inflammatory pathways that are similarly turned on by infectious or non-infectious stress responses. These thus add to HF progression or relapse. TNF-α plasma levels are associated with disease severity and progression in HF. In addition, several cytokines (e.g., IL-1β, IL-6) are involved in deteriorating left ventricular function. Those observations are based on clinical studies using inhibitors of cytokines or their receptors or they stem from animal studies examining the effect of cytokine mediated inflammation on myocardial remodeling in models of heart failure. This short review summarizes the known underlying immunological processes that are shared by and drive all: chronic heart failure, select infectious diseases, and inflammatory stress responses. In conclusion the text provides a brief summary of the current development in immunomodulatory therapies for HF and their overlap with treatments of other disease entities.
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Affiliation(s)
- Lisa Hasselbach
- Division of Cardiology and Division of Perioperative Inflammation and Infection, Department Human Medicine, University of Oldenburg, Oldenburg, Germany
| | - Johannes Weidner
- Division of Perioperative Inflammation and Infection, Department Human Medicine, University of Oldenburg, Oldenburg, Germany
| | - Albrecht Elsässer
- Division of Cardiology, Department Human Medicine, University of Oldenburg, Oldenburg, Germany
| | - Gregor Theilmeier
- Division of Perioperative Inflammation and Infection, Department Human Medicine, University of Oldenburg, Oldenburg, Germany
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30
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Alazouny ZM, Alghonamy NM, Mohamed SR, Abdel Aal SM. Mesenchymal stem cells microvesicles versus granulocytes colony stimulating factor efficacy in ameliorating septic induced acute renal cortical injury in adult male albino rats (Histological and Immunohistochemical Study). Ultrastruct Pathol 2022; 46:164-187. [PMID: 35193482 DOI: 10.1080/01913123.2022.2039826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Sepsis is the most common cause of acute kidney injury in ICU patients, with increasing mortalities. Treatment septic AKI is unsatisfactory; therefore, more effective therapies must be investigated. MSCs-MVs have the same effectiveness in tissue repair as their original cells. Granulocyte colony-stimulating factor (G-CSF) is considered a simple and convenient tool in regenerative medicine. This study aimed to compare the probable therapeutic effect of MSCs-MVs versus G-CSF on septic AKI in rats. Forty-eight adult male rats were divided into four groups; I control group (IA-ID), II induced-sepsis group, III G-CSF, and IV MSC-MVs groups. Sepsis was induced in groups II, III, IV through a single IV injection of 10 mg/ kg of E.Coli-LPS dissolved in 1 ml saline. Four hours later, group IV received a single IV injection of MSCs-MVs, while group III received a SC injection of Neupogen for 5 days. All animals were sacrificed 7 days from the start. Serum and tissue samples of each group were used for biochemical study. Sections from all groups were subjected to light and electron microscopic examination. A fluorescent microscope examination for subgroup ID and group IV was done. Morphometric and statistical analyses were performed. Group II showed features of acute tubular injury. Group III showed some improvement (biochemically, LM & EM level) however, group IV showed more improvement. MVs injection caused a marked improvement in septic AKI; G-CSF can also meliorate the degenerative effect of sepsis on renal cortex, but to a lesser extent than MSCs-MVs.
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Affiliation(s)
- Zeinab M Alazouny
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Nabila M Alghonamy
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Samar R Mohamed
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Sara M Abdel Aal
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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31
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Yu YY, Li XQ, Hu WP, Cu SC, Dai JJ, Gao YN, Zhang YT, Bai XY, Shi DY. Self-developed NF-κB inhibitor 270 protects against LPS-induced acute kidney injury and lung injury through improving inflammation. Biomed Pharmacother 2022; 147:112615. [PMID: 35026488 DOI: 10.1016/j.biopha.2022.112615] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 01/02/2022] [Accepted: 01/02/2022] [Indexed: 12/11/2022] Open
Abstract
Sepsis-induced acute kidney injury (AKI) and acute lung injury (ALI) have high morbidity and mortality, with no effective clinically available drugs. Anti-inflammation is effective strategy in the therapy of AKI and ALI. NF-κB is a target for the development of anti‑inflammatory agents. The purpose of the study is to evaluate the effect of 270, self-developed NF-κB inhibitor, in LPS-induced AKI and ALI. LPS-induced macrophages were used to examine the anti-inflammation activity of 270 in vitro. Sepsis-induced AKI and ALI mice models were established by intraperitoneal injection of LPS (10 mg/kg) for 24 h. Oral administration 270 for 14 days before LPS stimulation. Plasma, kidney and lung tissues were collected and used for histopathology, biochemical assay, ELISA, RT-PCR, and western blot analyses. In vitro, we showed that 270 suppressed the inflammation response in LPS-induced RAW 264.7 macrophages and bone marrow derived macrophages. In vivo, we found that 270 ameliorated LPS-induced AKI and ALI, as evidenced by improving various pathological changes, reducing the expression of pro-inflammation genes, blocking the activation of NF-κB and JNK pathways, attenuating the elevated myeloperoxidase (MPO) activity and malondialdehyde (MDA) content, ameliorating the activated ER stress, reversing the inhibition effect on autophagy in kidney and lung tissues, and alleviating the enhanced plasma level of creatinine (Crea), blood urea nitrogen (BUN) and pro-inflammation cytokines. Our investigations provides evidence that NF-κB inhibitor 270 is a potential drug that against LPS-induced AKI and ALI in the future.
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Affiliation(s)
- Yan-Yan Yu
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200 China
| | - Xiang-Qian Li
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200 China
| | - Wen-Peng Hu
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200 China
| | - Shi-Chao Cu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, China
| | - Jia-Jia Dai
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200 China
| | - Ya-Nan Gao
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200 China
| | - Yi-Ting Zhang
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200 China
| | - Xiao-Yi Bai
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200 China
| | - Da-Yong Shi
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266200 China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China.
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32
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Abdelsalam M, Abd El Wahab AM, Nassar MK, Samaan E, Eldeep A, Abdalbary M, Tawfik M, Saleh M, Shemies RS, Sabry A. Kidneys in SARS-CoV-2 Era; a challenge of multiple faces. Ther Apher Dial 2022; 26:552-565. [PMID: 34989119 DOI: 10.1111/1744-9987.13792] [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: 09/11/2021] [Revised: 12/31/2021] [Accepted: 01/03/2022] [Indexed: 01/08/2023]
Abstract
INTRODUCTION With the evolution of SARS-CoV-2 pandemic, it was believed to be a direct respiratory virus. But, its deleterious effects were observed on different body systems, including kidneys. AIM OF WORK In this review, we tried as much as we can to summarize what has been discussed in the literature about the relation between SARS-CoV-2 infection and kidneys since December, 2019. METHODS Each part of the review was assigned to one or two authors to search for relevant articles in three databases (Pubmed, Scopus and Google scholar) and collected data were summarized and revised by two independent researchers. CONCLUSION The complexity of COVID-19 pandemic and kidney could be attributed to the direct effect of SARS-CoV-2 infection on the kidneys, different clinical presentation, difficulties confronting dialysis patients, restrictions of the organ transplant programs, poor outcomes and bad prognosis in patients with known history of kidney diseases who got infected with SARS-CoV-2. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Mostafa Abdelsalam
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura, Egypt
| | | | | | - Emad Samaan
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura, Egypt
| | - Ahmed Eldeep
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura, Egypt
| | - Mohamed Abdalbary
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura, Egypt.,Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, US
| | - Mona Tawfik
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura, Egypt
| | - Marwa Saleh
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura, Egypt
| | | | - Alaa Sabry
- Mansoura Nephrology and Dialysis Unit, Mansoura University, Mansoura, Egypt
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Fujita K, Takata I, Yoshida I, Takashima H, Sugiyama H. TP0586532, a non-hydroxamate LpxC inhibitor, reduces LPS release and IL-6 production both in vitro and in vivo. J Antibiot (Tokyo) 2022; 75:136-145. [PMID: 34987187 PMCID: PMC8728711 DOI: 10.1038/s41429-021-00498-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/06/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022]
Abstract
UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is an essential enzyme in the biosynthesis of Lipid A, an active component of lipopolysaccharide (LPS), from UDP-3-O-acyl-N-acetylglicosamine. LPS is a major component of the cell surface of Gram-negative bacteria. LPS is known to be one of causative factors of sepsis and has been associated with high mortality in septic shock. TP0586532 is a novel non-hydroxamate LpxC enzyme inhibitor. In this study, we examined the inhibitory effect of TP0586532 on the LPS release from Klebsiella pneumoniae both in vitro and in vivo. Our results confirmed the inhibitory effect of TP0586532 on LPS release from the pathogenic bacterial species. On the other hand, meropenem and ciprofloxacin increase the level of LPS release. Furthermore, the effects of TP0586532 on LPS release and interleukin (IL)-6 production in the lung were determined using a murine model of pneumonia caused by K. pneumoniae. As observed in the in vitro study, TP0586532 showed the marked inhibitory effect on LPS release in the lungs, whereas meropenem- and ciprofloxacin-treated mice showed higher levels of LPS release and IL-6 production in the lungs as compared to those in the lungs of vehicle-treated mice. Moreover, TP0586532 used in combination with meropenem and ciprofloxacin attenuated the LPS release and IL-6 production induced by meropenem and ciprofloxacin in the lung. These results indicate that the inhibitory effect of TP0586532 on LPS release from pathogenic bacteria might be of benefit in patients with sepsis.
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Affiliation(s)
- Kiyoko Fujita
- Pharmacology Laboratotries, Taisho Pharmaceutical Co., Ltd, Saitama, Japan
| | - Iichiro Takata
- Pharmacology Laboratotries, Taisho Pharmaceutical Co., Ltd, Saitama, Japan
| | - Ippei Yoshida
- Pharmacology Laboratotries, Taisho Pharmaceutical Co., Ltd, Saitama, Japan
| | - Hajime Takashima
- Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd, Saitama, Japan
| | - Hiroyuki Sugiyama
- Pharmacology Laboratotries, Taisho Pharmaceutical Co., Ltd, Saitama, Japan. .,Medical information, Taisho Pharmaceutical Co., Ltd, Tokyo, Japan.
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Miao Z, Miao Z, Wang S, Wu H, Xu S. Exposure to imidacloprid induce oxidative stress, mitochondrial dysfunction, inflammation, apoptosis and mitophagy via NF-kappaB/JNK pathway in grass carp hepatocytes. FISH & SHELLFISH IMMUNOLOGY 2022; 120:674-685. [PMID: 34954370 DOI: 10.1016/j.fsi.2021.12.017] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/12/2021] [Accepted: 12/13/2021] [Indexed: 06/14/2023]
Abstract
Imidacloprid (IMI) is a neonicotinoid compound widely used in agriculture production, causing surface water pollution and threatening non-target organisms. The aim of this study was to analyze the effects of IMI on grass carp (Ctenopharyngodon idellus) liver cell (L8824) injury. The L8824 cells were exposed to different doses of IMI (65 mg/L, 130 mg/L and 260 mg/L) for 24 h. Our results demonstrated that exposure IMI significantly suppressed the activity of anti-oxidant enzymes (SOD, CAT and T-AOC) and accumulated oxidase (MDA) levels, and promoting reactive oxygen species (ROS) generation in L8824 cells. Additionally, mitochondrial membrane potential (ΔΨ m), mitochondria-derived ROS and ATP content and the MitoTracker Green indicated that IMI aggravated mitochondrial dysfunction, thereby inducing inflammation and enhancing pro-inflammatory genes (NF-kappaB, TNFα, IL-1β and IL-6) expressions. However, the addition of 2 mM N-acetyl-l-cysteine (NAC) can reverse these adverse effects of high-dose IMI- induced. Hence, ROS is the main factor of IMI-induced mitochondrial dysfunction and inflammation. We further found that exposure to IMI induced apoptosis, which is characterized by promoting release of cytochrome c (Cyt-C), and increasing the expression of Bcl-2-Associated X (BAX), cysteinyl aspartate specific proteinases (Caspase 9 and 3), decreasing Bcl-2 level. Immunofluorescent staining, qRT-PCR and Western Blot results indicated that IMI exposure also activated mitophagy, which was demonstrated by the expression of mitophagy-related genes (BNIP3, LC3B and P62). Conversely, scavenging JNK by SP600125(10 μM) alleviated the expression of mitochondrial apoptosis and mitophagy-related gene induced by high-dose IMI. Therefore, these results of study demonstrated that IMI-induced oxidative stress to regulate mitochondrial dysfunction, thus causing inflammation, mitochondrial apoptosis and mitophagy in grass carp hepatocytes through NF-kappaB/JNK pathway.
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Affiliation(s)
- Zhiruo Miao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Zhiying Miao
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Shengchen Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Hao Wu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Shiwen Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
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35
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Zisman D, Safieh M, Simanovich E, Feld J, Kinarty A, Zisman L, Gazitt T, Haddad A, Elias M, Rosner I, Kaly L, Rahat MA. Tocilizumab (TCZ) Decreases Angiogenesis in Rheumatoid Arthritis Through Its Regulatory Effect on miR-146a-5p and EMMPRIN/CD147. Front Immunol 2021; 12:739592. [PMID: 34975837 PMCID: PMC8714881 DOI: 10.3389/fimmu.2021.739592] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 11/29/2021] [Indexed: 01/25/2023] Open
Abstract
Background Angiogenesis is a major contributor to the development of inflammation during Rheumatoid arthritis (RA), as the vascularization of the pannus provides nutrients and oxygen for the infiltrating immune cells and proliferating synoviocytes. Tocilizumab (TCZ) is an anti-IL-6 receptor antibody that is used in the treatment of RA patients, and has been shown to exert anti-inflammatory effects. However, its effects on angiogenesis are not fully elucidated, and the molecular mechanisms regulating this effect are unknown. Methods We evaluated the concentrations of several pro- and anti-angiogenic factors and the expression levels of several microRNA molecules that are associated with RA and angiogenesis in serum samples obtained from 40 RA patients, before and 4 months after the initiation of TCZ treatment. Additionally, we used an in vitro co-culture system of fibroblasts (the HT1080 cell line) and monocytes (the U937 cell line) to explore the mechanisms of TCZ action. Results Serum samples from RA patients treated with TCZ exhibited reduced circulating levels of EMMPRIN/CD147, enhanced expression of circulating miR-146a-5p and miR-150-5p, and reduced the angiogenic potential as was manifested by the lower number of tube-like structures that were formed by EaHy926 endothelial cell line. In vitro, the accumulation in the supernatants of the pro-angiogenic factors EMMPRIN, VEGF and MMP-9 was increased by co-culturing the HT1080 fibroblasts and the U937 monocytes, while the accumulation of the anti-angiogenic factor thrombospondin-1 (Tsp-1) and the expression levels of miR-146a-5p were reduced. Transfection of HT1080 cells with the miR-146a-5p mimic, decreased the accumulation of EMMPRIN, VEGF and MMP-9. When we neutralized EMMPRIN with a blocking antibody, the supernatants derived from these co-cultures displayed reduced migration, proliferation and tube formation in the functional assays. Conclusions Our findings implicate miR-146a-5p in the regulation of EMMPRIN and propose that TCZ affects angiogenesis through its effects on EMMPRIN and miR-146a-5p.
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Affiliation(s)
- Devy Zisman
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Department of Rheumatology, Carmel Medical Center, Haifa, Israel
| | - Mirna Safieh
- Department of Rheumatology, Carmel Medical Center, Haifa, Israel
- Immunotherapy Laboratory, Carmel Medical Center, Haifa, Israel
| | | | - Joy Feld
- Department of Rheumatology, Carmel Medical Center, Haifa, Israel
| | - Amalia Kinarty
- Immunotherapy Laboratory, Carmel Medical Center, Haifa, Israel
| | - Liron Zisman
- Immunotherapy Laboratory, Carmel Medical Center, Haifa, Israel
| | - Tal Gazitt
- Department of Rheumatology, Carmel Medical Center, Haifa, Israel
| | - Amir Haddad
- Department of Rheumatology, Carmel Medical Center, Haifa, Israel
| | - Muna Elias
- Department of Rheumatology, Carmel Medical Center, Haifa, Israel
| | - Itzhak Rosner
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Rheumatology Unit, Bnei Zion Medical Center, Haifa, Israel
| | - Lisa Kaly
- Rheumatology Unit, Bnei Zion Medical Center, Haifa, Israel
| | - Michal A. Rahat
- Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Immunotherapy Laboratory, Carmel Medical Center, Haifa, Israel
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Zou H, Yang Y, Dai H, Xiong Y, Wang JQ, Lin L, Chen ZS. Recent Updates in Experimental Research and Clinical Evaluation on Drugs for COVID-19 Treatment. Front Pharmacol 2021; 12:732403. [PMID: 34880750 PMCID: PMC8646041 DOI: 10.3389/fphar.2021.732403] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 10/13/2021] [Indexed: 12/17/2022] Open
Abstract
Since the outbreak of corona virus disease 2019 (COVID-19) in Wuhan (China) in December 2019, the epidemic has rapidly spread to many countries around the world, posing a huge threat to global public health. In response to the pandemic, a number of clinical studies have been initiated to evaluate the effect of various treatments against COVID-19, combining medical strategies and clinical trial data from around the globe. Herein, we summarize the clinical evaluation about the drugs mentioned in this review for COVID-19 treatment. This review discusses the recent data regarding the efficacy of various treatments in COVID-19 patients, to control and prevent the outbreak.
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Affiliation(s)
| | - Yuqi Yang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Huiqiang Dai
- Cell Research Center, Shenzhen Bolun Institute of Biotechnology, Shenzhen, China
| | - Yunchuang Xiong
- Cell Research Center, Shenzhen Bolun Institute of Biotechnology, Shenzhen, China
| | - Jing-Quan Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Lusheng Lin
- Cell Research Center, Shenzhen Bolun Institute of Biotechnology, Shenzhen, China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
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Hu Y, Jiang Y, Liu S, Shen J, An Y. Phenotypes, Lung Microbiota and Cytokine Responses in Pneumonia After Hematopoietic Stem Cell Transplantation. J Inflamm Res 2021; 14:6055-6065. [PMID: 34824541 PMCID: PMC8610763 DOI: 10.2147/jir.s338914] [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: 09/12/2021] [Accepted: 11/12/2021] [Indexed: 12/15/2022] Open
Abstract
Objective We aim to identify phenotypes of hematopoietic stem cell transplantation (HSCT) patients with pneumonia, discover relations of microbiota composition, cytokine profile, and outcomes between phenotypes. Specific cytokines will be evaluated for their role in lung injury in a murine model. Methods HSCT patients with pneumonia were included, and clustering of variables including cytokine levels provided the phenotypes. Outcomes were compared between phenotypes. Analysis of lung microbiota identified marker species of phenotypes. In the murine model, marker species-related cytokine regulations and the role of cytokines in lung injury were evaluated. Results Seventy-two patients were included, and two phenotypes were identified, namely "reactive" (N=21) and "nonreactive" (N=51) phenotype. Compared to their counterparts, patients with nonreactive phenotype had lower serum IL-6, IL-8, less severe inflammation, worse outcomes and more viruses as marker species in lung microbiota. The animal study validated the pathogens specific cytokine responses that presented in the human study and the potential protective role of IL-6 in these patients. Conclusion HSCT patients with pneumonia can be clustered into two phenotypes with different marker species and outcomes: the "nonreactive" phenotype and the "reactive" phenotype. Serum cytokine levels were different between the two phenotypes, which indicate the existence of the pathogen-related cytokine responses. For patients with the "nonreactive" phenotype, IL-6 therapy may improve their prognosis, which should be further tested in clinical studies.
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Affiliation(s)
- Yan Hu
- Department of Respiratory and Critical Care Medicine, Peking University International Hospital, Beijing, People's Republic of China
| | - Yanwen Jiang
- Department of Respiratory and Critical Care Medicine, Peking University International Hospital, Beijing, People's Republic of China
| | - Shuang Liu
- Department of Respiratory and Critical Care Medicine, Peking University International Hospital, Beijing, People's Republic of China
| | - Jiawei Shen
- Department of Critical Care Medicine, Peking University People's Hospital, Beijing, People's Republic of China
| | - Youzhong An
- Department of Critical Care Medicine, Peking University People's Hospital, Beijing, People's Republic of China
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38
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Davis J, Umeh U, Saba R. Treatment of SARS-CoV-2 (COVID-19): A safety perspective. World J Pharmacol 2021; 10:1-32. [DOI: 10.5497/wjp.v10.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/22/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
The goal of this review is to report a balanced perspective of current evidence for efficacy of treatments for coronavirus disease 2019 (COVID-19) against the historical safety of these treatments as of May 2021. We preselected therapies of interest for COVID-19 based on national guidelines and modified over time. We searched PubMed and Medline for these specific COVID-19 treatments and data related to their efficacy. We also searched for prior randomized controlled trials of each therapy to assess adverse effects, and we obtained the Food and Drug Administration Approval label for this information. Several drugs have been approved for the treatment of COVID-19, and many more are under study. This includes dexamethasone, remdesivir, hydroxychloroquine/chloroquine, lopinvir/ritonavir, interferon or interleukin inhibitors, convalescent plasma and several vitamins and minerals. The strongest evidence for benefit is mortality benefit with dexamethasone in patients with COVID-19 and hypoxemia, although there is a signal of harm if this is started too early. There are several other promising therapies, like interleukin inhibitors and ivermectin. Hydroxychloroquine/chloroquine, lopinvir/ritonavir, and convalescent plasma do not have enough evidence of benefit to outweigh the known risks of these drugs.
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Affiliation(s)
- Joshua Davis
- Department of Emergency Medicine, Vituity, Wichita, KS 67214, United States
| | - Ugochukwu Umeh
- College of Medicine, Medical University of Lublin, Lublin 20-093, Poland
| | - Rand Saba
- Department of Surgery, Ascension Providence Hospital, Southfield, MI 48075, United States
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Interleukin-6 in Critical Coronavirus Disease 2019, a Driver of Lung Inflammation of Systemic Origin? Crit Care Explor 2021; 3:e0542. [PMID: 34604785 PMCID: PMC8480937 DOI: 10.1097/cce.0000000000000542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
To examine whether interleukin-6 in critical coronavirus disease 2019 is higher in arterial than in central venous blood, as a sign of predominantly local pulmonal rather than systemic interleukin-6 production.
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40
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Al-Kadi A, El-Daly M, El-Tahawy NFG, Khalifa MMA, Ahmed ASF. Angiotensin aldosterone inhibitors improve survival and ameliorate kidney injury induced by sepsis through suppression of inflammation and apoptosis. Fundam Clin Pharmacol 2021; 36:286-295. [PMID: 34309069 DOI: 10.1111/fcp.12718] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 07/21/2021] [Indexed: 12/14/2022]
Abstract
Sepsis is an extensive life-threatening illness that occurs due to an abnormal host response that extends through the initial storm of inflammation and oxidative stress and terminates at the late stage of immunosuppression. Among global intensive care units, sepsis-induced acute kidney injury is reported with high mortality rate. The purpose of this study was to evaluate the protective effect of the renin angiotensin aldosterone system (RAAS) inhibition on sepsis outcomes. Cecal ligation and puncture (CLP) procedure was applied for sepsis induction. The experimental design constituted of five groups of rats: sham, CLP-nontreated and CLP-treated with ramipril (10 mg/kg, p.o.), losartan (20 mg/kg, i.p.) and spironolactone (25 mg/kg, p.o.). Twenty-four hours after surgery, rats were euthanized for blood and tissue samples, which were used for assessment of serum inflammatory markers, and oxidative stress parameters, as well as to kidney function parameters. The tissue samples were used for histological and caspase-3 assessment. A survival study was conducted using another set of animals. Our results showed that the different RAAS inhibitors showed protective effects evidenced by enhanced overall survival following sepsis (80% in ramipril and spironolactone-treated and 60% in losartan-treated vs. 10% in the septic group), in addition to improved renal function parameters and reduction of oxidative stress and inflammation. The timely use of RAAS inhibitors during sepsis might represent a new therapeutic approach in septic patient.
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Affiliation(s)
- Alaa Al-Kadi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Deraya University, El-Minia, Egypt
| | - Mahmoud El-Daly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt
| | - Nashwa F G El-Tahawy
- Department of Histology and Cell biology, Faculty of Medicine, Minia University, El-Minia, Egypt
| | | | - Al-Shaimaa F Ahmed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt
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41
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Morsy MA, Khalaf HM, Rifaai RA, Bayoumi AMA, Khalifa EMMA, Ibrahim YF. Canagliflozin, an SGLT-2 inhibitor, ameliorates acetic acid-induced colitis in rats through targeting glucose metabolism and inhibiting NOX2. Biomed Pharmacother 2021; 141:111902. [PMID: 34328119 DOI: 10.1016/j.biopha.2021.111902] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 06/29/2021] [Accepted: 07/06/2021] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Inflammatory bowel disease is defined as chronic noninfectious inflammation of the gastrointestinal tract, including ulcerative colitis and Crohn's disease. Its incidence and predominance have increased globally, with no effective agents for preventing its recurrence or treatment until now. AIM The current study aimed to investigate the possible role of canagliflozin (CANA), a sodium-glucose co-transporter-2 inhibitor (SGLT-2), to prevent and treat acetic acid (AA)-induced colitis in a rat model. METHODS Colitis was induced in male Wistar rats by intrarectal instillation of 1 ml of 4% (v/v) AA. Rats were treated orally with either CANA (30 mg/kg/day, p.o.) for 10 days before or after colitis induction or sulfasalazine (360 mg/kg/day, p.o.) for 10 days before colitis induction. RESULTS AA resulted in a significant increase in disease activity index, colonic weight over length ratio, colon macroscopic damage score, and histological signs of colitis. All of these effects were significantly decreased by CANA administration. Additionally, CANA markedly inhibited AA-induced oxidative stress and inflammatory responses by significantly reducing the up-regulated levels in malondialdehyde, total nitrite, NF-κB, interleukin-1β, and TNF-α, and significantly increasing the down-regulated levels in reduced glutathione, superoxide dismutase, and interleukin-10. CANA significantly inhibited caspase-3 level while rescued survivin expression in colons. Finally, CANA reduced the elevated levels of pyruvic acid and G6PDH activity, as well as the levels of p22phox and NOX2 in the AA-induced colitis. CONCLUSION Our findings provide novel evidence that CANA has protective and therapeutic effects against AA-induced colitis by the impact of its antioxidant, anti-inflammatory, and anti-apoptotic effects.
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Affiliation(s)
- Mohamed A Morsy
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia; Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt.
| | - Hanaa M Khalaf
- Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
| | - Rehab A Rifaai
- Department of Histology and Cell Biology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
| | - Asmaa M A Bayoumi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia 61511, Egypt
| | - Esraa M M A Khalifa
- Department of Biochemistry, Faculty of Pharmacy, Deraya University, El-Minia 61111, Egypt
| | - Yasmine F Ibrahim
- Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
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Chen J, Wang W, Tang Y, Huang XR, Yu X, Lan HY. Inflammatory stress in SARS-COV-2 associated Acute Kidney Injury. Int J Biol Sci 2021; 17:1497-1506. [PMID: 33907513 PMCID: PMC8071761 DOI: 10.7150/ijbs.58791] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 03/01/2021] [Indexed: 01/08/2023] Open
Abstract
Increasing clinical evidence shows that acute kidney injury (AKI) is a common and severe complication in critically ill COVID-19 patients. The older age, the severity of COVID-19 infection, the ethnicity, and the history of smoking, diabetes, hypertension, and cardiovascular disease are the risk factor for AKI in COVID-19 patients. Of them, inflammation may be a key player in the pathogenesis of AKI in patients with COVID-19. It is highly possible that SARS-COV-2 infection may trigger the activation of multiple inflammatory pathways including angiotensin II, cytokine storm such as interleukin-6 (IL-6), C-reactive protein (CRP), TGF-β signaling, complement activation, and lung-kidney crosstalk to cause AKI. Thus, treatments by targeting these inflammatory molecules and pathways with a monoclonal antibody against IL-6 (Tocilizumab), C3 inhibitor AMY-101, anti-C5 antibody, anti-TGF-β OT-101, and the use of CRRT in critically ill patients may represent as novel and specific therapies for AKI in COVID-19 patients.
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Affiliation(s)
- Junzhe Chen
- Departments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China
- Department of Nephrology, The Third Affiliated hospital, Southern Medical university, Guangzhou, China
| | - Wenbiao Wang
- Departments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China
- Guangdong Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, China
| | - Ying Tang
- Department of Nephrology, The Third Affiliated hospital, Southern Medical university, Guangzhou, China
| | - Xiao-ru Huang
- Departments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China
- Guangdong-Hong Kong Joint Laboratory for Immunity and Genetics of Chronic Kidney Disease, Guangdong Academy of Medical Science, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Xueqing Yu
- Guangdong-Hong Kong Joint Laboratory for Immunity and Genetics of Chronic Kidney Disease, Guangdong Academy of Medical Science, Guangdong Provincial People's Hospital, Guangzhou, China
| | - Hui-Yao Lan
- Departments of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China
- Guangdong-Hong Kong Joint Laboratory for Immunity and Genetics of Chronic Kidney Disease, The Chinese University of Hong Kong, Hong Kong, China
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Jensen IJ, McGonagill PW, Butler NS, Harty JT, Griffith TS, Badovinac VP. NK Cell-Derived IL-10 Supports Host Survival during Sepsis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 206:1171-1180. [PMID: 33514512 PMCID: PMC7946778 DOI: 10.4049/jimmunol.2001131] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 12/29/2020] [Indexed: 02/06/2023]
Abstract
The dysregulated sepsis-induced cytokine storm evoked during systemic infection consists of biphasic and interconnected pro- and anti-inflammatory responses. The contrasting inflammatory cytokine responses determine the severity of the septic event, lymphopenia, host survival, and the ensuing long-lasting immunoparalysis state. NK cells, because of their capacity to elaborate pro- (i.e., IFN-γ) and anti-inflammatory (i.e., IL-10) responses, exist at the inflection of sepsis-induced inflammatory responses. Thus, NK cell activity could be beneficial or detrimental during sepsis. In this study, we demonstrate that murine NK cells promote host survival during sepsis by limiting the scope and duration of the cytokine storm. Specifically, NK cell-derived IL-10, produced in response to IL-15, is relevant to clinical manifestations in septic patients and critical for survival during sepsis. This role of NK cells demonstrates that regulatory mechanisms of classical inflammatory cells are beneficial and critical for controlling systemic inflammation, a notion relevant for therapeutic interventions during dysregulated infection-induced inflammatory responses.
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Affiliation(s)
- Isaac J Jensen
- Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242
- Department of Pathology, University of Iowa, Iowa City, IA 52242
| | | | - Noah S Butler
- Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242
- Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242
| | - John T Harty
- Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242
- Department of Pathology, University of Iowa, Iowa City, IA 52242
| | - Thomas S Griffith
- Microbiology, Immunology, and Cancer Biology PhD Program, University of Minnesota, Minneapolis, MN 55455
- Department of Urology, University of Minnesota, Minneapolis, MN 55455
- Center for Immunology, University of Minnesota, Minneapolis, MN 55455
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455; and
- Minneapolis Veterans Affairs Health Care System, Minneapolis, MN 55417
| | - Vladimir P Badovinac
- Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242;
- Department of Pathology, University of Iowa, Iowa City, IA 52242
- Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242
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Ni SY, Xu WT, Liao GY, Wang YL, Li J. LncRNA HOTAIR Promotes LPS-Induced Inflammation and Apoptosis of Cardiomyocytes via Lin28-Mediated PDCD4 Stability. Inflammation 2021; 44:1452-1463. [PMID: 33665757 DOI: 10.1007/s10753-021-01431-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 01/06/2021] [Accepted: 02/01/2021] [Indexed: 02/05/2023]
Abstract
Sepsis is one of the primary causes of death in intensive care units. Recently, increasing evidence has identified lncRNA HOTAIR is involved in septic cardiomyopathy. However, the potential mechanism underlying HOTAIR on septic cardiomyopathy is still unknown. H9C2 cells were treated with lipopolysaccharide (LPS) after transfection with sh-HOTAIR, sh-Lin28, pcDNA3.1-HOTAIR, and pcDNA3.1-PDCD4. qRT-PCR was used to examine the level of HOTAIR, Lin28, PDCD4, and sepsis-related inflammatory cytokines. Flow cytometric analysis was applied to detect cell apoptosis. The interaction between Lin28 and HOTAIR or PDCD4 was verified by RNA pull-down and RIP assay. HOTAIR levels were interfered by AAV9-sh-HOTAIR in LPS-induced septic cardiomyopathy mice. ELISA analysis was used to evaluate TNF-α, IL-6, and IL-1β level. Western blot was used to detect the expression of LIN28 and PDCD4 in mouse cardiomyocytes. Echocardiography was used to evaluate the cardiac function. In our study, knockdown of HOTAIR inhibited LPS-induced inflammation and H9C2 cells apoptosis. HOTAIR promoted LPS-induced inflammatory response and apoptosis of H9C2 cells by enhancing PDCD4 stability. RNA pull-down and RIP assay exhibited that Lin28, a highly conserved RNA-binding protein, was combined with HOTAIR and PDCD4. The in vivo experiments verified that the HOTAIR knockdown alleviated the cardiac function injury and secretion of inflammatory factors caused by sepsis. In conclusion, our findings supported that the HOTAIR/Lin28/PDCD4 axis serves as a critical regulator of sepsis, which may open a new direction for the development of sepsis therapeutic.
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Affiliation(s)
- Shu-Yuan Ni
- Department of Intensive Care Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong Province, People's Republic of China.
| | - Wen-Ting Xu
- Department of Intensive Care Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong Province, People's Republic of China
| | - Guang-Yuan Liao
- Department of Intensive Care Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong Province, People's Republic of China
| | - Yin-Ling Wang
- Department of Intensive Care Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong Province, People's Republic of China
| | - Jing Li
- Department of Intensive Care Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong Province, People's Republic of China
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Abstract
IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is an NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6-STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6-STAT3 axis is a critical target for treating diseases.
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Affiliation(s)
- Toshio Hirano
- National Institutes for Quantum and Radiological Science and Technology, Anagawa, Inage-ku, Chiba, Japan
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Cortegiani A, Ippolito M, Greco M, Granone V, Protti A, Gregoretti C, Giarratano A, Einav S, Cecconi M. Rationale and evidence on the use of tocilizumab in COVID-19: a systematic review. Pulmonology 2021; 27:52-66. [PMID: 32713784 PMCID: PMC7369580 DOI: 10.1016/j.pulmoe.2020.07.003] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 07/07/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Tocilizumab is an IL-6 receptor-blocking agent proposed for the treatment of severe COVID-19. The aim of this systematic review was to describe the rationale for the use of tocilizumab for the treatment of COVID-19 and to summarize the available evidence regarding its efficacy and safety. METHODS MEDLINE, PubMed, EMBASE, pre-print repositories (bioRxiv and medRxiv) and two trial Registries were searched for studies on the use of tocilizumab in COVID-19 or SARS-CoV-2 infection, viral pneumonia, and/or sepsis until 20th June 2020. RESULTS We identified 3 indirect pre-clinical studies and 28 clinical studies including 5776 patients with COVID-19 (13 with a comparison group, 15 single-arm). To date, no randomized trials have been published. We retrieved no studies at low risk of bias. Forty-five ongoing studies were retrieved from trial registries. CONCLUSIONS There is insufficient evidence regarding the clinical efficacy and safety of tocilizumab in patients with COVID-19. Its use should be considered experimental, requiring ethical approval and clinical trial oversight.
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Affiliation(s)
- A Cortegiani
- Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.), University of Palermo. Department of Anesthesia Intensive Care and Emergency, Policlinico Paolo Giaccone, Palermo, Italy.
| | - M Ippolito
- Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.), University of Palermo. Department of Anesthesia Intensive Care and Emergency, Policlinico Paolo Giaccone, Palermo, Italy.
| | - M Greco
- Department of Anesthesiology and Intensive Care, Humanitas Clinical and Research Center - IRCCS, Milan, Italy; Department of Biomedical Science, Humanitas University, Milan, Italy.
| | - V Granone
- Department of Anesthesiology and Intensive Care, Humanitas Clinical and Research Center - IRCCS, Milan, Italy; Department of Biomedical Science, Humanitas University, Milan, Italy.
| | - A Protti
- Department of Anesthesiology and Intensive Care, Humanitas Clinical and Research Center - IRCCS, Milan, Italy; Department of Biomedical Science, Humanitas University, Milan, Italy.
| | - C Gregoretti
- Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.), University of Palermo. Department of Anesthesia Intensive Care and Emergency, Policlinico Paolo Giaccone, Palermo, Italy; Fondazione "Giglio", Cefalù, Italy.
| | - A Giarratano
- Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.), University of Palermo. Department of Anesthesia Intensive Care and Emergency, Policlinico Paolo Giaccone, Palermo, Italy.
| | - S Einav
- IntensiveCare Unit of the Shaare Zedek Medical Medical Centre and Hebrew University Faculty of Medicine, Jerusalem, Israel.
| | - M Cecconi
- Department of Anesthesiology and Intensive Care, Humanitas Clinical and Research Center - IRCCS, Milan, Italy; Department of Biomedical Science, Humanitas University, Milan, Italy.
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Margraf A, Ludwig N, Zarbock A, Rossaint J. Systemic Inflammatory Response Syndrome After Surgery: Mechanisms and Protection. Anesth Analg 2020; 131:1693-1707. [PMID: 33186158 DOI: 10.1213/ane.0000000000005175] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The immune system is an evolutionary hallmark of higher organisms that defends the host against invading pathogens and exogenous infections. This defense includes the recruitment of immune cells to the site of infection and the initiation of an inflammatory response to contain and eliminate pathogens. However, an inflammatory response may also be triggered by noninfectious stimuli such as major surgery, and, in case of an overshooting, still not comprehensively understood reaction, lead to tissue destruction and organ dysfunction. Unfortunately, in some cases, the immune system may not effectively distinguish between stimuli elicited by major surgery, which ideally should only require a modest inflammatory response, and those elicited by trauma or pathogenic infection. Surgical procedures thus represent a potential trigger for systemic inflammation that causes the secretion of proinflammatory cytokines, endothelial dysfunction, glycocalyx damage, activation of neutrophils, and ultimately tissue and multisystem organ destruction. In this review, we discuss and summarize currently available mechanistic knowledge on surgery-associated systemic inflammation, demarcation toward other inflammatory complications, and possible therapeutic options. These options depend on uncovering the underlying mechanisms and could include pharmacologic agents, remote ischemic preconditioning protocols, cytokine blockade or clearance, and optimization of surgical procedures, anesthetic regimens, and perioperative inflammatory diagnostic assessment. Currently, a large gap between basic science and clinically confirmed data exists due to a limited evidence base of translational studies. We thus summarize important steps toward the understanding of the precise time- and space-regulated processes in systemic perioperative inflammation.
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Affiliation(s)
- Andreas Margraf
- From the Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
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Khokhar M, Purohit P, Roy D, Tomo S, Gadwal A, Modi A, Banerjee M, Sharma P. Acute kidney injury in COVID 19 - an update on pathophysiology and management modalities. Arch Physiol Biochem 2020; 129:626-639. [PMID: 33320717 DOI: 10.1080/13813455.2020.1856141] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Acute kidney injury (AKI), characterised by fluid imbalance and overload, is prevalent in severe disease phenotypes of coronavirus disease 2019 (COVID-19). The elderly immunocompromised patients with pre-existing comorbidities being more risk-prone to severe COVID-19, the importance of early diagnosis and intervention in AKI is imperative. Histopathological examination of COVID-19 patients with AKI reveals viral invasion of the renal parenchyma and evidence of AKI. The definitive treatment for AKI includes renal replacement therapy and renal transplant. Immunosuppressant regimens and its interactions with COVID-19 have to be further explored to devise effective treatment strategies in COVID-19 transplant patients. Other supportive strategies for AKI patients include hemodynamic monitoring and maintenance of fluid balance. Antiviral drugs should be meticulously monitored in the management of these high-risk patients. We have focussed on the development of renal injury provoked by the SARS-CoV-2, the varying clinical characteristics, and employment of different management strategies, including renal replacement therapy, alongside the emerging cytokine lowering approaches.
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Affiliation(s)
- Manoj Khokhar
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Purvi Purohit
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Dipayan Roy
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Sojit Tomo
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Ashita Gadwal
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Anupama Modi
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Mithu Banerjee
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Praveen Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
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Piccirillo MC, Ascierto P, Atripaldi L, Cascella M, Costantini M, Dolci G, Facciolongo N, Fraganza F, Marata A, Massari M, Montesarchio V, Mussini C, Negri EA, Parrella R, Popoli P, Botti G, Arenare L, Chiodini P, Gallo C, Salvarani C, Perrone F. TOCIVID-19 - A multicenter study on the efficacy and tolerability of tocilizumab in the treatment of patients with COVID-19 pneumonia. Study protocol. Contemp Clin Trials 2020; 98:106165. [PMID: 33031955 PMCID: PMC7536129 DOI: 10.1016/j.cct.2020.106165] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 09/30/2020] [Accepted: 10/01/2020] [Indexed: 01/08/2023]
Abstract
BACKGROUND Pneumonia is the most frequent complication of COVID-19, due to an aberrant host immune response that is associated with an acute respiratory distress syndrome, and, in most critical patients, with a "cytokine storm". IL-6 might play a key role in the cytokine storm and might be a potential target to treat severe and critical COVID-19. Tocilizumab is a recombinant humanized monoclonal antibody, directed against IL-6 receptor. METHODS This multicentre study project includes a single-arm phase 2 study and a further parallel cohort, enrolling hospitalized patients with COVID-19 pneumonia and oxygen saturation at rest in ambient air ≤93% or requiring respiratory support. Patients receive tocilizumab 8 mg/kg (up to 800 mg) as one intravenous administration. A second administration (same dose) after 12 h is optional. Two-week and one-month lethality rates are the co-primary endpoints. Sample size planned for the phase 2 study is 330 patients. The parallel cohort will include patients who cannot enter the phase 2 study because being intubated from more than 24 h, or having already received tocilizumab, or the phase 2 study has reached sample size. Primary analysis will include patients enrolled in the phase 2 study. Results of the primary analysis will be validated in the prospective cohort of patients consecutively registered after phase 2 closure from March 20 to March 24, who were potentially eligible for the phase 2 study. CONCLUSION This trial aims to verify the safety and efficacy of tocilizumab in the Italian population with COVID-19 pneumonia and respiratory impairment. EudraCT Number: 2020-001110-38; Clinicaltrials.gov ID NCT04317092.
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Affiliation(s)
| | - Paolo Ascierto
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Luigi Atripaldi
- AORN Ospedali dei Colli -Monaldi -Cotugno- CTO, Napoli, Italy
| | - Marco Cascella
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | | | - Giovanni Dolci
- Azienda USL-IRCCS di Reggio Emilia, Italy; Università degli Studi di Modena e Reggio Emilia, Italy
| | | | | | | | | | | | | | | | | | | | - Gerardo Botti
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Laura Arenare
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Paolo Chiodini
- Università degli Studi della Campania Luigi Vanvitelli, Italy
| | - Ciro Gallo
- Università degli Studi della Campania Luigi Vanvitelli, Italy
| | - Carlo Salvarani
- Azienda USL-IRCCS di Reggio Emilia, Italy; Università degli Studi di Modena e Reggio Emilia, Italy
| | - Francesco Perrone
- Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy.
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West TA, Malik S, Nalpantidis A, Tran T, Cannon C, Bhonagiri D, Chan K, Cheong E, Wan Sai Cheong J, Cheung W, Choudhury F, Ernest D, Farah CS, Fernando S, Kanapathipillai R, Kol M, Murfin B, Naqvi H, Shah A, Wagh A, Ojaimi S, Frankum B, Riminton S, Keat K. Tocilizumab for severe COVID-19 pneumonia: Case series of 5 Australian patients. Int J Rheum Dis 2020; 23:1030-1039. [PMID: 32881350 PMCID: PMC7436606 DOI: 10.1111/1756-185x.13913] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 06/17/2020] [Accepted: 06/17/2020] [Indexed: 01/08/2023]
Abstract
AIM To describe the first Australian cases of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) disease (COVID-19) pneumonia treated with the interleukin-6 receptor antagonist tocilizumab. METHODS Retrospective, open-label, real-world, uncontrolled, single-arm case series conducted in 2 tertiary hospitals in NSW, Australia and 1 tertiary hospital in Victoria, Australia. Five adult male patients aged between 46 and 74 years with type 1 respiratory failure due to COVID-19 pneumonia requiring intensive care unit (ICU) admission and biochemical evidence of systemic hyperinflammation (C-reactive protein greater than 100 mg/L; ferritin greater than 700 μg/L) were administered variable-dose tocilizumab. RESULTS At between 13 and 26 days follow-up, all patients are alive and have been discharged from ICU. Two patients have been discharged home. Two patients avoided endotracheal intubation. Oxygen therapy has been ceased in three patients. Four adverse events potentially associated with tocilizumab therapy occurred in three patients: ventilator-associated pneumonia, bacteremia associated with central venous catheterization, myositis and hepatitis. All patients received broad-spectrum antibiotics, 4 received corticosteroids and 2 received both lopinavir/ritonavir and hydroxychloroquine. The time from first tocilizumab administration to improvement in ventilation, defined as a 25% reduction in fraction of inspired oxygen required to maintain peripheral oxygen saturation greater than 92%, ranged from 7 hours to 4.6 days. CONCLUSIONS Tocilizumab use was associated with favorable clinical outcome in our patients. We recommend tocilizumab be included in randomized controlled trials of treatment for patients with severe COVID-19 pneumonia, and be considered for compassionate use in such patients pending the results of these trials.
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Affiliation(s)
- Timothy A. West
- Department of Immunology and AllergyCampbelltown HospitalSydneyNSWAustralia
| | - Sameer Malik
- Department of Respiratory MedicineConcord HospitalSydneyNSWAustralia
| | | | - Tuan Tran
- Department of MedicineCampbelltown HospitalSydneyNSWAustralia
| | | | | | - Kevin Chan
- Department of Respiratory MedicineCampbelltown HospitalSydneyNSWAustralia
| | - Elaine Cheong
- Department of Microbiology and Infectious DiseasesConcord HospitalSydneyNSWAustralia
| | | | | | - Faisal Choudhury
- Department of Respiratory MedicineCampbelltown HospitalSydneyNSWAustralia
| | - David Ernest
- Intensive Care UnitMonash HealthMelbourneVICAustralia
| | - Claude S. Farah
- Department of Respiratory MedicineConcord HospitalSydneyNSWAustralia
| | - Shelanah Fernando
- Department of Microbiology and Infectious DiseasesConcord HospitalSydneyNSWAustralia
| | | | - Mark Kol
- Intensive Care UnitConcord HospitalSydneyNSWAustralia
| | | | - Haider Naqvi
- Department of Respiratory MedicineCampbelltown HospitalSydneyNSWAustralia
| | - Asim Shah
- Intensive Care UnitConcord HospitalSydneyNSWAustralia
| | - Atul Wagh
- Intensive Care UnitConcord HospitalSydneyNSWAustralia
| | - Samar Ojaimi
- Monash Infectious DiseasesMonash UniversityMelbourneVICAustralia
| | - Bradley Frankum
- Department of Immunology and AllergyCampbelltown HospitalSydneyNSWAustralia
| | - Sean Riminton
- Department of Respiratory MedicineConcord HospitalSydneyNSWAustralia
| | - Karuna Keat
- Department of Immunology and AllergyCampbelltown HospitalSydneyNSWAustralia
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