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Li Q, Shi X, Huang H, Gao Q, Sun Q, Meng Y, Niu L, Xie C, Yang C. 5β-hydroxycostic acid from Laggera alata ameliorates sepsis-associated acute kidney injury through its anti-inflammatory and anti-ferroptosis effects via NF-κB and MAPK pathways. JOURNAL OF ETHNOPHARMACOLOGY 2025; 341:119359. [PMID: 39800248 DOI: 10.1016/j.jep.2025.119359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 12/02/2024] [Accepted: 01/10/2025] [Indexed: 01/15/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The whole plant of Laggera alata is frequently utilize to remedy inflammatory diseases including nephritis as a traditional Chinese medicine. However, its active ingredients and mechanism of action against sepsis-associated acute kidney injury (SA-AKI) are unknown. AIM OF THE STUDY This study aimed to identify active compounds from L. alata that inhibit renal inflammation and ameliorate SA-AKI, and to elucidate their mechanisms of action. MATERIALS AND METHODS The chemical constituents were separated from the ethyl acetate layer of L. alata methanol extract by column chromatography over silica gel, medium-pressure liquid chromatography and semipreparative high-performance liquid chromatography. Extensive spectroscopic techniques were applied to determine the chemical structures. The anti-inflammatory efficiency was measured by analyzing the NO production in RAW 264.7 cells. The levels of IL-6, IL-1β, CCL-2 and CCL-5 mRNA were determined by qRT-PCR. Cecal ligation and puncture (CLP) surgery is a frequently applied method to establish the mouse sepsis model. Sepsis was thus induced in mice via CLP. The effect in the treatment of SA-AKI was evaluated by H&E staining and ELISA detection. Western blotting was used to evaluate the protein levels involved in ferroptosis, NF-κB and MAPK signaling pathways. RESULTS Twelve compounds were obtained from L.alata including four unreported sesquiterpenoids (1-4). Compound 5 exhibited the most significant inhibitory effect on NO production with the IC50 value of 6.034 μM and could restrain the mRNA expression of inflammatory factors IL-6, IL-1β, CCL-2 and CCL-5. The in vivo results demonstrated that compound 5 alleviated the renal injury by decreasing the serum IL-6, IL-1β, Cr, and BUN levels, reducing the kidney contents of Cys-C and KIM-1, and regulating the kidney levels of MDA, GSH, ferrous iron, GPX4, FTH1, and SLC7A11. Furthermore, Compound 5 also repressed the NF-κB and MAPK pathways in vitro and in vivo. CONCLUSIONS This study revealed that compound 5 could ameliorate SA-AKI through exerting its anti-inflammatory and anti-ferroptosis effects via NF-κB and MAPK pathways. The current research supported the traditional use of L.alata in the treatment of renal diseases.
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Affiliation(s)
- Qing Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, People's Republic of China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin, 300070, People's Republic of China
| | - Xue Shi
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, People's Republic of China
| | - Hong Huang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, People's Republic of China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin, 300070, People's Republic of China
| | - Qian Gao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, People's Republic of China
| | - Qingya Sun
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, People's Republic of China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin, 300070, People's Republic of China
| | - Yao Meng
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, People's Republic of China; High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin, 300070, People's Republic of China
| | - Lihang Niu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, People's Republic of China
| | - Chunfeng Xie
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, People's Republic of China.
| | - Cheng Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, People's Republic of China.
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Guo S, Li Z, Liu Y, Cheng Y, Jia D. Ferroptosis: a new target for hepatic ischemia-reperfusion injury? Free Radic Res 2024; 58:396-416. [PMID: 39068663 DOI: 10.1080/10715762.2024.2386075] [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: 02/29/2024] [Revised: 06/20/2024] [Accepted: 06/21/2024] [Indexed: 07/30/2024]
Abstract
Ischemia-reperfusion injury (IRI) can seriously affect graft survival and prognosis and is an unavoidable event during liver transplantation. Ferroptosis is a novel iron-dependent form of cell death characterized by iron accumulation and overwhelming lipid peroxidation; it differs morphologically, genetically, and biochemically from other well-known cell death types (autophagy, necrosis, and apoptosis). Accumulating evidence has shown that ferroptosis is involved in the pathogenesis of hepatic IRI, and targeting ferroptosis may be a promising therapeutic approach. Here, we review the pathways and phenomena involved in ferroptosis, explore the associations and implications of ferroptosis and hepatic IRI, and discuss possible strategies for modulating ferroptosis to alleviate the hepatic IRI.
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Affiliation(s)
- Shanshan Guo
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zexin Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China
| | - Yi Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China
| | - Ying Cheng
- Department of Organ Transplantation, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Degong Jia
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Zheng Y, Gao Y, Zhu W, Bai XG, Qi J. Advances in molecular agents targeting toll-like receptor 4 signaling pathways for potential treatment of sepsis. Eur J Med Chem 2024; 268:116300. [PMID: 38452729 DOI: 10.1016/j.ejmech.2024.116300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 01/23/2024] [Accepted: 03/01/2024] [Indexed: 03/09/2024]
Abstract
Sepsis is a systemic inflammatory response syndrome caused by an infection. Toll-like receptor 4 (TLR4) is activated by endogenous molecules released by injured or necrotic tissues. Additionally, TLR4 is remarkably sensitive to infection of various bacteria and can rapidly stimulate host defense responses. The TLR4 signaling pathway plays an important role in sepsis by activating the inflammatory response. Accordingly, as part of efforts to improve the inflammatory response and survival rate of patients with sepsis, several drugs have been developed to regulate the inflammatory signaling pathways mediated by TLR4. Inhibition of TLR4 signal transduction can be directed toward either TLR4 directly or other proteins in the TLR4 signaling pathway. Here, we review the advances in the development of small-molecule agents and peptides targeting regulation of the TLR4 signaling pathway, which are characterized according to their structural characteristics as polyphenols, terpenoids, steroids, antibiotics, anthraquinones, inorganic compounds, and others. Therefore, regulating the expression of the TLR4 signaling pathway and modulating its effects has broad prospects as a target for the treatment of lung, liver, kidneys, and other important organs injury in sepsis.
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Affiliation(s)
- Yunyun Zheng
- Medicine College of Pingdingshan University, Pingdingshan, Henan, 467000, China
| | - Yingying Gao
- Medicine College of Pingdingshan University, Pingdingshan, Henan, 467000, China
| | - Weiru Zhu
- Medicine College of Pingdingshan University, Pingdingshan, Henan, 467000, China
| | - Xian-Guang Bai
- Medicine College of Pingdingshan University, Pingdingshan, Henan, 467000, China.
| | - Jinxu Qi
- Medicine College of Pingdingshan University, Pingdingshan, Henan, 467000, China.
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Abdel-Wahab ND, Kabil MF, El-Sherbiny IM, Salama MF, El-Sayed G, El-Sherbini ES. Potential anticancer effect of free and nanoformulated Deferasirox for breast cancer treatment: in-vitro and in-vivo evaluation. Drug Dev Ind Pharm 2024; 50:223-235. [PMID: 38305197 DOI: 10.1080/03639045.2024.2314189] [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: 01/12/2024] [Accepted: 01/30/2024] [Indexed: 02/03/2024]
Abstract
BACKGROUND Breast cancer (BC) stands as the second-leading cause of mortality among women worldwide. Many chemotherapeutic treatments for BC come with significant adverse effects. Additionally, BC is recognized as one of the most resistant forms of malignancy to treatment. Consequently, there exists a critical need for innovative therapeutic agents that are both highly effective and exhibit reduced toxicity and side effects for patients. Deferasirox (DFX), an iron-chelating drug approved by the FDA for oral use, emerges as a promising contender in the fight against BC proliferation. DFX, primarily administered orally, is utilized to address chronic iron excess resulting from blood transfusions, and it is the inaugural treatment for chronic iron overload syndrome. However, DFX encounters limitations due to its poor water solubility. AIM This study aimed at incorporating DFX into lipid nanocapsules (DFX-LNCs) followed by investigating the anticancer effect of the DFX nanoform as compared to free DFX in-vitro and on an orthotopic BC mouse model in-vivo. METHODS The DFX-LNCs was prepared and imaged using TEM and also characterized in terms of particle size (PS), zeta potential (ZP), and polydispersity index (PDI) using DLS. Moreover, drug release, cytotoxicity, and anticancer effect were assessed in-vitro, and in-vivo. RESULTS The results revealed that DFX-LNCs are more cytotoxic than free DFX with IC50 of 4.417 µg/ml and 16.114 µg/ml, respectively, while the plain LNCs didn't show any cytotoxic effect on the 4T1 cell line (IC50 = 122.797 µg/ml). Besides, the apoptotic effect of DFX-LNCs was more pronounced than that of free DFX, as evidenced by Annexin V/PI staining, increased BAX expression, and decreased expression of BcL-2. Moreover, DFX-LNCs showed a superior antitumor effect in-vivo with potent antioxidant and anti-proliferative effects. CONCLUSION The newly developed DFX nanoform demonstrated a high potential as a promising therapeutic agent for BC treatment.
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Affiliation(s)
- Nadeen Diaa Abdel-Wahab
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Mansoura University, Egypt
| | - Mohamed Fawzi Kabil
- Nanomedicine Research Labs, Center for Materials Science, Zewail City of Science and Technology, Giza, Egypt
| | - Ibrahim M El-Sherbiny
- Nanomedicine Research Labs, Center for Materials Science, Zewail City of Science and Technology, Giza, Egypt
| | - Mohamed F Salama
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Mansoura University, Egypt
| | - Gehad El-Sayed
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Mansoura University, Egypt
| | - El-Said El-Sherbini
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Mansoura University, Egypt
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Liu X, Pan B, Wang X, Xu J, Wang X, Song Z, Zhang E, Wang F, Wang W. Ischemia/reperfusion-activated ferroptosis in the early stage triggers excessive inflammation to aggregate lung injury in rats. Front Med (Lausanne) 2023; 10:1181286. [PMID: 37425328 PMCID: PMC10327590 DOI: 10.3389/fmed.2023.1181286] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 06/05/2023] [Indexed: 07/11/2023] Open
Abstract
Objective Lung ischemia/reperfusion injury (LIRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. Ferroptosis and inflammation are involved in the pathogenesis of LIRI according to the results of several studies on animal models. However, the interactive mechanisms between ferroptosis and inflammation contributing to LIRI remain unclear. Methods HE staining and indicators of oxidative stress were used to evaluated the lung injury. The reactive oxygen species (ROS) level was examined by DHE staining. The quantitative Real-time PCR (qRT-PCR) and western blot analysis were employed to detect the level of inflammation and ferroptosis, and deferoxamine (DFO) was used to assess the importance of ferroptosis in LIRI and its effect on inflammation. Results In the present study, the link of ferroptosis with inflammation was evaluated at reperfusion 30-, 60- and 180-minute time points, respectively. As the results at reperfusion 30-minute point shown, the pro-ferroptotic indicators, especially cyclooxygenase (COX)-2 and acyl-CoA synthetase long-chain family member 4 (ACSL4), were upregulated while the anti-ferroptotic factors glutathione peroxidase 4 (GPX4), cystine-glumate antiporter (XCT) and ferritin heavy chain (FTH1) were downregulated. Meanwhile, the increased level of interleukin (IL)-6, tumor necrosis factor alpha (TNF-α) and IL-1β were observed beginning at reperfusion 60-minute point but mostly activated at reperfusion 180-minute point. Furthermore, deferoxamine (DFO) was employed to block ferroptosis, which can alleviate lung injury. Expectedly, the survival rate of rats was increased and the lung injury was mitigated containing the improvement of type II alveolar cells ultrastructure and ROS production. In addition, at the reperfusion 180-minute point, the inflammation was observed to be dramatically inhibited after DFO administration as verified by IL-6, TNF-α and IL-1β detection. Conclusion These findings suggest that ischemia/reperfusion-activated ferroptosis plays an important role as the trigger for inflammation to further deteriorate lung damages. Inhibiting ferroptosis may have therapeutic potential for LIRI in clinical practice.
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Affiliation(s)
- Xiujie Liu
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China
- Institute of Ischemia/Reperfusion Injury, Wenzhou Medical University, Wenzhou, China
| | - Binhui Pan
- Nephrology Department, Wenzhou Central Hospital, Wenzhou, China
| | - Xiaoting Wang
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China
- Institute of Ischemia/Reperfusion Injury, Wenzhou Medical University, Wenzhou, China
| | - Junpeng Xu
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China
- Institute of Ischemia/Reperfusion Injury, Wenzhou Medical University, Wenzhou, China
| | - Xinyu Wang
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China
- Institute of Ischemia/Reperfusion Injury, Wenzhou Medical University, Wenzhou, China
| | - Zhengyang Song
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China
- Institute of Ischemia/Reperfusion Injury, Wenzhou Medical University, Wenzhou, China
| | - Eryao Zhang
- Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Fangyan Wang
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China
- Institute of Ischemia/Reperfusion Injury, Wenzhou Medical University, Wenzhou, China
| | - Wantie Wang
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China
- Institute of Ischemia/Reperfusion Injury, Wenzhou Medical University, Wenzhou, China
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Li M, Li M, Hou Y, HE H, Jiang R, Wang C, Sun S. Ferroptosis triggers airway inflammation in asthma. Ther Adv Respir Dis 2023; 17:17534666231208628. [PMID: 37947059 PMCID: PMC10638875 DOI: 10.1177/17534666231208628] [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: 01/14/2023] [Accepted: 09/29/2023] [Indexed: 11/12/2023] Open
Abstract
Ferroptosis is a regulatory cell death characterized by intracellular iron accumulation and lipid peroxidation that leads to oxidative stress. Many signaling pathways such as iron metabolism, lipid metabolism, and amino acid metabolism precisely regulate the process of ferroptosis. Ferroptosis is involved in a variety of lung diseases, such as acute lung injury, chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis. Increasing studies suggest that ferroptosis is involved in the development of asthma. Ferroptosis plays an important role in asthma. Iron metabolism disorders, lipid peroxidation, amino acid metabolism disorders lead to the occurrence of ferroptosis in airway epithelial cells, and then aggravate clinical symptoms in asthmatic patients. Moreover, several regulators of ferroptosis are involved in the pathogenesis of asthma, such as Nrf2, heme oxygenase-1, mevalonate pathway, and ferroptosis inhibitor protein 1. Importantly, ferroptosis inhibitors improve asthma. Thus, the pathogenesis of ferroptosis and its contribution to the pathogenesis of asthma help us better understand the occurrence and development of asthma, and provide new directions in asthma treatment. This article aimed to review the role and mechanism of ferroptosis in asthma, describing the relationship between ferroptosis and asthma based on signaling pathways and related regulatory factors. At the same time, we summarized current observations of ferroptosis in eosinophils, airway epithelial cells, and airway smooth muscle cells in asthmatic patients.
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Affiliation(s)
- Minming Li
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
- Pediatric Medicine Class One, Kunming Medical University, Kunming, China
| | - Min Li
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Yunjiao Hou
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Huilin HE
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Ruonan Jiang
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
- Pediatric Medicine Class One, Kunming Medical University, Kunming, China
| | - Chu Wang
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Shibo Sun
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, No.295, Xichang Road, Wuhua District, Kunming 650032, China
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Mantelou AG, Barbouti A, Goussia A, Zacharioudaki A, Papoudou-Bai A, Vlachou C, Kokkoris S, Papalois A, Galaris D, Glantzounis GK. Combined administration of membrane-permeable and impermeable iron-chelating drugs attenuates ischemia/reperfusion-induced hepatic injury. Free Radic Biol Med 2022; 193:227-237. [PMID: 36243210 DOI: 10.1016/j.freeradbiomed.2022.10.266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND The underlying pathophysiological mechanisms of hepatic ischemia-reperfusion (I/R) injury have not been completely elucidated. However, it is well known that oxidative stress, caused by a burst of reactive oxygen species (ROS) production during the reperfusion phase, plays a crucial role. A growing body of evidence indicates that the intracellular availability of free iron represents a requirement for ROS-induced adverse effects, as iron catalyzes the generation of highly reactive free radicals. The aim of this study was to examine whether a combination of iron chelators with varying lipophilicity could offer enhanced protection against I/R by diminishing the conversion of weak oxidants, like H2O2, to extremely reactive ones such as hydroxyl radicals (HO.). METHODS HepG2 cells (hepatocellular carcinoma cell line) were exposed to oxidative stress conditions after pre-treatment with the iron chelators desferrioxamine (DFO) and deferiprone (DFP) alone or in combination. Labile iron pool was estimated using the calcein-acetoxymethyl ester (calcein-AM) method and DNA damage with the comet assay. We subsequently used a rabbit model (male New Zealand white rabbits) of hepatic I/R-induced injury to investigate, by measuring biochemical (ALT, ALT, ALP, γGT) and histological parameters, whether this may be true for in vivo conditions. RESULTS The combination of a membrane-permeable iron chelator (DFP) with a strong membrane-impermeable one (DFO) raises the level of protection in both hepatic cell lines exposed to oxidative stress conditions and hepatic I/R rabbit model. CONCLUSIONS Our results show that combinations of iron chelators with selected lipophilicity and iron-binding properties may represent a valuable strategy to protect against tissue damage during reperfusion after a period of ischemia.
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Affiliation(s)
- Athina G Mantelou
- HPB Unit, Department of Surgery, University Hospital of Ioannina and Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 45110, Greece
| | - Alexandra Barbouti
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 45110, Greece
| | - Anna Goussia
- Department of Pathology, University Hospital of Ioannina and Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 45110, Greece
| | | | - Alexandra Papoudou-Bai
- Department of Pathology, University Hospital of Ioannina and Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 45110, Greece
| | - Chara Vlachou
- Laboratory of Biological Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 45110, Greece
| | - Stelios Kokkoris
- First Department of Critical Care, School of Medicine, National and Kapodistrian University of Athens, Athens, 10676, Greece
| | - Apostolos Papalois
- Experimental, Educational and Research Center ELPEN, Athens, 19009, Greece; European University of Cyprus, School of Medicine, Nicosia, 2404, Cyprus
| | - Dimitrios Galaris
- Laboratory of Biological Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 45110, Greece
| | - Georgios K Glantzounis
- HPB Unit, Department of Surgery, University Hospital of Ioannina and Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, 45110, Greece.
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Zhang C, Fang Z, Wang K, Wang J, Wan X. Role of iron in the treatment of sepsis. Biointerphases 2022; 19:060801. [PMID: 39540794 DOI: 10.1116/6.0003879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024] Open
Abstract
Iron is an important microelement in human and microbial life activities. During the pathophysiological process of sepsis, iron metabolism changes and the body undergoes a series of changes to fight microbial infection. Meanwhile, alterations in iron metabolism during sepsis lead to the development of some diseases, such as transfusion-induced siderosis and anemia. In recent years, several studies have demonstrated the use of iron-chelating agents to fight microbial infections, and new antimicrobial agents have been developed using "Trojan horse" and siderophores immunity. In addition, the use of iron-based nanomaterials as drug delivery systems for gene delivery may be applied to the treatment of sepsis in the future. In this review, we describe the pathophysiological changes in the development and course of sepsis, focusing on the potential of iron in the treatment of sepsis.
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Affiliation(s)
- Chenyang Zhang
- Department of Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116021, China
| | - Zhiyao Fang
- Department of Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116021, China
| | - Kaixuan Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116021, China
| | - Jia Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116021, China
| | - Xianyao Wan
- Department of Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116021, China
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Platt E, Klootwijk E, Salama A, Davidson B, Robertson F. Literature review of the mechanisms of acute kidney injury secondary to acute liver injury. World J Nephrol 2022; 11:13-29. [PMID: 35117976 PMCID: PMC8790308 DOI: 10.5527/wjn.v11.i1.13] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/12/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
People exposed to liver ischaemia reperfusion (IR) injury often develop acute kidney injury and the combination is associated with significant morbidity and mortality. Molecular mediators released by the liver in response to IR injury are the likely cause of acute kidney injury (AKI) in this setting, but the mediators have not yet been identified. Identifying the mechanism of injury will allow the identification of therapeutic targets which may modulate both liver IR injury and AKI following liver IR injury.
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Affiliation(s)
- Esther Platt
- Division of Surgery and Interventional Science, University College London, London NW3 2QG, United Kingdom
| | - Enriko Klootwijk
- Department of Renal Medicine, University College London, London NW3 2PF, United Kingdom
| | - Alan Salama
- Department of Renal Medicine, University College London, London NW3 2PF, United Kingdom
| | - Brian Davidson
- Division of Surgery and Interventional Science, University College London, London NW3 2QG, United Kingdom
| | - Francis Robertson
- Division of Surgery and Interventional Science, University College London, London NW3 2QG, United Kingdom
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Li Q, Cui Y, Xu B, Wang Y, Lv F, Li Z, Li H, Chen X, Peng X, Chen Y, Wu E, Qu D, Jian Y, Si H. Main active components of Jiawei Gegen Qinlian decoction protects against ulcerative colitis under different dietary environments in a gut microbiota-dependent manner. Pharmacol Res 2021; 170:105694. [PMID: 34087350 DOI: 10.1016/j.phrs.2021.105694] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/20/2021] [Accepted: 05/23/2021] [Indexed: 02/07/2023]
Abstract
As an effective drug against acute enteritis diarrhea, Gegen Qinlian decoction (GQD) has a history of 2000 years. However, the potential molecular mechanism through which GQD could protect intestinal barrier from ulcerative colitis (UC) still remains undefined. As an important part of the homeostasis of the colon, gut microbiota is closely related to the dynamic evolution of the surrounding environment and the adjustment of dietary structure. At present, the effectiveness and mechanism of Jiawei Gegen Qinlian decoction against UC in different dietary environments are not clear. Here, the main active components of Jiawei Gegen Qinlian Decoction (PBM), were selected to construct a reasonable and effective compound scheme. We adopted "5% dextran sulfate sodium (DSS)" and "high temperature and humidity + high sugar and high fat + alcohol + 5%DSS" to induce UC rat models in general environment and UC rat models in Lingnan area, respectively. Then, we examined the therapeutic effects of PBM (89.96 mg/kg and 179.92 mg/kg) on two kinds of UC rats. The role of gut microbiota in the anti-UC effect of PBM was identified by intestinal flora consumption and fecal microbiota transplantation (FMT) experiments. Subsequently, we monitored the alterations of gut microbiota and fecal metabolism in the rat colon by 16Sr DNA technique and targeted metabonomics, respectively. The colon inflammation of the PBM-treated and the FMT-treated rats both showed significant relief, as evidenced by a reduction in body weight loss, bloody stool, diarrhea, disease activity index (DAI) score, shortening of colon length as well as decreased colon histology damage. Interestingly enough, the depletion of intestinal flora took away the protective effect of PBM, confirming the importance of intestinal flora in the anti-UC effect of PBM. Then our findings suggested that PBM could not only regulate the gut microbiota by increasing Akkermansia and Romboutsia but also decrease Escherichia-Shigella. More importantly, PBM could increase the production of propionate and total short-chain fatty acids (SCFAs) in colitis rats, regulate medium and long chain fatty acids (M-LCFAs), maintain bile acids (BAs) homeostasis, and regulate amino acids (AAs) metabolism. The transformation of intestinal environment might be related to the upregulation of anti-inflammation, anti-oxidation and tight junction protein expression in colonic mucosa. In summary, PBM showed potential for anti-UC activity through gut microbiota dependence and was expected to be a complementary and alternative medicine herb therapy.
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Affiliation(s)
- Qinmei Li
- College of Animal Sciences and Technology, Guangxi University, Nanning, China.
| | - Yao Cui
- College of Animal Sciences and Technology, Guangxi University, Nanning, China.
| | - Baichang Xu
- College of Animal Sciences and Technology, Guangxi University, Nanning, China.
| | - Yuhan Wang
- College of Animal Sciences and Technology, Guangxi University, Nanning, China.
| | - Feifei Lv
- College of Animal Sciences and Technology, Guangxi University, Nanning, China.
| | - Zheng Li
- College of Animal Sciences and Technology, Guangxi University, Nanning, China.
| | - Huan Li
- College of Animal Sciences and Technology, Guangxi University, Nanning, China.
| | - Xiaogang Chen
- College of Animal Sciences and Technology, Guangxi University, Nanning, China.
| | - Xiaomin Peng
- College of Animal Sciences and Technology, Guangxi University, Nanning, China.
| | - Yating Chen
- College of Animal Sciences and Technology, Guangxi University, Nanning, China.
| | - Enyun Wu
- College of Animal Sciences and Technology, Guangxi University, Nanning, China.
| | - Dongshuai Qu
- College of Animal Sciences and Technology, Guangxi University, Nanning, China.
| | - Yichen Jian
- College of Animal Sciences and Technology, Guangxi University, Nanning, China.
| | - Hongbin Si
- College of Animal Sciences and Technology, Guangxi University, Nanning, China.
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11
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The Cross-Link between Ferroptosis and Kidney Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6654887. [PMID: 34007403 PMCID: PMC8110383 DOI: 10.1155/2021/6654887] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 03/31/2021] [Accepted: 04/15/2021] [Indexed: 02/08/2023]
Abstract
Acute and chronic kidney injuries result from structural dysfunction and metabolic disorders of the kidney in various etiologies, which significantly affect human survival and social wealth. Nephropathies are often accompanied by various forms of cell death and complex microenvironments. In recent decades, the study of kidney diseases and the traditional forms of cell death have improved. Nontraditional forms of cell death, represented by ferroptosis and necroptosis, have been discovered in the field of kidney diseases, which have reshuffled the role of traditional cell death in nephropathies. Although interactions between ferroptosis and acute kidney injury (AKI) have been continuously explored, studies on ferroptosis and chronic kidney disease (CKD) remain limited. Here, we have reviewed the therapeutic significance of ferroptosis in AKI and anticipated the curative potential of ferroptosis for CKD in the hope of providing insights into ferroptosis and CKD.
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12
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Liu Q, Wu J, Zhang X, Wu X, Zhao Y, Ren J. Iron homeostasis and disorders revisited in the sepsis. Free Radic Biol Med 2021; 165:1-13. [PMID: 33486088 DOI: 10.1016/j.freeradbiomed.2021.01.025] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/31/2020] [Accepted: 01/11/2021] [Indexed: 12/26/2022]
Abstract
Sepsis is a life-threatening condition caused by a dysregulated host-response to inflammation, although it currently lacks a fully elucidated pathobiology. Iron is a crucial trace element that is essential for fundamental processes in both humans and bacteria. During sepsis, iron metabolism is altered, including increased iron transport and uptake into cells and decreased iron export. The intracellular sequestration of iron limits its availability to circulating pathogens, which serves as a conservative strategy against the pathogens. Although iron retention has been showed to have protective protect effects, an increase in labile iron may cause oxidative injury and cell death (e.g., pyroptosis, ferroptosis) as the condition progresses. Moreover, iron disorders are substantial and correlate with the severity of sepsis. This also suggests that iron may be useful as a diagnostic marker for evaluating the severity and predicting the outcome of the disease. Further knowledge about these disorders could help in evaluating how drugs targeting iron homeostasis can be optimally applied to improve the treatment of patients with sepsis. Here, we present a comprehensive review of recent advances in the understanding of iron metabolism, focusing on the regulatory mechanisms and iron-mediated injury in sepsis.
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Affiliation(s)
- Qinjie Liu
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China.
| | - Jie Wu
- Department of General Surgery, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210002, PR China.
| | - Xufei Zhang
- Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, PR China.
| | - Xiuwen Wu
- Research Institute of General Surgery, Jinling Hospital, Nanjing, 210002, PR China.
| | - Yun Zhao
- Department of General Surgery, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210002, PR China.
| | - Jianan Ren
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China; Department of General Surgery, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210002, PR China; Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, PR China.
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13
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Veltman M, De Sanctis JB, Stolarczyk M, Klymiuk N, Bähr A, Brouwer RW, Oole E, Shah J, Ozdian T, Liao J, Martini C, Radzioch D, Hanrahan JW, Scholte BJ. CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells. Front Physiol 2021; 12:619442. [PMID: 33613309 PMCID: PMC7891400 DOI: 10.3389/fphys.2021.619442] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 01/07/2021] [Indexed: 12/20/2022] Open
Abstract
A deficiency in cystic fibrosis transmembrane conductance regulator (CFTR) function in CF leads to chronic lung disease. CF is associated with abnormalities in fatty acids, ceramides, and cholesterol, their relationship with CF lung pathology is not completely understood. Therefore, we examined the impact of CFTR deficiency on lipid metabolism and pro-inflammatory signaling in airway epithelium using mass spectrometric, protein array. We observed a striking imbalance in fatty acid and ceramide metabolism, associated with chronic oxidative stress under basal conditions in CF mouse lung and well-differentiated bronchial epithelial cell cultures of CFTR knock out pig and CF patients. Cell-autonomous features of all three CF models included high ratios of ω-6- to ω-3-polyunsaturated fatty acids and of long- to very long-chain ceramide species (LCC/VLCC), reduced levels of total ceramides and ceramide precursors. In addition to the retinoic acid analog fenretinide, the anti-oxidants glutathione (GSH) and deferoxamine partially corrected the lipid profile indicating that oxidative stress may promote the lipid abnormalities. CFTR-targeted modulators reduced the lipid imbalance and oxidative stress, confirming the CFTR dependence of lipid ratios. However, despite functional correction of CF cells up to 60% of non-CF in Ussing chamber experiments, a 72-h triple compound treatment (elexacaftor/tezacaftor/ivacaftor surrogate) did not completely normalize lipid imbalance or oxidative stress. Protein array analysis revealed differential expression and shedding of cytokines and growth factors from CF epithelial cells compared to non-CF cells, consistent with sterile inflammation and tissue remodeling under basal conditions, including enhanced secretion of the neutrophil activator CXCL5, and the T-cell activator CCL17. However, treatment with antioxidants or CFTR modulators that mimic the approved combination therapies, ivacaftor/lumacaftor and ivacaftor/tezacaftor/elexacaftor, did not effectively suppress the inflammatory phenotype. We propose that CFTR deficiency causes oxidative stress in CF airway epithelium, affecting multiple bioactive lipid metabolic pathways, which likely play a role in CF lung disease progression. A combination of anti-oxidant, anti-inflammatory and CFTR targeted therapeutics may be required for full correction of the CF phenotype.
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Affiliation(s)
- Mieke Veltman
- Cell Biology Department, Erasmus Medical Center, Rotterdam, Netherlands.,Pediatric Pulmonology, Sophia Children's Hospital, Erasmus Medical Center, Rotterdam, Netherlands
| | - Juan B De Sanctis
- Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacký University, Olomouc, Czechia
| | - Marta Stolarczyk
- Cell Biology Department, Erasmus Medical Center, Rotterdam, Netherlands
| | - Nikolai Klymiuk
- Large Animal Models for Cardiovascular Research, TU Munich, Munich, Germany.,Center for Innovative Medical Models, LMU Munich, Munich, Germany
| | - Andrea Bähr
- Large Animal Models for Cardiovascular Research, TU Munich, Munich, Germany.,Center for Innovative Medical Models, LMU Munich, Munich, Germany
| | - Rutger W Brouwer
- Cell Biology Department, Erasmus Medical Center, Rotterdam, Netherlands.,Center for Biomics, Erasmus Medical Center, Rotterdam, Netherlands
| | - Edwin Oole
- Cell Biology Department, Erasmus Medical Center, Rotterdam, Netherlands.,Center for Biomics, Erasmus Medical Center, Rotterdam, Netherlands
| | - Juhi Shah
- Department of Medicine, The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada
| | - Tomas Ozdian
- Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacký University, Olomouc, Czechia
| | - Jie Liao
- Department of Physiology, CF Translational Research Centre, McGill University, Montreal, QC, Canada
| | - Carolina Martini
- Department of Physiology, CF Translational Research Centre, McGill University, Montreal, QC, Canada
| | - Danuta Radzioch
- Department of Medicine, The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada
| | - John W Hanrahan
- Department of Medicine, The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada.,Department of Physiology, CF Translational Research Centre, McGill University, Montreal, QC, Canada
| | - Bob J Scholte
- Cell Biology Department, Erasmus Medical Center, Rotterdam, Netherlands.,Pediatric Pulmonology, Sophia Children's Hospital, Erasmus Medical Center, Rotterdam, Netherlands
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14
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Lehmann C, Aali M, Zhou J, Holbein B. Comparison of Treatment Effects of Different Iron Chelators in Experimental Models of Sepsis. Life (Basel) 2021; 11:life11010057. [PMID: 33466819 PMCID: PMC7830599 DOI: 10.3390/life11010057] [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: 12/28/2020] [Revised: 01/09/2021] [Accepted: 01/11/2021] [Indexed: 01/19/2023] Open
Abstract
Growing evidence indicates that dysregulated iron metabolism with altered and excess iron availability in some body compartments plays a significant role in the course of infection and sepsis in humans. Given that all bacterial pathogens require iron for growth, that iron withdrawal is a normal component of innate host defenses and that bacterial pathogens have acquired increasing levels of antibiotic resistance, targeting infection and sepsis through use of appropriate iron chelators has potential to provide new therapeutics. We have directly compared the effects of three Food and Drug Administration (FDA)-approved chelators (deferoxamine—DFO; deferiprone—DFP; and deferasirox—DFX), as were developed for treating hematological iron overload conditions, to DIBI, a novel purpose-designed, anti-infective and anti-inflammatory water-soluble hydroxypyridinone containing iron-selective copolymers. Two murine sepsis models, endotoxemia and polymicrobial abdominal sepsis, were utilized to help differentiate anti-inflammatory versus anti-infective activities of the chelators. Leukocyte adhesion, as measured by intravital microscopy, was observed in both models, with DIBI providing the most effective reduction and DFX the poorest. Inflammation in the abdominal sepsis model, assessed by cytokine measurements, indicated exacerbation by DFX and DFO for plasma Interleukin (IL)-6 and reductions to near-control levels for DIBI and DFP. Peritoneal infection burden was reduced 10-fold by DIBI while DFX and DFP provided no reductions. Overall, the results, together with those from other studies, revealed serious limitations for each of the three hematological chelators, i.e., as potentially repurposed for treating infection/sepsis. In contrast, DIBI provided therapeutic benefits, consistent with various in vitro and in vivo results from other studies, supporting the potential for its use in treating sepsis.
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Affiliation(s)
- Christian Lehmann
- Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada;
- Correspondence:
| | - Maral Aali
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS B3H 4R2, Canada;
| | - Juan Zhou
- Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada;
| | - Bruce Holbein
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada;
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15
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Laws M, Surani YM, Hasan MM, Chen Y, Jin P, Al-Adhami T, Chowdhury M, Imran A, Psaltis I, Jamshidi S, Nahar KS, Rahman KM. Current Trends and Future Approaches in Small-Molecule Therapeutics for COVID-19. Curr Med Chem 2021; 28:3803-3824. [PMID: 32693756 PMCID: PMC7611096 DOI: 10.2174/0929867327666200721161840] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/29/2020] [Accepted: 06/30/2020] [Indexed: 02/06/2023]
Abstract
The novel coronavirus (SARS-CoV-2) pandemic has created a global public health emergency. The pandemic is causing substantial morbidity, mortality and significant economic loss. Currently, no approved treatments for COVID-19 are available, and it is likely to takes at least 12-18 months to develop a new vaccine. Therefore, there is an urgent need to find new therapeutics that can be progressed to clinical development as soon as possible. Repurposing regulatory agency-approved drugs and experimental drugs with known safety profiles can provide important repositories of compounds that can be fast-tracked to clinical development. Globally, over 500 clinical trials involving repurposed drugs have been registered, and over 150 have been initiated, including some backed by the World Health Organisation (WHO). This review is intended as a guide to research into small-molecule therapies to treat COVID-19; it discusses the SARS-CoV-2 infection cycle and identifies promising viral therapeutic targets, reports on a number of promising pre-approved small-molecule drugs with reference to over 150 clinical trials worldwide, and offers a perspective on the future of the field.
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Affiliation(s)
- Mark Laws
- Institute of Pharmaceutical Sciences, School of Cancer and Pharmaceutical Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Yasmin M. Surani
- Institute of Pharmaceutical Sciences, School of Cancer and Pharmaceutical Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Md. Mahbub Hasan
- Institute of Pharmaceutical Sciences, School of Cancer and Pharmaceutical Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Yiyuan Chen
- Institute of Pharmaceutical Sciences, School of Cancer and Pharmaceutical Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Peiqin Jin
- Institute of Pharmaceutical Sciences, School of Cancer and Pharmaceutical Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Taha Al-Adhami
- Institute of Pharmaceutical Sciences, School of Cancer and Pharmaceutical Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Madiha Chowdhury
- Institute of Pharmaceutical Sciences, School of Cancer and Pharmaceutical Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Aqeel Imran
- Institute of Pharmaceutical Sciences, School of Cancer and Pharmaceutical Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Ioannis Psaltis
- Institute of Pharmaceutical Sciences, School of Cancer and Pharmaceutical Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Shirin Jamshidi
- Institute of Pharmaceutical Sciences, School of Cancer and Pharmaceutical Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Kazi S. Nahar
- Institute of Pharmaceutical Sciences, School of Cancer and Pharmaceutical Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Khondaker Miraz Rahman
- Institute of Pharmaceutical Sciences, School of Cancer and Pharmaceutical Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
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16
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Vlahakos VD, Marathias KP, Arkadopoulos N, Vlahakos DV. Hyperferritinemia in patients with COVID-19: An opportunity for iron chelation? Artif Organs 2020; 45:163-167. [PMID: 32882061 DOI: 10.1111/aor.13812] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 08/21/2020] [Accepted: 08/24/2020] [Indexed: 12/18/2022]
Abstract
Studies from China on COVID-19 revealed that nonsurvivors had cytokine storm with high IL-6 and hyperferritinemia. Iron liberated from necrotic cells may catalyze free radical production and amplify lipid peroxidation causing membrane dysfunction and multiorgan failure. Consequently, iron chelators have been successfully utilized in various experimental and clinical models of cytokine storm and multiorgan damage, such as in ischemia-reperfusion injury, sepsis, and infections. Since viral replication may be influenced by iron accumulation, iron chelation has been proven beneficial in a variety of viral infections, such as HIV-1, hepatitis B virus, Mengovirus, Marburg hemorrhagic fever, Enterovirus 71, and West Nile virus. In this commentary, we elaborate on the idea of considering iron chelation as a therapeutic modality in patients with severe COVID-19 infection. For critically ill patients in the ICU, intravenous deferoxamine would provide sufficient and rapid iron chelation to ameliorate cytokine storm, whereas in less severe cases an oral chelator could prevent the development of excessive inflammatory response.
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Affiliation(s)
- Vassilios D Vlahakos
- Department of Pulmonary and Critical Care Services, Evangelismos Hospital, Athens, Greece
| | | | - Nikolaos Arkadopoulos
- 4th Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Demetrios V Vlahakos
- 2nd Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
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17
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Gazeri A, Aminzadeh A. Protective effects of deferoxamine on lead-induced cardiotoxicity in rats. Toxicol Ind Health 2020; 36:800-806. [PMID: 32812511 DOI: 10.1177/0748233720947231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Because of the numerous industrial applications of lead (Pb), Pb poisoning is an important public health threat in the world particularly in developing and industrialized countries. Oxidative stress is one of the important mechanisms of Pb-mediated toxicity. Deferoxamine (DFO) is an iron chelating agent that has recently shown antioxidant and antiapoptotic effects. This study investigated the protective capacity of DFO against Pb-induced cardiotoxicity in rats. We used five groups in this study: control, DFO (300 mg/kg), Pb (50 mg/kg), DFO (150 mg/kg) + Pb, DFO (300 mg/kg) + Pb. DFO was administered intraperitoneally 30 min before intraperitoneal injection of Pb for 5 days. After drug treatment, the levels of lactate dehydrogenase (LDH), lipid peroxidation (LPO), glutathione (GSH), and antioxidant enzymes were measured in serum and heart samples. The results showed that pretreatment with DFO reduced Pb-induced oxidative stress markers in serum and cardiac tissues. We found that LDH and LPO levels were significantly increased in Pb-treated rats and decreased with DFO pre-administration. Furthermore, the decreased activities of total antioxidant capacity, and GSH were observed after Pb treatment. However, DFO administration effectively prevented the Pb-induced alterations of these antioxidant enzymes activities. In conclusion, the results presented here indicate that DFO has protective effects in Pb-induced cardiotoxicity in rats, probably due to its antioxidant action and inhibition of oxidative stress.
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Affiliation(s)
- Alireza Gazeri
- Student Research Committee, Faculty of Pharmacy, 48463Kerman University of Medical Sciences, Kerman, Iran.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, 48463Kerman University of Medical Sciences, Kerman, Iran
| | - Azadeh Aminzadeh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, 48463Kerman University of Medical Sciences, Kerman, Iran.,Pharmaceutics Research Center, Institute of Neuropharmacology, 48463Kerman University of Medical Sciences, Kerman, Iran
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18
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Wang XX, Sha XL, Li YL, Li CL, Chen SH, Wang JJ, Xia Z. Lung injury induced by short-term mechanical ventilation with hyperoxia and its mitigation by deferoxamine in rats. BMC Anesthesiol 2020; 20:188. [PMID: 32738874 PMCID: PMC7395352 DOI: 10.1186/s12871-020-01089-5] [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: 01/14/2020] [Accepted: 07/09/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Long-term mechanical ventilation with hyperoxia can induce lung injury. General anesthesia is associated with a very high incidence of hyperoxaemia, despite it usually lasts for a relatively short period of time. It remains unclear whether short-term mechanical ventilation with hyperoxia has an adverse impact on or cause injury to the lungs. The present study aimed to assess whether short-term mechanical ventilation with hyperoxia may cause lung injury in rats and whether deferoxamine (DFO), a ferrous ion chelator, could mitigate such injury to the lungs and explore the possible mechanism. METHODS Twenty-four SD rats were randomly divided into 3 groups (n = 8/group): mechanical ventilated with normoxia group (MV group, FiO2 = 21%), with hyperoxia group (HMV group, FiO2 = 90%), or with hyperoxia + DFO group (HMV + DFO group, FiO2 = 90%). Mechanical ventilation under different oxygen concentrations was given for 4 h, and ECG was monitored. The HMV + DFO group received continuous intravenous infusion of DFO at 50 mg•kg- 1•h- 1, while the MV and HMV groups received an equal volume of normal saline. Carotid artery cannulation was carried out to monitor the blood gas parameters under mechanical ventilation for 2 and 4 h, respectively, and the PaO2/FiO2 ratio was calculated. After 4 h ventilation, the right anterior lobe of the lung and bronchoalveolar lavage fluid from the right lung was sampled for pathological and biochemical assays. RESULTS PaO2 in the HMV and HMV + DFO groups were significantly higher, but the PaO2/FiO2 ratio were significantly lower than those of the MV group (all p < 0.01), while PaO2 and PaO2/FiO2 ratio between HMV + DFO and HMV groups did not differ significantly. The lung pathological scores and the wet-to-dry weight ratio (W/D) in the HMV and HMV + DFO groups were significantly higher than those of the MV group, but the lung pathological score and the W/D ratio were reduced by DFO (p < 0.05, HMV + DFO vs. HMV). Biochemically, HMV resulted in significant reductions in Surfactant protein C (SP-C), Surfactant protein D (SP-D), and Glutathion reductase (GR) levels and elevation of xanthine oxidase (XOD) in both the Bronchoalveolar lavage fluid and the lung tissue homogenate, and all these changes were prevented or significantly reverted by DFO. CONCLUSIONS Mechanical ventilation with hyperoxia for 4 h induced oxidative injury of the lungs, accompanied by a dramatic reduction in the concentrations of SP-C and SP-D. DFO could mitigate such injury by lowering XOD activity and elevating GR activity.
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Affiliation(s)
- Xiao-Xia Wang
- Department of Anesthesiology, First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Xiao-Lan Sha
- Department of Anesthesiology, First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Yu-Lan Li
- Department of Anesthesiology, First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China.
| | - Chun-Lan Li
- Department of Anesthesiology, First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Su-Heng Chen
- Department of Anesthesiology, First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Jing-Jing Wang
- Department of Anesthesiology, First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China
| | - Zhengyuan Xia
- Department of Anesthesiology, The University of Hong Kong, Hong Kong, 999077, People's Republic of China
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524000, People's Republic of China
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19
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Rodrigues de Morais T, Gambero A. Iron chelators in obesity therapy – Old drugs from a new perspective? Eur J Pharmacol 2019; 861:172614. [DOI: 10.1016/j.ejphar.2019.172614] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 07/16/2019] [Accepted: 08/14/2019] [Indexed: 02/08/2023]
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20
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Ahn YH, Seok PR, Oh SJ, Choi JW, Shin JH. A Study on the Protective Effect of Antioxidants on Damage Induced by Liver Ischemia/Repefusion in a Rat Model. KOREAN JOURNAL OF CLINICAL LABORATORY SCIENCE 2019. [DOI: 10.15324/kjcls.2019.51.3.370] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Affiliation(s)
- Yong Ho Ahn
- Department of Clinical Laboratory Science, Dongnam Health University, Suwon, Korea
| | - Pu Reum Seok
- Department of Biomedical Laboratory Science, Eulji University, Sungnam, Korea
| | - Su Jin Oh
- Department of Biomedical Laboratory Science, Eulji University, Sungnam, Korea
| | - Jin Woo Choi
- Department of Biomedical Laboratory Science, Eulji University, Sungnam, Korea
| | - Jae-Ho Shin
- Department of Biomedical Laboratory Science, Eulji University, Sungnam, Korea
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Sharma S, Leaf DE. Iron Chelation as a Potential Therapeutic Strategy for AKI Prevention. J Am Soc Nephrol 2019; 30:2060-2071. [PMID: 31554656 DOI: 10.1681/asn.2019060595] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AKI remains a major public health concern. Despite years of investigation, no intervention has been demonstrated to reliably prevent AKI in humans. Thus, development of novel therapeutic targets is urgently needed. An important role of iron in the pathophysiology of AKI has been recognized for over three decades. When present in excess and in nonphysiologic labile forms, iron is toxic to the kidneys and multiple other organs, whereas iron chelation is protective across a broad spectrum of insults. In humans, small studies have investigated iron chelation as a novel therapeutic strategy for prevention of AKI and extrarenal acute organ injury, and have demonstrated encouraging initial results. In this review, we examine the existing data on iron chelation for AKI prevention in both animal models and human studies. We discuss practical considerations for future clinical trials of AKI prevention using iron chelators, including selection of the ideal clinical setting, patient population, iron chelating agent, and dosing regimen. Finally, we compare the key differences among the currently available iron chelators, including pharmacokinetics, routes of administration, and adverse effects.
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Affiliation(s)
- Shreyak Sharma
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - David E Leaf
- Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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22
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Influence of Hydrogen-rich Saline on Hepatocyte Autophagy During Laparoscopic Liver Ischaemia-reperfusion Combined Resection Injury in Miniature Pigs. J Vet Res 2018; 62:395-403. [PMID: 30584622 PMCID: PMC6295994 DOI: 10.2478/jvetres-2018-0056] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 08/22/2018] [Indexed: 12/26/2022] Open
Abstract
Introduction The purpose of this study was to investigate the protective effect of hydrogen-rich saline (HRS) against liver ischaemia-reperfusion combined resection injury. Material and Methods Eighteen miniature pigs were randomly divided into three groups: a sham operated group (sham group, laparoscopic liver ischaemia-reperfusion combined resection injury group (IRI group), and a hydrogen-rich saline intervention group (IRI + HRS group). Samples of hepatic tissue and serum were collected at the time of reperfusion and then 3 h, 1 d, and 3 d post reperfusion. Liver function, oxidative stress, autophagy-related mRNA genes, and protein expression were evaluated. Changes in cell and tissue ultrastructure were examined by transmission electron microscopy. Results Compared with the sham group, the level of autophagy of hepatocytes increased in the IRI and IRI + HRS groups, corresponding to high oxidative stress and severe liver function injury. Liver function, antioxidant content, autophagy levels, and liver injury were improved after intervention with HRS in the IRI + HRS group compared with the IRI group. Conclusion Intervention with hydrogen-rich saline could exert a protective effect against liver ischaemia-reperfusion combined resection injury through the reduction of oxidative stress and hepatocyte autophagy.
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Sarhan M, Land WG, Tonnus W, Hugo CP, Linkermann A. Origin and Consequences of Necroinflammation. Physiol Rev 2018; 98:727-780. [PMID: 29465288 DOI: 10.1152/physrev.00041.2016] [Citation(s) in RCA: 135] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
When cells undergo necrotic cell death in either physiological or pathophysiological settings in vivo, they release highly immunogenic intracellular molecules and organelles into the interstitium and thereby represent the strongest known trigger of the immune system. With our increasing understanding of necrosis as a regulated and genetically determined process (RN, regulated necrosis), necrosis and necroinflammation can be pharmacologically prevented. This review discusses our current knowledge about signaling pathways of necrotic cell death as the origin of necroinflammation. Multiple pathways of RN such as necroptosis, ferroptosis, and pyroptosis have been evolutionary conserved most likely because of their differences in immunogenicity. As the consequence of necrosis, however, all necrotic cells release damage associated molecular patterns (DAMPs) that have been extensively investigated over the last two decades. Analysis of necroinflammation allows characterizing specific signatures for each particular pathway of cell death. While all RN-pathways share the release of DAMPs in general, most of them actively regulate the immune system by the additional expression and/or maturation of either pro- or anti-inflammatory cytokines/chemokines. In addition, DAMPs have been demonstrated to modulate the process of regeneration. For the purpose of better understanding of necroinflammation, we introduce a novel classification of DAMPs in this review to help detect the relative contribution of each RN-pathway to certain physiological and pathophysiological conditions.
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Affiliation(s)
- Maysa Sarhan
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna , Vienna , Austria ; INSERM UMR_S 1109, Laboratory of Excellence Transplantex, University of Strasbourg , Strasbourg , France ; German Academy of Transplantation Medicine, Munich , Germany ; and Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden , Dresden , Germany
| | - Walter G Land
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna , Vienna , Austria ; INSERM UMR_S 1109, Laboratory of Excellence Transplantex, University of Strasbourg , Strasbourg , France ; German Academy of Transplantation Medicine, Munich , Germany ; and Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden , Dresden , Germany
| | - Wulf Tonnus
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna , Vienna , Austria ; INSERM UMR_S 1109, Laboratory of Excellence Transplantex, University of Strasbourg , Strasbourg , France ; German Academy of Transplantation Medicine, Munich , Germany ; and Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden , Dresden , Germany
| | - Christian P Hugo
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna , Vienna , Austria ; INSERM UMR_S 1109, Laboratory of Excellence Transplantex, University of Strasbourg , Strasbourg , France ; German Academy of Transplantation Medicine, Munich , Germany ; and Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden , Dresden , Germany
| | - Andreas Linkermann
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna , Vienna , Austria ; INSERM UMR_S 1109, Laboratory of Excellence Transplantex, University of Strasbourg , Strasbourg , France ; German Academy of Transplantation Medicine, Munich , Germany ; and Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden , Dresden , Germany
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Iron chelation for the treatment of uveitis. Med Hypotheses 2017; 103:1-4. [DOI: 10.1016/j.mehy.2017.03.029] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 02/04/2017] [Accepted: 03/06/2017] [Indexed: 12/21/2022]
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Xia Y, Farah N, Maxan A, Zhou J, Lehmann C. Therapeutic iron restriction in sepsis. Med Hypotheses 2016; 89:37-9. [PMID: 26968906 DOI: 10.1016/j.mehy.2016.01.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 01/18/2016] [Accepted: 01/30/2016] [Indexed: 01/27/2023]
Abstract
Sepsis represents the systemic immune response to an infection. Mortality of sepsis slightly decreased over the past years, but due to the growing incidence, the absolute number of deaths still increases and belongs to the three most frequent causes of death worldwide. To date, there is no specific treatment for sepsis available yet. Iron is essential to both human beings and microbes and of great significance in many physiological and biochemical processes. Since iron is involved in the bacterial proliferation and immune dysregulation, we hypothesize that restricting host iron levels by application of iron chelators attenuates bacterial growth and improves the detrimental dysregulation of the systemic immune response in sepsis.
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Affiliation(s)
- Yanfang Xia
- School of Basic Medical Sciences, Zhejiang University, Zhejiang, China
| | - Nizam Farah
- Department of Pharmacology, Dalhousie University, Halifax, Canada
| | - Alexander Maxan
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Canada
| | - Juan Zhou
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Canada; Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, Canada
| | - Christian Lehmann
- Department of Pharmacology, Dalhousie University, Halifax, Canada; Department of Microbiology and Immunology, Dalhousie University, Halifax, Canada; Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, Canada; Department of Physiology and Biophysics, Dalhousie University, Halifax, Canada
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Islam S, Jarosch S, Zhou J, Parquet MDC, Toguri JT, Colp P, Holbein BE, Lehmann C. Anti-inflammatory and anti-bacterial effects of iron chelation in experimental sepsis. J Surg Res 2016; 200:266-73. [DOI: 10.1016/j.jss.2015.07.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 06/18/2015] [Accepted: 07/01/2015] [Indexed: 12/01/2022]
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Moraes LHR, de Burgos RR, Macedo AB, de Almeida Hermes T, de Faria FM, Minatel E. Reduction of Oxidative Damage and Inflammatory Response in the Diaphragm Muscle of mdx Mice Using Iron Chelator Deferoxamine. Biol Trace Elem Res 2015; 167:115-20. [PMID: 25762099 DOI: 10.1007/s12011-015-0290-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 02/26/2015] [Indexed: 11/25/2022]
Abstract
Oxidative stress and inflammatory processes strongly contribute to pathogenesis in Duchenne muscular dystrophy (DMD). Based on evidence that excess iron may increase oxidative stress and contribute to the inflammatory response, we investigated whether deferoxamine (DFX), a potent iron chelating agent, reduces oxidative stress and inflammation in the diaphragm (DIA) muscle of mdx mice (an experimental model of DMD). Fourteen-day-old mdx mice received daily intraperitoneal injections of DFX at a dose of 150 mg/kg body weight, diluted in saline, for 14 days. C57BL/10 and control mdx mice received daily intraperitoneal injections of saline only, for 14 days. Grip strength was evaluated as a functional measure, and blood samples were collected for biochemical assessment of muscle fiber degeneration. In addition, the DIA muscle was removed and processed for histopathology and Western blotting analysis. In mdx mice, DFX reduced muscle damage and loss of muscle strength. DFX treatment also resulted in a significant reduction of dystrophic inflammatory processes, as indicated by decreases in the inflammatory area and in NF-κB levels. DFX significantly decreased oxidative damage, as shown by lower levels of 4-hydroxynonenal and a reduction in dihydroethidium staining in the DIA muscle of mdx mice. The results of the present study suggest that DFX may be useful in therapeutic strategies to ameliorate dystrophic muscle pathology, possibly via mechanisms involving oxidative and inflammatory pathways.
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MESH Headings
- Animals
- Blotting, Western
- Body Weight/drug effects
- Deferoxamine/administration & dosage
- Deferoxamine/pharmacology
- Diaphragm/drug effects
- Diaphragm/metabolism
- Female
- Inflammation/metabolism
- Inflammation/prevention & control
- Injections, Intraperitoneal
- Iron Chelating Agents/administration & dosage
- Iron Chelating Agents/pharmacology
- Male
- Mice, Inbred C57BL
- Mice, Inbred mdx
- Muscle Strength/drug effects
- Muscle, Skeletal/drug effects
- Muscle, Skeletal/metabolism
- Muscular Dystrophy, Animal/metabolism
- Muscular Dystrophy, Animal/prevention & control
- Muscular Dystrophy, Duchenne/metabolism
- Muscular Dystrophy, Duchenne/prevention & control
- NF-kappa B/metabolism
- Oxidative Stress/drug effects
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Affiliation(s)
- Luis Henrique Rapucci Moraes
- Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, 13083-970, Brazil
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The utility of iron chelators in the management of inflammatory disorders. Mediators Inflamm 2015; 2015:516740. [PMID: 25878400 PMCID: PMC4386698 DOI: 10.1155/2015/516740] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 09/01/2014] [Accepted: 09/01/2014] [Indexed: 01/19/2023] Open
Abstract
Since iron can contribute to detrimental radical generating processes through the Fenton and Haber-Weiss reactions, it seems to be a reasonable approach to modulate iron-related pathways in inflammation. In the human organism a counterregulatory reduction in iron availability is observed during inflammatory diseases. Under pathological conditions with reduced or increased baseline iron levels different consequences regarding protection or susceptibility to inflammation have to be considered. Given the role of iron in development of inflammatory diseases, pharmaceutical agents targeting this pathway promise to improve the clinical outcome. The objective of this review is to highlight the mechanisms of iron regulation and iron chelation, and to demonstrate the potential impact of this strategy in the management of several acute and chronic inflammatory diseases, including cancer.
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Moraes LHR, Bollineli RC, Mizobuti DS, Silveira LDR, Marques MJ, Minatel E. Effect of N-acetylcysteine plus deferoxamine on oxidative stress and inflammation in dystrophic muscle cells. Redox Rep 2014; 20:109-15. [PMID: 25361473 DOI: 10.1179/1351000214y.0000000112] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
OBJECTIVES Oxidative stress and inflammatory process play an important role in the pathogenesis of Duchenne muscular dystrophy (DMD). We investigated whether deferoxamine (DFX) improves the antioxidant effects of N-acetylcysteine (NAC) on primary cultures of dystrophic muscle cells from mdx mice, the experimental model of DMD. METHODS Primary cultures of skeletal muscle cells from mdx mice were treated with either NAC (10 mM), DFX (5 mM), or NAC plus DFX for 24 hours. The muscle cells of C57BL/10 mice were used as controls. RESULTS Production of hydrogen peroxide (H2O2) and levels of 4-hydroxynonenal (4-HNE), tumor necrosis factor alpha (TNF-α), and nuclear factor kappa-B (NF-κB) were significantly higher in mdx muscle cells than in C57BL/10 muscle cells. Treatment with NAC, DFX, or NAC plus DFX significantly decreased H2O2 production (24, 58, and 72%, respectively), and levels of 4-HNE-protein adducts (62, 33, and 71%, respectively), TNF-α (32, 29, and 31%, respectively), and NF-κB (34, 38, and 52%, respectively) on dystrophic muscle cells. DISCUSSION This study demonstrates that mdx muscle cells are able to produce key oxidative stress and inflammatory markers, without the interference of inflammatory cells, and shows that NAC plus DFX reduced the inflammatory and oxidative stress indicators, mainly H2O2 production and NF-κB levels by dystrophic fibers.
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30
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Bibi H, Vinokur V, Waisman D, Elenberg Y, Landesberg A, Faingersh A, Yadid M, Brod V, Pesin J, Berenshtein E, Eliashar R, Chevion M. Zn/Ga-DFO iron-chelating complex attenuates the inflammatory process in a mouse model of asthma. Redox Biol 2014; 2:814-9. [PMID: 25009783 PMCID: PMC4085351 DOI: 10.1016/j.redox.2014.06.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 06/12/2014] [Accepted: 06/13/2014] [Indexed: 12/13/2022] Open
Abstract
Background Redox-active iron, a catalyst in the production of hydroxyl radicals via the Fenton reaction, is one of the key participants in ROS-induced tissue injury and general inflammation. According to our recent findings, an excess of tissue iron is involved in several airway-related pathologies such as nasal polyposis and asthma. Objective To examine the anti-inflammatory properties of a newly developed specific iron–chelating complex, Zn/Ga−DFO, in a mouse model of asthma. Materials and methods Asthma was induced in BALBc mice by ovalbumin, using aluminum hydroxide as an adjuvant. Mice were divided into four groups: (i) control, (ii) asthmatic and sham-treated, (iii) asthmatic treated with Zn/Ga−DFO [intra-peritoneally (i/p) and intra-nasally (i/n)], and (iv) asthmatic treated with Zn/Ga−DFO, i/n only. Lung histology and cytology were examined. Biochemical analysis of pulmonary levels of ferritin and iron-saturated ferritin was conducted. Results The amount of neutrophils and eosinophils in bronchoalveolar lavage fluid, goblet cell hyperplasia, mucus secretion, and peri-bronchial edema, showed markedly better values in both asthmatic-treated groups compared to the asthmatic non-treated group. The non-treated asthmatic group showed elevated ferritin levels, while in the two treated groups it returned to baseline levels. Interestingly, i/n-treatment demonstrated a more profound effect alone than in a combination with i/p injections. Conclusion In this mouse model of allergic asthma, Zn/Ga−DFO attenuated allergic airway inflammation. The beneficial effects of treatment were in accord with iron overload abatement in asthmatic lungs by Zn/Ga−DFO. The findings in both cellular and tissue levels supported the existence of a significant anti-inflammatory effect of Zn/Ga−DFO.
Asthma pathophysiology was shown to be associated with iron overload. A therapeutic effect of the novel iron–chelating complexes was demonstrated. Histological and cytological markers of inflammation were studied. The complexes could be administered intranasally or by intraperitonneal injections.
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Affiliation(s)
- Haim Bibi
- Pediatric Department, Barzilai Medical Center, Ben Gurion University School of Medicine, Ashkelon, Be'er Sheva, Israel
| | - Vladimir Vinokur
- Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University, Jerusalem, Israel
| | - Dan Waisman
- Department of Neonatology, Carmel Medical Center, Haifa, Israel
| | - Yigal Elenberg
- Pediatric Department, Barzilai Medical Center, Ben Gurion University School of Medicine, Ashkelon, Be'er Sheva, Israel
| | | | - Anna Faingersh
- Faculty of Biomedical Engineering, Technion, Haifa, Israel
| | - Moran Yadid
- Faculty of Biomedical Engineering, Technion, Haifa, Israel
| | - Vera Brod
- Ischemia-Shock Research Laboratory, Department of Medicine, Carmel Medical Center, Faculty of Medicine, Technion, Haifa, Israel
| | - Jimy Pesin
- Faculty of Biomedical Engineering, Technion, Haifa, Israel
| | - Eduard Berenshtein
- Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University, Jerusalem, Israel
| | - Ron Eliashar
- Department of Otolaryngology/Head & Neck Surgery, Hebrew University School of Medicine, - Hadassah Medical Center, Jerusalem, Israel
| | - Mordechai Chevion
- Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University, Jerusalem, Israel
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Kono M, Saigo K, Takagi Y, Takahashi T, Kawauchi S, Wada A, Hashimoto M, Minami Y, Imoto S, Takenokuchi M, Morikawa T, Funakoshi K. Heme-related molecules induce rapid production of neutrophil extracellular traps. Transfusion 2014; 54:2811-9. [PMID: 24865940 DOI: 10.1111/trf.12700] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 03/07/2014] [Accepted: 03/07/2014] [Indexed: 01/19/2023]
Abstract
BACKGROUND Pulmonary endothelial cell damages caused by neutrophil overactivation could result in acute lung injuries including transfusion-related acute lung injury (TRALI). We previously reported that heme-related molecules derived from hemolysis induced the production of reactive oxygen species from neutrophils. Recently, neutrophil extracellular traps (NETs) have been demonstrated to associate with the onset of TRALI. STUDY DESIGN AND METHODS In this study, neutrophils' morphologic changes induced by the heme-related molecule hemin were confirmed to be NETs via confocal laser scanning microscopy and electron microscopy (EM). Additionally, concentrations of hemin in red blood cell (RBC) components were measured via enzyme-linked immunosorbent assay and possible contribution of these molecules to the onset of TRALI was discussed. RESULTS SYTOX green staining observation via confocal laser scanning microscopy revealed that neutrophil morphology changed rapidly upon addition of hemin. The nuclei began to be enlarged and become segmented after 5 minutes, and NET-like structures were released from neutrophils after 15 minutes. In EM observation, NET-like structures appeared after 10 minutes and the nucleoplasm was partially separated from the nuclear membrane, which were consistent with the features of NET formation. These structures stained positively for both myeloperoxidase and histone H3 antibodies. CONCLUSION Thus, our results suggest that hemin induced NETs in 15 minutes, a quicker reaction than NET induction by phorbol myristate acetate requiring 3 hours. Moreover, since RBC components, especially those with long-term storage, contained sufficient hemin concentration to induce NETs, special attention to hemolysis of stored RBC components is important.
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Affiliation(s)
- Mari Kono
- Cell Analysis Center, Scientific Affairs, Sysmex Corporation, Kobe, Japan
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Inflammatory Response in Patients under Coronary Artery Bypass Grafting Surgery and Clinical Implications: A Review of the Relevance of Dexmedetomidine Use. ACTA ACUST UNITED AC 2014. [DOI: 10.1155/2014/905238] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Despite the fact that coronary artery bypass grafting surgery (CABG) with cardiopulmonary bypass (CPB) prolongs life and reduces symptoms in patients with severe coronary artery diseases, these benefits are accompanied by increased risks. Morbidity associated with cardiopulmonary bypass can be attributed to the generalized inflammatory response induced by blood-xenosurfaces interactions during extracorporeal circulation and the ischemia/reperfusion implications, including exacerbated inflammatory response resembling the systemic inflammatory response syndrome (SIRS). The use of specific anesthetic agents with anti-inflammatory activity can modulate the deleterious inflammatory response. Consequently, anti-inflammatory anesthetics may accelerate postoperative recovery and better outcomes than classical anesthetics. It is known that the stress response to surgery can be attenuated by sympatholytic effects caused by activation of central (α-)2-adrenergic receptor, leading to reductions in blood pressure and heart rate, and more recently, that they can have anti-inflammatory properties. This paper discusses the clinical significance of the dexmedetomidine use, a selective (α-)2-adrenergic agonist, as a coadjuvant in general anesthesia. Actually, dexmedetomidine use is not in anesthetic routine, but this drug can be considered a particularly promising agent in perioperative multiple organ protection.
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Thompson JW, Narayanan SV, Perez-Pinzon MA. Redox signaling pathways involved in neuronal ischemic preconditioning. Curr Neuropharmacol 2013; 10:354-69. [PMID: 23730259 PMCID: PMC3520045 DOI: 10.2174/157015912804143577] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2012] [Revised: 07/23/2012] [Accepted: 08/16/2012] [Indexed: 12/28/2022] Open
Abstract
There is extensive evidence that the restoration of blood flow following cerebral ischemia contributes greatly to the pathophysiology of ischemia mediated brain injury. The initiating stimulus of reperfusion injury is believed to be the excessive production of reactive oxygen (ROS) and nitrogen (RNS) species by the mitochondria. ROS and RNS generation leads to mitochondrial protein, lipid and DNA oxidation which impedes normal mitochondrial physiology and initiates cellular death pathways. However not all ROS and RNS production is detrimental. It has been demonstrated that low levels of ROS production are protective and may serve as a trigger for activation of ischemic preconditioning. Ischemic preconditioning is a neuroprotective mechanism which is activated upon a brief sublethal ischemic exposure and is sufficient to provide protection against a subsequent lethal ischemic insult. Numerous proteins and signaling pathways have been implicated in the ischemic preconditioning neuroprotective response. In this review we examine the origin and mechanisms of ROS and RNS production following ischemic/reperfusion and the role of free radicals in modulating proteins associated with ischemic preconditioning neuroprotection.
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Affiliation(s)
- John W Thompson
- Cerebral Vascular Disease Research Center, Department of Neurology, University of Miami, Miller School of Medicine, Miami, Fl 33136
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34
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Deferoxamine: emerging, new neuro-protective benefits. Neurol Sci 2013; 34:2069-70. [PMID: 23609462 DOI: 10.1007/s10072-013-1441-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Accepted: 04/11/2013] [Indexed: 10/26/2022]
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Masuda T, Iwashita Y, Hagiwara S, Ohta M, Inomata M, Noguchi T, Kitano S. WITHDRAWN: Alpha-lipoic acid derivate DHLHZn reduces hepatic ischemia/reperfusion injury by inhibition of pro-inflammatory signaling. J Surg Res 2012. [DOI: 10.1016/j.jss.2012.04.059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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