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Joelsson JP, Karason S. Ventilator-induced lung injury in rat models: are they all equal in the race? Lab Anim Res 2025; 41:14. [PMID: 40390135 PMCID: PMC12090643 DOI: 10.1186/s42826-025-00240-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 02/10/2025] [Accepted: 02/14/2025] [Indexed: 05/21/2025] Open
Abstract
Risk of ventilator-induced lung injury (VILI) is an inevitable and precarious accompaniment of ventilator treatment in critically ill patients worldwide. It can both instigate and aggravate acute respiratory distress syndrome (ARDS) where the only prevention or treatment so far has been empirical approach of what is considered to be lung protective ventilator settings in an attempt to shield the lung tissues against the mechanical stress that unavoidably follows ventilator treatment. The weakened state of the patients limits clinical drug research and pushes for drug discovery in animal models. Mice and rats are often the choice of small animal model, representing about 95% of all laboratory animal studies, as their physiology can mimic that which is found in humans. Mice have been a more popular choice for ventilator studies but due to technical issues, there is some advantage gained in using rats as they are substantially larger. Inducing VILI and ARDS in these models can prove challenging and often the acute nature of the injury used to produce similar tissue damage as in humans does not necessarily fully reflect clinical reality. The aim of this review was to analyse and summarize methods of recent publications in the field, describing what approaches have been utilized to simulate these conditions, possibly identifying a common track enabling comparison of results between studies. However, the study shows a high variety of methods employed by researchers causing comparisons of results difficult and perhaps implying that a more standardized approach should be used.
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Affiliation(s)
| | - Sigurbergur Karason
- University of Iceland, Reykjavik, Iceland
- Landspitali-University Hospital, Reykjavik, Iceland
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Wang X, Long D, Peng X, Li J, Zhou M, Wang Y, Hu X. Diphenyl diselenide protects against diabetic kidney disease through modulating gut microbiota dysbiosis in streptozotocin-induced diabetic rats. Front Pharmacol 2024; 15:1506398. [PMID: 39697537 PMCID: PMC11653185 DOI: 10.3389/fphar.2024.1506398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 11/18/2024] [Indexed: 12/20/2024] Open
Abstract
Introduction Diphenyl diselenide (DPDS) ameliorates nephropathy in streptozotocin (STZ)-induced type 1 diabetic rats by inhibiting oxidative stress and inflammatory reactions. However, it has not been clarified whether DPDS alleviates type 1 diabetic kidney disease (DKD) is related to the inhibition of extracellular matrix (ECM) production and the regulation of intestinal flora disorder. Methods The present study investigated the effects of DPDS on ECM generation in the kidney and intestinal microflora composition in feces. The rats were orally administered DPDS or metformin for eight weeks. Various indices were measured to assess the severity of renal injury. After euthanizing the rats, oxidative stress markers in serum and kidney were assessed using biochemical methods, and the expressions of ECM-related proteins in kidney were analyzed using Western blot. Additionally, 16S rRNA high-throughput sequencing was used to evaluate the diversity and composition of the intestinal flora in feces. Results The results showed DPDS and metformin improved the DKD in STZ rats, as evidenced by decreased blood glucose, BUN, urine volume, urine microalbumin, urinary β2 microglobulin, and improvement of renal pathological morphology. Furthermore, DPDS intervention markedly reduced the protein expression of α-SMA, COI Ⅳ, FN, and vimentin in the kidneys. Besides, DPDS not only improved dyslipidemia in STZ diabetic rats, but also enhanced the activities of antioxidant enzymes, decreased the level of MDA in serum and kidney, and regulated the expression of proteins related to the Nrf2/Keap1 signaling pathway in the kidney. Moreover, we found that DPDS could selectively improve the relative abundance of probiotics as well as the diversity of flora, thus ameliorating the intestinal microbial composition of the STZ rats, significantly regulating the intestinal microbial homeostasis. Discussion Overall, DPDS inhibited ECM production and improved renal pathological changes, which may be related to reducing oxidative stress damage in the kidney and improving intestinal flora imbalance, providing data support for the further development and application of DPDS in DKD.
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Affiliation(s)
- Xing Wang
- Department of Pharmacology, School of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Dongmei Long
- Nanchong Key Laboratory of Disease Prevention, Control and Detection in Livestock and Poultry, Nanchong Vocational and Technical College, Nanchong, China
| | - Xingcan Peng
- Department of Pharmacology, School of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Jiaxuan Li
- Department of Pharmacology, School of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Maoting Zhou
- Department of Pharmacology, School of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Yu Wang
- Department of Pharmacology, School of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Xianghong Hu
- Department of Pharmacology, School of Pharmacy, North Sichuan Medical College, Nanchong, China
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Luo J, Yan R, Ding L, Ning J, Chen M, Guo Y, Liu J, Chen Z, Zhou R. Electroacupuncture Attenuates Ventilator-Induced Lung Injury by Modulating the Nrf2/HO-1 Pathway. J Surg Res 2024; 295:811-819. [PMID: 38160492 DOI: 10.1016/j.jss.2023.11.055] [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: 12/19/2022] [Revised: 10/06/2023] [Accepted: 11/12/2023] [Indexed: 01/03/2024]
Abstract
INTRODUCTION Ventilator-induced lung injury (VILI) is the most common complication associated with mechanical ventilation. Electroacupuncture (EA) has shown potent anti-inflammatory effects. This study aimed to investigate the effects of EA on VILI and explore the underlying mechanisms. METHODS Male C57BL/6 mice were subjected to high tidal volume ventilation to induce VILI. Prior to mechanical ventilation, mice received treatment with EA, nonacupoint EA, or EA combined with zinc protoporphyrin. RESULTS EA treatment significantly improved oxygenation, as indicated by increased PaO2 levels in VILI mice. Moreover, EA reduced lung injury score, lung wet/dry weight ratio, and protein concentration in bronchoalveolar lavage fluid. EA also decreased the expression of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor-α, IL-18, chemokine keratinocyte chemoattractant, macrophage inflammatory protein 2, and malondialdehyde. Furthermore, EA increased the activities of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase in VILI mice. At the molecular level, EA upregulated the expression of Nrf2 (nucleus) and heme oxygenase -1, while down-regulating the expression of p-NF-κB p65, NLR Family Pyrin Domain Containing 3, Cleaved Caspase-1, and ASC in VILI mice. Notably, the effects of EA were reversed by zinc protoporphyrin treatment, nonacupoint EA did not affect the aforementioned indicators of VILI. CONCLUSIONS EA alleviates VILI by inhibiting the NLR Family Pyrin Domain Containing three inflammasome through activation of the Nrf2/HO-1 pathway.
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Affiliation(s)
- Jiansheng Luo
- Department of Anesthesiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Ruyu Yan
- Department of Anesthesiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Lingling Ding
- Department of Anesthesiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
| | - Jiaqi Ning
- Department of Anesthesiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Mengjie Chen
- Department of Anesthesiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Yuhong Guo
- Department of Emergency, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Jiaxi Liu
- Department of Anesthesiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Zhuoya Chen
- Department of Anesthesiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Ruiling Zhou
- Department of Anesthesiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
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Xu G, Lu X, Liu S, Zhang Y, Xu S, Ma X, Xia X, Lu F, Zou F, Wang H, Song J, Jiang J. MSC-Derived Exosomes Ameliorate Intervertebral Disc Degeneration By Regulating the Keap1/Nrf2 Axis. Stem Cell Rev Rep 2023; 19:2465-2480. [PMID: 37528254 DOI: 10.1007/s12015-023-10570-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2023] [Indexed: 08/03/2023]
Abstract
Bone marrow mesenchymal stem cell derived exosomes (BMSC-exos) are a crucial means of intercellular communication and can regulate a range of biological processes by reducing inflammation, decreasing apoptosis and promoting tissue repair. The process of intervertebral disc degeneration (IVDD) is accompanied by increased reactive oxygen species (ROS) because of a decrease in the expression of Nrf2, a critical transcription factor that resists excessive ROS. Our study demonstrated that BMSC-exos decreased ROS production by inhibiting Keap1 and promoting Nrf2 expression, attenuating the apoptosis, inflammation, and degeneration of nucelus pulposus (NP) cells. BMSC-exos promoted an increase in Nrf2 and nuclear translocation, while NF-κB expression was downregulated during this process. Additionally, the expression of antioxidative proteins was elevated after treatment with BMSC-exos. In vivo, we found more NP tissue retention in the BMSC-exos-treated group, along with more expression of Nrf2 and antioxidant-related proteins. Our findings demonstrated for the first time that BMSC-exos could restore the down-regulated antioxidant response system in degenerating NP cells by modulating the Keap1/Nrf2 axis. BMSC-exos could be used as an immediate ROS modulator in the treatment of intervertebral disc degeneration. When BMSC-exos were uptaken by NPCs, the expression of Keap1 decreased and this led to increased expression of Nrf2. Nuclear translocation of Nrf2 then promoted the synthesis of antioxidants against ROS and inhibited NF-kB signalling. Cellular inflammation, apoptosis, and ECM-related indicators were further reduced. Together, the process of IVDD was alleviated.
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Affiliation(s)
- Guangyu Xu
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Xiao Lu
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Siyang Liu
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yuxuan Zhang
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Shun Xu
- Department of Orthopedics, Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200240, China
| | - Xiaosheng Ma
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Xinlei Xia
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Feizhou Lu
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China
- Department of Orthopedics, Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200240, China
| | - Fei Zou
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Hongli Wang
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Jian Song
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Jianyuan Jiang
- Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200040, China.
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A cross-talk between sestrins, chronic inflammation and cellular senescence governs the development of age-associated sarcopenia and obesity. Ageing Res Rev 2023; 86:101852. [PMID: 36642190 DOI: 10.1016/j.arr.2023.101852] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/20/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023]
Abstract
The rapid increase in both the lifespan and proportion of older adults is accompanied by the unprecedented rise in age-associated chronic diseases, including sarcopenia and obesity. Aging is also manifested by increased susceptibility to multiple endogenous and exogenous stresses enabling such chronic conditions to develop. Among the main physiological regulators of cellular adaption to various stress stimuli, such as DNA damage, hypoxia, and oxidative stress, are sestrins (Sesns), a family of three evolutionarily conserved proteins, Sesn1, 2, and 3. Age-associated sarcopenia and obesity are characterized by two key processes: (i) accumulation of senescent cells in the skeletal muscle and adipose tissue and (ii) creation of a systemic, chronic, low-grade inflammation (SCLGI). Presumably, failed SCLGI resolution governs the development of these chronic conditions. Noteworthy, Sesns activate senolytics, which are agents that selectively eliminate senescent cells, as well as specialized pro-resolving mediators, which are factors that physiologically provide inflammation resolution. Sesns reveal clear beneficial effects in pre-clinical models of sarcopenia and obesity. Based on these observations, we propose a novel treatment strategy for age-associated sarcopenia and obesity, complementary to the conventional therapeutic modalities: Sesn activation, SCLGI resolution, and senescent cell elimination.
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Xu J, Gao C, He Y, Fang X, Sun D, Peng Z, Xiao H, Sun M, Zhang P, Zhou T, Yang X, Yu Y, Li R, Zou X, Shu H, Qiu Y, Zhou X, Yuan S, Yao S, Shang Y. NLRC3 expression in macrophage impairs glycolysis and host immune defense by modulating the NF-κB-NFAT5 complex during septic immunosuppression. Mol Ther 2023; 31:154-173. [PMID: 36068919 PMCID: PMC9840117 DOI: 10.1016/j.ymthe.2022.08.023] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 06/23/2022] [Accepted: 08/30/2022] [Indexed: 01/28/2023] Open
Abstract
Impairment of innate immune cell function and metabolism underlies immunosuppression in sepsis; however, a promising therapy to orchestrate this impairment is currently lacking. In this study, high levels of NOD-like receptor family CARD domain containing-3 (NLRC3) correlated with the glycolytic defects of monocytes/macrophages from septic patients and mice that developed immunosuppression. Myeloid-specific NLRC3 deletion improved macrophage glycolysis and sepsis-induced immunosuppression. Mechanistically, NLRC3 inhibits nuclear factor (NF)-κB p65 binding to nuclear factor of activated T cells 5 (NFAT5), which further controls the expression of glycolytic genes and proinflammatory cytokines of immunosuppressive macrophages. This is achieved by decreasing NF-κB activation-co-induced by TNF-receptor-associated factor 6 (TRAF6) or mammalian target of rapamycin (mTOR)-and decreasing transcriptional co-activator p300 activity by inducing NLRC3 sequestration of mTOR and p300. Genetic inhibition of NLRC3 disrupted the NLRC3-mTOR-p300 complex and enhanced NF-κB binding to the NFAT5 promoter in concert with p300. Furthermore, intrapulmonary delivery of recombinant adeno-associated virus harboring a macrophage-specific NLRC3 deletion vector significantly improved the defense of septic mice that developed immunosuppression upon secondary intratracheal bacterial challenge. Collectively, these findings indicate that NLRC3 mediates critical aspects of innate immunity that contribute to an immunocompromised state during sepsis and identify potential therapeutic targets.
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Affiliation(s)
- Jiqian Xu
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chenggang Gao
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yajun He
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiangzhi Fang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Deyi Sun
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhekang Peng
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hairong Xiao
- Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Miaomiao Sun
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Pei Zhang
- Department of Paediatrics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210016, China
| | - Ting Zhou
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaobo Yang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yuan Yu
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ruiting Li
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaojing Zou
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Huaqing Shu
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yang Qiu
- State Key Laboratory of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan Institute of Virology, Wuhan 43007, China
| | - Xi Zhou
- State Key Laboratory of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan Institute of Virology, Wuhan 43007, China
| | - Shiying Yuan
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shanglong Yao
- Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - You Shang
- Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Keskinidou C, Vassiliou AG, Dimopoulou I, Kotanidou A, Orfanos SE. Mechanistic Understanding of Lung Inflammation: Recent Advances and Emerging Techniques. J Inflamm Res 2022; 15:3501-3546. [PMID: 35734098 PMCID: PMC9207257 DOI: 10.2147/jir.s282695] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 05/04/2022] [Indexed: 12/12/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury characterized by an acute inflammatory response in the lung parenchyma. Hence, it is considered as the most appropriate clinical syndrome to study pathogenic mechanisms of lung inflammation. ARDS is associated with increased morbidity and mortality in the intensive care unit (ICU), while no effective pharmacological treatment exists. It is very important therefore to fully characterize the underlying pathobiology and the related mechanisms, in order to develop novel therapeutic approaches. In vivo and in vitro models are important pre-clinical tools in biological and medical research in the mechanistic and pathological understanding of the majority of diseases. In this review, we will present data from selected experimental models of lung injury/acute lung inflammation, which have been based on clinical disorders that can lead to the development of ARDS and related inflammatory lung processes in humans, including ventilation-induced lung injury (VILI), sepsis, ischemia/reperfusion, smoke, acid aspiration, radiation, transfusion-related acute lung injury (TRALI), influenza, Streptococcus (S.) pneumoniae and coronaviruses infection. Data from the corresponding clinical conditions will also be presented. The mechanisms related to lung inflammation that will be covered are oxidative stress, neutrophil extracellular traps, mitogen-activated protein kinase (MAPK) pathways, surfactant, and water and ion channels. Finally, we will present a brief overview of emerging techniques in the field of omics research that have been applied to ARDS research, encompassing genomics, transcriptomics, proteomics, and metabolomics, which may recognize factors to help stratify ICU patients at risk, predict their prognosis, and possibly, serve as more specific therapeutic targets.
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Affiliation(s)
- Chrysi Keskinidou
- First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, "Evangelismos" Hospital, Athens, Greece
| | - Alice G Vassiliou
- First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, "Evangelismos" Hospital, Athens, Greece
| | - Ioanna Dimopoulou
- First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, "Evangelismos" Hospital, Athens, Greece
| | - Anastasia Kotanidou
- First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, "Evangelismos" Hospital, Athens, Greece
| | - Stylianos E Orfanos
- First Department of Critical Care Medicine and Pulmonary Services, School of Medicine, National and Kapodistrian University of Athens, "Evangelismos" Hospital, Athens, Greece
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Zhu CJ, Yang WG, Li DJ, Song YD, Chen SY, Wang QF, Liu YN, Zhang Y, Cheng B, Wu ZW, Cui ZC. Calycosin attenuates severe acute pancreatitis-associated acute lung injury by curtailing high mobility group box 1 - induced inflammation. World J Gastroenterol 2021; 27:7669-7686. [PMID: 34908806 PMCID: PMC8641048 DOI: 10.3748/wjg.v27.i44.7669] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/09/2021] [Accepted: 09/10/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute lung injury (ALI) is a common and life-threatening complication of severe acute pancreatitis (SAP). There are currently limited effective treatment options for SAP and associated ALI. Calycosin (Cal), a bioactive constituent extracted from the medicinal herb Radix Astragali exhibits potent anti-inflammatory properties, but its effect on SAP and associated ALI has yet to be determined.
AIM To identify the roles of Cal in SAP-ALI and the underlying mechanism.
METHODS SAP was induced via two intraperitoneal injections of L-arg (4 g/kg) and Cal (25 or 50 mg/kg) were injected 1 h prior to the first L-arg challenge. Mice were sacrificed 72 h after the induction of SAP and associated ALI was examined histologically and biochemically. An in vitro model of lipopolysaccharide (LPS)-induced ALI was established using A549 cells. Immunofluorescence analysis and western blot were evaluated in cells. Molecular docking analyses were conducted to examine the interaction of Cal with HMGB1.
RESULTS Cal treatment substantially reduced the serum amylase levels and alleviated histopathological injury associated with SAP and ALI. Neutrophil infiltration and lung tissue levels of neutrophil mediator myeloperoxidase were reduced in line with protective effects of Cal against ALI in SAP. Cal treatment also attenuated the serum levels and mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, IL-1β, HMGB1 and chemokine (CXC motif) ligand 1 in lung tissue. Immunofluorescence and western blot analyses showed that Cal treatment markedly suppressed the expression of HMGB1 and phosphorylated nuclear factor-kappa B (NF-κB) p65 in lung tissues and an in vitro model of LPS-induced ALI in A549 cells suggesting a role for HGMB1 in the pathogenesis of ALI. Furthermore, molecular docking analysis provided evidence for the direct interaction of Cal with HGMB1.
CONCLUSION Cal protects mice against L-arg-induced SAP and associated ALI by attenuating local and systemic neutrophil infiltration and inflammatory response via inhibition of HGMB1 and the NF-κB signaling pathway.
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Affiliation(s)
- Chang-Ju Zhu
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Wan-Guang Yang
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - De-Jian Li
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yao-Dong Song
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - San-Yang Chen
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Qiao-Fang Wang
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yan-Na Liu
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yan Zhang
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Bo Cheng
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhong-Wei Wu
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zong-Chao Cui
- Henan Medical Key Laboratory of Emergency and Trauma Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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Lipoxin A4 Reduces Ventilator-Induced Lung Injury in Rats with Large-Volume Mechanical Ventilation. Mediators Inflamm 2020; 2020:6705985. [PMID: 33299377 PMCID: PMC7704204 DOI: 10.1155/2020/6705985] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/08/2020] [Accepted: 11/11/2020] [Indexed: 01/04/2023] Open
Abstract
Ventilator-induced lung injury (VILI) is a severe and inevitable complication in patients who require mechanical ventilation (MV) for respiratory support. Lipoxin A4 is an endogenous anti-inflammatory and antioxidant mediator. The present study determined the effects of lipoxin A4 on VILI. Twenty-four rats were randomized to the sham, VILI, and lipoxin A4 (LX4) groups. The rats in the VILI and LX4 groups received large-volume MV for 4 hours to simulate VILI. Capillary permeability was evaluated using the PaO2/FiO2 ratio, lung wet/dry weight ratio, and protein level in the lung. VILI-induced inflammation was assessed by measuring cytokines in serum and lung tissue, the expression and activity of NF-κB, and phosphorylated myosin light chain. The oxidative stress response, lung tissue injury, and apoptosis in lung tissue were also estimated, and the expression of apoptotic proteins was examined. MV worsened all of the indices compared to the sham group. Compared to the VILI group, the LX4 group showed significantly improved alveolar-capillary permeability (increased PaO2/FiO2 and decreased wet/dry weight ratios and protein levels), ameliorated histological injury, and reduced local and systemic inflammation (downregulated proinflammatory factors and NF-κB expression and activity). Lipoxin A4 notably inhibited the oxidative stress response and apoptosis and balanced apoptotic protein levels in lung tissue. Lipoxin A4 protects against VILI via anti-inflammatory, antioxidant, and antiapoptotic effects.
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Hu Q, Wang Q, Han C, Yang Y. Sufentanil attenuates inflammation and oxidative stress in sepsis-induced acute lung injury by downregulating KNG1 expression. Mol Med Rep 2020; 22:4298-4306. [PMID: 33000200 PMCID: PMC7533471 DOI: 10.3892/mmr.2020.11526] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 07/20/2020] [Indexed: 12/16/2022] Open
Abstract
The present study aimed to investigate the effects of sufentanil on sepsis-induced acute lung injury (ALI), and identify the potential molecular mechanisms underlying its effect. In order to achieve this, a rat sepsis model was established. Following treatment with sufentanil, the lung wet/dry (W/D) weight ratio was calculated. Histopathological analysis was performed via hematoxylin and eosin staining. Levels of inflammatory factors in bronchoalveolar lavage fluid were determined via ELISA. Furthermore, malondialdehyde (MDA) content and the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in tissue homogenates were assessed using commercial kits. Western blot analysis was performed to determine kininogen-1 (KNG1) protein expression. In addition, alveolar epithelial type II cells (AEC II) were stimulated with lipopolysaccharide (LPS) to mimic ALI. The levels of inflammation and oxidative stress were evaluated following overexpression of KNG1. Protein expression levels of nuclear factor-κB (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling were determined via western blot analysis. The results of the present study demonstrated that sufentanil alleviated histopathological injury and the W/D ratio in lung tissue. Following treatment with sufentanil, levels of inflammatory factors also decreased, accompanied by decreased concentrations of MDA, and increased activities of SOD, CAT and GSH-Px. Notably, KNG1 was decreased in lung tissues following treatment with sufentanil. Furthermore, overexpression of KNG1 attenuated the inhibitory effects of sufentanil on LPS-induced inflammation and oxidative stress in AEC II. Sufentanil markedly downregulated NF-κB expression, while upregulating Nrf2 and HO-1 expression levels, which was reversed following overexpression of KNG1. Taken together, the results of the present study suggested that sufentanil may alleviate inflammation and oxidative stress in sepsis-induced ALI by downregulating KNG1 expression.
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Affiliation(s)
- Quan Hu
- Intensive Care Unit, The First People's Hospital, Wuhan, Hubei 430200, P.R. China
| | - Qin Wang
- Department of Pathology, Hubei Women and Children Health Care Hospital, Wuhan, Hubei 430200, P.R. China
| | - Chuangang Han
- Department of Anesthesiology, The First People's Hospital, Wuhan, Hubei 430200, P.R. China
| | - Yan Yang
- Department of Anesthesiology, The First People's Hospital, Wuhan, Hubei 430200, P.R. China
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The Lipoxin Receptor/FPR2 Agonist BML-111 Protects Mouse Skin Against Ultraviolet B Radiation. Molecules 2020; 25:molecules25122953. [PMID: 32604968 PMCID: PMC7356842 DOI: 10.3390/molecules25122953] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Revised: 12/30/2019] [Accepted: 01/02/2020] [Indexed: 12/30/2022] Open
Abstract
Excessive exposure to UV, especially UVB, is the most important risk factor for skin cancer and premature skin aging. The identification of the specialized pro-resolving lipid mediators (SPMs) challenged the preexisting paradigm of how inflammation ends. Rather than a passive process, the resolution of inflammation relies on the active production of SPMs, such as Lipoxins (Lx), Maresins, protectins, and Resolvins. LXA4 is an SPM that exerts its action through ALX/FPR2 receptor. Stable ALX/FPR2 agonists are required because SPMs can be quickly metabolized within tissues near the site of formation. BML-111 is a commercially available synthetic ALX/FPR2 receptor agonist with analgesic, antioxidant, and anti-inflammatory properties. Based on that, we aimed to determine the effect of BML-111 in a model of UVB-induced skin inflammation in hairless mice. We demonstrated that BML-111 ameliorates the signs of UVB-induced skin inflammation by reducing neutrophil recruitment and mast cell activation. Reduction of these cells by BML-111 led to lower number of sunburn cells formation, decrease in epidermal thickness, collagen degradation, cytokine production (TNF-α, IL-1β, IL-6, TGF, and IL-10), and oxidative stress (observed by an increase in total antioxidant capacity and Nrf2 signaling pathway), indicating that BML-111 might be a promising drug to treat skin disorders.
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Lin L, Luo X, Wang L, Xu F, He Y, Wang Q, Yuan C, Xu J, Yan L, Hao H. BML-111 inhibits EMT, migration and metastasis of TAMs-stimulated triple-negative breast cancer cells via ILK pathway. Int Immunopharmacol 2020; 85:106625. [PMID: 32485356 DOI: 10.1016/j.intimp.2020.106625] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/27/2020] [Accepted: 05/19/2020] [Indexed: 02/05/2023]
Abstract
Triple-negative breast cancer (TNBC) has a more aggressive phenotype and higher metastasis and recurrence rates than other breast cancer subtypes. The immune microenvironment and hypoxic microenvironment of breast cancer constitute the survival environment of cancer cells, which is an important environment to support cancer cells. LXA4 and its analog, BML-111 is an important regulator of inflammatory cytokines, which provides a possible way for the treatment of inflammatory-related tumors. Here, in the in vitro experiment, we showed that BML-111 could inhibit the EMT and migration of TAMs-stimulated TNBC by down-regulating ILK as well as p-Akt and p-GSK3β. And it could prevent the formation of breast cancer cell clusters. In the in vivo experiment, BML-111 could inhibit the metastasis of 4T1 breast cancer cells. We also demonstrated that BML-111 could affect macrophages in tumor microenvironment to prevent metastasis. These results showed that BML-111 could be a possible candidate for breast cancer therapy by targeting ILK and TAMs.
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Affiliation(s)
- Lan Lin
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Xuliang Luo
- Department of Breast Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Lin Wang
- Department of Breast Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Fen Xu
- Department of General Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Yuanqiao He
- Department of Laboratory Animal Science, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Qingyu Wang
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Chunlei Yuan
- Department of Breast Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Jing Xu
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Liping Yan
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Hua Hao
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China.
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Liu J, Peng L, Li J. The Lipoxin A4 Receptor Agonist BML-111 Alleviates Inflammatory Injury and Oxidative Stress in Spinal Cord Injury. Med Sci Monit 2020; 26:e919883. [PMID: 31971927 PMCID: PMC6996263 DOI: 10.12659/msm.919883] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Spinal cord injury (SCI) has a high incidence and causes serious harm. Lipoxin A4 (LXA4) receptor agonist BML-111 was reported to regulate inflammation and oxidative stress. The goal of this study was to assess whether BML-111 could protect against SCI by suppressing inflammation and oxidative stress. Material/Methods We developed a rat SCI model, then BML-111 was intraperitoneally injected into SCI rats to observe the BML-111 function. The pathological changes of SCI were observed with hematoxylin and eosin (HE) staining. Motor function of rats were assessed by the modified Tarlov’s scale. ELISA was used to assess the changes in levels of TNF-α, IL-1β, and IL-6. Western blot analysis was performed to assess the expressions of TNF-α, IL-1β, IL-6, Bcl2, Bax, and cleaved caspase3 in spinal cord tissue. TOS and TAS in rat serum were detected by xylenol orange method and ABTS method, respectively. The apoptotic cells in spinal cord tissue were observed with TUNEL assay. Results The results indicated that BML-111 effectively improved the SCI and motor function of rats. BML-111 treatment decreased the levels of TNF-α, IL-1β, and IL-6 in serum and spinal cord tissue, as well as decreasing the levels of TOS and TAS and cell apoptosis. Conclusions BML-111 alleviated inflammation and oxidative stress in SCI rats.
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Affiliation(s)
- Jian Liu
- Department of Orthopedics, Chongqing Emergency Medical Center, Chongqing, China (mainland)
| | - Lei Peng
- Department of Orthopedics, Chongqing Emergency Medical Center, Chongqing, China (mainland)
| | - Jie Li
- Department of Orthopedics, Chongqing Emergency Medical Center, Chongqing, China (mainland)
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Wu X, Pan C, Chen R, Zhang S, Zhai Y, Guo H. BML-111 attenuates high glucose-induced inflammation, oxidative stress and reduces extracellular matrix accumulation via targeting Nrf2 in rat glomerular mesangial cells. Int Immunopharmacol 2019; 79:106108. [PMID: 31881376 DOI: 10.1016/j.intimp.2019.106108] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/25/2019] [Accepted: 11/29/2019] [Indexed: 12/13/2022]
Abstract
Diabetic nephropathy (DN) is the most paradigmatic complication of diabetes mellitus (DM) and brings about severe social and economic burdens. BML-111 is a potent agonist of Lipoxin A4 and has shown anti-inflammatory function in many diseases. The aim of the study is to investigate the effects of BML-111 on high glucose (HG) -induced mesangial cells. HBZY-1 cells were stimulated by HG with or without BML-111. ML385 was used as an Nrf2 inhibitor. Cell proliferation was measured by CC-K 8 assay. Besides, levels of TNF-α, IL-1, IL-6 and MCP-1 were detected by corresponding ELISA kits. DCFH-DA staining and an available ROS kit were employed to determine the ROS generation. In addition, extracellular matrix (ECM) accumulation was evaluated by immunofluorescence assay and western blot analysis. The protein expressions involved in Nrf2/HO-1 and MAPK pathway were assessed by western blot assay. Results indicated that BML-111 extremely inhibited HBZY-1 cell proliferation induced by HG. Moreover, BML-111 reduced the levels of TNF-α, IL-1, IL-6 and MCP-1, declined intracellular ROS level, and attenuated expression of ECM proteins laminin, fibronectin, collagen IV and TGF-β1. In addition, BML-111 promoted the activation of Nrf2, HO-1, and NQO1, while suppressed the phosphorylation of p38 and JNK. Further, NRF2 silence reversed the inhibitory effects of BML-111 on HG-induce inflammation, oxidative stress and ECM accumulation, accelerate the MAPK signaling, and diminished the expression of Nrf2 pathway. In summary, BML-111 alleviated HG-induced injury in HBZY-1 cells by repressing inflammatory response, oxidative stress and ECM accumulation via activating Nrf2 and inhibiting MAPK pathway.
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Affiliation(s)
- Xiaoming Wu
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
| | - Congqing Pan
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China.
| | - Rui Chen
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
| | - Shuo Zhang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
| | - Yangkui Zhai
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
| | - Hang Guo
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China
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Ren J, Su D, Li L, Cai H, Zhang M, Zhai J, Li M, Wu X, Hu K. Anti-inflammatory effects of Aureusidin in LPS-stimulated RAW264.7 macrophages via suppressing NF-κB and activating ROS- and MAPKs-dependent Nrf2/HO-1 signaling pathways. Toxicol Appl Pharmacol 2019; 387:114846. [PMID: 31790703 DOI: 10.1016/j.taap.2019.114846] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 11/17/2019] [Accepted: 11/28/2019] [Indexed: 12/19/2022]
Abstract
Aureusidin, a naturally-occurring flavonoid, is found in various plants of Cyperaceae such as Heleocharis dulcis (Burm. f.) Trin., but its pharmacological effect and active mechanism are rarely reported. This study aimed to investigate the anti-inflammatory effect and action mechanism of Aureusidin in LPS-induced mouse macrophage RAW264.7 cells. The results suggested that lipopolysaccharide (LPS)-induced nitric oxide (NO), tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) production were obviously inhibited by Aureusidin. Moreover, Aureusidin also significantly decreased the mRNA expression of various inflammatory factors in LPS-stimulated RAW264.7 cells. Furthermore, mechanistic studies showed that Aureusidin significantly inhibited nuclear transfer of nuclear factor-κB (NF-κB), while increasing the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) as well as expression of Nrf2 target genes such as heme oxygenase (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), but the addition of the HO-1 inhibitor Sn-protoporphyrin (Snpp) significantly abolished the anti-inflammatory effect of Aureusidin in LPS-stimulated RAW264.7 cells, confirming the view that HO-1 was involved in the anti-inflammatory effect. In addition, Aureusidin increased the levels of reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) phosphorylation in RAW264.7 cells. Antioxidant N-acetylcysteine (NAC) or three MAPK inhibitors blocked the nuclear translocation of Nrf2 and HO-1 expression induced by Aureusidin, indicating that Aureusidin activated the Nrf2/HO-1 signaling pathway through ROS and MAPKs pathways. At the same time, co-treatment with the NAC blocked the phosphorylation of MAPKs. Results from molecular docking indicated that Aureusidin inhibited the NF-κB pathway by covalently binding to NF-κB. Thus, Aureusidin exerted the anti-inflammatory activity through blocking the NF-κB signaling pathways and activating the MAPKs and Nrf2/HO-1 signaling pathways. Based on the above results, Aureusidin may be an attractive therapeutic candidate for the inflammation-related diseases.
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Affiliation(s)
- Jie Ren
- School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou, Jiangsu 213164, People's Republic of China.
| | - Dan Su
- Changzhou No.2 People's Hospital, Changzhou, Jiangsu 213164, People's Republic of China.
| | - Lixia Li
- School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou, Jiangsu 213164, People's Republic of China
| | - Heng Cai
- School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou, Jiangsu 213164, People's Republic of China
| | - Meiju Zhang
- School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou, Jiangsu 213164, People's Republic of China
| | - Jingchen Zhai
- School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou, Jiangsu 213164, People's Republic of China
| | - Minyue Li
- School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou, Jiangsu 213164, People's Republic of China
| | - Xinyue Wu
- School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou, Jiangsu 213164, People's Republic of China
| | - Kun Hu
- School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou, Jiangsu 213164, People's Republic of China
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Guo K, Jin F. Dipeptidyl Peptidase-4 (DPP-4) Inhibitor Saxagliptin Alleviates Lipopolysaccharide-Induced Acute Lung Injury via Regulating the Nrf-2/HO-1 and NF- κB Pathways. J INVEST SURG 2019; 34:695-702. [PMID: 31694415 DOI: 10.1080/08941939.2019.1680777] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE We aimed at investigating the effects of Dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin (Saxa) on mouse acute lung injury (ALI)-induced by lipopolysaccharide (LPS) and the potential mechanisms. MATERIALS/METHODS Animals were divided into four groups: control, Saxa, LPS, and LPS + Saxa. Histopathology changes of lung tissues were assessed by hematoxylin and eosin staining and periodic acid-Schiff staining. The degree of edema was determined by wet/dry ratio. The levels of oxidative stress markers and inflammatory cytokines in lung homogenate and bronchoalveolar lavage fluid were detected using kits. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to test apoptosis and Western blotting was applied to measure the expression of apoptosis-associated proteins. The expression of nuclear factor erythroid 2-related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1) and nuclear factor-kappa B (NF-κB) pathways were detected by Western blotting. RESULTS The results revealed that Saxa attenuated LPS-induced pathological injury and edema. Saxa decreased the levels of reactive oxygen species (ROS), malondialdehyde (MDA), myeloperoxidase (MPO) and increased the levels of superoxide dismutase (SOD) and catalase (CAT). The contents of inflammatory cytokines were reduced in the Saxa intervention group. Saxa attenuated apoptosis accompanied by alterations in the expression of apoptosis-associated proteins. Furthermore, the expression of Nrf-2 and HO-1 were upregulated whereas phospho (p)-NF-κB p65 and phospho-inhibitory subunit of NF-κB alpha (p-IκB-α) were downregulated after Saxa treatment. CONCLUSION These findings concluded that Saxa alleviates oxidative stress, inflammation and apoptosis in ALI induced by LPS via modulating the Nrf-2/HO-1 and NF-κB pathways, which provides evidence for employing Saxa in ALI treatment.
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Affiliation(s)
- Kai Guo
- Department of Respiration, 161th Hospital of PLA, Wuhan, Hubei, China
| | - Faguang Jin
- Department of Respiration, TangDu Hospital, Air Force Medical University of PLA, Xi'an, Shaanxi, China
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Lipoxin A4 Ameliorates Acute Pancreatitis-Associated Acute Lung Injury through the Antioxidative and Anti-Inflammatory Effects of the Nrf2 Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:2197017. [PMID: 31781326 PMCID: PMC6875318 DOI: 10.1155/2019/2197017] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 08/08/2019] [Accepted: 09/12/2019] [Indexed: 02/08/2023]
Abstract
Acute lung injury (ALI) is a critical event involved in the pathophysiological process of acute pancreatitis (AP). Many methods have been widely used for the treatment of AP-ALI, but few are useful during early inflammation. Lipoxin A4 (LXA4), a potent available anti-inflammatory and novel antioxidant mediator, has been extensively studied in AP-ALI, but its underlying mechanism as a protective mediator is not clear. This research was conducted to identify the possible targets and mechanisms involved in the anti-AP-ALI effect of LXA4. First, we confirmed that LXA4 strongly inhibited AP-ALI in mice. Next, using ELISA, PCR, and fluorescence detection to evaluate different parameters, LXA4 was shown to reduce the inflammatory cytokine production induced by AP and block reactive oxygen species (ROS) generation in vivo and in vitro. In addition, TNF-α treatment activated the nuclear factor E2-related factor 2 (Nrf2) signaling pathway and its downstream gene heme oxygenase-1 (HO-1) in human pulmonary microvascular endothelial cells (HPMECs), and LXA4 further promoted their expression. This study also provided evidence that LXA4 phosphorylates Ser40 and triggers its nuclear translocation to activate Nrf2. Moreover, when Nrf2-knockout (Nrf2−/−) mice and cells were used to further assess the effect of the Nrf2/HO-1 pathway, we found that Nrf2 expression knockdown partially eliminated the effect of LXA4 on the reductions in inflammatory factor levels while abrogating the inhibitory effect of LXA4 on the ROS generation stimulated by AP-ALI. Overall, LXA4 attenuated the resolution of AP-induced inflammation and ROS generation to mitigate ALI, perhaps by modulating the Nrf2/HO-1 pathway. These findings have laid a foundation for the treatment of AP-ALI.
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