Dehydrocorydaline Protects Against Sepsis-Induced Myocardial Injury Through Modulating the TRAF6/NF-κB Pathway

We aim to investigate the effect and mechanism of dehydrocorydaline (Deh), an alkaloidal component isolated from Rhizoma corydalis, in the treatment of sepsis-mediated myocardial injury. Lipopolysaccharide (LPS) was taken to construct an in-vitro sepsis-myocardial injury models H9C2 cardiomyocytes. The in-vivo model of sepsis in C57BL/6 mice was induced by intraperitoneal injection of Escherichia coli (E. coli). The in-vitro and in-vivo models were treated with Deh in different concentrations, respectively. Hematoxylin-eosin (HE) staining, Masson staining, and immunohistochemistry (IHC) staining were taken to evaluate the histopathological changes of the heart. ELISA was applied to evaluate the levels of inflammatory factors, including IL-6, IL-1β, TNFα, IFNγ, and oxidized factors SOD, GSH-PX in the plasma or culture medium. Western blot was used to measure the expressions of Bax, Bcl2, Caspase3, iNOS, Nrf2, HO-1, TRAF6, NF-κB in heart tissues and cells. The viability of H9C2 cardiomyocytes was detected by the CCK8 method and BrdU assay. The ROS level in the H9C2 cardiomyocytes were determined using immunofluorescence. As a result, Deh treatment improved the survival of sepsis mice, reduced TUNEL-labeled apoptosis of cardiomyocytes. In vitro, Deh enhanced the viability of LPS-induced H9C2 cardiomyocytes and inhibited cell apoptosis. Additionally, Deh showed significant anti-inflammatory and anti-oxidative stress functions via decreasing IL-1β, IL-6, TNFα, and IFNγ levels, mitigating ROS level, up-regulating Nrf2/HO-1, SOD, and GSH-PX expressions dose-dependently. Mechanistically, Deh inhibited TRAF6 expression and the phosphorylation of NF-κB p65. The intervention with a specific inhibitor of TRAF6 (C25-140) or NF-κB inhibitor (BAY 11-7082) markedly repressed the protective effects mediated by Deh. In conclusion, Deh restrains sepsis-induced cardiomyocyte injury by inhibiting the TRAF6/NF-κB pathway.

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Propofol attenuates lung ischemia/reperfusion injury though the involvement of the MALAT1/microRNA-144/GSK3β axis

Molecular Medicine ◽

10.1186/s10020-021-00332-0 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Jian-Ping Zhang ◽

Wei-Jing Zhang ◽

Miao Yang ◽

Hua Fang

Keyword(s):

Cell Apoptosis ◽

Ischemia Reperfusion Injury ◽

Glycogen Synthase ◽

Ischemia Reperfusion ◽

Inflammatory Factors ◽

Therapeutic Effects ◽

Protective Effects ◽

Loss Of Function

Abstract Background Propofol, an intravenous anesthetic, was proven to protect against lung ischemia/reperfusion (I/R) injury. However, the detailed mechanism of Propofol in lung I/R injury is still elusive. This study was designed to explore the therapeutic effects of Propofol, both in vivo and in vitro, on lung I/R injury and the underlying mechanisms related to metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-144 (miR-144)/glycogen synthase kinase-3β (GSK3β). Methods C57BL/6 mice were used to establish a lung I/R injury model while pulmonary microvascular endothelial cells (PMVECs) were constructed as hypoxia/reperfusion (H/R) cellular model, both of which were performed with Propofol treatment. Gain- or loss-of-function approaches were subsequently employed, followed by observation of cell apoptosis in lung tissues and evaluation of proliferative and apoptotic capabilities in H/R cells. Meanwhile, the inflammatory factors, autophagosomes, and autophagy-related proteins were measured. Results Our experimental data revealed that Propofol treatment could decrease the elevated expression of MALAT1 following I/R injury or H/R induction, indicating its protection against lung I/R injury. Additionally, overexpressing MALAT1 or GSK3β promoted the activation of autophagosomes, proinflammatory factor release, and cell apoptosis, suggesting that overexpressing MALAT1 or GSK3β may reverse the protective effects of Propofol against lung I/R injury. MALAT1 was identified to negatively regulate miR-144 to upregulate the GSK3β expression. Conclusion Overall, our study demonstrated that Propofol played a protective role in lung I/R injury by suppressing autophagy and decreasing release of inflammatory factors, with the possible involvement of the MALAT1/miR-144/GSK3β axis.

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Protective effects of ginsenoside Rg1 on intestinal ischemia/reperfusion injury-induced oxidative stress and apoptosis via activation of the Wnt/β-catenin pathway

Scientific Reports ◽

10.1038/srep38480 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 27

Author(s):

Guo Zu ◽

Jing Guo ◽

Ningwei Che ◽

Tingting Zhou ◽

Xiangwen Zhang

Keyword(s):

Signaling Pathway ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Inflammatory Factors ◽

Therapeutic Effects ◽

Protective Effects ◽

Ginsenoside Rg1 ◽

Intestinal Ischemia Reperfusion

Abstract Ginsenoside Rg1 (Rg1) is one of the major bioactive ingredients in Panax ginseng, and it attenuates inflammation and apoptosis. The aims of our study were to explore the potential of Rg1 for the treatment of intestinal I/R injury and to determine whether the protective effects of Rg1 were exerted through the Wnt/β-catenin signaling pathway. In this study, Rg1 treatment ameliorated inflammatory factors, ROS and apoptosis that were induced by intestinal I/R injury. Cell viability was increased and cell apoptosis was decreased with Rg1 pretreatment following hypoxia/reoxygenation (H/R) in the in vitro study. Rg1 activated the Wnt/β-catenin signaling pathway in both the in vivo and in vitro models, and in the in vitro study, the activation was blocked by DKK1. Our study provides evidence that pretreatment with Rg1 significantly reduces ROS and apoptosis induced by intestinal I/R injury via activation of the Wnt/β-catenin pathway. Taken together, our results suggest that Rg1 could exert its therapeutic effects on intestinal I/R injury through the Wnt/β-catenin signaling pathway and provide a novel treatment modality for intestinal I/R injury.

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Piperine Alleviates Doxorubicin-Induced Cardiotoxicity via Activating PPAR-γ in Mice

PPAR Research ◽

10.1155/2019/2601408 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Jie Yan ◽

Si-Chi Xu ◽

Chun-Yan Kong ◽

Xiao-Yang Zhou ◽

Zhou-Yan Bian ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Injury ◽

Inflammatory Factors ◽

Peroxisome Proliferator ◽

Protective Effects ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Myocardial Oxidative Stress

Background. Oxidative stress, inflammation and cardiac apoptosis were closely involved in doxorubicin (DOX)-induced cardiac injury. Piperine has been reported to suppress inflammatory response and pyroptosis in macrophages. However, whether piperine could protect the mice against DOX-related cardiac injury remain unclear. This study aimed to investigate whether piperine inhibited DOX-related cardiac injury in mice. Methods. To induce DOX-related acute cardiac injury, mice in DOX group were intraperitoneally injected with a single dose of DOX (15 mg/kg). To investigate the protective effects of piperine, mice were orally treated for 3 weeks with piperine (50 mg/kg, 18:00 every day) beginning two weeks before DOX injection. Results. Piperine treatment significantly alleviated DOX-induced cardiac injury, and improved cardiac function. Piperine also reduced myocardial oxidative stress, inflammation and apoptosis in mice with DOX injection. Piperine also improved cell viability, and reduced oxidative damage and inflammatory factors in cardiomyocytes. We also found that piperine activated peroxisome proliferator-activated receptor-γ (PPAR-γ), and the protective effects of piperine were abolished by the treatment of the PPAR-γ antagonist in vivo and in vitro. Conclusions. Piperine could suppress DOX-related cardiac injury via activation of PPAR-γ in mice.

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LncRNA KCNQ1OT1 attenuates sepsis-induced myocardial injury via regulating miR-192-5p/XIAP axis

Experimental Biology and Medicine ◽

10.1177/1535370220908041 ◽

2020 ◽

Vol 245 (7) ◽

pp. 620-630 ◽

Cited By ~ 3

Author(s):

Fangyuan Sun ◽

Weifang Yuan ◽

Hao Wu ◽

Gang Chen ◽

Yuxia Sun ◽

...

Keyword(s):

Myocardial Injury ◽

Myocardial Dysfunction ◽

Health Care Systems ◽

Cardiac Injury ◽

Convincing Evidence ◽

Luciferase Reporter ◽

H9c2 Cardiomyocytes ◽

Care Systems

Myocardial dysfunction is a prime cause of death in sepsis. This study is to delve into the function of lncRNA KCNQ1OT1 in myocardial injury induced by sepsis. Sepsis-induced myocardial injury model in rat was initiated by intraperitoneally injecting of LPS (10 mg/kg) in vivo, and cardiomyocyte H9c2 was treated with LPS to mimic sepsis in vitro. KCNQ1OT1 and miR-192-5p expressions were detected by qRT-PCR. The cell viability was probed with CCK-8 experiment and the apoptosis of the cardiomyocytes was tested using flow cytometry analysis. Western blot was operated to determine apoptosis-related proteins expressions. ELISA was used to evaluate the levels of TNF-α, IL-6, and IL-1β. Bioinformatics analysis, RT-PCR, dual luciferase reporter assay, and RNA immunoprecipitation experiment were utilized to detect the interrelation of genes. Herein, we proved that KCNQ1OT1 was considerably down-regulated, whereas miR-192-5p was markedly increased in myocardial tissues of septic rats. KCNQ1OT1 interrelated with miR-192-5p, and negatively modulated its expression levels. Overexpression of KCNQ1OT1 or the transfection of miR-192-5p inhibitors greatly facilitated the viability and impeded the apoptosis of H9c2 cardiomyocytes. miR-192-5p paired with the 3ʹUTR of XIAP, and repressed its protein expression, and XIAP was modulated positively by KCNQ1OT1. In conclusion, our work indicates that down-regulation of KCNQ1OT1 advances cardiac injury through regulating miR-192-5p/XIAP axis during sepsis. Impact statement Sepsis-induced cardiomyopathy remains to be a major challenge to health care systems around the globe. There are no known therapies currently available that can cure the disease. This study provides convincing evidence that KCNQ1OT1 could attenuate sepsis-mediated myocardial injury. We further demonstrate that the beneficial function of KCNQ1OT1 was achieved by regulating the miR-192-5p/XIAP axis. We therefore found a new mechanism of cardioprotective effect of KCNQ1OT1, one which also offers a novel theoretical basis for the therapy of sepsis-induced cardiomyopathy.

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Protective Effects of 6-(Methylsulfinyl)hexyl Isothiocyanate on Aβ1-42-Induced Cognitive Deficit, Oxidative Stress, Inflammation, and Apoptosis in Mice

International Journal of Molecular Sciences ◽

10.3390/ijms19072083 ◽

2018 ◽

Vol 19 (7) ◽

pp. 2083 ◽

Cited By ~ 9

Author(s):

Fabiana Morroni ◽

Giulia Sita ◽

Agnese Graziosi ◽

Eleonora Turrini ◽

Carmela Fimognari ◽

...

Keyword(s):

Bioactive Compound ◽

Biological Properties ◽

Neuroprotective Activity ◽

Inflammatory Factors ◽

Protective Effects ◽

Behavioral Recovery ◽

Memory Impairments ◽

Wasabia Japonica

Alzheimer’s disease (AD) is the most common form of dementia among older people. Although soluble amyloid species are recognized triggers of the disease, no therapeutic approach is able to stop it. 6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a major bioactive compound in Wasabia japonica, which is a typical Japanese pungent spice. Recently, in vivo and in vitro studies demonstrated that 6-MSITC has several biological properties. The aim of the present study was to investigate the neuroprotective activity of 6-MSITC in a murine AD model, induced by intracerebroventricular injection of β-amyloid oligomers (Aβ1-42O). The treatment with 6-MSITC started 1 h after the surgery for the next 10 days. Behavioral analysis showed that 6-MSITC ameliorated Aβ1-42O-induced memory impairments. The decrease of glutathione levels and increase of reactive oxygen species in hippocampal tissues following Aβ1-42O injection were reduced by 6-MSITC. Moreover, activation of caspases, increase of inflammatory factors, and phosphorylation of ERK and GSK3 were inhibited by 6-MSITC. These results highlighted an interesting neuroprotective activity of 6-MSITC, which was able to restore a physiological oxidative status, interfere positively with Nrf2-pathway, decrease apoptosis and neuroinflammation and contribute to behavioral recovery. Taken together, these findings demonstrated that 6-MSITC could be a promising complement for AD therapy.

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Sphingolipids as a Novel Therapeutic Target in Radiation-Induced Lung Injury

Cell Biochemistry and Biophysics ◽

10.1007/s12013-021-01022-8 ◽

2021 ◽

Author(s):

Jeffrey R. Jacobson

Keyword(s):

Lung Injury ◽

Cell Injury ◽

Inflammatory Responses ◽

Small Animal ◽

Protective Effects ◽

Sphingosine 1 Phosphate ◽

Radiation Induced ◽

Injury Models

AbstractRadiation-induced lung injury (RILI) is a potential complication of thoracic radiotherapy that can result in pneumonitis or pulmonary fibrosis and is associated with significant morbidity and mortality. The pathobiology of RILI is complex and includes the generation of free radicals and DNA damage that precipitate oxidative stress, endothelial cell (EC), and epithelial cell injury and inflammation. While the cellular events involved continue to be elucidated and characterized, targeted and effective therapies for RILI remain elusive. Sphingolipids are known to mediate EC function including many of the cell signaling events associated with the elaboration of RILI. Sphingosine-1-phosphate (S1P) and S1P analogs enhance EC barrier function in vitro and have demonstrated significant protective effects in vivo in a variety of acute lung injury models including RILI. Similarly, statin drugs that have pleiotropic effects that include upregulation of EC S1P receptor 1 (S1PR1) have been found to be strongly protective in a small animal RILI model. Thus, targeting of EC sphingosine signaling, either directly or indirectly, to augment EC function and thereby attenuate EC permeability and inflammatory responses, represents a novel and promising therapeutic strategy for the prevention or treatment of RILI.

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Ononin Alleviates Doxorubicin-Induced Cardiotoxicity by Inhibiting ER Stress Through Activation of SIRT3

10.21203/rs.3.rs-813164/v2 ◽

2021 ◽

Author(s):

Shimin Sun ◽

Jingfan Weng ◽

Qi Yang ◽

Xingxiao Huang ◽

Hanlin Zhang ◽

...

Keyword(s):

Er Stress ◽

Myocardial Injury ◽

Molecular Mechanisms ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Protective Effects ◽

H9c2 Cells ◽

Rat Cardiomyocytes

Abstract Introduction Doxorubicin (DOX) is a powerful anthracycline antineoplastic drug, but the clinical application of DOX is seriously limited by its dose-dependent cardiotoxicity. Ononin is a natural isoflavone glycoside and plays a key role in modulating apoptosis related signaling pathways. The aim of this study was to assess the possible cardioprotective effects of Ononin in DOX-induced cardiotoxicity and the underlying molecular mechanisms. Materials and methods Wistar rats were treated with normal saline, DOX with or without Ononin. After the last administration, cardiac function was evaluated by echocardiography. Rats were then sacrificed for histological and TUNEL analyses, with immunological detection for β-actinin, Bax, Bcl-2, GRP78, CHOP and SIRT3. An enzyme-linked immunosorbent assay was performed to assess the myocardial injury markers. H9C2 cells were treated with vehicle, DOX with or without Ononin. Then, 3-TYP was used to find out the relationship between ER stress and SIRT3. Results Ononin treatment ameliorated DOX-induced myocardial injury as demonstrated by echocardiography. Ononin partially restored DOX-induced cardiac dysfunction, both LVEF and LVFS were increased under the cotreatment of Ononin. Ononin also inhibited DOX-induced ER stress and apoptosis in rat cardiomyocytes and H9C2 cells. DOX group had a higher Bax/Bcl-2 ratio, GRP78 and CHOP expression then control group, but Ononin treatment improved these results. This effect was associated with SIRT3 activity, moreover, selective inhibition of SIRT3 blocked the protective effects of Ononin. Conclusion In the present study, we tested the hypothesis that Ononin may protect against DOX-induced cardiomyopathy through ER stress both in vitro and in vivo. Ononin is able to protect against DOX-induced cardiotoxicity by inhibiting ER stress and apoptosis, this effect may via stimulation of the SIRT3 pathway.

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Hispidulin Attenuates Cardiac Hypertrophy by Improving Mitochondrial Dysfunction

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2020.582890 ◽

2020 ◽

Vol 7 ◽

Author(s):

Yan Wang ◽

Zengshuo Xie ◽

Nan Jiang ◽

Zexuan Wu ◽

Ruicong Xue ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Cardiac Hypertrophy ◽

Mitochondrial Function ◽

Specific Inhibitor ◽

Cardiomyocyte Hypertrophy ◽

Mitochondrial Morphology ◽

Protective Effects

Cardiac hypertrophy is a pathophysiological response to harmful stimuli. The continued presence of cardiac hypertrophy will ultimately develop into heart failure. The mitochondrion is the primary organelle of energy production, and its dysfunction plays a crucial role in the progressive development of heart failure from cardiac hypertrophy. Hispidulin, a natural flavonoid, has been substantiated to improve energy metabolism and inhibit oxidative stress. However, how hispidulin regulates cardiac hypertrophy and its underlying mechanism remains unknown. We found that hispidulin significantly inhibited pressure overload-induced cardiac hypertrophy and improved cardiac function in vivo and blocked phenylephrine (PE)-induced cardiomyocyte hypertrophy in vitro. We further proved that hispidulin remarkably improved mitochondrial function, manifested by increased electron transport chain (ETC) subunits expression, elevated ATP production, increased oxygen consumption rates (OCR), normalized mitochondrial morphology, and reduced oxidative stress. Furthermore, we discovered that Sirt1, a well-recognized regulator of mitochondrial function, might be a target of hispidulin, as evidenced by its upregulation after hispidulin treatment. Cotreatment with EX527 (a Sirt1-specific inhibitor) and hispidulin nearly completely abolished the antihypertrophic and protective effects of hispidulin on mitochondrial function, providing further evidence that Sirt1 could be the pivotal downstream effector of hispidulin in regulating cardiac hypertrophy.

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Protective effects of total flavonoids from Clinopodium chinense (Benth.) O. Ktze on myocardial injury in vivo and in vitro via regulation of Akt/Nrf2/HO-1 pathway

Phytomedicine ◽

10.1016/j.phymed.2018.01.004 ◽

2018 ◽

Vol 40 ◽

pp. 88-97 ◽

Cited By ~ 18

Author(s):

Hai-Jing Zhang ◽

Rong-Chang Chen ◽

Gui-Bo Sun ◽

Long-Po Yang ◽

Yin-di Zhu ◽

...

Keyword(s):

Myocardial Injury ◽

Total Flavonoids ◽

Protective Effects

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Exploring the mechanism of astaxanthin against lipopolysaccharide-induced acute lung injury by network pharmacology and experimental validation

10.21203/rs.3.rs-334157/v1 ◽

2021 ◽

Author(s):

lianxiang luo ◽

Xiaoling Li ◽

Riming Huang ◽

Hui Luo

Keyword(s):

Lung Injury ◽

Signaling Pathway ◽

Interaction Analysis ◽

Signal Pathway ◽

Inflammatory Factors ◽

Network Pharmacology ◽

Protective Effects ◽

Myd88 Signaling

Abstract BackgroundAcute lung injury (ALI) is a leading cause of morbidity and mortality in respiratory disease. Astaxanthin, a natural antioxidant xanthophyll carotenoid, has been shown to possess anti-inflammatory activity. However, poor evidence has been reported that whether it has protective effects against ALI.Methods A network pharmacology analysis was carried out combining the construction of the GeneCards database and the Pharmmapper database, The potential active compounds and targets were predicted by compound-target prediction, protein-protein interaction analysis, GO and KEGG pathway analysis. Then, the anti-inflammation effect of astaxanthin was investigated in LPS-induced RAW264.7 cells in vitro and LPS-induced ALI mice in vivo.ResultsThe results screened by GO and KEGG enrichment analysis suggested that astaxanthin had extensive associations with 25 known therapeutic targets of ALI. These target genes were further found to be associated with pathways involved in inflammatory pathways in ALI, such as the Toll-like receptor signal pathway, TNF signal pathway, Hif signal pathway, and NF-Kappa B signal pathway. Pre-treatment with astaxanthin inhibited the TLR4/MyD88 signaling pathway and attenuated LPS-increased inflammatory factors in vitro. Furthermore, the administration of astaxanthin significantly protected lung injury in vivo. Subsequently, we validated astaxanthin binds to the TLR4 pocket using molecular docking. ConclusionTaken together, astaxanthin exerts impressively protective effects on LPS-induced ALI in vitro and in vivo via suppressing the TLR4/MyD88 signaling pathway.

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