scholarly journals The apelin-13 peptide protects the heart against apoptosis through the ERK/MAPK and PI3K/AKT signaling pathways.

2020 ◽  
Author(s):  
Xuejun Wang ◽  
Li Zhang ◽  
Mengwen Feng ◽  
Hao Zhang ◽  
Jia Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Signaling Pathways ◽  
Akt Signaling ◽  
Blue Staining ◽  
Endocrine Activity ◽  
Multiple Systems ◽  
Erk Mapk

Abstract Background: It has been acknowledged that endocrine activity is associated with the function of multiple systems in vivo. The apelin-13 peptide has been demonstrated to play a crucial role in various physiological and pathological processes. However, whether apelin-13 peptide function in DOX induced cardiotoxicity is unknown. Methods: We explored the function and mechanism of the apelin-13 peptide in apoptosis and oxidative stress by CCK-8, trypan blue staining, TUNEL, LDH, JC-1 and western blot in vitro. Then we verified the effect of apelin-13 in vivo by serum CKMB and LDH, echocardiography, sirius red staining and HE staining assay.Results: Treatment with the apelin-13 peptide significantly enhanced cell viability, mitochondrial membrane potential, and reduced LDH release, rate of apoptosis and activation of caspase-3 in vitro. In mice, the apelin-13 peptide alleviated the heart failure induced by DOX treatment. ML-221 inhibited the activation of ERK, PI3K and AKT proteins phosphorylation by apelin-13.Conclusion: The apelin-13 and APJ interaction on the cell membrane inhibits apoptosis though the ERK/MAPK and PI3K/AKT signaling pathways. The application of apelin-13 may be a novel therapeutic strategy in oxidative stress-induced heart failure therapy.

scholarly journals The apelin-13 peptide protects the heart against apoptosis through the ERK/MAPK and PI3K/AKT signaling pathways.

2020 ◽  
Author(s):  
Xuejun Wang ◽  
Li Zhang ◽  
Mengwen Feng ◽  
Hao Zhang ◽  
Jia Xu ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Mitochondrial Membrane Potential ◽  
Cardiac Troponin ◽  
Mitochondrial Membrane ◽  
Akt Signaling ◽  
Blue Staining

Abstract Background: It has been acknowledged that endocrine activity is associated with the function of multiple systems in vivo. The apelin-13 peptide has been demonstrated to play a crucial role in physiological and pathological processes. However, the function of apelin-13 peptide in doxorubicin (DOX)-induced cardiotoxicity is unknown. Methods: We explored the function and mechanism of apelin-13 peptide in apoptosis and oxidative stress by cell counting kit-8 (CCK-8) assay, trypan blue staining, TUNEL, lactate dehydrogenase (LDH), mitochondrial membrane potential assay kit with JC-1 (JC-1) and western blot in vitro. Then we verified the effect of apelin-13 in vivo by detecting serum apelin-13, CKMB, LDH, cardiac troponin I (cTnI) and cardiac troponin T (cTnT). EF, FS and LVEDs were used to identify the structural modification by echocardiography. Sirius red staining and HE staining assay were used to detecting the myocardial fibers alteration under apelin-13 treatment.Results: Treatment with apelin-13 peptide significantly enhanced cell viability, mitochondrial membrane potential, but reduced LDH release, rate of apoptotic cells and activation of caspase-3 in vitro. In mice, apelin-13 alleviated the heart dysfunction induced by DOX. 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221) inhibited the effect of extracellular signal-related kinases (ERK), phosphatidylinositol 3 kinases (PI3K) and protein kinase B (AKT) proteins phosphorylation expression compared with DOX.Conclusion: The apelin-13 and apelin receptor (APJ) interaction on the cell membrane inhibits apoptosis through the ERK/mitogen-activated protein kinase (MAPK) and PI3K/AKT signaling pathways. Our research gives a first glimpse on the biological function and mechanism of apelin-13 on cardiotoxicity.

Exosomes Derived From Human Umbilical Cord Mesenchymal Stem Cells Alleviate Acetaminophen-induced Acute Liver Failure Through Activating ERK and IGF-1R/PI3K/AKT Signaling Pathways

2020 ◽  
Author(s):  
Han-You Wu ◽  
Xiang-Cheng Zhang ◽  
Ye Cao ◽  
Kai Yan ◽  
Jing-Yuan Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Mouse Model ◽  
Signaling Pathways ◽  
Akt Signaling ◽  
Human Umbilical Cord ◽  
Induced Apoptosis

Abstract Background: Human umbilical cord mesenchymal stem cells (hUCMSCs) transplantation has been proposed as a promising therapeutic approach for treating acute liver failure (ALF), but its application is limited by immune rejection and tumor formation. Exosomes contain various bioactive cargos including mRNA, microRNA, and protein that can alter the cellular enviroment to enhance tissue repair. However, the exact effects of hUCMSCs derived exosomes (hUCMSC-Exo) on the healing of ALF and their potential mechanisms are not explored.Methods: In vivo, mouse model of ALF were set up through a single intraperitoneal injection of acetaminophen (APAP, 380 mg/kg). In vitro, human hepatocyte cells LO2 were treated with APAP (5 mM). Then APAP-induced ALF mice and APAP-injured LO2 cells were treated with hUCMSC-Exo. Finally, the effects and the mechanisms were estimated.Results: We found that a single tail vein administration of hucMSC-Exo effectively enhanced the survival rate, inhibited apoptosis in hepatocytes, and improved liver function in APAP-induced mouse model of ALF. Furthermore, the deletion of glutathione (GSH) and superoxide dismutase (SOD), generation of malondialdehyde (MDA), and the over expression of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) caused by APAP were also inhibited by hucMSC-Exo, indicating that hucMSC-Exo inhibited APAP-induced apoptosis of hepatocytes by reducing oxidative stress. Moreover, hucMSC-Exo significantly down-regulated the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α in APAP-treated livers. Western blot showed that hucMSC-Exo significantly promoted the activation of ERK1/2 and IGF-1R/PI3K/AKT signaling pathways in APAP-injured LO2 cells, resulting in the inhibition of apoptosis of LO2 cells. Importantly, PI3K inhibitor LY294002 and ERK1/2 inhibitor PD98059 could reverse the function of hucMSC-Exo on APAP-injured LO2 cells in some extent. Conclusions: Our results suggest that hucMSC-Exo offer antioxidant hepatoprotection against APAP in vitro and in vivo by inhibitiing oxidative stress-induced apoptosis via upregulation of ERK1/2 and PI3K/AKT signaling pathways, suggesting that administration of hucMSC-Exo may be an alternative approach for the treatment of ALF.

scholarly journals Proanthocyanidins against Oxidative Stress: From Molecular Mechanisms to Clinical Applications

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Lingyu Yang ◽  
Dehai Xian ◽  
Xia Xiong ◽  
Rui Lai ◽  
Jing Song ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Low Cost ◽  
Natural Agents ◽  
Molecular Damage ◽  
And Control

Proanthocyanidins (PCs) are naturally occurring polyphenolic compounds abundant in many vegetables, plant skins (rind/bark), seeds, flowers, fruits, and nuts. Numerousin vitroandin vivostudies have demonstrated myriad effects potentially beneficial to human health, such as antioxidation, anti-inflammation, immunomodulation, DNA repair, and antitumor activity. Accumulation of prooxidants such as reactive oxygen species (ROS) exceeding cellular antioxidant capacity results in oxidative stress (OS), which can damage macromolecules (DNA, lipids, and proteins), organelles (membranes and mitochondria), and whole tissues. OS is implicated in the pathogenesis and exacerbation of many cardiovascular, neurodegenerative, dermatological, and metabolic diseases, both through direct molecular damage and secondary activation of stress-associated signaling pathways. PCs are promising natural agents to safely prevent acute damage and control chronic diseases at relatively low cost. In this review, we summarize the molecules and signaling pathways involved in OS and the corresponding therapeutic mechanisms of PCs.

scholarly journals Tanshinone IIA Inhibits Osteosarcoma Growth through a Src Kinase-Dependent Mechanism

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Chao Hu ◽  
Xiaobin Zhu ◽  
Taogen Zhang ◽  
Zhouming Deng ◽  
Yuanlong Xie ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Src Kinase ◽  
Akt Signaling ◽  
Cellular Level ◽  
Tanshinone Iia

Introduction. Osteosarcoma is a malignant tumor associated with high mortality rates due to the toxic side effects of current therapeutic methods. Tanshinone IIA can inhibit cell proliferation and promote apoptosis in vitro, but the exact mechanism is still unknown. The aims of this study are to explore the antiosteosarcoma effect of tanshinone IIA via Src kinase and demonstrate the mechanism of this effect. Materials and Methods. Osteosarcoma MG-63 and U2-OS cell lines were stable transfections with Src-shRNA. Then, the antiosteosarcoma effect of tanshinone IIA was tested in vitro. The protein expression levels of Src, p-Src, p-ERK1/2, and p-AKt were detected by Western blot and RT-PCR. CCK-8 assay and BrdU immunofluorescence assay were used to detect cell proliferation. Transwell assay, cell scratch assay, and flow cytometry were used to detect cell invasion, migration, and cell cycle. Tumor-bearing nude mice with osteosarcoma were constructed. The effect of tanshinone IIA was detected by tumor HE staining, tumor inhibition rate, incidence of lung metastasis, and X-ray. Results. The oncogene role of Src kinase in osteosarcoma is reflected in promoting cell proliferation, invasion, and migration and in inhibiting apoptosis. However, Src has different effects on cell proliferation, apoptosis, and cell cycle regulation among cell lines. At a cellular level, the antiosteosarcoma effect of tanshinone IIA is mediated by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. At the animal level, tanshinone IIA played a role in resisting osteosarcoma formation by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. Conclusion. Tanshinone IIA plays an antiosteosarcoma role in vitro and in vivo and inhibits the progression of osteosarcoma mediated by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways.

scholarly journals Inhibition effects of patchouli alcohol against influenza a virus through targeting cellular PI3K/Akt and ERK/MAPK signaling pathways

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Yunjia Yu ◽  
Yang Zhang ◽  
Shuyao Wang ◽  
Wei Liu ◽  
Cui Hao ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Influenza A ◽  
Plaque Assay ◽  
Mapk Signaling ◽  
Western Blot Assay ◽  
Patchouli Alcohol ◽  
Erk Mapk ◽  
Mapk Signaling Pathways

Abstract Background Patchouli alcohol (PA) is a tricyclic sesquiterpene extracted from Pogostemonis Herba, which is a traditional Chinese medicine used for therapy of inflammatory diseases. Recent studies have shown that PA has various pharmacological activities, including anti-bacterial and anti-viral effects. Methods In this study, the anti-influenza virus (IAV) activities and mechanisms were investigated both in vitro and in vivo. The inhibitory effects of PA against IAV in vitro were evaluated by plaque assay and immunofluorescence assay. The neuraminidase inhibition assay, hemagglutination inhibition (HI) assay, and western blot assay were used to explore the anti-viral mechanisms. The anti-IAV activities in vivo were determined by mice pneumonia model and HE staining. Results The results showed that PA significantly inhibited different IAV strains multiplication in vitro, and may block IAV infection through inactivating virus particles directly and interfering with some early stages after virus adsorption. Cellular PI3K/Akt and ERK/MAPK signaling pathways may be involved in the anti-IAV actions of PA. Intranasal administration of PA markedly improved mice survival and attenuated pneumonia symptoms in IAV infected mice, comparable to the effects of Oseltamivir. Conclusions Therefore, Patchouli alcohol has the potential to be developed into a novel anti-IAV agent in the future.

scholarly journals Cytochrome c oxidase III as a mechanism for apoptosis in heart failure following myocardial infarction

2009 ◽  
Vol 297 (4) ◽  
pp. C928-C934 ◽  
Author(s):  
Changgong Wu ◽  
Lin Yan ◽  
Christophe Depre ◽  
Sunil K. Dhar ◽  
You-Tang Shen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Cytochrome C ◽  
Protein Expression ◽  
Cell Viability ◽  
Cytochrome C Oxidase ◽  
Mitochondrial Gene

Cytochrome c oxidase (COX) is composed of 13 subunits, of which COX I, II, and III are encoded by a mitochondrial gene. COX I and II function as the main catalytic components, but the function of COX III is unclear. Because myocardial ischemia affects mitochondrial oxidative metabolism, we hypothesized that COX activity and expression would be affected during postischemic cardiomyopathy. This hypothesis was tested in a monkey model following myocardial infarction (MI) and subsequent pacing-induced heart failure (HF). In this model, COX I protein expression was decreased threefold after MI and fourfold after HF ( P < 0.05 vs. sham), whereas COX II expression remained unchanged. COX III protein expression increased 5-fold after MI and further increased 10-fold after HF compared with sham ( P < 0.05 vs. sham). The physiological impact of COX III regulation was examined in vitro. Overexpression of COX III in mitochondria of HL-1 cells resulted in an 80% decrease in COX I, 60% decrease in global COX activity, 60% decrease in cell viability, and threefold increase in apoptosis ( P < 0.05). Oxidative stress induced by H2O2 significantly ( P < 0.05) increased COX III expression. H2O2 decreased cell viability by 47 ± 3% upon overexpression of COX III, but only by 12 ± 5% in control conditions ( P < 0.05). We conclude that ischemic stress in vivo and oxidative stress in vitro lead to upregulation of COX III, followed by downregulation of COX I expression, impaired COX oxidative activity, and increased apoptosis. Therefore, upregulation of COX III may contribute to the increased susceptibility to apoptosis following MI and subsequent HF.

scholarly journals Oridonin Promotes Apoptosis and Restrains the Viability and Migration of Bladder Cancer by Impeding TRPM7 Expression via the ERK and AKT Signaling Pathways

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Xianping Che ◽  
Jiangtao Zhan ◽  
Fan Zhao ◽  
Zunhe Zhong ◽  
Mianchuan Chen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Akt Signaling ◽  
Bladder Cancer Cell Line ◽  
Anticancer Efficacy ◽  
T24 Cells

Background. Oridonin is a powerful anticancer compound found in Rabdosia rubescens. However, its potential impact on bladder cancer remains uninvestigated. In this work, we aimed to detect the anticancer effect of oridonin on bladder cancer and explore the molecular mechanisms involved. Methods. The anticancer activity of oridonin was assessed in vitro with a CCK8 assay, an annexin V-FITC apoptosis analysis, and colony formation and Transwell migration assays which were performed with the human bladder cancer cell line T24. Levels of apoptosis-related proteins, melastatin transient receptor potential channel 7 (TRPM7), and signaling molecules were examined in oridonin-treated T24 cells by western blotting or RT-PCR. Oridonin anticancer efficacy was further validated in vivo with a T24 xenograft mouse model. Results. Oridonin repressed the proliferative, colony-forming, and migratory capacities of T24 cells, triggered extensive apoptosis in vitro, and retarded tumor growth in vivo. Moreover, oridonin treatment significantly increased expression levels of p53 and cleaved caspase-3 and reduced expression of TRPM7, p-AKT, and p-ERK. Conclusion. Oridonin exhibited outstanding antiproliferative and antimigratory effects on bladder cancer, and these effects were at least partially associated with targeting of TRPM7 through inactivation of the ERK and AKT signaling pathways. These findings provide insight for the clinical application of oridonin in bladder cancer prevention.

scholarly journals IL-13 promotes in vivo neonatal cardiomyocyte cell cycle activity and heart regeneration

2019 ◽  
Vol 316 (1) ◽  
pp. H24-H34 ◽  
Author(s):  
Dylan J. Wodsedalek ◽  
Samantha J. Paddock ◽  
Tina C. Wan ◽  
John A. Auchampach ◽  
Aria Kenarsary ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signaling Pathways ◽  
Rna Sequencing ◽  
Akt Signaling ◽  
Heart Regeneration ◽  
Newborn Mice ◽  
Neonatal Cardiomyocyte

There is great interest in identifying signaling mechanisms by which cardiomyocytes (CMs) can enter the cell cycle and promote endogenous cardiac repair. We have previously demonstrated that IL-13 stimulated cell cycle activity of neonatal CMs in vitro. However, the signaling events that occur downstream of IL-13 in CMs and the role of IL-13 in CM proliferation and regeneration in vivo have not been explored. Here, we tested the role of IL-13 in promoting neonatal CM cell cycle activity and heart regeneration in vivo and investigated the signaling pathway(s) downstream of IL-13 specifically in CMs. Compared with control, CMs from neonatal IL-13 knockout (IL-13−/−) mice showed decreased proliferative markers and coincident upregulation of the hypertrophic marker brain natriuretic peptide ( Nppb) and increased CM nuclear size. After apical resection in anesthetized newborn mice, heart regeneration was significantly impaired in IL-13−/− mice compared with wild-type mice. Administration of recombinant IL-13 reversed these phenotypes by increasing CM proliferation markers and decreasing Nppb expression. RNA sequencing on primary neonatal CMs treated with IL-13 revealed activation of gene networks regulated by ERK1/2 and Akt. Western blot confirmed strong phosphorylation of ERK1/2 and Akt in both neonatal and adult cultured CMs in response to IL-13. Our data demonstrated a role for endogenous IL-13 in neonatal CM cell cycle and heart regeneration. ERK1/2 and Akt signaling are important pathways known to promote CM proliferation and protect against apoptosis, respectively; thus, targeting IL-13 transmembrane receptor signaling or administering recombinant IL-13 may be therapeutic approaches for activating proregenerative and survival pathways in the heart. NEW & NOTEWORTHY Here, we demonstrate, for the first time, that IL-13 is involved in neonatal cardiomyocyte cell cycle activity and heart regeneration in vivo. Prior work has shown that IL-13 promotes cardiomyocyte cell cycle activity in vitro; however, the signaling pathways were unknown. We used RNA sequencing to identify the signaling pathways activated downstream of IL-13 in cardiomyocytes and found that ERK1/2 and Akt signaling was activated in response to IL-13.

1, 8-cineole protects against ISO-induced heart failure by inhibiting oxidative stress and ER stress in vitro and in vivo

2021 ◽  
Vol 910 ◽  
pp. 174472
Author(s):  
Yu Wang ◽  
Xuan Zhang ◽  
Yao Fu ◽  
Danni Fu ◽  
Dong Zhen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Er Stress
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