Effect of CrkL silence on hypoxia/reoxygenation-induced apoptosis and survival inhibition in cardiomyocytes and the underlying mechanisms

Reperfusion therapy is widely utilized for acute myocardial infarction (AMI), but further injury induced by rapidly initiating reperfusion of the heart is often encountered in clinical practice. Ginsenoside RK3 (RK3) is reportedly present in the processed Radix notoginseng that is often used as a major ingredient of the compound preparation for ischemic heart diseases. This study aimed to investigate the possible protective effect of RK3 against hypoxia-reoxygenation (H/R) induced H9c2 cardiomyocytes damage and its underlying mechanisms. Our results showed that RK3 pretreatment caused increased cell viability and decreased levels of LDH leakage compared with the H/R group. Moreover, RK3 pretreatment inhibited cell apoptosis, as evidenced by decreased caspase-3 activity, TUNEL-positive cells, and Bax expression, as well as increased Bcl-2 level. Further mechanism investigation revealed that RK3 prevented H9c2 cardiomyocytes injury and apoptosis induced by H/R via AKT/Nrf-2/HO-1 and MAPK pathways. These observations indicate that RK3 has the potential to exert cardioprotective effects against H/R injury, which might be of great importance to clinical efficacy for AMI treatment.

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Ox-LDL induces apoptosis in human coronary artery endothelial cells: role of PKC, PTK, bcl-2, and Fas

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.275.2.h568 ◽

1998 ◽

Vol 275 (2) ◽

pp. H568-H576 ◽

Cited By ~ 24

Author(s):

Dayuan Li ◽

Baichun Yang ◽

Jawahar L. Mehta

Keyword(s):

Endothelial Cells ◽

Protein Tyrosine Kinase ◽

Low Density Lipoprotein ◽

Critical Role ◽

Light And Electron Microscopy ◽

Density Lipoprotein ◽

Human Coronary Artery ◽

Underlying Mechanisms ◽

Induced Apoptosis ◽

Hypoxia Reoxygenation

Oxidized low-density lipoprotein (ox-LDL) plays a critical role in the development of atherosclerosis. Recent studies show that ox-LDL may induce apoptosis of cultured rabbit smooth muscle cells and human macrophages. This study was designed to determine the modulation by ox-LDL of apoptosis in cultured human coronary arterial endothelial cells (HCAEC) during hypoxia-reoxygenation and to determine underlying mechanisms. When HCAEC were ∼85% confluent, the cells were exposed to hypoxia (24 h)-reoxygenation (3 h), native LDL, or ox-LDL. Fragmented DNA end-labeling, DNA laddering, and light and electron microscopy were used to determine changes characteristic of apoptosis. Ox-LDL (20 μg/ml) increased apoptosis during hypoxia-reoxygenation compared with hypoxia-reoxygenation alone ( P < 0.05). Low concentrations of ox-LDL (5 μg/ml) and native LDL (20 μg/ml) under identical conditions had no effect on the degree of apoptosis. Ox-LDL markedly decreased endogenous superoxide dismutase activity and increased lipid peroxidation in HCAEC. The presence of ox-LDL, but not native LDL, in cultured HCAEC resulted in the activation of protein kinase C (PKC) and protein tyrosine kinase (PTK). The specific PKC and PTK inhibitors significantly reduced ox-LDL-mediated apoptosis of HCAEC ( P < 0.05). Hypoxia-reoxygenation significantly increased Fas expression and decreased bcl-2 expression in HCAEC lysate as determined by Western analysis. Ox-LDL further increased Fas expression and decreased bcl-2 expression. These data indicate that ox-LDL enhances hypoxia-reoxygenation-mediated apoptosis in HCAEC. Ox-LDL-mediated apoptosis of HCAEC appears to involve activation of PKC and PTK. In addition, ox-LDL modulates Fas and bcl-2 protein expression in HCAEC. This study also suggests that ox-LDL is more important than native LDL in hypoxia-reoxygenation-induced apoptosis.

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Intranasal insulin rescues repeated anesthesia-induced deficits in synaptic plasticity and memory and prevents apoptosis in neonatal mice via mTORC1

Scientific Reports ◽

10.1038/s41598-021-94849-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Patricia Soriano Roque ◽

Mehdi Hooshmandi ◽

Laura Neagu-Lund ◽

Shelly Yin ◽

Noosha Yousefpour ◽

...

Keyword(s):

Cognitive Impairment ◽

Synaptic Plasticity ◽

General Anesthesia ◽

Preventive Treatment ◽

Intranasal Insulin ◽

Translational Repressor ◽

Beneficial Effects ◽

Underlying Mechanisms ◽

Induced Apoptosis ◽

Preclinical And Clinical Studies

AbstractLong-lasting cognitive impairment in juveniles undergoing repeated general anesthesia has been observed in numerous preclinical and clinical studies, yet, the underlying mechanisms remain unknown and no preventive treatment is available. We found that daily intranasal insulin administration to juvenile mice for 7 days prior to repeated isoflurane anesthesia rescues deficits in hippocampus-dependent memory and synaptic plasticity in adulthood. Moreover, intranasal insulin prevented anesthesia-induced apoptosis of hippocampal cells, which is thought to underlie cognitive impairment. Inhibition of the mechanistic target of rapamycin complex 1 (mTORC1), a major intracellular effector of insulin receptor, blocked the beneficial effects of intranasal insulin on anesthesia-induced apoptosis. Consistent with this finding, mice lacking mTORC1 downstream translational repressor 4E-BP2 showed no induction of repeated anesthesia-induced apoptosis. Our study demonstrates that intranasal insulin prevents general anesthesia-induced apoptosis of hippocampal cells, and deficits in synaptic plasticity and memory, and suggests that the rescue effect is mediated via mTORC1/4E-BP2 signaling.

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Interleukin 35 protects cardiomyocytes following ischemia/reperfusion-induced apoptosis via activation of mitochondrial STAT3

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmab007 ◽

2021 ◽

Author(s):

Fengyun Zhou ◽

Ting Feng ◽

Xiangqi Lu ◽

Huicheng Wang ◽

Yangping Chen ◽

...

Keyword(s):

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Protective Role ◽

Cytochrome C Release ◽

Neonatal Cardiomyocytes ◽

Myocardial Ischemia Reperfusion Injury ◽

Myocardial Ischemia Reperfusion ◽

Underlying Mechanisms ◽

Induced Apoptosis

Abstract Mitochondrial reactive oxygen species (mtROS)-induced apoptosis has been suggested to contribute to myocardial ischemia/reperfusion injury. Interleukin 35 (IL-35), a novel anti-inflammatory cytokine, has been shown to protect the myocardium and inhibit mtROS production. However, its effect on cardiomyocytes upon exposure to hypoxia/reoxygenation (H/R) damage has not yet been elucidated. The present study aimed to investigate the potential protective role and underlying mechanisms of IL-35 in H/R-induced mouse neonatal cardiomyocyte injury. Mouse neonatal cardiomyocytes were challenged to H/R in the presence of IL-35, and we found that IL-35 dose dependently promotes cell viability, diminishes mtROS, maintains mitochondrial membrane potential, and decreases the number of apoptotic cardiomyocytes. Meanwhile, IL-35 remarkably activates mitochondrial STAT3 (mitoSTAT3) signaling, inhibits cytochrome c release, and reduces apoptosis signaling. Furthermore, co-treatment of the cardiomyocytes with the STAT3 inhibitor AG490 abrogates the IL-35-induced cardioprotective effects. Our study identified the protective role of IL-35 in cardiomyocytes following H/R damage and revealed that IL-35 protects cardiomyocytes against mtROS-induced apoptosis through the mitoSTAT3 signaling pathway during H/R.

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MiR-489-3p inhibits cell proliferation, migration, and invasion, and induces apoptosis, by targeting the BDNF-mediated PI3K/AKT pathway in glioblastoma

Open Life Sciences ◽

10.1515/biol-2020-0024 ◽

2020 ◽

Vol 15 (1) ◽

pp. 274-283

Author(s):

Bo Zheng ◽

Tao Chen

Keyword(s):

Cell Proliferation ◽

Luciferase Reporter ◽

Akt Pathway ◽

Migration And Invasion ◽

Bdnf Mrna ◽

Protein Levels ◽

Rna Immunoprecipitation ◽

Underlying Mechanisms ◽

Induced Apoptosis ◽

Protein Cell

AbstractAmong astrocyte tumors, glioblastoma (GBM) is the most malignant glioma, highly aggressive and invasive, with extremely poor prognosis. Previous research has reported that microRNAs (miRNAs) participate in the progression of many cancers. Thus, this study aimed to explore the role and the underlying mechanisms of microRNA (miR)-489-3p in GBM progression. The expression of miR-489-3p and brain-derived neurotrophic factor (BDNF) mRNA was measured by quantitative real-time polymerase chain reaction. Western blot analysis was used to detect BDNF protein and the PI3K/AKT pathway-related protein. Cell proliferation, apoptosis, migration, and invasion were analyzed using CKK-8 assay, flow cytometry, and transwell assay, respectively. The interaction between BDNF and miR-489-3p was explored by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. MiR-489-3p was down-regulated and BDNF was up-regulated in GBM tissues and cells. MiR-489-3p re-expression or BDNF knockdown inhibited GBM cell proliferation, migration, and invasion, and promoted apoptosis. BDNF was a target of miR-489-3p, and BDNF up-regulation reversed the effects of miR-489-3p on GBM cells. The protein levels of p-AKT and p-PI3K were notably reduced in GBM cells by overexpression of miR-489-3p, but were rescued following BDNF up-regulation. Therefore, miR-489-3p inhibited proliferation, migration, and invasion, and induced apoptosis, by targeting the BDNF-mediated PI3K/AKT pathway in GBM, providing new strategies for clinical treatment of GBM.

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Inhibiting (pro)renin receptor-mediated p38 MAPK signaling decreases hypoxia/reoxygenation-induced apoptosis in H9c2 cells

Molecular and Cellular Biochemistry ◽

10.1007/s11010-015-2356-8 ◽

2015 ◽

Vol 403 (1-2) ◽

pp. 267-276 ◽

Cited By ~ 13

Author(s):

Yan Liu ◽

Shenglin Zhang ◽

Dechun Su ◽

Jinqiu Liu ◽

Yunpeng Cheng ◽

...

Keyword(s):

P38 Mapk ◽

Mapk Signaling ◽

H9c2 Cells ◽

Induced Apoptosis ◽

Hypoxia Reoxygenation

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MicroRNA-15b enhances hypoxia/reoxygenation-induced apoptosis of cardiomyocytes via a mitochondrial apoptotic pathway

APOPTOSIS ◽

10.1007/s10495-013-0899-2 ◽

2013 ◽

Vol 19 (1) ◽

pp. 19-29 ◽

Cited By ~ 40

Author(s):

Lifeng Liu ◽

Guoming Zhang ◽

Zhuo Liang ◽

Xiuhua Liu ◽

Tiande Li ◽

...

Keyword(s):

Apoptotic Pathway ◽

Mitochondrial Apoptotic Pathway ◽

Induced Apoptosis ◽

Hypoxia Reoxygenation

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HDAC6 inhibitor WT161 performs antitumor effect on osteosarcoma and synergistically interacts with 5-FU

Bioscience Reports ◽

10.1042/bsr20203905 ◽

2021 ◽

Author(s):

Jun Sun ◽

Wei Wu ◽

Xiaofeng Tang ◽

Feifei Zhang ◽

Cheng Ju ◽

...

Keyword(s):

Dependent Manner ◽

Osteosarcoma Cells ◽

Synergistic Inhibition ◽

Proliferative Effect ◽

Xenograft Models ◽

Hdac6 Inhibitor ◽

Underlying Mechanisms ◽

Induced Apoptosis

Background: WT161, as a selective HDAC6 inhibitor, has been shown to play anti-tumor effects on several kinds of cancers. The aim of this study is to explore the roles of WT161 in osteosarcoma and its underlying mechanisms. Methods: The anti-proliferative effect of WT161 on osteosarcoma cells was examined using MTT assay and colony formation assay. Cell apoptosis was analyzed using flow cytometer. The synergistic effect was evaluated by isobologram analysis using CompuSyn software. The osteosarcoma xenograft models were established to evaluate the anti-proliferative effect of WT161 in vivo. Results: WT161 suppressed the cell growth and induced apoptosis of osteosarcoma cells in a dose- and time-dependent manner. Mechanistically, we found that WT161 treatment obviously increased the protein level of PTEN and decreased the phosphorylation level of AKT. More importantly, WT161 show synergistic inhibition with 5-FU on osteosarcoma cells in vitro and in vivo. Conclusions: These results indicate that WT161 inhibits the growth of osteosarcoma through PTEN and has a synergistic efficiency with 5-FU.

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HDAC6 Inhibitor WT161 Performs Antitumor Effect on Ostersarcoma and Synergistically Interacts with 5-FU

10.21203/rs.3.rs-49194/v1 ◽

2020 ◽

Author(s):

Jun Sun ◽

Xiaofeng Tang ◽

Feifei Zhang ◽

Cheng Ju ◽

Renfeng Liu ◽

...

Keyword(s):

Osteosarcoma Cell ◽

Dependent Manner ◽

Osteosarcoma Cells ◽

Proliferative Effect ◽

Xenograft Models ◽

Hdac6 Inhibitor ◽

Underlying Mechanisms ◽

Induced Apoptosis

Abstract Background: WT161 as a new selective HDAC6 inhibitor has been shown to play anti-tumor effects on multiple myeloma and breast cancer. However, the role of WT161 in osteosarcoma remains unclear. The aim of this study is to explore the role of WT161 in osteosarcoma and its underlying mechanisms.Methods: The anti-proliferative effect of WT161 on osteosarcoma cells was examined using MTT assay and colony formation assay. Cell apoptosis was analyzed using flow cytometer. The synergistic effect was evaluated by isobologram analysis using CompuSyn software. The osteosarcoma xenograft models were esatablished to evaluate the anti-proliferative effect of WT161 in vivo.Results: WT161 suppressed the cell growth and induced apoptosis of osteosarcoma cells in a dose- and time-dependent manner. Mechanistically, we found that WT161 treatment obviously increased the protein expression level of PTEN and decreased the phosphorylation level of AKT. Notably, WT161 shows synergistically inhibitory effects on osteosarcoma cell combined with 5-FU. Animal experiment results show WT161 inhibits the growth of osteosarcoma tumor and further illustrates that WT161 and 5-FU have a synergistic efficiency in osteosarcoma.Conclusions: These results indicate that WT161 inhibiting the growth of osteosarcoma through PTEN and has a synergistic efficiency with 5-FU.

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Curcumin Enhanced Busulfan-Induced Apoptosis through Downregulating the Expression of Survivin in Leukemia Stem-Like KG1a Cells

BioMed Research International ◽

10.1155/2015/630397 ◽

2015 ◽

Vol 2015 ◽

pp. 1-16 ◽

Cited By ~ 11

Author(s):

Guangyang Weng ◽

Yingjian Zeng ◽

Jingya Huang ◽

Jiaxin Fan ◽

Kunyuan Guo

Keyword(s):

Specific Inhibitor ◽

Annexin V ◽

Chemotherapeutic Agents ◽

Combination Group ◽

Hematopoietic Stem ◽

Leukemia Relapse ◽

Conditioning Regimens ◽

Underlying Mechanisms ◽

Induced Apoptosis ◽

Related Proteins

Leukemia relapse and nonrecurrence mortality (NRM) due to leukemia stem cells (LSCs) represent major problems following hematopoietic stem cell transplantation (HSCT). To eliminate LSCs, the sensitivity of LSCs to chemotherapeutic agents used in conditioning regimens should be enhanced. Curcumin (CUR) has received considerable attention as a result of its anticancer activity in leukemia and solid tumors. In this study, we investigated the cytotoxic effects and underlying mechanisms in leukemia stem-like KG1a cells exposed to busulfan (BUS) and CUR, either alone or in combination. KG1a cells exhibiting BUS-resistance demonstrated by MTT and annexin V/propidium iodide (PI) assays, compared with HL-60 cells. CUR induced cell growth inhibition and apoptosis in KG1a cells. Apoptosis of KG1a cells was significantly enhanced by treatment with CUR+BUS, compared with either agent alone. CUR synergistically enhanced the cytotoxic effect of BUS. Seven apoptosis-related proteins were modulated in CUR- and CUR+BUS-treated cells analyzed by proteins array analysis. Importantly, the antiapoptosis protein survivin was significantly downregulated, especially in combination group. Suppression of survivin with specific inhibitor YM155 significantly increased the susceptibility of KG1a cells to BUS. These results demonstrated that CUR could increase the sensitivity of leukemia stem-like KG1a cells to BUS by downregulating the expression of survivin.

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