Troxerutin Reduces Kidney Damage against BDE-47-Induced Apoptosis via Inhibiting NOX2 Activity and Increasing Nrf2 Activity

2,2,4,4-Tetrabromodiphenyl ether (BDE-47), one of the persistent organic pollutants, seriously influences the quality of life; however, its pathological mechanism remains unclear. Troxerutin is a flavonoid with pharmacological activity of antioxidation and anti-inflammation. In the present study, we investigated troxerutin against BDE-47-induced kidney cell apoptosis and explored the underlying mechanism. The results show that troxerutin reduced renal cell apoptosis and urinary protein secretion in BDE-47-treated mice. Western blot analysis shows that troxerutin supplement enhanced the ratio of Bcl-2/Bax; inhibited the release of cytochrome c from mitochondria, the activation of procaspase-9 and procaspase-3, and the cleavage of PARP; and reduced FAS, FASL, and caspase-8 levels induced by BDE-47. In addition, troxerutin decreased the production of reactive oxygen species (ROS) and increased the activities of antioxidative enzymes. Furthermore, troxerutin blunted Nrf2 ubiquitylation, enhanced the activity of Nrf2, decreased the activity of NOX2, and ameliorated kidney oxidant status of BDE-47-treated mice. Together, these results confirm that troxerutin could alleviate the cytotoxicity of BDE-47 through antioxidation and antiapoptosis, which suggests that its protective mechanism is involved in the inhibition of apoptosis via suppressing NOX2 activity and increasing Nrf2 signaling pathway.

Download Full-text

Selective Activation of Endoplasmic Reticulum Stress by Reactive-Oxygen-Species-Mediated Ochratoxin A-Induced Apoptosis in Tubular Epithelial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms222010951 ◽

2021 ◽

Vol 22 (20) ◽

pp. 10951

Author(s):

Chong-Sun Khoi ◽

Yu-Wen Lin ◽

Jia-Huang Chen ◽

Biing-Hui Liu ◽

Tzu-Yu Lin ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Ochratoxin A ◽

Reactive Oxygen ◽

Underlying Mechanism ◽

Oxygen Species ◽

Food And Feed ◽

Renal Proximal Tubular Cells ◽

Induced Apoptosis

Ochratoxin A (OTA), one of the major food-borne mycotoxins, impacts the health of humans and livestock by contaminating food and feed. However, the underlying mechanism of OTA nephrotoxicity remains unknown. This study demonstrated that OTA induced apoptosis through selective endoplasmic reticulum (ER) stress activation in human renal proximal tubular cells (HK-2). OTA increased ER-stress-related JNK and precursor caspase-4 cleavage apoptotic pathways. Further study revealed that OTA increased reactive oxygen species (ROS) levels, and N-acetyl cysteine (NAC) could reduce OTA-induced JNK-related apoptosis and ROS levels in HK-2 cells. Our results demonstrate that OTA induced ER stress-related apoptosis through an ROS-mediated pathway. This study provides new evidence to clarify the mechanism of OTA-induced nephrotoxicity.

Download Full-text

Dehydroxyhispolon Methyl Ether, A Hispolon Derivative, Inhibits WNT/β-Catenin Signaling to Elicit Human Colorectal Carcinoma Cell Apoptosis

International Journal of Molecular Sciences ◽

10.3390/ijms21228839 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8839

Author(s):

Hueng-Chuen Fan ◽

Ya-Chu Hsieh ◽

Li-Hsuan Li ◽

Ching-Chin Chang ◽

Karolína Janoušková ◽

...

Keyword(s):

Methyl Ether ◽

Cell Apoptosis ◽

Ectopic Expression ◽

Annexin V ◽

B Cell Lymphoma ◽

Human Colon ◽

Underlying Mechanism ◽

Parp Cleavage ◽

Signaling Axis ◽

Induced Apoptosis

Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide. Aberrant activation of WNT/β-catenin signaling present in the vast majority of CRC cases is indispensable for CRC initiation and progression, and thus is a promising target for CRC therapeutics. Hispolon is a fungal-derived polyphenol with a pronounced anticancer effect. Several hispolon derivatives, including dehydroxyhispolon methyl ether (DHME), have been chemically synthesized for developing lead molecules with stronger anticancer activity. Herein, a DHME-elicited anti-CRC effect with the underlying mechanism is reported for the first time. Specifically, DHME was found to be more cytotoxic than hispolon against a panel of human CRC cell lines, while exerting limited toxicity to normal human colon cell line CCD 841 CoN. Additionally, the cytotoxic effect of DHME appeared to rely on inducing apoptosis. This notion was evidenced by DHME-elicited upregulation of poly (ADP-ribose) polymerase (PARP) cleavage and a cell population positively stained by annexin V, alongside the downregulation of antiapoptotic B-cell lymphoma 2 (BCL-2), whereas the blockade of apoptosis by the pan-caspase inhibitor z-VAD-fmk attenuated DHME-induced cytotoxicity. Further mechanistic inquiry revealed the inhibitory action of DHME on β-catenin-mediated, T-cell factor (TCF)-dependent transcription activity, suggesting that DHME thwarted the aberrantly active WNT/β-catenin signaling in CRC cells. Notably, ectopic expression of a dominant–active β-catenin mutant (∆N90-β-catenin) abolished DHME-induced apoptosis while also restoring BCL-2 expression. Collectively, we identified DHME as a selective proapoptotic agent against CRC cells, exerting more potent cytotoxicity than hispolon, and provoking CRC cell apoptosis via suppression of the WNT/β-catenin signaling axis.

Download Full-text

Overexpression of FGF2 delays the progression of osteonecrosis of the femoral head activating the PI3K/Akt signaling pathway

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-021-02715-9 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Pei Lu ◽

Yi-min Shen ◽

Ting Hua ◽

Ting Pan ◽

Gang Chen ◽

...

Keyword(s):

Femoral Head ◽

Protein Expression ◽

Signaling Pathway ◽

Cell Apoptosis ◽

Underlying Mechanism ◽

Treated Group ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Gene And Protein Expression ◽

Induced Apoptosis

Abstract Background The purpose of the current study was to explore the role and underlying mechanism of FGF-2 in dexamethasone (DEX)-induced apoptosis in MC3T3-E1 cells. Methods GSE21727 was downloaded from the Gene Expression Omnibus (GEO) database to identify the differentially expressed genes (DEGs) by the limma/R package. MC3T3-E1 cells were exposed to DEX at different concentrations (0, 10−8, 10−7, 10−6, 10−5 and 10−4 mol/L), and cell viability, flow cytometry and TUNEL assay were used to detect cell proliferation and apoptosis. An FGF-2-pcDNA3 plasmid (oe-FGF-2) was used to overexpress FGF-2, and western blotting was conducted to detect protein expression. Results We found that FGF-2 was downregulated in the DEX-treated group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that DEGs were associated with PI3K/Akt signaling pathway. DEX downregulated FGF-2 gene and protein expression, inhibited viability and induced MC3T3-E1 cell apoptosis. Overexpression of FGF-2 reversed DEX-induced apoptosis in MC3T3-E1 cells. FGF-2-mediated anti-apoptosis was impaired by inactivating the PI3K/AKT pathway with LY294002. Moreover, overexpression of FGF2 delayed the progression of DEX-induced osteonecrosis of the femoral head (ONFH) animal model by regulation PI3K/Akt signaling pathway. Conclusion In conclusion, FGF-2 is effective at inhibiting DEX-induced MC3T3-E1 cell apoptosis through regulating PI3K/Akt signaling pathway.

Download Full-text

l-Arginine Alleviates LPS-Induced Oxidative Stress and Apoptosis via Activating SIRT1-AKT-Nrf2 and SIRT1-FOXO3a Signaling Pathways in C2C12 Myotube Cells

Antioxidants ◽

10.3390/antiox10121957 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1957

Author(s):

Ye Zhao ◽

Qin Jiang ◽

Xuefei Zhang ◽

Xiaoxiao Zhu ◽

Xia Dong ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathways ◽

Cell Apoptosis ◽

Muscle Injury ◽

Protective Mechanism ◽

Nrf2 Signaling Pathway ◽

Wide Range ◽

Range Of Functions ◽

Sirt1 Inhibitor ◽

C2c12 Myotube

l-arginine (l-Arg) has been reported to possess a wide range of functions, including anti-inflammatory, anti-oxidative, and anti-apoptosis. However, the role of l-Arg in LPS-induced muscle injury and its potential protective mechanism has not been well elucidated. This study aimed to investigate the effects of l-Arg on the LPS-induced oxidative stress and apoptosis in differentiated C2C12 myotube cells. Our results demonstrated that myotube cells treated with 0.2 mg/mL LPS significantly decreased cell viability. l-Arg treatment significantly suppressed LPS induced ROS accumulation and cell apoptosis. Furthermore, l-Arg improved antioxidant-related enzymes’ activities; increased antioxidant ability via Akt-Nrf2 signaling pathway; maintained the mitochondrial membrane potential (MMP); and enhanced FOXO3a expression, leading to a decrease in the mitochondrial-associated apoptotic proteins. In addition, l-Arg exposure dramatically increased the mRNA and protein expressions of SIRT1. The cytoprotective effect of l-Arg was restricted by the SIRT1 inhibitor EX527, which led to an increase in ROS level, apoptosis rate, and decreased cell MMP. The results also demonstrated that EX527 treatment significantly eliminated the effect of l-Arg on LPS-induced oxidative damage and mitochondria-mediated cell apoptosis. Our findings revealed that l-Arg could be used as a potential nutraceutical in reducing muscle injury via regulating SIRT1-Akt-Nrf2 and SIRT1-FOXO3a-mitochondria apoptosis signaling pathways.

Download Full-text

Pterostilbene promotes mitochondrial apoptosis and inhibits proliferation in glioma cells

Scientific Reports ◽

10.1038/s41598-021-85908-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Haijun Gao ◽

Ziqiang Liu ◽

Weidong Xu ◽

Qunhui Wang ◽

Chaochao Zhang ◽

...

Keyword(s):

Cell Apoptosis ◽

Glioma Cell ◽

Tumor Volume ◽

Glioma Cells ◽

Underlying Mechanism ◽

Jnk Signaling ◽

Phase Arrest ◽

New Treatment ◽

Induced Apoptosis

AbstractGlioma is the most general primary and lethal intracranial malignant tumor. Pterostilbene (PTE), an analog of stilbene and resveratrol, has attracted attention in recent years due to its significant antitumor activity in multiple solid tumors; however, its effect on drug-resistant glioma cells and the underlying mechanism have not yet been reported. In this study, we found that pterostilbene inhibited proliferation, induced intrinsic mitochondria-mediated apoptosis and caused S phase arrest, inhibited migration and excessive invasion in glioma cells. Pretreatment with the pan-caspase-inhibitor Z-VAD-FMK attenuated the PTE-induced apoptosis of glioma cells. Moreover, PTE significantly increased the production of reactive oxygen species (ROS) and reduce the mitochondrial membrane potential (MMP). Inhibition of ROS with N-acetyl-l-cysteine not only rescued PTE-induced reduction of cellular viability but also prevented glioma cell apoptosis. We also discovered ERK 1/2 and JNK signaling pathways were activated by PTE and contributed to induce glioma cell apoptosis. In addition, specific inhibitors of ERK 1/2 and JNK attenuated PTE-induced apoptosis. Besides, PTE significantly reduced tumor volume and prolonged median survival of tumor-bearing rats in vivo. In summary, the results of this study indicate that the anti-tumor effect of PTE on glioma cells may provide a new treatment option for glioma patients.

Download Full-text

L-Arginine Alleviates LPS-induced Oxidative Stress and Apoptosis via Activating SIRT1-AKT-Nrf2 and SIRT1-FOXO3a Signaling Pathways in C2C12 Myotube Cells

10.21203/rs.3.rs-1045345/v1 ◽

2021 ◽

Author(s):

Ye Zhao ◽

Qin Jiang ◽

Xuefei Zhang ◽

Xiaoxiao Zhu ◽

Xia Dong ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathways ◽

Cell Apoptosis ◽

Muscle Injury ◽

In Vitro Models ◽

Protective Mechanism ◽

Nrf2 Signaling Pathway ◽

Wide Range ◽

C2c12 Myotube

Abstract BackgroundAs a highly plasticized tissue, muscle could exert a spontaneous immune behavior in response to external pathogen stimulation. L-arginine (L-Arg) has been reported to possess a wide range of functions, including anti-inflammatory, anti-oxidative, and anti-apoptosis. However, the role of L-Arg in LPS-induced muscle injury and its potential protective mechanism has not been well elucidated. This study aimed to investigate the effects of L-Arg on the LPS-induced oxidative stress and apoptosis in vitro models of well-differentiated C2C12 myotube cells. ResultsIn the present study, we first demonstrated that myotube cells treated with 0.2 mg/mL lipopolysaccharide (LPS) significantly decreased cell viability. Then, different concentrations of L-Arg (0, 0.5, 2.5, 5 mM)-pretreated myotube cells were exposed to LPS. The results showed that L-Arg treatment significantly suppressed reactive oxygen species (ROS) accumulation and cell apoptosis. Furthermore, L-Arg improved antioxidant-related enzymes’ activities; increased antioxidant ability via Akt-Nrf2 signaling pathway; maintained the mitochondrial membrane potential (MMP) and enhanced forkhead box protein 3a (FOXO3a) expression, lead to a decrease in the mitochondrial-associated apoptotic proteins. In addition, L-Arg exposure dramatically increased the mRNA and protein expressions of Sirtuin1 (SIRT1). The cytoprotective effect of L-Arg was restricted by the SIRT1 inhibitor EX527, which led to an increase in ROS level, apoptosis rate, and decreased cell MMP. The results also demonstrated that EX527 treatment significantly eliminated the effect of L-Arg on LPS-induced oxidative damage and mitochondria-mediated cell apoptosis. ConclusionsOur findings revealed that L-Arg could be used as a potential nutraceutical in reducing muscle injury via regulating SIRT1-Akt-Nrf2 and SIRT1-FOXO3a-mitochondria apoptosis signaling pathways.

Download Full-text

Costunolide-Induced Apoptosis via Promoting the Reactive Oxygen Species and Inhibiting AKT/GSK3β Pathway and Activating Autophagy in Gastric Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.722734 ◽

2021 ◽

Vol 9 ◽

Author(s):

Cuixiang Xu ◽

Xiaoyan Huang ◽

Xiaohua Lei ◽

Zhankui Jin ◽

Min Wu ◽

...

Keyword(s):

Gastric Cancer ◽

Reactive Oxygen Species ◽

Cell Cycle ◽

Gastric Carcinoma ◽

Cell Apoptosis ◽

Reactive Oxygen ◽

Carcinoma Cells ◽

Tunel Staining ◽

Oxygen Species ◽

Induced Apoptosis

Objective: Costunolide (Cos) is a sesquiterpene lactone extracted from chicory. Although it possesses anti-tumor effects, the underlying molecular mechanism against gastric cancer cells remains unclear. This study aimed to explore the effect and potential mechanism of Cos on gastric cancer.Methods: The effect of Cos on HGC-27 and SNU-1 proliferation was detected by CCK-8 and clone formation assay. The changes in cell apoptosis were determined using Hoechst 33258 and tunel staining. The morphology of autophagy was analyzed by autophagosomes with the electron microscope and LC3-immunofluorescence with the confocal microscope. The related protein levels of the cell cycle, apoptosis, autophagy and AKT/GSK3β pathway were determined by Western blot. The anti-tumor activity of Cos was evaluated by subcutaneously xenotransplanting HGC-27 into Balb/c nude mice. The Ki67 and P-AKT levels were examined by immunohistochemistry.Results: Cos significantly inhibited HGC-27 and SNU-1 growth and induced cell cycle arrest in the G2/M phase. Cos activated intrinsic apoptosis and autophagy through promoting cellular reactive oxygen species (ROS) levels and inhibiting the ROS-AKT/GSK3β signaling pathway. Moreover, preincubating gastric carcinoma cells with 3-methyladenine (3-MA), a cell-autophagy inhibitor, significantly alleviated the effects of Cos in inducing cell apoptosis.Conclusion: Cos induced apoptosis of gastric carcinoma cells via promoting ROS and inhibiting AKT/GSK3β pathway and activating pro-death cell autophagy, which may be an effective strategy to treat gastric cancer.

Download Full-text

8-Methoxypsoralen Induces Intrinsic Apoptosis in HepG2 Cells: Involvement of Reactive Oxygen Species Generation and ERK1/2 Pathway Inhibition

Cellular Physiology and Biochemistry ◽

10.1159/000430360 ◽

2015 ◽

Vol 37 (1) ◽

pp. 361-374 ◽

Cited By ~ 14

Author(s):

Huan Yang ◽

Jing Xiong ◽

Wenjing Luo ◽

Jian Yang ◽

Tao Xi

Keyword(s):

Reactive Oxygen Species ◽

Cell Viability ◽

Signaling Pathway ◽

Cell Apoptosis ◽

Hepg2 Cells ◽

Ros Generation ◽

Oxygen Species ◽

Intrinsic Apoptosis ◽

Induced Apoptosis

Background/Aims: 8-Methoxypsoralen (8-MOP), a formerly considered photosensitizing agent, induces apoptosis when used alone. On this basis, the present study was designed to explore the effects and mechanisms of 8-MOP-induced apoptosis in human hepatocellular carcinoma HepG2 cells, independent of its photoactivation. Methods: We analyzed the cell viability with MTT assay. Flow cytometry was used to examine the apoptosis rate, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) generation after specific staining. The expression and location of apoptosis-associated protein as well as the activation status of cell signaling pathway were determined by Western blot analysis. Results: 8-MOP significantly decreased cell viability and induced cell apoptosis through mitochondrial apoptotic pathway, as demonstrated by increased Bax/Bcl-2 ratio, collapsed MMP, and induced cytochrome c release (Cyt c) and apoptosis-inducing factor (AIF) transposition. ROS generation was significantly increased by 8-MOP and the eradication of ROS significantly abolished 8-MOP-induced apoptosis. In addition, the activation of ERK1/2 was drastically decreased by 8-MOP as ERK inhibitor PD98059, indicating a role of ERK1/2 signaling pathway in 8-MOP-induced cell apoptosis. Conclusion: 8-MOP induces intrinsic apoptosis by increasing ROS generation and inhibiting ERK1/2 pathway in HepG2 cells. The findings are important in substantiating the anti-tumor role of 8-MOP in cancer therapy.

Download Full-text

Protective Effect of Lycium Barbarum Polysaccharides on Anti-Tuberculosis Drug-Induced Injury to Human Hepatocytes and Its Mechanism

10.21203/rs.3.rs-698780/v1 ◽

2021 ◽

Author(s):

Jianteng Wei ◽

Yongsheng Li ◽

Han Wang ◽

Dong Pei ◽

Ningli Wang ◽

...

Keyword(s):

Liver Injury ◽

Protective Effect ◽

Underlying Mechanism ◽

Dependent Manner ◽

Lycium Barbarum ◽

Drug Induced ◽

Nrf2 Signaling Pathway ◽

Induced Apoptosis ◽

Dose Dependent ◽

Lycium Barbarum Polysaccharides

Abstract Studies have shown that Lycium barbarum polysaccharides (LBPs) have a protective effect on liver injury, but the mechanism is not fully understood. In this work, the effect of LBPs on L-02 cells exposed to anti-tuberculosis drug was investigated and the potential molecular mechanism was explored. Results showed that LBPs significantly prevented anti-tuberculosis drug-induced hepatotoxicity in a dose-dependent manner, as indicated by cell viability and diagnostic indicators of liver injury. The anti-tuberculosis drug promoted the production of reactive oxygen species and enhanced the oxidative stress, as evidenced by an increase in the malondialdehyde level and a decrease in the antioxidant enzyme levels in the liver. These effects were suppressed by treatment with LBPs. Furthermore, exploration of the underlying mechanism of LBPs revealed that the caspase-3 activity was markedly inhibited by the treatment with LBPs in the liver of anti-tuberculosis drug-treated mice. LBPs increased the expression level of Nrf2, thereby inactivating proapoptotic signaling events and restoring the balance between proapoptotic Bax and antiapoptotic Bcl-2 proteins in the cell of anti-tuberculosis drug-treated mice. In conclusion, LBPs inhibited anti-tuberculosis drug-induced apoptosis partly due to its antioxidant and antiapoptosis activities via the Nrf2 signaling pathway.

Download Full-text