FOXO1, a Potential Therapeutic Target, Regulates Autophagic Flux, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis in Human Cholangiocarcinoma QBC939 Cells

Background/Aims: Autophagy is an evolutionarily conserved catabolic mechanism to maintain energy homeostasis and to remove damaged cellular components, which plays an important role in the survival of various cells. Inhibiting autophagy is often applied as a new strategy to halt the growth of cancer cells. Methods: The effect of FOXO1 gene on cellular function and apoptosis and its underlying mechanisms were investigated in cultured QBC939 cells by the methylthiazoletetrazolium (MTT) assay, western blot, DCFDA mitochondrial membrane potential, and ATP content measurement. FOXO1 siRNA was applied to down-regulate FOXO1 expression in QBC939 cells. Results: Here we reported that FOXO1, acetylation of FOXO1 (Ac-FOXO1) and the following interaction between Ac-FOXO1 and Atg7 regulated the basal and serum starvation (SS)-induced autophagy as evidenced by light chain 3 (LC3) accumulation and p62 degration. Either treatment with FOXO1 siRNA or resveratrol, a sirt1 agonist, inhibited autophagic flux, resulting in oxidative stress, mitochondrial dysfunction (MtD) and apoptosis in QBC939 cells, which were attenuated by enhancing autophagy with rapamycin. On the contrary, inhibiting autophagic flux with 3-MA worsened all these effects in QBC939 cells. Conclusions: Taken together, our study for the first time identified FOXO1 as a potential therapeutic target to cure against human cholangiocarcinoma via regulation of autophagy, oxidative stress and MtD.

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FoxO1, a Potential Therapeutic Target, Regulates Mitochondrial Dysfunction and Pyroptosis in LPS-Induced Human Cervical Cancer Cells

10.21203/rs.3.rs-110897/v1 ◽

2020 ◽

Author(s):

Huizhi Wang ◽

Zhi Ma ◽

Fanshu Gao ◽

Wei Jiang ◽

Yang Li ◽

...

Keyword(s):

Cervical Cancer ◽

Mitochondrial Dysfunction ◽

Cancer Cells ◽

Therapeutic Target ◽

Mitochondrial Morphology ◽

Potential Therapeutic Target ◽

Cervical Cancer Cells ◽

Foxo1 Gene ◽

Human Cervical Cancer Cells ◽

Human Cervical Cancer

Abstract Background: Chronic inflammation plays an important role in the development of cervical cancer. Studies have demonstrated that transcription factors forkhead box protein O1 (FoxO1) have been reported to play important roles in various cancers. Aim: The purpose of this study was to investigate the effect of FoxO1 gene on lipopolysaccharide (LPS)-induced inflammation and intracellular pyroptosis in the development and progression of human cervical cancer cells (SiHa).Methods: In this study, FoxO1 expression was examined using real-time polymerase chain reaction (PCR), western blotting and immunohistochemical staining. SiHa cells migration and proliferation was detected using the transwell assay and 3H‑TdR assay. Mitochondrial function was assessed based on reactive oxygen species (ROS) generation and changes in the mitochondrial membrane potential (ΔΨm). Results: Our study demonstrated that LPS inhibited FoxO1 gene expression, and the silence of FoxO1 gene caused the accumulation of ROS, decreases in the ΔΨm and mitochondrial morphology change). However, either overexpression of FoxO1 or metformin could reverse the LPS-induced mitochondrial dysfunction, cell pyroptosis, migration and proliferation.Conclusions: Our study indicated that FoxO1 as a potential therapeutic target to cure against LPS-induced human cervical cancer in a mitochondria-dependent manner.

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YiQiFuMai Powder Injection Protects against Ischemic Stroke via Inhibiting Neuronal Apoptosis and PKCδ/Drp1-Mediated Excessive Mitochondrial Fission

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/1832093 ◽

2017 ◽

Vol 2017 ◽

pp. 1-17 ◽

Cited By ~ 7

Author(s):

Yingqiong Xu ◽

Yan Wang ◽

Guangyun Wang ◽

Xinyi Ye ◽

Jiangwei Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Ischemic Stroke ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Neuronal Apoptosis ◽

Mitochondrial Fission ◽

Powder Injection ◽

Mitochondria Membrane Potential ◽

Protein Levels ◽

Underlying Mechanisms

YiQiFuMai (YQFM) powder injection has been reported to be used in cardiovascular and nervous system diseases with marked efficacy. However, as a treatment against diseases characterized by hypoxia, lassitude, and asthenia, the effects and underlying mechanisms of YQFM in neuronal mitochondrial function and dynamics have not been fully elucidated. Here, we demonstrated that YQFM inhibited mitochondrial apoptosis and activation of dynamin-related protein 1 (Drp1) in cerebral ischemia-injured rats, producing a significant improvement in cerebral infarction and neurological score. YQFM also attenuated oxidative stress-induced mitochondrial dysfunction and apoptosis through increasing ATP level and mitochondria membrane potential (Δψm), inhibiting ROS production, and regulating Bcl-2 family protein levels in primary cultured neurons. Moreover, YQFM inhibited excessive mitochondrial fission, Drp1 phosphorylation, and translocation from cytoplasm to mitochondria induced by oxidative stress. We provided the first evidence that YQFM inhibited the activation, association, and translocation of PKCδ and Drp1 upon oxidative stress. Taken together, we demonstrate that YQFM ameliorates ischemic stroke-induced neuronal apoptosis through inhibiting mitochondrial dysfunction and PKCδ/Drp1-mediated excessive mitochondrial fission. These findings not only put new insights into the unique neuroprotective properties of YQFM associated with the regulation of mitochondrial function but also expand our understanding of the underlying mechanisms of ischemic stroke.

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Daphnetin Attenuated Cisplatin-Induced Acute Nephrotoxicity With Enhancing Antitumor Activity of Cisplatin by Upregulating SIRT1/SIRT6-Nrf2 Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2020.579178 ◽

2020 ◽

Vol 11 ◽

Author(s):

Xiaoye Fan ◽

Wei Wei ◽

Jingbo Huang ◽

Liping Peng ◽

Xinxin Ci

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Cell Damage ◽

Protective Effects ◽

Normal Tissues ◽

Nrf2 Signaling Pathway ◽

Apoptosis Pathways ◽

Underlying Mechanisms

Cisplatin (CDDP) is a widely used drug for cancer treatment that exhibits major side effects in normal tissues, such as nephrotoxicity in kidneys. The Nrf2 signaling pathway, a regulator of mitochondrial dysfunction, oxidative stress and inflammation, is a potential therapeutic target in CDDP-induced nephrotoxicity. We explored the underlying mechanisms in wild-type (WT) and Nrf2−/− mice on CDDP-induced renal dysfunction in vivo. We found that Nrf2 deficiency aggravated CDDP-induced nephrotoxicity, and Daph treatment significantly ameliorated the renal injury characterized by biochemical markers in WT mice and reduced the CDDP-induced cell damage. In terms of the mechanism, Daph upregulated the SIRT1 and SIRT6 expression in vivo and in vitro. Furthermore, Daph inhibited the expression level of NOX4, whereas it activated Nrf2 translocation and antioxidant enzymes HO-1 and NQO1, and alleviated oxidative stress and mitochondrial dysfunction. Moreover, Daph suppressed CDDP-induced NF-κB and MAPK inflammation pathways, as well as p53 and cleaved caspase-3 apoptosis pathways. Notably, the protective effects of Daph in WT mice were completely abrogated in Nrf2−/− mice. Moreover, Daph enhanced, rather than attenuated, the tumoricidal effect of CDDP.

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Restoration of Autophagic Flux Rescues Oxidative Damage and Mitochondrial Dysfunction to Protect against Intervertebral Disc Degeneration

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/7810320 ◽

2019 ◽

Vol 2019 ◽

pp. 1-27 ◽

Cited By ~ 5

Author(s):

Liang Kang ◽

Qian Xiang ◽

Shengfeng Zhan ◽

Yu Song ◽

Kun Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Intervertebral Disc ◽

Oxidative Damage ◽

Mitochondrial Dysfunction ◽

Disc Degeneration ◽

Cell Apoptosis ◽

Intervertebral Disc Degeneration ◽

Autophagic Flux ◽

Ecm Degradation

Oxidative stress-induced mitochondrial dysfunction and nucleus pulposus (NP) cell apoptosis play crucial roles in the development of intervertebral disc degeneration (IDD). Increasing studies have shown that interventions targeting impaired autophagic flux can maintain cellular homeostasis by relieving oxidative damage. Here, we investigated the effect of curcumin (CUR), a known autophagy activator, on IDD in vitro and in vivo. CUR suppressed tert-butyl hydroperoxide- (TBHP-) induced oxidative stress and mitochondrial dysfunction and thereby inhibited human NP cell apoptosis, senescence, and ECM degradation. CUR treatment induced autophagy and enhanced autophagic flux in an AMPK/mTOR/ULK1-dependent manner. Notably, CUR alleviated TBHP-induced interruption of autophagosome-lysosome fusion and impairment of lysosomal function and thus contributed to the restoration of blocked autophagic clearance. These protective effects of CUR in TBHP-stimulated human NP cells resembled the effects produced by the autophagy inducer rapamycin, but the effects were partially eliminated by 3-methyladenine- and compound C-mediated inhibition of autophagy initiation or chloroquine-mediated obstruction of autophagic flux. Lastly, CUR also exerted a protective effect against puncture-induced IDD progression in vivo. Our results showed that suppression of excessive ROS production and mitochondrial dysfunction through enhancement of autophagy coupled with restoration of autophagic flux ameliorated TBHP-induced human NP cell apoptosis, senescence, and ECM degradation. Thus, maintenance of the proper functioning of autophagy represents a promising therapeutic strategy for IDD, and CUR might serve as an effective therapeutic agent for IDD.

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Trehalose ameliorates oxidative stress-mediated mitochondrial dysfunction and ER stress via selective autophagy stimulation and autophagic flux restoration in osteoarthritis development

Cell Death and Disease ◽

10.1038/cddis.2017.453 ◽

2017 ◽

Vol 8 (10) ◽

pp. e3081-e3081 ◽

Cited By ~ 60

Author(s):

Qian Tang ◽

Gang Zheng ◽

Zhenhua Feng ◽

Yu Chen ◽

Yiting Lou ◽

...

Keyword(s):

Oxidative Stress ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Autophagic Flux ◽

Selective Autophagy

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Oleate prevents palmitate-induced mitochondrial dysfunction in chondrocytes: a potential therapeutic target in metabolic osteoarthritis

Osteoarthritis and Cartilage ◽

10.1016/j.joca.2019.02.307 ◽

2019 ◽

Vol 27 ◽

pp. S198-S199

Author(s):

M. Vazquez Mosquera ◽

M. Fernández Moreno ◽

S. Relaño Fernández ◽

A. Dalmao Fernández ◽

P. Ramos Louro ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Therapeutic Target ◽

Potential Therapeutic Target

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Nrf2, a Potential Therapeutic Target against Oxidative Stress in Corneal Diseases

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/2326178 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Xiu-Fen Liu ◽

Dan-Dan Zhou ◽

Tian Xie ◽

Tayyab Hamid Malik ◽

Cheng-Bo Lu ◽

...

Keyword(s):

Oxidative Stress ◽

Therapeutic Target ◽

Expression Profiles ◽

Corneal Dystrophy ◽

Antioxidant Response ◽

Erythroid Cell ◽

Defense Systems ◽

Promising Therapeutic Target ◽

Corneal Wound ◽

Underlying Mechanisms

Corneal diseases are one of the major causes of blindness worldwide. Conservative medical agents, which may prevent sight-threatening corneal disease progression, are urgently desired. Numerous evidences have revealed the involvement of oxidative stress in various corneal diseases, such as corneal wound healing and Fuchs endothelial corneal dystrophy (FECD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like erythroid-cell-derived protein with CNC homology- (ECH-) associated protein 1 (Keap1)/antioxidant response element (ARE) signaling is well known as one of the main antioxidative defense systems. To the best of our knowledge, this is the first review to elucidate the different expression profiles of Nrf2 signaling as well as the underlying mechanisms in corneal diseases, implicating that Nrf2 may serve as a potentially promising therapeutic target for corneal diseases.

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