scholarly journals Fasting Induces Hepatocellular Carcinoma Cell Apoptosis by Inhibiting SET8 Expression

2020 ◽  
Vol 2020 ◽  
pp. 1-19 ◽  
Author(s):  
Jie Qi ◽  
Xiangyuan Chen ◽  
Qichao Wu ◽  
Jing Wang ◽  
Hao Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Viability ◽  
Cell Apoptosis ◽  
Antioxidant Response ◽  
Signalling Pathway ◽  
Related Factor ◽  
Apoptosis Resistance ◽  
Cancer Proliferation

Background. Hepatocellular carcinoma (HCC) is a life-threatening cancer, and the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signalling pathway plays a crucial role in apoptosis resistance in cancer cells. Fasting is reported to mediate tumour growth reduction and apoptosis. SET8 is involved in cancer proliferation, invasiveness, and migration. However, whether SET8 participates in fasting-mediated apoptosis in HCC remains unclear. Methods. We used immunohistochemical staining to analyse the expression of SET8, Keap1, and Nrf2 in HCC tissues. Cell viability, apoptosis, and cellular reactive oxygen species (ROS) were assessed, and Western blot and qPCR analyses were used to examine the expression of Keap1/Nrf2 in HCC cells under fasting, SET8 overexpression, and PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1α interacts with SET8. In vivo experiments were performed to verify the conclusions from the in vitro experiments. Results. Our data indicate that SET8 expression is associated with poor survival in HCC patients. Both in vitro and in vivo results demonstrated that fasting decreased cell viability and downregulated expression of SET8, Nrf2, and downstream effectors of Nrf2, while it upregulated Keap1 expression, mediated ROS accumulation, and induced HCC cell apoptosis. These results were similar to what is observed in SET8-deficient cells. Furthermore, SET8 was found to interact with PGC1α, and both PGC1α and H4K20me1, a downstream target of SET8, were found to be enriched at the Keap1 promoter region. These two factors were further determined to attenuate Keap1 promoter activity. Conclusions. The results of our study demonstrate that fasting induces HCC apoptosis by inhibiting SET8 expression and that SET8 interacts with PGC1α to activate the Nrf2/ARE signalling pathway by inhibiting Keap1 expression.

Targeting NOX4 Disrupts the Resistance of Papillary Thyroid Carcinoma to Chemotherapeutic Drugs and Lenvatinib

2021 ◽  
Author(s):  
Ping Tang ◽  
Jianfeng Sheng ◽  
Xiujuan Peng ◽  
Renfei Zhang ◽  
Tao Xu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Viability ◽  
Cell Apoptosis ◽  
Underlying Mechanism ◽  
Serum Starvation ◽  
Chemotherapeutic Drugs ◽  
Nadph Oxidase 4 ◽  
Cell Death Detection Elisaplus

Abstract Background: Advanced differentiated thyroid cancer cells are subjected to extreme nutritional starvation which contributes to develop resistance to treatments; however, the underlying mechanism remains unclear.Methods: We used 0.5% serum to mimic starvation during cell culture. A CCK8 assay, cell death Detection ELISAPLUS kit, PI staining were measured to determine cell viability, cell apoptosis and cell cycle respectively in BCPAP cells and TPC-1 cells expressing shRNA against NOX4. The cells were then treated with etoposide and doxorubicin, two chemotherapeutic drugs, as well as lenvatinib to determine the role of NOX4 in resistance. Lenvatinib-resistant BCPAP cells (LRBCs) were also established to confirm the role. Finally, GLX351322, a chemical inhibitor targeting NOX4, was used to inhibit NOX4-derived ROS and detect the the contribution of NOX4 to resistance in vitro and in vivo. Results: NADPH oxidase 4 (NOX4) is highly expressed under serum starvation in BCPAP or TPC-1 cells. NOX4 knockdown impairs cell viability, increases cell apoptosis, extends G1 phase in cell cycle and modulates the level of energy-associated metabolites in starved cells. When these starved cells or Lenvatinib-resistant BCPAP cells (LRBCs) are treated with chemotherapeutic drugs or Lenvatinib, NOX4 knockdown inhibits cell viability and aggravates cell apoptosis depending on NOX4-derived ROS production. GLX351322, a NOX4-derived ROS inhibitor, has a significantly inhibitory effect on cell growth in vitro and the growth of BPCPA-derived even LRBCs-derived xenografts in vivo.Conclusions: These findings highlight NOX4 and NOX4-derived ROS as a potential therapeutic target in resistance of PTC patients.

scholarly journals Ethyl Vanillin Protects against Kidney Injury in Diabetic Nephropathy by Inhibiting Oxidative Stress and Apoptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Yuna Tong ◽  
Shan Liu ◽  
Rong Gong ◽  
Lei Zhong ◽  
Xingmei Duan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Cell Apoptosis ◽  
Cell Model ◽  
Critical Role ◽  
Kidney Injury ◽  
Related Factor ◽  
Ethyl Vanillin

Diabetes-induced oxidative stress and apoptosis is regarded as a critical role in the pathogenesis of diabetic nephropathy (DN). Treating diabetes-induced kidney damage and renal dysfunction has been thought a promising therapeutic option to attenuate the development and progression of DN. In this study, we investigated the renoprotective effect of ethyl vanillin (EVA), an active analogue of vanillin isolated from vanilla beans, on streptozotocin- (STZ-) induced rat renal injury model and high glucose-induced NRK-52E cell model. The EVA treatment could strongly improve the deterioration of renal function and kidney cell apoptosis in vivo and in vitro. Moreover, treating with EVA significantly decreased the level of MDA and reactive oxygen species (ROS) and stabilized antioxidant enzyme system in response to oxidative stress by enhancing the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in vivo and in vitro. Furthermore, EVA also markedly suppressed cleaved caspase-3, Bax, and nuclear transcription factor erythroid 2-related factor (Nrf2) expression in STZ-induced rats. Therefore, these results of our investigation provided that EVA might protect against kidney injury in DN by inhibiting oxidative stress and cell apoptosis.

Bone mesenchymal stem cells derived extracellular vesicles promotes TRAIL-related apoptosis of hepatocellular carcinoma cells via the delivery of microRNA-20a-3p

2020 ◽  
pp. 1-13
Author(s):  
Lu Deng ◽  
Chang Wang ◽  
Chao He ◽  
Li Chen
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Extracellular Vesicles ◽  
Cell Apoptosis ◽  
Bone Mesenchymal Stem Cells ◽  
Hcc Cells

OBJECTIVE: Bone mesenchymal stem cells (BMSCs) have been widely researched in cancer treatment, including hepatocellular carcinoma (HCC). This study intended to discuss the mechanism of miR-20a-3p in BMSCs-extracellular vesicles (EVs) in HCC apoptosis. METHODS: BMSCs were isolated and identified. EVs derived from BMSCs were extracted and identified. After overexpressing or inhibiting miR-20a-3p expression in BMSCs, EVs were extracted and acted on HCC cells and transplanted tumors. HCC cell apoptosis in the treatment of BMSCs-conditioned medium, BMSCs-EVs and/or miR-20a-3p mimic/inhibitor were evaluated, with the detection of levels of TRAIL and TRAIL-related proteins. A functional rescue experiment about c-FLIP was carried out in HCC cells. The target binding relationship between miR-20a-3p and c-FLIP was detected. The subcutaneous tumorigenesis model of mice was established and injected with BMSCs-EVs to estimate the effect of BMSCs-EVs-miR-20a-3p on HCC growth. RESULTS: EVs isolated from BMSCs conditioned medium promoted the apoptosis of HCC cells. After BMSCs-EVs treatment, TRAIL levels, downstream proteins and miR-20a-3p were increased significantly, but the expression of c-FLIP was decreased. miR-20a-3p could target c-FLIP. BMSCs-EVs inhibited the growth of HCC cells, decreased c-FLIP expression, increased TRAIL levels, and promote the of HCC cell apoptosis. BMSCs-EVs with overexpressing miR-20a-3p further enhanced the apoptotic effect of HCC cells in vitro and in vivo. CONCLUSION: BMSCs-EVs-carried miR-20a-3p targets c-FLIP and increases TRAIL levels in HCC cells, thus promoting TRAIL-related apoptosis.

scholarly journals Fasting Drives Nrf2-Related Antioxidant Response in Skeletal Muscle

2020 ◽  
Vol 21 (20) ◽  
pp. 7780
Author(s):  
Daniele Lettieri-Barbato ◽  
Giuseppina Minopoli ◽  
Rocco Caggiano ◽  
Rossella Izzo ◽  
Mariarosaria Santillo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Energy Homeostasis ◽  
Antioxidant Response ◽  
Protective Mechanism ◽  
Related Factor ◽  
Adaptive Responses ◽  
Positive Role

A common metabolic condition for living organisms is starvation/fasting, a state that could play systemic-beneficial roles. Complex adaptive responses are activated during fasting to help the organism to maintain energy homeostasis and avoid nutrient stress. Metabolic rearrangements during fasting cause mild oxidative stress in skeletal muscle. The nuclear factor erythroid 2-related factor 2 (Nrf2) controls adaptive responses and remains the major regulator of quenching mechanisms underlying different types of stress. Here, we demonstrate a positive role of fasting as a protective mechanism against oxidative stress in skeletal muscle. In particular, by using in vivo and in vitro models of fasting, we found that typical Nrf2-dependent genes, including those controlling iron (e.g., Ho-1) and glutathione (GSH) metabolism (e.g., Gcl, Gsr) are induced along with increased levels of the glutathione peroxidase 4 (Gpx4), a GSH-dependent antioxidant enzyme. These events are associated with a significant reduction in malondialdehyde, a well-known by-product of lipid peroxidation. Our results suggest that fasting could be a valuable approach to boost the adaptive anti-oxidant responses in skeletal muscle.

scholarly journals Protective Effects and Mechanisms of Procyanidins on Parkinson’s Disease In Vivo and In Vitro

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5558
Author(s):  
Juan Chen ◽  
Yixuan Chen ◽  
Yangfan Zheng ◽  
Jiawen Zhao ◽  
Huilin Yu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Pc12 Cells ◽  
Antioxidant Activities ◽  
Antioxidant Response ◽  
Related Factor ◽  
Protective Effects ◽  
Neuroprotective Effects

This research assessed the molecular mechanism of procyanidins (PCs) against neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite 1-methyl-4-phenylpyridinium (MPP+) induced Parkinson’s disease (PD) models. In vitro, PC12 cells were incubated with PCs or deprenyl for 24 h, and then exposed to 1.5 mM MPP+ for 24 h. In vivo, zebrafish larvae (AB strain) 3 days post-fertilization (dpf) were incubated with deprenyl or PCs in 400 μM MPTP for 4 days. Compared with MPP+/MPTP alone, PCs significantly improved antioxidant activities (e.g., glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT)), and decreased levels of reactive oxygen species (ROS) and malondialdehyde (MDA). Furthermore, PCs significantly increased nuclear Nrf2 accumulation in PC12 cells and raised the expression of NQO1, HO-1, GCLM, and GCLC in both PC12 cells and zebrafish compared to MPP+/MPTP alone. The current study shows that PCs have neuroprotective effects, activate the nuclear factor-erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway and alleviate oxidative damage in MPP+/MPTP-induced PD models.

scholarly journals Circ_0015756 aggravates hepatocellular carcinoma development by regulating FGFR1 via sponging miR-610

2020 ◽  
Author(s):  
Weisheng Guo ◽  
Lin Zhao ◽  
Yaguang Wei ◽  
Peng Liu ◽  
Yu Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Viability ◽  
Colony Formation ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Therapeutic Effects

Abstract Background: Hepatocellular carcinoma (HCC) is the leading threat of cancer-related death in humans with poor therapeutic effects. Circular RNAs (circRNAs) are important indicators in cancer diagnosis and prognosis. This study intended to explore the function and mechanism of circ_0015756 in HCC, providing the additional opinion for HCC treatment.Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to detect the expression of circ_0015756 and miR-610. Cell viability was assessed by cell counting kit-8 (CCK-8) assay, and colony formation capacity was ascertained by colony formation assay. Cell proliferation and invasion were monitored by transwell assay. Cell cycle progression and apoptosis were analyzed by flow cytometry assay. Circ_0015756 oncogenicity was determined by Xenograft models. The prediction of targets was performed using the bioinformatics tools, and the verification of targeted relationship was conducted using RNA pull-down, RNA immunoprecipitation (RIP) and dual-luciferase reporter assays. The expression level of fibroblast growth factor receptor 1 (FGFR1) was measured by western blot.Result: The expression of circ_0015756 was increased in HCC tissues, serums and cells. Circ_0015756 downregulation impaired HCC cell viability, colony formation capacity, invasion and migration, induced cell cycle arrest and apoptosis, and inhibited tumor growth in vivo. MiR-610 was ensured as a target of circ_0015756, and miR-610 absence reversed the effects of circ_0015756 downregulation. Further, FGFR1 was interacted by miR-610, and FGFR1 overexpression overturned the effects of miR-610 restoration in vitro. Circ_0015756 could regulate FGFR1 expression by targeting miR-610.Conclusion: Circ_0015756 played its tumorigenic properties in HCC by activating FGFR1 and sponging miR-610, and circ_0015756 was expected to be a vital indicator in HCC diagnosis and treatment.

scholarly journals PCSK9 promotes tumor growth by inhibiting tumor cell apoptosis in hepatocellular carcinoma

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Shi-Zhe Zhang ◽  
Xiao-Dong Zhu ◽  
Long-Hai Feng ◽  
Xiao-Long Li ◽  
Xue-Feng Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Apoptosis ◽  
Xenograft Model ◽  
Disease Free Survival ◽  
High Expression ◽  
Cell Counting ◽  
Mechanistic Study ◽  
Cell Cycle Distribution

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key enzymes in the process of lipid transport, is involved in the disease progression of various types of tumors. This article is to study the role of PCSK9 in the progression of hepatocellular carcinoma (HCC). Methods Immunohistochemistry was used to assess the expression of PCSK9 in tumor specimens from 105 HCC patients who underwent curative resection. Western blotting and quantitative real-time PCR were used to test the protein and mRNA expression levels in HCC cell lines. Cell Counting Kit-8 (CCK-8) and clone formation assays were performed to evaluate the proliferation ability of different kinds of cells in vitro. Flow cytometry was used to analyze cell cycle distribution and apoptosis rate. A xenograft model was established to study the effect of PCSK9 on HCC growth in vivo. TUNEL and immunofluorescence assays were used to detect cell apoptosis. Results High expression of PCSK9 in tumor tissues was related to microvascular invasion (p = 0.036) and large tumor size (p = 0.001) in HCC patients. Overall survival and disease-free survival after surgery were poor in patients with high expression of PCSK9 (p = 0.035 and p = 0.007, respectively). In vivo and in vitro experiments showed that PCSK9 promoted the growth of HCC by inhibiting cell apoptosis. A mechanistic study revealed that PCSK9 increases FASN expression, thereby inhibiting apoptosis of HCC cells via the Bax/Bcl-2/Caspase9/Caspase3 pathway. Conclusions PCSK9 expression level in HCC is an indicator of poor prognosis for patients with HCC. FASN-mediated anti-apoptosis plays an important role in PCSK9-induced HCC progression.

scholarly journals Tricholoma matsutake Aqueous Extract Induces Hepatocellular Carcinoma Cell Apoptosis via Caspase-Dependent Mitochondrial Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Yanzhen Wang ◽  
Yiling Chen ◽  
Xinrui Zhang ◽  
Guangsheng Cai ◽  
Shengshu An ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Aqueous Extract ◽  
Cell Apoptosis ◽  
B Cell Lymphoma ◽  
Mitochondrial Pathway ◽  
Tricholoma Matsutake ◽  
Migration Ability ◽  
Cytotoxicity Activities

Tricholoma matsutake, one of widely accepted functional mushrooms, possesses various pharmacological activities, and its antitumor effect has become an important research point. Our study aims to evaluate the cytotoxicity activities of T. matsutake aqueous extract (TM) in HepG2 and SMMC-7721 cells. In in vitro experiments, TM strikingly reduced cell viability, promoted cell apoptosis, inhibited cell migration ability, induced excessive generation of ROS, and caused caspases cascade and mitochondrial membrane potential dissipation in hepatocellular carcinoma cells. In in vivo experiments, 14-day TM treatment strongly suppressed tumor growth in HepG2 and SMMC-7721-xenografted nude mice without influence on their body weights and liver function. Furthermore, TM increased the levels of cleaved poly-ADP-ribose polymerase (PARP), Bad, and Bax and reduced the expressions of B-cell lymphoma 2 (Bcl-2) in treated cells and tumor tissues. All aforementioned results suggest that caspase-dependent mitochondrial apoptotic pathways are involved in TM-mediated antihepatocellular carcinoma.

scholarly journals TLR4 Influences Hepatitis B Virus Related Hepatocellular Carcinoma by Regulating the Wnt/β-Catenin Pathway

2017 ◽  
Vol 42 (2) ◽  
pp. 469-479 ◽  
Author(s):  
Yuanqin Yin ◽  
Fei Li ◽  
Songlin Li ◽  
Jingjing Cai ◽  
Jing Shi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cell Apoptosis ◽  
Migration And Invasion ◽  
Control Group ◽  
B Virus ◽  
Sirna Group

Background/Aims: We investigated the correlation between toll-like receptor 4 (TLR4) and β-catenin for disclosing the potential pathogenesis of hepatocellular carcinoma (HCC). Methods: Immunohistochemical toolkit was implemented to measure the expression of TLR4 and β-catenin in 98 cases of HCC tissues and adjacent tissues. After setting up the HepG2.2.15 hepatitis B virus (HBV) related HCC cell line, we divided the cells into the control group, TLR4 siRNA group, β-catenin siRNA group, and pcDNA.3.1 TLR4 + β-catenin siRNA group. Western blot, CCK-8 method, Transwell and flow cytometry were used to detect protein expression, cell proliferation, cell migration and invasion as well as cell apoptosis, respectively. Nude mice tumor model was established to observe the effects of TLR4 and β-catenin on the progression of HBV-related HCC in vivo. Results:The positive rates of TLR4 and β-catenin were higher in HCC tissues compared with normal tissues. Both the TLR4 siRNA group and β-catenin siRNA group exhibited a decreased expression of β-catenin. The proliferation, migration and invasion of tumor cells in the above two groups were suppressed, while the cell apoptosis appeared to be stimulated. As suggested by the results from in vivo and in vitro experiments, the up-regulation of TLR4 could antagonize the corresponding effect of β-catenin siRNA. Conclusions: TLR4 can affect the expression of β-catenin and hence influence the progression of HBV-related HCC.

scholarly journals miR-455 Inhibits the Viability and Invasion by Targeting RAB18 in Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Chenghong Wang ◽  
Guicai Zhu ◽  
Miaolin Yu ◽  
Xiufang Mi ◽  
Honghua Qu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Viability ◽  
Cell Lines ◽  
Luciferase Reporter ◽  
Common Cancer ◽  
Huh7 Cells ◽  
Proliferation In Vitro

Background. Hepatocellular carcinoma (HCC) has been regarded as the fifth most common cancer worldwide with a low prognosis. miR-455 usually played the role of a tumor suppressor in multiple cancers. The aim of this study was to investigate the roles of miR-455 in HCC. Materials and Methods. Cell viability and invasion were measured by CCK8 and Transwell assays. Luciferase reporter assay was performed to verify that miR-455 directly binds to the 3′-noncoding region (UTR) of RAB18 mRNA in Huh7 cells. Results. The expression of miR-455 was lower in HCC tissues and cell lines than in nontumor tissues and normal cell line, and downregulation of miR-455 was connected with worse outcome of HCC patients. miR-455 suppressed cell proliferation in vitro and in vivo, and it inhibited the abilities of cell invasion and EMT in HCC. RAB18 was upregulated in HCC tissues and cell lines, and the expression of RAB18 was regulated by miR-455. RAB18 reversed partial roles of miR-455 on cell viability and invasion in HCC. Conclusion. miR-455 inhibited cell viability and invasion by directly targeting the 3′-UTR of RAB18 mRNA of hepatocellular carcinoma.

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