scholarly journals SOCS3-mediated activation of p53-p21-NRF2 axis and cellular adaptation to oxidative stress in SOCS1-deficient hepatocellular carcinoma

2021 ◽  
Author(s):  
MdGulam Musawwir Khan ◽  
Nadia Boufaied ◽  
Mehdi Yeganeh ◽  
Amit Ghosh ◽  
Rajani Kandhi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatocellular Carcinoma ◽  
Drug Target ◽  
Genotoxic Stress ◽  
Antioxidant Response ◽  
Oncogenic Potential ◽  
Nrf2 Activation ◽  
Socs3 Expression ◽  
Elevated Expression ◽  
P53 Activation

SOCS1 and SOCS3 genes, frequently repressed in hepatocellular carcinoma (HCC), function as tumor suppressors in hepatocytes. However, TCGA transcriptomic data revealed that SOCS1-low/SOCS3-high specimens displayed more aggressive HCC than SOCS1-low/SOCS3-low cases. We show that hepatocyte-specific Socs1-deficient livers upregulate Socs3 expression following genotoxic stress. Whereas deletion of Socs1 or Socs3 increased HCC susceptibility, ablation of both genes attenuated HCC growth. SOCS3 promotes p53 activation in SOCS1-deficient livers, leading to increased expression of CDKN1A (p21WAF1/CIP1), which coincides with elevated expression and transcriptional activity of NRF2. Deleting Cdkn1a in SOCS1-deficient livers diminished NRF2 activation, oxidative stress and HCC progression. Elevated CDKN1A expression and enrichment of antioxidant response genes also characterized SOCS1-low/SOCS3-high HCC. SOCS1 expression in HCC cell lines reduced oxidative stress, p21 expression and NRF2 activation. Our findings demonstrate that SOCS1 controls the oncogenic potential of SOCS3-driven p53-p21-NRF2 axis and suggest that NRF2-mediated antioxidant response represents a drug target in SOCS1-deficient HCC.

Fumonisin B1-induced oxidative stress triggers Nrf2-mediated antioxidant response in human hepatocellular carcinoma (HepG2) cells

2018 ◽  
Vol 35 (1) ◽  
pp. 99-109 ◽  
Author(s):  
Thilona Arumugam ◽  
Yashodani Pillay ◽  
Terisha Ghazi ◽  
Savania Nagiah ◽  
Naeem Sheik Abdul ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatocellular Carcinoma ◽  
Hepg2 Cells ◽  
Fumonisin B1 ◽  
Antioxidant Response ◽  
Human Hepatocellular Carcinoma

Oxidative stress indicated by elevated expression of Nrf2 and 8-OHdG promotes hepatocellular carcinoma progression

2017 ◽  
Vol 34 (4) ◽  
Author(s):  
Chakriwong Ma-on ◽  
Anapat Sanpavat ◽  
Patcharawalai Whongsiri ◽  
Surasit Suwannasin ◽  
Nattiya Hirankarn ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatocellular Carcinoma ◽  
Elevated Expression

Abstract 17514: Hydrogen Sulfide Levels and NRF2 Activity are Attenuated in the Setting of Critical Limb Ischemia (CLI)

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Kazi N Islam ◽  
David J Polhemus ◽  
Erminia Donnarumma ◽  
Hiroyuki Otsuka ◽  
Shashi Bhushan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Hydrogen Sulfide ◽  
Limb Ischemia ◽  
Antioxidant Response ◽  
Protein Carbonyl ◽  
Related Factor ◽  
Mobility Shift ◽  
Protein Levels ◽  
Nrf2 Activation

Background: Cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST) are enzymatic sources of hydrogen sulfide (H2S). Functions of H2S are mediated by several targets including ion channels and signaling proteins. Nuclear factor-erythriod 2-related factor 2 (NRF2) is responsible for the expression of antioxidant response element (ARE)-regulated genes and is known to be upregulated by H2S. We examined the levels of H2S producing enzymes, H2S, and NRF2 activation status in skeletal muscle obtained from CLI patients. Methods: Gastrocnemius tissues were attained post amputation from human CLI and aged-matched control patients. Tissue H2S levels were measured using gas chromatography methods coupled with sulfur chemiluminescence. RT-qPCR, immunoblot, and electrophoretic mobility shift assay (EMSA) were used to analyze respective gene expression, protein levels, and DNA binding activity, respectively. Results: We found mRNA and protein levels of CSE, CBS, and 3-MST were significantly decreased in skeletal muscle of CLI (~2 fold, p < 0.05) patients as compared to control. H2S and sulfane sulfur levels were significantly decreased in skeletal muscle of CLI patients. We also observed significant reductions in NRF2 activation (2 fold, p < 0.05) as well as antioxidant proteins, such as CuZn-superoxide dismutase (2 fold, p < 0.05), catalase (2 fold, p < 0.05), and glutathione peroxidase (2 fold, p < 0.05) in skeletal muscle of CLI patients. Biomarkers of oxidative stress, such as malondialdehyde and protein carbonyl formation were significantly increased (2 fold, p < 0.05) in skeletal muscle of CLI patients as compared to age-matched controls. Conclusions: The data demonstrate that H2S bioavailability and NRF2 activation are both attenuated in CLI tissues concomitant with significantly increased oxidative stress. Reductions in the activity of H2S producing enzymes may contribute to the pathogenesis of CLI.

scholarly journals Nrf2 activation as a future target of therapy for chronic diseases

2014 ◽  
Vol 4 (12) ◽  
pp. 510 ◽  
Author(s):  
Rame Taha ◽  
Gilbert Blaise
Keyword(s):  
Oxidative Stress ◽  
Chronic Diseases ◽  
Therapeutic Potential ◽  
Antioxidant Response ◽  
Premature Aging ◽  
Therapeutic Effects ◽  
Related Factor ◽  
Nrf2 Activation ◽  
Inflammatory Drugs ◽  
Therapeutic Alternatives

Background: Chronic inflammation integrally related to oxidative stress has been increasingly recognized as a contributing factor in various chronic diseases such as neurodegenerative diseases, pulmonary diseases, metabolic syndrome, and cardiovascular diseases as well as premature aging. Thus, inhibiting this vicious circle has the potential to delay, prevent progression, and treat those diseases. However, adverse effects of current anti-inflammatory drugs and the failure of exogenous antioxidant encourage scientists to develop new therapeutic alternatives. The nuclear factor E2-related factor 2 (Nrf2) is the transcription factor that is responsible for the expression of antioxidant response element (ARE)-regulated genes and have been described as having many therapeutic effects. In this review, we have discussed the role of oxidative stress in various chronic diseases. Furthermore, we have also explored various novel ways to activate Nrf2 either directly or indirectly, which may have therapeutic potential in attenuating oxidative stress, inflammation and mitochondrial dysfunction that contributes to chronic diseases.Keywords: Oxidative stress, Mitochondria, Inflammation, Nrf2, Nutrition, Chronic diseases

scholarly journals The Protective Effects of Isoliquiritigenin and Glycyrrhetinic Acid against Triptolide-Induced Oxidative Stress in HepG2 Cells Involve Nrf2 Activation

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Ling-Juan Cao ◽  
Huan-De Li ◽  
Miao Yan ◽  
Zhi-Hua Li ◽  
Hui Gong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepg2 Cells ◽  
Target Genes ◽  
Biological Activities ◽  
Antioxidant Response ◽  
Current Data ◽  
Glycyrrhetinic Acid ◽  
Protective Effects ◽  
Nrf2 Activation ◽  
Wide Range

Triptolide (TP), an active ingredient ofTripterygium wilfordiiHook f., possesses a wide range of biological activities. Oxidative stress likely plays a role in TP-induced hepatotoxicity. Isoliquiritigenin (ISL) and glycyrrhetinic acid (GA) are potent hepatoprotection agents. The aim of the present study was to investigate whether Nrf2 pathway is associated with the protective effects of ISL and GA against TP-induced oxidative stress or not. HepG2 cells were treated with TP (50 nM) for 24 h after pretreatment with ISL and GA (5, 10, and 20 μM) for 12 h and 24 h, respectively. The results demonstrated that TP treatment significantly increased ROS levels and decreased GSH levels. Both ISL and GA pretreatment decreased ROS and meanwhile enhanced intracellular GSH content. Additionally, TP treatment obviously decreased the protein expression of Nrf2 and its target genes including HO-1 and MRP2 except NQO1. Moreover, both ISL and GA displayed activities as inducers of Nrf2 and increased the expression of HO-1, NQO1, and MRP2. Taken together the current data confirmed that ISL and GA could activate the Nrf2 antioxidant response in HepG2 cells, increasing the expression of its target genes which may be partly associated with their protective effects in TP-induced oxidative stress.

scholarly journals Dysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 481 ◽  
Author(s):  
Azhwar Raghunath ◽  
Kiruthika Sundarraj ◽  
Frank Arfuso ◽  
Gautam Sethi ◽  
Ekambaram Perumal
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcription Factor ◽  
Cancer Progression ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Related Factor ◽  
Liver Malignancy ◽  
Beneficial Effects ◽  
Nrf2 Activation ◽  
Key Factor

The liver executes versatile functions and is the chief organ for metabolism of toxicants/xenobiotics. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third foremost cause of cancer death worldwide. Oxidative stress is a key factor related with the development and progression of HCC. Nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2) is a cytosolic transcription factor, which regulates redox homeostasis by activating the expression of an array of antioxidant response element-dependent genes. Nrf2 displays conflicting roles in normal, healthy liver and HCC; in the former, Nrf2 offers beneficial effects, whereas in the latter it causes detrimental effects favouring the proliferation and survival of HCC. Sustained Nrf2 activation has been observed in HCC and facilitates its progression and aggressiveness. This review summarizes the role and mechanism(s) of action of Nrf2 dysregulation in HCC and therapeutic options that can be employed to modulate this transcription factor.

scholarly journals BRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival

2013 ◽  
Vol 210 (8) ◽  
pp. 1529-1544 ◽  
Author(s):  
Chiara Gorrini ◽  
Pegah S. Baniasadi ◽  
Isaac S. Harris ◽  
Jennifer Silvester ◽  
Satoshi Inoue ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mammary Epithelial Cells ◽  
Antioxidant Response ◽  
Mammary Epithelial ◽  
Oxygen Species ◽  
Nrf2 Activation ◽  
The Impact ◽  
Low Expression

Oxidative stress plays an important role in cancer development and treatment. Recent data implicate the tumor suppressor BRCA1 in regulating oxidative stress, but the molecular mechanism and the impact in BRCA1-associated tumorigenesis remain unclear. Here, we show that BRCA1 regulates Nrf2-dependent antioxidant signaling by physically interacting with Nrf2 and promoting its stability and activation. BRCA1-deficient mouse primary mammary epithelial cells show low expression of Nrf2-regulated antioxidant enzymes and accumulate reactive oxygen species (ROS) that impair survival in vivo. Increased Nrf2 activation rescues survival and ROS levels in BRCA1-null cells. Interestingly, 53BP1 inactivation, which has been shown to alleviate several defects associated with BRCA1 loss, rescues survival of BRCA1-null cells without restoring ROS levels. We demonstrate that estrogen treatment partially restores Nrf2 levels in the absence of BRCA1. Our data suggest that Nrf2-regulated antioxidant response plays a crucial role in controlling survival downstream of BRCA1 loss. The ability of estrogen to induce Nrf2 posits an involvement of an estrogen-Nrf2 connection in BRCA1 tumor suppression. Lastly, BRCA1-mutated tumors retain a defective antioxidant response that increases the sensitivity to oxidative stress. In conclusion, the role of BRCA1 in regulating Nrf2 activity suggests important implications for both the etiology and treatment of BRCA1-related cancers.

Dihydromyricetin Reduces TGF-β Via P53 Activation-dependent Mechanism in Hepatocellular Carcinoma HepG2 Cells

2017 ◽  
Vol 24 (5) ◽  
pp. 419-424 ◽  
Author(s):  
Xiaojie Huang ◽  
Tianming Lian ◽  
Xiaoqian Guan ◽  
Bin Liu ◽  
Siyuan Hao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepg2 Cells ◽  
P53 Activation ◽  
Dependent Mechanism

Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
Author(s):  
Barbara D'Orio ◽  
Anna Fracassi ◽  
Maria Paola Cerù ◽  
Sandra Moreno
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Peroxisome Proliferator ◽  
Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

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