-glucan Salecan Improves Exercise Performance and Displays Anti-Fatigue Effects through Regulating Energy Metabolism and Oxidative Stress in Mice
Xu X, Ding Y, Yang Y, Gao Y, Sun Q, Liu J, Yang X, Wang J and Zhang J
Fatigue induced by prolonged exercise not only leads to the decrease of exercise capacity, but also might be the cause of many diseases. In consideration of the side effects of pharmacological drugs, dietary supplements seem to be a better choice to ameliorate exercise-induced fatigue. The present study aimed to investigate the anti-fatigue effect of Salecan, a novel water-soluble -glucan, during exercise and explore the underlying mechanisms. Male Institute of Cancer Research (ICR) mice were divided into five groups, including the Rest group and the other four Swim-groups treated with Salecan at 0, 25, 50, and 100 mg/kg/day for four weeks. Salecan treatment markedly increased the exhaustive swimming time of mice in the forced swimming test. Exercise fatigue and injury-related biochemical biomarkers including lactate, blood urea nitrogen (BUN), creatinine kinase (CK), alanine transaminase (ALT), and aspartate transaminase (AST) were ameliorated by Salecan. Salecan reversed the decreased serum glucose levels and glycogen contents caused by exercise. In addition, Salecan improved oxidative stress induced by exercise through regulating Nrf2/HO⁻1/Trx signaling pathway. Thus, the beneficial effects of Salecan against fatigue may be due to its positive effects on energy metabolism and antioxidation defence. Our results suggest that Salecan could be a novel potential candidate for anti-fatigue dietary supplements.
Glucose starvation induces LKB1-AMPK-mediated MMP-9 expression in cancer cells
Endo H, Owada S, Inagaki Y, Shida Y and Tatemichi M
Cancer cells utilise the glycolytic pathway to support their rapid growth and proliferation. Since cells in most solid tumours are subjected to severe microenvironmental stresses including low nutrient and oxygen availability, such cancer cells must develop mechanisms to overcome these unfavourable growth conditions by metabolic adaptation. Although the liver kinase B1 (LKB1)-adenosine monophosphate-activated kinase (AMPK) signalling pathway plays a pivotal role in maintaining energy homeostasis under conditions of metabolic stress, the role of LKB1-AMPK signalling in aiding cancer cell survival and in malignant tumours has not yet been fully elucidated. We show that glucose starvation promotes cancer cell invasiveness and migration through LKB1-AMPK-regulated MMP-9 expression. Most intriguingly, triggering the LKB1-AMPK signalling pathway by glucose starvation-induced oxidative stress facilitates selective autophagy, which in turn enhances Keap1 degradation and the subsequent activation of Nrf2. Following this, Nrf2 regulates the transactivation of MMP-9 via Nrf2 binding sites in the promoter region of the MMP-9 gene. These mechanisms also contribute to the suppression of excessive oxidative stress under glucose starvation, and protect against cell death. Our data clearly shows that LKB1-AMPK signalling not only maintains energy and oxidative stress homeostasis, but could also promote cancer progression during metabolic stress conditions by MMP-9 induction.
Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling
Luo M, Shang L, Brooks MD, Jiagge E, Zhu Y, Buschhaus JM, Conley S, Fath MA, Davis A, Gheordunescu E, Wang Y, Harouaka R, Lozier A, Triner D, McDermott S, Merajver SD, Luker GD, Spitz DR and Wicha MS
Although breast cancer stem cells (BCSCs) display plasticity transitioning between quiescent mesenchymal-like (M) and proliferative epithelial-like (E) states, how this plasticity is regulated by metabolic or oxidative stress remains poorly understood. Here, we show that M- and E-BCSCs rely on distinct metabolic pathways and display markedly different sensitivities to inhibitors of glycolysis and redox metabolism. Metabolic or oxidative stress generated by 2DG, HO, or hypoxia promotes the transition of ROS M-BCSCs to a ROS E-state. This transition is reversed by N-acetylcysteine and mediated by activation of the AMPK-HIF1α axis. Moreover, E-BCSCs exhibit robust NRF2-mediated antioxidant responses, rendering them vulnerable to ROS-induced differentiation and cytotoxicity following suppression of NRF2 or downstream thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Co-inhibition of glycolysis and TXN and GSH pathways suppresses tumor growth, tumor-initiating potential, and metastasis by eliminating both M- and E-BCSCs. Exploiting metabolic vulnerabilities of distinct BCSC states provides a novel therapeutic approach targeting this critical tumor cell population.
Applying an electrophilicity-based strategy to develop a novel Nrf2 activator inspired from dietary [6]-shogaol
Du YT, Zheng YL, Ji Y, Dai F, Hu YJ and Zhou B
Activation of nuclear factor erythroid-2-related factor 2 (Nrf2) is a crucial cellular defense mechanisms against oxidative stress, and also an effective means to decrease the risk of oxidative stress-related diseases including cancer. Thus, identifying novel Nrf2 activators is highly anticipated. Inspired from [6]-shogaol (6S), an active component of ginger, herein we developed a novel potent Nrf2 activator, (1E,4E)-1-(4-hydroxy-3-methoxyphenyl)-7- methylocta-1,4,6-trien-3-one (SA) by an electrophilicity-based strategy. Compared with the parent 6S, SA bearing a short but entirely conjugated unsaturated ketone chain manifested the improved electrophilicity and cytoprotection (cell viability for the 10 µM 6S- and SA-treated group being 48.9 ± 5.3% and 76.1 ± 3.2%, respectively) against tert-butylhydroperoxide (t-BHP)-induced cell death (cell viability for the t-BHP-stimulated group being 42.4 ± 0.4%) of HepG2. Mechanistic study uncovers that SA works as a potent Nrf2 activator by inducing Keap1 modification, inhibiting Nrf2 ubiquitylation and phosphorylating ERK in a Michael acceptor-dependent fashion. Taking 6S as an example, this works illustrates the feasibility and importance of applying an electrophilicity-based strategy to develop Nrf2 activators with dietary molecules as an inspiration due to their low toxicity and extraordinarily diverse chemical scaffolds.
Targeting heme oxygenase-1 by quercetin ameliorates alcohol-induced acute liver injury via inhibiting NLRP3 inflammasome activation
Liu S, Tian L, Chai G, Wen B and Wang B
Alcoholic hepatitis (AH) is characterized by inflammation and necrosis of liver tissue caused by excessive alcohol consumption and it even causes organ failure sometimes, in which oxidative stress plays an important role. Quercetin is a bioactive flavonoid in the class of polyphenols with a free-radical scavenging ability and anti-inflammatory activity. Recently it has aroused great interest because of its potential benefits in the prevention and intervention of cancer, cardiovascular abnormalities, neurodegenerative diseases, metabolic disorders and liver fibrosis. However, its role in alcoholic liver injury is still unclear and needs to be elucidated. Through database analysis and serum measurements, we found that there was a decline in the level of heme oxygenase-1 (HO-1) in patients with acute alcoholic hepatitis compared to healthy controls. Quercetin could elevate the expression of nuclear factor E2-related factor 2(Nrf2)/HO-1 and ameliorate ethanol-induced acute liver injury in rats. Moreover, this protective effect of quercetin could be diminished when combined with the HO-1 inhibitor ZnppIX which demonstrated a critical role of HO-1 in quercetin's hepatoprotection. The underlying mechanism of quercetin's benefit on the liver may be explained by its anti-oxidant properties and inhibitory effect on the ROS/NF-κB/NLRP3 inflammasome/IL-1β and IL-18 pathway by inducing HO-1. Meanwhile, quercetin also upregulated the anti-inflammatory factor IL-10, while it was found uncorrelated with HO-1 expression. In conclusion, quercetin can preserve the function of the liver in acute alcoholic injury by upregulating the expression of IL-10 and HO-1 and thus inhibiting NLRP3 inflammasome activation and inflammatory factor secretion. In other words, quercetin looks promising as an alternative treatment and HO-1 may be a potential target in the crosstalk of inflammation and oxidative stress in alcoholic liver damage.
Standardized Morinda citrifolia L. and Morinda elliptica L. leaf extracts alleviated fatigue by improving glycogen storage and lipid/carbohydrate metabolism
Osman WNW and Mohamed S
The antifatigue properties of Morinda elliptica (ME) leaf were compared with Morinda citrifolia (MC) leaf extracts. Sixty Balb/C mice were administered (N = 10): control water, standardized green tea extract (positive control 200 mg/kg body weight [BW]), either 200 or 400 mg MC/kg BW, or either 200 or 400 mg ME/kg BW). The mice performances, biochemical, and mRNA expressions were evaluated. After 6 weeks, the weight-loaded swimming time to exhaustion in the mice consuming 400 mg MC/kg, were almost five times longer than the control mice. The gene expressions analysis suggested the extracts enhanced performance by improving lipid catabolism, carbohydrate metabolism, electron transport, antioxidant responses, energy production, and tissue glycogen stores. The MC and ME extracts enhanced stamina by reducing blood lactate and blood urea nitrogen levels, increasing liver and muscle glycogen reserve through augmenting the glucose metabolism (glucose transporter type 4 and pyruvate dehydrogenase kinase 4), lipid catabolism (acyl-Coenzyme A dehydrogenases and fatty acid translocase), antioxidant (superoxide dismutase 2) defence responses, electron transport (COX4I2), and energy production (PGC1α, NRF1, NRF2, cytochrome C electron transport, mitochondrial transcription factor A, UCP1, and UCP3) biomarkers. The MC (containing scopoletin and epicatechin) was better than ME (containing only scopoletin) or green tea (containing epicatechin and GT catechins) for alleviating fatigue.
Protective properties of Huperzine A through activation Nrf2/ARE-mediated transcriptional response in X-rays radiation-induced NIH3T3 cells
Zhu HF, Yan PW, Wang LJ, Liu YT, Wen J, Zhang Q, Fan YX and Luo YH
Huperzine A (HupA), derived from Huperzia Serrata, has exhibited a variety of biological actions, in particular neuroprotective effect. However, the protective activities of HupA on murine embryonic fibroblast NIH3T3 cells after X-rays radiation have not been fully elucidated. Herein, HupA treatment dramatically promoted cell viability, abated a G0/G1 peak accumulation, and ameliorated increase of cell apoptosis in NIH3T3 cells after X-rays radiation. Simultaneously, HupA notably enhanced activities of anti-oxidant enzymes, inhibited activity of lipid peroxide, and efficiently eliminated production of reactive oxygen species in NIH3T3 cells after X-rays radiation. Dose-dependent increase of antioxidant genes by HupA were associated with up-regulated Nrf2 and down-regulated Keap-1 expression, which was confirmed by increasing nuclear accumulation, and inhibiting of degradation of Nrf2. Notably, augmented luciferase activity of ARE may explained Nrf2/ARE-mediated signaling pathways behind HupA protective properties. Moreover, expression of Nrf2 HupA-mediated was significant attenuated by AKT inhibitor (LY294002), p38 MAPK inhibitor (SB202190) and ERK inhibitor (PD98059). Besides, HupA-mediated cell viability, and ROS production were dramatically bated by LY294002, SB202190, and PD98059. Taken together, HupA effectively ameliorated X-rays radiation-induced damage Nrf2-ARE-mediated transcriptional response via activation AKT, p38, and ERK signaling in NIH3T3 cells.
Dual effects of the Nrf2 inhibitor for inhibition of hepatitis C virus and hepatic cancer cells
Murakami Y, Sugiyama K, Ebinuma H, Nakamoto N, Ojiro K, Chu PS, Taniki N, Saito Y, Teratani T, Koda Y, Suzuki T, Saito K, Fukasawa M, Ikeda M, Kato N, Kanai T and Saito H
We previously showed that knockdown of nuclear factor E2-related factor 2 (Nrf2) resulted in suppression of hepatitis C virus (HCV) infection. In this study, whether brusatol, an Nrf2 inhibitor, has dual anti-HCV and anticancer effects was explored.
Dl-3-n-Butylphthalide improves lipopolysaccharide-induced depressive-like behavior in rats: involvement of Nrf2 and NF-κB pathways
Yang M, Dang R, Xu P, Guo Y, Han W, Liao D and Jiang P
Dl-3-n-Butylphthalide (NBP), a small molecule compound extracted from the seeds of Apium graveolens, possesses a large range of biological effects. Here, we attempted to explore the therapeutic effects of NBP on lipopolysaccharide (LPS)-induced major depressive disorder (MDD) and gain further insight into the underlying mechanisms of the antidepressant effects of NBP.
Peroxidasin is a novel target of the redox-sensitive transcription factor Nrf2
Hanmer KL and Mavri-Damelin D
Peroxidasin (PXDN) facilitates peroxidative reactions via utilisation of hydrogen peroxide (HO) and has been shown to crosslink collagen IV through sulfilimine bond formation in the presence of hypohalous acids. Aberrant PXDN expression has been associated with kidney fibrosis, cancer, congenital eye defects and various cardiovascular disorders. Since PXDN expression is modified by HO, we hypothesized that a major antioxidant response transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), may regulate PXDN expression. PXDN expression in response to HO and the Nrf2-specific inducers, tert-butylhydroquinone (tBHQ) and sulforaphane (SFN), was determined by western blotting and immunofluorescence microscopy, in HeLa and HEK293 cells. Chromatin immunoprecipitation and luciferase reporter assays were used to investigate the regulation of PXDN by Nrf2. We observed elevated Nrf2 nuclear translocation and increased PXDN protein expression in response to HO, tBHQ and SFN, in both cell lines. We found that Nrf2 binds to and increases luciferase reporter gene expression from the PXDN promoter via a putative Nrf2-binding site. In summary, we show that PXDN is a novel target of the redox sensitive transcription factor Nrf2. This finding further highlights the role of PXDN in redox-related processes and compliments the currently understood pathophysiological functions of PXDN.
Resveratrol: An overview of its anti-cancer mechanisms
Elshaer M, Chen Y, Wang XJ and Tang X
Cancer is one of the leading causes of death worldwide. Chemotherapy and radiotherapy are the conventional primary treatments for cancer patients. However, most of cancer cells develop resistance to both chemotherapy and radiotherapy after a period of treatment, besides their lethal side-effects. This motivated investigators to seek more effective alternatives with fewer side-effects. In the last few years, resveratrol, a natural polyphenolic phytoalexin, has attracted much attention due to its wide biological effects. In this concise review, we highlight the role of resveratrol in the prevention and therapy of cancer with particular focus on colorectal and skin cancer. Also, we discuss the molecular mechanisms underlying its chemopreventive and therapeutic activity. Finally, we highlight the problems associated with the clinical application of resveratrol and how attempts have been made to overcome these drawbacks.
The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress
Kim KH, Son JM, Benayoun BA and Lee C
Cellular homeostasis is coordinated through communication between mitochondria and the nucleus, organelles that each possess their own genomes. Whereas the mitochondrial genome is regulated by factors encoded in the nucleus, the nuclear genome is currently not known to be actively controlled by factors encoded in the mitochondrial DNA. Here, we show that MOTS-c, a peptide encoded in the mitochondrial genome, translocates to the nucleus and regulates nuclear gene expression following metabolic stress in a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent manner. In the nucleus, MOTS-c regulated a broad range of genes in response to glucose restriction, including those with antioxidant response elements (ARE), and interacted with ARE-regulating stress-responsive transcription factors, such as nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2). Our findings indicate that the mitochondrial and nuclear genomes co-evolved to independently encode for factors to cross-regulate each other, suggesting that mitonuclear communication is genetically integrated.
Increased Nrf2 expression by renal cell carcinoma is associated with postoperative chronic kidney disease and an unfavorable prognosis
Yuki H, Kamai T, Murakami S, Higashi S, Narimatsu T, Kambara T, Betsunoh H, Abe H, Arai K, Shirataki H and Yoshida KI
Chronic kidney disease (CKD) is a worldwide health problem, and prevention of CKD is important for preservation of renal function after kidney surgery. There is evidence that transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has a vital antioxidant and detoxifying role in protecting the kidneys against various diseases. Impaired activation of Nrf2 is associated with oxidative stress related to CKD, and Nrf2 is also a key player in the development of cancer. However, the clinical impact of Nrf2 has not been investigated in patients with renal cell carcinoma (RCC). A retrospective study was performed in 89 patients undergoing nephrectomy for RCC. The estimated glomerular filtration rate (eGFR) and serum uric acid (SUA) were investigated over time after surgery. We investigated Nrf2 protein expression in all tumors and single nucleotide polymorphisms (SNPs) of the Nrf2 gene in 7 tumors. In patients whose tumors showed higher Nrf2 expression, there was a more rapid decrease of eGFR and increase of SUA after nephrectomy. Multivariate analysis confirmed that increased Nrf2 expression was an independent poor prognostic factor related to shorter overall survival. Among the 7 tumor samples, an SNP on exon 5 of the Nrf2 gene in one tumor and three genotypes (C/C, C/A, and A/A) of rs6721961 at the promoter region of the Nrf2 gene were observed. Although the mechanisms underlying the influence of Nrf2 are still unclear, our findings suggested that elevated tumor expression of Nrf2 was associated with postoperative CKD and biologically aggressive RCC with an unfavorable prognosis.
MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells
Kuosmanen SM, Sihvola V, Kansanen E, Kaikkonen MU and Levonen AL
Oxidative stress predisposes to several aging-associated diseases, such as cardiovascular diseases and cancer. In aging, increase in the production of reactive oxygen species is typically accompanied with a decline in adaptive stress responses to oxidative stress. The decline is primarily due to a decrease in antioxidant production. Nuclear factor E2-Related Factor 2 (NRF2) is a key transcription factor regulating oxidative and electrophilic stress responses, but it has also been shown to play a role in the regulation of cell metabolism. NRF2 expression declines in aging, but the mechanisms remain unclear. In this study, we show that microRNAs (miRNAs) that are abundant in old endothelial cells decrease NRF2 expression by direct targeting of NRF2 mRNA. The effect is reversed by miRNA inhibition. The senescence-associated downregulation of NRF2 decreases endothelial glycolytic activity and stress tolerance both of which are restored after reinstating NRF2. Manipulation of the senescence-associated miRNA levels affects the glycolytic activity and stress tolerance consistently with the NRF2 results. We conclude that senescence-associated miRNAs are involved in the decline of NRF2 expression, thus contributing to the repression of adaptive responses during cell senescence.
Anticancer Activity of Sulforaphane: The Epigenetic Mechanisms and the Nrf2 Signaling Pathway
Su X, Jiang X, Meng L, Dong X, Shen Y and Xin Y
Sulforaphane (SFN), a compound derived from cruciferous vegetables that has been shown to be safe and nontoxic, with minimal/no side effects, has been extensively studied due to its numerous bioactivities, such as anticancer and antioxidant activities. SFN exerts its anticancer effects by modulating key signaling pathways and genes involved in the induction of apoptosis, cell cycle arrest, and inhibition of angiogenesis. SFN also upregulates a series of cytoprotective genes by activating nuclear factor erythroid-2- (NF-E2-) related factor 2 (Nrf2), a critical transcription factor activated in response to oxidative stress; Nrf2 activation is also involved in the cancer-preventive effects of SFN. Accumulating evidence supports that epigenetic modification is an important factor in carcinogenesis and cancer progression, as epigenetic alterations often contribute to the inhibition of tumor-suppressor genes and the activation of oncogenes, which enables cells to acquire cancer-promoting properties. Studies on the mechanisms underlying the anticancer effects of SFN have shown that SFN can reverse such epigenetic alterations in cancers by targeting DNA methyltransferases (DNMTs), histone deacetyltransferases (HDACs), and noncoding RNAs. Therefore, in this review, we will discuss the anticancer activities of SFN and its mechanisms, with a particular emphasis on epigenetic modifications, including epigenetic reactivation of Nrf2.

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