Effect of the Nrf2-ARE signaling pathway on biological characteristics and sensitivity to sunitinib in renal cell carcinoma
Ji S, Xiong Y, Zhao X, Liu Y and Yu LQ
The aim of the present study was to examine the effects of the nuclear factor erythroid-2 related factor 2-antioxidant-responsive element (Nrf2-ARE) signaling pathway on the biological characteristics and sensitivity to targeted therapy in human renal cell carcinoma (RCC) cells. RCC tissues and adjacent tissues were collected and assessed by immunohistochemistry to determine the expression of Nrf2, NAD(P)H dehydrogenase [quinone] 1 (NQO1) and heme oxygenase-1 (HO-1) to analyze the clinicopathological features of RCC. A series of experiments were conducted to analyze the biological characteristics of Nrf2-ARE signaling in RCC. The renal cancer cell line, 786-0 was used, and cells was divided into a mock group, negative control group and small hairpin (sh)RNA-Nrf2 group. A Cell Counting Kit-8 assay was performed alongside flow cytometry to detect cell viability, cell cycle stage and apoptosis following treatment with sunitinib. The results demonstrated that Nrf2, NQO1 and HO-1 were significantly upregulated in RCC tissues compared with adjacent tissues and were associated with tumor node metastasis stage, Fuhrman classification and lymph node metastasis. Following shRNA-Nrf2 transfection, the 786-0 cells demonstrated a significant decrease in viability, cell invasion and scratch healing rate, and the mRNA and protein expression levels of Nrf2, NQO1, HO-1 and glutathione transferase were significantly decreased, which enhanced the sensitivity to sunitinib, arrested cells in the G0/G1 phase and increased apoptosis. In conclusion, Nrf2-ARE signaling is important for RCC progression, and its inhibition may increase sensitivity to targeted drugs to provide novel developments for RCC treatment.
Autophagy manipulation as a strategy for efficient anticancer therapies: possible consequences
Cirone M, Gilardini Montani MS, Granato M, Garufi A, Faggioni A and D'Orazi G
Autophagy is a catabolic process whose activation may help cancer cells to adapt to cellular stress although, in some instances, it can induce cell death. Autophagy stimulation or inhibition has been considered an opportunity to treat cancer, especially in combination with anticancer therapies, although autophagy manipulation may be viewed as controversial. Thus, whether to induce or to inhibit autophagy may be the best option in the different cancer patients is still matter of debate. Her we will recapitulate the possible advantages or disadvantages of manipulating autophagy in cancer, not only with the aim to obtain cancer cell death and disable oncogenes, but also to evaluate its interplay with the immune response which is fundamental for the success of anticancer therapies.
Impairment of Nrf2- and Nitrergic-Mediated Gastrointestinal Motility in an MPTP Mouse Model of Parkinson's Disease
Sampath C, Kalpana R, Ansah T, Charlton C, Hale A, Channon KM, Srinivasan S and Gangula PR
Gastrointestinal (GI) motility dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Studies have indicated that GI motility functions are impaired before the onset of PD.
Association between elevated placental polycyclic aromatic hydrocarbons (PAHs) and PAH-DNA adducts from Superfund sites in Harris County, and increased risk of preterm birth (PTB)
Suter MA, Aagaard KM, Coarfa C, Robertson M, Zhou G, Jackson BP, Thompson D, Putluri V, Putluri N, Hagan J, Wang L, Jiang W, Lingappan K and Moorthy B
The preterm birth (PTB) rate in Harris County, Texas, exceeds the U.S. rate (11.4% vs.9.6%), and there are 15 active Superfund sites in Harris County. Polycyclic aromatic hydrocarbons (PAHs) are contaminants of concern (COC) at Superfund sites across the nation. In this investigation, we tested the hypothesis that higher levels of exposure to PAHs and PAH-DNA adducts in placenta of women living near Superfund sites contribute to the increased rate of PTBs. Levels of benzo[a]pyene (BP), benzo[b]fluorene (BbF) and dibenz[a,h]anthracene (DBA), were higher in placentae from preterm deliveries compared with term deliveries in women living near Superfund sites, whereas this was not the case for women living in non-Superfund site areas. Among the PAHs, DBA levels were significantly higher than BP or BbF, and DBA levels were inversely correlated with gestational age at delivery and birth weight. Bulky PAH-DNA adducts are more prevalent in placental tissue from individuals residing near Superfund sites. Expression of Ah receptor (AHR) and NF-E2-related factor 2 (NRF2) was decreased in preterm deliveries in subjects residing near Superfund sites. Unbiased metabolomics revealed alterations in pathways involved in pentose phosphate, inositol phosphate and starch and sucrose metabolism in preterm subjects in Superfund site areas. In summary, this is the first report showing an association between PAH levels, DNA adducts, and modulation of endogenous metabolic pathways with PTBs in subjects residing near Superfund sites, and further studies could lead to novel strategies in the understanding of the mechanisms by which PAHs contribute to PTBs in women.
ERK/Nrf2 pathway activation by caffeic acid in HepG2 cells alleviates its hepatocellular damage caused by t-butylhydroperoxide-induced oxidative stress
Yang SY, Pyo MC, Nam MH and Lee KW
Several studies have found that caffeic acid (CA), a well-known phytochemical, displays important antioxidant and anti-cancer activities. However, no evidence exists on the protective effect and its mechanisms that CA treatment alone has against oxidative stress induced by tert-butyl hydroperoxide (t-BHP) in HepG2 cells.
Mediators of Physical Activity Protection against ROS-Linked Skeletal Muscle Damage
Di Meo S, Napolitano G and Venditti P
Unaccustomed and/or exhaustive exercise generates excessive free radicals and reactive oxygen and nitrogen species leading to muscle oxidative stress-related damage and impaired contractility. Conversely, a moderate level of free radicals induces the body's adaptive responses. Thus, a low oxidant level in resting muscle is essential for normal force production, and the production of oxidants during each session of physical training increases the body's antioxidant defenses. Mitochondria, NADPH oxidases and xanthine oxidases have been identified as sources of free radicals during muscle contraction, but the exact mechanisms underlying exercise-induced harmful or beneficial effects yet remain elusive. However, it is clear that redox signaling influences numerous transcriptional activators, which regulate the expression of genes involved in changes in muscle phenotype. The mitogen-activated protein kinase family is one of the main links between cellular oxidant levels and skeletal muscle adaptation. The family components phosphorylate and modulate the activities of hundreds of substrates, including transcription factors involved in cell response to oxidative stress elicited by exercise in skeletal muscle. To elucidate the complex role of ROS in exercise, here we reviewed the literature dealing on sources of ROS production and concerning the most important redox signaling pathways, including MAPKs that are involved in the responses to acute and chronic exercise in the muscle, particularly those involved in the induction of antioxidant enzymes.
Evaluation of 2-thiothiazolidine-4-carboxylic Acid, a Common Metabolite of Isothiocyanates as a Potential Biomarker of Cruciferous Vegetable Intake (P06-017-19)
Palliyaguru D, Salvatore S, Schopfer F, Cheng X, Zhou J and Wendell S
Cruciferous vegetable consumption is associated with favorable health outcomes that are attributed to bioreactivity of isothiocyanates. These compounds exert effects that contribute to prevention of disease, in large part through attenuation of inflammation and oxidative stress. However, much about isothiocyanate metabolites and their role as biomarkers of crucifer intake remain unknown.
Isoflavone ME-344 disrupts redox homeostasis and mitochondrial function by targeting Heme Oxygenase 1
Zhang L, Zhang J, Ye Z, Manevich Y, Ball LE, Bethard JR, Jiang YL, Broome AM, Dalton AC, Wang GY, Townsend DM and Tew KD
ME-344 is a second generation isoflavone with unusual cytotoxic properties that is in clinical testing in cancer. To identify targets that contribute to its anticancer activity and therapeutic index, we used lung cancer cell lines that are naturally sensitive or resistant to ME-344. Drug-induced apoptosis was linked with enhanced levels of reactive oxygen species (ROS) and this initiated an Nrf2 (Nuclear erythroid factor 2-like 2) signaling response, downstream of which, heme oxygenase 1 (HO-1) was also found to be time-dependently inhibited by ME-344. ME-344 specifically bound to, and altered, HO-1 structure and increased HO-1 translocation from the rough endoplasmic reticulum to mitochondria, but only in drug-sensitive cells. These effects did not occur in either drug-resistant or primary lung fibroblasts, with lower HO-1 basal levels. HO-1 was confirmed as a drug target by using surface plasmon resonance (SPR) technology and through interaction with a clickable ME-344 compound (M2F) and subsequent proteomic analyses, showing direct binding of ME-344 with HO-1. Proteomic analysis showed that clusters of mitochondrial proteins, including voltage-dependent anion-selective channels (VDACs), were also impacted by ME-344. Human lung cancer biopsies expressed higher levels of Nrf2 and HO-1 compared to normal tissues. Overall, our data show that ME-344 inhibits HO-1 and impacts its mitochondrial translocation. Other mitochondrial proteins are also affected resulting in interference in tumor cell redox homeostasis and mitochondrial function. These factors contribute to a beneficial therapeutic index and support continued clinical development of ME-344.
Xin-Ji-Er-Kang ameliorates kidney injury following myocardial infarction by inhibiting oxidative stress via Nrf2/HO-1 pathway in rats
Lian FZ, Cheng P, Ruan CS, Ling XX, Wang XY, Pan M, Chen ML, Shen AZ and Gao S
Cardiovascular diseases, such as coronary heart disease and myocardial infarction (MI) are currently considered as the leading causes of death and disability. The aim of the present study is to investigate the effects of Xin-Ji-Er-Kang (XJEK) on kidney injury and renal oxidative stress. In addition, the associated mechanism involved in these processes was examined in an MI model, and particularly focused on the nuclear factor erythroid 2-related factor (NRF2)/heme oxygenase-1 (HO-1) pathway.
Heat shock induces the cellular antioxidant defenses peroxiredoxin, glutathione and glucose 6-phosphate dehydrogenase through Nrf2
Tchouagué M, Grondin M, Glory A and Averill-Bates D
Hyperthermia is a promising anticancer treatment used in combination with radiotherapy and/or chemotherapy. Heat (42-45 °C) can kill cancer cells. Low doses of heat at milder temperatures (39-41 °C) induce thermotolerance, an adaptive survival response that upregulates defense molecules to protect cells against subsequent exposure to toxic stress. Although hyperthermia has proven effective in clinical trials, there is still much to learn about its cellular mechanisms. This study aims to understand the role of reactive oxygen species (ROS), antioxidants and the antioxidant transcription factor Nrf2 in cellular stress responses to mild and lethal heat shock. Mild thermotolerance (40 °C) and hyperthermia (42-43 °C) caused increased expression of the antioxidants peroxiredoxin-3 (Prx2) and Prx2, and its hyperoxidized form Prx-SO. Cellular levels of superoxide and peroxides increased at 40 °C and 42 °C. Heat shock (42 °C)-induced increases in Prx3 and Prx-SO were inhibited by antioxidants (PEG-catalase, MnTBAP) and a Nrf2 shRNA. Glucose metabolism by the pentose phosphate pathway produces NADPH, which maintains the antioxidant glutathione in its reduced form, GSH. Heat shock (40°C-42 °C) increased GSH levels, expression of glucose transporter GLUT1, and enzymatic activity and expression of glucose 6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose cycle. Heat-induced increases in GSH levels and G6PD expression were inhibited by antioxidants and Nrf2 knockdown. These results suggest that heat shock-generated ROS were involved in induction of cellular defense molecules Prxs, GSH and G6PD through Nrf2 activation. Our study sheds new light on the role of Nrf2 and antioxidants in cellular responses to heat shock at mild and lethal temperatures.
6-shogaol, a active constiuents of ginger prevents UVB radiation mediated inflammation and oxidative stress through modulating NrF2 signaling in human epidermal keratinocytes (HaCaT cells)
Chen F, Tang Y, Sun Y, Veeraraghavan VP, Mohan SK and Cui C
Disclosure of ultraviolet (UV) radiation is the key feature from environment to cause redness of the skin, inflammation, photoaging and skin cancer. 6-Shogaol, a spicy compound secluded from ginger, which shows anti-inflammatory effects. Present study was demonstrated the role of 6-Shogaol on UVB induced oxidative stress and photoaging signaling in human epidermal keratinocytes (HaCaT cells). In this study, UVB-irratiation (180 mJ/cm) significantly elevated the intracellular ROS levels, depletion of antioxidants resulted in apoptotic HaCaT cells. MAPKs signaling are concerned in oxidative stress; these signaling events are measured as differentiation. We found that 6-shogaol prevents over expression of MAPKs (ERK1, JNK1 & p38), in disclosure of UVB in HaCaT cells. Moreover, 6-shogaol infringed Bax and Bcl-2 in which 20 μg 6-shogaol influenced apoptosis in HaCaT cells by investigating augmented appearance of Bax and condensed appearance of Bcl-2 in contrast to control HaCaT cells. These results suggest that 6-shogaol could be a successful healing agent provides fortification against UVB-induced provocative and oxidative skin reimbursement.
TRIM16 employs NRF2, ubiquitin system and aggrephagy for safe disposal of stress-induced misfolded proteins
Jena KK, Mehto S, Kolapalli SP, Nath P, Chauhan S and Chauhan S
The cellular stresses, genetic mutations, and environmental factors can critically affect the protein quality control checkpoints resulting in protein misfolding. Molecular chaperones play a crucial role in maintaining the healthy proteome by refolding the misfolded proteins into the native functional conformations. However, if they fail to refold the misfolded proteins into the native state, they are targeted by proteolytic systems for degradation. If the misfolded protein numbers increase more than what a cell can resolve, they get converted protein aggregates/inclusion bodies. The inclusion bodies are less cytotoxic than misfolded proteins. The enhanced production of misfolded proteins and protein aggregates are linked to several diseases collectively termed proteinopathies, which includes several neurodegenerative disorders. The understanding of molecular mechanisms that regulate the turnover of protein aggregates will pave path for therapeutic interventions of proteinopathies. In a recent report, we showed that a tripartite motif (TRIM) family protein, TRIM16 streamlines the process of protein aggregates turnover by regulating the NRF2-p62 axis and autophagy.
Brusatol, an NRF2 inhibitor for future cancer therapeutic
Cai SJ, Liu Y, Han S and Yang C
Natural products from herbal medicines have long been investigated for their potentials as cancer therapeutics. Besides the development of several herbal medicine-derived anti-cancer agents, such as paclitaxel, vincristine and podophyllotoxin, many recent laboratory findings demonstrated that brusatol, a quassinoid from the seeds of , exhibits potent tumor suppressing effect with improved disease outcome. Our recent finding further demonstrated that brusatol synergizes with the intrinsic metabolic burden in cancer cells.
Curcumin as an Alternative Epigenetic Modulator: Mechanism of Action and Potential Effects
Hassan FU, Rehman MS, Khan MS, Ali MA, Javed A, Nawaz A and Yang C
Curcumin (a polyphenolic compound in turmeric) is famous for its potent anti-inflammatory, anti-oxidant, and anti-cancer properties, and has a great potential to act as an epigenetic modulator. The epigenetic regulatory roles of curcumin include the inhibition of DNA methyltransferases (DNMTs), regulation of histone modifications via the regulation of histone acetyltransferases (HATs) and histone deacetylases (HDACs), regulation of microRNAs (miRNA), action as a DNA binding agent and interaction with transcription factors. These mechanisms are interconnected and play a vital role in tumor progression. The recent research has demonstrated the role of epigenetic inactivation of pivotal genes that regulate human pathologies such as cancers. Epigenetics helps to understand the mechanism of chemoprevention of cancer through different therapeutic agents. In this regard, dietary phytochemicals, such as curcumin, have emerged as a potential source to reverse epigenetic modifications and efficiently regulate the expression of genes and molecular targets that are involved in the promotion of tumorigenesis. The curcumin may also act as an epigenetic regulator in neurological disorders, inflammation, and diabetes. Moreover, curcumin can induce the modifications of histones (acetylation/deacetylation), which are among the most important epigenetic changes responsible for altered expression of genes leading to modulating the risks of cancers. Curcumin is an effective medicinal agent, as it regulates several important molecular signaling pathways that modulate survival, govern anti-oxidative properties like nuclear factor E2-related factor 2 (Nrf2) and inflammation pathways, e.g., nuclear factor kappa B (NF-κB). Curcumin is a potent proteasome inhibitor that increases p-53 level and induces apoptosis through caspase activation. Moreover, the disruption of 26S proteasome activity induced by curcumin through inhibiting DYRK2 in different cancerous cells resulting in the inhibition of cell proliferation opens up a new horizon for using curcumin as a potential preventive and treatment approach in proteasome-linked cancers. This review presents a brief summary of knowledge about the mechanism of epigenetic changes induced by curcumin and the potential effects of curcumin such as anti-oxidant activity, enhancement of wound healing, modulation of angiogenesis and its interaction with inflammatory cytokines. The development of curcumin as a clinical molecule for successful chemo-prevention and alternate therapeutic approach needs further mechanistic insights.
Corrigendum: Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases
Zgheib E, Limonciel A, Jiang X, Wilmes A, Wink S, van de Water B, Kopp-Schneider A, Bois FY and Jennings P
[This corrects the article DOI: 10.3389/fgene.2018.00429.].