Purified Tetrastigma hemsleyanum vines polysaccharide attenuates EC-induced toxicity in Caco-2 cells and Caenorhabditis elegans via DAF-16/FOXO pathway
Chu Q, Jia R, Chen W, Liu Y, Li Y, Ye X, Jiang Y and Zheng X
Ethyl Carbamate (EC), as a carcinogen widely found in fermented foods, was verified that its cytotoxicity was associated with oxidative stress. Polysaccharides from natural sources due to their antioxidative capacity have attracted great attention in the past time. In this study, purified polysaccharide from Tetrastigma hemsleyanum vines (TVP) with 64.89 kDA was extracted and conducted multiple analysis to identify its structural information. It could be discovered that TVP was composed of mannose, rhamnose, glucuronic acid, glucose, galactose, and arabinose. In vitro, TVP could inhibit cytotoxicity and genotoxicity, attenuate oxidative damage and mitochondrial dysfunction induced by EC in Caco-2 cells. Meanwhile, TVP could suppress apoptosis by mTOR and Bcl-2 signaling pathways, ameliorate oxidative via Sirt1-FoxO1 and Nrf2-Keap1 signaling pathways. In vivo, EC as well triggered the decline of survival and athletic ability in Caenorhabditis elegans (C. elegans) and TVP could reverse the decline. In the meantime, TVP could ameliorate oxidative damage in N2 and daf-2 (-) mutant but fail in daf-16 (-) mutant, which suggested that DAF-16 (FOXO) might affect the antioxidative protection of TVP in C. elegans. In brief, our results manifested that TVP could attenuate EC-induced cytotoxicity both in vitro and in vivo.
Ginsenoside Rg1 protects mice against streptozotocin-induced type 1 diabetic by modulating the NLRP3 and Keap1/Nrf2/HO-1 pathways
Gao Y, Li J, Chu S, Zhang Z, Chen N, Li L and Zhang L
Ginseng has been traditionally used to treat diabetes mellitus (DM) in China. Ginsenoside Rg1 is a major active ingredient in processed ginseng, which elicits proven biological and pharmacological effects. Although a correlation between nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and predisposition to type 1 diabetes mellitus (T1DM) has been identified, the mechanism underlying the potential function and activation of NLRP3 inflammasome in DM have not been elucidated to date. The present study aimed to elucidate the effects and underlying mechanism of Rg1 on streptozotocin (STZ)-induced T1DM in mice through short or long-term observation. Concurrently, we intended to explore the relationships between inflammasome, pyroptosis and oxidative stress and the role of NLRP3 and Keap1/Nrf2/HO-1 pathways in the development and progression of DM. Using ELISA and Western blot analysis, we found that Rg1 attenuated abnormally elevated blood glucose, reduced inflammatory factors IL-1β and IL-18 in the blood, decreased ALT and AST levels, promoted insulin secretion, and weakened the function of NLRP3 in mouse liver and pancreas. In addition, Rg1 protected against STZ-induced reactive oxygen species-mediated inflammation by upregulating Nrf2/ARE pathway, which further activated antioxidant enzymes. Interestingly, Rg1 also regulated H3K9 methylation in liver and pancreas, as detected by immunohistochemistry. In summary, these data provide new understanding about the mechanism of Rg1 action, suggesting that it is a potential drug applied for preventing the occurrence and development of T1DM.
Chitosan Oligosaccharide Attenuates Nonalcoholic Fatty Liver Disease Induced by High Fat Diet through Reducing Lipid Accumulation, Inflammation and Oxidative Stress in C57BL/6 Mice
Tao W, Sun W, Liu L, Wang G, Xiao Z, Pei X and Wang M
Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease closely associated with metabolic syndrome, but there are no validated pharmacological therapies. The aim of this study was to investigate the effect of chitosan oligosaccharide (COS) on NAFLD. Mice were fed either a control diet or a high-fat diet (HFD) with or without COS (200 or 400 mg/kg body weight (BW)) by oral gavage for seven weeks. Administration with COS significantly lowered serum lipid levels in the HFD-fed mice. The hepatic lipid accumulation was significantly decreased by COS, which was attributed to decreased expressions of lipogenic genes and increased expressions of fatty β-oxidation-related genes. Moreover, pro-inflammatory cytokines, neutrophils infiltration, and macrophage polarization were decreased by COS in the liver. Furthermore, COS ameliorated hepatic oxidative stress by activating the nuclear factor E2-related factor 2 (Nrf2) pathway and upregulating gene expressions of antioxidant enzymes. These beneficial effects were mediated by the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Therefore, COS might be a potent dietary supplement to ameliorate NAFLD.
Targets and mechanisms of sulforaphane derivatives obtained from cruciferous plants with special focus on breast cancer - contradictory effects and future perspectives
Jabbarzadeh Kaboli P, Afzalipour Khoshkbejari M, Mohammadi M, Abiri A, Mokhtarian R, Vazifemand R, Amanollahi S, Yazdi Sani S, Li M, Zhao Y, Wu X, Shen J, Cho CH and Xiao Z
Breast cancer is the most common type of cancer among women. Therefore, discovery of new and effective drugs with fewer side effects is necessary to treat it. Sulforaphane (SFN) is an organosulfur compound obtained from cruciferous plants, such as broccoli and mustard, and it has the potential to treat breast cancer. Hence, it is vital to find out how SFN targets certain genes and cellular pathways in treating breast cancer. In this review, molecular targets and cellular pathways of SFN are described. Studies have shown SFN inhibits cell proliferation, causes apoptosis, stops cell cycle and has anti-oxidant activities. Increasing reactive oxygen species (ROS) produces oxidative stress, activates inflammatory transcription factors, and these result in inflammation leading to cancer. Increasing anti-oxidant potential of cells and discovering new targets to reduce ROS creation reduces oxidative stress and it eventually reduces cancer risks. In short, SFN effectively affects histone deacetylases involved in chromatin remodeling, gene expression, and Nrf2 anti-oxidant signaling. This review points to the potential of SFN to treat breast cancer as well as the importance of other new cruciferous compounds, derived from and isolated from mustard, to target Keap1 and Akt, two key regulators of cellular homeostasis.
New addiction to the NRF2-related factor NRF3 in cancer cells: Ubiquitin-independent proteolysis via the 20S proteasome
Kobayashi A and Waku T
Accumulating evidence has revealed that human cancers develop by sequentially mutating pivotal genes, including driver genes, and acquiring cancer hallmarks. For instance, cancer cells are addicted to the transcription factor NRF2 (NFE2L2), which is a driver gene and that utilizes the cellular cytoprotection system against oxidative stress and metabolic pathway reprogramming for sustaining high growth. Our group has recently discovered new addiction to the NRF2-related factor NRF3 (NFE2L3) in cancer. For many years, the physiological function of NRF3 remained obscure, in part because Nrf3-deficient mice do not exhibit apparent abnormalities. Nevertheless, human cancer genome databases suggest critical roles of NRF3 in cancer because of high NRF3 mRNA induction in several cancer types, such as colorectal cancer and pancreatic adenocarcinoma, with a poor prognosis. We found that NRF3 promotes tumor growth and malignancy by activating ubiquitin-independent 20S proteasome assembly through inducing the expression of the POMP chaperone and thereby degrading the tumor suppressors p53 and Rb. The NRF3-POMP-20S proteasome axis has an entirely different effect on cancer than NRF2. In this review, we describe recent research advances regarding the new cancer effector NRF3, including unclarified ubiquitin-independent proteolysis by the NRF3-POMP-20S proteasome axis. The expected development of cancer therapeutic interventions for this axis is also discussed.
Photoprotective effects of 2S,3R-6-methoxycarbonylgallocatechin isolated from Anhua dark tea on UVB-induced inflammatory responses in human keratinocytes
Kim D, Hu R, Fan Y, Xu YN, Park HJ and Lee SK
Ultraviolet B (UVB) induces inflammation and causes skin aging. The signs of skin aging, such as wrinkles, discolored spots, loss of skin moisture, and disruption of the skin barrier, are mostly caused by inflammatory signaling among various skin layers. The cells on the outermost surface of the skin are keratinocytes; these cells protect the skin against environmental stress and play an important role in immunomodulation by secreting cytokines in response to environmental stress. In the present study, we found that UVB activates STAT1 to mediate inflammatory signaling, yet STAT1 (S272) and STAT (Y702) shows different responses against UVB exposure. Anhua drak tea is a post-fermented dark tea produced in Anhua and Xinhua country in Hunan province of China. Treatment with 2S,3R-6-methoxycarbonylgallocatechin (MCGE), an epigallocatechin gallate derivative isolated from black tea (Anhua dark tea), effectively suppresses STAT1 activation and inflammatory cytokines, and activates Nrf2 pathway to protect cells from reactive oxygen species production in UVB exposed keratinocyte cells (HaCaT). Interestingly, the effects of MCGE were independent on MAPK signaling pathway. Moreover, MCGE regulates inflammatory cytokines in monocyte-keratinocyte (THP-1, HaCaT) co-culture and macrophage differentiation models. These results suggest that MCGE potentially can be used as a photoprotective agent against UVB-induced inflammatory responses.
The prognostic value of NRF2 in breast cancer patients: a systematic review with meta-analysis
Almeida M, Soares M, Ramalhinho AC, Moutinho JF, Breitenfeld L and Pereira L
Nuclear factor E2-related factor 2 (NRF2) is a transcription factor that plays a major role in the regulation of intracellular antioxidant response. The effect of NRF2 overexpression in many malignancies is still unclear and recent meta-analysis correlated NRF2 overexpression with poor prognosis in a variety of human cancers. However, the effect of NRF2 overexpression in breast cancer is still unclear. Thus, the main goal of this work was to clarify the role of NRF2 expression in survival and relapse of breast cancer patients by performing a systematic review according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) statement, followed by a meta-analysis.
Cardio protective role of wogonin loaded nanoparticle against isoproterenol induced myocardial infarction by moderating oxidative stress and inflammation
Bei W, Jing L and Chen N
Wogonin, one of the main active ingredients of Scutellaria radix, is a kind of flavonoid compound. In the present study, we report that wogonin nanoparticles (Wog np) protect Isoproterenol (ISO) induced Myocardial Infarction (MI) rats. Nanoparticles of sizes less than 200 nm with spherical shape were prepared using Polylactic-co-glycolic acid (PLGA) and Polyvinyl alcohol (PVA) respectively as polymer and stabilizer. Male Wistar rats were divided into 4 groups. Group 1 as a control group administered with physiological saline solution with 0.5 % carboxymethylcellulose (1 mL/day). Group 2 served as toxic group; rats received physiological saline solution with 0.5 % carboxymethylcellulose (1 mL/day) orally for 21 days Groups 3 and 4 received Wog np (25 and 50 mg/kg/day) orally for 21 days and on the 20th and 21 st days group 2, 3, and 4 were administered with ISO (85 mg/kg) through s.c. route at 24 h interval. pre-treatment with Wog np (25 and 50 mg/kg) could significantly reduce the cardiac infarct size, serum cardiac markers, lipid peroxidation product (MDA) and inflammatory markers as well as markedly upregulated the protein expression of nuclear factor erythroid 2-related factor (Nrf2)and heme oxygenase-1 (HO-1) to confer its strong cardioprotective activity against ISO induced myocardial damage.
Epigallocatechin 3-gallate attenuates arthritis by regulating Nrf-2, HO-1 and cytokine levels in an experimental arthritis model
Karatas A, Dagli AF, Orhan C, Gencoglu H, Ozgen M, Sahin N, Sahin K and Koca SS
Epigallocatechin 3-gallate (EGCG) is a polyphenol that has been shown to have antioxidant and anti-inflammatory effects. In this study, collagen-induced arthritis (CIA) model, in Wistar-albino rats, was used to elucidate the effect of EGCG on pathogenetic pathways in inflammatory arthritis. The levels of serum TNF-α, IL-17, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx); the expression levels of tissue heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 factor 2 (Nrf2); histopathologically, perisynovial inflammation and cartilage-bone destruction were examined. In the sham group, serum TNF-α, IL-17, and MDA levels increased, while SOD, CAT, GPx levels, and the expressions of Nrf2 and HO-1 decreased. On the other hand, in the EGCG administered groups, serum TNF-α, IL-17, and MDA levels improved, while SOD, CAT, GPx levels and the expressions of Nrf2 and HO-1 increased. Moreover, histopathological analysis has shown that perisynovial inflammation and cartilage-bone destruction decreased in the EGCG administered groups. These results suggest that EGCG has an antiarthritic effect by regulating the oxidative-antioxidant balance and cytokine levels in the CIA model, which is a surrogate experimental model of rheumatoid arthritis. EGCG has reduced the level of proinflammatory cytokines such as TNF-α and IL-17. EGCG has shown antioxidant activity by increasing Nrf-2 and HO-1 expressions. EGCG shows protective and therapeutic effects on the experimental arthritis model at a dose of 50mg /kg/day three times a week. This article is protected by copyright. All rights reserved.
Brassicaphenanthrene A from Brassica rapa protects HT22 neuronal cells through the regulation of Nrf2‑mediated heme oxygenase‑1 expression
Lee H, Ko W, Chowdhury A, Li B, Kim SC, Oh H, Kim YC, Woo ER, Baek NI and Lee DS
Brain cell damage that results from oxidative toxicity contributes to neuronal degeneration. The transcription factor nuclear factor‑E2‑related factor 2 (Nrf2) regulates the expression of heme oxygenase (HO)‑1 and glutathione (GSH), and serves a key role in the pathogenesis of neurological diseases. Brassica rapa is a turnip that is unique to Ganghwa County, and is used mainly for making kimchi, a traditional Korean food. In the current study, brassicaphenanthrene A (BrPA) from B. rapa was demonstrated to exhibit protective effects against neurotoxicity induced by glutamate via Nrf2‑mediated HO‑1 expression. Similarly, BrPA increased the expression of cellular glutathione and glutamine‑cysteine ligase genes. Furthermore, BrPA caused the nuclear translocation of Nrf2 and increased antioxidant response element (ARE) promoter activity. Nrf2 also mediated HO‑1 induction by BrPA through the PI3K/Akt and JNK regulatory pathways. The results of the present study indicated the neuroprotective effect of BrPA, a natural food component from B. rapa.
Rhizoma Paridis total saponins alleviate H2O2‑induced oxidative stress injury by upregulating the Nrf2 pathway
Zhao B, Wang Z, Han J, Wei G, Yi B and Li Z
Rhizoma Paridis total saponins (RPTS) is an active substance isolated from the traditional Chinese medicine Rhizoma Paridis, which possesses multiple biological activities. The aim of the present study was to explore the roles and mechanisms of RPTS in oxidative stress injury of ARPE‑19 human retinal pigment epithelial cells. Cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP) and apoptosis were determined by Cell Counting kit‑8 assay and flow cytometry, respectively. Enzyme‑linked immunosorbent assay was performed to detect the expression of oxidative stress markers. Western blotting and reverse transcription‑quantitative polymerase chain reaction were used to determine the expression levels of related genes and proteins. The results revealed that RPTS enhanced cell viability and reduced H2O2‑induced oxidative stress of ARPE‑19 human retinal pigment epithelial cells. RPTS increased the MMP of ARPE‑19 cells compared with in H2O2‑treated ARPE‑19 cells. In addition, RPTS suppressed ROS production and apoptosis of H2O2‑treated ARPE‑19 cells. Additionally, RPTS modulated the expression levels of apoptosis‑associated proteins and the nuclear factor 2‑related factor 2 (Nrf2) pathway. In conclusion, RPTS alleviated H2O2‑induced oxidative stress injury by upregulating the Nrf2 pathway. The potential effects of RPTS on protection against H2O2‑induced apoptosis of ARPE‑19 cells suggested that RPTS may be a potential therapeutic target for preventing age‑related macular degeneration.
LQB‑118 compound inhibits migration and induces cell death in glioblastoma cells
Bernardo PS, Guimarães GHC, De Faria FCC, Longo GMDC, Lopes GPF, Netto CD, Costa PRR and Maia RC
Glioblastoma (GBM) is the most frequent malignant brain tumor. It represents the most aggressive astrocytoma with an overall survival of 14 months. Despite improvements in surgery techniques, radio‑ and chemotherapy, most patients present treatment resistance, recurrence and disease progression. Therefore, development of effective alternative therapies is essential to overcome treatment failure. The purpose of the study was to evaluate the antitumoral activity of the synthetic compound LQB‑118, in vitro. Monolayer and three‑dimensional (3D) cell culture systems of human‑derived GBM cell lines were used to evaluate the effect of LQB‑118 on cell viability, cell death and migration. LQB‑118 reduced cell viability as determined by MTT and trypan blue exclusion assays and promoted apoptosis in monolayer cell lines with an intrinsic temozolomide (TMZ)‑resistance profile. In 3D culture models, LQB‑118 reduced cell viability as evaluated by APH assay and inhibited cell migration while the TMZ resistance profile was maintained. Moreover, LQB‑118 reduced p38 and AKT expression and phosphorylation, whereas it reduced only the phosphorylated ERK1/2 form. LQB‑118 reduced p38 and NRF2 expression, an axis that is associated with TMZ resistance, revealing a mechanism to overcome resistance. LQB‑118 also demonstrated an additional effect when combined with ionizing radiation and cisplatin. In conclusion, the present data demonstrated that LQB‑118 maintained its effectiveness in a 3D cell conformation, which shares more similarities with the tumor mass. LQB‑118 is a promising agent for GBM treatment as monotherapy and associated with radiotherapy or cisplatin. Its effect is associated with inhibition of GBM‑related survival signaling pathways.
Induction of the Antioxidant Response by the Transcription Factor NRF2 Increases Bioactivation of the Mutagenic Air Pollutant 3-Nitrobenzanthrone in Human Lung Cells
Murray JR, de la Vega L, Hayes JD, Duan L and Penning TM
3-Nitrobenzanthrone (3-NBA) is a suspected human carcinogen present in diesel exhaust. It requires metabolic activation via nitroreduction in order to form DNA adducts and promote mutagenesis. We have determined that human aldo-keto reductases (AKR1C1-1C3) and NAD(P)H:quinone oxidoreductase 1 (NQO1) contribute equally to the nitroreduction of 3-NBA in lung epithelial cell lines and collectively represent 50% of the nitroreductase activity. The genes encoding these enzymes are induced by the transcription factor NF-E2 p45-related factor 2 (NRF2), which raises the possibility that NRF2 activation exacerbates 3-NBA toxification. Since A549 cells possess constitutively active NRF2, we examined the effect of heterozygous (NRF2-Het) and homozygous NRF2 knockout (NRF2-KO) by CRISPR-Cas9 gene editing on the activation of 3-NBA. To evaluate whether NRF2-mediated gene induction increases 3-NBA activation, we examined the effects of NRF2 activators in immortalized human bronchial epithelial cells (HBEC3-KT). Changes in AKR1C1-1C3 and NQO1 expression by NRF2 knockout or use of NRF2 activators were confirmed by qPCR, immunoblots, and enzyme activity assays. We observed decreases in 3-NBA activation in the A549 NRF2 KO cell lines (53% reduction in A549 NRF2-Het cells and 82% reduction in A549 NRF2-KO cells) and 40-60% increases in 3-NBA bioactivation due to NRF2 activators in HBEC3-KT cells. Together, our data suggest that activation of the transcription factor NRF2 exacerbates carcinogen metabolism following exposure to diesel exhaust which may lead to an increase in 3-NBA-derived DNA adducts.
Blueberry extract decreases oxidative stress and improves functional parameters in lungs from rats with pulmonary arterial hypertension
Türck P, Fraga S, Salvador I, Campos-Carraro C, Lacerda D, Bahr A, Ortiz V, Hickmann A, Koetz M, Belló-Klein A, Henriques A, Agostini F and da Rosa Araujo AS
Pulmonary arterial hypertension (PAH) is a condition characterized by an increased resistance of pulmonary vasculature, culminating in an increase in pulmonary pressure. This process involves disturbances in lung redox homeostasis, causing progressive right heart failure. In this context, the use of natural antioxidants, such as those found in blueberries, may represent a therapeutic approach. The aim of this study was to evaluate the effect of blueberry extract (BB) on functional parameters and oxidative stress levels in rat lungs with induced PAH.
- Phytochemistry and mechanisms of neuroprotection and cognitive enhancement
Gray NE, Alcazar Magana A, Lak P, Wright KM, Quinn J, Stevens JF, Maier CS and Soumyanath A
This review describes in detail the phytochemistry and neurological effects of the medicinal herb (L.) Urban. is a small perennial plant that grows in moist, tropical and sub-tropical regions throughout the world. Phytochemicals identified from to date include isoprenoids (sesquiterpenes, plant sterols, pentacyclic triterpenoids and saponins) and phenylpropanoid derivatives (eugenol derivatives, caffeoylquinic acids, and flavonoids). Contemporary methods for fingerprinting and characterization of compounds in extracts include liquid chromatography and/or ion mobility spectrometry in conjunction with high-resolution mass spectrometry. Multiple studies in rodent models, and a limited number of human studies support 's traditional reputation as a cognitive enhancer, as well as its anxiolytic and anticonvulsant effects. Neuroprotective effects of are seen in several models, for example against beta amyloid toxicity, and appear to be associated with increased mitochondrial activity, improved antioxidant status, and/or inhibition of the pro-inflammatory enzyme, phospholipase A2. Neurotropic effects of include increased dendritic arborization and synaptogenesis, and may be due to modulations of signal transduction pathways such as ERK1/2 and Akt. Many of these neurotropic and neuroprotective properties of have been associated with the triterpene compounds asiatic acid, asiaticoside and madecassoside. More recently, caffeoylquinic acids are emerging as a second important group of active compounds in , with the potential of enhancing the Nrf2-antioxidant response pathway. The absorption, distribution, metabolism and excretion of the triterpenes, caffeoylquinic acids and flavonoids found in have been studied in humans and animal models, and the compounds or their metabolites found in the brain. This review highlights the remarkable potential for extracts and derivatives to be used in the treatment of neurological conditions, and considers the further research needed to actualize this possibility.