Nrf2-ARE Signaling Pathway Research Articles

Metformin ameliorates neuroinflammatory environment for neurons and astrocytes during in vitro and in vivo stroke and tobacco smoke chemical exposure: Role of Nrf2 activation

Despite the protective nature of the blood-brain barrier (BBB) and brain-protecting tissues, some types of CNS injury or stress can cause cerebral cytokine production and profound alterations in brain function. Neuroinflammation, which can also be accompanied by increased cerebral cytokine production, has a remarkable impact on the pathogenesis of many neurological illnesses, including loss of BBB integrity and ischemic stroke, yet effective treatment choices for these diseases are currently lacking. Although little is known about the brain effects of Metformin (MF), a commonly prescribed first-line antidiabetic drug, prior research suggested that it may be useful in preventing BBB deterioration and the increased risk of stroke caused by tobacco smoking (TS). Therefore, reducing neuroinflammation by escalating anti-inflammatory cytokine production and declining pro-inflammatory cytokine production could prove an effective therapeutic strategy for ischemic stroke. Hence, the current investigation was planned to explore the potential role of MF against stroke and TS-induced neuroinflammation and reactive oxygen species (ROS) production. Our studies revealed that MF suppressed releasing pro-inflammatory mediators like tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) by aiming at the nuclear factor kappa B (NF-κB) signaling pathway in primary neurons and astrocytes. MF also upregulated anti-inflammatory mediators, like interleukin-10 (IL-10), and interleukin-4 (IL-4), by upregulating the Nrf2-ARE signaling pathway. Adolescent mice receiving MF along with TS exposure also showed a notable decrease in NF-κB expression compared to the mice not treated with MF and significantly decreased the level of TNF-α, IL-1β, MCP-1, and MIP-2 and increased the levels of IL-10 and IL-4 through the activation of Nrf2-ARE signaling pathway. These results suggest that MF has anti-neuroinflammatory effects via inhibiting NF-κB signaling by activating Nrf2-ARE. These studies support that MF could be a strong candidate drug for treating and or preventing TS-induced neuroinflammation and ischemic stroke.

Extraction, structural characterization, and antioxidant activity of polysaccharides from three microalgae

Microalgal polysaccharides have received much attention due to their potential value in preventing and regulating oxidative damage. This study aims to reveal the mechanisms of regulating oxidative stress and the differences in the yield, structure, and effect of polysaccharides extracted from three microalgae: Golenkinia sp. polysaccharides (GPS), Chlorella sorokiniana polysaccharides (CPS), and Spirulina subsalsa polysaccharides (SPS). Using the same extraction method, GPS, CPS, and SPS were all heteropoly- saccharides composed of small molecular fraction: the monosaccharides mainly comprised galactose (Gal). Among the three, SPS had a higher proportion of small molecular fraction, and a higher proportion of Gal; thus it had the highest yield and antioxidant activity. GPS, CPS, and SPS all showed strong antioxidant activity in vitro, and showed strong ability to regulate oxidative stress, among which SPS was slightly higher. From the analysis of gene expression, the Nrf2-ARE signalling pathway was an important pathway for GPS, CPS, and SPS to regulate cellular oxidative stress. This study provides a theoretical foundation for further research on the utilization of microalgae polysaccharides and product development.

Human umbilical cord mesenchymal stem cells protect MC3T3-E1 osteoblasts from dexamethasone-induced apoptosis via induction of the Nrf2-ARE signaling pathway

ObjectiveTo investigate the protective effect human umbilical cord mesenchymal stem cells (hUC-MSCs) have on Dexamethasone (Dex)-induced apoptosis in osteogenesis via the Nrf2-ARE signaling pathway. MethodsGlucocorticoid-induced osteonecrosis of the femoral head (GC-ONFH) was developed in rats through the administration of lipopolysaccharide and methylprednisolone. The incidence of femoral head necrosis, cavity notch, apoptosis of osteoblasts, and bone density were observed by HE staining, TUNEL staining, and Micro-CT. HUC-MSCs were co-cultured with mouse pre-osteoblast MC3T3-E1. The survival rate of osteoblasts was determined by CCK8, and apoptosis and ROS levels of osteoblasts were determined by flow cytometer. The viability of antioxidant enzymes SOD, GSH-Px, and CAT was analyzed by biochemistry. Nrf2 expression levels and those of its downstream proteins and apoptosis-related proteins were analyzed by Western blotting. ResultsIn rats, hUC-MSCs can reduce the rates of empty bone lacuna and osteoblast apoptosis that are induced by glucocorticoids (GCs), while reducing the incidence of GC-ONFH. hUC-MSCs can significantly improve the survival rate and antioxidant SOD, GSH-Px, and CAT activity of MC3T3-E1 cells caused by Dex, and inhibit apoptosis and oxidative stress levels. In addition, hUC-MSCs can up-regulate the expression of osteoblast antioxidant protein Nrf2 and its downstream protein HO-1, NQO-1, GCLC, GCLM, and apoptosis-related protein bcl-2, while also down-regulating the expression of apoptosis-related protein bax, cleaved caspase-3, cleaved caspase-9, and cytochrome C in MC3T3-E1 cells. hUC-MSCs improve the ability of MC3T3-E1 cells to mineralize to osteogenesis. However, the promoting effects of hUC-MSCs were abolished following the blocking of the Nrf2-ARE signaling pathway for osteoblasts. ConclusionThe results reveal that hUC-MSCs can reduce Dex-induced apoptosis in osteoblasts via the Nrf2-ARE signaling pathway.

Effect of tea polyphenols supplement on growth performance, antioxidation, and gut microbiota in squabs.

Early life nutritional supplementation can significantly improve pigeon health. Both the nutritional crops of parental pigeons and the intestinal development of squabs play key roles in the growth rate of squabs. Tea polyphenols (TPs), as natural plant extracts, exhibit potential biological activities. However, the impact of TPs on the intestinal function of squabs is not known. This study evaluated the effects of TPs on growth performance, immunity, antioxidation, and intestinal function in squabs. A total of 432 young pigeons (1 day old) were divided into four groups: a control group (fed a basic diet) and three treatment groups (low, medium, and high dose groups; 100, 200, and 400 mg/kg TPs, respectively). On the 28th day, samples of serum, mucosal tissue, and digests from the ileum of squabs were collected for analysis. The results revealed that TP supplementation significantly reduced the feed-to-meat ratio and improved the feed utilization rate and serum biochemical indices in squabs. Additionally, it enhanced the intestinal barrier function of birds by promoting intestinal development and integrity of tight junctions and regulating digestive enzyme activities and intestinal flora. Mechanistically, TPs activated the Nrf2-ARE signaling pathway, which may be associated with improved antioxidant and immune responses, correlating with an increased abundance of Candida arthritis and Corynebacterium in the ileum.

The Application of Berberine in Fibrosis and the Related Diseases.

The formation of fibrotic tissue, characterized by the excessive accumulation of extracellular matrix (ECM) components such as collagen and fibronectin, is a normal and crucial stage of tissue repair in all organs. The over-synthesis, deposition, and remodeling of ECM components lead to organ dysfunction, posing a significant medical burden. Berberine, an isoquinoline alkaloid, is commonly used in the treatment of gastrointestinal diseases. With the deepening of scientific research, it has been gradually discovered that berberine also plays an important role in fibrotic diseases. In this review, we systematically introduce the effective role of berberine in fibrosis-related diseases. Specifically, this paper aims to provide a comprehensive review of the therapeutic role of berberine in treating fibrosis in organs such as the heart, liver, lungs, and kidneys. By summarizing its various pathways and mechanisms of action, including the inhibition of the transforming growth factor-[Formula: see text]/Smad signaling pathway, PI3K/Akt signaling pathway, MAPK signaling pathway, RhoA/ROCK signaling, and mTOR/p70S6K signaling pathway, as well as its activation of the Nrf2-ARE signaling pathway, AMPK signaling pathway, phosphorylated Smad 2/3 and Smad 7, and other signaling pathways, this review offers additional evidence to support the treatment of fibrotic diseases.

Astaxanthin Protects against Alcoholic Liver Injury via Regulating Mitochondrial Redox Balance and Calcium Homeostasis.

Increasing evidence points to the critical role of calcium overload triggered by mitochondrial dysfunction in the development of alcoholic liver disease (ALD). As an important organelle for aerobic respiration with a double-layered membrane, mitochondria are pivotal targets of alcohol metabolism-mediated lipid peroxidation, wherein mitochondria-specific phospholipid cardiolipin oxidation to 4-hydroxynonenal (4-HNE) ultimately leads to mitochondrial integrity and function impairment. Therefore, it is absolutely essential to identify effective nutritional intervention targeting mitochondrial redox function for an alternative therapy of ALD, in order to compensate for the difficulty in achieving alcohol withdrawal due to addiction. In this study, we confirmed the significant advantages of astaxanthin (AX) against alcohol toxicity among various carotenoids via cell experiments and identified the potential in mitochondrion morphogenesis and calcium signaling pathway by bioinformatics analysis. The ALD model of Sprague-Dawley (SD) rats was also generated to investigate the effectiveness of AX on alcohol-induced liver injury, and the underlying mechanisms were further explored. AX intervention attenuated alcohol-induced oxidative stress and lipid peroxidation as well as mitochondrial dysfunction characterized by degenerative morphology changes and collapsed membrane potential. Also, AX reduced the production of 4-HNE by activating the Nrf2-ARE signaling pathway, which is closely associated with the redox balance of mitochondria. In addition, relieved mitochondrial Ca2+ accumulation caused by AX was observed both in vivo and in vitro. Furthermore, we revealed the structure-activity relationship of AX and mitochondrial membrane channel proteins MCU and VDAC1, implying potential acting targets. Altogether, our data indicated a new mechanism of AX intervention which protects against alcohol-induced liver injury through restoring redox balance and Ca2+ homeostasis in mitochondria, as well as provided novel insights into the development of AX as a therapeutic option for the management of ALD.

Unraveling the Nrf2-ARE Signaling Pathway in the DF-1 Chicken Fibroblast Cell Line: Insights into T-2 Toxin-Induced Oxidative Stress Regulation.

The T-2 toxin (T2) poses a major threat to the health and productivity of animals. The present study aimed to investigate the regulatory mechanism of Nrf2 derived from broilers against T2-induced oxidative damage. DF-1 cells, including those with normal characteristics, as well as those overexpressing or with a knockout of specific components, were exposed to a 24 h treatment of 50 nM T2. The primary objective was to evaluate the indicators associated with oxidative stress and the expression of downstream antioxidant factors regulated by the Nrf2-ARE signaling pathway, at both the mRNA and protein levels. The findings of this study demonstrated a noteworthy relationship between the up-regulation of the Nrf2 protein and a considerable reduction in the oxidative stress levels within DF-1 cells (p < 0.05). Furthermore, this up-regulation was associated with a notable increase in the mRNA and protein levels of antioxidant factors downstream of the Nrf2-ARE signaling pathway (p < 0.05). Conversely, the down-regulation of the Nrf2 protein was linked to a marked elevation in oxidative stress levels in DF-1 cells (p < 0.05). Additionally, this down-regulation resulted in a significant decrease in both the mRNA and protein expression of antioxidant factors (p < 0.05). This experiment lays a theoretical foundation for investigating the detrimental impacts of T2 on broiler chickens. It also establishes a research framework for employing the Nrf2 protein in broiler chicken production and breeding. Moreover, it introduces novel insights for the prospective management of oxidative stress-related ailments in the livestock and poultry industry.

The Role of Nrf2-ARE Signaling Pathway and Tatarinow Sweetflag Extract to Regulate the Acute Phase of Pilocarpine-Induced Epilepsy in Juvenile Rats.

To analyze the role of Nrf2-ARE signaling pathway in the regulation of the acute phase of pilocarpine-induced epilepsy in juvenile rats by Tatarinow Sweetflag Extract (TSE). One hundred and twenty SPF-grade Wistar male rats were were divided into five groups by random number table method, namely, normal group, model group, low-dose TSE group, high-dose TSE group, low-dose TSE + Nrf2 inhibitor Brusatol group (low-dose TSE + BRU group), and high-dose TSE + Nrf2 inhibitor Brusatol group (high-dose TSE + BRU group), with 20 rats in each group. The success rate of modelling in the model group, low-dose TSE group, high-dose TSE group, low-dose TSE + BRU group, high-dose TSE + BRU group were 60.00% (12/20), 65.00% (13/20), 65.00% (13/20), 70.00% (14/20), and 70.00% (14/20), respectively, showing no significant difference (P > 0.05). The latency and incidence of class IV and V, discharge amplitude as well as frequency of rats in the low- and high-dose TSE groups were lower than those in the model group (P < 0.05); the lipid peroxide and malondialdehyde concentrations in hippocampal tissues in the low- and high-dose TSE groups were lower than those in the model group (P < 0.05); The Nrf2, NQO-1 and HO- 1 protein and mRNA expression levels were increased in the low- and high-dose TSE groups compared with the model group (P < 0.05). The therapeutic effect of TSE in rats with acute epilepsy was satisfactory, and its mechanism of action may be related to activation of Nrf2-ARE signaling pathway to reduce the degree of oxidative stress.

Pentoxifylline promotes spermatogenesis via upregulation of the Nrf2-ARE signalling pathway in a mouse model of germ-cell apoptosis induced by testicular torsion-detorsion.

Testicular torsion-detorsion results in loss of germ cells and infertility. Pentoxifylline has been shown to prevent tissue damage. To determine the effect of pentoxifylline on germ cell survival in torsion-detorsion induced apoptosis Methods: Twenty male mice were divided into four groups of five animals each: Control, T1 (Torsion-detorsion+single dose 100mg/kg Pentoxifylline/IP), T2 (Torsion-detorsion+daily 20mg/kg pentoxifylline/IP for 2weeks, and T/D (Torsion-detorsion only). 35thday after torsion-detorsion, the left testes of all the animals were harvested for histological and biochemical analysis. Histomorpholoical analysis showed significant increase (P <0.05) in seminiferous tubule diameter, Johnsen's score and germ cells of Control and T1 compared to T2 and T/D, with no significant difference (P >0.05) in testis weight, sertoli, leydig and myoid cells. Tunnel assay showed significant increase (P <0.05) in apoptotic cells of T/D and T2 animals compared to Control and T1. RT-PCR analysis showed significant high (P <0.01) mRNA expression of Bax gene in T/D compared to T1 and T2 and significant increase (P <0.05) of Bcl2 in Control, T1, T2 compared to T/D. Nrf2-ARE transcripts revealed significant increase (P <0.05) in Control and T1 compared to T2 and T/D. Western blot showed significantly increased (P <0.05) caspase-3 in T/D compared to Control, T1 and T2. Pentoxifylline promotes spermatogenesis and suppressed apoptosis induced by testicular torsion-detorsion. Pentoxifylline could serve as adjunct therapy to surgery in the treatment of torsion-detorsion induced germ cell apoptosis.

Protective effect of antioxidant peptides from bass (Lateolabrax japonicus) on oxidative stress injury in Caco‐2 cells

AbstractExcessive reactive oxygen species (ROS) can induce oxidative damage to cell membranes and biomolecules, leading to various chronic diseases. Therefore, the exploration of effective natural antioxidants that can replace traditional synthetic antioxidants to reduce excess free radicals without side effects is important. Herein, the antioxidant peptide (Lateolabrax japonicus protein hydrolysates; LPH) was obtained from bass (L. japonicus) by an optimal enzymatic hydrolysis process. The protective effect of LPH on the Caco‐2 cell oxidative stress model and the potential antioxidant signaling pathways were explored. The results showed that LPH was rich in hydrophobic amino acids, and the IC50 for 2,2‐diphenyl‐1‐picrylhydrazyl radical scavenging activity was 0.9667 mg/mL. Furthermore, the LPH treatment reduced cellular ROS levels and lipid peroxidation while increasing antioxidant enzyme activity in a dose‐dependent manner (p &lt; .05). LPH also upregulated the expression of mRNAs related to antioxidant enzymes in the Nrf2 signaling pathway (p &lt; .05), demonstrating the efficacy of LPH on the Nrf2–ARE signaling pathway. These results suggested that LPH could be used as a potential food‐derived antioxidant in the food and healthcare industries.

Curcumin protects against doxorubicin induced oxidative stress by regulating the Keap1-Nrf2-ARE and autophagy signaling pathways

BackgroundDoxorubicin (DOX)-induced neurotoxicity is widely reported in previous studies. Oxidative stress has been validated as a critical event involved in DOX-induced neurotoxicity. As a selective autophagy adaptor protein, p62 is reported to regulate Keap1-Nrf2-ARE antioxidant pathway in response to oxidative stress. Curcumin (CUR) relieves depressive-like state through the mitigation of oxidative stress and the activation of Nrf2-ARE signaling pathway. However, the exact mechanism of CUR in alleviating DOX-induced neurotoxicity is still unknown.Materials and methodsThe rats were randomly divided into three groups: control group, DOX group, and DOX + CUR group. At the end of 3 weeks, the behavior tests as sucrose preference test (SPT), forced swimming test (FST), and novelty-suppressed feeding test (NSFT) were performed to assess anxiety- and depression-like behaviors. The rats were sacrificed after behavior tests, and the brain tissues were collected for biochemical analysis.ResultsIt was observed that the administration of CUR could effectively reverse DOX-induced depressive-like behaviors. The exposure of DOX activated autophagy and increased oxidative stress levels, and the administration of CUR could significantly inhibit DOX-induced autophagy and suppress oxidative stress. More importantly, we also found that Keap1-Nrf2-ARE signaling pathway was involved in DOX-induced neurotoxicity and oxidative stress regulated by autophagy.ConclusionOur study demonstrated that CUR could effectively reverse DOX-induced neurotoxicity through suppressing autophagy and mitigating oxidative stress and endoplasmic reticulum (ER) stress.

Mechanism of SET8 Activates the Nrf2-KEAP1-ARE Signaling Pathway to Promote the Recovery of Motor Function after Spinal Cord Injury.

Spinal cord injury (SCI) is a common injury of the central nervous system (CNS), and astrocytes are relatively abundant glial cells in the CNS that impairs the recovery of motor function after SCI. It was confirmed that the oxidative stress of mitochondria leads to the accumulation of reactive oxygen species (ROS) in cells, which plays a key role in the motor function of astrocytes. However, the mechanism by which oxidative stress affects astrocyte motility after SCI is still unexplained. Therefore, this study investigated the influence of SET8-regulated oxidative stress on astrocyte autophagy levels after SCI in rats and the potential mechanisms of action. We used real-time quantitative PCR, western blotting, and immunohistochemical staining to analyze SET8, Keap1, and Nrf2 expression at the cellular level and in SCI tissues. ChIP to detect H4K20me1 enrichment in the Keap1 promoter region under OE-SET8 (overexpression of SET8) conditions. Western blotting was used to assess the expression of signature proteins of astrocytes, proteins associated with autophagy, proteins associated with glial scar formation, reactive oxygen species (ROS) levels in cells using DHE staining, and astrocyte number, morphological alterations, and induction of glial scar formation processes using immunofluorescence. In addition, the survival rate of neurons after SCI in rats was examined by using NiSSl staining. OE-SET8 upregulates the enrichment of H4K20me1 in Keap1, inhibits Keap1 expression, activates the Nrf2-ARE signaling pathway to suppress ROS accumulation, inhibits oxidative stress-induced autophagy and glial scar formation in astrocytes, and leads to reduced neuronal loss, which promoted the recovery and improvement of motor function after SCI in rats. Overexpression of SET8 alleviated oxidative stress by regulating Keap1/Nrf2/ARE, inhibited astrocyte autophagy levels, and reduced glial scar formation as well as neuronal loss, thereby promoting improved recovery of motor function after SCI. Thus, the SET8/H4K20me1 regulatory function may be a promising cellular therapeutic intervention point after SCI.

Delivery of Transcriptional Factors for Activating Antioxidant Defenses against Inflammatory Bowel Disease.

Oxidative stress caused by the overproduction of reactive oxygen species (ROS) plays an important role in inflammatory bowel disease (IBD). It is well-known that the Nrf2-ARE (antioxidative response element) pathway is important in the regulation mechanism of antioxidant defense. Therefore, Nrf2 activation may be an effective therapeutic strategy for IBD. Here, we reported the development of a nucleus-targeted Nrf2 delivery nanoplatform, termed N/LC, that could accumulate in inflamed colonic epithelium, reduce inflammatory responses, and restore epithelium barriers in a murine model of acute colitis. N/LC nanocomposites could quickly escape from lysosomes, so Nrf2 largely accumulated in the nucleus of colonic cells, activated the Nrf2-ARE signaling pathway, further elevated the expression levels of downstream detoxification and antioxidant genes, and protected cells from oxidative damage. These results suggested that N/LC might be a potential nanoplatform for IBD therapy. The study provided the basis for the biomedical applications of Nrf2-based therapeutics in various diseases.

The Regulatory Effect of Phytochemicals on Chronic Diseases by Targeting Nrf2-ARE Signaling Pathway

Redox balance is essential to maintain the body's normal metabolism. Once disrupted, it may lead to various chronic diseases, such as diabetes, neurodegenerative diseases, cardiovascular diseases, inflammatory diseases, cancer, aging, etc. Oxidative stress can cause or aggravate a series of pathological processes. Inhibition of oxidative stress and related pathological processes can help to ameliorate these chronic diseases, which have been found to be associated with Nrf2 activation. Nrf2 activation can not only regulate the expression of a series of antioxidant genes that reduce oxidative stress and its damage, but also directly regulate genes related to the above-mentioned pathological processes to counter the corresponding changes. Therefore, targeting Nrf2 has great potential for the prevention or treatment of chronic diseases, and many natural phytochemicals have been reported as Nrf2 activators although the defined mechanisms remain to be elucidated. This review article focuses on the possible mechanism of Nrf2 activation by natural phytochemicals in the prevention or treatment of chronic diseases and the regulation of oxidative stress. Moreover, the current clinical trials of phytochemical-originated drug discovery by targeting the Nrf2-ARE pathway were also summarized; the outcomes or the relationship between phytochemicals and chronic diseases prevention are finally analyzed to propose the future research strategies and prospective.

Protective Effect of Sulforaphane on Oxidative Stress and Mitochondrial Dysfunction Associated with Status Epilepticus in Immature Rats

The present study aimed to elucidate the effect of sulforaphane (a natural isothiocyanate) on oxidative stress and mitochondrial dysfunction during and at selected periods following status epilepticus (SE) induced in immature 12-day-old rats by Li-pilocarpine. Dihydroethidium was employed for the detection of superoxide anions, immunoblot analyses for 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) levels and respiratory chain complex I activity for evaluation of mitochondrial function. Sulforaphane was given i.p. in two doses (5 mg/kg each), at PD 10 and PD 11, respectively. The findings of the present study indicate that both the acute phase of SE and the early period of epileptogenesis (1 week and 3 weeks following SE induction) are associated with oxidative stress (documented by the enhanced superoxide anion production and the increased levels of 3-NT and 4-HNE) and the persisting deficiency of complex I activity. Pretreatment with sulforaphane either completely prevented or significantly reduced markers of both oxidative stress and mitochondrial dysfunction. Since sulforaphane had no direct anti-seizure effect, the findings suggest that the ability of sulforaphane to activate Nrf2 is most likely responsible for the observed protective effect. Nrf2-ARE signaling pathway can be considered a promising target for novel therapies of epilepsy, particularly when new compounds, possessing inhibitory activity against protein–protein interaction between Nrf2 and its repressor protein Keap1, with less “off-target” effects and, importantly, with an optimal permeability and bioavailability properties, become available commercially.

Effects of Dietary Carbohydrate Levels on Growth Performance, Body Composition, Antioxidant Capacity, Immunity, and Liver Morphology in Oncorhynchus mykiss under Cage Culture with Flowing Freshwater.

The purpose of this study is to investigate the effects of dietary carbohydrate levels on growth performance, body composition, antioxidant capacity, immunity, and liver morphology in Oncorhynchus mykiss under cage culture with flowing freshwater. Fish (initial body weight 25.70 ± 0.24 g) were fed five isonitrogenous (420 g/kg protein) and isolipidic (150 g/kg lipid) diets containing 50.6, 102.1, 151.3, 200.9 and 251.8 g/kg carbohydrate levels, respectively. The results indicated that fish fed diets containing 50.6-200.9 g/kg carbohydrate showed significantly higher growth performance, feed utilization, and feed intake than those fed 251.8 g/kg dietary carbohydrate levels. Based on the analysis of the quadratic regression equation for weight gain rate, the appropriate dietary carbohydrate requirement of O. mykiss was estimated to be 126.2 g/kg. 251.8 g/kg carbohydrate level activated Nrf2-ARE signaling pathway, suppressed superoxide dismutase activity and total antioxidant capacity, and increased MDA content in the liver. Besides, fish fed a diet containing 251.8 g/kg carbohydrate showed a certain degree of hepatic sinus congestion and dilatation in the liver. Dietary 251.8 g/kg carbohydrate upregulated the mRNA transcription level of proinflammatory cytokines and downregulated the mRNA transcription level of lysozyme and complement 3. Whole-body compositions were not affected by dietary carbohydrate levels. In conclusion, 251.8 g/kg carbohydrate level suppressed the growth performance, antioxidant capacity and innate immunity, resulting in liver injury and inflammatory response of O. mykiss. A diet containing more than 200.9 g/kg carbohydrate is not efficiently utilized by O. mykiss under cage culture with flowing freshwater.

Evaluation of Proanthocyanidins from Kiwi Leaves (Actinidia chinensis) against Caco-2 Cells Oxidative Stress through Nrf2-ARE Signaling Pathway.

Proanthocyanidins (PAs) are considered to be effective natural byproduct and bioactive antioxidants. However, few studies have focused on their mode of action pathways. In this study, reactive oxygen species (ROS), oxidative stress indices, real-time PCR, Western blotting, confocal microscopy, and molecular docking were used to investigate the protective effect of purified kiwi leaves PAs (PKLPs) on Caco-2 cells’ oxidative stress mechanisms. The results confirmed that pre-treatment with PKLPs significantly reduced H2O2-induced oxidative damage, accompanied by declining ROS levels and malondialdehyde (MDA) accumulation in the Caco-2 cells. The PKLPs upregulated the expression of antioxidative enzymes (GSH-px, CAT, T-SOD) and the relative mRNA (Nrf, HO-1, SOD-1, CAT) of the nuclear factor erythroid 2-related factor (Nrf2) signaling pathway. The protein-expressing level of the Nrf2 and its relative protein (NQO-1, HO-1, SOD-1) were significantly increased (p < 0.05) in the PKLPs pre-treatment group compared to the model group. In conclusion, the novelty of this study is that it explains how PKLPs’ efficacy on the Nrf2-ARE signaling pathway, in protecting vital cells from oxidative stress, could be used for cleaner production.

Resveratrol Alleviating the Ovarian Function Under Oxidative Stress by Alternating Microbiota Related Tryptophan-Kynurenine Pathway.

Oxidative stress (OS) is a key factor regulating the systemic pathophysiological effects and one of the fundamental mechanisms associated with aging and fertility deterioration. Previous studies revealed that resveratrol (RV) exhibits a preventive effect against oxidative stress in the ovary. However, it remains unknown whether gut microbiota respond to resveratrol during an OS challenge. In Exp. 1, layers received intraperitoneal injection of tert-butyl hydroperoxide (tBHP) (0 or 800 μmol/kg BW) or received resveratrol diets (0 or 600 mg/kg) for 28 days. In Exp. 2, the role of intestinal microbiota on the effects of resveratrol on tBHP-induced oxidative stress was assessed through fecal microbiota transplantation (FMT). The OS challenge reduced the egg-laying rate and exhibited lower pre-hierarchical follicles and higher atretic follicles. Oral RV supplementation ameliorated the egg-laying rate reduction and gut microbiota dysbiosis. RV also reversed the tryptphan-kynurenine pathway, upregulated nuclear factor E2-related factor 2 (Nrf2) and silent information regulator 1(SIRT1) levels, and decreased the expression of forkhead box O1 (FoxO1) and P53. These findings indicated that the intestinal microbiota-related tryptophan-kynurenine pathway is involved in the resveratrol-induced amelioration of ovary oxidative stress induced by tBHP in the layer model, while SIRT1-P53/FoxO1 and Nrf2-ARE signaling pathway were involved in this process.

Beneficial Changes in Growth Performance, Antioxidant Capacity, Immune Response, Hepatic Health, and Flesh Quality of Trachinotus ovatus Fed With Oedocladium carolinianum.

The purpose of this study is to assess the feasibility of astaxanthin-rich Oedocladium carolinianum as an immunostimulant in the diet for Trachinotus ovatus. Three experimental diets containing 0% (OC0), 1% (OC1), and 5% (OC5) O. carolinianum powder were formulated for 6-week feeding trials. The results indicated that the OC5 diet boosted the growth performance through decreasing the feed conversion ratio and increasing digestive enzyme activities and intestinal villus length. Meanwhile, fish fed with the OC5 diet promoted antioxidant ability via stimulating the Nrf2-ARE signal pathway and enhancing antioxidant enzyme activities. Furthermore, the OC5 diet exerted hepatoprotective effects by suppressing the lipid deposition and inflammation response and enhancing the transport capacity of cholesterol. Besides, the OC5 diet improved the non-specific immunity by activating the lysozyme and complement system and increasing the nitric oxide content and total nitric oxide synthase activity. Dietary O. carolinianum supplementation promoted the deposition of astaxanthin in the whole body. Therefore, a diet supplemented with 5% O. carolinianum is recommended to boost the growth, antioxidant capacity, immune response, and flesh quality of T. ovatus.

Methotrexate Induces an Antioxidant Hormetic Response in Primary Rat Astrocytes.

Neurodegenerative diseases have increased worldwide in recent years. Their relationship with oxidative stress has motivated the research to find therapies and medications capable of suppressing oxidative damage and therefore slowing the progression of these diseases. Glutathione (GSH) is the most important cellular antioxidant in living beings and is responsible for regulating the cellular redox state. However, GSH cannot be administered by any route of administration, so molecules that increase its levels by activating Nrf2-ARE signaling pathway are explored; since Nrf2 regulates the main genes involved in GSH de novo synthesis and recycling. Astrocytes are the most important cell-type in the antioxidant cell response and are responsible for providing GSH and other substrates for neurons to have an efficient antioxidant response. Methotrexate (MTX) is an anti-inflammatory agent that has different cellular effects when administered at low or high concentrations. So in this study, we used MTX different concentrations and exposure times to induce a hormetic antioxidant response in rat primary astrocytes. Our results showed that 20nM MTX pre-conditioning for 12h augmented the GSH/GSSG ratio and protected cellular viability against a toxic MTX and H2O2 insult, which was abrogated when Nrf2 was inhibited by brusatol. Hence, MTX subsequent studies as a drug to counteract the progression of some stress-associated neurodegenerative diseases are suggested.