HO-1 Gene Expression Research Articles

Glia-related Acute Effects of Risperidone and Haloperidol in Hippocampal Slices and Astrocyte Cultures from Adult Wistar Rats: A Focus on Inflammatory and Trophic Factor Release.

Antipsychotics are drugs commonly prescribed to treat a variety of psychiatric conditions. They are classified as typical and atypical, depending on their affinity for dopaminergic and serotonergic receptors. Although neurons have been assumed to be the major mediators of the antipsychotic pharmacological effects, glia, particularly astrocytes, have emerged as important cellular targets for these drugs. In the present study, we investigated the effects of acute treatments with the antipsychotics risperidone and haloperidol of hippocampal slices and astrocyte cultures, focusing on neuron-glia communication and how antipsychotics act in astrocytes. For this, we obtained hippocampal slices and primary astrocyte cultures from 30-day-old Wistar rats and incubated them with risperidone or haloperidol (1 and 10μM) for 30min and 24h, respectively. We evaluated metabolic and enzymatic activities, the glutathione level, the release of inflammatory and trophic factors, as well as the gene expression of signaling proteins. Haloperidol increased glucose metabolism; however, neither of the tested antipsychotics altered the glutathione content or glutamine synthetase and Na+K+-ATPase activities. Haloperidol induced a pro-inflammatory response and risperidone promoted an anti-inflammatory response, while both antipsychotics seemed to decrease trophic support. Haloperidol and risperidone increased Nrf2 and HO-1 gene expression, but only haloperidol upregulated NFκB and AMPK gene expression. Finally, astrocyte cultures confirmed the predominant effect of the tested antipsychotics on glia and their opposite effects on astrocytes. Therefore, antipsychotics cause functional alterations in the hippocampus. This information is important to drive future research for strategies to attenuate antipsychotics-induced neural dysfunction, focusing on glia.

Comparing fermented food and vitamin E on exercise-mediated Nrf2/ARE activation in middle-aged/ elderly: A randomized, double-blind clinical study

Objective: This study investigated the effects of fermented papaya preparation (FPP®) and vitamin E on gene expression in middle-aged/elderly individuals, leveraging FPP’s established antioxidant and immune-regulatory benefits. Methods: Graded Exercise Walking Test was administered twice weekly for 6 months. Total Antioxidant capacity (TAC) and gene expression (Nrf2, NQO1, HO-1) in PBMC were measured monthly. Results: Throughout the 6-month study, routine biochemistry and BMI remained stable. Both treatments significantly improved Total Antioxidant Capacity (TAC), Vitamin E exhibiting earlier effects (3 months). Notably, FPP® supplementation led to sustained over-expression of nuclear Nrf2 in all subjects, surpassing Vitamin E’s effects. NQO1 gene expression was rapidly and consistently upregulated in the FPP group, exceeding baseline and Vitamin E levels throughout the study. HO-1 gene expression was upregulated by FPP at 1 month in younger age quartiles (Q1-2) and at 3 and 6 months in all subjects, regardless of age and gender. In contrast Vitamin E did not significantly impact Nrf2, NQO1, or HO-1 gene expression. Conclusion: These findings demonstrate that FPP, unlike Vitamin E, potentiates Nrf2 signaling, triggering a downstream epigenetic cascade. Notably, our clinical data reveal that physical exercise combined with functional food supplementation partially restores impaired Nrf2 signaling in elderly individuals.

The Growth Inhibitory Effect of Resveratrol and Gallic Acid on Prostate Cancer Cell Lines through the Alteration of Oxidative Stress Balance: The Interplay between Nrf2, HO-1, and BACH1 Genes.

The association between oxidative stress and prostate cancer (PC) has been demonstrated both epidemiologically and experimentally. Balance in reactive oxygen species (ROS) levels depends on multiple factors, such as the expression of Nrf2, HO-1, and BACH1 genes. Natural polyphenols, such as resveratrol (RSV) and gallic acid (GA), affect cellular oxidative profiles. The present study investigated the possible effects of GA and RSV on the oxidative profiles of PC3 and DU145 cells, as well as Nrf2, HO-1, and BACH1 gene expression to achieve an understanding of the mechanisms involved. PC3 and DU145 cells were treated with ascending concentrations of RSV and GA for 72 h. Then cell growth and mRNA expression of Nrf2, HO-1, and BACH1 genes were analyzed by real-time PCR. Various spectrophotometric analyses were performed to measure oxidative stress markers. RSV and GA significantly decreased the growth of PC3 and DU145 cells compared to the control group in a concentration-dependent manner. RSV and GA also decreased ROS production in PC3 cells, but in DU145 cells, only the latter polyphenol significantly decreased ROS content. In addition, RSV and GA had ameliorating effects on SOD, GR, GPX, and CAT activities and GSH levels in both cell lines. Also, RSV and GA induced HO- 1 and Nrf2 gene expression in both cell lines. BACH1 gene expression was induced by RSV only at lower concentrations, in contrast to GA in both cell lines. Our data suggest that RSV and GA can prevent the growth of prostate cancer cells by disrupting oxidative stress-related pathways, such as changes in Nrf2, HO-1, and BACH1 gene expression.

Evaluation of Antioxidant Effects of Coenzyme Q10 against Hyperglycemia-Mediated Oxidative Stress by Focusing on Nrf2/Keap1/HO-1 Signaling Pathway in the Liver of Diabetic Rats.

Hyperglycemia-induced oxidative stress can damage the liver and lead to diabetes complications. Coenzyme Q10 (CoQ-10) reduces diabetes-related oxidative stress. However, its molecular mechanisms are still unclear. This study aimed to examine CoQ-10's antioxidant capabilities against hyperglycemia-induced oxidative stress in the livers of diabetic rats, specifically targeting the Nrf2/Keap1/ARE signaling pathway. This study was conducted between 2020-2021 at Arak University of Medical Sciences. A total of 30 male adult Wistar rats (8 weeks old) weighing 220-250 g were randomly assigned to five groups (n=6 in each group): control healthy, sesame oil (CoQ-10 solvent), CoQ-10 (10 mg/Kg), diabetic, and diabetic+CoQ-10. Liver oxidative stress indicators, including malondialdehyde, catalase, glutathione peroxidase, and glutathione, were estimated using the spectrophotometry method. Nrf2, Keap1, HO-1, and NQO1 gene expressions were measured using real-time PCR tests in the liver tissue. All treatments were conducted for 6 weeks. Statistical analysis was performed using SPSS software. One-way ANOVA followed by LSD's or Tukey's post hoc tests were used to compare the results of different groups. P<0.05 was considered statistically significant. The findings showed that induction of diabetes significantly increased Keap1 expression (2.1±0.9 folds, P=0.01), and significantly inhibited the mRNA expression of Nrf2 (0.38±0.2 folds, P=0.009), HO-1 (0.27±0.1 folds, P=0.02), and NQO1 (0.26±0.1 folds P=0.01), compared with the healthy group. In the diabetic group, the activity of glutathione peroxidase, catalase enzymes, and glutathione levels was decreased with an increase in malondialdehyde level. CoQ-10 supplementation significantly up-regulated the expressions of Nrf2 (0.85±0.3, P=0.04), HO-1 (0.94±0.2, P=0.04), NQO1 (0.88±0.5, P=0.03) genes, and inhibited Keap1 expression (1.1±0.6, P=0.02). Furthermore, as compared to control diabetic rats, CoQ-10 ameliorated oxidative stress by decreasing malondialdehyde levels and increasing catalase, glutathione peroxidase activities, and glutathione levels in the liver tissues of the treated rats in the treatment group. The findings of this study revealed that CoQ-10 could increase the antioxidant capacity of the liver tissue in diabetic rats by modulating the Nrf2/Keap1/HO-1/NQO1 signaling pathway.

Structural characterization and hypolipidemic activity of a natural polysaccharide from Suaeda salsa L.

Herein, the identification and analysis of a newly discovered hypolipidemic polysaccharide extracted from Suaeda salsa L., SS3-N1, is reported. The weight-average molecular weight (Mw), number-average molecular weight (Mn), and dispersity (Ð) of SS3-N1 were determined to be 45.50 kDa, 34.21 kDa, and 1.33, respectively. This polysaccharide primarily consists of galactose (50.80 %) and arabinose (30.70 %), with lower proportions of xylose, mannose, guluronic acid, rhamnose, glucuronic acid, ribose, and fucose. Methylation and NMR analyses indicated that its backbone was primarily composed of R → 3,6)-β-D-Galp-(1 → R and R → 5)-α-L-Araf-(1→ residues. The sugar units at the reducing and nonreducing ends were identified as R → 4)-β-D-Xylp-(1 → R and R → 3)-β-D-Galp-(1 → R, respectively. In addition, α-L-Araf (1 → R side branches were incorporated at the C-3 position of R → 3,6)-β-D-Galp-(1 → R. At 100 μg/mL, SS3-N1 surpassed the lipid-lowering efficacy of the positive control, atorvastatin (0.4 μM), in an egg yolk powder (EYP)-induced hyperlipidemic zebrafish model. This effect may be attributed to the modulation of cholesterol metabolism due to the upregulation of nrf2, ho-1, ampk, ppara, and cyp7a1 gene expression and the downregulation of acaca and hmgcr gene expression. Such dual gene regulation inhibits fatty acid and cholesterol synthesis, suggesting potential applications for the natural hypolipidemic polysaccharide derived from S. salsa L.

Evaluation of Terminalia arjuna Bark Powder Supplementation on Isoprenaline-Induced Oxidative Stress and Inflammation in the Heart of Long Evans Rats, Understanding the Molecular Mechanism of This Old Medicinal Plant

Article Evaluation of Terminalia arjuna Bark Powder Supplementation on Isoprenaline-Induced Oxidative Stress and Inflammation in the Heart of Long Evans Rats, Understanding the Molecular Mechanism of This Old Medicinal Plant Mirza Alimullah 1, Nafiur Rahman 1, Puspa Sornaker 1, Kazi Akramuddaula 2, Sumaia Sarif 1, Shahnaz Siddiqua 3, Kaniz Fatima Mitu 1, Ishrat Jahan 1, Ferdous Khan 1, Nusrat Subhan 1 and Md. Ashraful Alam 1,* 1 Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh 2 Pharmacy Discipline, Khulna University, Khulna 9208, Bangladesh 3 Department of Pharmacy, East West University, Dhaka 1212, Bangladesh * Correspondence: ashraful.alam@northsouth.edu or sonaliagun@yahoo.com Received: 27 July 2024; Revised: 28 August 2024; Accepted: 28 August 2024; Published: 5 September 2024 Abstract: This study was conducted to determine the effect of Terminalia arjuna bark powder supplementation on the oxidative stress of the cardiovascular system. Isoprenaline (ISO) was administered to the rats to develop the cardiac hypertrophy and myocardial infarction (MI). Terminalia arjuna bark powder was mixed with the food powder and provided for two weeks. At the end of the experiment, all rats were sacrificed and tissue samples were collected. ISO administration in rats increased the oxidative stress markers such as malondialdehyde (MDA), nitric oxide (NO), advanced oxidation protein product (APOP), and myeloperoxidase (MPO) in plasma and heart. Terminalia arjuna bark powder lowered the MDA, NO, and AOPP concentration level in ISO administered rats. Additionally, Terminalia arjuna restored the antioxidant enzymes (catalase and SOD) activities. Gene expression of antioxidant enzymes and inflammatory markers in the heart were studied. Terminalia arjuna restored Nrf-2, HO-1, HO-2, catalase, SOD, and GPx gene expression in the heart of ISO administered rats. ISO induced increased transcription levels of inflammatory genes such as IL-1, IL-6, TNF-α, TGF-β, iNOS, and NF-κB, which were decreased by Terminalia arjuna bark powder. Histopathology was checked and hematoxylin and eosin and Sirius red staining were performed on heart sections. ISO administration resulted in mononuclear cells infiltration and collagen deposition in the heart which were lowered by Terminalia arjuna bark powder. In conclusion, this study suggests that the Terminalia arjuna bark powder alleviated the oxidative stress by restoring the antioxidant genes and prevented the increase in inflammatory markers in the heart of ISO administered rats.

Ameliorative Effect of Chitosan/Spirulina platensis Ethanolic Extract Nanoformulation against Cyclophosphamide-Induced Ovarian Toxicity: Role of PPAR-γ/Nrf-2/HO-1 and NF-kB/TNF-α Signaling Pathways.

Cyclophosphamide (CP) is an anticancer drug that causes infertility disorders. This study was designed to evaluate a nanoformulation of chitosan with an ethanolic extract from Spirulina platensis in terms of its protection against cyclophosphamide-induced ovarian toxicity. Nine groups of female Wistar rats were randomly assigned as follows: 1: control vehicle, 2: chitosan polymer, 3: telmisartan, 4: Spirulina platensis extract, 5: nanoformulation of the Spirulina platensis, and 6: single injection of CP; groups 7, 8, and 9 received the same treatments as those used in groups 3, 4, and 5, respectively, with a single dose of CP (200 mg/kg, I.P). The results displayed that the CP treatment decreased estradiol, progesterone, anti-mullerian hormone, and GSH content, and it downregulated PPAR-γ, Nrf-2, and HO-1 gene expression. In addition, the CP treatment caused an increase in the FSH, LH, and MDA levels. In the same manner, the protein expression of caspase-3, NF-kB, and TNF-α was upregulated in response to the CP treatment, while PPAR-γ was downregulated in comparison with the control. The rats treated with SPNPs exhibited a substantial reduction in the detrimental effects of oxidative stress and inflammation of the ovarian tissue. This study's conclusions showed that SPNPs counteracted the effects of CP, preventing the death of ovarian follicles and restoring the gonadotropin hormone balance and normal ovarian histological appearance.

Design and Synthesis of Novel Antioxidant 2-Substituted-5,7,8-Trimethyl-1,4-Benzoxazine Hybrids: Effects on Young and Senescent Fibroblasts.

The exponential growth of the aged population worldwide is followed by an increase in the prevalence of age-related disorders. Oxidative stress plays central role in damage accumulation during ageing and cell senescence. Thus, a major target of today's anti-ageing research has been focused on antioxidants counteracting senescence. In the current work, six novel 5,7,8-trimethyl-1,4-benzoxazine/catechol or resorcinol hybrids were synthesized connected through a methoxymethyl-1,2,3-triazolyl or a 1,2,3-triazoly linker. The compounds were evaluated for their antioxidant capacity in a cell-free system and for their ability to reduce intracellular ROS levels in human skin fibroblasts, both young (early-passage) and senescent. The most efficient compounds were further tested in these cells for their ability to induce the expression of the gene heme oxygenase-1 (ho-1), known to regulate redox homeostasis, and cellular glutathione (GSH) levels. Overall, the two catechol derivatives were found to be more potent than the resorcinol analogues. Furthermore, these two derivatives were shown to act coordinately as radical scavengers, ROS inhibitors, ho-1 gene expression inducers, and GSH enhancers. Interestingly, one of the two catechol derivatives was also found to enhance human skin fibroblast viability. The properties of the synthesized compounds support their potential use in cosmetic applications, especially in products targeting skin ageing.

Portulaca oleracea L seed extracts counteract diabetic nephropathy through SDF-1/IL10/PPARγ–mediated tuning of keap1/Nrf2 and NF-κB transcription in Sprague Dawley rats

Background & objective: While oxidative stress is the key player driving diabetic nephropathy (DN), firm glycemic control remains the pillar prophylactic measure. Purslane was extensively described as a potent hypoglycemic and hypolipidemic agent owing to its rich content of antioxidants. Therefore, this report aimed to assess the renoprotective potentials of methanol (MO) and methylene chloride (MC) fixed oil extracts of purslane seeds in a diabetic nephropathy (DN) model.MethodsPurslane seeds were extracted using absolute methanol and methylene chloride, and type-1 diabetes was induced with a single 55 mg/kg dose of Streptozotocin (STZ) dissolved in 100 mmol/L citrate buffer (pH 4.5), and then diabetic animals were received MO, MC, for 42 consecutive days to compare their antidiabetic effect relative to the reference drug “Losartan”. Renal functions and DN biomarkers were weekly assessed, and the relative expression of different oxido-inflammatory mediators was quantified in diabetic kidneys by RT-PCR. Data were statistically analyzed using GraphPad Prism 9.0.2.ResultsThe oral administration of MO and MC extracts (250 mg/kg/day) significantly ameliorated the body weight loss (P < 0.0001 / each), fasting blood glucose levels (FBG) (P < 0.0001 / each), urine volume (P < 0.0001 / each), as well as serum creatinine (P < 0.0001 / each), uric acid (P = 0.0022, 0.0052), and blood urea nitrogen (BUN) (P = 0.0265, 0.0338); respectively, compared with the untreated diabetic rats. In addition, both extracts restored the effectuality of antioxidative machinery in diabetic kidneys as indicated by a significant reduction of ROS accumulation and lipid peroxidation; higher GSH content, and promoted activity of glutathione reductase and superoxide dismutase antioxidant enzymes (P < 0.0001 / each). Histologically, both extracts alleviated the DN-structural alterations including the glomerular congestion and tubular degeneration, with MC-treated kidneys showing near to normal architecture. The transcription profiles of all treated kidneys revealed a significantly downregulated expression of TNF-α, IL-6, Keap1 and NF-κB genes, concomitant with a significant upregulation of SDF-1, IL-10, Nrf2, HO-1, and PPARγ gene expression (P < 0.0001 / all).ConclusionThese findings highlight the remarkable DN-prophylactic potentials of purslane extracts mediated by neutralizing the hyperglycemia-induced ROS accumulation, and circumventing the downstream inflammatory cascades, surpassing the reference angiotensin receptor blocker; i.e. Losartan.

NLRX1 Inhibits LPS-Induced Microglial Death via Inducing p62-Dependent HO-1 Expression, Inhibiting MLKL and Activating PARP-1.

The activation of microglia and the production of cytokines are key factors contributing to progressive neurodegeneration. Despite the well-recognized neuronal programmed cell death regulated by microglial activation, the death of microglia themselves is less investigated. Nucleotide-binding oligomerization domain, leucine-rich repeat-containing X1 (NLRX1) functions as a scaffolding protein and is involved in various central nervous system diseases. In this study, we used the SM826 microglial cells to understand the role of NLRX1 in lipopolysaccharide (LPS)-induced cell death. We found LPS-induced cell death is blocked by necrostatin-1 and zVAD. Meanwhile, LPS can activate poly (ADP-ribose) polymerase-1 (PARP-1) to reduce DNA damage and induce heme oxygenase (HO)-1 expression to counteract cell death. NLRX1 silencing and PARP-1 inhibition by olaparib enhance LPS-induced SM826 microglial cell death in an additive manner. Less PARylation and higher DNA damage are observed in NLRX1-silencing cells. Moreover, LPS-induced HO-1 gene and protein expression through the p62-Keap1-Nrf2 axis are attenuated by NLRX1 silencing. In addition, the Nrf2-mediated positive feedback regulation of p62 is accordingly reduced by NLRX1 silencing. Of note, NLRX1 silencing does not affect LPS-induced cellular reactive oxygen species (ROS) production but increases mixed lineage kinase domain-like pseudokinase (MLKL) activation and cell necroptosis. In addition, NLRX1 silencing blocks bafilomycin A1-induced PARP-1 activation. Taken together, for the first time, we demonstrate the role of NLRX1 in protecting microglia from LPS-induced cell death. The underlying protective mechanisms of NLRX1 include upregulating LPS-induced HO-1 expression via Nrf2-dependent p62 expression and downstream Keap1-Nrf2 axis, mediating PARP-1 activation for DNA repair via ROS- and autophagy-independent pathway, and reducing MLKL activation.

Effects of Cycloastragenol on Alzheimer's Disease in Rats by Reducing Oxidative Stress, Inflammation, and Apoptosis.

As individuals age, they may develop Alzheimer's disease (AD), which is characterized by difficulties in speech, memory loss, and other issues related to neural function. Cycloastragenol is an active ingredient of Astragalus trojanus and has been used to treat inflammation, aging, heart disease, and cancer. This study aimed to explore the potential therapeutic benefits of cycloastragenol in rats with experimentally induced AD. Moreover, the underlying molecular mechanisms were also evaluated by measuring Nrf2 and HO-1, which are involved in oxidative stress, NFκB and TNF-α, which are involved in inflammation, and BCL2, BAX, and caspase-3, which are involved in apoptosis. Sprague-Dawley rats were given 70 mg/kg of aluminum chloride intraperitoneally daily for six weeks to induce AD. Following AD induction, the rats were given 25 mg/kg of cycloastragenol daily by oral gavage for three weeks. Hippocampal sections were stained with hematoxylin/ eosin and with anti-caspase-3 antibodies. The Nrf2, HO-1, NFκB, TNF-α, BCL2, BAX, and caspase-3 gene expressions and protein levels in the samples were analyzed. Cycloastragenol significantly improved rats' behavioral test performance. It also strengthened the organization of the hippocampus. Cycloastragenol significantly improved behavioral performance and improved hippocampal structure in rats. It caused a marked decrease in the expression of NFκB, TNF-α, BAX, and caspase-3, which was associated with an increase in the expression of BCL2, Nrf2, and HO-1. Cycloastragenol improved the structure of the hippocampus in rats with AD. It enhanced the outcomes of behavioral tests, decreased the concentration of AChE in the brain, and exerted antioxidant and anti-inflammatory effects. Antiapoptotic effects were also noted, leading to significant improvements in cognitive function, memory, and behavior in treated rats.

Neuroprotective effects of polysaccharide of Schisandrae Chinensis Fructus in aging mice

This study aimed to investigate the effects of Schisandra Chinensis Fructus polysaccharide (SCP) on learning and memory, hippocampal antioxidant activity and Keap1/Nrf2 signal transduction pathway in an aging mouse model. The step-down test was used to observe learning and memory. Biochemical analysis was used to detect Superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Nrf2, HO-1, and Keap1 gene expression in the hippocampus were measured by quantitative real-time polymerase chain reaction (qRT-PCR). SCP can improve the learning and memory ability (P&lt;0.05), increase hippocampal SOD activity, decrease MDA levels, up-regulate Nrf2 and HO-1 gene expressions, down-regulate Keap1 gene expression (P&lt;0.05). Our findings suggest that SCP can improve brain damage in D-galactose-induced aging mice, improve antioxidant enzyme activity, reduce lipid peroxidation, and has obvious anti-aging effects. Its anti-aging activity may be related to activating the Keap1/Nrf2 signal transduction pathway in the hippocampus.

Leishmanicidal and immunomodulatory activity of Terminalia catappa in Leishmania amazonensisin vitro infection

Leishmaniases are infectious-parasitic diseases that impact public health around the world. Antileishmanial drugs presented toxicity and increase in parasitic resistance. Studies with natural products show an alternative to this effect, and several metabolites have demonstrated potential in the treatment of various diseases. Terminalia catappa is a plant species with promising pharmaceutical properties. The objective of this work was to evaluate the therapeutic potential of extracts and fractions of T. catappa on Leishmania amazonensis and investigate the immunomodulatory mechanisms associated with its action. In anti-Leishmania assays, the ethyl acetate fraction exhibited activity against promastigotes (IC50 86.07 ± 1.09 μg/mL) and low cytotoxicity (CC50 517.70 ± 1.68 μg/mL). The ethyl acetate fraction also inhibited the intracellular parasite (IC50 25.74 ± 1.08 μg/mL) with a selectivity index of 20.11. Treatment with T. catappa ethyl acetate fraction did not alter nitrite production by peritoneal macrophages stimulated with L. amazonensis, although there was a decrease in unstimulated macrophages treated at 50 μg/mL (p = 0.0048). The T. catappa ethyl acetate fraction at 100 μg/mL increased TNF-α levels (p = 0.0238) and downregulated HO-1 (p = 0.0030) and ferritin (p = 0.0002) gene expression in L. amazonensis-stimulated macrophages. Additionally, the total flavonoid and ellagic acid content for ethyl acetate fraction was 13.41 ± 1.86 mg QE/g and 79.25 mg/g, respectively. In conclusion, the T. catappa ethyl acetate fraction showed leishmanicidal activity against different forms of L. amazonensis and displayed immunomodulatory mechanisms, including TNF-α production and expression of pro and antioxidant genes.

Characterization and Exploration of the Neuroprotective Potential of Oat-Protein-Derived Peptides in PC12 Cells and Scopolamine-Treated Zebrafish.

Neurodegenerative disorders pose a substantial risk to human health, and oxidative stress, cholinergic dysfunction, and inflammation are the major contributors. The purpose of this study was to explore the neuroprotective effects of oat protein hydrolysate (OPH) and identify peptides with neuroprotective potential. This study is the first to isolate and identify OPH peptides with neuroprotective potential, including DFVADHPFLF (DF-10), HGQNFPIL (HL-8), and RDFPITWPW (RW-9), by screening via peptidomes and molecular-docking simulations. These peptides showed positive effects on the activity of antioxidant enzymes and thus reduced oxidative stress through regulation of Nrf2-keap1/HO-1 gene expression in vitro and in vivo. The peptides also significantly ameliorated scopolamine-induced cognitive impairment in the zebrafish model. This improvement was correlated with mitigation of MDA levels, AChE activity, and levels of inflammatory cytokines in the brains of zebrafish. Furthermore, these peptides significantly upregulated the mRNA expression of Bdnf, Nrf2, and Erg1 in the brains of zebrafish with neurodegenerative disorders. Collectively, oat peptides have potential for use as active components in nutraceutical applications for the prevention of neurodegenerative diseases.

Macroporous resin purification of phenolics from Irish apple pomace: Chemical characterization, and cellular antioxidant and anti-inflammatory activities

Apple pomace (AP) is a highly prevalent waste product worldwide in the fruit processing sector. This study compared the chemical profile, antioxidant, and anti-inflammatory activities of crude (CE) and an extract purified using XAD-7 resin (PE). The purification process increased the total phenolic content, flavonoids, and tannins by 3.35, 40.31, and 8.87-fold, respectively. The main phenolic compounds identified in PE were phlorizin (20.54 mg/g), chlorogenic acid (10.01 mg/g), and hyperoside (2.77 mg/g). No difference was found between CE and PE in protecting human plasma against oxidation. In human erythrocytes, both CE and PE decreased the reactive oxygen species (ROS) generation and decreased lipoperoxidation. However, PE had stronger anti-inflammatory effects than CE by promoting HO-1 gene expression, suppressing NO production, and inhibiting IL-1β, IL-6, and IL-10 mRNA expression in lipopolysaccharide-challenged RAW.264.7 macrophages. Therefore, purifying apple pomace crude extract is a promising approach to boosting valuable antioxidants and anti-inflammatory phenolics.

A Novel Polysaccharide from Sargassum weizhouense: Extraction Optimization, Structural Characterization, Antiviral and Antioxidant Effects.

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important pathogens in the global swine industry over the past three decades. There is no licensed antiviral medication that can effectively control this infection. In the present study, the structure of SP-1 isolated and purified from Sargassum weizhouense was analyzed, and its antioxidant capacity and antiviral effect in MARC-145 cells against PRRSV were investigated. The results showed that SP-1 is a novel polysaccharide which mainly is composed of →4)-β-D-ManpA-(1→, →4)-α-L-GulpA-(1→ and a small amount of →4)-β-D-GalpA-(1→. PRRSV adsorption, replication, and release were all suppressed by SP-1. SP-1 therapy down-regulated mRNA expression of the CD163 receptor while increasing the antioxidant gene expression of Nrf2, TXNIP, and HO-1; increasing the protein expression of NQO1 and HO-1; and drastically reducing the protein expression of p-p65. The findings indicated that SP-1 reduces PRRSV adsorption, replication, and release through blocking the expression of the crucial CD163 receptor during infection. Meanwhile, SP-1 exerts antioxidant effects in PRRSV-infected cells through the activation of the Nrf2-HO1 signaling pathway.

Fucoidan from Sargassum wightii reduces oxidative stress through upregulating Nrf2/HO-1 signaling pathway in alloxan-induced diabetic cardiomyopathy rats.

Diabetic cardiomyopathy (DCM) is a form of cardiac dysfunction caused by diabetes, increasing heart failure and death. Studies shown that hyperglycemia-induced oxidative stress significantly affects heart structure and functional changes during diabetic cardiomyopathy. Fucoidans are sulfated polysaccharide derived from naturally available seaweeds and reported for various biological functions such as antioxidant, anti-diabetic, and anti-inflammatory. However, the therapeutic potential of Indian seaweeds against DCM remains largely unexplored. Therefore, the current study aimed to work on the cardioprotective effect of extracted fucoidan from Sargassum wightii (SwF) in alloxan-induced DCM. Diabetes (DM) was induced with alloxan monohydrate (150mg/kg-1) dissolved in Nacl (0.9%) overnight-fasted rats. Group III, IV rats were DM induced, followed by treated with SwF (150mg/kg-1) and (300mg/kg-1). Group V and VI were non-diabetic rats and received SwF (150mg/kg-1) and (300mg/kg-1). SwF reduced classical progressive DM complications such as hyperglycemia, polydipsia, polyphagia, and polyurea in alloxan-induced diabetic rats. Biochemical analysis showed that SwF decreased blood glucose, cardiac markers enzymes, and lipid peroxidation levels compared to diabetic rats. SwF administration significantly increased Nrf2, HO-1, SOD, Catalase, and NQO1 gene expression. In addition, SwF-treated rats showed reduced heart tissue damage with increased Nrf2 and HO-1 protein expression. The current research concludes that targeting oxidative stress with SwF provided an effective role inthe prevention of DCM. Thus, fucoidan could be used to develop functional food ingredients for DCM.

New Insight on the Cytoprotective/Antioxidant Pathway Keap1/Nrf2/HO-1 Modulation by Ulva intestinalis Extract and Its Selenium Nanoparticles in Rats with Carrageenan-Induced Paw Edema.

Currently, there is growing interest in exploring natural bioactive compounds with anti-inflammatory potential to overcome the side effects associated with the well-known synthetic chemicals. Algae are a rich source of bioactive molecules with numerous applications in medicine. Herein, the anti-inflammatory effect of Ulva intestinalis alone or selenium nanoparticles loaded with U. intestinalis (UISeNPs), after being fully characterized analytically, was investigated by a carrageenan-induced inflammation model. The pretreated groups with free U. intestinalis extract (III and IV) and the rats pretreated with UISeNPs (groups V and VI) showed significant increases in the gene expression of Keap1, with fold increases of 1.9, 2.27, 2.4, and 3.32, respectively. Similarly, a remarkable increase in the Nrf2 gene expression, with 2.09-, 2.36-, 2.59-, and 3.7-fold increases, was shown in the same groups, respectively. Additionally, the groups III, IV, V, and VI revealed a significantly increased HO-1 gene expression with a fold increase of 1.48, 1.61, 1.87, and 2.84, respectively. Thus, both U. intestinalis extract and the UISeNPs boost the expression of the cytoprotective/antioxidant pathway Keap1/Nrf2/HO-1, with the UISeNPs having the upper hand over the free extract. In conclusion, U. intestinalis and UISeNPs have proven promising anti-inflammatory activity through mediating different underlying mechanisms.

The interaction of pterostilbene with Kelch-like ECH-associated protein 1 and its regulation on the nuclear factor erythroid 2-related factor 2/antioxidant response element pathway

Pterostilbene is a naturally occurring stilbene compound known for its anti-tumor effect. However, the molecular mechanism is still not explored well. Thus, the present work was designed to investigate the regulation effect of pterostilbene on the Nrf2-ARE pathway. The results of molecular docking showed that pterostilbene bound at the top of the central pore of the Keap1 Kelch domain, and the hydrogen bond and hydrophobic interactions were crucial for their stable binding. The western blot analysis confirmed that pterostilbene treatment promoted Nrf2 nuclear translocation. Reported gene assays confirmed the ARE luciferase activity of pterostilbene. RT-PCR and western blot assays showed that pterostilbene regulated the gene and protein expression of HO-1, NQO1, and GCLM. In vitro free radical scavenging assays have shown that pterostilbene can be effective in scavenging DPPH, ABTS, and hydroxyl radicals. In summary, pterostilbene activates the Nrf2-ARE pathway for exerting its bioactivities.

A new ginger extract characterization: Immunomodulatory, antioxidant effects and differential gene expression

Ginger (Zingiber officinale) is commonly consumed as spice or herbal medicine with anti-inflammatory, antioxidant, and anticancer properties. It is rich of many bioactive constituents, mainly gingerols and shogaols. Although the bioactive constituents have been identified, the molecular mechanisms of ginger action are still limited, and the related signalling pathways not completely defined. Here, we used a simple ethanol/freeze-drying method to obtain a new ginger extract (GE), which was chemically characterised by Folin-Ciocalteu, antioxidant ORAC and HPLC assays. At cellular level, anti-inflammatory/antioxidant properties of GE, in addition to the commercial [6]-gingerol, were evaluated using RAW264.7 murine macrophages. Cell viability tests verified the non-toxic doses of GE and [6]-gingerol, and the glutathione assay confirmed the antioxidant property of GE. By quantitative PCR, we analysed the differential expression of various genes in LPS-treated cells, after GE/[6]-gingerol pre-treatments. The genes belonged to different categories: immune signalling, pro-/anti-inflammatory cytokines, pro-/anti-antioxidant enzymes, hallmarks of macrophage polarization and endoplasmic reticulum stress response. Results showed that pre-treatment with two doses of GE reduced the LPS-induced expression of TLR4, MyD88, Rel-A, IL-1α, IL-6, TNF-α, IL-10, iNOS and TRIB3 genes to varying degrees, whereas increased Jun, Light/Tnfsf14, HO-1 and Arg-1 gene expression. No effect was found on MIF expression in LPS-induced cells after GE pre-treatments. These results also suggested that GE pre-treatment promotes the expression of specific markers of macrophage polarization in LPS-stimulated cells, with a trend to activate an anti-inflammatory M2 phenotype. Further analyses will broaden the understanding of the role of individual GE components in cellular inflammation/immunomodulation.