جستجوی مقالات مرتبط با کلیدواژه « nrf2 » در نشریات گروه « پزشکی »

This investigation explored the mechanism by which the total flavonoids of Selaginella tamariscina (P.Beauv.) Spring (TFST) mitigate oxidative stress through the activation of the heme oxygenase-1 (HO-1) signaling pathway mediated by nuclear factor erythroid 2-related factor 2 (Nrf2), thereby ameliorating acute lung injury (ALI) induced by diabetes. 

Male mice weighing 20–25 grams were divided into four groups: a control group, a diabetic group, a diabetic group treated with TFST, and a diabetic group treated with TFST and ML385. Various biological specimens were collected for analysis, including bronchoalveolar lavage fluid (BALF), blood, and tissue samples. These were subjected to a range of assessments covering hematological and BALF parameters tumor necrosis factor-alpha (TNF-α), interleukin-6 [IL-6]), biochemical markers (malondialdehyde [MDA], superoxide dismutase [SOD], glutathione peroxidase [GSH], Nrf2, and HO-1 levels), along with histopathological evaluations.

Pre-treatment with TFST demonstrated a significant decrease in pulmonary tissue damage, evidenced by decreased wet-to-dry (W/D) lung ratios (P<0.001), reduced lung injury scores (P<0.0001), and lower levels of TNF-α, IL-6 (P<0.0001), as well as oxidative stress markers like MDA (P<0.05). Moreover, there was an elevation in the activity of anti-oxidative enzymes, specifically SOD and GSH (P<0.05), coupled with an enhanced expression of Nrf2 and HO-1 in the diabetic group (P<0.01). 

The study findings demonstrate that TFST can suppress oxidative stress by modulating the Nrf2 pathway and up-regulating HO-1 activity, thereby ameliorating diabetes-induced acute lung injury.

Hepatic ischemia-reperfusion (HIR) is a severe process in pathophysiology that occurs clinically in hepatectomy, and hepatic transplantations. The present study aimed to investigate the effect of PKC θ deletion against HIR injury and elucidate its mechanism in pathophysiology.

HIR injury was induced in wild-type and PKC θ deletion mice treated with or without heme.  The ALT and AST levels were determined to evaluate liver function. HIR injury was observed via histological examination. Oxidative stress and inflammatory response markers, and their signaling pathways were detected.

The study found that PKC θ knockout decreased serum AST and ALT levels when compared to the WT mice. Furthermore, heme treatment significantly reduced the ALT and AST levels of the PKC θ deletion mice compared with the untreated PKC θ deletion mice. PKC θ deletion markedly elevated superoxide dismutase activity in the liver tissue, reduced malondialdehyde content in the tissue, and the serum TNF-α and IL-6 levels compared with the WT mice. Heme treatment was observed to elevate the activity of SOD and reduced MDA content and serum of TNF-α and IL 6 in the PKC θ deletion animals. Meanwhile, heme treatment increased HO-1 and Nrf 2 protein expression, and reduced the levels of TLR4, phosphorylated NF-κB, and IKB-α.

These findings suggested that PKC θ deletion ameliorates HIR, and heme treatment further improves HIR, which is related to regulation of PKC θ deletion on Nrf 2/HO-1 and TLR4/NF-κB/IKB α pathway.

Multiple Sclerosis (MS) is a prevalent non-traumatic disabling disease affecting young adults, characterized by complexity in its pathogenesis. Nuclear factor erythroid 2-Related Factor 2 (NRF2) serves as a crucial transcriptional regulator of anti-inflammatory and antioxidant enzymes, influenced by the ubiquitous protein p62. It acts as a scaffold directing substrates to autophagosomes. This study aims to explore the potential association between microRNA 135-5p and p62 and their impact on inflammation and oxidative stress through the NRF2 pathway in MS.

The study included 30 healthy controls and 60 MS patients (relapsing-remitting and secondary progressive). Real-time PCR was employed for the detection of Nrf2, p62, miRNA135-5P, and NF-κB in serum, while p53 levels were determined using ELISA.

Nrf2 and p62 expression was significantly downregulated in the MS group compared to controls. Conversely, miRNA135-5P, NF-κB expression, and P53 levels were significantly elevated in the MS group.

This study reveals a potential association between miRNA 135-5p and p62, indicating their role in the pathogenesis of MS. Results suggest that miRNA 135-5p and p62 may influence inflammation and oxidative stress in MS through the NRF2 pathway, potentially mediated by NF-κB and p53.

This study assessed the cardioprotective properties ofPersicaria maculosa (PME) and Citrus sinensis (CME) hydromethanolic extracts, besides Citrus sinensis aqueous extract(CWE) against doxorubicin (DOX)-induced cardiotoxicity. The extracts were characterized. Micewere divided into eight groups: control (saline), DOX, protected(injected with 200 mg/kg of PME, CWE or CME for 21 days,orally, and DOX), and extracts (PME, CWE or CMEadministration, orally, for 21 days). DOX was injected (5 mg/kg,ip) on days 8, 13 and 18 of the experiment. Cardiac tumor necrosisfactor-alpha (TNF-α), nuclear factor (erythroid-derived 2)-like 2(Nrf2) and carbonyl reductase 1 (CBR1) expression levels, besidessuperoxide dismutase, catalase, malondialdehyde, nitric oxide andtotal protein levels were evaluated. Serum lactate dehydrogenase,creatine phosphokinase cardiac isoenzyme, aspartate transaminase,cholesterol, triglycerides and creatinine levels, as well as thecardiac tissues were examined. Comparing with the control, DOX considerably (p<0.01)up-regulated TNF-α expression, malondialdehyde, nitric oxide,cardiac enzymes, lipids and creatinine levels, while it significantly(p<0.01) down-regulated Nrf2 and CBR1. Additionally, DOXinterfered with antioxidant enzymes' activities (p<0.01).Conversely, protected groups showed a significant (p<0.01)amelioration of DOX-induced cardiotoxic effects. The current study provides a new understanding of P.maculosa and C. sinensis cardioprotective mechanisms. Theextracts' cardioprotective effects may be due to their antioxidantactivities, ability to maintain the redox homeostasis throughregulation of important antioxidant genes and primary antioxidantenzymes, and capability to recover inflammatory cytokines andlipids levels. Noteworthy, the tested extracts showed no toxicchanges on the normal mice.

Non-alcoholic fatty liver disease (NAFLD) is a chronic steatohepatitis disorder. If left untreated, it can progress to hepatocellular carcinoma. Several studies have shown that saroglitazar, a PPARα/γ dual agonist, and curcumin (the principal constituent of turmeric) may be effective in the treatment of NAFLD. This research aimed to study the pharmacological mechanism of these compounds in rats with NAFLD.

NAFLD was induced in male Wistar rats (aged 6–8 weeks) by feeding them a high-fat diet (HFD) for 6 weeks. Subsequently, the rats were divided into four groups, with Group 1 continuing on HFD, while groups 2, 3, and 4 received HFD supplemented with saroglitazar, curcumin, and both saroglitazar and curcumin, respectively. We evaluated the expression of Nrf2, ERK1/2, NOX1,2,4, antioxidant enzymes, PPARα, γ, and genes regulating lipid metabolism in the liver. Histopathology of liver tissue was also examined. Furthermore, we analyzed serum levels of lipid profiles and hepatic enzymes.

Rats with NAFLD that received treatment involving saroglitazar and curcumin showed a significant decrease in the expression of ERK1/2, SREBP1, PPARγ, pro-inflammatory cytokines, NOXs, and ROS levels. Additionally, the levels of Nrf2, PPARα, and antioxidant enzymes showed a significant increase. The serum levels of lipid profiles and hepatic enzymes also decreased significantly after drug treatment.

Our results confirm that both saroglitazar and curcumin ameliorate NAFLD by regulating the Nrf2 and ERK1/2 signaling pathways. These findings suggest that curcumin could serve as a suitable substitute for saroglitazar, although they appear to have a synergistic effect.

Aminoglycosides like gentamicin can cause nephrotoxicity by increasing reactive oxygen species (ROS) and reducing antioxidants. The transcription factor Nrf2 regulates antioxidant genes like NQO1 to combat oxidative stress. This study evaluated Nrf2/NQO1 involvement in gentamicin renal toxicity and vitamin E protection.

24 rats were divided into control, gentamicin, vitamin E, and gentamicin plus vitamin E groups. Gentamicin (100 mg/kg) and vitamin E (250 mg/kg) were given intraperitoneally for 8 days. Kidney function, oxidative stress, Nrf2/NQO1 expression, and histology were analyzed.

Gentamicin significantly increased serum creatinine by 1.98-fold (1.43 ± 0.49 vs 0.72 ± 0.16 mg/dl, p <0.01) and BUN by 5.58-fold (252.3 ± 78.13 vs 45.18 ± 7.26 mg/dl, p <0.0001) compared to control. Gentamicin also markedly suppressed renal Nrf2 mRNA expression by 83% and NQO1 by 79% versus control (p <0.0001). Vitamin E partially alleviated the functional impairment and downregulation of Nrf2 and NQO1 caused by gentamicin. The vitamin E group displayed the highest Nrf2 (2.8-fold vs control) and NQO1 (1.6-fold vs control) expression among all groups (p <0.0001).

Gentamicin appears to cause nephrotoxicity partly by suppressing Nrf2/NQO1 antioxidant defense. Vitamin E provided renoprotection by scavenging ROS and potentially reactivating Nrf2/NQO1. The study suggests oxidative stress is an important mechanism in aminoglycoside kidney toxicity that may be mitigated by appropriate antioxidants. Evaluating Nrf2/NQO1 modulation provides insights into gentamicin nephrotoxicity and related kidney injuries.

Ulcerative colitis is a chronic inflammatory bowel disease (IBD) that causes inflammation and ulcers in the rectum and the innermost layer of the large intestine. Our study aimed to elucidate the ameliorative effect of cetirizine (CTZ) and loratadine (LOR) against acetic acid-induced ulcerative colitis in rats via assessment of the PI3K/p-Akt/Nrf2 signaling pathway and proinflammatory cytokine release.

Thirty-two rats were allocated into four groups (n=8). Group (I) was considered normal control. Acetic acid (AA) was injected intrarectally in groups (2-4). Group (2) was kept untreated. Group (3) was administered CTZ (20 mg/kg/day) for 7 days. Group (4) was administered LOR (10 mg/kg/day) for 7 days.

AA showed severe macroscopic colonic lesions associated with increased ulcer number, area, and severity with significantly elevated PI3K, p-Akt, Nrf2, TNF-α, and IL-6 in colorectal tissue as compared to the normal control group. All the aforementioned indicators were greatly improved by CTZ and LOR therapy.

This is the first study to elucidate the ameliorative effect of CTZ and LOR against AA-induced UC in rats. CTZ and LOR treatment mitigates UC via amelioration of the PI3K/p-Akt/Nrf2 pathway and proinflammatory cytokine release.

 The association between oxidative stress and the pathogenesis of neurodegenerative diseases has been documented. Besides, there is evidence that antidepressant agents, such as fluvoxamine maleate (Flv), can ameliorate neurotoxicity. The date palm (Phoenix dactylifera L.) pollen (DPP) contains various compounds with antioxidant capacity; however, its underlying mechanism of function has not been fully understood.

 The present study aimed to compare the neuroprotective effects of DPP and Flv on H2O2-induced oxidative damage and their effects on Nrf2, SIGMAR1, and Bcl2 gene expression in PC12 cells.

 First, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay examined the toxicities of DPP, Flv, and H2O2 at various concentrations on the PC12 cells. Real-time polymerase chain reaction (PCR) measured the expression of Nrf2, SIGMAR1, and Bcl2 in PC12 cells in the presence or absence of DPP or Flv after 4 h of treatment with 100 μM H2O2.

 Based on the MTT results, DPP at concentrations of 200 - 1000 µg/mL had no toxic effect on PC12 cells. The IC50 was evaluated at 57.26 μM and 109.5 μM under treatment with Flv and H2O2. Real-time PCR analysis showed a decrease in the expression of Nrf2 and SIGMAR1 in PC12 cells treated with 100 μM H2O2, an indicator of oxidative stress recruitment in PC12 cells. Pretreatment with DPP and Flv (500 µg/mL and 10 µM, respectively) for 24 h resulted in the upregulation of Nrf2 relative to the vehicle control. In addition, pretreatment with DPP increased the level of SIGMAR1 in PC12 cells compared with H2O2-exposed cells. Considering the role of SIGMAR1 in endoplasmic reticulum oxidative stress, the SIGMAR1 level should be evaluated at the translational level. Compared to the untreated cells, the expression of Bcl2 decreased in all the experimental cases, and the difference in Bcl2 expression was not significant between the co-treatment experimental cases.

 Taken together, DPP and Flv have neuroprotective effects against oxidative damage in PC12 cells. Exposure of PC12 cells to 500 μg/mL DPP and 10 μM Flv for 24 h protected the morphology and function of PC12 cells under H2O-induced oxidative stress via regulating oxidative stress-involved genes.

The imbalance between M1 and M2 macrophage activation is closely associated with the pathogenesis of inflammatory bowel diseases (IBDs). Sulforaphane (SFN) plays an important role in the treatment of inflammatory diseases. To investigate the effect of SFN on macrophage polarization and its underlying regulatory mechanism. Mouse bone marrow-derived macrophages (BMDMs) were treated with SFN and an Nrf2 inhibitor, Brusatol. M1 macrophages were induced by LPS and IFN-γ stimulation, whereas M2 macrophages were induced by stimulation with IL-4 and IL-13. LPS-stimulated BMDMs were co-cultured with Caco-2 cells. Flow cytometry, qRT-PCR, and Western blot were performed to assess macrophage polarization. Cell function was assessed using CCK8 assay, transepithelial electrical resistance (TEER) assay, and biochemical analysis. Higher concentrations of SFN resulted in better intervention effects, with an optimal concentration of 10 μM. SFN decreased the levels of IL-12, IL-6, and TNF-α, as well as the percentages of CD16/32 in M1 BMDMs. At the same time, SFN increased the levels of YM1, Fizz1, and Arg1 as well as the percentages of CD206+ cells in M2 BMDMs. In addition, SFN enhanced the accumulation of Nrf2, NQO1, and HO-1 in M1 BMDMs, and the downregulation of Nrf2 reversed the regulatory effect of SFN on M1/M2 macrophages. LPS-stimulated BMDMs induced Caco-2 cell damage, which was partially alleviated by SFN. Our findings indicate that SFN may act as an Nrf2 agonist to regulate macrophage polarization from M1 to M2. Furthermore, SFN may represent a potential protective ingredient against IBD.

Farnesoid-X-activated receptor (FXR) is considered as an upstream controller which could influence the other key regulatory genes encoding cellular antioxidant defense system.

Thirty-five male Wistar rats (240 ± 20 g) were randomly allocated into five groups: 1) control, 2) received gentamicin (100 mg/kg/d) for three days (GM-3d), 3) seven days (GM-7d), 4) 10 days (GM-10d), and 5) 14 consecutive days (GM-14d). Biochemical measurements of BUN and serum creatinine (SCr), histological assessment of renal samples as well as molecular analysis using real-time qRT-PCR were used to investigate the pattern of changes in different levels.

Administration of gentamicin was associated with a significant increase in the BUN and SCr until the 10th day, which then suddenly dropped at the day 14. Meantime, the maximum histological distortion was also seen on the 10th day but in a similar pattern, 14th day was associated with clear improvement. Compared to the control value, the maximum reduction in the mRNA expression of Farnesoid X-activated receptor (FXR), nuclear factor erythroid 2–related factor 2 (Nrf2) and Glutathione cysteine ligase-modulatory subunit (GCLM), occurred at the 3rd and 7th days, respectively. Compared to the control, the mRNA expression of the mentioned genes significantly increased up to day 14. Apart from the 3rd day, the mRNA expression of alpha-glutathione S-transferase (α-GST) and superoxide dismutase (SOD) showed a similar descending and ascending pattern at 7th and 10th days, respectively.

The expression of FXR, as an upstream controller gene and its downstream pathways mediated by Nrf2, could play a role in gentamicin-induced nephrotoxicity but the pattern of expression was rather biphasic at the acute phase or the subacute ones.

This study aimed to evaluate the effects of voluntary exercise as an anti-inflammatory intervention on the pulmonary levels of inflammatory cytokines in type 2 diabetic male rats.

Twenty-eight male Wistar rats were divided into four groups (n=7), including control (Col), diabetic (Dia), voluntary exercise (Exe), and diabetic with voluntary exercise (Dia+Exe). Diabetes was induced by a high-fat diet (4 weeks) and intraperitoneal injection of streptozotocin (35 mg/kg), and animals did training on the running wheel for 10 weeks as voluntary exercise. Finally, the rats were euthanized and the lung tissues were sampled for the evaluation of the levels of pulmonary interleukin (IL)-10, IL-11, and TNF-α using ELISA, and the protein levels of Nrf-2 and NF-κB using western blotting and tissue histopathological analysis. 

Diabetes reduced the IL-10, IL-11, and Nrf2 levels (P<0.001 to P<0.01) and increased the levels of TNF-α and NF-κB compared to the Col group (P<0.001). Lung tissue levels of IL-10, IL-11, and Nrf2 in the Dia+Exe group enhanced compared to the Dia group (P<0.001 to P<0.05), however; the TNF-α and NF-κB levels decreased (P<0.001). The level of pulmonary Nrf2 in the Dia+Exe group was lower than that of the Exe group while the NF-κB level increased (P<0.001). Moreover, diabetes caused histopathological changes in lung tissue which improved with exercise in the Dia+Exe group. 

These findings showed that voluntary exercise could improve diabetes-induced pulmonary complications by ameliorating inflammatory conditions.

The increase in age-related cognitive impairment (CIs) and diabetes mellitus is a global health concern. Exercise training has been reported to activate the Nrf2/Keap1/ARE signaling and enhance the antioxidant defense pathways in some animal models. This study aimed to investigate the effects of ursolic acid (UA) associated with resistance or endurance training on antioxidant markers, and the Nrf2/Keap1/ARE pathway in the brain of older diabetic rats. 23-month-aged diabetes induced male Wistar rats were randomly assigned to seven groups (n=8). UA supplementation (250 mg/kg, daily) was administered along with resistance (60% maximum capacity of voluntary carrying [MVCC], 14-20 climbs) or endurance training (60-75% velocity at maximal oxygen uptake [vVO2max]), five days/week for eight weeks. Cognitive-motor functioning was assessed through open-field and passive avoidance response tests. Nrf2, Keap1, and antioxidant markers including SOD, CAT, GPx, and GSH were measured in the hippocampus tissue. The results showed positive effect of resistance training (P≤0.001) on Nrf2. There was endurance training with supplementation main effect (P=0.018) on Keap1 concentration. SOD revealed a significant endurance/resistance training by supplementation interaction effect (P≤0.05); however, there was no main training or UA supplementation effects on CAT, GPx, and GSH, despite improving spatial memory changes in exercise or UA groups.  It appears that UA treatment with resistance or endurance exercise has some beneficial effects on Nrf2 and some antioxidant markers. However, more research is needed to elucidate UA’s interaction effects and exercise interventions in diabetic situations.

This study aims to investigate the potential role of relaxin, a peptide hormone, in preventing cellular deterioration and death in gastric carcinoma cells under hypoxic conditions. It explores the effects of recombinant relaxin 2 (RLXH2) on growth, cell differentiation, invasive potential, and oxidative damage in these cells.

In this experimental study, the NCI-N87 cell line was cultured under normal conditions and then subjected to hypoxia using cobalt chloride (CoCl2). The cells were treated with RLXH2, and various assays were performed to assess cellular deterioration, death, and oxidative stress. Western blot and quantitative real time polymerase chain reaction (qRT-PCR) were used to measure the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1, and the translocation of Nrf2 to the nucleus was confirmed through Western blot analysis.

This study demonstrates, for the first time, that RLXH2 significantly reduces the formation of reactive oxygen species (ROS) and the release of lactate dehydrogenase (LDH) in gastric cancer cells under hypoxic conditions. RLXH2 also enhances the activities of superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT), leading to a decrease in hypoxia-induced oxidative damage. RLXH2 promotes the translocation of Nrf2 to the nucleus, resulting in HO-1 expression.

Our findings suggest that RLXH2 plays a significant protective role against hypoxia-induced oxidative damage in gastric carcinoma cells through the Nrf2/HO-1 signalling pathway. This research contributes to a better understanding of the potential therapeutic applications of RLXH2 in gastric cancer treatment.

To examine the impact of aging on the response of rats to pentylenetetrazole (PTZ)-induction of epilepsy and the possible role of oxidative stress and nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase (HO)-1 pathway in this response.

Forty male albino rats were equally allocated into 4 groups; 1) Young control (YC) group, aged 8-12 weeks, 2) Old control (OC) group, aged 24 months, 3) PTZ-Young group: young rats received PTZ (50 mg/Kg, i.p. every other day) for 2 weeks and 4) PTZ-Old group: as group 3 but rats were old. The seizure score stage and latency to the first jerk were recorded in rats. Redox state markers in brain tissues including malondialdehyde (MDA), catalase and total antioxidant capacity (TAC) were evaluated. Also, the expression of Nrf2 and HO-1 genes were measured in the brain tissues.

Old rats showed an early and a significant rise in the seizure score with PTZ administration and a significant drop in the seizure latency compared to young rats (P <0.01). Also, old rats showed a significantly higher MDA concentration and a significantly lower TAC and catalase activity than young rats (P <0.01). Moreover, the expression of Nrf2 and HO-1 was significantly lowered in old rats compared to young rats with PTZ administration (P < 0.01).

Aging increases the vulnerability of rats to PTZ-induced epilepsy. An effect might come down to the up-regulation of oxidative stress and the down regulation of antioxidant pathways including Nrf2 and HO-1.