Protective effect of dimethyl fumarate against ethanol-provoked gastric ulcers in rats via regulation of HMGB1/TLR4/NF-κB, and PPARγ/SIRT1/Nrf2 pathways: Involvement of miR-34a-5p.

Aberration of the gastric mucosal barrier homeostasis circuit is one of the key features linked to the onset of gastric ulcers (GU). This work aimed to inspect the gastroprotective influence of dimethyl fumarate (DMF) on ethanol-induced GU in rats and to decipher the possible mechanisms entailed. Rats were pretreated with either DMF (80 mg/kg) or omeprazole (OMP) (20 mg/kg) by oral gavage for 2 weeks. After 24 h of starvation, ethanol (5 ml/kg, oral) was employed to trigger GU in rats, while carboxymethyl cellulose (CMC) was used as a control. Ethanol notably elevated both macroscopic and microscopic gastric damage. DMF and OMP exhibited similar effects on gastric ulcer healing. DMF intervention led to a substantial improvement in gastric insults. DMF significantly reduced ethanol-triggered gastric lesions, as manifested by decreased gastric secretion, acidity, ulcer surface area percent, reduced leukocyte incursion, and increased mucus percent. DMF upregulated miR-34a-5p expression concomitant with the suppression of high mobility group box1 (HMGB1) and inflammatory responses in gastric mucosal homogenate. DMF improved GU by restoring reduced antioxidant defense mechanisms through the coactivation of nuclear factor erythroid 2-related factor-2 (Nrf2), peroxisome proliferator-activated receptor gamma (PPARγ), and sirtuin1 (SIRT1), indicating the protective role of the PPARγ/SIRT1/Nrf2 pathway. Intriguingly, DMF mitigated apoptosis in ethanol-elicited GU. Taken together, this research implies the potential for the repurposing of DMF as an innovative gastroprotective medication to reestablish the balance of the gastric mucosal barrier via the attenuation of gastric inflammation, oxidative stress, and apoptosis.

Pinocembrin's protective effect against acute pancreatitis in a rat model: The correlation between TLR4/NF-κB/NLRP3 and miR-34a-5p/SIRT1/Nrf2/HO-1 pathways.

BACKGROUND: Acute pancreatitis (APS) is a prevalent acute pancreatic inflammation, where oxidative stress, inflammatory signaling pathways, and apoptosis activation contribute to pancreatic injury. METHODS: Pinocembrin, the predominant flavonoid in propolis, was explored for its likely shielding effect against APS provoked by two intraperitoneal doses of L-arginine (250 mg / 100 g) in a rat model. RESULTS: Pinocembrin ameliorated the histological and immunohistochemical changes in pancreatic tissues and lowered the activities of pancreatic amylase and lipase that were markedly elevated with L-arginine administration. Moreover, pinocembrin reinstated the oxidant/antioxidant equilibrium, which was perturbed by L-arginine, and boosted the pancreatic levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Pinocembrin markedly reduced the elevation in serum C-reactive protein (CRP) level induced by L-arginine. Additionally, it decreased the expression of high motility group box protein 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and NOD-like receptor (NLR) Family Pyrin Domain Containing 3 (NLRP3) inflammasome in the pancreas. Furthermore, it also reduced myeloperoxidase (MPO) activity. Pinocembrin markedly downregulated miR-34a-5p expression and upregulated the protein levels of peroxisome proliferator-activated receptor alpha (PPAR-α) and Sirtuin 1 (SIRT1) and the gene expression level of the inhibitor protein of NF-κB (IκB-α), along with normalizing the Bax/Bcl-2 ratio. CONCLUSIONS: Pinocembrin notably improved L-arginine-induced APS by its antioxidant, anti-inflammatory, and anti-apoptotic activities. Pinocembrin exhibited a protective role in APS by suppressing inflammatory signaling via the TLR4/NF-κB/NLRP3 pathway and enhancing cytoprotective signaling via the miR-34a-5p/SIRT1/Nrf2/HO-1 pathway.

Sesamol defends neuronal damage following cerebral ischemia/reperfusion: a crosstalk of autophagy and Notch1/NLRP3 inflammasome signaling.

OBJECTIVE: Sesamol (SES) is a phenolic compound found in sesame seed oil. Several studies have revealed its anti-inflammatory and antioxidant properties. However, its complete underlying mechanistic perspective about cerebral ischemia/reperfusion (I/R) lesions has not yet been disclosed. Consequently, we aimed to scrutinize its neuroprotective mechanism against cerebral injury during a global cerebral I/R in a rat model, considering its impact on autophagy and Notch1/NLRP3 inflammasome signaling regulation. METHODS: To affirm our purpose, adult Wistar rats were allotted into five groups: sham and the other four groups in which transient global cerebral ischemia was induced by bilateral common ligation (2VO) for 1 h, then reperfusion for either 24 h or 5 days: I/R (1/24), I/R (1/5), SES + I/R (1/24), and SES + I/R (1/5). In treated groups, SES (100 mg/kg, p.o., for 21 days) was administered before cerebral I/R induction. The assessment of histopathological changes in brain tissues, immunohistochemistry, biochemical assays, ELISA, and qRT-PCR were utilized to investigate our hypothesis. RESULTS: Advantageously, SES halted the structural neuronal damage with lessened demyelination induced by cerebral I/R injury. Restoring oxidant/antioxidant balance was evident by boosting the total antioxidant capacity and waning lipid peroxidation. Furthermore, SES reduced inflammatory and apoptosis markers. Additionally, SES recovered GFAP, Cx43, and autophagy signaling, which in turn switched off the Notch-1/NLRP3 inflammasome trajectory. CONCLUSIONS: Our results revealed the neuroprotective effect of SES against cerebral I/R injury through alleviating injurious events and boosting autophagy, consequently abolishing Notch1/NLRP3 inflammasome signaling.

The deleterious effect of xylene-induced ear edema in rats: Protective role of dexketoprofen trometamol transdermal invasomes via inhibiting the oxidative stress/NF-κB/COX-2 pathway.

Pain and inflammation could have a negative impact on a patient's quality of life and performance, causing them to sleep less. Dexketoprofen trometamol (DKT) is a water-soluble, nonselective NSAIDs. Because DKT is quickly eliminated in the urine after oral delivery, its efficacy is limited and must be taken repeatedly throughout the day. The main ambition of this work is to develop and characterize the potential of invasomes to enhance the transdermal transport of DKT to achieve efficient anti-inflammatory and pain management. The optimum formulation (C1) showed the least %RE (53.29 ± 2.68 %), the highest %EE (86.51 ± 1.05 %), and spherical nanosized vesicles (211.9 ± 0.57 nm) with (PDI) of 0.353 ± 0.01 and (ZP) of -19.15 ± 2.45 mV. DKT flux and deposition in stratum corneum, epidermal, and dermal skin layers were significantly augmented by 2.6 and 3.51 folds, respectively, from the optimum invasomal gel formulation (C1-G) compared to DKT conventional gel (DKT-G). The anti-inflammatory activity of C1-G was evaluated using a model of xylene-induced ear edema in rats. Xylene exposure upregulated the ear expression of COX-2 level and MPO activity. Xylene also significantly increased the ear NF-κB p65, TNF-α, IL-Iß, and MDA levels. Furthermore, xylene induced oxidative stress, as evidenced by a significant decrease in ear GSH and serum TAC levels. These impacts were drastically improved by applying C1-G compared to rats that received DKT-G and plain invasomal gel formulation (plain C1-G). The histopathological findings imparted substantiation to the biochemical and molecular investigations. Thereby, C1-G could be a promising transdermal drug delivery system to improve the anti-inflammatory and pain management of DKT.

Mangiferin mitigates di-(2-ethylhexyl) phthalate-induced testicular injury in rats by modulating oxidative stress-mediated signals, inflammatory cascades, apoptotic pathways, and steroidogenesis.

Di-(2-ethylhexyl) phthalate (DEHP) is an endocrine disruptor that causes reproductive defects in male animal models. This study was conducted to explore the plausible modulatory effects of mangiferin (MF) against DEHP-induced testicular injury in rats. Thirty-two adult male albino rats were allocated into four groups. Two groups were given DEHP (2 g/kg/day, p.o) for 14 days. One of these groups was treated with MF (20 mg/kg/day, i.p) for 7 days before and 14 days after DEHP administration. A vehicle-treated control was included, and another group of rats was given MF only. Results revealed that MF treatment suppressed oxidative testicular injury by amplifying the mRNA expression of nuclear factor-erythroid 2 related factor-2 (Nrf2) and increasing hemoxygenase-1 (HO-1), glutathione, and total antioxidant capacity (TAC) levels. This treatment also enhanced superoxide dismutase activity, but it decreased malondialdehyde and nitric oxide levels. MF had an anti-inflammatory characteristic, as demonstrated by the downregulation of the mRNA of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The content of tumor necrosis factor-alpha also decreased. MF modulated the apoptotic pathway by suppressing the mRNA of cytochrome c (Cyt c), Fas ligand content, Bax IHC expression, caspase-3 activity and cleaved caspase-3 IHC expression. It also upregulated the expression levels of heat-shock protein 70 (HSP70) and B-cell lymphoma 2. Moreover, MF upregulated the mRNA expression levels of HSP70 and c-kit and enriched the content of steroidogenic acute regulatory (StAR) protein, which were reflected in serum testosterone levels. This result indicated that MF played crucial roles in steroidogenesis and spermatogenesis. Besides, the activities of testicular marker enzymes, namely, acid and alkaline phosphatases, and lactate dehydrogenase, significantly increased. Histopathological observations provided evidence supporting the biochemical and molecular measurements. In conclusion, MF provided protective mechanisms against the DEHP-mediated deterioration of testicular functions partially through its antioxidant, anti-inflammatory, and anti-apoptotic properties. It also involved the restoration of steroidogenesis and spermatogenesis through the modulation of Nrf2/HO-1, NF-κB/Cyt c/HSP70, and c-Kit signaling cascades.

The deleterious effect of stress-induced depression on rat liver: Protective role of resveratrol and dimethyl fumarate via inhibiting the MAPK/ERK/JNK pathway.

This study aimed to uncover the protective potentiality of resveratrol and dimethyl fumarate (DMF) in the liver of a chronic unpredictable mild stress (CUMS)-induced depression animal model. Resveratrol and DMF significantly alleviated CUMS-induced behavioral abnormalities in stressed rats through improving sucrose preference in sucrose preference test and decreasing immobility time in a forced swimming test. They also mitigated serum corticosterone levels and elevated serum serotonin levels, which were formerly disturbed in CUMS rats. The hepatoprotective effect is evidenced by improvement in hepatic histopathological examinations, as well as normalized serum alanine aminotransferase and aspartate aminotransferase activities. Molecular signaling of resveratrol and DMF was estimated by diminishing hepatic expression of phosphorylated p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK). Consequently, they improved the hepatic antioxidant and anti-inflammatory activities as elaborated by the normalization of total antioxidant capacity, glutathione, malondialdehyde, nuclear factor-κB, tumor necrosis factor-α, and myeloperoxidase levels. In addition, they inhibited hepatocyte apoptosis as evidenced by the increased expression of B-cell lymphoma 2, the decreased expression of Bax, as well as the suppressed activity of caspase-3. In conclusion, resveratrol and DMF purveyed a significant anti-depressant effect, which may be mediated, at least in part, via inhibiting the MAPK/ERK/JNK pathway in the CUMS rat model.

Resveratrol and dimethyl fumarate ameliorate testicular dysfunction caused by chronic unpredictable mild stress-induced depression in rats.

Chronic stress is a major factor contributing to male infertility. Increasing evidence has demonstrated that resveratrol or dimethyl fumarate (DMF) has antioxidant and anti-inflammatory functions. Our study aimed to evaluate the protective effects of resveratrol or DMF against testicular dysfunction associated with chronic unpredictable mild stress (CUMS)-induced depression in rats. Rats were subjected to 8 weeks of CUMS to induce depressive-like symptoms. CUMS-induced depressive-like behaviours in rats were evidenced by increased serum corticosterone levels and decreased serum and hippocampal serotonin levels as well as decreased hippocampal BDNF levels. CUMS significantly reduced sucrose preference and increased immobility time in stressed rats. Furthermore, CUMS exposure resulted in a significant decrease in serum testosterone levels and testicular expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 side chain cleavage (CYP450scc) enzyme and C-kit. CUMS significantly decreased and increased testicular expression of ß-catenin and GSK-3ß, respectively. CUMS also resulted in a significant increase in testicular expression of NF-κB, TNF-α, IL-Iß, and Bax and decreased Bcl-2 expression levels. CUMS increased testicular MDA levels and significantly decreased testicular GSH and serum total antioxidant capacity levels. The histopathological results provided evidence for the biochemical and molecular analyses. All of these effects were significantly ameliorated by the administration of resveratrol or DMF. In conclusion, our study reveals that resveratrol or DMF exert profound testicular protective effects in CUMS rats that are mediated in part by suppressing oxidative stress, inflammation, and apoptosis leading to the upregulation of serum testosterone levels, and testicular StAR, CYP450scc, c-kit and ß-catenin levels.

Resveratrol and dimethyl fumarate ameliorate depression-like behaviour in a rat model of chronic unpredictable mild stress.

Chronic stress occurs in everyday life and induces depression. Emerging evidence shows that oxidative stress, inflammation and apoptosis are main contributing pathophysiologic mechanisms of depression. Resveratrol and dimethyl fumarate (DMF) are natural antioxidants that have diverse biological activities. Our study aimed to determine whether resveratrol and DMF affected these systems in rats exposed to chronic unpredictable mild stress (CUMS)-induced depression-like behaviours. Rats were submitted to 8 weeks of CUMS to induce depressive-like behaviour. The depressive-like behaviour of rats induced by CUMS was revealed by an elevated serum corticosterone level and decreased serum and hippocampal serotonin levels. Our results showed that CUMS significantly-induced behavioural abnormalities (reduced sucrose preference and increased immobility time) in stressed rats. CUMS exposure significantly decreased BDNF and ß-catenin expression levels as well as increased GSK-3ß expression level in hippocampus. Furthermore, CUMS exposure resulted in a significant increase in expression levels of NF-κB, TNF-α and IL-Iß accompanied by decreased Bcl-2 expression level. CUMS increased hippocampal MDA level and significantly decreased hippocampal GSH and serum total antioxidant capacity levels compared to the control group. Histopathological examinations provided evidence for the biochemical and molecular analysis. All of these effects were significantly ameliorated by administration of resveratrol and DMF. In conclusion, our study revealed that resveratrol and DMF exerted promising antidepressant-like effects in CUMS rats that are mediated in part by suppressing the neuroinflammation, oxidative stress, apoptosis and up-regulating hippocampal BDNF and ß-catenin levels. Serum serotonin analysis may be a reliable indicator for monitoring depression.

Longitudinal assessment of hepatic fibrosis in responders to direct-acting antivirals for recurrent hepatitis C after liver transplantation using noninvasive methods.

Successful eradication of recurrent hepatitis C virus (HCV) infection following liver transplantation (HCV) improves graft survival. This study aimed at evaluation of hepatic fibrosis changes among long-term responders to DAA therapy for recurrent HCV after liver transplantation using noninvasive methods. Patients with significant hepatic fibrosis (≥F2) who achieved SVR12 after treatment with DAAs for recurrent HCV were included (n = 52). Hepatic fibrosis status was assessed, noninvasively, by calculation of fibrosis-4 score (FIB-4) and Aspartate Aminotransferase Platelet Ratio Index (APRI) and by measurement of graft stiffness using FibroScan at baseline and 12 and 18 months post-treatment. Acoustic radiation force imaging (ARFI) was done for all patients 12 and 18 months post-treatment. Patients were classified into two groups based on baseline liver stiffness measurement (LSM) by FibroScan; significant fibrosis (F2; n = 28) and advanced fibrosis groups (≥F3). Over 18-month follow-up period, there was serial improvement of FIB-4, APRI, and LSM by FibroScan in both groups. Higher baseline LSM and delayed initiation of antiviral therapy were significant predictors of lack of fibrosis regression (P-value 0.01 and 0.04, respectively). Fibroindices and LSM improved over time in liver transplant recipients who responded to DAAs. Baseline LSM can predict post-treatment fibrosis regression.

Resveratrol and curcumin ameliorate di-(2-ethylhexyl) phthalate induced testicular injury in rats.

The present study aimed to evaluate the protective role of resveratrol and curcumin on oxidative testicular damage induced by di-(2-ethylhexyl) phthalate (DEHP). Male Wistar rats were divided into six groups; three groups received oral daily doses of DEHP (2g/kgBW) for 45days to induce testicular injury. Two of these groups received either resveratrol (80mg/kgBW) or curcumin (200mg/kgBW) orally for 30days before and 45days after DEHP administration. A vehicle-treated control group was also included. Another two groups of rats received either resveratrol or curcumin alone. Oxidative damage was observed by decreased levels of total antioxidant capacity (TAC) and glutathione (GSH) and increased malondialdehyde (MDA) level in the testes of DEHP-administered rats. Serum testosterone level as well as testicular marker enzymes activities; acid and alkaline phosphatases (ACP and ALP) and lactate dehydrogenase (LDH) showed severe declines. DEHP administration caused significant increases in the testicular gene expression levels of Nrf2, HO-1, HSP60, HSP70 and HSP90 as well as a significant decrease in c-Kit protein when compared with the control group. Histopathological observations provided evidence for the biochemical and molecular analysis. These DEHP-induced pathological alterations were attenuated by pretreatment with resveratrol and curcumin. We conclude that DEHP-induced injuries in biochemical, molecular and histological structure of testis were recovered by pretreatment with resveratrol and curcumin. The chemoprotective effects of these compounds may be due to their intrinsic antioxidant properties along with boosting Nrf2, HSP 60, HSP 70 and HSP 90 gene expression levels and as such may be useful potential tools in combating DEHP-induced testicular dysfunction.