Human Wharton's jelly-derived mesenchymal stromal stem cells preconditioned with valproic acid promote cell migration and reduce renal inflammation in ischemia/reperfusion injury by activating the AKT/P13K and SDF1/CXCR4 pathways.

OBJECTIVE: To determine whether WJ-MSCs pretreated with VPA would enhance their migration to improve functional recovery of renal IRI in rats. METHODS: 150 Sprague-Dawley rats were distributed into 5 groups; Sham, IRI, WJ-MSC, VPA, and WJ-MSCs + VPA. 10 rats were sacrificed after 3, 5, and 7 days. Role of WJ-MSCs pretreated with VPA was evaluated by assessment of renal function, antioxidant enzymes together with renal histopathological and immunohistopathological analyses and finally by molecular studies. RESULTS: WJ-MSCs and VPA significantly improved renal function and increased antioxidants compared to IRI group. Regarding gene expression, WJ-MSCs and VPA decreased BAX and TGF-ß1, up-regulated Akt, PI3K, BCL2, SDF1α, and CXCR4 related to IRI. Additionally, WJ-MSCs pretreated with VPA improved the measured parameters more than either treatment alone. CONCLUSION: WJ-MSCs isolated from the umbilical cord and pretreated with VPA defended the kidney against IRI by more easily homing to the site of injury.

Lipid nanoparticles of quercetin (QU-Lip) alleviated pancreatic microenvironment in diabetic male rats: The interplay between oxidative stress - unfolded protein response (UPR) - autophagy, and their regulatory miRNA.

BACKGROUND: Autophagy is a well-preserved mechanism essential in minimizing endoplasmic reticulum stress (ER)-related cell death. Defects in ß-cell autophagy have been linked to type 1 diabetes, particularly deficits in the secretion of insulin, boosting ER stress sensitivity and possibly promoting pancreatic ß-cell death. Quercetin (QU) is a potent antioxidant and anti-diabetic flavonoid with low bioavailability, and the precise mechanism of its anti-diabetic activity is still unknown. Aim This study aimed to design an improved bioavailable form of QU (liposomes) and examine the impact of its treatment on the alleviation of type 1 diabetes induced by STZ in rats. METHODS: Seventy SD rats were allocated into seven equal groups 10 rats of each: control, STZ, STZ + 3-MA, STZ + QU-Lip, and STZ + 3-MA + QU-Lip. Fasting blood glucose, insulin, c-peptide, serum IL-6, TNF-α, pancreatic oxidative stress, TRAF-6, autophagy, endoplasmic reticulum stress (ER stress) markers expression and their regulatory microRNA (miRNA) were performed. As well as, docking analysis for the quercetin, ER stress, and autophagy were done. Finally, the histopathological and immunohistochemical analysis were conducted. SIGNIFICANCE: QU-Lip significantly decreased glucose levels, oxidative, and inflammatory markers in the pancreas. It also significantly downregulated the expression of ER stress and upregulated autophagic-related markers. Furthermore, QU-Lip significantly ameliorated the expression of several MicroRNAs, which both control autophagy and ER stress signaling pathways. However, the improvement of STZ-diabetic rats was abolished upon combination with an autophagy inhibitor (3-MA). The findings suggest that QU-Lip has therapeutic promise in treating type 1 diabetes by modulating ER stress and autophagy via an epigenetic mechanism.

Protective Effect of Topiramate against Diabetic Retinopathy and Computational Approach Recognizing the Role of NLRP3/IL-1ß/TNF-α Signaling.

The possible impact of topiramate against diabetic retinopathy (DREN) and its molecular mechanisms in relation to the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome has not been studied before. Thus, in the present study, we aimed to utilize a computational approach to investigate the possible protective effect of topiramate on experimental DREN and explore its impact on NLRP3/interlukin-1ß signaling and brain-derived neurotrophic factor (BDNF) expression. Male albino mice were distributed to four experimental groups and assigned the following categorizations: (i) saline, (ii) diabetic, (iii) diabetic + topiramate 10 mg/kg and (iv) diabetic + topiramate 30 mg/kg. We observed shrinkage of total retinal thickness and elevation in retinal glutamate, malondialdehyde, NLRP3 and interlukin-1ß but decreased glutathione (GSH) levels in the diabetic mice. Additionally, retinal ultra-structures in the diabetic group showed abnormalities and vacuolations in the pigmented epithelium, the photoreceptor segment, the outer nuclear layer, the inner nuclear layer and the ganglion cell layer (GCL). Mice treated with topiramate 10 or 30 mg/kg showed downregulation in retinal malondialdehyde, NLRP3 and interlukin-1ß levels; improvements in the retinal pathologies; enhanced immunostaining for BDNF and improved ultra-structures in different retinal layers. Overall, the current results suggest topiramate as a neuroprotective agent for DREN, and future studies are warranted to further elucidate the mechanism of its protective action.

Revealing how phenytoin triggers liver damage and the potential protective effects of Balanites Aegyptiaca fruit extracts: Exploring Nrf2/MAPK/ Beclin-1 signaling pathways.

Phenytoin-induced liver injury (PHT ILII) is a serious condition that may necessitate discontinuation of the drug. This study investigates the mechanisms of PHT ILII and evaluates the protective effects of Balanites Aegyptiaca (BA) fruit extracts on the liver. We focus on the Nrf2/MAPK/NF-κB/Beclin-1 signaling pathways involved in oxidative stress and inflammation from drug-induced liver injury. Phytochemical analyses of BA fruit extracts (Bu-F and EA-F) are conducted. Molecular docking techniques explore the interaction between phenytoin (PHT) and the Nrf2/MAPK/NF-κB/Beclin-1 pathways. Thirty-six male rats are divided into Control, Bu-F, EA-F, PHT, Bu-F/PHT, and EA-F/PHT groups, and they are observed for 45 days. EA-F extract is rich in phenolics/flavonoids, while Bu-F extract mainly contains saponins.PHT ILII causes histological damage in liver tissues and affects Nrf-2, MAPK, TNF-α, IL-1ß, Mcp-1, Beclin-1, iNOS expression, and liver function markers (ALT, AST, ALP). However, EA-F/Bu-F extracts effectively improve the histological structure and significantly reduce biochemical/immunohistochemical parameters, restoring them to near-normal levels. EA-F extract is particularly effective.In conclusion, the Nrf2/MAPK /Beclin-1 pathways play a critical role in the development of PHT ILII. BA fruit extracts show promise as hepato-protective agents, with the EA-F extract demonstrating superior efficacy. These results lay the groundwork for new treatments for PHT ILII and drug-induced liver injuries.

Enhanced Wound Healing Potential of Spirulina platensis Nanophytosomes: Metabolomic Profiling, Molecular Networking, and Modulation of HMGB-1 in an Excisional Wound Rat Model.

Excisional wounds are considered one of the most common physical injuries. This study aims to test the effect of a nanophytosomal formulation loaded with a dried hydroalcoholic extract of S. platensis on promoting excisional wound healing. The Spirulina platensis nanophytosomal formulation (SPNP) containing 100 mg PC and 50 mg CH exhibited optimum physicochemical characteristics regarding particle size (598.40 ± 9.68 nm), zeta potential (-19.8 ± 0.49 mV), entrapment efficiency (62.76 ± 1.75%), and Q6h (74.00 ± 1.90%). It was selected to prepare an HPMC gel (SPNP-gel). Through metabolomic profiling of the algal extract, thirteen compounds were identified. Molecular docking of the identified compounds on the active site of the HMGB-1 protein revealed that 12,13-DiHome had the highest docking score of -7.130 kcal/mol. SPNP-gel showed higher wound closure potential and enhanced histopathological alterations as compared to standard (MEBO® ointment) and S. platensis gel in wounded Sprague-Dawley rats. Collectively, NPS promoted the wound healing process by enhancing the autophagy process (LC3B/Beclin-1) and the NRF-2/HO-1antioxidant pathway and halting the inflammatory (TNF-, NF-κB, TlR-4 and VEGF), apoptotic processes (AIF, Caspase-3), and the downregulation of HGMB-1 protein expression. The present study's findings suggest that the topical application of SPNP-gel possesses a potential therapeutic effect in excisional wound healing, chiefly by downregulating HGMB-1 protein expression.