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.

Baicalein and Αlpha-Tocopherol Inhibit Toll-like Receptor Pathways in Cisplatin-Induced Nephrotoxicity.

Cisplatin (CP) is a conventional chemotherapeutic agent with serious adverse effects. Its toxicity was linked to the stimulation of oxidative stress and inflammation. As a result, this study explored the protective effect of baicalein and alpha-tocopherol in nephrotoxicity induced by cisplatin. Until receiving an intraperitoneal injection of CP (3 mg/kg BW), rats were given baicalein orally 100 mg/kg for seven days or/and a single intraperitoneal injection of α-tocopherol 250 mg/kg. Renal function was tested to explore whether baicalein and α-tocopherol have any beneficial effects; blood urea nitrogen (BUN), serum creatinine, malondialdehyde (MDA) content, antioxidant activity biomarkers and histopathology of renal tissue, oxidative stress biomarkers, inflammatory response markers, and histopathological features of kidney architecture were measured. Cisplatin treatment resulted in extreme renal failure, as measured by high serum creatinine and BUN levels and severe renal changes. Cisplatin therapy resulted in increased lipid peroxidation and decreased glutathione and superoxide dismutase levels, reflecting oxidative stress. Upon treatment with α-tocopherol, baicalein, and combined therapy, there was augmentation in the antioxidant status as well as a reduction in IL-6, NF-κB, TNF, TLR2, and TLR4 and a significant increase in Keap-1 and NRF-2. The combined treatment was the most effective and the nearest to the normal status. These findings suggest that baicalein and α-tocopherol may be useful in preventing cisplatin-induced nephrotoxicity.

Sesquiterpene nootkatone counteracted the melamine-induced neurotoxicity via repressing of oxidative stress, inflammatory, and apoptotic trajectories.

Melamine (ML), a chemical substance of high nitrogen content, is used as a food adulterant. Former evidences implied that ML could induce a variety of toxic effects including neurotoxicity and cognitive impairment. Therefore, the aim of this study was to delineate the protective effect of the nootkatone (NK) against ML-induced neural adverse effects. Rats were orally pretreated with NK (5 and 10 mg/kg) prior to the oral administration of ML (700 mg/kg) for a period of 28 days. Our findings unveiled remarkable alleviating effect of NK on MK-induced neurobehavioral disturbance in open field test. Furthermore, NK lessened ML-caused increases in the acetylcholine esterase level in the brain tissue of exposed rats. NK also decreased the neural oxidative stress as represented by elevated levels of SOD, CAT, and GSH along with decreased MDA and NO levels. Upregulated mRNA expression levels of neural NRF-2 and HO-1 were noticed after NK administration. Remarkable anti-inflammatory impact was prominent by decreased neural IL-1ß, and TNF-α along with downregulated NF-κB and TLR-4 gene expression levels in NK-treated rats. Noteworthily, pre-treatment with NK decreased the immune reaction of RAGE and HMGB-1 induced by oral ML exposure. Brain histological examination validated the obtained biochemical and molecular results. To sum up, these outcomes reveal that NK successfully alleviated the neural damage induced by ML via blocking of oxidative stress, and inflammatory signaling pathways. Consequently, our study may suggest NK as a new effective therapeutic supplement for treatment of ML-mediated neurotoxicity in rats via inhibition of HMGB-1-RAGE/TLR-4/NF-κB.

Zinc oxide nanoparticles and spironolactone-enhanced Nrf2/HO-1 pathway and inhibited Wnt/ß-catenin pathway in adenine-induced nephrotoxicity in rats.

OBJECTIVE: To investigate the renoprotective, the antioxidant, and the anti-inflammatory impact of a combination of SPL and ZnO-NPs to combat against chronic kidney disease (CKD). METHODS: In total, 50 males of rats were distributed into 5 groups (10 rats each); normal group, adenine sulfate (0.25% in diet for 10 days) (CKD) group. After the last dose of adenine sulfate, rats were divided into three groups: SPL + Adenine sulfate group; rats were treated orally by mixing SPL (20 mg/kg/day) into chow for 8 weeks, ZnO-NPs + Adenine sulfate group; rats were injected intraperitoneally with ZnO-NPs (5 mg/kg) three times weekly for 8 weeks, ZnO-NPs + SPL + Adenine sulfate group; rats were injected with the same previous doses for 8 weeks. RESULTS: Each of SPL and ZnO-NPs up-regulated antioxidant genes (Nrf2 and HO-1), down-regulated fibrotic and inflammatory genes (TGF-ß1, Wnt7a, ß-catenin, fibronectin, collagen IV, α-SMA, TNF-α, and IL-6) compared to CKD. Furthermore, a combination of SPL and ZnO-NPs resulted in a greater improvement in the measured parameters than a single treatment. CONCLUSION: The therapeutic role of SPL was enhanced by the antioxidant and the anti-inflammatory role of ZnO-NPs, which presented a great renoprotective effect against CKD.

Neuroprotective effect of naringin against cerebellar changes in Alzheimer's disease through modulation of autophagy, oxidative stress and tau expression: An experimental study.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by gradual cognitive decline. Strong antioxidants that inhibit free radicals, such as polyphenols, reduce the likelihood of developing oxidative stress-related degenerative diseases such as AD. Naringin, a flavonoid found in citrus fruit shown to be neuroprotective, reduce oxidative damage and minimize histopathological changes caused by ischemic reperfusion, enhance the long-term memory in AD animal models. This work aimed to comprehend the role of naringin in the defense of the cerebellum against aluminum chloride (AlCl3)-induced AD in rats by investigating the behavioral, neurochemical, immunohistochemical, and molecular mechanisms that underpin its possible neuroprotective effects. Twenty-four adult albino rats were divided into four groups (n = 6/group): (i) Control (C) received saline per oral (p.o.), (ii) Naringin(N)-received naringin (100 mg/kg/d) p.o, (iii) AlCl3-recived AlCl3 (100 mg/kg/d) p.o and (iv) AlCl3 + Naringin (AlCl3 + N) received both AlCl3 and naringin p.o for 21 days. Behavioral tests showed an increase in the time to reach the platform in Morris water maze, indicating memory impairment in the AlCl3-treated group, but co-administration of naringin showed significant improvement. The Rotarod test demonstrated a decrease in muscle coordination in the AlCl3-treated group, while it was improved in the AlCl3 + N group. Neurochemical analysis of the hippocampus and cerebellum revealed that AlCl3 significantly increased lipid peroxidation and oxidative stress and decreased levels of reduced glutathione. Administration of naringin ameliorated these neurochemical changes via its antioxidant properties. Cerebellar immunohistochemical expression for microtubule assembly (tau protein) and oxidative stress (iNOS) increased in A1C13-treated group. On the other hand, the expression of the autophagic marker (LC3) in the cerebellum showed a marked decline in AlCl3-treated group. Western blot analysis confirmed the cerebellar immunohistochemical findings. Collectively, these findings suggested that naringin could contribute to the combat of oxidative and autophagic stress in the cerebellum of AlCl3-induced AD.

L. Cucurbita pepo Alleviates Chronic Unpredictable Mild Stress via Modulation of Apoptosis, Neurogenesis, and Gliosis in Rat Hippocampus.

Pumpkin has received significant attention due to its nutritional compounds that have antioxidant, antifatigue, and anti-inflammatory effects. This study is aimed at assessing the antidepressant-like effect of L. Cucurbita pepo, sweet pumpkin, in an animal model of chronic unpredictable mild stress (CUMS) and investigating its effect on the histological structure of hippocampus compared to fluoxetine. Forty male albino rats assigned into the negative control, positive control (CUMS), and Flu-treated and pumpkin-treated groups (n = 10) were utilized in this study. Exposing rats to CUMS continued for 28 days, and treatments used were applied during the last 14 days of exposure. Behavioral, biochemical, and histopathological changes were assessed after 28 days. In this study, pumpkin significantly reduced the immobility time (p = 0.02), corticosterone (p < 0.001), TNF-α, IL-6 (p < 0.001), and malondialdehyde (p = 0.003), whereas it significantly increased the level of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) in the serum of rats exposed to CUMS. Pumpkin markedly relieved the degenerative and atrophic changes observed in the CA3 region and the dentate gyrus of the hippocampus. It significantly reduced caspase-3 and increased glial fibrillary acidic protein (GFAP) immunoexpression in the CA3 and DG. In conclusion, administration of pumpkin extract improved the behavioral, biochemical, and hippocampal pathological alternations induced in rats after exposure to CUMS in a comparable pattern to fluoxetine. This study highlighted the potential efficacy of pumpkin in alleviating depression disorder either alone or in conjugation with conventional antidepressant therapy.

Evaluation of the modulation of nitric oxide synthase expression in the cerebellum of diabetic albino rats and the possible protective effect of ferulic acid.

INTRODUCTION: Diabetes mellitus is a multisystem disease. Oxidative stress and nitric oxide isoforms are involved in diabetic pathogenesis. Ferulic acid is a natural substance that is distributed broadly in plants with strong potent properties. THE AIM OF THE RESEARCH: This research was designed to study the possible protective role of ferulic acid on oxidative stress and different Nitric oxide synthase isoforms (NOS) in the cerebellum of streptozotocin-induced diabetic rats. MATERIALS AND METHODS: Twenty-four albino male rats were randomly divided into equal four groups: control group, group 2 received ferulic acid orally (10 mg/kg), group 3 diabetic group, group 4 diabetic rats received ferulic acid. After 8 weeks, the left cerebellar hemisphere was taken for tissue homogenate for oxidative markers and real-time PCR for NOS isoforms. Paraffin sections of the right cerebellar hemisphere were stained with cresyl violet, Luxol fast blue and immnunohistochemically stained for neuronal NOS, inducible NOS and endothelial NOS. RESULTS: Degenerative changes were seen in the cerebella of the diabetic rats with significant elevation of Malondialdehyde, Nitric Oxide, and decrease of Superoxide dismutase levels. nNOS expression decreased and iNOS expression increased significantly. The ferulic acid-treated group showed a reduction of the degenerative changes in the cerebellum with significant improvement in oxidative stress marker, an increase of nNOS expression, and a decrease of iNOS expression. CONCLUSIONS: Ferulic acid improves cerebellar functional and histopathological changes induced by diabetes which can be attributed mainly to its anti-oxidative effect and its ability to modulate NOS isoforms.

Modulation of the Endothelin System in Colorectal Cancer Liver Metastasis: Influence of Epigenetic Mechanisms?

Targeting of endothelin system genes is a promising strategy in cancer therapy. The modulation of these genes was explored in a model of colorectal cancer (CRC) liver metastasis and in a panel of CRC tumor cell lines that were exposed to the demethylating agent decitabine. The CC531 rat model mimicking CRC liver metastasis was used for tumor cell re-isolation and analysis of the endothelin system genes and DNA methyltransferases (DNMTs) by microarray. To mimic the effects caused by methylation changes, a panel of seven CRC cell lines was treated with the demethylating agent decitabine. Three genes of the endothelin system were potently modulated at messenger RNA (mRNA) level in rat CC531 cells during liver colonization. The concomitant decrease of two DNMTs suggested an influence from altered methylation. Changes in gene expression were also accomplished by exposure of CRC cells to the demethylating agent decitabine, when using daily low concentrations for 3 days, with minimal cytotoxic effects. Sensitive human SW480 cells showed an almost 100fold upregulation of endothelin-1 mRNA compared to untreated cells. This, however, was different in LS174T cells, which showed no significant increase in gene expression although the methylation levels were significantly decreased at a variety of corresponding loci. We suggest that the mechanism induced by methylation on gene expression in metastatic CRC cells can be compromised. The results question the overall success of treating metastatic CRC by methylation inhibitors.