Wafaa R. Mohamed

Tangeretin Alleviates Cisplatin-Induced Acute Hepatic Injury in Rats: Targeting MAPKs and Apoptosis

Despite its broad applications, cisplatin affords considerable nephro- and hepatotoxicity through triggering inflammatory and oxidative stress cascades. The aim of the current investigation was to study the possible protective effects of tangeretin on cisplatin-induced hepatotoxicity. The impact of tangeretin on cisplatin-evoked hepatic dysfunction and histopathologic changes along with oxidative stress, inflammatory and apoptotic biomarkers were investigated compared to silymarin. Tangeretin pre-treatment significantly improved liver function tests (ALT and AST), inhibited cisplatin-induced lipid profile aberrations (total cholesterol and triglycerides) and diminished histopathologic structural damage in liver tissues. Tangeretin also attenuated cisplatin-induced hepatic inflammatory events as indicated by suppression of tumor necrosis factor-α (TNF-α) and enhancement of interleukin-10 (IL-10). Meanwhile, it lowered malondialdehyde (MDA), nitric oxide (NO) and nuclear factor erythroid 2-related factor 2 (NRF-2) levels with restoration of glutathione (GSH), and glutathione peroxidase (GPx). Regarding mitogen-activated protein kinase (MAPK) pathway, tangeretin attenuated cisplatin-induced increase in phospho-p38, phospho-c-Jun N-terminal kinase (p-JNK) and phospho-extracellular signal-regulated kinase (p-ERK1/2) in liver tissues. In addition, tangeretin downregulated Bax expression with augmentation of Bcl-2 promoting liver cell survival. Our results highlight the protective effects of tangeretin against cisplatin-induced acute hepatic injury via the concerted modulation of inflammation, oxidative stress, MAPKs and apoptotic pathways.

Hesperidin alleviates cisplatin-induced hepatotoxicity in rats without inhibiting its antitumor activity

BACKGROUND Hesperidin, a naturally occurring flavonoid, exerts many clinically appreciable effects such as anti-oxidant, anti-allergic and anti-inflammatory actions. The present study aimed to investigate the possible protective effects of multiple doses of hesperidin against cisplatin-induced acute hepatotoxicity in rats. METHODS Hesperidin (100 or 200mg/kg po) was given to rats one day before cisplatin (7.5mg/kg, ip) injection. All animals were sacrificed 5 days after cisplatin injection and blood samples were collected for determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, triglycerides (TG) and total cholesterol levels. Liver samples were used for the determination of malondialdehyde (MDA), glutathione (GSH), total nitrate and nitrite contents. Western blot analysis was used for the assessment of NF-κB and p-Akt expression and histopathological examination was also performed. RESULTS Results showed that hesperidin significantly reduced cisplatin-induced elevations in serum ALT and AST activities, TG and total cholesterol levels. It also reduced cisplatin-induced oxidative stress by significant reduction in liver MDA and NO content and elevation of GSH content. In addition, hesperidin significantly counteracted cisplatin-induced increased NF-κB expression and decreased p-Akt expression. Histopathological examination revealed that hesperidin greatly protected liver against cisplatin-induced injury. Moreover hesperidin did not inhibit the cytotoxic effect of cisplatin on cancer cells as determined by MTT assay. CONCLUSION Hesperidin decreased cisplatin-induced functional and histopathological liver damage in a dose-dependent manner without affecting its potential cytotoxic effect.

Design, synthesis and antitumor activity of novel pyrazolo[3,4-d]pyrimidine derivatives as EGFR-TK inhibitors.

A novel series of 2-(3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(4-substitutedbenzylidene)acetohydrazide (12a-g) was prepared and their structures were confirmed by spectral and elemental analyses. The cytotoxic activity of the newly synthesized compounds was evaluated against breast carcinoma (MCF-7), non-small cell lung cancer (A549) and human colorectal adenocarcinoma (HT-29) cell lines using MTT and colony formation assays. The tested compounds showed a marked anticancer activity against all the tested cell lines, especially compound 12g, which was the most potent anticancer agent with half maximal inhibitory concentrations (IC50) between 5.36 and 9.09μM. Docking studies into ATP binding site of EGFR protein tyrosine kinase were performed to predict their scores and mode of binding to amino acids, In addition, the inhibitory activity of the target compounds against epidermal growth factor receptor tyrosine kinase (EGFR-TK) was evaluated. Results indicated the ability of the target compounds to inhibit EGFR-TK with half maximal inhibitory concentrations (IC50) in the range of 4.18-35.88μM. Furthermore, The most active compounds 12g, 12c and 12d were assayed against Fibroblast Growth Factor Receptor (FGFR), Insulin Receptor (IR) and Vascular Endothelial Growth Factor Receptor (VEGFR). The activity of the reported compounds warrants further optimization as novel members in cancer treatment protocols.

A neuroprotective role of kaempferol against chlorpyrifos-induced oxidative stress and memory deficits in rats via GSK3β-Nrf2 signaling pathway

Chlorpyrifos (CPF) is an agricultural pesticide and a potential food contaminant, which causes neurotoxicity. Here, we aimed at exploring the link between the repeated exposure to CPF and memory dysfunction in rats and the possible protective effect of kaempferol, a flavonoid with appreciable antioxidant and anti-inflammatory activities. Rats were divided into: Control group (received drug vehicles for 14 days); CPF-treated group (received subcutaneous 18 mg/kg BW of CPF daily for 14 days and CPF + Kaempferol treated group (received the same CPF dose +21 mg/kg BW of Kaempferol intraperitoneally for 14 days. On the 14th day, Y-maze and novel target recognition behavioral tests were employed to evaluate memory deficits. 24 h after the last dose of CPF, animals were sacrificed, and brain tissues were used for the determination of oxidative stress biomarkers and gene expression levels of GSK3β and Nrf2. The results revealed that CPF-treated rats suffered from severe deterioration of spatial and non-spatial memory functions with low activities of antioxidant enzymes and acetylcholinesterase (AChE). The administration of kaempferol significantly protected against CPF-induced neuronal damage, increased the activities of antioxidant enzymes and AChE and induced a better performance in the behavioral tests. The protective effect of kaempferol was mediated through the inhibition of GSK3β gene expression and the induction of Nrf2 expression in the brain tissues. In conclusion, the repeated exposure to CPF is associated with oxidative stress and memory deficits in rats. However, kaempferol administration effectively alleviated CPF- induced brain toxicity, possibly through the modulation of GSK3β-Nrf2 signaling pathway.

Alpha lipoic acid protects against chlorpyrifos-induced toxicity in Wistar rats via modulating the apoptotic pathway

The chronic exposure to chlorpyrifos (CPF) pesticide induces several human disorders including hepatotoxicity. Alpha-lipoic acid (ALA) is a natural antioxidant compound found in plants and animals. The present study aimed to investigate the possible protective effect of ALA against CPF-induced hepatotoxicity and the possible underlying molecular mechanism. Thirty-two male Wistar rats were divided into: Normal rats received only vehicle; ALA group received ALA (10 mg/kg, i.p.); CPF group received CPF (18 mg/kg, s.c.) and CPF-ALA group received CPF (18 mg/kg, s.c.) once daily for 14 days. The present results demonstrated that administration of ALA significantly improved liver functions (p < 0.05) and limited the histopathological lesions induced by CPF in liver tissues. Furthermore, ALA decreased hepatic malondialdehyde contents while increased the glutathione peroxidase, catalase, superoxide dismutase and acetylcholinesterase activities. Interestingly, ALA showed significant antiapoptotic effects through downregulation of Bax and Caspase-3 expression levels. In conclusion, ALA possess protective effects against CPF-induced liver injury through attenuation of apoptosis and oxidative stress.