Phosphodiesterase1 inhibitor "Vinpocetine" ameliorates the inflammation, apoptosis and oxidative stress induced by cyclophosphamide in urinary bladder: an experimental study.

BACKGROUND: Hemorrhagic cystitis often develops in patients treated with cyclophosphamide (CP). Vincamine (vinca alkaloid) is the source of the synthetic derivative vinpocetine (Vinpo). Worldwide, Vinpo is used as a cerebroprotective drug. As it has anti-oxidant, anti-thrombotic and anti-inflammatory effects but the power of Vinpo to prevent CP induced cystitis has not been studied. AIM OF STUDY: This research was planned to explore the effect of Vinpo (10-30 mg/kg, orally) administered 1 or 4 h before inducing cystitis by CP injection (300 mg/kg, i.p.) on the urinary bladder of mice. RESULTS: Administration of Vinpo 30 mg/kg, 4 h before CP injection ameliorated inflammatory markers. It reduced inducible nitric oxide synthase (iNOS), tumor necrosis factor- α (TNF-α), and BCL2 Associated X (Bax) expression in the bladder and increased the total antioxidant capacity level. Histological examination of the bladder has further supported these results. The present study suggests a protective effect of Vinpo (30 mg/kg, 4 h before CP injection) against CP-induced bladder inflammation. CONCLUSION: This proposes that Vinpo 30 mg/kg may become a promising pharmacological drug to prevent urinary adverse effects in patients treated with chemotherapy using CP.

Autophagy Promotes the Survival of Adipose Mesenchymal Stem/Stromal Cells and Enhances Their Therapeutic Effects in Cisplatin-Induced Liver Injury via Modulating TGF-ß1/Smad and PI3K/AKT Signaling Pathways.

Autophagy is a key metabolic process where cells can recycle its proteins and organelles to regenerate its own cellular building blocks. Chemotherapy is indispensable for cancer treatment but associated with various side-effects, including organ damage. Stem cell-based therapy is a promising approach for reducing chemotherapeutic side effects, however, one of its main culprits is the poor survival of transplanted stem cells in damaged tissues. Here, we aimed to test the effects of activating autophagy in adipose-derived mesenchymal stem/stromal cells (ADSCs) on the survival of ADSCs, and their therapeutic value in cisplatin-induced liver injury model. Autophagy was activated in ADSCs by rapamycin (50 nM/L) for two hours before transplantation and were compared to non-preconditioned ADSCs. Rapamycin preconditioning resulted in activated autophagy and improved survival of ADSCs achieved by increased autophagosomes, upregulated autophagy-specific LC3-II gene, decreased protein degradation/ubiquitination by downregulated p62 gene, downregulated mTOR gene, and finally, upregulated antiapoptotic BCL-2 gene. In addition, autophagic ADSCs transplantation in the cisplatin liver injury model, liver biochemical parameters (AST, ALT and albumin), lipid peroxidation (MDA), antioxidant profile (SOD and GPX) and histopathological picture were improved, approaching near-normal conditions. These promising autophagic ADSCs effects were achieved by modulation of components in TGF-ß1/Smad and PI3K-AKT signaling pathways, besides reducing NF-κB gene expression (marker for inflammation), reducing TGF-ß1 levels (marker for fibrosis) and increasing SDF-1 levels (liver regeneration marker) in liver. Therefore, current results highlight the importance of autophagy in augmenting the therapeutic potential of stem cell therapy in alleviating cisplatin-associated liver damage and opens the path for improved cell-based therapies, in general, and with chemotherapeutics, in particular.

Comparative nephroprotective effects of curcumin and etoricoxib against cisplatin-induced acute kidney injury in rats.

OBJECTIVE: Although cisplatin (CIS) acts as potent chemotherapy, nephrotoxicity still its major life-threatening side effect. The purpose of this study was to discuss and compare the renoprotective effects of curcumin (CUR) and etoricoxib (ETB) against CIS-induced nephrotoxicity. MATERIALS & METHODS: Thirty six adult female rats were divided equally into 6 groups: Group I (control), Group II (CIS) received cisplatin (7.5 mg/kg i.p), Group III (CUR) and group IV (ETB) received curcumin (200 mg/kg/day) or etoricoxib (10 mg/kg/day) respectively via gavage for seven continuous days. Group V (CIS + CUR) and Group VI (CIS + ETB) received curcumin (200 mg/kg/day) or etoricoxib (10 mg/kg/day) via gavage for seven continuous days. On the 4th day, the rats received cisplatin (7.5 mg/kg i.p) as a single injection 1 h after last curcumin or etoricoxib administration. At the assigned time, blood and tissue samples were collected for biochemical, histochemical, histopathological, immunohistochemical, and RT-PCR gene expression studies. RESULTS: Curcumin administration significantly decreased CIS-induced elevation of serum creatinine and blood urea nitrogen (BUN), and reversed oxidative stress markers; glutathione (GSH) and malondialdehyde (MDA) to control level. Suppression of inflammatory and apoptotic responses by CUR co-treatment was evidenced by decreased iNOS and BAX immunohistochemical reactions, and TNF-α and Caspase3 gene expressions which were detected by RT-PCR in kidney tissues. To our knowledge, this is the first time to discuss the effect of ETB on CIS induced nephrotoxicity. Although ETB reduced the previously mentioned inflammatory and apoptotic markers, its effect was less than that of CUR. Administration of ETB couldn't modify the disturbed levels of creatinine, BUN, GSH, and MDA. CONCLUSION: In conclusion, CUR provided a promising renoprotective effect against CIS induced nephrotoxicity. Further studies are recommended to approve or disapprove the protective role of ETB in CIS induced nephrotoxicity.