Gallic acid and/or cerium oxide nanoparticles synthesized by gamma-irradiation protect cisplatin-induced nephrotoxicity via modulating oxidative stress, inflammation and apoptosis.

Cisplatin is one of the most significant anticancer. However, its use is associated with numerous toxicities especially nephrotoxicity. The main aim of this work was to examine the protective effect of Gallic acid (GA) and/or cerium oxide nanoparticles (CONPs) synthesized by gamma-irradiation on cisplatin-induced nephrotoxicity in rats. To do that, 48 adult male albino rats were separated into eight groups and received GA (100 mg/kg orally) and/or CONPs (15 mg/kg i. p.) for 10 days before injection with a single dose of cisplatin (7.5 mg/kg i. p.). The findings showed that cisplatin treatment impaired kidney functioning as shown by elevated serum levels of urea and creatinine. Additionally, the oxidative stress indicators (MDA and NO), levels of NF-kB, pro-inflammatory cytokines (IL1-and TNF-) and pro-apoptotic proteins (BAX and caspase-3) were raised after cisplatin injection, while levels of intrinsic anti-oxidants (CAT, SOD, and GSH) and anti-apoptotic protein (Bcl-2) were reduced. Moreover, renal toxicity was confirmed by alteration in normal histological architecture of the kidneys. On the other hand, pretreatment with CONPs and/or GA ameliorated cisplatin-induced nephrotoxicity as evidenced by improvement of renal function parameters and levels of oxidative stress, inflammatory and apoptotic markers in renal tissue along with the renal histopathological changes. This study clarifies how GA and CONPs protect against cisplatin-induced nephrotoxicity and demonstrates any potential synergism between them. Therefore, they can be considered as promising nephroprotective agents during chemotherapy.

In Vitro and In Vivo Antitumor Activity of Indolo[2,3-b] Quinolines, Natural Product Analogs from Neocryptolepine Alkaloid.

Neocryptolepine (5-methyl-5H-indolo[2,3-b] quinoline) analogs were synthesized and evaluated in vitro and in vivo for their effect versus Ehrlich ascites carcinoma (EAC). The analogs showed stronger cytotoxic activity against EAC cells than the reference drug. The in vivo evaluation of the target compounds against EAC-induced solid tumor in the female albino Swiss mice revealed a remarkable decrease in the tumor volume (TV) and hepatic lipid peroxidation. A noticeable increase of both superoxide dismutase (SOD) and catalase (CAT) levels was reported (p < 0.001), which set-forth proof of their antioxidant effect. In addition, the in vitro antioxidant activity of the neocryptolepine analogs was screened out using the DPPH method and showed promising activities activity. The histopathological investigations affirmed that the tested analogs have a remarkable curative effect on solid tumors with minimal side-effect on the liver. The study also includes illustrated mechanism of the antitumor activity at the cell level by flow cytometry. The cell cycle analysis showed that the neocryptolepine analogs extensively increase the aggregation of tumor cells in three phases of the cell cycle (G0/G1, S and G2/M) with the emergence of a hypo-diploid DNA content peak (sub-G1) in the cell cycle experiments, which is a clear-cut for the apoptotic cell population. Furthermore, the immunological study manifested a significant elevation in splenic lymphocyte count (p < 0.001) with the elevation of the responsiveness of lymphocytes to phytohemagglutinin (PHA). These results indicate that these naturally-based neocryptolepine alkaloids exhibit marked antitumor activity in vivo and represent an important lead in the development of natural-based anticancer drugs.