RESUMO
Natural products have long been utilized in traditional medicine as remedies to improve health and treat illnesses, and have had a key role in modern drug discovery. Recently, there has been a revived interest in the search for bioactives from natural sources as alternative or complementary modalities to synthetic medicines; especially for cancer treatment, which incidence and mortality rates are on the rise worldwide. Ziziphus nummularia has been widely used in traditional medicine for the treatment of various diseases. Its traditional uses and numerous ethnopharmacological properties may be attributed to its richness in bioactive metabolites. However, its phytochemical composition or chemopreventive effects against the aggressive triple-negative breast cancer (TNBC) are still poorly explored. Here, phytochemical composition of an ethanolic extract of Z. nummularia leaves (ZNE) and its chromatographically isolated fractions was identified both qualitatively by spectrophotometric assays and analytically by HPLC-PDA-MS/MS. The anti-proliferative effects of ZNE were tested in several cancer cell lines, but we focused on its anti-TNBC effects since they were not explored yet. The anti-cancerous potential of ZNE and its fractions was tested in vitro in MDA-MB-231, a TNBC cell line. Results showed that ZNE and its Fraction 6 (F6) reduced the viability of MDA-MB-231 cells. F6 decreased MDA-MB-231 viability more than crude ZNE or its other fractions. ZNE and F6 are rich in phytochemicals and HPLC-PDA-MS/MS analysis identified several metabolites that were previously reported to have anti-cancerous effects. Both ZNE and F6 showed potent antioxidant capacity in the DPPH assay, but promoted reactive oxygen species (ROS) production in MDA-MB-231 cells; an effect which was blunted by the antioxidant N-acetyl cysteine (NAC). NAC also blunted ZNE- and F6-induced reduction in TNBC cell viability. We also demonstrated that ZNE and F6 induced an arrest of the cell cycle, and triggered apoptosis- and autophagy-mediated cell death. ZNE and F6 inhibited metastasis-related cellular processes by modifying cell migration, invasion, and adhesion. Taken together, our findings reveal that Z. nummularia is rich in phytochemicals that can attenuate the malignant phenotype of TNBC and may offer innovative avenues for the discovery of new drug leads for treatment of TNBC and other cancers.
RESUMO
In the therapy of cisplatin (CP), nephrotoxicity is a main limiting issue that associated with oxidative stress and apoptosis. According to many studies, the antioxidant and anti-inflammatory properties of Ajwa dates are very strong, due to the unique phytochemical profile. Here, we investigated the possible mitigative effects of Ajwa dates fruits extract (ADFE) vs CP-induced nephrotoxicity in rats, in addition to phytochemical profiling of its components via LC-MS/MS. Six groups were formed from forty-two male rats. G1: control, G2: ADFE 0.25 g/kg, G3: ADFE 0.5 g/kg (for 21 days), G4: CP -intoxicated group (single i.p. dose of 7.0 mg/kg b.w) on day 16th, G5: ADFE 0.25 + CP, G6: ADFE 0.5 + CP. LC-MS/MS analysis revealed the tentative identification of 17 compounds of different chemical nature, including organic/phenolic acids, and flavonoids and their sulphated/glycosides derivatives. ADFE has considerable antioxidant potential (DPPH with IC50 326.65 µg/ml and FRAP= 20.91 mM FeSO4/g extract) and total phenolic content (TPC = 35.44 mg/GAE/g extract). It (especially at dose 0.5 g/kg b.w) significantly modulated the toxicity of CP via enhancing food intake and hematobiochemical indices (renal functions, anemia, and leucopenia), increasing the renal antioxidant status (GSH, SOD, and CAT), decreasing the production of oxidative stress and inflammatory markers (MDA, NO, H2O2, MPO, MCP-1, TNF-α and IL-6), augmenting mRNA expression of Nrf2, and modulating NOX4 mRNA expression. The existence of bioactive compounds in ADFE may be responsible for their prophylactic properties, demonstrating natural usefulness in the treatment of oxidative stress, hypochromic anemia, immunodeficiency, and inflammatory complications, all of which are chemotherapy side effects.