The ameliorative effect of rosmarinic acid and epigallocatechin gallate against doxorubicin-induced genotoxicity.

Doxorubicin (Dox), an effective anticancer agent, is known for its genotoxic effects on normal cells. Phenolic compounds, renowned for their antitumor, antioxidant, and antigenotoxic properties, have gained prominence in recent years. This study investigates the individual and combined protective effects of rosmarinic acid (RA) and epigallocatechin gallate (EGCG) against Dox-induced genotoxicity using various in vitro test systems. The synergistic/antagonistic interaction of these combinations on Dox's chemotherapeutic effect is explored in breast cancer cell lines. Both RA and EGCG significantly mitigate Dox-induced genotoxicity in comet, micronucleus, and Ames assays. While Dox exhibits higher selectivity against MCF-7 cells, EGCG and RA show greater selectivity against MDA-MB-231 cells. The coefficient of drug interaction reveals a synergistic effect when RA or EGCG is combined with Dox in breast cancer cells. In conclusion, both EGCG and RA effectively reduce Dox-induced genetic damage and enhance Dox's cell viability-reducing effect in breast cancer cells.

Rosmarinic acid (RA) showed protective effect against doxorubicin-induced genotoxicity.Epigallocatechin gallate (EGCG) demonstrated pro-oxidant properties at high concentrations.EGCG and RA selectively targeted MDA-MB-231 cells.Synergistic effect was observed when EGCG or RA was administered together with Dox on breast cancer cells.

Comprehensive estrogenic/anti-estrogenic, anticancer, mutagenic/anti-mutagenic, and genotoxic/anti-genotoxic activity studies on chemically characterized black poplar and Eurasian aspen propolis types.

Propolis is mainly composed of plant resins, and its type is named according to the primary plant origin in its composition. Identification of propolis botanical origin is essential for predicting and repeating its pharmacological activity because of the variations in chemical composition. This study aimed to compare chemical composition of black poplar (Populus nigra L.) type-propolis (PR1 and PR2) and Eurasian aspen (P. tremula L.)-type propolis (PR3) by liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique and to evaluate their biological activity profiles. According to LC-MS/MS results, in addition to marked caffeic acid phenethyl ester content in PR1 and PR2, flavonoid aglycones such as pinocembrin, chrysin, pinobanksin, and galangin were found to be dominant in these samples. On the other hand, PR3 contained relatively high concentrations of phenolic acids such as ferulic acid, p-coumaric acid, and trans-cinnamic acid. The anti-estrogenic activity test showed that PR2 exerted the highest anti-estrogenic activity by inhibiting cell proliferation by 44.6%. All propolis extracts showed anticancer activity, which was justified by decreasing activity on the 3D spheroid size in a concentration-dependent manner. Besides, all extracts showed moderate or potent antimutagenic activity in Salmonella typhimurium TA98 and TA100 strains with and without metabolic activation, respectively. In addition, the Comet assay results revealed that propolis extracts have a geno-protective effect against H2O2-induced DNA damage in CHO-K1 cells at 0.625 and 1.25 µg/mL concentrations. Overall, the result of this study may help in preparing standardized propolis extracts and developing products with defined pharmacological benefits in the food supplements industry.

Novel 1,2,4-triazoles derived from Ibuprofen: synthesis and in vitro evaluation of their mPGES-1 inhibitory and antiproliferative activity.

Some novel triazole-bearing ketone and oxime derivatives were synthesized from Ibuprofen. In vitro cytotoxic activities of all synthesized molecules against five cancer lines (human breast cancer MCF-7, human lung cancer A549, human prostate cancer PC-3, human cervix cancer HeLa, and human chronic myelogenous leukemia K562 cell lines) were evaluated by MTT assay. In addition, mouse embryonic fibroblast cells (NIH/3T3) were also evaluated to determine the selectivity. Compounds 18, 36, and 45 were found to be the most cytotoxic, and their IC50 values were in the range of 17.46-68.76 µM, against the tested cancer cells. According to the results, compounds 7 and 13 demonstrated good anti-inflammatory activity against the microsomal enzyme prostaglandin E2 synthase-1 (mPGES-1) enzyme at IC50 values of 13.6 and 4.95 µM. The low cytotoxicity and non-mutagenity of these compounds were found interesting. Also, these compounds significantly prevented tube formation in angiogenesis studies. In conclusion, the anti-inflammatory and angiogenesis inhibitory activities of these compounds without toxicity suggested that they may be promising agents in anti-inflammatory treatment and they may be supportive agents for the cancer treatment.

Lead Optimization and Structure-Activity Relationship Studies on Myeloid Ecotropic Viral Integration Site 1 Inhibitor.

The pivotal role of the myeloid ecotropic viral integration site 1 (MEIS1) transcriptional factor was reported in cardiac regeneration and hematopoietic stem-cell (HSC) regulation with our previous findings. MEIS1 as a promising target in the context of pharmacological inhibition, we identified a potent myeloid ecotropic viral integration site (MEIS) inhibitor, MEISi-1, to induce murine and human HSC expansion ex vivo and in vivo. In this work, we performed lead optimization on MEISi-1 by synthesizing 45 novel analogues. Structure-activity relationship studies revealed the significance of a para-methoxy group on ring A and a hydrophobic moiety at the meta position of ring B. Obtained biological data were supported by inhibitor docking and molecular dynamics simulation studies. Eleven compounds were depicted as potent inhibitors demonstrating a better inhibitory profile on MEIS1 and target genes Meis1, Hif-1α, and p21. Among those, 4h, 4f, and 4b were the most potent inhibitors. The predicted pharmacokinetics properties fulfill drug-likeness criteria. In addition, compounds exerted neither cytotoxicity on human dermal fibroblasts nor mutagenicity.

Protective Effect of Nigella sativa and Nigella damascena Fixed Oils Against Aflatoxin Induced Mutagenicity in the Classical and Modified Ames Test.

The antioxidant and mutagenic/antimutagenic activities of the fixed oils from Nigella sativa (NSO) and Nigella damascena (NDO) seeds, obtained by cold press-extraction from the cultivar samples, were comparatively investigated for the first time. The antimutagenicity test was carried out using classical and modified Ames tests. The fatty acid composition of the fixed oils was characterized by gas chromatography-mass spectrometry (GC-MS) while the quantification of thymoquinone in the fixed oils was determined by UPC2 . The main components of the NSO and NDO were found to be linoleic acid, oleic acid, and palmitic acid. The results of the Ames test confirmed the safety of NSO and NDO from the viewpoint of mutagenicity. The results of the three antioxidant test methods were correlated with each other, indicating NDO as having a superior antioxidant activity, when compared to the NSO. Both NSO and NDO exhibited a significant protective effect against the mutagenicity induced by aflatoxin B1 in Salmonella typhimurium TA98 and TA100 strains. When microsomal metabolism was terminated after metabolic activation of the mycotoxin, a significant increase in antimutagenic activity was observed, suggesting that the degradation of aflatoxin B1 epoxides by these oils may be a possible antimutagenic mechanism. It is worthy to note that this is the first study to assess the mutagenicity of NSO and NDO according to the OECD 471 guideline and to investigate antimutagenicity of NDO in comparison to NSO against aflatoxin.

Synthesis, anticancer activity, toxicity evaluation and molecular docking studies of novel phenylaminopyrimidine-(thio)urea hybrids as potential kinase inhibitors.

Thirty-two novel urea/thiourea compounds as potential kinase inhibitor were designed, synthesized and evaluated for their cytotoxic activity on breast (MCF7), colon (HCT116) and liver (Huh7) cancer cell lines. Compounds 10, 19 and 30 possessing anticancer activity with IC50 values of 0.9, 0.8 and 1.6µM respectively on Huh7 cells were selected for further studies. These hit compounds were tested against liver carcinoma panel. Real time cell electronic sensing assay was used to evaluate the effects of the compounds 10, 19 and 30 on the growth pattern of liver cancer cells. Apoptotic cell death and cell cycle analysis upon treatment of liver carcinoma cells with hit compounds were determined. A significant apoptotic cell death was detected upon treatment of Huh7 and Mahlavu cells with compound 30 after 48 h of treatment. Additionally, compound 10 caused cell cycle arrest at G0/G1 phase. Mutagenicity of hit compounds was evaluated. Assertively, these compounds were not found to be mutagenic on Salmonella typhimurium strains TA98 and TA100. To understand the binding modes of the synthesized compounds, molecular docking studies were performed using the crystal data of VEGFR and Src-kinase enzymes in correlation with anticancer activities.

Safety evaluation of styrax liquidus from the viewpoint of genotoxicity and mutagenicity.

ETHNOPHARMACOLOGICAL RELEVANCE: Styrax liquidus is a resinous exudate (balsam) obtained from the wounded trunk of the Liquidambar orientalis Mill. (Hamamelidaceae). Styrax has been used for treatment of various ailments in Turkish folk medicine such as skin problems, peptic ulcers, nocturnal enuresis, parasitic infections, antiseptic or as expectorant. AIM OF STUDY: In spite of frequent use of styrax in Turkish folk medicine as well as once as a stabilizer in perfumery industry, negative reports have been noticed by the international authority for restriction its use based on some limited evidences from an in vitro study. The aim of the present study was to evaluate the genotoxic and cytotoxic potential of styrax and its ethanolic extract using in vivo and in vitro assays, as well as an antimutagenic assay and also to determine its phenolic constituents with chromatographic analysis. MATERIALS AND METHODS: In vitro mutagenicity and antimutagenicity of styrax and its ethanolic extract were evaluated by Ames test performed on Salmonella TA98 and TA100 strains with and without metabolic activation (10- 30,000µg/plate). The genotoxicity was also studied in vivo by chromosomal aberrations assay on bone marrow of Balb C mice with different its concentrations (500-2000mg/kg body weight). Cytotoxicity has been evaluated by the MTT assay using L929 cell line. Its phenolic constituents were determined by HPLC analysis. RESULTS: Genotoxicological investigations of styrax or its ethanolic extract showed that none of the tested concentrations induced a significant increase in the revertant number of TA98 and TA100 strains with or without metabolic activation, indicating no mutagenicity to the tested strains. Also results indicated that up to 2000mg/kg body weight, styrax is not genotoxic in mammalian bone marrow chromosome aberration test in vivo. In cytotoxicity study, the IC50 values of styrax and its ethanolic extract were found to be 50.22±1.80 and 59.69±11.77µg/mL, respectively. Among the studied reference standards the major phenolic acids in styrax balsam was found to be p-coumaric acid (2.95mg/g), while in its ethanolic extract not only p-coumaric acid (11.46mg/g), but also gallic acid (1.60mg/g) were found to the main components. CONCLUSION: The findings of the present study provide scientific basis to the safety of styrax from the viewpoint of genotoxicity risk, and in fact, it was found to be beneficial against genotoxicity.