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Long-term glucocorticoids can alter sperm motility, vitality, or morphology, disrupting male reproductive function. This study scrutinized the synergistic benefits of two Egyptian plants against dexamethasone (Dexa)-induced testicular and autophagy dysfunction in male rats. Phytochemical ingredients and the combination index were estimated for Purslane ethanolic extract (PEE) and Chicory water extract (CWE). Four control groups received saline and 100 mg/kg of each PEE, CWE, and PEE/CWE, daily for 8 weeks. Dexa (1 mg/kg daily for 6 weeks) induced infertility where PEE, CWE, and PEE/CWE were given. Seminal analysis, male hormones, glycemic and oxidative stress markers, endoplasmic reticulum (ER) stress markers (Sigma 1R and GRP78), and autophagy regulators (Phospho-mTOR, LC3I/II, PI3KC3, and Beclin-1, P62, ATG5, and ATG7) were measured. The in vitro study illustrated the synergistic (CI < 1) antioxidant capacity of the PEE/CWE combination. Dexa exerts testicular damage by inducing oxidative reactions, a marked reduction in serum testosterone, TSH and LH levels, insulin resistance, ER stress, and autophagy. In contrast, the PEE and CWE extracts improve fertility hormones, sperm motility, and testicular histological alterations through attenuating oxidative stress and autophagy, with a synergistic effect upon combination. In conclusion, the administration of PEE/CWE has promised ameliorative impacts on male infertility and can delay disease progression.

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ETHNOPHARMACOLOGICAL RELEVANCE: Herbal medicines (HMs) often exert integration effects, including synergistic, additive and antagonistic effects, in such ways that they act on multiple targets and multiple pathways on account of their multiple components. Turmeric, made from the rhizome of Curcuma longa L., is a well-known HM prescribed in the polyherbal formulas for cancer treatment in traditional Chinese medicines (TCMs). However, neither the multiple anticancer compounds of turmeric nor the integration effects of these components are fully known. AIM OF THE STUDY: This work aims to develop a systematic approach to reveal the integration effect mechanisms of multiple anticancer compounds in turmeric against prostate cancer PC3 cells. MATERIALS AND METHODS: Combination index and omics technologies were applied to profile the integration effect mechanisms of bioactive compounds in proportions naturally found in turmeric. PC3 cell line (a prostate cancer cell line) fishing and high resolution mass spectrometry were employed to screen and identify the anticancer compounds from turmeric. The combinations which contain different cell-bound compounds in natural proportions were prepared for further evaluation of anti-cancer activity by using cell viability assays, and assessment of cell apoptosis and cell cycle analysis. Combination index analysis was applied to study the integration effects of the anticancer compounds in their natural proportions. Finally, quantitative glycoproteomics/proteomics and Western blot were implemented to reveal the potential synergistic effect mechanisms of the anticancer compounds based on their natural proportions in turmeric. RESULTS: Three curcuminoids (curcumin, CUR; demethoxycurcumin, DMC; bisdemethoxycurcumin, BDMC) in turmeric were discovered and shown to possess significant synergistic anticancer activities. Combination index analysis revealed an additive effect of CUR combined with DMC or BDMC and a slight synergistic effect of DMC combined with BDMC in natural proportions in turmeric, while a combination of all three curcuminoids (CUR, DMC and BDMC) at a ratio of 1:1:1 yielded superior synergistic effects. Interestingly, the presence of BDMC and DMC are essential for synergistic effect. Glycoproteomics and proteomics demonstrated that different curcuminoids regulate various protein pathways, such as ribosome, glycolysis/gluconeogenesis, biosynthesis of amino acids, and combination of CUR + DMC + BDMC showed the most powerful effects on down-regulation of protein expression. CONCLUSIONS: Our analytical approach provides a systematic understanding of the holistic activity and integration effects of the anti-cancer compounds in turmeric and three curcuminoids of turmeric showed a synergistic effect on PC3 cells.

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Ciprofloxacin (CIP) is a broad-spectrum antibiotic found within µg/L concentration range in the aquatic environment. It is a known contributor of umuC induction in hospital wastewater samples. CIP can undergo photolysis to result in many transformation products (TPs) of mostly unknown toxicity. The aims of this study were to determine the genotoxicity of the UV mixtures and to understand the possible genotoxic role of the stable TPs. As such, CIP and its UV-irradiated mixtures were investigated in a battery of genotoxicity and cytotoxicity in vitro assays. The combination index (CI) analysis of residual CIP in the irradiated mixtures was performed for the umu assay. Further, Quantitative Structure-Activity Relationships (QSARs) predicted selected genotoxicity endpoints of the identified TPs. CIP achieved primary elimination after 128 min of irradiation but was not completely mineralized. Nine photo-TPs were identified. The irradiated mixtures were neither mutagenic in the Ames test nor genotoxic in the in vitro micronucleus (MN) test. Like CIP, the irradiated mixtures were umuC inducing. The CI analysis revealed that the irradiated mixtures and the corresponding CIP concentration in the mixtures shared similar umuC potentials. QSAR predictions suggested that the TPs may be capable of inducing chromosome aberration, MN in vivo, bacterial mutation and mammalian mutation. However, the experimental testing for a few genotoxic endpoints did not show significant genotoxic activity for the TPs present as a component of the whole mixture analysis and therefore, further genotoxic endpoints may need to be investigated to fully confirm this.

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