Maternal resveratrol supplementation ameliorates bisphenol A-induced atherosclerotic lesions formation in adult offspring ApoE-/- mice.

Current evidence suggests that intrauterine bisphenol A (BPA) exposure increases the risk of developing cardiovascular diseases in later stages of life. The beneficial effect of resveratrol (Rsv) on developmental programming of atherosclerosis lesions formation in offspring is seldom reported. Hence, we sought to study the effect of maternal Rsv in ameliorating perinatal BPA exposure-induced atherosclerosis lesions formation in adult offspring using the apolipoprotein E-deficient (ApoE-/-) mice model. The pregnant ApoE-/- mice were allocated into three groups: control, BPA, BPA + resveratrol (BPA + Rsv). The BPA group mice received BPA in their drinking water (1 µg/ml). BPA + Rsv group mice received BPA in their drinking water (1 µg/ml) and were treated orally with Rsv (20 mg kg-1 day-1). All the treatments were continued throughout the gestation and lactation period. Quantitative analysis of Sudan IV-stained aorta revealed a significantly increased area of atherosclerotic lesions in both female (p < 0.01) and male adult offspring mice (p < 0.01) in the BPA group. Supplementation with Rsv significantly reduced the BPA-induced atherosclerotic lesion development in the female offspring mice (p < 0.05). Transmission electron microscopy revealed the presence of a significantly high incidence of autophagic endothelial, smooth muscle, and macrophage cells in the aorta of BPA-exposed mice. Rsv treatment reduced the incidence of autophagic cells in BPA-exposed mice. In conclusion, maternal Rsv supplementation significantly prevents the BPA-induced atherosclerotic lesions formation in a sex-dependent manner potentially by acting as an autophagy modulator. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-021-03078-y.

Curcumin Ameliorates Kidney Function and Oxidative Stress in Experimental Chronic Kidney Disease.

Chronic kidney disease (CKD) is known to involve inflammation, oxidative stress and apoptosis. Here, we investigated the impact of curcumin (diferuloyl methane, a phenolic turmeric pigment), which has strong antioxidant, anti-inflammatory and anti-apoptotic activities on kidney structure and function in rats with adenine-induced CKD. Rats were treated for 5 weeks with adenine to induce CKD-like renal damage and combined with three doses of curcumin. Markers of kidney function and oxidative stress were quantified in plasma, urine, renal homogenates and on kidney tissue. Curcumin was found to significantly abate adenine-induced toxic effects such as reduced creatinine clearance, elevated neutrophil gelatinase-associated lipocalin levels and raised urinary N-acetyl-ß-D-glucosaminidase activities. Curcumin markedly reduced renal morphological damage and histopathological markers of inflammation, fibrosis and apoptosis. Curcumin further reduced adenine-induced hypertension, urinary albumin, the inflammatory cytokines IL-1ß, IL-6 and TNF-α, cystatin C and adiponectin. It restored plasma sclerostin concentrations and lowered oxidative stress in renal homogenates. In animals treated with the two higher curcumin concentrations, alone or in combination with adenine, an increased expression of the antioxidative transcription factor Nrf2 was found as well as up-regulation of the activity of its direct target glutathione reductase, and of an indirect target, the glutathione level. In conclusion, curcumin exhibits salutary effects against adenine-induced CKD in rats by reducing inflammation and oxidative stress via up-regulation of the transcription factor Nrf2.

Fatty acid synthase regulates the chemosensitivity of breast cancer cells to cisplatin-induced apoptosis.

Fatty acid synthase (FASN) is a key enzyme in fat biosynthesis that is over-expressed in advanced breast cancer stages. Cisplatin (CDDP) is a platinum-based drug used in the treatment of certain types of this disease. Although it was shown that FASN inhibition induced apoptosis by enhancing the cytotoxicity of certain drugs in breast cancer, its role in regulating the chemosensitivity of different types of breast cancer cells to CDDP-induced apoptosis is not established yet. Therefore, two different breast cancer cell lines; triple negative breast cancer (TNBC; MDA-MB-231) and triple positive breast cancer (TPBC; BT-474) cells were used to examine such role. We show that TNBC cells had naturally less fat content than TPBC cells. Subsequently, the fat content increased in both cells when treated with Palmitate rather than Oleate, whereas both fatty acids produced apoptotic ultra-structural effects and attenuated FASN expression. However, Oleate increased FASN expression in TPBC cells. CDDP decreased FASN expression and increased apoptosis in TNBC cells. These effects were further enhanced by combining CDDP with fatty acids. We also illustrate that the inhibition of FASN by either siRNA or exogenous inhibitor decreased CDDP-induced apoptosis in TPBC cells suggesting its role as an apoptotic factor, while an opposite finding was observed in TNBC cells when siRNA and fatty acids were used, suggesting its role as a survival factor. To our knowledge, we are the first to demonstrate a dual role of FASN in CDDP-induced apoptosis in breast cancer cells and how it can modulate their chemosensitivity.

Cisplatin Induces Apoptosis Through the Endoplasmic Reticulum-mediated, Calpain 1 Pathway in Triple-negative Breast Cancer Cells.

BACKGROUND: Breast cancer is the most common cancer in women worldwide. Triple-negative breast cancer (TNBC) is an aggressive type that can be treated using platinum-based chemotherapy such as cisplatin (cis-diamminedichloroplatinum II). Although the calpain protein is essential in many cellular processes, including apoptosis, cell signaling, and proliferation, its role in cisplatin-induced apoptosis in TNBC cells is not fully understood. The present study assessed calpain 1-dependent, cisplatin-induced apoptosis in TNBC cells. MATERIALS AND METHODS: MDA-MB231 cells were treated with different concentrations of cisplatin (0, 20, and 40 µM). The cisplatin deposit and its effect on endoplasmic reticulum and, subsequently, calcium release were detected using transmission electron microscopy and Von Koss staining, respectively. Calpain 1 messenger RNA, protein content, and apoptosis was measured using reverse transcriptase-polymerase chain reaction, Western blotting, and Hoechst stain, respectively. In addition, calpain modulation, by either activation or inhibition, and its effect on cisplatin-induced apoptosis were assessed. RESULTS: Our results showed that cisplatin induced endoplasmic reticulum stress, indicated by an increase in calcium staining and protein expression of glucose-regulated protein 78 and calmodulin, followed by cleavage of α-fodrin and caspase-12 and, eventually, apoptosis. Cyclopiazonic acid showed a similar effect and enhanced the sensitivity of these cells to cisplatin treatment. In contrast, calpain 1 inhibition by both specific small interfering RNA and exogenous inhibitor (calpeptin) attenuated cisplatin-induced apoptosis in these cells. CONCLUSION: Altogether, these findings suggest, for the first time, that calpain 1 activation by endoplasmic reticulum plays an essential role in sensitizing TNBC cells to cisplatin-induced apoptosis. This finding will allow exploration of new insights for the treatment of TNBC by overcoming its resistance to apoptosis.