Most of diabetic cardiovascular complications are attributed to endothelial dysfunction and impaired angiogenesis. Endoplasmic Reticulum (ER) and oxidative stresses were shown to play a pivotal role in the development of endothelial dysfunction in diabetes.Hemeoxygenase-1 (HO-1) was shown to protect against oxidative stress in diabetes; however, its role in alleviating ER stress-induced endothelial dysfunction remains not fully elucidated. We aim here to test the protective role of HO-1 against high glucose-mediated ER stress and endothelial dysfunction and understand the underlying mechanisms with special emphasis on oxidative stress, inflammation and cell death. Altogether, we show here the critical role of ER stress-mediated cell death in diabetesinduced endothelial dysfunction and impaired angiogenesis and underscore the role of HO-1 induction as a key therapeutic modulator for ER stress response in ischemic disorders and diabetes. Our results also highlight the complex interplay between ER stress response and oxidative stress.

Herein, we report the synthesis of mixed-ligand Cu(II) complexes of metformin and ciprofloxacin drugs together with 1,10-phenanthroline as a co-ligand. The synthesized complexes were characterized using different spectroscopic and spectrometric techniques. In vitro cytotoxic activity against human breast adenocarcinoma cancer cell line (MCF-7) as well as antibacterial activity against two gram-negative and two gram-positive bacterial strains were also investigated. The analyses of the experimental results were supported using quantum chemical calculations and molecular docking studies against estrogen receptor alpha (ERα; PDB: 5GS4). The cytotoxicity of the [Cu(II) (metformin) (1,10-phenanthroline)] complex (1), with IC50 of 4.29 µM, and the [Cu(II) (ciprofloxacin) (1,10-phenanthroline)] complex (2), with IC50 of 7.58 µM, were found to be more effective than the referenced drug, cisplatin which has IC50 of 18.62 µM against MCF-7 cell line. The molecular docking analysis is also in good agreement with the experimental results, with binding affinities of –7.35, –8.76 and –6.32 kcal/mol, respectively, for complexes 1, 2 and cisplatin against ERα. Moreover, complex 2 showed significant antibacterial activity against E. coli (inhibition diameter zone, IDZ, = 17.3 mm), P. aeruginosa (IDZ = 17.08 mm), and S. pyogen (IDZ = 17.33 mm), at 25 μg/ml compared to ciprofloxacin (IDZ = 20.0, 20.3, and 21.3 mm), respectively. Our BOILED-egg model indicated that the synthesized metal complexes have potentially minimal neurotoxicity than that of cisplatin.

Selenium is an essential trace element important for human health. A balanced intake is, however, crucial to maximize the health benefits of selenium. At physiological concentrations, selenium mediates antioxidant, anti-inflammatory, and prosurvival actions. However, supra-nutritional selenium intake was associated with increased diabetes risk leading potentially to endothelial dysfunction, the initiating step in atherosclerosis. High selenium causes apoptosis in cancer cells via endoplasmic reticulum (ER) stress, a mechanism also implicated in endothelial dysfunction. Nonetheless, whether ER stress drives selenium-induced endothelial dysfunction, remains unknown. Here, we investigated the effects of increasing concentrations of selenium on endothelial cells. High selenite reduced nitric oxide bioavailability and impaired angiogenesis. High selenite also induced ER stress, increased reactive oxygen species (ROS) production, and apoptosis. Pretreatment with the chemical chaperone, 4-phenylbutyrate, prevented the toxic effects of selenium. Our findings support a model where high selenite leads to endothelial dysfunction through activation of ER stress and increased ROS production. These results highlight the importance of tailoring selenium supplementation to achieve maximal health benefits and suggest that prophylactic use of selenium supplements as antioxidants may entail risk.

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3 (2) have been synthesized and characterized by ultraviolet−visible (UV−vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, mass spectrometry, thermogravimetric analysis/differential thermal analysis (TGA/ DTA), X-ray diffraction (XRD), scanning electron microscopy− energy-dispersive X-ray spectroscopy (SEM-EDX), and molar conductance, and supported by density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. Square pyramidal and tetrahedral geometries are proposed for Cu(II) and Zn(II) complexes, respectively, and the XRD patterns showed the polycrystalline nature of the complexes. Furthermore, in vitro cytotoxic activity of the complexes was evaluated against the human breast cancer cell line (MCF-7). A Cu(II) centered complex with an IC 50 value of 4.09 μM was more effective than the Zn(II) centered complex and positive control, cisplatin, which displayed IC 50 values of 75.78 and 18.62 μM, respectively. In addition, the newly synthesized complexes experienced the innate antioxidant nature of the metal centers for scavenging the DPPH free radical (up to 81% at 400 ppm). The biological significance of the metal complexes was inferred from the highest occupied molecular orbital−lowest unoccupied molecular orbital (HOMO−LUMO) energy band gap, which was found to be 2.784 and 3.333 eV, respectively for 1 and 2, compared to the ligands, 1,10-phenathroline (4.755 eV) and chrysin (4.403 eV). Moreover, the molecular docking simulations against estrogen receptor alpha (ERα; PDB: 5GS4) were strongly associated with the in vitro biological activity results (E B and K i are −8.35 kcal/mol and 0.76 μM for 1, −7.52 kcal/mol and 3.07 μM for 2, and −6.32 kcal/mol and 23.42 μM for cisplatin). However, more research on in vivo cytotoxicity is suggested to confirm the promising cytotoxicity results.

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Selenium is an essential trace element important to human health. Recently, supra-nutritional selenium intake was shown to be associated with insulin resistance and may therefore affect endothelial function increasing type II diabetes risk and associated cardiovascular-disease risk. However the underpinning molecular mechanisms involved are not clear. High selenium doses cause apoptosis in some cancer cells through the induction of endoplasmic reticulum (ER) stress response. ER stress is also a mechanism involved in the pathogenesis of insulin resistance and endothelial dysfunction (ED), which are implicated in the development of atherosclerosis, thus we hypothesised that high selenium intake could cause endothelial dysfunction through ER stress.Endothelial cells were treated with 0.5–20 µM of selenite in the presence or absence of the chemical chaperone, 4-phenylbutryic acid (PBA), which increases ER homeostasis. ER stress activation was evaluated by qPCR. Endothelial dysfunction was then assessed by investigating nitric oxide (NO) production (Griess assay), reactive oxygen species (ROS) release (flow cytometry), eNOS activation (western blot), apoptosis (flow cytometry) and caspases 3/7 activity.Treatment of cells with supra-nutritional concentrations of selenium (5–20 µM of selenite) compared to physiological concentration (0.5 µM) enhanced mRNA expression of several pro-apoptotic ER-stress markers; such as activating transcription factor-4 (ATF4) and CAAA/enhanced-binding homologous protein (CHOP). Interestingly, the pre-incubation of cells with chemical chaperone PBA completely reversed ER stress response mediated by high selenium treatment. In addition, high selenite treatment (5–20 µM) reduced NO production and enhanced ROS production indicating oxidative stress. Also, high selenium caused a decrease in the expression of active phosphorylated form of eNOS. The pre-treatment of cells with PBA significantly reduced high selenium-induced oxidative stress and enhanced eNOS phosphorylation. Finally, supra-nutritional concentrations of selenite also enhanced apoptosis and increased caspases 3/7 activity in endothelial cells compared to the physiological concentration. Importantly, pre-treatment of cells with PBA completely reversed high selenium-mediated cell death.Overall, we show here that high selenium treatment causes endothelial dysfunction and cell death through the activation of ER stress response. These results highlight the importance of a balanced selenium intake in order to achieve maximal health benefits. These findings also underscore the importance to monitor cardiovascular risk development in cancer patients supplemented with high amounts of selenium as part of their chemotherapeutic intervention.