A Novel Resveratrol-Induced Pathway Increases Neuron-Derived Cell Resilience against Oxidative Stress.

A promising therapeutic strategy to delay and/or prevent the onset of neurodegenerative diseases (NDs) could be to restore neuroprotective pathways physiologically triggered by neurons against stress injury. Recently, we identified the accumulation of neuroglobin (NGB) in neuronal cells, induced by the 17ß-estradiol (E2)/estrogen receptor ß (ERß) axis, as a protective response that increases mitochondria functionality and prevents the activation of apoptosis, increasing neuron resilience against oxidative stress. Here, we would verify if resveratrol (Res), an ERß ligand, could reactivate NGB accumulation and its protective effects against oxidative stress in neuronal-derived cells (i.e., SH-SY5Y cells). Our results demonstrate that ERß/NGB is a novel pathway triggered by low Res concentrations that lead to rapid and persistent NGB accumulation in the cytosol and in mitochondria, where the protein contributes to reducing the apoptotic death induced by hydrogen peroxide (H2O2). Intriguingly, Res conjugation with gold nanoparticles increases the stilbene efficacy in enhancing neuron resilience against oxidative stress. As a whole, ERß/NGB axis regulation is a novel mechanism triggered by low concentration of Res to regulate, specifically, the neuronal cell resilience against oxidative stress reducing the triggering of the apoptotic cascade.

Resveratrol Analogs and Prodrugs Differently Affect the Survival of Breast Cancer Cells Impairing Estrogen/Estrogen Receptor α/Neuroglobin Pathway.

Breast cancer is the first leading tumor in women in terms of incidence worldwide. Seventy percent of cases are estrogen receptor (ER) α-positive. In these malignancies, 17ß-estradiol (E2) via ERα increases the levels of neuroglobin (NGB), a compensatory protein that protects cancer cells from stress-induced apoptosis, including chemotherapeutic drug treatment. Our previous data indicate that resveratrol (RSV), a plant-derived polyphenol, prevents E2/ERα-induced NGB accumulation in this cellular context, making E2-dependent breast cancer cells more prone to apoptosis. Unfortunately, RSV is readily metabolized, thus preventing its effectiveness. Here, four different RSV analogs have been developed, and their effect on the ERα/NGB pathway has been compared with RSV conjugated with highly hydrophilic gold nanoparticles as prodrug to evaluate if RSV derivatives maintain the breast cancer cells' susceptibility to the chemotherapeutic drug paclitaxel as the original compound. Results demonstrate that RSV conjugation with gold nanoparticles increases RSV efficacy, with respect to RSV analogues, reducing NGB levels and enhancing the pro-apoptotic action of paclitaxel, even preventing the anti-apoptotic action exerted by E2 treatment on these cells. Overall, RSV conjugation with gold nanoparticles makes this complex a promising agent for medical application in breast cancer treatment.

Divergent Effects of Daidzein and its Metabolites on Estrogen-Induced Survival of Breast Cancer Cells.

Although soy consumption is associated with breast cancer prevention, the low bioavailability and the extensive metabolism of soy-active components limit their clinical application. Here, the impact of daidzein (D) and its metabolites on estrogen-dependent anti-apoptotic pathway has been evaluated in breast cancer cells. In estrogen receptor α-positive breast cancer cells treated with D and its metabolites, single or in mixture, ERα activation and Neuroglobin (NGB) levels, an anti-apoptotic estrogen/ERα-inducible protein, were evaluated. Moreover, the apoptotic cascade activation, as well as the cell number after stimulation was assessed in the absence/presence of paclitaxel to determine the compound effects on cell susceptibility to a chemotherapeutic agent. Among the metabolites, only D-4'-sulfate maintains the anti-estrogenic effect of D, reducing the NGB levels and rendering breast cancer cells more prone to the paclitaxel treatment, whereas other metabolites showed estrogen mimetic effects, or even estrogen independent effects. Intriguingly, the co-stimulation of D and gut metabolites strongly reduced D effects. The results highlight the important and complex influence of metabolic transformation on isoflavones physiological effects and demonstrate the need to take biotransformation into account when assessing the potential health benefits of consumption of soy isoflavones in cancer.