Regulation of cholesterol metabolism: New players for an old physiological process.

Identified more than two centuries ago, cholesterol plays a pivotal role in human physiology. Since cholesterol metabolism is a physiologically significant process, it is not surprising that its alterations are associated with several pathologies. The discovery of new molecular targets or compounds able to modulate this sophisticated metabolism has been capturing the attention of research groups worldwide since many years. Endogenous and exogenous compounds are known to regulate cellular cholesterol synthesis and uptake, or reduce cholesterol absorption at the intestinal level, thereby regulating cholesterol homeostasis. However, there is a great need of new modulators and diverse new pathways have been uncovered. Here, after illustrating cholesterol metabolism and its well-known regulators, some new players of this important physiological process are also described.

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.

Brain Cholesterol Biosynthetic Pathway Is Altered in a Preclinical Model of Fragile X Syndrome.

Fragile X Syndrome (FXS) is the most frequent form of inherited X-linked pathology, associated with an intellectual and developmental disability, and currently considered the first monogenic cause of autism spectrum disorder (ASD). Low levels of total cholesterol reported in the serum of FXS patients, and evidence that FMRP targets a subset of mRNAs encoding proteins of lipid synthesis and transport suggests that the cholesterol metabolism impairments could be involved in FXS. Thus, the aim of the presented work was to investigate the modulations of the cholesterol biosynthetic pathway and its end-products in a recently developed Fmr1-Δexon 8 rat model of FXS. Here, we show that this experimental model mimics what is found in FXS patients, exhibiting a lower serum cholesterol content, accompanied by a reduction in food intake and body weight compared to WT animals. Moreover, alterations of proteins committed to cholesterol synthesis and uptake have been observed in the amygdala, prefrontal cortex and nucleus accumbens. Interestingly, the end-products show a brain region-dependent modulation in Fmr1-Δexon 8 rats. Overall, our results demonstrate that the cholesterol biosynthetic pathway is altered in some brain regions of this preclinical model of FXS. This finding has relevance for future studies to delve deeper into the involvement of this metabolic process in FXS, and thus its possible role as a therapeutic target.

A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells.

17ß-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as "anti-estrogens"-like drugs. Remarkably, the present "anti-estrogen" discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.