BET proteins function as histone code readers of acetylated lysins that determine the positive regulation in transcription of genes involved in cell cycle progression, differentiation, inflammation, and many other pathways. In recent years, thanks to the development of BET inhibitors, interest in this protein family has risen for its relevance in brain development and function. For example, experimental evidence has shown that BET modulation affects neuronal activity and the expression of genes involved in learning and memory. In addition, BET inhibition strongly suppresses molecular pathways related to neuroinflammation. These observations suggest that BET modulation may play a critical role in the onset and during the development of diverse neurodegenerative and neuropsychiatric disorders, such as Alzheimer’s disease, fragile X syndrome, and Rett syndrome. In this review article, we summarize the most recent evidence regarding the involvement of BET proteins in brain physiology and pathology, as well as their pharmacological potential as targets for therapeutic purposes.

Background: Rett syndrome (RTT) is an early-onset neurological disorder primarily affecting females, leading to severe cognitive and physical disabilities. Recent studies indicate that an imbalance of redox homeostasis and exacerbated inflammatory responses are key players in the clinical manifestations of the disease. Emerging evidence highlights that the p75 neurotrophin receptor (p75NTR) is implicated in the regulation of oxidative stress (OS) and inflammation. Thus, this study is aimed at investigating the effects of p75NTR modulation by LM11A-31 on fibroblasts derived from RTT donors. Methods: RTT cells were treated with 0.1 µM of LM11A-31 for 24 h, and results were obtained using qPCR, immunofluorescence, ELISA, and Western blot techniques. Results: Our findings demonstrate that LM11A-31 reduces OS markers in RTT fibroblasts. Specifically, p75NTR modulation by LM11A-31 restores protein glutathionylation and reduces the expression of the pro-oxidant enzyme NOX4. Additionally, LM11A-31 significantly decreases the expression of the pro-inflammatory mediators interleukin-6 and interleukin-8. Additionally, LM11A-31 normalizes the expression levels of transcription factors involved in the regulation of the antioxidant response and inflammation. Conclusions: Collectively, these data suggest that p75NTR modulation may represent an effective therapeutic target to improve redox balance and reduce inflammation in RTT.

Cholesterol is an essential lipid that guarantees several biological processes in eukaryotic cells. Its metabolism is regulated by a complex protein network that could be significantly influenced by numerous exogenous sources, such as essential oils (EOs). For instance, it has been speculated that monoterpenoid and sesquiterpenoid compounds contained in lavender essential oil (LEO) may exert important hypocholesterolemic activities. However, the molecular mechanisms by which LEO influences cholesterol homeostasis are not characterized. In this work, we evaluated the ability of LEO to regulate the protein network that controls cholesterol metabolism in the HepG2 cell line. The main findings indicate that LEO administration increases intracellular cholesterol content. Concurrently, LEO affects the expression of proteins involved in cholesterol uptake, biosynthesis, and trafficking. These effects are partially mediated by terpinene-4-ol, one of the most abundant compounds in LEO. These results demonstrate that LEO modulates cholesterol metabolism in hepatic cells.

Background/Objectives: Parkinson’s disease (PD) is one of the most prevalent neurodegenerative disorders. Despite its multifactorial etiology, PD pathophysiology shared specific features such as cytoplasmic α-synuclein inclusions, oxidative stress, mitochondrial dysfunction, and impaired autophagy. Bromodomain and Extra-Terminal domain (BET) proteins, functioning as epigenetic readers, have recently emerged as promising therapeutic targets due to their regulatory role in redox homeostasis, neuroinflammation, and autophagy. However, their potential involvement in PD pathophysiology remains largely unexplored. Therefore, we aimed at evaluating whether BET modulation could ameliorate the parkinsonian phenotype in two cellular models. Methods: Differentiated SH-SY5Y and N1E-115 neuronal cells were exposed to rotenone toxin to mimic PD phenotype and co-treated with the small BET inhibitor JQ1. Results: BET inhibition significantly counteracted rotenone-induced cell death, neuromorphological alterations, and α-synuclein accumulation. These protective effects were accompanied by restoration of redox balance, as indicated by enhanced activation of the antioxidant system and suppression of the pro-oxidant NADPH oxidase complex. Moreover, JQ1 treatment alleviated mitochondrial dysfunction and corrected autophagy impairments triggered by rotenone. Conclusions: These data highlight a novel role for BET proteins in neurodegeneration, suggesting that their modulation may represent a promising approach to counteract PD neuropathology.

Neurotrophins play pivotal roles in the development and proper functioning of the nervous system. The effects of these growth factors are mediated through the binding of high-affinity receptors, known as Trks, as well as the low-affinity receptor p75NTR. The latter has the capacity to induce complex signal pathways, as it favors both pro-survival and pro-apoptotic cascades depending on the physiopathological condition. Recent findings have indicated that p75NTR expression is increased in post-mortem Parkinson’s disease (PD) brains, and this upregulation is associated with a significant reduction in neuroprotection. Given its double-edged sword nature, p75NTR has recently been identified as a promising therapeutic target to counteract neurodegenerative events. The present study aims to assess the neuroprotective effects of p75NTR modulation in a rotenone-induced neuronal model of PD. To this end, differentiated SH-SY5Y cells were exposed to rotenone to mimic the PD phenotype, and the small molecule LM11A-31 was used to modulate p75NTR activity. The main results revealed that LM11A-31 significantly mitigated the hallmarks of PD, including cell death, neuromorphological aberrations, and α-synuclein accumulation. Pharmacological manipulation of p75NTR also reduced oxidative damage by increasing the expression of transcriptional factors that regulate the antioxidant response and by decreasing the expression of the pro-oxidant NADPH-oxidase modulatory subunits. Furthermore, LM11A-31 hampered cholesterol buildup induced by rotenone, normalizing the expression of proteins involved in cholesterol biosynthesis, uptake and intracellular trafficking. Taken together, these findings suggest that p75NTR modulation may represent a novel approach to counteracting PD abnormalities of redox and cholesterol metabolism.