Endometriosis is a chronic, estrogen-dependent inflammatory disorder that is increasingly recognized as a systemic condition with profound implications for female reproductive potential. In addition to pelvic distortion and impaired folliculogenesis, growing evidence indicates that intrinsic alterations in oocyte morphology, mitochondrial function, and developmental competence contribute to infertility. The disease is driven by a multifactorial interplay of somatic mutations, epigenetic remodeling, immune dysregulation, and aberrant steroid signaling, which together create a pro-inflammatory, oxidative, and fibrotic microenvironment. Elevated cytokines, reactive oxygen species, and disrupted granulosa-cell function within the follicular niche impair meiotic progression, cytoplasmic maturation, and mitochondrial integrity, potentially accelerating oocyte aging and diminishing reproductive longevity. Epigenetic and post-transcriptional disturbances—including altered DNA methylation, histone modifications, and RNA-splicing defects—further reinforce estrogen dominance, progesterone resistance, and impaired decidualization, with downstream consequences for ovarian–endometrial communication. Although morphological abnormalities have been documented in oocytes from women with endometriosis, clinical outcomes remain heterogeneous, highlighting the need for integrative models that connect molecular alterations to functional reproductive endpoints. A deeper understanding of these mechanisms is essential for identifying biomarkers of oocyte competence and modifiable strategies—ranging from nutritional optimization to reduction of environmental risk factors—in clinical care to safeguard the reproductive potential of women with endometriosis.

Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the deficiency of the UBE3A gene that for a E3 ligase protein part of the ubiquitin–proteasome system (UPS). Autophagy and UPS systems remove abnormal proteins, but any dysfunction in these processes can affect neuronal development and wellbeing. Herein, the involvement of the UPS/autophagy system in the regulation of intracellular signaling pathways related to toxic protein accumulation was investigated in cellular/mice AS models, silenced for UB3A (UB3A⁻). The main findings are as follows: (i) autophagy was upregulated in UBE3A⁻ cells with respect to control cells; (ii) a dysregulation of the AKT/mTOR pathway, linked to autophagy/synaptic development, was evidenced in cellular/animal models of AS with respect to controls; (iii) the ubiquitin ligase MDM2 was downregulated, and the tumor suppressor p53, normally inhibited by MDM2, enhanced its expression and transcriptional activity in UB3A⁻ cells with respect to controls. Finally, UB3A⁻ cells presented a significant alteration in the levels of β-amyloids with respect to control cells, and a reduction of α-synuclein levels, typical of neurodevelopmental disorder. Nevertheless, UB3A⁻ cells do not show evident morphological abnormalities. Overall, these data suggest that AS models presented an altered signaling pathway related to autophagy/UPS systems, potentially leading to the accumulation of toxic proteins affecting synaptic development.

Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the deficiency of the UBE3A gene that for a E3 ligase protein part of the ubiquitin-proteasome system (UPS). Autophagy and UPS systems remove abnormal proteins, but any dysfunction in these processes can affect neuronal development and wellbeing. Herein, the involvement of the UPS/autophagy system in the regulation of intracellular signaling pathways related to toxic protein accumulation was investigated in cellular and mice AS models, silenced for UB3A (UB3A-). The main findings are as follows: i)autophagy markers were upregulated in UBE3A- cells respect to control cells; ii)a dysregulation of AKT/mTOR pathway, which is linked to autophagy/synaptic development, was evidenced in cellular and animal models of AS with respect to controls; iii) the ubiquitin ligase MDM2 was downregulated, and the tumor suppressor p53, normally inhibited by MDM2, enhanced its expression and transcriptional activity in UB3A-cells with respect to controls. Finally, UB3A-cells presented a significant alteration in the levels of β-amyloids with respect to control cells, and a reduction of α-synuclein levels, typical of neurodevelopmental disorder. Overall, these data suggest that AS models presented altered signaling pathway related to autophagy/UPS systems, potentially leading to the accumulation of toxic proteins that impact synaptic development.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of maternal UBE3A expression, leading to disrupted proteostasis and synaptic dysfunction. Adenosine is a ubiquitous neuromodulator whose G protein-coupled receptors (ARs) regulate neuronal differentiation and neurite outgrowth during development. Here, we investigated AR signaling and their influence on survival–autophagy balance and neuronal morphology in an AS cellular model. Using SH-SY5Y cells with silenced UBE3A, we found that UBE3A loss markedly decreased A1AR, A2BAR, and A3AR protein levels while significantly increasing A2AR expression. Ligand affinity was preserved across genotypes, but A1AR and A2AAR desensitization kinetics were significantly slower in UBE3A-deficient cells. These effects were associated with reduced recruitment of G protein-coupled receptor kinase 2 (GRK2) to the plasma membrane and decreased GRK2–AR association in UBE3A-deficient cells, suggesting a possible contribution of altered GRK2 dynamics to prolonged AR signaling. Functionally, A1AR and A2AR agonists preferentially promoted survival of UBE3A-deficient cells and modulated the MDM2–p53 axis and autophagy markers; A1R stimulation also increased neurite density in UBE3A-deficient cells. Together, these results identify AR-level alterations and defective desensitization machinery in AS neuronal cells and link receptor changes to downstream proteostasis and morphological phenotypes relevant to AS pathophysiology.

Adenosine is a ubiquitous molecule distributed in all eukaryotic cells of the human body. The function of adenosine varies depending on the cell type and receptor subtypes involved. For instance, adenosine 2A and 2B receptors couple with stimulatory G proteins, leading to increased intracellular cyclic adenosine 3’,5’-monophosphate (cAMP) levels upon activation. In contrast, adenosine 1 and 3 receptors couple with inhibitory G proteins, resulting in decreased intracellular cAMP levels. Consequently, an imbalance of adenosine receptor expression can affect several biological pathways and mechanisms. In the brain, where adenosine plays an important role, dysregulation of adenosine receptors has been linked to several neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, epilepsy, and Huntington’s disease. Adenosine also modulates cardiovascular function, influencing vasodilatation, blood pressure regulation, heart rate, and platelet activity. In addition, growing evidence highlights the impact of adenosine receptors on decision-making, habits, and goal-directed behaviors, linking them to stress-induced mood depression and other psychiatric disorders. Given the importance of adenosine modulation on human health, studying nutraceuticals and natural substances that influence adenosine could provide valuable insights. Considering the extensive physiological roles of adenosine, this review aims to summarize the diverse functions of adenosine receptors across various human tissues, emphasizing their connection to various diseases and the potential influence of external factors on their expression and functionality.