Mitochondrial dysfunction is a hallmark of Parkinson’s disease (PD) pathogenesis, contributing to increased oxidative stress and impaired endo-lysosomal-proteasome system efficiency underlying neuronal injury. Genetic studies have identified 19 monogenic mutations—accounting for ~10% of PD cases—that affect mitochondrial function and are associated with early- or late-onset PD. Early-onset forms typically involve genes encoding proteins essential for mitochondrial quality control, including mitophagy and structural maintenance, while late-onset mutations impair mitochondrial dynamics, bioenergetics, and trafficking. Atypical juvenile genetic syndromes also exhibit mitochondrial abnormalities. In idiopathic PD, environmental neurotoxins such as pesticides and MPTP act as mitochondrial inhibitors, disrupting complex I activity and increasing reactive oxygen species. These converging pathways underscore mitochondria as a central node in PD pathology. This review explores the overlapping and distinct mitochondrial mechanisms in genetic and non-genetic PD, emphasizing their role in neuronal vulnerability. Targeting mitochondrial dysfunction finally offers a promising therapeutic avenue to slow or modify disease progression by intervening at a key point of neurodegenerative convergence.

Pancreatic islet transplantation is a therapeutic option for achieving physiologic regulation of plasma glucose in Type 1 diabetic patients. At the same time, mesenchymal stem cells (MSCs) have demonstrated their potential in controlling graft rejection, the most fearsome complication in organ/tissue transplantation. MSCs can interact with innate and adaptive immune system cells either through direct cell-cell contact or through their secretome including exosomes. In this review, we discuss current findings regarding the graft microenvironment of pancreatic islet recipient patients and the crucial role of MSCs operation as cell managers able to control the immune system to prevent rejection and promote endogenous repair. We also discuss how challenging stressors, such as oxidative stress and impaired vasculogenesis, may jeopardize graft outcomes. In order to face these adverse conditions, we consider either hypoxia-exposure preconditioning of MSCs or human stem cells with angiogenic potential in organoids to overcome islets’ lack of vasculature. Along with the shepherding of carbon nanotubes-loaded MSCs to the transplantation site by a magnetic field, these studies look forward to exploiting MSCs stemness and their immunomodulatory properties in pancreatic islet transplantation.

The retina is an oxidative stress-prone tissue due to high content of polyunsaturated lipids, exposure to visible light stimuli in the 400–480 nm range, and high oxygen availability provided by choroidal capillaries to support oxidative metabolism. Indeed, lipids’ peroxidation and their conversion into reactive species promoting inflammation have been reported and connected to retinal degenerations. Here, we review recent evidence showing how retinal polyunsaturated lipids, in addition to oxidative stress and damage, may counteract the inflammatory response triggered by blue light-activated carotenoid derivatives, enabling long-term retina operation despite its prooxidant environment. These two aspects of retinal polyunsaturated lipids require tight control over their synthesis to avoid overcoming their protective actions by an increase in lipid peroxidation due to oxidative stress. We review emerging evidence on different transcriptional control mechanisms operating in retinal cells to modulate polyunsaturated lipid synthesis over the life span, from the immature to the ageing retina. Finally, we discuss the antioxidant role of food nutrients such as xanthophylls and carotenoids that have been shown to empower retinal cells’ antioxidant responses and counteract the adverse impact of prooxidant stimuli on sight.

Antipsychotic medications are a vast class of drugs used for the treatment of psychotic disorders such as schizophrenia. Although numerous compounds have been developed since their introduction in the 1950s, several patients do not adequately respond to current treatments, or they develop adverse reactions that cause treatment discontinuation. Moreover, in the past few decades, discoveries in the pathophysiology of psychotic disorders have opened the way for experimenting with novel compounds that have alternative mechanisms of action, with some of them showing promising results in early trials. The scope of this review was to summarize the novel antipsychotics developed, their current experimental status, and their mechanisms of action. In particular, we analyzed the main classes of investigational antipsychotics, such as monoamine, glutamate, acetylcholine, cannabinoid receptor modulators, enzyme inhibitors, ion channel modulators, and mixed receptor modulators. In addition, the safety profiles and adverse effects of these drugs were carefully evaluated, considering the relevance of these aspects for patients’ drug adherence and quality of life, especially in the long-term treatment. Lastly, we tried to understand which compounds have greater potential to be approved by the principal drug regulatory agencies in the next years and if they could be used for diseases other than psychotic disorders.

Therapeutic drug monitoring (TDM) is an effective tool used to improve the pharmacological treatment in clinical practice, especially to detect subtherapeutic drug plasma concentration (Cp) in order to consider a change of dosage during treatment and reach its putative therapeutic range. In this study, we report the Cp values of lithium and valproic acid (VPA), alone and in combination, mostly in bipolar patients admitted to an Italian clinical center of the University of Pisa during the years 2016–2020, which include 12,294 samples of VPA, 7449 of lithium and 1118 of both in combination. Lithium and VPA are the most utilized drugs in treating bipolar disorders, and their TDM is strongly recommended by recent guidelines. In relation to lithium Cp monitoring, several studies have underlined that 0.5–0.8 mmol/L is the optimal range for chronic treatment, and below 0.4 mmol/L, it is unlikely to produce a clinical response. For VPA, the therapeutic range is 50–100 μg/mL and a linear correlation between Cp and clinical efficacy has been proposed, where below 50 μg/mL, the clinical efficacy of VPA has not been proven thus far. Toxic levels of both drugs were rarely found in our study, while a high percentage of patients, about one-third, had sub-therapeutic Cp during their treatments. In addition, in several cases of patients receiving multiple blood sampling, the initial subtherapeutic Cp changed only partially without reaching its therapeutic window. In relation to age, we found a higher percentage of lithium and VPA Cp values in range in the adolescents than in the adults and elderly groups. No differences were reported when analyzing the distribution of Cp values in males and females. In conclusion, this present study suggests that TDM is widely used by many specialists, but there is still a window of improvement for optimizing pharmacological treatments in clinical practice.

Vision starts in retinal photoreceptors when specialized proteins (opsins) sense photons via their covalently bonded vitamin A derivative 11cis retinaldehyde (11cis-RAL). The reaction of non-enzymatic aldehydes with amino groups lacks specificity, and the reaction products may trigger cell damage. However, the reduced synthesis of 11cis-RAL results in photoreceptor demise and suggests the need for careful control over 11cis-RAL handling by retinal cells. This perspective focuses on retinoid(s) synthesis, their control in the adult retina, and their role during retina development. It also explores the potential importance of 9cis vitamin A derivatives in regulating retinoid synthesis and their impact on photoreceptor development and survival. Additionally, recent advancements suggesting the pivotal nature of retinoid synthesis regulation for cone cell viability are discussed.