Federica Barbagallo, Maria Rita Assenza, Antonino Messina. Clin Psychopharmacol Neurosci 2025;23:15-31. https://doi.org/10.9758/cpn.24.1229

Smoking habits (from classic cigarettes to e-cigarettes and heated tobacco) are a relatively common finding in the medical histories of couples referred to fertility centers. Tobacco smoke and e-cigarettes may deliver many substances with known harmful effects on both general and reproductive health, including nicotine. Nicotinic Acetylcholine receptors (nAChRs) form a heterogeneous family of ion channels that are differently expressed in different tissues. According to the homomeric or heteromeric combination of at least five different subunits (named from α to ε), they have peculiar pharmacological and biophysical properties. nAChRs respond to the neurotransmitter acetylcholine, which influences a number of physiological functions not restricted to neurons and plays an important role in the structure and function of non-neuronal tissues such as the testis. nAChRs are also the target of Nicotine, the active element responsible for tobacco addiction. This review summarizes recent findings on the involvement of nAChRs in testicular physiology, highlighting the effects of nicotine exposure observed in animal studies and clinical settings. We will discuss the latest data on fertility outcomes and the implications for understanding nAChR functions in reproductive health.

Intracellular calcium (Ca²⁺) is the central regulator of heart contractility. Indeed, it couples the electrical signal, which pervades the myocardium, with cardiomyocytes contraction. Moreover, alterations in calcium management are the main factors contributing to the mechanical and electrical dysfunction observed in failing hearts. So, simultaneous analysis of the contractile function and intracellular Ca²⁺ is indispensable to evaluate cardiomyocytes activity. Intracellular Ca²⁺ variations and fraction shortening are commonly studied with fluorescent Ca²⁺ indicator dyes associated with microscopy techniques. However, tracking and dealing with multiple files manually is time-consuming and error-prone and often requires expensive apparatus and software. Here, we announce a new, user-friendly image processing and analysis tool, based on ImageJ-Fiji/MATLAB^® software, to evaluate the major cardiomyocyte functional parameters. We succeeded in analyzing fractional cell shortening, Ca²⁺ transient amplitude, and the kinematics/dynamics parameters of mouse isolated adult cardiomyocytes. The proposed method can be applied to evaluate changes in the Ca²⁺ cycle and contractile behavior in genetically or pharmacologically induced disease models, in drug screening and other common applications to assess mammalian cardiomyocyte functions.

Phosphodiesterases are key regulators that fine tune the intracellular levels of cyclic nucleotides, given their ability to hydrolyze cAMP and cGMP. They are critical regulators of cAMP/cGMP-mediated signaling pathways, modulating their downstream biological effects such as gene expression, cell proliferation, cell-cycle regulation but also inflammation and metabolic function. Recently, mutations in PDE genes have been identified and linked to human genetic diseases and PDEs have been demonstrated to play a potential role in predisposition to several tumors, especially in cAMP-sensitive tissues. This review summarizes the current knowledge and most relevant findings regarding the expression and regulation of PDE families in the testis focusing on PDEs role in testicular cancer development.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that accumulate in cancer and represent one of the major drivers of tumor-associated immunosuppression. MDSCs actively contribute to tumor progression by inhibiting both innate and adaptive immune responses, promoting angiogenesis, metastatic dissemination, and resistance to immunotherapy. Two major subsets have been identified, polymorphonuclear (PMN-) and monocytic (Mo-) MDSCs, each characterized by distinct phenotypic, metabolic, and suppressive properties. Within the tumor microenvironment (TME), MDSCs establish a complex network of interactions with T-, B-, NK-cells, dendritic cells, and macrophages, thereby orchestrating immune escape and tumor persistence. Recent evidence highlights the pivotal role of metabolic rewiring in regulating MDSC survival and suppressive activity. Enhanced aerobic glycolysis, fatty acid oxidation, amino acid depletion, reactive oxygen species (ROS) production, and adenosine metabolism collectively sustain MDSC-mediated immune dysfunction and shape the immunosuppressive TME. In particular, the crosstalk between PMN-MDSCs and NK cells has emerged as a critical mechanism of tumor immune evasion, leading to impaired NK cell cytotoxicity, altered activating receptor expression, and defective cytokine production. In this review, we summarize the current knowledge on the phenotypic and functional heterogeneity of MDSCs, their metabolic adaptations, and their interactions with immune effector populations in cancer. Furthermore, we discuss emerging therapeutic strategies aimed at targeting MDSC recruitment, differentiation, metabolic pathways, and suppressive functions. Understanding the molecular and metabolic mechanisms governing MDSC biology may provide novel opportunities to overcome tumor-induced immunosuppression and improve the efficacy of current cancer immunotherapies.

Phosphodiesterases (PDEs) are a huge superfamily of enzymes that fine-tune the intracellular levels of cyclic nucleotides —cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)—thus playing a pivotal role in the control of many cellular processes. While traditionally studied in the context of cardiovascular and neurological systems, mounting evidences highlight a crucial involvement of PDEs in metabolic homeostasis. This review explores the expanding landscape of PDEs function beyond classical cyclic nucleotide degradation, focusing on their roles in glucose and lipid metabolism and their implications in metabolic disorders, including obesity, type 2 diabetes (T2DM), and metabolic syndrome (MetS). Starting from an overview of the PDE superfamily, this work deeply examines the compartmentalized actions of cAMP-dependent protein kinase A (PKA) and cGMP-dependent protein kinase G (PKG) signaling pathways in key metabolically active tissues integrating PDE activities across different organs and disease states to offer a holistic view of their metabolic relevance. Special attention is given to the therapeutic relevance of PDE inhibitors (PDEi), distinguishing between established applications and emerging strategies targeting specific PDE isoforms in metabolic disease contexts to underscore the evolving concept that PDEs act as dynamic regulators of metabolic signaling networks. Understanding their isoform-specific and tissue-specific actions could thus open new avenues for therapeutic intervention in complex metabolic disorders.