Publications

BACKGROUND: Statin therapy has been associated with increased risk of type 2 diabetes (T2D). We investigated the relationship between Low-Density Lipoprotein Cholesterol (LDL-C) plasma concentrations and incident T2D and evaluated the modifying effect of statin therapy in a large population-based cohort.

METHODS: Individuals free of T2D and cardiovascular disease at baseline were followed longitudinally for the development of new-onset T2D. Cox proportional hazards models were applied to evaluate the associations of LDL-C levels and statin therapy with T2D risk.

RESULTS: From a population of 202,545 individuals, we selected 13,674 participants free of T2D and cardiovascular disease (of whom 52% were on statins), who were followed for a median of 71.6 months (IQR 34.5-149.9), during which 1,819 (13%) developed incident T2D. Cox multiple regression analysis revealed a significant inverse association between LDL-C plasma levels and incident T2D (p < 0.001). When stratifying LDL-C into quartiles [i.e. low (< 84 mg/dL), medium (≥ 84 to < 107 mg/dL), high (≥ 107 to < 131 mg/dL), and very high (≥ 131 mg/dL)], we observed that patients with LDL-C < 84 mg/dL had the highest risk of developing T2D. The interaction between statin therapy and T2D incidence was significant only in the very high LDL-C group, where statin users had a greater risk than non-users (p = 0.018); in the other three LDL-C groups, statin therapy did not significantly modify the association between LDL-C and T2D risk.

CONCLUSIONS: Taken together, our findings demonstrate a strong inverse association between LDL-C and incident T2D in the general population. The increased risk of T2D at lower LDL-C levels appears to be independent of statin use, supporting the role of LDL-C as a potential biomarker of T2D susceptibility.

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by diastolic dysfunction, systemic comorbidities, and chronic low-grade inflammation. Emerging evidence suggests that immune dysregulation plays a central role in its pathophysiology. Both innate and adaptive immune responses contribute to myocardial remodeling, endothelial dysfunction, and comorbidity-driven inflammation that are hallmarks of HFpEF.

AREAS COVERED: We summarize current evidence on the contribution of immunological pathways to HFpEF, including the role of proinflammatory cytokines, immune cell infiltration (particularly macrophages, mast cells, and T cells), and immune - endothelial interactions. We also highlight findings from experimental models linking systemic metabolic inflammation to myocardial fibrosis, coronary microvascular dysfunction, and cardiomyocyte stiffness in HFpEF. Finally, we explore potential immunomodulatory therapeutic approaches currently under investigation and discuss biomarkers of immune activation with potential clinical relevance.

EXPERT OPINION: While no immunologically targeted therapy is yet approved for HFpEF, interventions that modulate inflammation - such as IL-1 blockade, mast cell stabilization, or myeloid-targeted therapies - offer promise. Future clinical trials should incorporate immune profiling to enable patient stratification and personalized treatment approaches. A deeper understanding of immune-mediated mechanisms in HFpEF will be essential to advance therapeutic innovation and improve outcomes in this challenging and growing patient population.

β-hydroxybutyrate (BHB), the predominant ketone body in human circulation, is synthesized in liver mitochondria and rises markedly during fasting, caloric restriction, ketogenic diets, and high-intensity exercise. Once considered a mere metabolic intermediate, BHB is now recognized as a potent signaling molecule that links nutrient status to gene regulation, inflammation, and cellular stress responses. In fact, beyond serving as an energy substrate, BHB functions as a versatile signaling metabolite that integrates environmental cues to epigenetic regulation, gene expression, and cellular physiology. Accumulating evidence highlights its protective and disease-modifying effects, positioning BHB as a promising therapeutic candidate for diverse conditions associated with energy deficits or metabolic imbalances. Nevertheless, the precise mechanisms underlying these benefits remain incompletely defined. This review discusses recently identified molecular pathways regulated by BHB, with a focus on its roles in cellular signaling, inflammation, transcriptional control, and post-translational protein modifications. For the first time, we also explore the translational relevance of BHB in endocrine pancreas biology, drawing mechanistic parallels with the nervous system. Although neurons and β-cells share remarkable functional similarities, the impact of BHB on β-cell survival and function remains unexplored. Clarifying these effects may uncover new strategies to harness ketosis for the treatment of diabetes.

Chronic limb-threatening ischemia (CLTI), the advanced stage of peripheral artery disease (PAD), remains a leading cause of morbidity and limb loss. Effective vascular regeneration strategies will require increased understanding of molecular mechanisms underlying angiogenesis. Recent evidence revealed a new role for the vascular smooth muscle cell-enriched (VSMC-enriched) long noncoding RNA (lncRNA) CARMN in endothelial angiogenesis and postischemic vascular repair. CARMN was downregulated in both human CLTI muscle tissue and murine ischemia models. In VSMCs, CARMN deficiency suppressed a specific miRNA-mediated paracrine signaling axis that regulates Hedgehog signaling. In mice, deleting CARMN caused impariment in capillary growth and blood flow recovery after limb ischemia, an effect that was reversed by restoring miR-143-3p or silencing the Hedgehog inhibitor HHIP. The identification of lncRNA-mediated crosstalk between VSMCs and endothelial cells in PAD pathophysiology reveals possible therapeutic targets for CLTI and underscores the translational potential of RNA-based strategies in ischemic vascular disease.

Chaperone-mediated autophagy (CMA) declines in ageing and neurodegenerative diseases. Loss of CMA in neurons leads to neurodegeneration and behavioural changes in mice but the role of CMA in neuronal physiology is largely unknown. Here we show that CMA deficiency causes neuronal hyperactivity, increased seizure susceptibility and disrupted calcium homeostasis. Pre-synaptic neurotransmitter release and NMDA receptor-mediated transmission were enhanced in CMA-deficient females, whereas males exhibited elevated post-synaptic AMPA-receptor activity. Comparative quantitative proteomics revealed sexual dimorphism in the synaptic proteins degraded by CMA, with preferential remodelling of the pre-synaptic proteome in females and the post-synaptic proteome in males. We demonstrate that genetic or pharmacological CMA activation in old mice and an Alzheimer's disease mouse model restores synaptic protein levels, reduces neuronal hyperexcitability and seizure susceptibility, and normalizes neurotransmission. Our findings unveil a role for CMA in regulating neuronal excitability and highlight this pathway as a potential target for mitigating age-related neuronal decline.

BACKGROUND: Recent evidence suggests that inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a key enzyme in cholesterol biosynthesis, has beneficial effects on lipid metabolism and blood pressure (BP), but detrimental consequences on glycemia. Nutraceuticals (NUTs) containing both Monacolin K (MK) and Morus alba have been shown to be more effective in lowering lipids compared to NUT formulations containing only MK. However, the effects of these NUTs on glucose homeostasis have not been fully determined.

METHODS: To evaluate the association between LDL-C-lowering therapy and glycemia in patients receiving NUT combinations with or without Morus alba, we analyzed data from a prospective, randomized, active-treatment controlled trial (NCT02898805), which enrolled 359 patients to compare the effects of a NUT combination containing MK alone (Formulation 1, F1; n = 170) versus one containing MK and Morus alba (Formulation 1, F2; n = 189).

RESULTS: Participants in the two treatment arms (F1 vs. F2) were comparable in terms of sex, age, metabolic parameters, and BP. After 3 months, both groups experienced significant reductions in LDL-C, fasting plasma glucose, HbA1c, and HOMA index. F2 treatment led to a significantly greater reduction in glycemic levels compared to F1 treatment (b = - 16, p < 0.001). Notably, a divergent trend emerged over time: an inverse relationship between LDL-C and glycemic levels was observed in the F1 group, while a significant direct association between LDL-C and glycemic levels was detected in the F2 group (b = 0.06, p = 0.002).

CONCLUSIONS: Taken together, our findings indicate that the treatment with a NUT combination containing Morus alba simultaneously reduces plasma levels of LDL-C and glucose.