Background: The heart depends on a continuous and flexible energy supply from fatty acids, glucose, and other substrates. Emerging evidence shows that gut microbiota-derived metabolites—such as trimethylamine-N-oxide (TMAO), short-chain fatty acids (SCFAs), secondary bile acids, indoles, phenylacetylglutamine (PAGln), and branched-chain amino acids—modulate cardiac metabolism and function. Although clinical evidence linking these metabolites to cardiovascular outcomes is expanding, most data remain associative, with limited causal or interventional proof. Methods: A comprehensive narrative review was conducted (PubMed 2010–2025) to integrate preclinical, clinical, and Mendelian randomization studies on microbiota-derived metabolites and cardiovascular disease, complemented by evidence from dietary and interventional trials. Results: Gut-derived metabolites regulate mitochondrial energetics, inflammatory, immune system, and oxidative pathways, and endothelial and platelet activation. Elevated plasma TMAO and PAGln levels are often associated with adverse cardiovascular outcomes, while SCFAs and indole derivatives may related to protective effects. However, findings across cohorts remain heterogeneous, largely due to differences in diet, renal function, and analytical methods. Dietary patterns rich in fiber and plant-based nutrients favor beneficial metabolite profiles, underscoring the nutritional modulation of the gut–heart axis. Conclusions: The diet–microbiota–metabolite axis represents an emerging pathway connecting nutrition to cardiovascular health. Translating this knowledge into prevention and therapy will require large-scale randomized studies and integrated multi-omics approaches. Dietary modulation of microbial metabolism may ultimately become a novel strategy for cardiometabolic protection.

Background: The treatment landscape for Multiple Sclerosis (MS) has increased significantly over the past few decades, thanks to the introduction of disease-modifying therapies (DMTs). Fingolimod, siponimod, ozanimod, and ponesimod belong to the newer generation of oral DMTs categorized as sphingosine 1-phosphate receptor modulators (S1PRMs). Because of their mechanism of action, they may increase the risk of lymphopenia, which could influence the therapeutic management of people with MS. The aim of this study was to describe and compare the reporting frequency of lymphopenia related to four S1PRMs. Methods: Individual case safety reports (ICSRs) were retrieved from the European spontaneous reporting system database (EudraVigilance) from January 1st, 2022, to December 31st, 2023. The reporting odds ratios (RORs) were computed to compare the reporting probability of lymphopenia between a S1PRM versus each other. Results: We retrieved 4017 ICSRs, of which 521 (13%) reported lymphopenia associated with fingolimod (53.3%), siponimod (38.4%), ozanimod (5.4%), and ponesimod (2.1%). The most common reporting source was the healthcare professional (94.2%), and more than half of the ICSRs (62.6%) reported serious lymphopenia. Fingolimod was associated with a lower reporting frequency of lymphopenia compared to siponimod. Both siponimod and fingolimod were associated with a higher reporting frequency of lymphopenia compared to ozanimod; siponimod also had a higher reporting probability in comparison with ponesimod. Conclusions: The most relevant clinical implication of the disproportionality analysis is to increase the awareness of the risk of lymphopenia related to these drugs, thus supporting proactive monitoring and optimizing treatment strategies for people with MS. Clinical trial number: Not applicable.

Background: Omega-3 fatty acids (FAs) are long-chain fatty acids that have shown cardioprotective effects through lipid lowering, anti-inflammatory, and membrane-stabilizing properties. In this study we investigated the molecular mechanism underlying the cardioprotective effects of icosapent ethyl (IPE), an ethyl ester of omega-3 fatty (EPA), focusing on its role on mechano-transduction, a process linking cardiac contractility to intracellular signaling, that becomes dysregulated in hyperglycaemia or disturbed blood flow, both major contributors to cardiovascular diseases. Methods: We conducted in vivo meta-analyses to assess the beneficial effects of omega-3 fatty acids on cardiac contractility and inflammation in patients with cardiovascular and cardiometabolic diseases. We investigated the effects of IPE on mechano-transduction, assessing the activation of the YAP/TAZ signalling pathway, in cardiomyocyte cells AC16 exposed to normal (NG) or high glucose (HG) conditions. We defined the role of IPE against hyperglycaemia-induced inflammation, oxidative stress, metabolism, and apoptosis by evaluating key biomarkers by Western Blot and Real-time PCR. We evaluated IPE’s impact on YAP/TAZ activation and on gene expression and protein levels of primary markers related to oxidative stress, inflammation, and metabolism in a dynamic flow model of AC16 cardiomyocytes, to mimic in vivo shear stress. Results: In vivo meta-analyses showed a significant increase of left ventricular ejection fraction (LVEF%) (mean: 0.5, 95% CI: 0.1–0.9) and a significant reduction of inflammatory markers (mean: − 1.24, 95% CI: 2.05–0.44) in patients treated with omega-3 . IPE treatment reduced the activation of YAP/TAZ pathway induced by HG exposure in AC16 cells. IPE partially reversed HG-induced changes in markers of inflammation, oxidative stress, metabolism and apoptosis ( p < 0.05). Similarly, in a dynamic model of shear stress, IPE treatment mitigated the turbulent flow-mediated changes in YAP/TAZ pathway, inflammation, oxidative stress and metabolism. Conclusions: Our results demonstrate a cardioprotective role of IPE through modulation of hyperglycaemia-induced mechano-transduction dysregulation, inflammation, and oxidative stress. Additionally, our results on a shear stress model showing that IPE restores upstream regulators of YAP/TAZ and reduces disturbed flow-induced activation of pro-inflammatory pathways, suggest that IPE may exert a therapeutic effect on cardiovascular disorders associated with disturbed blood flow and hemodynamic stress. Graphical

Fentanyl is associated with significant respiratory, cardiovascular, and neurological adverse events (AEs). This study aimed to describe the safety of fentanyl administered through different routes of administration, with a focus on brain lesions. Safety data related to fentanyl were extracted from the EudraVigilance database up to March 7, 2024. Descriptive and disproportionality analyses were performed. A total of 6,441 cases were classifiable for the administration route. The transdermal route (80.9%) was the most reported route. Most cases were from adults and females. Overall, 92.8% of AEs were serious. The intravenous route had a higher disproportionate reporting of “nervous system disorders” than transdermal (ROR 1.31; [95% CI, 1.12–1.41]) and oral transmucosal (1.30; [1.12–1.49]). Among central nervous system disorders, 50 brain lesions were identified, with no statistically significant difference observed. Nasal administration had a higher reporting frequency of “central nervous system vascular disorders” compared to transdermal (2.45; [1.14–5.24]), intravenous (2.53; [1.09–5.87]), and oral transmucosal routes (4.89; [1.54–15.51]). On the other hand, the intravenous had a higher disproportionate reporting of “seizures” compared to nasal (3.19; [1.17–8.69]), oral transmucosal (2.09; [1.31–3.32]), and transdermal routes (2.41; [1.96–2.96]). The study provides a comprehensive safety profile of fentanyl across different administration routes, highlighting a higher disproportionate reporting of central neurologic and cardiovascular AEs with nasal and intravenous routes.

Background/Objectives: Dietary patterns characterized by excess saturated fat intake contribute to obesity, type 2 diabetes, and cardiac metabolic dysfunction. Ceramides, bioactive sphingolipids synthesized in response to nutrient overload, have emerged as key molecular mediators linking dietary lipid composition to alterations in cardiac metabolic signaling. This review aims to integrate current evidence on diet-induced ceramide remodeling and its impact on intracellular pathways regulating cardiac metabolism. Methods: We analyzed experimental and clinical studies investigating the effects of high-fat and Western-type diets on myocardial ceramide synthesis, lipidomic remodeling, and downstream signaling pathways. Evidence from animal models, genetic and pharmacological interventions, nutritional studies, and circulating biomarker analyses was examined to delineate mechanistic and translational insights. Results: Saturated fatty acid excess, particularly palmitate, activates the de novo ceramide synthesis pathway in the myocardium, promoting accumulation of specific ceramide species. This remodeling impairs insulin signaling through Akt inhibition, protein phosphatase 2A activation, and PKCζ-dependent mechanisms, contributing to cardiac metabolic inflexibility. Ceramides further disrupt mitochondrial function by altering electron transport chain activity, increasing reactive oxygen species production, and modulating mitophagy and apoptotic signaling. Lipidomic studies highlight species-specific effects, with C16-ceramides frequently associated with adverse metabolic and cardiovascular outcomes, whereas very-long-chain ceramides may exert distinct functional roles. Circulating ceramide profiles have also been linked to diet-associated cardiovascular risk. Conclusions: Diet-induced ceramide remodeling represents a central molecular axis connecting dietary lipid excess to altered cardiac metabolic signaling. Targeting sphingolipid metabolism through nutritional or pharmacological strategies may offer novel opportunities for preventing and managing diet-associated cardiac dysfunction.

Background: Teriparatide is approved for the treatment of osteoporosis and is generally well-tolerated. However, concerns remain about a possible association with osteosarcoma, a rare but aggressive bone malignancy. This pharmacovigilance study aims to evaluate the reporting frequency of osteosarcoma associated with teriparatide in the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Individual case safety reports (ICSRs) listing teriparatide as a suspected drug and osteosarcoma as an adverse event were extracted from the FAERS public dashboard up to 20 February 2025. Both descriptive and disproportionality analyses were performed. Results: A total of 112,798 ICSRs involving teriparatide were retrieved, of which 29 were reported. Most cases involved female patients (72.4%) and older patients (48.3%). Almost all reports (96.6%) were classified as serious, with death being the most common outcome (44.8%). Of the reports with information on concomitant medications, 31% included five or more medications, with vitamins being the most common. The disproportionality analysis showed a significantly higher reporting frequency of osteosarcoma with teriparatide compared to all other drugs (reporting odds ratio, ROR: 15.31; 95% CI: 10.53–22.26). This signal remained consistent when the analysis was restricted to reports submitted since 2006 (ROR: 15.88; 95% CI: 10.92–23.09). The information component (IC) analysis confirmed this finding (IC: 3.56; 95% CI: 2.95–4), and similar results were observed for the post-2006 subset (IC: 3.60; 95% CI: 2.99–4.05). However, the analysis compared to another osteoporosis drug (romosozumab) did not confirm any safety signal for teriparatide. Conclusions: This study highlights a disproportionate signal between teriparatide use and osteosarcoma when compared to all other drugs but not compared to romosozumab. Based on this and considering that previous evidence did not support an increased risk, further research is warranted to better understand this association.