Cardiovascular and neurodegenerative disorders remain major contributors to global morbidity and mortality, underpinned by overlapping pathogenic processes including chronic inflammation, oxidative stress, endothelial dysfunction, and mitochondrial impairment. Therapeutic strategies capable of simultaneously modulating these interconnected pathways are increasingly recognized as essential for improving clinical outcomes. Curcumin (CUR), a pleiotropic polyphenolic compound derived from Curcuma longa, and statins, widely prescribed lipid-lowering agents, exhibit a broad spectrum of anti-inflammatory, antioxidant, and cytoprotective effects that extend beyond their canonical pharmacological actions. This review critically examines the molecular and pharmacological synergy between CUR and statins, with particular emphasis on their coordinated regulation of key signaling cascades, including NF-κB, iNOS, MAPK, and Nrf2-mediated antioxidant responses. Evidence from in vitro, in vivo, and emerging clinical studies indicates that CUR–statin co-administration may elicit additive or synergistic protective effects across diverse pathological contexts, such as atherosclerosis, myocardial ischemia–reperfusion injury, Alzheimer’s disease, Parkinson’s disease, and spinal cord injury, Myopathy, wound healing, and anti-cancer effects. Unfortunately, the majority of available experiments are preclinical and fewer clinical studies have been performed until now. At the cellular and tissue levels, this combinatorial approach appears to restore vascular homeostasis, preserve mitochondrial function, enhance neuronal survival, and suppress sustained inflammatory signaling. Collectively, the available data underscore a compelling pharmacological rationale for CUR–statin combination therapy as a multitarget intervention for complex cardiometabolic, neurodegenerative diseases, and a wide variety of disorders. Future investigations should focus on optimizing dosing regimens, improving CUR bioavailability, elucidating pharmacokinetic–pharmacodynamic interactions, and validating therapeutic efficacy through well-designed clinical trials.

ABSTRACT:Heart failure (HF) remains a leading cause of global mortality. β3-adrenergic receptors are upregulated in HF, and their activation has demonstrated cardioprotective effects in preclinical studies. This systematic review and meta-analysis evaluated the efficacy and safety of the β3-adrenergic agonist mirabegron in patients with HF. Five randomized controlled trials including 538 participants were analyzed. Mirabegron showed no definitive evidence of improved physical capacity, quality of life, left ventricular ejection fraction (LVEF) (pooled mean difference of change from baseline = +0.51%, 95% CI, -4.56 to 5.57) or NT-proBNP (pooled mean difference of change from baseline = +5.42 pg/mL, 95% CI, -292.15 to 302.98). However, isolated benefits in cardiac index and pulmonary vascular resistance were noted in severe HF. Mirabegron did not demonstrate definitive evidence of safety in patients with HF, with a 4% higher odds of serious adverse events compared with placebo (odds ratio = 1.04, 95% CI, 0.63-1.72) and a 4:0 imbalance in deaths with mirabegron compared with placebo. No statistically significant changes were seen in systolic or diastolic blood pressure, heart rate, QT interval, or urinary adverse events. The GRADE certainty of evidence for LVEF, systolic blood pressure, and urinary adverse events was rated low due to serious imprecision and high risk of publication bias. Mirabegron did not demonstrate definitive evidence of improved physical capacity, quality of life, or cardiac function in HF, although isolated benefits were noted. Mirabegron's safety profile in patients with HF remains uncertain. Larger, long-term trials targeting patients with severe HF are warranted.

Diabetic kidney disease (DKD) is a major complication of diabetes characterized by progressive renal dysfunction driven by oxidative stress and inflammation involving mammalian target of rapamycin (mTOR) and NADPH oxidase (NOX) pathways. Mesenchymal stem cells (MSCs) have gained attention for their regenerative and immunomodulatory properties in attenuating DKD, but the mechanisms behind their protective effects are still being explored. Moreover, concerns regarding tumorigenic risks hinder their direct clinical use. In this study, we compared MSCs and their conditioned media (MSCs-CM; secretome) in a type 1 diabetic rodent model, demonstrating that both treatments attenuated glomerular injury, preserved podocyte integrity, reduced NOX4 expression and activity, and tempered inflammation, by inhibiting mTORC1 and mTORC2 signaling. Importantly, MSCs-CM replicated the renoprotective effects of MSCs, indicating that soluble factors mediate these benefits. To our knowledge, this is the first study to directly compare MSCs and their conditioned media (MSCs-CM) in DKD, revealing that MSCs-CM delivers equivalent therapeutic efficacy while circumventing the safety concerns inherent to cell-based therapies. These findings identify the mTOR/NOX axis as a therapeutic target and support MSCs-CM as a promising, safer, cell-free alternative for DKD treatment, potentially advancing regenerative strategies to mitigate diabetic renal injury. ARTICLE HIGHLIGHTS:Despite advances in diabetes management, diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease. We investigated whether mesenchymal stem cells (MSCs) and their conditioned medium, containing the MSC-derived secretome, protect against DKD by modulating the mammalian target of rapamycin (mTOR)/NADPH oxidase (NOX) pathway. MSCs and MSCs-conditioned medium both reduced kidney injury, podocyte structural integrity, oxidative stress, and inflammation by inhibiting mTORC1/mTORC2 and NOX4. MSCs-conditioned medium offers a safe, secretome-based, cell-free approach for DKD therapy.

ABSTRACT:Cardiovascular diseases remain the leading cause of global morbidity and mortality, highlighting the urgent need for more efficient, precise, and cost-effective drug development strategies. Traditional drug discovery pipelines face persistent challenges, including elevated expenses, prolonged timelines, and high attrition rates, particularly with the complex pathophysiology of cardiovascular conditions. Artificial intelligence (AI) has emerged as a transformative force capable of addressing these barriers across all stages of cardiovascular drug development. This review explores the integration of AI in target identification, compound screening, drug design, pharmacokinetic and toxicity prediction, and clinical trial optimization. We highlight state-of-the-art AI tools such as large language models (eg, BioGPT, Geneformer), generative frameworks (eg, Generative Tensorial Reinforcement Learning, Variational Autoencoders, Generative Adversarial Networks), and neural ordinary differential equations, illustrating their ability to accelerate drug discovery, personalize therapy, and improve clinical success rates. In the context of clinical trials, platforms such as Trial Pathfinder have been used to optimize patient recruitment and improve generalizability. Despite these advancements, several challenges persist, particularly those related to data quality, population representativeness, interpretability, and regulatory oversight. Future directions involving the integration of AI with quantum computing, blockchain technology, and precision medicine offer additional opportunities to advance the field. Collectively, these innovations mark a paradigm shift toward faster, safer, and more personalized cardiovascular drug development.

Background Flavonoids are postulated to modulate the complex pathophysiological mechanisms underlying atrial fibrillation (AF), the most prevalent cardiac arrhythmia driven by an interplay of structural, electrical, and inflammatory processes. Current management strategies for AF primarily involve rhythm control procedures and pharmacological interventions, but emerging evidence suggests that flavonoid intake may offer adjunctive benefits owing to their antioxidant, anti-inflammatory, and anti-arrhythmic properties. Purpose While preclinical studies demonstrate promising effects on atrial remodeling and arrhythmogenesis, clinical data remain limited and heterogeneous. To this end, flavonoids remain underexplored, and their multifactorial actions on cardiac physiology warrant further investigation. Study design : This is a comprehensive review that synthesizes current preclinical and clinical evidence regarding the role of dietary flavonoids in the prevention and management of atrial fibrillation (AF). Methods We systematically surveyed and critically appraised recent literature on the mechanistic actions, efficacy, and safety of flavonoid subclasses in AF, as demonstrated in both experimental models and human studies. Results : Preclinical studies consistently demonstrate that flavonoids exert antioxidant, anti-inflammatory, and anti-arrhythmic effects, attenuating atrial fibrosis, modulating ion channel activity, and reducing arrhythmogenesis in experimental models of atrial fibrillation. However, available clinical data are limited and heterogeneous, with some observational studies suggesting a potential benefit of higher dietary flavonoid intake on AF risk, but robust evidence from randomized controlled trials is lacking. Conclusion clinical evidence remains limited and heterogeneous, underscoring the need for large-scale randomized trials to establish the therapeutic potential of flavonoids in AF.

We have recently demonstrated that 7-O-methylpunctatin (MP), a novel homoisoflavonoid, suppresses inflammation-induced arterial pathogenesis. However, the precise biochemical mechanisms underlying its atheroprotective effects remain elusive. In this study, we employed various in silico studies to elucidate MP’s plausible potential and the specific molecular pathways through which it exerts its influence on atherosclerosis. Our analysis of MP’s pharmacokinetic, physicochemical, and toxicological properties revealed a profile characterized by favorable absorption, efficient metabolism and excretion, and minimal toxicity. Through target identification and protein-protein interaction analyses, we identified ALOX5 as a pivotal hub gene—an enzyme critically involved in the pathogenesis of atherosclerosis. Furthermore, we identified ten transcription factors and four kinases as potential targets. Molecular mechanics/generalized-born surface area calculations, complemented by time-scale molecular dynamics simulations, revealed that MP binds to ALOX5 with high affinity, modulating its structural stability, rigidity, compactness, overall folding pattern, and residual correlations and motions. These findings corroborate previous in vitro and in vivo investigations that underscore the anti-atherosclerotic effects of ALOX5 inhibition, thereby positioning MP as a promising therapeutic candidate for combating atherosclerosis.

ABSTRACT:Severe hypertriglyceridemia (sHTG) is a critical metabolic disorder that substantially elevates the risk of atherosclerotic vascular disease and acute pancreatitis. Despite its clinical significance, many conventional triglyceride-lowering therapies often fail to adequately reduce triglyceride levels or prevent these life-threatening complications. This unmet need has spurred interest in targeting regulatory proteins involved in triglyceride metabolism, such as apolipoprotein C3, a key inhibitor of lipoprotein lipase activity that promotes triglyceride-rich lipoprotein accumulation. Plozasiran, an investigational small interfering RNA therapy, has emerged as a breakthrough in sHTG management by selectively degrading hepatic APOC3 messenger RNA. Indeed, clinical trials demonstrate this drug's robust efficacy in reducing triglyceride levels, concomitant with reduced non-high-density lipoprotein (HDL) cholesterol and apolipoprotein B-key markers of cardiovascular risk. Notably, the Phase III PALISADE trial in familial chylomicronemia syndrome patients revealed plozasiran's potential to mitigate acute pancreatitis risk by normalizing triglyceride levels with a favorable safety profile. Current guidelines emphasize a multimodal approach to sHTG, combining dietary restriction of fats and simple carbohydrates with pharmacotherapy. However, plozasiran's prolonged dosing interval and mechanism-based action position it as a transformative option, particularly for patients refractory to existing treatments. Although long-term cardiovascular outcome data remain pending, its ability to durably modulate APOC3 expression offers new hope for breaking the cycle of dyslipidemia-driven organ damage. As research progresses, this therapy may redefine standards of care for high-risk populations, bridging a critical gap in preventive cardiology and pancreatology.

Objective: Vertical sleeve gastrectomy (VSG) and Roux-en-Y Gastric Bypass (RYGB) are common types of bariatric surgery. In this study, our aim was to identify differentially expressed genes in the duodenal tissue of Rattus norvegicus in a rat model after RYGB compared with VSG. Methods: We obtained the microarray profile of GSE169402 from the GEO database and identified differentially expressed genes by comparing the expression profiles of duodenal tissue genes after RYGB with those after VSG. Protein–protein interactions were analyzed using the STRING online tool. Results: Our analysis revealed that cluster 2, consisting of 20 nodes and 42 edges ( p -value < 1.0e-16), was the most significant cluster. The GO enrichment analysis demonstrated the roles of these genes in the GO Component of Lipid droplet. Moreover, KEGG analysis results discovered that the PPAR signaling pathway had the highest scores. We also explored the associations of these genes with diseases using DisGeNET. Our findings showed that ANGPTL4 , APOC2 , CIDEC , HMGCS2 , INSIG1 , PCK1 , PDK4 , PLIN2 , SERPINE1 , and SREBF1 , after RYGB were showed expression patterns overlapping with known CVD risk genes. On the other hand, upregulated genes such as Klf15 were found to inhibit lipogenesis. Conclusion: Overall, the present study suggests that RYGB is associated with differential expression of CVD-related genes in duodenal tissue, which may contribute to its superior cardiovascular outcomes compared with VSG. These hypothesis-generating findings from rat duodenal tissue require validation in human multitissue studies to confirm translational relevance to cardiovascular health outcomes.

Selective estrogen receptor modulators (SERMs) are nonsteroidal compounds that exert context-dependent agonist or antagonist effects on estrogen receptors through ligand-induced conformational changes that govern coactivator or corepressor recruitment. This biochemical selectivity underlies their tissue-specific pharmacological actions. In the vasculature, SERMs modulate endothelial nitric oxide synthase (eNOS) activity, attenuate vascular smooth muscle cell (VSMC) proliferation, and regulate oxidative stress pathways, while also influencing platelet reactivity through NADPH oxidase–dependent mechanisms. Among the most studied SERMs are Tamoxifen and Raloxifene. Tamoxifen functions as a prodrug, requiring hepatic bioactivation, primarily by CYP2D6 and CYP3A4, to form active metabolites, notably 4-hydroxytamoxifen and endoxifen, with enhanced receptor affinity. In contrast, raloxifene undergoes extensive glucuronidation, resulting in low systemic bioavailability of the active compound. However, the systemic concentrations achieved are sufficient to confer measurable vascular effects. Despite these pharmacokinetic differences, both agents improve lipid and fibrinogen profiles, but also increase venous thromboembolism risk through modulation of coagulation pathways. Clinical trials confirm benefits in oncology and bone health, yet fail to demonstrate consistent reductions in cardiovascular endpoints. The pharmacological profile of SERMs therefore reflects a delicate equilibrium between receptor-mediated vascular protection and thrombotic liability. Indeed, their raison d’être increasingly extends beyond oncology into cardiovascular endocrine pharmacology, where they serve as prototypes for designing next-generation agents with optimized receptor selectivity and safer vascular outcomes.

Statins, traditionally used for managing hypercholesterolemia, have emerged as promising agents for cancer therapy. By targeting the mevalonate pathway—a cornerstone of cellular metabolism and tumorigenesis—statins disrupt critical processes for cancer cell survival and proliferation. Some of these processes include cholesterol biosynthesis, protein prenylation, and post-translational modifications. This review discusses repurposing statins for cancer treatment given their anti-tumoral effects across many cancers, including breast, prostate, colorectal and hepatocellular carcinoma. Despite statins’ ability to induce apoptosis or autophagy, arrest cell cycle, or modulate favorable epigenetic reprogramming, their efficacy is highly context-dependent, influenced by cancer type, molecular subtype and genetic variations. Challenges such as statin resistance, low bioavailability and pharmacokinetic variability further complicate their application in oncology. Nonetheless, emerging strategies, including nanoparticle-based drug delivery systems and combination therapies with chemotherapy, radiotherapy or immunotherapy, appear to help overcome these limitations. Despite encouraging preclinical findings, clinical evidence remains tantalizingly inconsistent. Future research should prioritize identifying biomarkers of statin sensitivity and optimizing nanoformulations to enhance tumor targeting while minimizing toxicity. Ultimately, statins represent an attractive opportunity to expand the anti-tumor armamentarium and highlight innovative treatment paradigms integrating metabolic modulation to precision oncology.

Raynaud's phenomenon (RP) is a vascular disease characterized by exaggerated vasoconstriction in response to stressors, mainly cold and emotional stress. This vasoconstriction is mediated solely by alpha 2C-adrenoceptors (α2C-AR) expressed in vascular smooth muscle cells of dermal arterioles. Several factors, among which is cigarette smoking, are associated with aggravated symptoms of and increased risk for RP. Evidence shows that cigarette smoking induces the production of reactive oxygen species (ROS), which is a major driver of RP pathogenesis. However, the exact mechanism by which smoking contributes to RP or α2C-AR remains unclear. Here, we show that cigarette smoke extract (CSE) upregulates the expression of α2C-AR in a concentration- and time-dependent manner in VSMCs extracted from human dermal arterioles. This increase is associated with the activation of p38 MAPK, as pretreatment with SB-202190, a p38 specific inhibitor, attenuated CSE-induced α2C-AR expression. Furthermore, our results show that CSE induces ROS production followed by increased RhoA activation. We also show that CSE induces translocation of vascular α2C-AR to the plasma membrane, and that this mobilization is attenuated by inhibiting ROS via N-acetylcysteine or apocynin. Similarly, inhibition of Rho kinase via H- 11522 abolished CSE-induced α2C-AR translocation. Collectively, these results indicate that CSE activates two different signaling pathways to induce the expression and the translocation of α2C-AR. While CSE activates a p38-dependent mechanism to increase α2C-AR expression, it initiates the receptor's spatial and functional rescue via a ROS/RhoA signaling pathway. These results provide mechanistic insight into the effect of cigarette smoking on RP, and further reinforce that smoking avoidance/cessation is critical to manage this disease, especially in the absence of a definitive drug for RP.

Familial hypercholesterolemia (FH) is a hereditary disorder with a semidominant inheritance pattern, characterized by elevated levels of low-density lipoprotein cholesterol, which significantly increases the risk of early atherosclerosis-related cardiovascular disease. This review discusses the genetics, epidemiology, diagnosis, and novel therapeutic approaches for FH. Mutations in the LDL receptor gene are the primary cause of FH. Less common causes include mutations in proprotein convertase subtilisin/kexin type 9 and apolipoprotein B-100. In extremely rare cases, LDLR adaptor protein 1 mutations can also cause FH. Epidemiological data indicate that FH is frequently underdiagnosed, particularly within certain ethnic populations. Diagnostic criteria often rely on clinical manifestations and family history, although genetic testing is increasingly advocated for confirmation. Recent advancements in pharmacotherapy offer substantial opportunities for effective low-density lipoprotein cholesterol control and management of FH, providing new hope for affected patients. This includes established drugs such as proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, lomitapide, and bempedoic acid. Emerging therapies include evinacumab, lerodalcibep, antisense oligonucleotide-based drugs, certain cholesteryl ester transfer protein inhibitors like obicetrapib, AZD8233, gemcabene, diacylglycerol O-acyltransferase-2 inhibitors, acyl-CoA:cholesterol acyltransferase-2 inhibitors, vupanorsen, volanesorsen, olezarsen, pelacarsen (TQJ230), olpasiran (AMG890), zerlasiran (SLN360), lepodisiran (LY3819469), and muvalaplin. However, some of these newer agents are specifically designed to lower elevated Lp(a), which often occurs in patients with FH, and triglycerides. Furthermore, gene-editing approaches, such as clustered regularly interspaced short palindromic repeats -Cas9 and meganuclease, as well as vaccines targeting key components of cholesterol metabolism, represent promising future directions for FH treatment. SIGNIFICANCE STATEMENT: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol levels, which increase the risk of atherosclerotic cardiovascular disease. Conventional therapies, such as statins, often have limited efficacy in patients with FH. Recent pharmacological advancements provide significant opportunities for successful low-density lipoprotein cholesterol management and control of FH. Although some of these agents are already used, several highly effective compounds are in development, heralding a promising future for FH treatment.