Search Results (1,077)

Background/Objectives: We conducted the first pharmacogenetic investigation of atopic dermatitis in a cohort of 43 Greek patients, focusing on key variants within the IL6/JAK/STAT signaling axis, a pathway central to inflammation and therapeutic targeting. Methods: Patients receiving dupilumab, JAK inhibitors, or topical corticosteroids were prospectively evaluated, with treatment response assessed by changes in the Eczema Area and Severity Index over four months. Targeted genotyping of IL6R rs2228145 A>C, JAK1 rs2780815 T>G, and TRAF3 rs12147254 G>A were performed using PCR-RFLP. Results: Across the full cohort, no robust pharmacogenetic effects were detected, while baseline disease severity was the strongest predictor of absolute clinical improvement. However, stratified analyses revealed a significant association between the IL6R rs2228145 minor allele and reduced upadacitinib response (p-value = 0.026). Consistently, the same variant demonstrated a nominal association with reduced likelihood of achieving ≥75% improvement (p = 0.065). Conclusions: Although limited by sample size, these findings suggest potential treatment-specific pharmacogenetic effects within the IL6 pathway, supporting further investigation in larger cohorts to inform personalized therapeutic strategies in eczema. Full article

Heat waves have intensified since the 1960s, leaving older adults uniquely susceptible to heat-related illnesses, including hyperthermia and fluid-electrolyte imbalances. While clinicians recognize that certain medications increase heat vulnerability, the specific interplay between drug use and patient characteristics remains unclear. This scoping review, following the Joanna Briggs Institute framework for scoping reviews and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines, investigated the risk of heat-related illness associated with medication use in older adults to identify research gaps. Investigators queried four databases for English-language primary literature (2000–2025) based on predefined Population, Concept, and Context criteria. Additionally, a grey literature search mapped existing United States (U.S.) mitigation strategies. Two reviewers independently screened studies via Covidence, and one extracted data. Results included 61 primary studies and 41 grey literature sources. While epidemiological data confirm higher heat-related morbidity and mortality in older populations, few experimental studies evaluate medication’s specific role. Despite many public health efforts, specific, evidence-based guidance on managing drug-heat interactions is limited. Diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), anticholinergics, and antipsychotics were the medication classes most frequently associated with heat-related illness. This review underscores a critical need for research into the confluence of age, multimorbidity, and polypharmacy to inform future clinical mitigation and protect vulnerable populations. Full article

This study evaluated the impact of lactic acid fermentation on microbiological and nutritional quality, bioactive compound profile, and bioactive properties of mashed navy beans (MNB). Lactic Acid Bacteria (LAB) viability and microbiological quality of fermented mashed navy beans (FMNBs) were maintained for up to 28 days at 4 °C. Fermentation improved protein quality while reducing trypsin inhibitor activity. Additionally, fermentation enhanced the extractability of phenolic compounds, especially of bound forms. Proteolytic activity during fermentation generated low-molecular-weight peptides enriched in hydrophobic residues. Although antioxidant capacity remained comparable between samples, fermented samples exhibited higher angiotensin-converting enzyme inhibitory (ACE-I) activity (IC₅₀ ACE-I = 0.635 ± 0.043 and 0.413 ± 0.002 mg solids mL⁻¹ for MNBs and FMNBs, respectively). Simulated gastrointestinal digestion enhanced both antioxidant (ABTS•+) and antihypertensive potential. ECA-I inhibition was higher in the fermented sample dialysates (D), with IC₅₀ values of 0.160 ± 0.005 and 0.117 ± 0.003 mg solids mL⁻¹ for MNB-D and FMNB-D, respectively, due to the increased dialyzability of phenolic compounds and the presence of hydrophobic low-molecular-weight peptides in FMNB-D. Furthermore, FMNB-D exhibited competitive ACE-I inhibition. These findings demonstrate that lactic fermentation is an effective strategy to enhance the nutritional and health-promoting properties of legume-based foods. Full article

Background/Objectives: While the functions of angiotensin-converting enzyme (ACE) 1 and 2 are well established in peripheral tissues, the role of the spinal ACE1 and ACE2 pathways in the development of neuropathic pain remains unclear. This study examined the role of the spinal ACE1 and ACE2 pathways in trigeminal neuropathic pain produced by inferior alveolar nerve (IAN) injury. Methods: The experiments were conducted using male Sprague-Dawley rats (6–8 weeks old, weighing 220–250 g). The left mandibular second molar was extracted, and a dental mini-implant was placed to induce IAN injury. IAN injury produced robust and long-lasting mechanical allodynia and markedly increased angiotensinogen (AGT) expression within the ipsilateral trigeminal subnucleus caudalis (iTSC). Results: Neuropathic mechanical allodynia was inhibited by intracisternally administered losartan (an angiotensin II type-1 receptor antagonist), but not by an angiotensin II type-2 receptor antagonist. Intracisternal treatment with captopril (an ACE1 inhibitor) and diminazene aceturate (an ACE2 activator) produced significant anti-allodynic effects. Intracisternally injected angiotensin-(1-7) reduced neuropathic mechanical allodynia, and this anti-allodynic effect was blocked by pretreatment with A779, a Mas receptor inhibitor. In naïve rats, the intracisternal administration of DX600 (an ACE2 inhibitor) resulted in mechanical allodynia, which was inhibited by intracisternal pretreatment with losartan. IAN injury led to upregulated ACE1 expression and downregulated ACE2 expression in the iTSC. Conclusions: Our findings indicate that IAN injury induces a polarized shift in the ACEs within the iTSC, characterized by increased ACE1 and decreased ACE2 expression. Their modulation may therefore offer a promising strategy for developing effective treatments for chronic pain. Full article

Angiotensin-converting enzymes (ACE and ACE2) are key components of the renin–angiotensin–aldosterone system (RAAS) and are present in the gastrointestinal tract and intestinal content, preserving their catalytic activity, and may interact with the gut microbiota. The present study aimed to determine the origin of fecal ACE and ACE2 activity. Fecal pellets from germ-free, ACE and ACE2 knockout (KO) mice, and from the corresponding controls were analyzed using fluorimetric enzyme activity assays. ACE activity was assessed using Hippuryl-His-Leu and Z-Phe-His-Leu as substrates; ACE2 activity was assessed using Mca-APK (Dnp), with and without the ACE2 inhibitor MLN-4760. Germ-free mice showed increased fecal ACE and ACE2 activity compared to controls. ACE2-KO mice lacked fecal ACE2 activity, whereas ACE activity was unaffected. In ACE-KO mice, fecal ACE activity was reduced, but not abolished, while ACE2 activity remained similar to controls. In ACE C- and N-domain KO mice, ACE activity was similar to controls, and inhibition with captopril completely abolished fecal ACE activity using Hippuryl-His-Leu, but not Z-Phe-His-Leu, in those animals. These findings indicate that fecal ACE and ACE2 activity results from combined intestinal shedding and microbiota-related mechanisms, supporting a modulatory role of the gut environment on luminal RAAS activity. Full article

Background: Glucagon-like peptide-1 receptor agonist (GLP-1 RA) use has increased exponentially as studies show significant benefits in cardiovascular and renal diseases and obesity. Accessibility to the public also increased after compounding pharmacies began direct-to-consumer distribution. Gastrointestinal side effects are common; however, hypersensitivity reactions are rare. Case Presentation: A 50-year-old female with a history of obesity, hypertension, and lisinopril-induced angioedema presented to the Emergency Department with swelling of the lips, tongue, and throat developing four hours after her first injection of compounded semaglutide for weight loss. She was treated with epinephrine, corticosteroids, and antihistamines, but due to progressive airway edema, she required intubation and mechanical ventilation for four days. After extubation, she reported accidentally injecting a ten-fold higher dose (2 mg) of semaglutide than was appropriate for the first dose. The hospitalization was complicated by hypoglycemia requiring dextrose infusion, but was otherwise unremarkable, and she was discharged home on day 7. Based on the temporal onset after semaglutide injection, this presentation was most consistent with GLP-1 RA-induced angioedema. While she also had a history of lisinopril-induced angioedema five years earlier, and had been taking valsartan for hypertension, the remoteness of the lisinopril exposure made this less likely. Conclusions: Semaglutide use may be associated with severe angioedema within hours of administration. Given the overlapping indications and patient populations, angioedema appearing in patients taking both GLP-1 RAs and ACE inhibitors may become increasingly common and present a diagnostic dilemma. Diagnosis of hypersensitivity to GLP-1 RAs can be supported with history and positive skin testing. Clinicians should be aware that inexperienced patients are at the highest risk of dosing errors. Full article

Aspirin has been the default backbone of antiplatelet therapy after percutaneous coronary intervention (PCI) for over two decades, anchored by landmark trials that established 12-month dual antiplatelet therapy (DAPT) as the standard of care. Three developments have prompted reassessment of this paradigm: the markedly lower thrombotic risk of contemporary drug-eluting stents, the greater potency and consistency of potent P2Y₁₂ inhibitors (ticagrelor, prasugrel), and increasing recognition that major bleeding independently worsens outcomes after PCI. Recent randomised trials have systematically tested aspirin withdrawal at varying time points. Immediate aspirin-free strategies (NEO-MINDSET, STOPDAPT-3) demonstrated an early signal of excess ischaemic events in the ACS component of enrolled populations, suggesting that aspirin remains important during the earliest post-PCI period in ACS. One-month strategies (T-PASS, ULTIMATE-DAPT, TARGET-FIRST) and three-month strategies (TWILIGHT, TICO, DUAL-ACS) showed that transition to P2Y₁₂ monotherapy after an initial DAPT period significantly reduces bleeding without increasing ischaemic events in selected populations. Beyond one year, long-term randomised trials including the HOST-EXAM 10-year follow-up (Lancet 2026) and the STOPDAPT-2 5-year landmark analysis (Circ Cardiovasc Interv 2026), together with study-level meta-analyses (PANTHER) and recent individual patient data meta-analyses, provide converging evidence that clopidogrel monotherapy outperforms aspirin for chronic secondary prevention without excess bleeding. The choice of P2Y₁₂ agent is critical: clopidogrel monotherapy in ACS during the first post-procedural year carries excess thrombotic risk owing to CYP2C19 pharmacogenomic variability, whereas ticagrelor and prasugrel provide more reliable protection. This review synthesises the mechanistic rationale, trial evidence across all time points, special clinical contexts (oral anticoagulation, coronary artery bypass grafting, high bleeding risk), guideline evolution, and methodological considerations, providing a practical framework for individualising post-PCI antiplatelet therapy. Full article

Background/Objectives: The ACE2/Ang-(1–7)/Mas receptor axis is a protective, counter-regulatory component of the RAAS that opposes Ang II/AT₁R-mediated vasoconstriction. The present study evaluated the pharmacological effects of Ang-(1–7) in the rat inferior vena cava (IVC), a venous capacitance vessel involved in the regulation of venous return and cardiac preload. We hypothesized that Ang-(1–7) exerts anti-contractile effects in the rat inferior vena cava through activation of potassium channel-dependent mechanisms in venous smooth muscle. Methods: Isolated IVC rings from Wistar rats were studied using organ bath assays. Ang-(1–7) effects were assessed on pre-constriction induced by angiotensin II (Ang II), phenylephrine (PE), endothelin-1 (ET-1), and thromboxane A₂ analog (U46619). Responses were recorded and quantified. Mechanistic involvement of nitric oxide (NO), prostaglandins, soluble guanylate cyclase (sGC), and K⁺ channels was evaluated using specific pharmacological inhibitors. Results: Ang-(1–7) attenuated Ang II-induced contraction. The effect was markedly reduced by tetraethylammonium (TEA), indicating a predominant role of potassium channel-dependent mechanisms in venous smooth muscle. In contrast, inhibition of nitric oxide synthase, soluble guanylate cyclase, or cyclooxygenase had minimal influence. Ang-(1–7) also produced concentration-dependent relaxation in PE-, ET-1-, and U46619-precontracted vessels, demonstrating agonist-dependent anti-contractile activity. Conclusions: Ang-(1–7) exerts significant anti-contractile effects in the rat inferior vena cava primarily through activation of TEA-sensitive K⁺ channels in venous smooth muscle. These findings demonstrate functional activity of the ACE2/Ang-(1–7)/Mas axis in a major venous capacitance vessel and provide mechanistic insight into Ang-(1–7)-mediated modulation of venous tone, supporting further investigation in in vivo models. Full article

Glucagon-like peptide (GLP)-1 receptor (GLP1R) agonists exert a multitude of beneficial cardiovascular effects beyond control of blood glucose levels and obesity reduction. GLP-1R is a G protein-coupled receptor (GPCR), coupling to adenylyl cyclase (AC)-stimulatory Gs proteins to raise cyclic 3′-5′-adenosine monophosphate (cAMP) levels in cells. cAMP exerts various effects mainly via protein kinase A (PKA) and Exchange protein directly activated by cAMP (Epac). Cardiac GLP-1R has been reported to induce atrial natriuretic peptide (ANP) secretion via Epac2, while ANP is known to inhibit aldosterone secretion from adrenocortical zona glomerulosa (AZG) cells. Herein, we tested the effects of the GLP-1R agonist liraglutide on ANP secretion in H9c2 cardiomyocytes and on angiotensin II (AngII)-induced aldosterone secretion. We also examined whether phosphodiesterase (PDE)-4 inhibition with roflumilast could potentiate liraglutide’s effects. We found that liraglutide stimulated ANP secretion from H9c2 cardiomyocytes, an effect potentiated by roflumilast but blocked by AC inhibition. Epac inhibition with ESI-09 also significantly reduced liraglutide-dependent ANP secretion in H9c2 cardiomyocytes. Moreover, application of medium from liraglutide-treated H9c2 cardiomyocytes, but not from control cardiomyocytes, led to suppression of AngII-dependent aldosterone secretion from H295R cells. This effect was blocked by cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibition (an effector of ANP) in H295R cells, while direct application of liraglutide to these cells failed to suppress AngII-induced aldosterone secretion. Again, aldosterone suppression was more potent when medium from liraglutide plus roflumilast-treated cardiomyocytes was applied to H295R cells. Taken together, these results suggest that roflumilast enhances the adrenocortical aldosterone suppression induced by GLP-1R agonists via cardiac GLP-1R/cAMP/Epac-dependent ANP secretion. Given the cardio-toxic effects of elevated aldosterone levels in the context of various heart diseases, such as post-myocardial infarction heart failure, combination of a GLP-1R agonist drug with a PDE4 inhibitor drug may be more advantageous than either agent alone in treatment of certain cardiovascular diseases. Full article

Cardiovascular diseases have high mortality rates and present a high burden on society and the global healthcare system. A large quantity of drugs have been developed, such as aspirin, ACE inhibitors, beta-blockers, and statins. Although these traditional drugs have decreased the morbidity and mortality of cardiovascular diseases, they still have multiple limitations. Due to their shortcomings, researchers have continued to search for novel targets for drug treatment. The tripartite motif (TRIM) protein family is a superfamily with E3 ubiquitin ligase activity and involves diversified processes including proliferation, development, signal transduction, and immune regulation. The latest research has shown that TRIM proteins participate in the progression of cardiovascular diseases, such as cardiac hypertrophy, cardiac ischemia–reperfusion injury, heart failure, hypertension, atherosclerosis, and so on. In this review, we summarize the structure and function of TRIM proteins, as well as the mechanisms of their involvement in various cardiovascular diseases, aiming to raise awareness of the importance of TRIM proteins in cardiovascular disease research and treatment. Advancing our understanding of mechanisms mediated by TRIM proteins may emphasize their contributions to cardiovascular diseases and provide the opportunity to develop novel and targeted therapeutic strategies to combat cardiovascular diseases. Full article

This paper presents the electrochemical behavior of stainless steel 304 (SS304), a material often utilized in the wine industry, in the presence of varying concentrations of ascorbic acid (AcAS), introduced in a neutral solution (Na₂SO₄ 0.25 M + 12% (v/v) EtOH). The experimental part of this paper included potentiodynamic polarization and chronoamperometry techniques to evaluate the influence of ascorbic acid on the corrosion processes in the test solutions. Electrochemical impedance spectroscopy (EIS) has been used to investigate the charge transfer at the interface and the formation of a protective film in the absence and presence of AcAS. The Tafel method was employed to determine the kinetic parameters of the corrosion process studied. Additionally, several models of adsorption isotherms were applied to describe the interactions between AcAS and the stainless steel surface, with the Freundlich and Dubinin–Radushkevich isotherms demonstrating the most robust correlation, based on the R² correlation coefficients. Quantum chemical calculations (DFT) were also performed to clarify the molecular mechanism via which AcAS functions as an eco-friendly corrosion inhibitor in winemaking-related environments. Full article

Chronic heart failure (CHF) remains a leading cause of global mortality, characterized by profound molecular and biochemical disturbances, including nitric oxide (NO) system dysfunction, mitochondrial impairment, and oxidative stress. While standard therapies such as ACE inhibitors, SGLT2 inhibitors, and beta-blockers address clinical symptoms, their capacity to interrupt the underlying biochemical mechanisms of cardiomyopathy is often limited. This review examines the pathophysiological role of impaired NO production and reactive oxygen species (ROS) accumulation in exacerbating myocardial contractile dysfunction and disease progression. Special focus is directed toward the development of next-generation β1-blockers with multifunctional properties, including antioxidant, NO-mimetic, and antiapoptotic effects. Evidence suggests that the novel compound Hypertril (1-(β-phenylethyl)-4-amino-1,2,4-triazolium bromide) exhibits significant cardioprotective potential. Experimental data indicate that Hypertril improves eNOS/iNOS expression and enhances NO bioavailability more effectively than conventional β-blockers, leading to stabilized ECG parameters and restored energy metabolism. These findings underscore the clinical relevance of developing NO-mimetic agents to optimize the pharmacological management of CHF. Full article

Background: Tumour glycosylation regulates immune modulation and progression, but whether the CRC sialylome—the complete repertoire of sialylated glycans—defines a biologically distinct subtype remains unclear. We investigated how the “sugar code” shapes CRC biology, immunity, and therapeutic response. Methods: Transcriptomic data from three CRC cohorts (TCGA, Sidra-LUMC, and CPTAC-2; n = 988) were batch-corrected and integrated. Single-sample gene set enrichment analysis (ssGSEA) quantified sialyltransferase expression, sialic acid metabolism, EMT, MDR mechanisms, immune phenotypes, and Siglec-associated transcriptional signatures. GSEA, gene ontology enrichment analysis (GOEA), and drug ontology enrichment analysis (DOEA) characterised pathways and identified drug response-associated transcriptional signatures. Results: High sialylome activity defined a genomically stable but clinically advanced CRC subset enriched for left-sided tumours, mucinous histology, MSI, and BRAF mutations. At the transcriptional level, Sialyl-High tumours were associated with a mesenchymal, stromal-remodelling programme accompanied by reduced proliferative activity. They demonstrated enrichment of vesicular trafficking-related pathways alongside reduced representation of canonical efflux-associated programmes. Critically, the sialylome was associated with Siglec-related immune signatures, with sialylated glycan-related gene expression correlating with Siglec receptor expression (CD33 and SIGLEC7/9/10), consistent with an immune-inflamed yet structurally excluded microenvironment. DOEA identified selective enrichment of drug-response signatures related to sialic acid metabolism inhibitors (oseltamivir and Neu5Ac) and glycocalyx-disrupting agents (ginsenosides and soyasaponins). Conclusions: The CRC sialylome is associated with tumour phenotypic variation, including immune-excluded states linked to Siglec-associated transcriptional signatures and patterns consistent with non-canonical drug resistance programmes. These findings position the “sugar code” as a central organising principle in CRC and identify glycan-directed therapies as a promising strategy for the targeting of this aggressive subtype. Full article

This work focused on the identification of angiotensin I-converting enzyme (ACE) inhibitory peptides from royal jelly (RJ) proteins and elucidated their inhibition patterns and mechanisms. RJ proteins were analyzed for ACE inhibition potential using in silico tools, and suitable enzymes were selected for peptide release. Hydrolysis conditions were optimized using response surface methodology (RSM), and the resulting peptides were fractionated and purified. Mass spectrometry identified 57 peptides, with seven selected for synthesis based on scoring. IDFDF, DVNFR, and SFHRL showed the highest ACE inhibition, with IC₅₀ values of 16.9 μM, 42.5 μM, and 242.6 μM, respectively. Lineweaver–Burk plots revealed IDFDF as a competitive inhibitor, DVNFR as a non-competitive inhibitor, and SFHRL as a mixed inhibitor. Molecular docking indicated that peptide–ACE interactions were primarily mediated through hydrogen bonds and Zn(II) coordination. This work promotes the sustainable utilization of RJ and the development of ACE inhibitory peptides derived from food sources. Full article

Background: A major challenge in antiviral development is the identification of novel virus–host interactions while ensuring therapeutic efficacy and safety. These challenges have renewed interest in phytochemicals derived from medicinal plants as alternative antiviral agents. Objectives: In this study, we investigated the antioxidant, antiviral, and immunomodulatory properties of a Mediterranean Urtica dioica extract (UdE) against SARS-CoV-2 using chemical, biochemical, and in vitro approaches. Methods: The physicochemical properties of UdE were characterized using microtiter assays and HPLC analysis. Cytocompatibility was evaluated in HEK293T, Vero E6, Caco-2, and Calu-3 cell lines while antioxidant activity was assessed using both chemical and cell-based assays. Antiviral activity was evaluated by assessing inhibition of SARS-CoV-2 receptor binding domain (RBD)–ACE2 interaction using ELISA, inhibition of SARS-CoV-2 main protease (Mpro) activity via FRET assay and inhibition of viral entry using SARS-CoV-2 S1 pseudovirus neutralization assay. Results: UdE (100 µg/mL) inhibited RBD–ACE2 binding by 94% and suppressed Mpro activity by 74%, while reducing moderate but significant inhibition of pseudovirus entry (33.6%) at 300 µg/mL dose level in ACE2 expressing HEK293T cells. Immunomodulatory analysis revealed significant suppression of IL-1β and IL-6 production, accompanied by increased TNF-α and IL-8 levels. Conclusions: Collectively, these findings highlight that UdE exhibits multi-target in vitro antioxidant, antiviral, and immunomodulatory activity against SARS-CoV-2; therefore, UdE represents a promising bioactive extract for the management of SARS-CoV-2 infection. Full article