Search Results (1,678)

Angiotensin-converting enzyme (ACE) inhibitors (ACEis) are one of the most successful drug classes for the treatment of hypertension and the prevention of its cardiovascular complications. ACE activates the pressor hormone angiotensin but also inactivates the vasodilator peptide bradykinin (BK). A rare side effect of ACEis, angioedema (AE), has been proposed to result from pro-inflammatory effects of BK. Novel considerations are offered in this debate: (1) the bradykinin B2 receptor antagonist icatibant has had an inconsistent effect on ACEi-associated AE, but its potency and duration of action are much inferior to those of a novel nonpeptide antagonist of this receptor, deucrictibant. (2) Tissue kallikrein (KLK-1) is an effective kininogenase, particularly abundant in the salivary glands, possibly related to orofacial presentation of ACEi-induced AE. (3) The strongly regulated human kinin B1 receptor, optimally responsive to Lys-des-Arg⁹-BK, is functionally compartmentalized with KLK-1 which produces Lys-BK from kininogens. Chronic treatment with ACEi drugs in laboratory animals induces the expression of vascular B1R that mediates vasodilation. Therefore, ACEi-AE may be largely or completely initiated by KLK-1. Inhibitors of this protease or combined antagonists of both kinin receptor subtypes may be useful for the management of this condition. Full article

One of the most critical aspects of post-acute COVID-19 syndrome (PACS) and post-acute COVID-19 vaccination syndrome (PACVS) is the presence of autoantibodies. These autoantibodies are directed against various receptors in the autonomic and cardiovascular systems, including those targeting proteins of the renin–angiotensin system (RAS). The RAS plays a central role in regulating vascular homeostasis, inflammation, and endothelial function. During SARS-CoV-2 infection, the interaction of the spike (S) protein with angiotensin-converting enzyme 2 (ACE2) can alter the balance of the RAS, favoring an imbalance towards the ACE/Angiotensin II/AT1R axis, known for its pro-inflammatory, pro-thrombotic, and vasoconstrictive properties. Similar pathological mechanisms also come into play in response to vaccinations that use the S protein as an antigen. Studies conducted by other groups and us on patients with PACS and PACVS have revealed the presence of autoantibodies directed against these RAS components and the mechanisms by which these antibodies can worsen the clinical situation. In particular, anti-ACE2, presumably formed by the anti-idiotype network or molecular mimicry, is correlated with PACVS symptoms in many patients. Furthermore, the presence of anti-MAS1 antibodies can reduce the efficiency of the ACE2/Angiotensin-(1–7)/MAS1 axis, which normally acts as a counter-regulator. Considering this evidence, an analysis of RAS molecules and the autoantibodies implicated in reactions to them may be useful for evaluating a state of persistent dysregulation associated with post-vaccination symptoms such as asthenia, headache, skin edema and bruising, cardiovascular alterations, and neurovegetative manifestations. Finally, we offer insights into diagnosing these multifaceted syndromes and working hypotheses to guide research into possible therapeutic approaches. Full article

Background: Despite the effectiveness of current SARS-CoV-2 vaccines, the genetic variability of the viral target has led to the emergence of variants capable of evading vaccine-induced protection. To ensure broader and more durable protection, we investigated the efficacy of a novel vaccine strategy. Methods: This vaccine utilizes the highly conserved nucleocapsid (N) protein as its primary antigen, rather than the spike (S) protein. It incorporates the Papaya Mosaic Virus (PapMV) nanoparticle, a Toll-like receptor (TLR) 7/8 agonist with intrinsic adjuvant properties, as a vaccine platform. Results: The vaccine formulations, comprising PapMV nanoparticles and the N antigen covalently or non-covalently attached to the PpaMV nano, generated robust humoral (antibody) and cellular (T-cell) immune responses. Protective efficacy was evaluated in K18-hACE2 transgenic mice challenged with either the ancestral SARS-CoV-2 strain or the Omicron XBB.1.5 variant. In both cases, the vaccine significantly reduced inflammation and viral titers in the lungs of vaccinated animals. Conclusions: These results highlight the potential of this PapMV-N vaccine to induce broad protection against diverse SARS-CoV-2 variants. Full article

Background: Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) were historically considered contraindicated in severe aortic stenosis (AS) due to theoretical haemodynamic risks. Contemporary evidence increasingly challenges this paradigm, yet data on preoperative use and postoperative outcomes remain limited. We examined the association between preoperative ACEi/ARB use and mortality following aortic valve replacement. Methods: We conducted a retrospective cohort study of 198 consecutive patients undergoing transcatheter (TAVI) or surgical aortic valve replacement (SAVR) at a single tertiary centre between May 2020 and March 2025. Complete one-year follow up was available for 185 patients (93%). The primary outcome was one-year all-cause mortality. Multivariable logistic regression adjusted for age, sex, hypertension, diabetes, LVEF, and procedure type. Results: Of 198 patients, 80 (40%) were receiving ACEi/ARB therapy preoperatively. ACEi/ARB users had a higher prevalence of hypertension (82% vs. 53%, p < 0.001) and diabetes (48% vs. 27%, p = 0.005) but similar age, valve area, and ejection fraction. Unadjusted one-year mortality was lower in the ACEi/ARB group (7% vs. 19%; odds ratio [OR] 0.33, 95% CI 0.12–0.91, p = 0.030). After multivariable adjustment for confounders including age, diabetes, and hypertension, the association did not reach statistical significance (adjusted OR 0.33, 95% CI 0.10–1.12, p = 0.075). Among diabetic patients, unadjusted one-year mortality was numerically lower in the ACEi/ARB group (12% vs. 35%, p = 0.038); however, six subgroup comparisons were performed and this result would not survive Bonferroni correction (threshold p < 0.008). This exploratory finding should be interpreted with caution given the small sample size and absence of adjustment for confounders. Conclusions: Preoperative ACEi/ARB use was associated with lower unadjusted one-year mortality, but this association did not reach statistical significance after multivariable adjustment and residual confounding cannot be excluded. ACEi/ARB use was not associated with increased mortality in this cohort. These hypothesis-generating findings from a single-centre observational study require confirmation in adequately powered prospective trials. Full article

Tongue squamous cell carcinoma (TSCC) is clinically heterogeneous, and patients with a similar TNM stage can experience markedly different outcomes. We systematically reviewed omics-driven studies to identify prognostic TSCC biomarkers. Although fundamentally prognostic, we discussed their theoretical translational relevance regarding future clinical decisions—such as treatment stratification or surveillance intensity—while strictly framing them as preliminary, hypothesis-generating targets. PubMed, Scopus, Web of Science, and Cochrane were searched for original human studies published between 2014 and 2024 using high-throughput genomic or transcriptomic profiling. Study selection followed referred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), data were extracted with a structured workbook, and risk of bias was assessed using QUIPS and PROBAST, with reporting completeness appraised using REMARK. Seventeen studies were included, identifying 85 distinct biomarkers. Across biomarkers supported by multivariable overall survival analyses, higher-risk associations were reported for NELL2, PDE4D, CTTN, HBEGF, and CA9, whereas lower-risk associations were reported for AC139530.1, LINC01711, CCDC96, CYP2J2, and SPAG16. Recurrent biological themes included IL-17 signaling, ECM-receptor interaction, and focal adhesion. CA9 was the only biomarker reported in more than one included study, supporting its prioritization for validation. Although the evidence remains heterogeneous and largely hypothesis-generating, these markers may support the future validation of response-oriented therapeutic stratification in TSCC. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells when the spike receptor-binding domain (RBD) engages angiotensin-converting enzyme 2 (ACE2). Cannabinoid scaffolds have recently been reported to bind S1/RBD, block spike-mediated membrane fusion, and modulate host inflammatory pathways, making them attractive candidates for entry inhibition. Here, we applied an integrated computational pipeline to prioritize cannabis-derived compounds as interfacial blockers of the RBD–ACE2 complex across variants. Eleven phytocannabinoids were docked into the wild-type (WT) RBD–ACE2 interface, identifying three cavities, with ligands preferentially occupying pocket 1. Complexes were subjected to triplicate 200 ns all-atom molecular dynamics (MD) simulations for WT, Delta, and Omicron BA.1 RBD–ACE2. Binding energetics were quantified using molecular mechanics/generalized Born surface area (MM/GBSA) and solvated interaction energy (SIE), and per-residue contributions were analyzed together with solvent-accessible surface area (SASA) and residue interaction networks. Among all compounds, cannabidiol (CBD) and cannabinol (CBN) were the only ligands that remained stably bound in pocket 1 for all variants. CBN showed the most favorable ligand–complex binding in WT, whereas CBD preserved favorable binding in Omicron BA.1 despite reduced interface burial, indicating that van der Waals/electrostatic complementarity and solvation, rather than surface coverage alone, govern affinity. Both ligands weakened modeled RBD–ACE2 binding by perturbing hot-spot residues centered on Y505 or N501Y in RBD and E37, A387, and R393 in ACE2. Overall, our results highlight CBD and CBN as tractable, variant-spanning interface disruptors and illustrate how MD-based free-energy calculations can support computational drug discovery against evolving viral protein–protein interfaces. Full article

Interleukin-10 (IL-10) is a key immunoregulatory cytokine that suppresses inflammatory gene transcription in myeloid cells through signal transducer and activator of transcription 3 (STAT3). In Alzheimer’s disease and neuroinflammation, microglia express IL10ra and exhibit STAT3 Tyr705 phosphorylation following IL-10 stimulation, indicating IL-10 receptor-dependent STAT3 activation. Recent studies demonstrate that IL-10 induces promoter-selective STAT3-dependent transcriptional regulation in microglia through chromatin-associated mechanisms, whereas gp130-dependent cytokines activate STAT3 to induce transcription of defined target genes, including Socs3 and Ccl5. Following IL-10 receptor activation, STAT3 binds regulatory regions of inflammatory genes, including Il1b, Tnf, Il6, and Nlrp3, with reduced RNA polymerase II and NF-κB binding. IL-10-dependent transcriptional repression involves formation of a nuclear SHIP1–STAT3 complex, localization of histone deacetylase (HDAC)1 and HDAC2 to H3K4me1-enriched enhancer regions, reduced H3K27ac, and decreased chromatin accessibility at regulatory regions of inflammatory genes. IL-10-activated STAT3 induces Socs3, which regulates JAK1 and TYK2 activity and STAT3 phosphorylation. Impairment of IL-10 receptor signaling in microglia is associated with increased inflammatory gene expression, enhanced inflammasome-related transcription, demyelination, and amyloid accumulation. This review focuses on IL-10–STAT3-dependent transcriptional regulation in microglia, including receptor signaling, chromatin-associated mechanisms, and disease-associated gene expression in Alzheimer’s disease and neuroinflammation. Full article

Pregnancy represents a distinct immunological and physiological state that modifies maternal susceptibility to SARS-CoV-2 and influences the clinical and biological course of COVID-19. Accumulating evidence indicates that the interaction between viral entry determinants, gestation-specific immune modulation, placental endocrine–angiogenic pathways, and systemic inflammatory responses underlies the characteristic manifestations of SARS-CoV-2 infection during pregnancy. This review consolidates current understanding of SARS-CoV-2 viral structure, receptor biology, and the gestational regulation of key entry cofactors, including ACE2, TMPRSS2, NRP1, CTSL and FURIN, within reproductive and placental tissues. The review further integrates documented mechanisms of cytokine-mediated immune dysregulation, endothelial injury, thrombo-inflammation, and steroidogenic alteration observed in affected pregnancies, and examines their contribution to placental malperfusion, preeclampsia-like presentations, fetal growth abnormalities and preterm birth. Published molecular and computational studies characterising trophoblast antiviral defenses, receptor expression patterns, and structural determinants of Spike–ACE2 affinity are synthesised to contextualise the biological basis of placental susceptibility and the rarity of confirmed transplacental transmission. Current evidence on maternal clinical outcomes, fetal and neonatal consequences, vaccination efficacy, therapeutic considerations and contemporary management guidelines is also critically reviewed. By integrating molecular, immunological, pathological and clinical insights, this article provides a comprehensive framework for understanding the interaction between SARS-CoV-2 infection and pregnancy-specific physiology, with implications for risk assessment, preventive strategies and maternal–fetal care. Full article

Atherosclerosis is a complex, multifactorial disease that progresses through distinct stages: initiation, progression, and complication, ultimately leading to acute coronary syndromes (ACS). Endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and macrophages are central players in this process, influencing plaque stability and vulnerability. Insulin-Like Growth Factor 1 (IGF-1), soluble-Klotho (S-Klotho), and the Growth Hormone Receptor exon 3 deletion polymorphism (GHRd3) have emerged as key modulators of vascular health, impacting these cellular components through various mechanisms. IGF-1 supports endothelial function, enhances VSMC survival and migration, and mitigates inflammation by inhibiting macrophage recruitment and activation, ultimately reducing the risk of plaque destabilization. S-Klotho, an anti-aging protein with potent anti-inflammatory and antioxidant properties, has been linked to vascular protection, with its deficiency associated with endothelial dysfunction, vascular calcification, and impaired VSMC survival. Evidence suggests that IGF-1 may enhance Klotho shedding, indicating a potential synergistic role in maintaining vascular integrity. This narrative review aims to outline the fundamental stages of atherosclerosis progression, consolidate current evidence on the roles of IGF-1 and S-Klotho in modulating key cellular components of atherosclerosis, and shed light on their potential involvement in plaque healing—an area that remains largely unexplored. By integrating established molecular mechanisms, we explore how these factors may contribute to endothelial integrity, VSMC survival, and macrophage activation and polarization, potentially shaping a more stable plaque phenotype and influencing future therapeutic strategies in cardiovascular disease. Full article

Pertussis toxin (PTx) is a major virulence factor of Bordetella pertussis and an AB5-type exotoxin that disrupts host signaling. Its enzymatic A subunit ADP-ribosylates the α-subunit of inhibitory G proteins (Gα_i), preventing them from mediating receptor-induced inhibition of adenylyl cyclase (AC). This leads to unrestrained cAMP accumulation in host cells, a canonical mechanism underlying many pertussis disease manifestations. PTx works in concert with the bacterium’s adenylate cyclase toxin (ACT) to subvert immune defenses and establish infection. Interestingly, PTx exerts both cAMP-dependent and cAMP-independent effects. In addition to the well-known cAMP-mediated pathway, PTx’s B oligomer can engage host cell surface receptors to trigger signaling cascades independent of the A subunit’s catalytic activity. Such B oligomer-mediated pathways modulate cellular responses in the absence of ADP-ribosylation. This review provides a comprehensive analysis of PTx’s dual functionality, distinguishing its G_i protein-dependent elevation of cAMP from the noncanonical activities of the B oligomer. It also highlights how disruption of constitutive G_i signaling and the interplay between PTx and ACT shape host–pathogen interaction in pertussis pathogenesis. Full article

Background/Objectives: Sweeteners and sweetness enhancers (S&SEs) have been proposed to potentially impair appetite regulation by stimulating sweet taste receptors beyond the perception of sweetness, similar to caloric sweeteners. The evidence is, however, not clear. Methods: This sub-study investigated the acute effects of a mixture of acesulfame potassium and cyclamate (Ace-K/Cyc) versus water on postprandial appetite sensations and energy intake at baseline, after a two-month weight loss period, and after a four-month weight loss maintenance period, including (S&SE group) or excluding S&SEs (Sugar group) in the diet. A total of 26 participants (18–65 years; BMI ≥ 25.0 kg/m²) were recruited from the one-year randomized controlled SWEET trial. Subjective appetite sensations were measured using visual analogue scales while fasting and nine times during a 250-min postprandial period. During this period, a standardized breakfast (0–10 min) was served and, 2 h later, a test drink containing either Ace-K/Cyc or water (120–130 min) was given. After 265 min, an ad libitum test meal was served. Results: Of 26 participants enrolled, 22 completed test day 2 and 16 completed test day 3. The S&SEs group rated lower prospective consumption and desire to eat something sweet after the test drink with Ace-K/Cyc compared to the sugar group consuming water (p < 0.05), with effects persisting after adjusting for taste. Initial differences in hunger were explained by taste palatability. This was true for all three test days. Ad libitum energy intake did not differ (p > 0.05). Conclusions: Ace-K/Cyc compared to water reduced feelings of prospective consumption and desire to eat something sweet acutely, after two months of weight loss, and after four months of weight loss maintenance. Due to the low sample size and power, larger studies are warranted to confirm these results. Full article

Background/Objectives: Neoadjuvant dual HER2 blockade is standard for HER2-positive breast cancer, yet response rates vary based on tumor biology. This multicenter study aimed to identify clinicopathological predictors of pathological complete response (pCR), focusing on quantitative hormone receptor (HR) expression and HER2 staining intensity, and to evaluate their impact on survival. Methods: This multicenter retrospective study included 290 female patients diagnosed with HER2-positive early or locally advanced breast cancer treated with neoadjuvant trastuzumab and pertuzumab-based regimens (anthracycline-based [AC-THP] or non-anthracycline [TCHP]) across six centers. HR expression was stratified into low (<50%) and high (≥50%) categories. Multivariable regression analyses identified predictors of pCR, Disease-Free Survival (DFS), and Overall Survival (OS). Results: The pCR rate was 51.4%. Multivariate analysis identified HR negativity (OR = 2.80; p < 0.001) and strong HER2 overexpression (IHC Score 3) (OR = 2.20; p = 0.037) as primary predictors. Uniquely, patients with low HR expression (<50%) achieved significantly higher pCR rates (65.9%) than strongly positive cases (36.6%; p = 0.001), biologically mimicking hormone-negative disease. The non-anthracycline TCHP regimen showed a strong trend toward superior efficacy (OR = 2.22; p = 0.054). pCR was the sole independent predictor of OS (HR = 0.134; p = 0.009). Crucially, adjusting for pCR unmasked hormone-negative status as a significant risk factor for recurrence (HR = 2.49; p = 0.028), highlighting its dual nature: high chemosensitivity but inherent biological aggression. Conclusions: “Strong” HER2 positivity and “weak” HR expression (<50%) are the primary determinants of pCR. pCR remains the strongest surrogate for survival, neutralizing initial risk factors. These findings support using quantitative biomarker thresholds for personalization and reinforce the efficacy of non-anthracycline regimens. Full article

In cardiac pathologies, levels of G protein-coupled receptor kinase 2 (GRK2)—which is involved in receptor desensitization and internalization—are elevated. Beyond these receptor-mediated effects, GRK2 also localizes to mitochondria, where it contributes to pathology. GRK2’s activity can be inhibited via S-nitrosylation at Cysteine 340, a post-translational modification mediated by both endogenous and exogenous nitric oxide. Thus, S-nitrosylation is considered as an endogenous brake on GRK2’s catalytic activity, counteracting its hyperactivity observed in disease states. However, it remains unclear whether S-nitrosylation also regulates GRK2’s influence on mitochondrial function. This study aims to investigate how S-nitrosylation regulates mitochondrial localization and function of GRK2 under hypoxia/reoxygenation stress. To prevent S-nitrosylation at Cys340, we infected AC16 cardiac cells with adenoviruses carrying a GRK2 C340S (Ser) mutation. Our results indicate that inhibiting S-nitrosylation enhances mitochondrial localization of GRK2, especially in response to pathological stimuli. Additionally, mitochondrial function was impaired, as measured by oxygen consumption rates at ATP production. Furthermore, alterations in mitochondrial dynamics and mitophagy led to adverse outcomes when GRK2 was not subject to S-nitrosylation, presumably due to increased catalytic activity. Our findings underscore the importance of GRK2 regulation in cardiac pathologies and suggest that targeting GRK2 or its post-translational modifications may provide therapeutic benefits. Full article

Background: Arterial hypertension (AH) is a frequent comorbidity in patients with osteoarthritis (OA). Among antihypertensive agents, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers (CCBs), angiotensin II receptor blockers (ARBs), and beta-blockers (βBs) have been suggested to influence OA progression and symptomatology. The aim of this study was to assess whether the duration of effectiveness (DE) of viscosupplementation (VS) differs between patients with knee OA who are receiving antihypertensive treatment and those who are not. Methods: This post hoc analysis was conducted using data from a cross-sectional clinical trial (ClinicalTrials.gov Identifier: NCT04988698). The study included consecutive patients with knee OA who came for consultation at the Rheumatology Department and had received intra-articular hyaluronic acid injections within the past three years. The primary outcome was DE, self-reported by patients as the number of weeks of symptom relief. Associations between DE and various factors, including demographics, disease duration, radiographic OA severity (Kellgren–Lawrence grade and affected compartments), comorbidities, OA treatment history, antihypertensive therapy, physical activity level, and prior VS sessions, were analyzed using bivariate and multivariate models. Results: A total of 105 patients (65 women, 149 treated knees) were included. The mean age was 66.1 ± 13.2 years, and the mean body mass index (BMI) was 27.5 kg/m². Thirty-eight percent of patients were receiving antihypertensive treatment (mean number of agents: 1.9; range: 1–4), including CCBs (n = 15), ACE inhibitors (n = 13), ARBs (n = 7), βBs (n = 6), and diuretics (n = 2). The overall mean DE of VS was 48.2 ± 24.8 weeks, with a trend toward longer DE in hypertensive patients compared to non-hypertensive patients (53.1 ± 31.3 vs. 45.4 ± 19.8 weeks, p = 0.06). Bivariate analysis identified significantly longer DE in patients with BMI < 27.5 kg/m² (p = 0.002), Kellgren–Lawrence grade < 4 (p = 0.008), an active lifestyle (p = 0.005), unicompartmental OA (p = 0.01), medial tibiofemoral joint space narrowing (p = 0.046), and fewer than four prior VS sessions (p = 0.02). In multivariate analysis, AH was strongly associated with prolonged DE (p < 0.001), despite AH patients having a higher BMI (29.8 ± 5.5 vs. 25.2 ± 5.2 kg/m², p = 0.001) and being more frequently sedentary (25.5% vs. 13.8%, p = 0.07). A trend toward longer DE was observed in patients treated with βBs and ARBs but not with CCBs or ACE inhibitors. Additional independent predictors of longer DE included BMI < 27.5 kg/m² (p < 0.001), unicompartmental OA (p = 0.02), fewer than four prior VS sessions (p = 0.02), and an active lifestyle (p = 0.027). Conclusions: These findings suggest that antihypertensive treatment may extend the effectiveness of viscosupplementation in knee OA. However, the sample size was insufficient to determine whether specific classes of antihypertensive agents provide greater benefits. Further large-scale, prospective studies are warranted to clarify the potential impact of antihypertensive medications on viscosupplementation outcomes in knee OA. Full article

The SARS-CoV-2 Omicron variant and its descendants accumulated unprecedented numbers of spike substitutions yet remained transmissible, implying compensatory mechanisms that preserve entry while eroding humoral immunity. We analyzed 32 variants for sequence-level mutation, physicochemical profiling, and epitope disruption; 25 had growth-advantage estimates, and 18 underwent molecular dynamics/MM-PBSA simulations. We applied a systems-virology framework to the SARS-CoV-2 receptor-binding domain (RBD), integrating immunodominance-weighted epitope conservation (567 B-cell and 97 T-cell epitopes) across variants (Wuhan-Hu-1 to KP.3) with molecular dynamics, molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) binding energetics, and deep mutational scanning (DMS) benchmarking. B-cell epitope conservation declined from a median of 72.7% in pre-Omicron variants to 28.8% in BA.1 and 10.6% in KP.3, and was strongly inversely associated with a breakthrough-infection proxy (Spearman ρ = −0.8246, p < 0.001), whereas RBD T-cell epitopes remained comparatively conserved (91.5% to 87.2%). Despite the loss of the ancestral K417–ACE2 D30 salt bridge, Omicron reconfigured the interface via alternative electrostatic contacts (Q493R–E35 and Q498R–D38), producing compensatory interactions captured by MM-PBSA, but with only modest agreement with DMS affinity changes (r = 0.682, p = 0.007), consistent with enthalpy–entropy compensation. Finally, mutation tolerance shifted toward stronger epistatic buffering in Omicron (two-fold higher epistasis than pre-Omicron; p = 0.0093), enabling extensive antigenic change without structural collapse. Together, these results support a multi-objective evolutionary strategy—epitope erosion, interface rewiring, and epistatic compensation—that can be operationalized to prioritize emerging lineages for surveillance and to inform vaccine designs that emphasize conserved T-cell targets. Full article