Search Results (3,590)

Background: The ACE Y215C mutation is a common, functionally damaging missense variant (~1.5% allele frequency) associated with reduced plasma ACE levels and increased Alzheimer’s disease (AD) risk. In CHO and HEK cell models, this mutation caused a ~3–6-fold decrease in ACE surface expression, soluble ACE levels, and ACE enzymatic activity compared to those of wild-type ACE. Methods: Circulating ACE levels and activity were measured in EDTA plasma obtained from 84 carriers of the ACE Y215C mutation using a set of mAbs to the ACE. The mAbs 5B3/1G12 binding ratio was revealed as a sensitive marker for the circulating Y215C ACE mutant. Whole-exome and whole-genome sequencing (WES/WGS) were performed to identify genetic variants potentially modifying circulating ACE levels. In parallel, published sequencing and proteomic data from 35,559 Icelanders participants were analyzed to identify genes influencing ACE shedding. Sequence comparison was performed between carriers with elevated and reduced ACE concentrations to identify the potential protective variants that may compensate for decreased ACE levels due to the Y215C mutation itself. Results: Most carriers of the Y215C ACE mutation demonstrated significantly decreased ACE levels (median is 62% of control ACE levels). However, substantial inter-individual variability was observed in plasma ACE activity among carriers. Comparative sequencing analysis revealed 9648 variants unique to individuals with elevated ACE, mapping to 5779 protein-coding genes and enriched for pathways related to intracellular and transmembrane transport. Conclusions: The presence of the damaging ACE mutation Y215C does not invariably result in low plasma ACE or, likely, elevated AD risk. Therefore, combined blood ACE phenotyping and whole-exome sequencing are recommended to more accurately assess ACE-related AD susceptibility in mutation carriers. Full article

Background/Objectives: Reduced-ejection-fraction heart failure (HFrEF) constitutes a challenge due to its high morbidity and mortality. The use of sacubitril/valsartan (angiotensin receptor–neprilysin inhibitors [ARNI]) and SGLT2 inhibitors (SGLT2i) represents a change in management approach with a demonstrated association with positive ventricular remodeling and a reduction in cardiovascular events. We describe the clinical and therapeutic course of patients with HFrEF in a specialized unit, comparing two consecutive periods (2011–2016 vs. 2017–2021), with emphasis on the impact of ARNI and SGLT2i upon clinical parameters and the use of devices. Methods: A retrospective, longitudinal observational study was carried out in 1363 outpatients with HFrEF, with at least two years of follow-up. Clinical characteristics, treatments, the evolution of left ventricular ejection fraction (LVEF), mortality, and the use of devices (implantable cardioverter–defibrillator [ICD], cardiac resynchronization therapy [CRT]) were evaluated. Results: A total of 1363 patients were analyzed, showing a significant therapeutic change in the 2017–2021 group with the incorporation of ARNI (40%) and SGLT2i (25%). This cohort achieved better ventricular recovery, with a significantly higher mean LVEF at one year compared to the 2011–2016 group (44.3% vs. 42.1%; p = 0.004). Regarding devices, ICD implantation rate decreased in the recent period (7.2% vs. 11.1%; p = 0.016), while CRT indication increased. Most importantly, all-cause mortality after two years fell from 9.4% to 5.9% (p = 0.023). Multivariate analysis confirmed that this survival improvement was independently associated with the study period (HR 1.57 for the earlier group) and was linked to the protective effect of contemporary pharmacological treatments. Conclusions: The systematic introduction of ARNI and SGLT2i in the treatment of HFrEF was associated with improved ventricular function, reduced need for device implantation, and lower mortality over the middle term in a real-life clinical setting. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by the viral spike proteins, which are key structural components that mediate host cell binding and entry and alter downstream signaling through multiple interactions with endothelial surface receptors. Endothelial dysfunction is a central consequence of COVID-19, contributing to vascular inflammation, barrier disruption, thrombosis, and multi-organ injury affecting the pulmonary, cardiovascular, cerebral, and renal systems. Emerging evidence demonstrates that spike protein-mediated effects, independent of productive viral infection, disrupt endothelial homeostasis through angiotensin-converting enzyme 2 (ACE2) dysregulation, integrin engagement, altered calcium signaling, junctional protein remodeling, oxidative stress, and pro-inflammatory and pro-apoptotic pathways. This review is intentionally focused on spike (S) protein-driven mechanisms of endothelial dysfunction; pathogenic vascular effects attributed to other SARS-CoV-2 structural proteins, including the nucleocapsid (N) protein, are beyond the scope of this discussion. In this review, we synthesize current experimental and translational data detailing the molecular mechanisms by which the SARS-CoV-2 spike protein drives endothelial dysfunction across multiple organ systems and discuss potential therapeutic strategies aimed at preserving endothelial integrity in acute COVID-19 and its long-term vascular sequela. Full article

Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) coexist in 40–60% of cases and mutually reinforce each other through adverse electrical, cellular, and functional remodelling. There is considerable overlap in signs and symptoms, and diagnosis may be challenging due to nonspecific clinical presentations and chronic course. AF is clearly linked with worsening morbidity and mortality in HFpEF with higher rates of HF hospitalizations, HF progression, stroke, systemic embolism, and all-cause death. Optimal management of HFpEF-AF patients requires aggressive treatment of comorbidities and risk factor modification. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated consistent benefit with respect to HF hospitalizations, symptoms and exercise haemodynamics, and potential to reduce AF burden. Gastric inhibitory polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) agonists, mineralocorticoid receptor antagonists (MRAs), angiotensin receptor-neprilysin inhibitors (ARNIs), and statins may provide benefit in selected phenotypes, though evidence remains heterogeneous. A rhythm control strategy in the early clinical course of HFpEF might be a reasonable strategy to improve symptoms and delay both AF and HFpEF disease progression. Catheter ablation appears to improve exercise haemodynamics and quality of life, and observational data suggest it may reduce mortality and HF hospitalization, though current evidence is inconsistent and not yet definitive. Emerging device-based and molecular therapies could represent promising avenues for future research. Overall, early detection of AF, comprehensive risk-factor modification, and tailored rhythm-control strategies are central to improving outcomes in the HFpEF-AF overlap syndrome. Full article

Traffic-related air pollution (TRAP) is known to contribute to oxidative stress in the central nervous system (CNS) and has been linked to increased risk of Alzheimer’s disease (AD). Alterations in the renin–angiotensin system (RAS), specifically increased angiotensin II (Ang II) signaling via the angiotensin II type 1 (AT₁) receptor, are implicated in increased oxidative stress in the CNS via activation of NADPH oxidase (NOX). As exposure to TRAP may further elevate AD risk, we investigated whether exposure to inhaled mixed gasoline and diesel vehicle emissions (MVE) promotes RAS-dependent expression of factors that contribute to AD pathophysiology in an apolipoprotein E-deficient (ApoE^−/−) mouse model. Male ApoE^−/− mice (6–8 weeks old) on a high-fat diet were treated with either an ACE inhibitor (captopril, 4 mg/kg/day) or water and exposed to filtered air (FA) or MVE (200 µg PM/m³) for 30 days. MVE exposure elevated plasma Ang II, inflammation, and oxidative stress in the hippocampus, associated with increased levels of Aph-1 homolog B (APH1B), a gamma-secretase subunit, and beta-secretase 1 (BACE1), involved in Aβ production. Each of these endpoints was normalized with ACEi treatment. These findings indicate that TRAP exposure in ApoE^−/− mice drives a RAS- and NOX-dependent oxidative and inflammatory response and shifts Aβ processing towards an amyloidogenic profile before overt Aβ deposition, suggesting a potential therapeutic approach for air pollution-induced AD risk. Full article

Abdominal aortic aneurysm (AAA) is a lethal vascular disease characterized by intramural hemorrhage. This study delineates the signatures of heme and its metabolic imbalance related to progression and inflammation in AAA. Clinical analyses of patients undergoing open AAA surgery show that AAA patients exhibit vascular inflammation, with elevated serum CRP, IL-6, and heme levels correlating with the expression of heme-regulated gene Hmox1/HO-1 (heme oxygenase-1) in the affected aortic wall. Oxidation of hemoglobin to ferri state leading to accumulation of methemoglobin readily releasing heme occurs in human AAA and in angiotensin II (AngII)-induced AAA in apolipoprotein E-deficient mice. Transcriptomic analysis for AngII-induced AAA identifies upregulated genes predominantly enriched in inflammatory signaling, extracellular matrix degradation, oxidative stress pathways, and altered expression of genes related to heme metabolism including Hmox1. Immunohistochemistry for IL1β and TNFα confirms inflammatory activation within AAA tissues. The signatures of heme-responsive gene inductions, enhanced expression of HO-1 and H-ferritin, are detected. Mechanistic studies employing endothelial cells and smooth muscle cells reveal that heme exposure of resident cells markedly enhances the expression of IL1β and ICAM1, as well as the inflammasome component NLRP3, and such inflammatory response is controlled by HO-1. Intervention with Normosang (heme arginate), an HO-1 inducer, attenuates aneurysm progression, whereas HO-1 inhibition by Tin protoporphyrin IX abolishes this protection. Induction of HO-1 accompanied by elevated H-ferritin level also mitigated aortic wall inflammation as reflected by lowering IL1β and TNFα. These findings highlight the heme-HO-1-H-ferritin axis as an element of AAA pathogenesis and a potential therapeutic target. Full article

Background: Myocardial fibrosis, a central pathological process leading to heart failure, lacks specific mechanism-based therapies. Although the anti-inflammatory activity of the natural compound protocatechuic acid is recognized, its direct anti-fibrotic mechanism, particularly concerning the critical role of endothelial–mesenchymal transition (EndMT), remains unexplored. This study aimed to investigate the protective effects and underlying mechanisms of protocatechuic acid. Methods: The study employed both in vivo and in vitro models. For in vivo evaluation, a rat model of myocardial fibrosis was induced by isoproterenol hydrochloride (ISO). For in vitro analysis, human umbilical vein endothelial cells (HUVECs) were stimulated with angiotensin II (Ang II) and subjected to siRNA-mediated histone deacetylase 1 (HDAC1) knockdown, alongside a co-culture model involving HUVECs and the AC16 human cardiomyocyte cells. Additionally, molecular docking and dynamics simulations were performed to evaluate the binding affinity and stability of protocatechuic acid with the target protein, HDAC1. Results: In vivo, protocatechuic acid significantly improved cardiac function, attenuated pathological injury, and reduced collagen deposition in ISO-induced fibrotic rats. It also potently suppressed inflammatory responses and inhibited the EndMT process. These beneficial effects were associated with decreased HDAC1 and increased GATA binding protein 4 (GATA4) expression in perivascular regions, which suggests the modulation of the HDAC1/GATA4 pathway. In vitro, protocatechuic acid suppressed Ang II-induced endothelial inflammation in HUVECs. This effect was replicated by HDAC1 knockdown, thus confirming that the HDAC1/GATA4 pathway mediates its anti-inflammatory action at the cellular level. Furthermore, molecular docking and dynamics simulations indicated that protocatechuic acid stably binds to a key target, HDAC1. Conclusions: Protocatechuic acid alleviates inflammation and EndMT by inhibiting the HDAC1/GATA4 signaling pathway, thereby preserving cardiac function and retarding the progression of myocardial fibrosis. These findings provide a theoretical and experimental foundation for the potential application of protocatechuic acid in treating cardiovascular diseases. Full article

The downregulation of Klotho in renal injury predicts the progression of chronic kidney disease (CKD). Klotho acts as an antagonist of the Wnt/β-catenin pathway, which is involved in the pathogenesis of proteinuria, glomerulosclerosis and tubulointerstitial fibrosis. We investigated whether losartan (L, angiotensin II type-1 receptor blocker) alone or combined with synthetic (tempol, T) or natural antioxidants (olive leaf extract, O) could alter Klotho/Wnt4/β-catenin signaling, thus reducing fibrosis and slowing the progression of focal segmental glomerulosclerosis (FSGS) in spontaneously hypertensive rats (SHR). The rats were divided into five groups. The control rats received a vehicle. The other groups received adriamycin (2 mg/kg, i.v., twice in a 3-week interval) for FSGS induction. Treatments with L, L+T and L+O (10, 10 + 100 and 10 + 80 mg/kg/day, respectively) were administered by gavage during six weeks. In the kidneys of model rats, Klotho and Wnt4 were downregulated, whereas β-catenin and fibronectin levels were increased compared with the control group. L+T did not alter Klotho, Wnt4 or fibronectin levels, while it further increased β-catenin. In contrast, L+O improved Klotho, and reduced β-catenin and fibronectin levels, although it increased PAI-1. The L+O combination reduced proteinuria more efficiently than L and decreased renal injury close to control levels. Although these findings indicate that combined treatment of losartan and olive leaf extract is promising in slowing the progression of the experimental FSGS, further clinical studies are needed to confirm its favorable outcomes and safety in CKD patients. Full article

Non-toxic Jatropha curcas cake is a by-product rich in protein that can be used in the food industry. Proteolytic kinetics were used to identify and quantify its antioxidant, antidiabetic, angiotensin-converting enzyme inhibitory, and hypocholesterolemic capacities. J. curcas cake was subjected to two systems of solid-state fermentation (SSF) hydrolysis by Pleurotus ostreatus (FPO) or Ganoderma lucidum (FGL), recording every 6 d until 24 d had passed. The maximum proteolytic capacity in FPO was reached on day 6 of the study, whereas FGL was achieved at 12 d. The FPO and FGL electrophoresis gels revealed the presence of 28 bands corresponding to peptides with molecular weights of less than 10 kDa in both systems analyzed. The highest FRAP values were obtained at 12 d for FPO and at the start of SSF for FGL. The highest antidiabetic capacity of FPO was obtained at 18 d and that of FGL at 24 d. The best antihypertensive activity obtained for FPO and FGL was observed at 6 d. FPO’s highest hypocholesterolemic activity was observed at the start of the SSF, while FGL’s was obtained at 24 d, which is the first report of the hypocholesterolemic activity of J. curcas. It should be noted that fermentation with G. lucidum outperformed fermentation with P. ostreatus, confirming its greater multi-bioactivity. The authors consider this method easy, practical, and generally recognized as safe (GRAS) for obtaining bioactive peptides. Full article

The circulating renin–angiotensin–aldosterone system (RAAS) plays a key role in regulating blood volume and electrolyte levels. While important for the maintenance of intravascular volume systemically, the local activation of tissue RAAS and the generation of angiotensin II contribute to inflammation and fibrosis. In the kidney, angiotensin II plays a key role in the development and progression of glomerular injury. Angiotensin-converting enzyme 2 (ACE2), an enzyme that degrades angiotensin II, is expressed in the glomerulus, focusing attention not only on the complexity of the RAAS but also identifying a potential new determinant of glomerular injury. Accordingly, we performed a narrative review using the search terms ACE2 and glomerulus in PubMed and Google Scholar to summarize the current understanding of the role of ACE2 in glomerular injury. We also discuss the role of ACE2 as a cellular receptor for SARS-CoV-2 and the potential impact of this function on glomerular injury in the setting of COVID-19. Full article

SARS-CoV-2, the virus responsible for coronavirus disease COVID-19, is a highly transmissible pathogen that has caused substantial global morbidity and mortality. The ongoing COVID-19 pandemic caused by this virus has had a significant impact on public health and the global economy. One approach to combating COVID-19 is the development of broadly neutralizing antibodies for prevention and treatment. In this work, we performed an in silico ligand-based screening of the PDB database to search for unique anti-SARS-CoV-2 motifs. The collected data were organized and presented in a classified SARS-CoV-2 Ligands Database, categorized based on the number of ligands and structural components of the spike glycoprotein. The database contains 1797 entries related to the structures of the spike glycoprotein (UniProt ID: P0DTC2), including both full-length molecules and their fragments (individual domains and their combinations) with various ligands, such as angiotensin-converting enzyme II and antibodies. The database’s capabilities allow users to explore various datasets according to the research objectives. To search for motifs in the receptor-binding domain (RBD) most frequently involved in antibody binding sites, antibodies were classified into four classes according to their location on the RBD; for each class, special binding motifs are revealed. In the RBD binding sites, specific tyrosine-containing motifs were found. Data obtained may help speed up the creation of new antibody-based therapies, and guide the rational design of next-generation vaccines. Full article

Audiovestibular disorders arising from the inner ear (e.g., hearing loss, tinnitus, vertigo) are widely prevalent in the United States. Yet, medical treatments targeting the underlying pathology of these disorders remain scarce. The practice of repurposing FDA-approved drugs for new therapeutic indications has become increasingly common, offering a lower risk route to treatment development with fewer barriers to implementation, as safety profiles are already established. The renin–angiotensin system (RAS) is well known for its role in blood pressure and fluid balance, and its overactivation induces acute and chronic inflammation and oxidative stress. This review discusses existing evidence and proposed otoprotective mechanisms of RAS inhibition, specifically using angiotensin II type 1 receptor blockers (ARBs), which support the repurposing of these medications as novel treatments to affect the inner ear pathologies that underlay hearing loss, tinnitus, and vertigo. Full article

Although the SARS-CoV-2 pandemic no longer poses a global emergency, the virus continues to diversify and acquire immunoevasive properties. Understanding the molecular pathways that shape SARS-CoV-2 pathogenesis has become essential. In this paper, we summarize the most recent current evidence on how the spike protein structurally evolves, on changes in key non-structural proteins, such as nsp14, and on host factors, such as TMPRSS2 and neuropilin-1. These changes, together, shape viral entry, replication fidelity and interferon antagonism. Given the emerging Omicron variants of SARS-CoV-2, recent articles in the literature, cryo-EM analyses, and artificial intelligence-assisted mutational modeling were analyzed to infer and contextualize mutation-driven mechanisms. It is through these changes that the virus adapts and evolves, such as optimizing angiotensin-converting enzyme binding, modifying antigenic surfaces, and accumulating mutations that affect CD8⁺ T-cell recognition. Multi-omics data studies further support SARS-CoV-2 pathogenesis through convergent evidence linking viral adaptation to host immune and metabolic reprogramming, as occurs in myocarditis, liver injury, and acute kidney injury. By integrating proteomic, transcriptomic, and structural findings, this work presents how the virus persists and dictates disease severity through interferon antagonism (ORF6, ORF9b, and nsp1), adaptive immune evasion, and metabolic rewiring. All these insights underscore the need for next-generation interventions that provide a multidimensional framework for understanding the evolution of SARS-CoV-2 and guiding future antiviral strategies. Full article

Background: Sarcoidosis is a multisystem inflammatory disorder characterized by non-caseating granulomas, most commonly affecting the lungs and intrathoracic lymph nodes. Angiotensin-converting enzyme (ACE) levels and calcium abnormalities are recognized biomarkers, while ^18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is increasingly used to assess disease activity. However, neither provides sufficient diagnostic accuracy alone. Therefore, this study aimed to investigate the relationship between FDG-PET/CT metabolic findings and serum ACE and calcium (Ca²⁺) levels as surrogate indicators of inflammatory metabolic intensity in sarcoidosis. Methods: In this retrospective single-center study, 127 patients with pulmonary sarcoidosis who underwent PET/CT at diagnosis were evaluated. Demographic and clinical data, ACE, and Ca²⁺ levels were recorded. FDG uptake in mediastinal, pulmonary, and extrapulmonary sites was analyzed, and correlations with biomarkers were assessed. Results: The cohort included 89 females (70.1%) and 38 males (29.9%), mean age 51.3 ± 11.9 years. FDG uptake was most frequent in mediastinal lymph nodes (84.3%) and lung parenchyma (40.9%). ACE levels correlated weakly with total SUVmax (r = 0.214, p = 0.019). Calcium levels correlated with extrapulmonary SUVmax (r = 0.327, p = 0.001) and were higher in patients with extrapulmonary involvement (p = 0.045). No associations were found between symptom presence and biomarkers or SUVmax values. Conclusions: FDG-PET/CT metabolic parameters, particularly total and extrapulmonary SUVmax, demonstrated modest yet statistically significant associations with ACE and calcium levels. These findings suggest that a combined biomarker-imaging approach may provide complementary information regarding inflammatory metabolic intensity and systemic involvement; however, the results should be interpreted as exploratory and require validation in prospective studies. Full article

Osteoporosis and chronic conditions such as type 2 diabetes mellitus, cardiovascular disease, heart failure, and chronic kidney disease share several common biological mechanisms, including chronic inflammation, oxidative stress, hormonal dysregulation, and metabolic alterations. In this context, multimorbidity presents an increasing clinical challenge, particularly in older populations, where osteoporosis remains frequently underdiagnosed and undertreated. This review aims to explore the complex interplay between skeletal fragility and cardiometabolic diseases, emphasizing the role of nutritional deficiencies (such as iron and vitamin C), shared molecular pathways (advanced glycation end-products, Renin–Angiotensin–Aldosterone System, RANK Ligand, RANK), and the systemic impact of chronic inflammation and tissue hypoperfusion. The review also addresses the effects of various drug classes—antidiabetics, antihypertensives, anticoagulants, and anti-osteoporotic agents—on bone metabolism and cardiovascular risk. Special focus is given to the implementation of integrated and personalized care models, particularly multidisciplinary team-based approaches, which have demonstrated significant reductions in mortality and refracture rates, despite their still limited adoption in clinical practice. In conclusion, this review highlights the shared mechanisms between osteoporosis and cardiometabolic conditions in the context of multimorbidity, underscoring persistent clinical challenges related to diagnosis, drug interactions, and care fragmentation that warrant further research into integrated care models. Full article