Search Results (3,731)

Background: In patients with type 2 diabetes mellitus (T2DM), angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are first-line antihypertensive treatments with important cardiovascular benefits, but their impacts on coronary-specific inflammation are unknown. Pericoronary adipose tissue (PCAT) attenuation, as assessed by coronary computed tomography angiography (CCTA), serves as a specific biomarker for coronary inflammation. Here, we aim to assess whether treatment with ACE-I or ARB is correlated with lower PCAT attenuation. Methods: In this retrospective observational study, we analyzed 223 patients with T2DM and coronary atherosclerosis who underwent CCTA from 1 January 2017 to 1 September 2024 at our institution. PCAT attenuation was measured in the proximal right coronary artery. Propensity score matching and multivariate linear regression analyses were performed for comparisons. Results: Of the 223 patients (mean age of 64.9 ± 8.8 years, 69.1% male), 122 patients were on ACE-I or ARB (ACE-I/ARB). ACE-I/ARB users had similar PCAT attenuation as their counterparts after propensity score matching (−72.1 ± 7.5 and −71.7 ± 8.1 HU, respectively; p = 0.722). Subgroup analysis in patients with glomerular filtration rate (GFR) < 90 mL/min revealed lower PCAT attenuation in ACE-I/ARB users (−74.8 ± 6.6 vs. −71.4 ± 7.1 HU; p = 0.038), with a significant interaction between these two factors in the multivariate analysis (p = 0.047). Other antihypertensive treatments (beta blockers, dihydropyridine calcium channel blockers, and thiazides) were not linked with lower coronary inflammation. Conclusions: In T2DM patients with coronary atherosclerosis, we did not find an association between ACE-I/ARB treatment and lower coronary inflammation as defined by PCAT attenuation, although such a relationship may exist in those with reduced GFRs. Full article

The renin–angiotensin system (RAS) regulates inflammation, tissue homeostasis, and barrier integrity in lung and colon epithelial cells. Beyond classical pathways, non-canonical components including angiotensin-converting enzyme 2 (ACE2), epidermal growth factor receptor (EGFR), insulin-like growth factor 2 receptor (IGF2R) and aminopeptidase N (ANPEP) are implicated in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and bacterial sepsis due to their roles in tissue repair and signaling. Despite their similar inflammatory and coagulopathic features, their impact on RAS-associated non-immune gene expression in epithelial tissues remains unclear. This study investigates the regulation of these targets in lung (BEAS-2B) and colon (CRL-1831) cells following exposure to recombinant SARS-CoV-2 spike protein N-terminal domain fragment (S1-NTD) and Pseudomonas aeruginosa-derived lipopolysaccharide (LPS). Cells were treated with 100 ng/mL of S1-NTD or LPS for 12–72 h. Viability was assessed via XTT assays, and molecular changes were analyzed through qRT-PCR and Western blotting. Both stimuli induced a time and dose-dependent decrease in metabolic activity. ACE2 was significantly downregulated in lung cells, while transient upregulation occurred in colon cells at 24 h. EGFR expression increased in colon cells following LPS exposure but decreased in lung cells after S1-NTD treatment. Both IGF2R and ANPEP were upregulated by S1-NTD in lung cells at 72 h, whereas colon cells showed earlier upregulation at 24–48 h. Our findings reveal that viral and bacterial stimuli elicit distinct, tissue-specific regulatory patterns in RAS-associated pathways. These alterations may contribute to epithelial barrier dysfunction and inflammation, highlighting these proteins as potential targets for managing secondary bacterial infections and inflammatory lung–gut complications in COVID-19. Full article

Periodontitis (P) and Type 2 Diabetes Mellitus (T2DM) are chronic inflammatory diseases that share pathophysiological pathways involving immune dysregulation and oxidative stress. Both conditions have been associated with increased susceptibility to viral infections, including SARS-CoV-2. In this regard, molecules associated with viral infection include angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). This study aimed to evaluate the clinical periodontal status, oral microbiota composition, and the expression of ACE2 and TMPRSS2 in the oral epithelium and gingival tissue of patients with and without T2DM and P. Methods: This cross-sectional study enrolled 120 participants allocated into four groups based on periodontal and glycemic status: periodontally healthy non-diabetic individuals (PH non-T2DM), periodontitis without diabetes (P non-T2DM), periodontally healthy individuals with type 2 diabetes mellitus (PH T2DM), and periodontitis with T2DM (P T2DM), with 30 participants per group. Full-mouth clinical periodontal parameters were recorded by a calibrated examiner. Oral microbiota was assessed from unstimulated whole saliva, labial swab samples, and subgingival biofilm by selective culture and checkerboard DNA-DNA hybridization. Gingival exfoliative cytology and full-thickness gingival biopsies were obtained for immunohistochemical evaluation of ACE2 and TMPRSS2 expression. Cytomorphometric analysis and polymorphonuclear cell counts were performed on epithelial smears. Additionally, primary human gingival fibroblasts (HGFs) isolated from each group were stimulated with bacterial ligands (LPS, LTA, and PGN) to assess ACE2 and TMPRSS2 modulation by Western blot. Intergroup comparisons were performed using one-way ANOVA with Bonferroni post hoc correction and the Mann–Whitney U test, with statistical significance set at p < 0.05. Results: Diabetic patients exhibited higher plaque accumulation, clinical attachment loss, and bleeding on probing compared with non-diabetic individuals (p < 0.05). The diabetic groups showed significantly higher levels of Actinomyces, Fusobacterium, and Streptococcus spp., with decreased Staphylococcus counts. ACE2 and TMPRSS2 expression were markedly elevated in gingival epithelial cells of P T2DM patients, predominantly in basal and suprabasal layers. The nuclear-to-cytoplasmic ratio and polymorphonuclear cell counts were also increased in diabetic subjects. Conclusions: T2DM and P synergistically upregulate ACE2 and TMPRSS2 expression and alter the oral microbiota. Full article

Telmisartan (TEL) is a non-peptide, orally administered antihypertensive agent primarily known as angiotensin II type 1 (AT1) blocker. In this review, we provide a detailed overview of how TEL modulates voltage-gated Na⁺ current (I_Na) and affects action potential (AP) firing behavior. TEL exerts differential stimulatory effects on the peak and late components of I_Na when subjected to brief depolarizing pulses across a range of cell types, such as mHippoE-14 hippocampal neuron, cultured dorsal root ganglion neurons, and HL-1 atrial cardiomyocytes. TEL can augment the non-inactivating (persistent) I_Na elicited by ascending long ramp pulse in mHippoE-14 cells. By using a parvalbumin-expressing interneuron-based modeled cell combined with bifurcation analysis, it is possible to predict how applied current influences subthreshold oscillations and the generation of somatic spiking in the presence of TEL. According to the Hodgkin-Huxley model, mimicking the action of TEL—characterized by an increased peak amplitude of I_Na and a slowed inactivation time course—leads to the emergence of periodic oscillations in membrane potential. Using a Markovian process, a separate model can also be mathematically constructed, showing that changes in certain rate constants can simulate the effect of TEL on I_Na in cardiac cells. The molecular docking prediction between TEL and the Na_V1.7 channel was made by expected formation of hydrophobic interactions as well as hydrogen bonding. In addition to its antagonistic action at the AT1 receptor and its agonistic activation of peroxisome proliferator-activator-γ, TEL may also directly enhance I_Na, thereby modulating AP firing in a variety of excitable cells. Current evidence supports TEL’s modulatory impact on Na_V channel activity and cellular excitability, while also acknowledging that the mechanism—whether direct or indirect—remains under investigation. Full article

Background/Objectives: Immunoglobulin A nephropathy (IgAN) is a type of chronic kidney disease (CKD) and the most common cause of kidney failure in patients <40 years of age. Previous economic models in CKD have generally defined health states solely by the progression of CKD. This manuscript presents an alternative method which also considers the level of proteinuria in a CKD patient. Methods: A cohort-level state transition model was developed, comparing the health benefits of sparsentan, a dual endothelin angiotensin receptor antagonist, to irbesartan, an angiotensin receptor blocker, in IgAN. Within four UP/C (proteinuria) states, patients are assigned to three sub-health states according to CKD stage. Patients with end-stage renal disease are grouped together, irrespective of UP/C, and are stratified instead by renal replacement therapy modality. Transition matrices are derived from a combination of data from PROTECT, a clinical trial comparing sparsentan to irbesartan, and the UK RaDaR registry. Health-related quality of life data from a general CKD population is used as a proxy. Results: Patients with IgAN who were modelled to receive treatment with sparsentan had an estimated total undiscounted life years of 25.5 years, a gain of 0.9 years in comparison with irbesartan. Patients were also more likely to spend more time in earlier CKD stages while in pre-ESRD. This translated to significant quality-adjusted life year gains for patients treated with sparsentan in comparison with irbesartan. Conclusions: This study presents a new structure for health economic models in IgAN that more comprehensively captures the effect of proteinuria in combination with CKD progression. This new approach ultimately allows for the more robust implementation of clinical trial data in IgAN and estimates of the cost-effectiveness of new treatments. Full article

Hypertension frequently remains uncontrolled despite pharmacological therapy, supporting interest in complementary nutritional strategies. This narrative review evaluates human clinical evidence and mechanistic pathways for minerals, polyphenols, omega-3 fatty acids, probiotics, coenzyme Q10, and L-arginine in blood pressure regulation. Across these categories, antihypertensive effects appear to depend largely on post-ingestion metabolic biotransformation into bioactive metabolites that influence endothelial nitric oxide availability, vascular inflammation, renal sodium handling, and renin–angiotensin system activity. Randomized controlled trials and meta-analyses consistently demonstrate modest reductions in systolic blood pressure of approximately 2–8 mmHg, although most studies are short-term and frequently use supplementation models. The overall certainty of evidence is moderate due to consistent but heterogeneous randomized trials. Variability in response is partly explained by metabolic phenotype and gut microbiota composition, and combined dietary patterns targeting multiple mechanisms may produce additive effects. Overall, nutraceuticals function as adjunct physiological modulators that may contribute to cardiovascular risk reduction but are not intended to replace pharmacological therapy. The present review integrates post-ingestion metabolism, microbiota-derived mediators, and clinical trial evidence into a unified physiological framework explaining why consistent but modest blood pressure reductions occur across heterogeneous interventions. Nutritional strategies remain underutilized in routine clinical practice despite reproducible physiological effects. Incorporating evidence-based nutraceutical approaches alongside pharmacological management may facilitate patient engagement with lifestyle modification, as dietary interventions are often perceived as more achievable than isolated behavioral recommendations. A holistic management model integrating medical therapy, nutrition, and patient education may therefore enhance long-term adherence to cardiovascular prevention strategies and support sustained risk reduction. Full article

Proteinuria is a strong predictor of graft failure in kidney transplant recipients (KTRs). While non-steroidal mineralocorticoid receptor antagonists (NS-MRAs), particularly finerenone, have demonstrated renoprotective benefits in chronic kidney disease, KTRs were excluded from pivotal trials. Evidence on finerenone’s safety and antiproteinuric effects in this population remains limited. This retrospective observational study evaluated 13 diabetic KTRs with persistent proteinuria despite optimized renin–angiotensin system blockade and sodium–glucose cotransporter 2 inhibitor therapy. Finerenone (10 mg/day) was added to standard care. Clinical and laboratory parameters, including estimated glomerular filtration rate (eGFR), serum electrolytes, total proteinuria, albuminuria, and their creatinine ratios, were assessed at baseline, 3 months, and 6 months. Safety outcomes focused on hyperkalemia and eGFR. Finerenone was discontinued in one patient due to hyperkalemia. In the remaining 12, 24-h proteinuria and urinary protein-to-creatinine ratio declined at 3 months and stabilized by 6 months. Conversely, no statistically significant changes were observed in albuminuria or the albumin-to-creatinine ratio. No clinically relevant changes occurred in eGFR, blood pressure, body weight, or serum electrolytes. This is the first study assessing finerenone in diabetic KTRs. Finerenone was well tolerated, was associated with an early reduction in proteinuria, and showed no adverse effects on graft function. These findings provide novel insights into the safety and potential role of finerenone in kidney transplant recipients. Full article

Hierarchical functionalisation of the UiO-66(Zr)-NH₂ metal–organic framework with cysteine, poly(ethylene glycol) (PEG), and the SARS-CoV-2 spike receptor-binding domain (RBD) was developed to enable receptor-specific interaction with the angiotensin-converting enzyme 2 receptor (ACE2) in model cells. Post-synthetic modification using cysteine and heterobifunctional PEG linkers allowed controlled bioconjugation of SpyTag-labelled RBD via SpyTag/SpyCatcher chemistry, while preserving the crystallinity, microporosity, and intrinsic optical properties of the UiO-66(Zr)-NH₂ framework. Comprehensive physicochemical characterisation confirmed successful surface functionalisation, tunable aggregation behaviour, and retention of multimodal optical characteristics. Cellular studies in HEK293T and HeLa cells overexpressing EGFP-tagged ACE2 demonstrated enhanced and selective association and uptake of RBD-functionalised nanoparticles compared with non-targeted analogues. Multimodal fluorescence imaging, fluorescence lifetime imaging microscopy, flow-cytometry, and electron microscopy indicated ACE2-dependent endocytic internalisation, with predominant localisation in endosomal and autophagosomal compartments, while both amine- and cysteine-modified formulations exhibited good biocompatibility. Overall, this study establishes a virus-mimetic, ACE2-targeted UiO-66(Zr)-based nanosystem as a proof-of-concept biointerface platform for receptor-specific cellular delivery and imaging, providing a foundation for future MOF-based nanocarriers exploiting ligand–receptor interactions. Full article

Hypertension is a common cardiovascular disorder, and current pharmacological treatments are often associated with significant side effects, highlighting the need for safer alternatives. Probiotics and their postbiotics have emerged as promising candidates due to their favorable safety profiles. This study evaluated the potential of Lactobacillus plantarum IOB602 and its 602P postbiotic to attenuate hypertension-induced damage. We first assessed their ACE inhibitory activity in vitro. Subsequently, we investigated their protective effects against organ damage and the underlying mechanisms in L-NAME-induced hypertensive rats using biochemical assays, real-time qPCR, histopathological analysis, and 16S rRNA sequencing. In vitro results showed that IOB602 exhibited strong tolerance to simulated gastric acid and bile salts, indicating good gastrointestinal survivability. Both the culture supernatant and the postbiotic displayed significant ACE inhibitory activity, with the postbiotic achieving an inhibition rate of 82.21%. In vivo, treatment with IOB602 or 602P significantly reduced plasma angiotensin II levels, upregulated the PI3K-Akt-eNOS pathway, restored nitric oxide bioavailability, and attenuated oxidative stress and inflammatory responses in hypertensive rats. Histological analysis revealed that both interventions alleviated pathological damage in the thoracic aorta, heart, and kidneys. Furthermore, IOB602 and its postbiotic reshaped the gut microbiota composition by decreasing harmful genera such as Ruminococcus and enriching beneficial taxa including Akkermansia and Christensenellaceae. In conclusion, L. plantarum IOB602 and its 602P postbiotic show potential for development as functional foods or pharmaceutical adjuvants for the treatment of hypertension-induced organ damage.: Full article

The aqueous extract of Diaphragma Juglandis Fructus (AED), a by-product of Juglans regia L., represents a promising food-derived functional ingredient with potential benefits for intestinal health. This study evaluated the anti-colitis effects of AED and explored its underlying mechanisms using LPS-stimulated RAW264.7 macrophages and a DSS-induced colitis mouse model. In DSS-induced colitis in mice, AED at 10 μg/mL suppressed pro-inflammatory cytokine production and inhibited JAK1/STAT3 signaling. In DSS-induced colitis in mice, AED at 600 mg/kg for 7 days mitigated DSS-induced colonic injury, restored tight junction proteins, and improved epithelial barrier integrity. Integrated transcriptomic and metabolomic analyses identified AED-associated alterations in arginine-polyamine and taurine-hypotaurine metabolism, while network pharmacology and molecular docking suggested angiotensin-converting enzyme (ACE) and von Willebrand factor (VWF) as candidate functional targets for further investigation. Collectively, these findings indicate that AED exerts anti-colitis effects in association with coordinated changes in inflammatory signaling, metabolic pathways, and barrier-related markers, supporting its potential as a food-derived functional ingredient candidate for ulcerative colitis management. Full article

Hypertension remains a leading cause of global morbidity and mortality, and angiotensin-converting enzyme (ACE) represents a central therapeutic target within the renin–angiotensin–aldosterone system. Marine microalgae, particularly Phaeodactylum tricornutum, provide an underexplored reservoir of structurally diverse metabolites with potential cardiovascular relevance. In this in silico study, we characterized metabolites putatively annotated by UPLC-ESI-HRMS and evaluated their predicted ACE inhibitory potential. We performed molecular docking with AutoDock 4 and assessed pharmacokinetic and toxicological properties using the SwissADME, PASS, and ProTox platforms. Several metabolites showed favorable binding orientations within the ACE catalytic pocket, including interactions with key residues and proximity to the zinc-binding motif. Lehualide G, Val–Asn–Pro, tanariflavanone B, hydroxyterbinafine, and anhydro-vitamin A exhibited the most favorable docking profiles. PASS predictions indicated vascular-related bioactivity signals for selected compounds, whereas ADMET modeling revealed heterogeneous but classifiable pharmacokinetic and safety characteristics. The convergence of predicted binding compatibility, bioactivity signals, and stratified safety margins supports P. tricornutum as a promising source of candidate molecules for further experimental validation in antihypertensive research. Full article

Cardiac safety assessment is an integral part of drug discovery and development. Drug candidates that adversely affect cardiac or hemodynamic function should be discontinued early unless a favorable benefit-risk ratio for patients can be justified. In this hypothesis-generating work, we aimed to develop a conceptual framework for informing early safety risk assessment based on in vitro drug affinities to pharmacological targets. For illustration, we used the drug-induced cardiotoxicity rank (DICTrank) data comprising 1318 drugs with cardiac safety concerns according to FDA labeling. The data was enriched with information on affinity to the most plausible mechanistic targets, clinical drug exposure, and human plasma protein binding. We descriptively identified 18 target classes potentially associated with elevated cardiovascular risk: potassium channels (accounting alone for 20% of the ‘most concern’ safety group); adrenergic, dopamine, serotonin, androgen, sex hormone, and opioid receptors; cyclooxygenase; sodium and calcium channels; muscarinic and glucocorticoid receptors; phosphodiesterase; topoisomerase; angiotensin-converting enzyme; angiotensin II type 1 receptor; monoamine transporters, and acetylcholinesterase. Overall, 80% of the ‘most concern’ drugs compared with only 12% of the ‘no concern’ drugs were associated with these targets in this exploratory descriptive analysis. Concentration–response analyses revealed differences in target potency and free drug exposure that appeared associated with variability in the severity of cardiotoxicity among drugs acting on the same target. This framework demonstrates how in vitro data can be used to benchmark new compounds early in development, enabling the timely discontinuation of candidates associated with substantial risk. Full article

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease characterized by vascular smooth muscle cell (VSMC) dysfunction and disrupted calcium homeostasis. While transient receptor potential canonical 6 (TRPC6) and transient receptor potential canonical 1 (TRPC1) are known to mediate receptor-operated calcium entry (ROCE) and store-operated calcium entry (SOCE), respectively, the specific contributions of SOCE and ROCE to AAA pathogenesis, and the regulatory interaction between transient receptor potential melastatin 8 (TRPM8) and TRPC1 remain unexplored. In this study, we analyzed human AAA tissues, a papain-induced mouse model, and angiotensin II (Ang II)-treated human aortic smooth muscle cells using histology, wire myography, calcium imaging, and patch-clamp electrophysiology. We observed significant upregulation of TRPM8, TRPC1, and TRPC6 in both human and experimental AAA, with TRPC1 identified as a key mediator of SOCE under pathological conditions. Pharmacological activation of TRPM8 by menthol attenuated TRPC1-mediated SOCE and associated vasoconstriction, effects that were partially reversed by the TRPM8 antagonist A-2. In Ang II-treated cells, TRPM8 activation reduced SOCE and store-operated calcium currents (I_SOCC), effects that were largely abolished by TRPC1 knockdown. These findings suggest that TRPM8 may limit excessive calcium ion (Ca²⁺) influx and vascular remodeling in AAA, pointing to a potential endogenous mechanism to counteract maladaptive calcium signaling in AAA progression. Full article

Background: COVID-19 severity shows marked interindividual variability, suggesting a role for host genetic factors. Polymorphisms in genes involved in the renin–angiotensin system and inflammatory response, such as the angiotensin-converting enzyme (ACE) and the tumor necrosis factor-alpha (TNF-α), have been proposed as potential modulators of disease severity. Objectives: To evaluate the association between the ACE I/D (rs4646994) and TNF-α-308 G/A (rs1800629) polymorphisms and COVID-19 severity in a Mexican population. Methods: A total of 235 individuals with RT-PCR–confirmed SARS-CoV-2 infection were included. Patients were classified as hospitalized (severe, n = 155) or non-hospitalized (asymptomatic–mild, n = 80). Genotyping was performed by PCR–RFLP. Genotype distributions were analyzed using χ² tests under dominant and recessive genetic models, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: The ACE I/D polymorphism showed a significant association with COVID-19 severity. Carriers of the I allele (ID + II) had a higher risk of hospitalization compared with DD homozygotes (OR = 2.78, 95% CI: 1.53–5.06, p = 0.001). After adjustment for sex, the association remained significant (adjusted OR = 2.55, 95% CI: 1.38–4.70, p = 0.003). Sex-stratified analysis revealed that this association was significant only in male patients. The DD genotype was more frequent among non-hospitalized individuals, suggesting a potential protective effect in this population. No significant association was observed between the TNF-α-308 G/A polymorphism. Conclusions: The ACE I/D polymorphism is associated with COVID-19 severity in a Mexican population, with a stronger association observed in males. These findings highlight the potential role of host genetic background and sex-specific effects in COVID-19 outcomes. Full article

Largemouth bass (Micropterus salmoides) represents an important freshwater aquaculture species. Dietary protein strategies significantly influence growth performance, immune markers, and intestinal microbiota homeostasis. This study evaluated the physiological effects of five phased protein regimens on juvenile largemouth bass (9.77 ± 0.03 g) over 60 days. A constant 46% protein diet (CON) served as the control, compared with four dynamic regimens (LLH, LMH, LHH, HML) comprising low (L, 43%), medium (M, 46%), or high (H, 50%) protein levels across three 20-day phases. Seven hundred fish were randomly allocated into five groups (four replicates each). Daily feed intake was recorded, body weight was measured at the start and end, and survival rates were monitored. Post-trial assessments included body composition, serum biomarkers, intestinal morphology, and intestinal microbiota. Results showed that the LHH regimen significantly increased immunoglobulin M, complement C3 and C4, lysozyme activity, catalase, glutathione peroxidase, and total antioxidant capacity compared to the CON group. The LHH group also exhibited a reduced relative abundance of Stenotrophomonas_A. Functional predictions indicated downregulation of limonene/pinene degradation and the renin–angiotensin system. The LHH feeding regimen synergistically enhances immune-antioxidant function and optimizes intestinal microbiota in juvenile largemouth bass. Full article