Search Results (313)

Captopril, a well-established angiotensin-converting enzyme (ACE) inhibitor, has garnered attention for its cardioprotective effects in preventing heart remodeling and maintaining cardiac function, significantly improving life quality. However, recent studies have revealed that in addition to known hemodynamic alterations, captopril exhibits significant antioxidant, anti-inflammatory, and immunomodulatory effects that may underlie its protective mechanisms. Although it appeared to be overlooked in clinical practice, in recent years, additional efforts have been made to uncover the mechanisms of all drug effects, as recent research studies predict a wide spectrum of diseases beyond the recommended indications. This review thoroughly examines the mechanisms by which captopril mediates its protective effects, bridging basic biochemical observations with applied clinical investigation, especially during ischemic reperfusion (I/R) injury, hypertension, and heart failure (HF). Evidence points to captopril as a promising agent for modulating oxidative and inflammatory pathways that are crucial for cardiovascular medicine. Directions for future research are defined to determine the molecular targets of captopril further and to optimize its clinical utility in the management of cardiovascular and possibly other diseases. Full article

Patients with ulcerative colitis exhibit an increased risk for supraventricular arrhythmia during the active disease phase of the disease and show signs of atrial electrophysiological remodeling in remission. The goal of this study was to determine the basis for colitis-induced changes in atrial excitability. In a mouse model (C57BL/6; 3 months) of dextran sulfate sodium (DSS)-induced active colitis (3.5% weight/volume, 7 days), electrocardiograms (ECG) revealed altered atrial electrophysiological properties with a prolonged P-wave duration and PR interval. ECG changes coincided with a decreased atrial conduction velocity in Langendorff perfused hearts. Action potentials (AP) recorded from isolated atrial myocytes displayed an attenuated maximal upstroke velocity and amplitude during active colitis, as well as a prolonged AP duration (APD). Voltage clamp analysis revealed a colitis-induced shift in the voltage-dependent activation of the Na-current (I_Na) to more depolarizing voltages. In addition, protein levels of Na_v1.5 protein and connexin isoform Cx43 were reduced. APD prolongation depended on a reduction in the transient outward K-current (I_to) mostly generated by K_v4.2 channels. The changes in ECG, atrial conductance, and APD were reversible upon remission. The change in conduction velocity predominantly depended on the reversibility of the reduced Cx43 and Na_v1.5 expression. Treatment of mice with inhibitors of Angiotensin-converting enzyme (ACE) or Angiotensin II (AngII) receptor type 1 (AT1R) prevented the colitis-induced atrial electrophysiological remodeling. Our data support a colitis-induced increase in AngII signaling that promotes atrial electrophysiological remodeling and puts colitis patients at an increased risk for atrial arrhythmia. Full article

Angiotensin-converting enzyme 2 (ACE2) is a cell-surface receptor that helps the body regulate blood pressure and endocrine secretions. Transmembrane serine protease 2 (TMPRSS2) is a cell surface protein expressed mainly by endothelial cells of the respiratory and digestive tract, which participates in the cleavage of protein peptide bonds with serine as the active site. These two proteins have been studied to be highly associated with infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soybean trypsin inhibitor (SBTI) has special bioactivities such as anticarcinogenic and anti-inflammatory functions, which can be widely used in functional foods or drugs. Our study involved in vitro and in vivo experiments to elucidate the effect of SBTI on SARS-CoV-2 host invasion. First, it was confirmed that being under 250 μg/mL of SBTI was not toxic to HepG2, HEK293T, and Calu-3 cells. The animal study administered SBTI to mice once daily for 14 days. In the lungs, liver, and kidneys, the histopathologic findings of the SBTI group were not different from those of the control group, but the expression of ACE2, TMPRSS2, and CD147 was reduced. Thus, our findings suggest that the inhibition of ACE2, TMPRSS,2 and CD147 proteins by SBTI shows promise in potentially inhibiting SARS-CoV-2 infection. Full article

This study explores the identification, characterization, and biological evaluation of angiotensin I-converting enzyme (ACE)-inhibitory peptides derived from enzymatic hydrolysates of crucian carp swim bladders. Following sequential purification by size-exclusion and reversed-phase chromatography, two bioactive peptides—Hyp-Gly-Ala-Arg (Hyp-GAR) and Gly-Ala-Hyp-Gly-Ala-Arg (GA-Hyp-GAR)—were identified using ultra-high-performance liquid chromatography coupled with linear ion trap–Orbitrap tandem mass spectrometry. The synthetic peptides demonstrated potent ACE-inhibitory activity in vitro, with IC₅₀ values of 12.2 μM (Hyp-GAR) and 4.00 μM (GA-Hyp-GAR). Molecular docking and enzyme kinetics confirmed competitive inhibition through key interactions with ACE active site residues and zinc coordination. In vivo antihypertensive activity was evaluated in spontaneously hypertensive rats, revealing that GA-Hyp-GAR significantly reduced systolic blood pressure in a dose-dependent manner. At a dose of 36 mg/kg, GA-Hyp-GAR reduced systolic blood pressure by 60 mmHg—an effect comparable in magnitude and timing to that of captopril. Mechanistically, GA-Hyp-GAR modulated levels of angiotensin II, bradykinin, endothelial nitric oxide synthase, and nitric oxide. A 90-day subchronic oral toxicity study in mice indicated no significant hematological, biochemical, or histopathological alterations, supporting the peptide’s safety profile. These findings suggest that GA-Hyp-GAR is a promising natural ACE inhibitor with potential application in functional foods or as a nutraceutical for hypertension management. Full article

The venom of Nemopilema nomurai jellyfish represents a promising source of bioactive compounds with potential pharmacological applications. In our previous work, we identified two novel angiotensin-converting enzyme (ACE)-inhibitory peptides—IVGRPLANG (896.48 Da) and IGDEPRHQYL (1227.65 Da)—isolated from N. nomurai venom hydrolysates via papain digestion. In this study, we conducted a detailed biochemical and computational characterization of these peptides. The IC₅₀ values were determined to be 23.81 µM for IVGRPLANG and 5.68 µM for IGDEPRHQYL. Kinetic analysis using Lineweaver–Burk plots revealed that both peptides act as competitive ACE inhibitors, with calculated inhibition constants (K_i) of 51.38 µM and 5.45 µM, respectively. To assess the structural stability of the ACE–peptide complexes, molecular dynamics simulations were performed. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analyses provided insights into complex stability, while interaction fraction analysis elucidated key bond types and residue–ligand contacts involved in binding. Furthermore, a network pharmacology approach was employed to predict therapeutic targets within the renin–angiotensin–aldosterone system (RAAS). Eleven target proteins were identified: IVGRPLANG was associated with REN, ACE, CTSB, CTSS, and AGTR2; IGDEPRHQYL was linked to REN, AGT, AGTR1, AGTR2, KNG1, and BDKR2. Molecular docking analyses using HADDOCK software (version 2.4) were conducted for all targets to evaluate binding affinities, providing further insight into the peptides’ therapeutic potential. Full article

Background: The COVID-19 (coronavirus disease 19) pandemic has underscored the urgent need for effective antiviral agents targeting viral entry mechanisms. This study investigated the inhibitory effects of heparan sulfate (HS) and enoxaparin (EX) on the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the angiotensin-converting enzyme 2 (ACE2) receptor. Methods: A pseudovirus model was employed to evaluate the efficacy of HS and EX under different treatment strategies: pre-treatment of host cells, pre-treatment of the viral particles, and simultaneous co-treatment. Results: Both compounds significantly inhibited viral entry. EX exhibited a dose-dependent effect under all treatment conditions. In cell pre-treatment, EX achieved the highest levels of inhibition, whereas HS demonstrated consistent inhibitory activity that was largely concentration-independent. Viral pre-treatment revealed that both compounds effectively reduced infectivity by interfering directly with viral particles. In the co-treatment experiments, HS demonstrated superior inhibitory activity at lower concentrations compared to EX. Conclusions: The results suggested that HS and EX inhibit SARS-CoV-2 entry via distinct mechanisms. HS likely acts via competitive inhibition at the host cell surface, while EX may bind directly to the spike protein, thereby preventing engagement with the ACE2 receptor. These findings highlight the therapeutic potential of HS and EX as entry inhibitors targeting the early stages of SARS-CoV-2 infection. Further studies are warranted to evaluate their efficacy against emerging variants and in vivo models. Full article

Cancer therapy-induced hypertension (HTN) is an increasingly recognized complication associated with a wide range of anticancer agents, including vascular endothelial growth factor (VEGF) inhibitors, proteasome inhibitors, tyrosine kinase inhibitors, and alkylating agents. The pathogenesis of HTN in this setting is multifactorial, involving mechanisms such as endothelial dysfunction, nitric oxide (NO) suppression, sympathetic nervous system activation, and vascular remodeling. Additional factors, including paraneoplastic syndromes, poorly controlled pain, mood disturbances, and overlapping cardiovascular risk factors like obesity and diabetes, further contribute to the complexity of diagnosis and management. Despite its prevalence and clinical implications, cancer therapy-induced HTN is often addressed using general population guidelines, with limited oncology-specific protocols available. Accurate blood pressure measurement and individualized treatment plans are critical to optimize outcomes and avoid interruptions to cancer therapy. Antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), and calcium channel blockers have shown efficacy in both blood pressure control and, in some cases, oncologic outcomes. A multidisciplinary approach involving oncologists, cardiologists, and primary care providers is essential to navigate the interplay between cancer treatment and cardiovascular health. Ongoing research is needed to develop targeted guidelines and improve the long-term care of cancer patients affected by treatment-induced HTN. Full article

Bovine milk protein preparations (MPPs), namely micellar casein concentrate (MCC), serum protein concentrate (SPC), and MCC with ultrafiltrated buttermilk permeate (MBP), were analyzed as sources of inhibitors of angiotensin-converting enzyme (i.e., ACE) and dipeptidylpeptidase IV (i.e., DPP-IV) as well as antioxidative peptides. The studies involved in silico predictions of the release of biopeptides from bovine milk proteins. Then, all MPPs were subjected to the simulated gastrointestinal digestion using the INFOGEST protocol. Results using a BIOPEP-UWM database tool indicated that 59 biopeptides exhibiting the above-mentioned activities could be produced upon the action of pepsin, trypsin, and chymotrypsin. Thirty-six biopeptides were identified in at least one of the three MPPs subjected to the INFOGEST protocol. MCC before simulated digestion exhibited the strongest ACE-inhibiting activity among all MPPs (IC₅₀ = 1.856 mg/mL). The weakest ACE inhibitory effect was demonstrated for MBP after duodenal digestion (i.e., MBP D; IC₅₀ = 7.627 mg/mL). The above MPP showed the strongest DPP-IV-inhibiting activity (IC₅₀ = 0.0067 mg/mL). All MPPs exhibited antioxidative activity, with the strongest ABTS^•+ (i.e., 2,2′-azino-bis(3-ethylbenzotialozline-6-sulfonic acid) radical scavenging effect shown for MBP D (IC₅₀ = 2.754 mg/mL), and the strongest DPPH^• (i.e., 2,2-diphenyl-β-picrylhydrazyl) radical scavenging activity (IC₅₀ = 1.238 mg/mL) demonstrated for SPC D. Among all MPPs, SPC D also exhibited the highest FRAP (i.e., Ferric Reducing Antioxidant Power) bioactivity (IC₅₀ = 13.720 mg/mL), whereas MBP D was the MPP with the lowest FRAP potential (IC₅₀ = 20.140 mg/mL). The present study results show the potential of all MPPs as functional additives to support health-beneficial functions of dairy products. Full article

Angiotensin-Converting Enzyme (ACE) plays a pivotal role in the renin–angiotensin system, modulating blood pressure and electrolyte homeostasis by deactivating bradykinin and activating angiotensin II. Metabolites from Senecio nutans (1 and 3), a plant indigenous to the Andean region of the Atacama Desert, and their respective oximes, 2 and 4, were subjected to molecular docking analysis, employing six ACE crystal structures. ACE activity assays revealed that oximes exhibited superior inhibitory effects compared to metabolites. Among the compounds investigated, 2 emerged as the most potent ACE inhibitor (2 = 11.5 μM and 4 = 13.4 μM). The vascular contractile response to Angiotensin I showed significant (p < 0.05) reductions in Ang I contraction with 2, 3, and 4 (97 ± 6%, 81 ± 6%, 81 ± 3% compared to control), while 1 exhibited no such effect. These results reinforce the potential of 2 as a promising ACE inhibitor and highlight its impact on vascular contractility. As such, it is a promising candidate for ACE inhibition and hypertension treatment. Full article

Background/Objectives: The current study aims to estimate the frequency of abnormal renal status (ARS, defined as chronic kidney disease (CKD) diagnosis in electronic medical records or current albuminuria) in people with newly diagnosed diabetes mellitus (DM), to determine the associated risk factors, and to evaluate the level of compliance with good clinical practice recommendations. Methods: Cross-sectional study with 1030 adults diagnosed with DM in the last 4 years. Anthropometric, clinical, analytical, and lifestyle variables were collected. Multivariate analyses were performed to determine the factors associated with ARS. Results: Hypercholesterolaemia, metabolic syndrome, hypertension, obesity, hypertriglyceridaemia, and cardiovascular disease (CVD) were the most prevalent comorbidities. ARS was present in 11.5% of patients. The variables associated with ARS were male sex (OR: 1.78; 95% CI, 1.16–2.75), age ≥70 years (OR: 2.96; 95% CI: 1.92–4.56), hypertension (OR: 1.59; 95% CI: 1.03–2.44), CVD (OR: 1.73; 95% CI: 1.03–2.90), and hemoglobin A1c (HbA1c) ≥8% (OR: 2.26; 95% CI, 1.19–4.27). Among patients with hypertension and albuminuria, 80% received angiotensin-converting enzyme inhibitors (ACE inhibitor) or an angiotensin receptor blocker (ARB), compared to 60% of those with albuminuria without hypertension. The 42.4% patients with ARS were treated with sodium-glucose cotransporter type 2 inhibitors (SGLT2i) and 72% with statins, but only 31.5% achieved the target low density lipoproteins cholesterol (LDLc) < 70 mg/dL. Conclusions: ARS in newly diagnosed patients with DM is less common than described in the literature, but risk factors for its development are highly prevalent. Adherence to good clinical practice recommendations was poor, especially in LDL cholesterol targets and the use of SGLT2i. Full article

Human angiotensin-I-converting enzyme (ACE) is involved in vasoregulation, inflammation, and neurodegenerative disorders. The enzyme is formed of two domains; the C-domain (cACE) is primarily involved in blood pressure regulation, whereas the N-domain (nACE) is strongly linked to fibrosis; hence, designing domain-specific inhibitors could make a difference between treating one condition without having a negative effect on another. AnCE (a close homologue of ACE) is derived from Drosophila melanogaster and has a high similarity specifically to cACE. Due to high similarity and ease of crystallisation, AnCE has been chosen as a model protein for ACE studies and for the design of ACE inhibitors. In this study, enzyme kinetic assays and X-ray crystallography techniques revealed the significance of using dipeptides as selective inhibitors for AnCE and how this knowledge could be applied to cACE and nACE. All the dipeptides tested in this study were shown to bind AnCE in two distinct locations, i.e., the non-prime and prime subsites. It was found that a hydrophobic residue at the S1 and S1′ subsites, with a tryptophan at the S2 and S2′ subsites, showed highest affinity towards AnCE. It was also observed that a key pocket within the S2′ subsite had a major influence on the binding orientation within the prime subsites and could potentially explain ACE’s dipeptidyl carboxypeptidase activity. Importantly these dipeptides are found in functional foods, making them potentially available from diets. Knowledge of the dipeptide binding presented here could aid in the development of ACE domain-specific inhibitors. Full article

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) can damage the endothelium and increase arterial stiffness, potentially leading to adverse cardiovascular events. In parallel, systemic inflammation in COVID-19 also impacts endothelial function. Angiotensin-converting enzyme 2 (ACE2) promotes vasodilation and anti-inflammatory effects, but also facilitates SARS-CoV-2 entry into human cells. Thus, concerns have been raised about the use of RAAS inhibitors (RAASi) in COVID-19 patients due to potential ACE2 upregulation. However, the clinical significance of increased plasma ACE2 (sACE2) in RAASi-treated COVID-19 patients remains unclear. Methods: This prospective, single-centre study evaluated RAASi, sACE2, and vascular function in acutely ill patients with COVID-19 in comparison with acutely ill patients without COVID-19. Adult emergency department patients with confirmed or suspected COVID-19 were enrolled and underwent pulse wave velocity, ankle brachial index, and sACE2 measurements. Results: In the 152 included patients (50% female, median age 62 years, 68% COVID-19 positive), the sACE2 values were slightly higher in the COVID-19 (0.485 [0.364–1.329]) than in the non-COVID-19 subgroup (0.458 [0.356–1.138]; p = 0.70). No significant differences in sACE2 were observed between patients with and without RAASi, regardless of COVID-19 status. Pulse wave velocity values differed significantly between groups (p = 0.015). Conclusions: In emergency department patients, sACE2 was upregulated in COVID-19 patients, probably due to oxidative stress and inflammation. RAASi did not increase sACE2, but may have protective effects against inflammation. Elevated sACE2 appeared to have a beneficial effect on arterial stiffness in all patients. These findings support continued RAASi therapy in COVID-19 patients to protect against chronic inflammation and apoptosis. Full article

Background: Ischemic heart disease remains the leading cause of death worldwide, with coronary microvascular dysfunction (CMD) as a key complication after ST-elevation myocardial infarction (STEMI). Endothelial dysfunction contributes to CMD, impairing vascular tone and increasing inflammation. While angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) aid vascular health, their efficacy may improve with therapeutic ultrasound, which enhances drug delivery and endothelial response. This study explores the combined effects of ultrasound and pharmacological treatment on the ACE axis and inflammation in endothelial and renal cells. Methods: Human umbilical vein endothelial cells (HUVECs) and human renal proximal tubular epithelial cell line RPTEC/TERT1 were treated with captopril, losartan, and dexamethasone, alone or combined with low-frequency ultrasound (LFU). Cell viability and wound-healing assays assessed cellular function, while nitric oxide (NO) and reactive oxygen species (ROS) assays were used to evaluate redox signaling. Gene expression related to the ACE axis, inflammation, and vascular and renal cell function was analyzed via qPCR. Results: Captopril and losartan combined with LFU improved endothelial cell viability, wound healing, and NO production at various concentrations, whereas only losartan with LFU enhanced cell viability and wound healing in renal cells. Dexamethasone with LFU increased ROS levels and had variable effects on RPTEC/TERT1 cell survival. Gene expression analysis showed that LFU alone reduced pro-inflammatory markers VCAM-1, ICAM-1, and PTGS2 in captopril-treated HUVECs and similarly affected CYP4F2 in losartan-treated HUVECs. LFU also decreased PTGS2 expression at higher dexamethasone concentrations. In RPTEC/TERT1 cells, LFU alone did not impact SGLT2 or GGT1 expression, but captopril with LFU downregulated GGT1, and dexamethasone with LFU upregulated SGLT2 at higher concentrations. Conclusions: This study demonstrates that LFU enhances the effects of RAS inhibitors by promoting NO synthesis and reducing oxidative stress, while its combination with dexamethasone may have variable, potentially cytotoxic effects on renal cells. Gene expression patterns suggest LFU’s anti-inflammatory potential and its role in modulating drug efficacy. Full article

The aim of this study was to identify and characterize the bioactive peptide profile of Podolica cow’s milk. This dairy product is known for its nutritional properties related to the presence of peculiar lipids and is a typical breed traditionally reared in southern Italy. Using top-down peptidomics, we identified 2213 peptides in milk samples from four different farms, with 19 matching bioactive sequences. Bioactivities include dipeptidyl peptidase-IV (DPP-IV) inhibition, angiotensin-converting enzyme (ACE) inhibition, antioxidant activity, enhanced calcium uptake, and other peptides with potential antimicrobial effects. DPP-IV-inhibitory peptides (e.g., LDQWLCEKL and VGINYWLAHK) suggest potential for type 2 diabetes management, while ACE inhibitors (such as YLGY and FFVAPFPEVFGK) could support cardiovascular health by reducing hypertension. Antimicrobial peptides such as SDIPNPIGSENSEK and VLNENLLR showed broad spectrum of activity against various harmful microorganisms, positioning Podolica milk as a promising source for natural antimicrobial agents. Additionally, peptides with osteoanabolic, antianxiety, and immunomodulatory properties further highlight the multifaceted health benefits associated with this type of milk. Our findings underline the functional richness of Podolica milk peptides with various bioactivity properties, which could enhance the value of derived dairy products and contribute to sustainable agricultural practices. Future research will aim to explore these bioactivity properties in vivo, establishing a foundation for functional foods and supplements based on Podolica milk. Full article

The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has led to resistance against multiple coronavirus disease 2019 (COVID-19) vaccines and therapeutic medications, making the development of effective therapeutics against SARS-CoV-2 a high priority. Studies have shown that bioactive polyphenols, particularly those with triphenol groups, can effectively inhibit the activity of SARS-CoV-2 3-chymotrypsin-like protease (3CL^pro). However, the structural instability of polyphenols necessitates further research. To address this, we conducted a literature review to identify triphenol compounds that are either approved or currently undergoing clinical trials, assessing their potential to inhibit SARS-CoV-2 3CL^pro. Exifone and benserazide hydrochloride were identified as the inhibitors of SARS-CoV-2 3CL^pro among these compounds, using a fluorescence resonance energy transfer (FRET)-based assay. Benserazide hydrochloride was confirmed as a covalent binder to SARS-CoV-2 3CL^pro through time-dependent inhibition and kinetic analysis, with its binding mode elucidated by molecular docking. Notably, exifone not only inhibited the protease activity but also blocked the interaction between the host cell receptor angiotensin-converting enzyme 2 (ACE2) and the SARS-CoV-2 spike protein receptor binding domain (S-RBD), as identified by surface plasmon resonance (SPR) and flow cytometry. Additionally, exifone demonstrated antiviral activity against various SARS-CoV-2-S pseudovirus variants. In conclusion, the discovery of exifone and benserazide hydrochloride underscores the potential of polyphenols in developing conserved 3CL^pro inhibitors for coronaviruses, offering new strategies for the rapid development of effective drugs against both current and future coronavirus pandemics. Full article