Bioactive peptides (BPs) are short amino acid sequences that that are known to exhibit physiological characteristics such as antioxidant, antimicrobial, antihypertensive and antidiabetic properties, suggesting that they could be exploited as functional foods in the nutraceutical industry. These BPs can be derived from a variety of food sources, including milk, meat, marine, and plant proteins. In the past decade, various methods including in silico, in vitro, and in vivo techniques have been explored to unravel underlying mechanisms of BPs. To forecast interactions between peptides and their targets, in silico methods such as BIOPEP, molecular docking and Quantitative Structure-Activity Relationship modeling have been employed. Additionally, in vitro research has examined how BPs affect enzyme activities, protein expressions, and cell cultures. In vivo studies on the contrary have appraised the impact of BPs on animal models and human subjects. Hence, in the light of recent literature, this review examines the multifaceted aspects of BPs production from milk, meat, marine, and plant proteins and their potential bioactivities. We envisage that the various concepts discussed will contribute to a better understanding of the food derived BP production, which could pave a way for their potential applications in the nutraceutical industry.

UNASSIGNED: Non-ischemic dilated cardiomyopathy (NIDCM) is a form of heart failure with a poor prognosis and unclear optimal management. The aim of the study was to systematically review the literature and assess the efficacy and safety of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors in the management of chronic heart failure secondary to NIDCM and explore their putative mechanisms of action.
UNASSIGNED: Studies from 1990 to 2023 were reviewed using PubMed and EMBASE, focusing on their effects on left ventricular ejection fraction (LVEF) in NIDCM patients, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
UNASSIGNED: Beta-blockers showed a significant beneficial effect on LVEF improvement in NIDCM, with an overall effect size of Cohen\'s d = 1.30, 95% confidence interval (CI) (0.76, 1.84), high heterogeneity (Tau2 = 0.90; Chi2 = 162.05, df = 13, P < 0.00001; I2 = 92%), and a significant overall effect (Z = 4.72, P < 0.00001). ACE inhibitors also showed a beneficial role, but with less heterogeneity (Tau2 = 0.02; Chi2 = 1.09, df = 1, P = 0.30; I2 = 8%) and a nonsignificant overall effect (Z = 1.36, P = 0.17), 95% CI (-0.24, 1.31).
UNASSIGNED: The study highlights the efficacy of carvedilol in improving LVEF in NIDCM patients over ACE inhibitors, recommends beta-blockers as first-line therapy, and advocates further research on ACE inhibitors.

Evaluation and mitigation of the potential carcinogenic risks associated with nitrosamines in marketed pharmaceutical products are areas of interest for pharmaceutical companies and health authorities alike. Significant progress has been made to establish acceptable intake (AI) levels for N-nitrosamine drug substance-related impurities (NDSRIs) using SAR, however some compounds require experimental data to support derivation of a recommended AI. Many angiotensin-converting enzyme inhibitors, identified by the suffix \"pril,\" have secondary amines that can potentially react to form nitrosamines. Here we consider a structural assessment and metabolism data, coupled with comprehensive in vitro and in vivo (mouse) genotoxicity testing to evaluate this particular class of nitrosamines. N-nitroso ramipril and N-nitroso quinapril, both of which are predicted to have inhibited nitrosamine bioactivation due to steric hinderance and branching at the α-position were non-genotoxic in the in vivo liver comet assay and non-mutagenic in the in vivo Big Blue® mutation and duplex sequencing assays. Predicted metabolism along with in vitro metabolism data and quantum chemical calculations related to DNA interactions offer a molecular basis for the negative results observed in both in vitro and in vivo testing. These nitrosamines are concluded to be non-mutagenic and non-carcinogenic; therefore, they should be controlled according to ICH Q3B guidance. Furthermore, these results for N-nitroso ramipril and N-nitroso quinapril should be considered when evaluating the appropriate AI and control strategy for other structurally similar \"pril\" NDSRIs.

A two-year-old male veiled chameleon (Chamaeleo calyptratus) was referred for a gular oedema and bilateral blepharoedema. The echocardiography revealed a ventricular hypertrophy, pericardial effusion, and valvular regurgitation of the right atrioventricular valve. Treatment with hydrochlorothiazide, enalapril, and carvedilol was commenced. Within 3 weeks of treatment, the valvular regurgitation was noticeably decreased. In the 4th week of treatment, the echocardiography revealed a reduction in the myocardium hypertrophy. After an additional month of home treatment, the patient was presented with anorexia and decreased activity. Despite the supportive care, the patient died. The histopathology revealed mild to moderate fibrosis of the epicardium. Moderate to severe fibrosis, degeneration of the myofibrils, fatty atrophy, interstitial oedema and mild calcification was seen in the atria. The tunica intima, media and adventitia of the major cardiac vessels were moderately fibrotic, swollen and interfused by myxoedema. The kidney histopathology revealed moderate sclerosis and atrophy of the glomeruli, vacuolation of the tubular epithelium, fibrosis, and infiltration of the leucocytes in the interstitium. The therapeutic protocol with hydrochlorothiazide, ACE inhibitor enalapril and β-blocker carvedilol reduced the myocardium hypertrophy and the valvular regurgitation; however, the prolonged use of diuretics jeopardized the renal function in our patient. Frequent blood analyses are necessary using diuretics in reptile patients.

Within the realm of pharmacological strategies for cardiovascular diseases (CVD) like hypertension, stroke, and heart failure, targeting the angiotensin-converting enzyme I (ACE-I) stands out as a significant treatment approach. This study employs QSAR modeling using Monte Carlo optimization techniques to investigate a range of compounds known for their ACE-I inhibiting properties. The modeling process involved leveraging local molecular graph invariants and SMILES notation as descriptors to develop conformation-independent QSAR models. The dataset was segmented into distinct sets for training, calibration, and testing to ensure model accuracy. Through the application of various statistical analyses, the efficacy, reliability, and predictive capability of the models were evaluated, showcasing promising outcomes. Additionally, molecular fragments derived from SMILES notation descriptors were identified to elucidate the activity changes observed in the compounds. The validation of the QSAR model and designed inhibitors was carried out via molecular docking, aligning well with the QSAR results. To ascertain the drug-worthiness of the designed molecules, their physicochemical properties were computed, aiding in the prediction of ADME parameters, pharmacokinetic attributes, drug-likeness, and medicinal chemistry compatibility.

Angiotensin converting enzyme (ACE) exerts strong modulation of myeloid cell function independently of its cardiovascular arm. The success of the ACE-overexpressing murine macrophage model, ACE 10/10, in treating microbial infections and cancer opens a new avenue into whether ACE overexpression in human macrophages shares these benefits. Additionally, as ACE inhibitors are a widely used antihypertensive medication, their impact on ACE expressing immune cells is of interest and currently understudied. In the present study, we utilized mass spectrometry to characterize and assess global proteomic changes in an ACE-overexpressing human THP-1 cell line. Additionally, proteomic changes and cellular uptake following treatment with an ACE C-domain selective inhibitor, lisinopril-tryptophan, were also assessed. ACE activity was significantly reduced following inhibitor treatment, despite limited uptake within the cell, and both RNA processing and immune pathways were significantly dysregulated with treatment. Also present were upregulated energy and TCA cycle proteins and dysregulated cytokine and interleukin signaling proteins with ACE overexpression. A novel, functionally enriched immune pathway that appeared both with ACE overexpression and inhibitor treatment was neutrophil degranulation. ACE overexpression within human macrophages showed similarities with ACE 10/10 murine macrophages, paving the way for mechanistic studies aimed at understanding the altered immune function.

The renin-angiotensin system (RAS) is known to affect diverse physiological processes that affect the functioning of many key organs. Angiotensin-converting enzyme (ACE) modulates a variety of bioactive peptides associated with pain. ACE inhibitors (ACEis) have found applications in the treatment of cardiovascular, kidney, neurological and metabolic disorders. However, ACEis also tend to display undesirable effects, resulting in increased pain sensitization and mechanical allodynia. In this review, we provide comprehensive discussion of preclinical and clinical studies involving the evaluation of various clinically approved ACEis. With the emerging knowledge of additional factors involved in RAS signaling and the indistinct pharmacological role of ACE substrates in pain, extensive studies are still required to elucidate the mechanistic role of ACE in pain perception.

Inhibition of ACE is considered as one of the main strategies to reduce hypertension. ACE inhibitors derived from Suaeda salsa (S. salsa) present a novel antihypertensive agent source. This study employed 3D-QSAR pharmacophore, metabolomics, docking-based screening, and molecular dynamics simulations to identify ACE inhibitors from S. salsa. A set of 53 known molecules was chemically diverse to construct a 3D-QSAR model for predictive purposes. S. salsa was characterized using UPLC-QqQ-MS/MS and UPLC-Q-TOF-LC-MS techniques, 211 and 586 kinds of bioactive metabolites were identified, respectively. A total of 680 compounds were collected for database construction and virtual screening. An ADMET assessment was conducted to evaluate drug-likeness and pharmacokinetics parameters. Moreover, molecular docking results show that six top hit compounds bind to ACE tightly. Specially, diosmin could interact with ACE by hydrogen bond, Pi-cation bond, and metal bond. Molecular dynamics (MD) simulation and MMPBSA calculations were subsequently employed to elucidate complex stability and the interaction between diosmin and ACE, indicating it a strong ACE inhibitory activity. In conclusion, this study suggests that S.salsa represents a potential source of antihypertensive agents.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s40203-024-00233-0.

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This study reports the effect of thermal pretreatment and the use of different commercial proteolytic enzymes (Protamex, Flavourzyme, Protana prime, and Alcalase) on the free amino acid content (FAA), peptide profile, and antioxidant, antidiabetic, antihypertensive, and anti-inflammatory potential (DPPH, FRAP, and ABTS assay, DPP-IV, ACE-I, and NEP inhibitory activities) of dry-cured ham bone hydrolyzates. The effect of in vitro digestion was also determined. Thermal pretreatment significantly increased the degree of hydrolysis, the FAA, and the DPP-IV and ACE-I inhibitory activities. The type of peptidase used was the most significant factor influencing antioxidant activity and neprilysin inhibitory activity. Protana prime hydrolyzates failed to inhibit DPP-IV and neprilysin enzymes and had low values of ACE-I inhibitory activity. After in vitro digestion, bioactivities kept constant in most cases or even increased in ACE-I inhibitory activity. Therefore, hydrolyzates from dry-cured ham bones could serve as a potential source of functional food ingredients for health benefits.