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The pharmaceutical and nutraceutical potentials of whole fruit, pulp and seeds of Rosa pimpinellifolia L. were evaluated. Forty-two phenolic compounds and two triterpenoids were identified in extracts by LC-MS/MS and GC-MS, respectively. The most prominent compounds were ellagic acid, catechin, epicatechin, tannic acid, quercetin, oleanolic acid, and ursolic acid. The highest enzyme inhibitory activities of the extracts (94.83%) were obtained against angiotensin-converting enzyme and were almost equal to those of the commercial standard (lisinopril, 98.99%). Whole fruit and pulp extracts (IC 50 :2.47 and 1.52 μg DW/mL) exhibited higher antioxidant capacity than the standards (α-tocopherol, IC 50 :9.89 μg DW/mL). The highest antibacterial activity was obtained against Bacillus cereus (MIC: 256 μg/mL) for the whole fruit extract. Correlation analyses were conducted to find the correlation between individual phenolics and enzyme inhibitory activities. The results showed the remarkable future of not only the edible part but also the seeds of black rose hips in phytochemical and functional aspects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Aims: The aim of the present review was to highlight natural product investigations in silico and in vitro to find plants and chemicals that inhibit or stimulate angiotensin-converting enzyme 2 (ACE-2)., Background: The global reduction of incidents and fatalities attributable to infections with SARS-CoV-2 is one of the most public health problems. In the absence of specific therapy for coronavirus disease 2019 (COVID-19), phytocompounds generated from plant extracts may be a promising strategy worth further investigation, motivating researchers to evaluate the safety and anti-SARS-CoV-2 effectiveness of these ingredients., Objective: To review phytochemicals in silico for anti-SARS-CoV-2 activity and to assess their safety and effectiveness in vitro and in vivo., Methods: The present review was conducted using various scientific databases and studies on anti-SARS-CoV-2 phytochemicals were analyzed and summarized. The results obtained from the in silico screening were subjected to extraction, isolation, and purification. The in vitro studies on anti-SarcoV-2 were also included in this review. In addition, the results of this research were interpreted, analyzed, and documented on the basis of the bibliographic information obtained., Results: This review discusses recent research on using natural remedies to cure or prevent COVID-19 infection. The literature analysis shows that the various herbal preparations (extracts) and purified compounds can block the replication or entrance of the virus directly to carry out their anti-SARS-CoV-2 effects. It is interesting to note that certain items can prevent SARS-CoV-2 from infecting human cells by blocking the ACE-2 receptor or the serine protease TMPRRS2. Moreover, natural substances have been demonstrated to block proteins involved in the SARS-CoV-2 life cycle, such as papain- or chymotrypsin-like proteases., Conclusion: The natural products may have the potential for use singly or in combination as alternative drugs to treat/prevent COVID-19 infection, including blocking or stimulating ACE-2. In addition, their structures may provide indications for the development of anti-SARS-CoV-2 drugs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Grifola frondosa has garnered significant popularity as an edible mushroom attributable to its exceptional taste and nutritional benefits. This study isolated APPLRP, a potent ACE-inhibitory peptide, from the alcohol-soluble fraction of Grifola frondosa. The underlying mechanisms of APPLRP in antihypertension were explored through computational chemistry, cell experiments, and zebrafish model. Results demonstrated that APPLRP was an active competitive ACE inhibitor (IC 50  = 29.93 μM) that could bind to the active pocket S2 and S1' of ACE. APPLRP exhibited resistance to pepsin and pancreatin digestion. In vitro experiments revealed that APPLRP significantly attenuated Ang II-induced VSMCs proliferation and migration by down-regulating AT1R expression and inhibiting ERK1/2 and STAT3 phosphorylation. APPLRP intervention significantly ameliorated myocardial fibrosis, as evidenced by reductions in cardiac output, blood flow velocity, and cardiac collagen deposition levels in Ang II-induced hypertensive zebrafish model. Furthermore, APPLRP improved vascular remodeling in hypertensive zebrafish, indicated by increased vessel diameter and decreased vessel wall thickness. Notably, APPLRP treatment resulted in down-regulation of ACE and up-regulation of ACE2 expression in the vessels of hypertensive zebrafish. These findings indicated that APPLRP was a representative component of Grifola frondosa peptides, and its antihypertensive effects were associated with ACE inhibition and the improvement of VSMCs-mediated vascular remodeling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The main objective of this work was to investigate the impact of ultrasonication assisted enzymatic treatment on the physicochemical and bioactive properties of broad bean (BBP), lentil bean (LBP), and mung bean (MBP) protein isolates. The protein was extracted using alkaline acid precipitation method, ultrasonicated at a frequency of 20 kHz, temperature 20-30 °C and then hydrolysed using alcalase enzyme (1 % w/w, pH 8.5, 30 min, 55 ο C). The generated hydrolysates were characterized by degree of hydrolysis (DH), SDS, FTIR, surface hydrophobicity, amino acid composition, antioxidant and antihypertensive properties. Results showed that the degree of hydrolysis was found to increase in ultrasonicated protein hydrolysate (18.9 to 40.71 %) in comparison to non- ultrasonicated protein hydrolysate (11 to 16.3 %). SDS-PAGE results showed significant changes in protein molecular weight profiles (100-11kDa) in comparison to their natives. However, no substantial change was found in ultrasonicated and non-ultrasonicated protein hydrolysates. The FTIR spectrum showed structural alterations in ultrasonicated and non-ultrasonicated protein hydrolysates, suggesting modifications in secondary structure such as amide A, amide I and amide II regions. The essential amino acid content varied in the range of 60.09 mg/g to 73.77 mg/g and 28.73 to 50.26 mg/g in case of ultrasonicated and non-ultrasonicated protein hydrolysates, and non-essential content varied in the range of 49.42 to 65.93 mg/g and 43.12 to 47.12 mg/g. Both antioxidant and antihypertensive activities were found to increase significantly in ultrasonicated and non-ultrasonicated protein hydrolysates in comparison to their native counterparts, highlighting their potential as functional ingredients for management of hypertension. It was concluded that ultrasonication assisted enzymatic hydrolysis is an efficient approach for production of bioactive pulse protein hydrolysates with enhanced nutracutical properties, thus offering promising avenues for their utilization in the food industry and beyond., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pharmacologic interventions to slow chronic kidney disease progression, such as ACE-inhibitors, angiotensin receptor blockers, or sodium glucose co-transporter 2 inhibitors, often produce acute treatment effects on glomerular filtration rate (GFR) that differ from their long-term chronic treatment effects. Observational studies assessing the implications of acute effects cannot distinguish acute effects from GFR changes unrelated to the treatment. Here, we performed meta-regression analysis of multiple trials to isolate acute effects to determine their long-term implications. In 64 randomized controlled trials (RCTs), enrolling 154,045 participants, we estimated acute effects as the mean between-group difference in GFR slope from baseline to three months, effects on chronic GFR slope (starting at three months after randomization), and effects on three composite kidney endpoints defined by kidney failure (GFR 15 ml/min/1.73m 2 or less, chronic dialysis, or kidney transplantation) or sustained GFR declines of 30%, 40% or 57% decline, respectively. We used Bayesian meta-regression to relate acute effects with treatment effects on chronic slope and the composite kidney endpoints. Overall, acute effects were not associated with treatment effects on chronic slope. Acute effects were associated with the treatment effects on composite kidney outcomes such that larger negative acute effects were associated with lesser beneficial effects on the composite kidney endpoints. Associations were stronger when the kidney composite endpoints were defined by smaller thresholds of GFR decline (30% or 40%). Results were similar in a subgroup of interventions with supposedly hemodynamic effects that acutely reduce GFR. For studies with GFR 60 mL/min/1.73m 2 or under, negative acute effects were associated with larger beneficial effects on chronic GFR slope. Thus, our data from a large and diverse set of RCTs suggests that acute effects of interventions may influence the treatment effect on clinical kidney outcomes., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

It has been demonstrated that ferulic acid (FA) can be effectively encapsulated using wheat gluten amyloid fibrils (AF) and chitosan (CS) in a double network hydrogel (DN) form, with cross-linking mediated by Genipin (GP). Within this system, the DN comprising gluten AF-FA and CS-FA exhibited optimal loading metrics at a formulation designated as DN8, achieving a load efficiency of 88.5 % and a load capacity of 0.78 %. Analysis through fluorescence quenching confirmed that DN8 harbored the highest quantity of FA. Fourier-transform infrared spectroscopy (FTIR) further verified a significant increase in β-sheet content post-hydrogel formation, enhancing the binding capacity for FA. Rheological assessments indicated a transition from solution to gel, delineating the phase state of the DN. Comprehensive in vitro digestion studies revealed that DN8 provided superior sustained release properties, exhibited the highest total antioxidant capacity, and displayed potent inhibitory activities against angiotensin I converting enzyme (ACE) and acetylcholinesterase (Ach-E). Additionally, the DN significantly bolstered the stability of FA against photothermal degradation. Collectively, these findings lay foundational insights for the advancement of the wheat gluten AF-based delivery system for bioactive compounds and provided a theoretical basis for the development of functional foods., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Huijuan Zhang reports financial support was provided by National Natural Science Foundation of China (No. 32372365). Huijuan Zhang reports financial support was provided by Beijing Natural Science Foundation (No. 6232001). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest We have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cardiovascular functions in diabetes greatly depend on constitutive NOS (cNOS) activity. A comparative study of the effects of a steroid hormone ecdysterone and enalapril, an ACE inhibitor widely used to treat cardiac disorders on cNOS, inducible NOS (iNOS), xanthine oxidoreductase (XOR) activity, RNS, ROS, and lipid peroxidation in heart tissue in experimental diabetes was conducted. The rat model of diabetes was established by streptozotocin injection. NOS activity, NO 2 - , NO 3 - , uric acid, nitrosothiols, hydroperoxide, superoxide, and diene conjugate formation were studied spectrophotomerically. In diabetes, cNOS downregulation correlated with a dramatic fall of NO 2 - production and ~4.5-fold elevation of nitrosothiols, which agreed with a steep rise of iNOS activity, while NO 3 - remained close to control. Dramatic activation of XOR was observed, which correlated with the elevation of both superoxide production and nitrate reductase activity and resulted in strong lipid peroxidation. Ecdysterone and enalapril differently affected RNS metabolism. Ecdysterone moderately restored cNOS but strongly suppressed iNOS, which resulted in the reduction of NO 3 - , but full restoration of NO 2 - production. Enalapril better restored cNOS but less effectively suppressed iNOS, which promoted NO 3 - formation. Both drugs similarly inhibited XOR, which equally alleviated oxidative stress and lipid peroxidation. The synergistic action of iNOS and XOR was a plausible explanation for strong lipid peroxidation, abolished by the inhibition of iNOS and XOR by ecdysterone or enalapril. Complementary effects of ecdysterone and enalapril on cNOS, iNOS, and RNS are a promising basis for their combined use in the treatment of cardiovascular disorders caused by cNOS dysfunction in diabetes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: Conflict of interest None declared.

Evidence suggests that angiotensin-converting enzyme inhibitors (ACEIs) may increase metabolic rate by promoting thermogenesis, potentially through enhanced fat oxidation and improved insulin. More research is, however, needed to understand this intricate process. In this study, we used 22 lines from the Drosophila Genetic Reference Panel to assess the metabolic rate of virgin female and male flies that were either fed a standard medium or received lisinopril for one week or five weeks. We demonstrated that lisinopril affects the whole-body metabolic rate in Drosophila melanogaster in a genotype-dependent manner. However, the effects of genotypes are highly context-dependent, being influenced by sex and age. Our findings also suggest that lisinopril may increase the Drosophila metabolic rate via the accumulation of a bradykinin-like peptide, which, in turn, enhances cold tolerance by upregulating Ucp4b and Ucp4c genes. Finally, we showed that knocking down Ance , the ortholog of mammalian ACE in Malpighian/renal tubules and the nervous system, leads to opposite changes in metabolic rate, and that the effect of lisinopril depends on Ance in these systems, but in a sex- and age-specific manner. In conclusion, our results regarding D. melanogaster support existing evidence of a connection between ACEI drugs and metabolic rate while offering new insights into this relationship.

Recently, jellyfish venom has gained attention as a promising reservoir of pharmacologically active compounds, with potential applications in new drug development. In this investigation, novel peptides, isolated from the hydrolysates of Nemopilema nomurai jellyfish venom (NnV), demonstrate potent inhibitory activities against angiotensin-converting enzyme (ACE). Proteolytic enzymes-specifically, papain and protamex-were utilized for the hydrolysis under optimized enzymatic conditions, determined by assessing the degree of hydrolysis through the ninhydrin test. Comparative analyses revealed that papain treatment exhibited a notably higher degree of NnV hydrolysis compared to protamex treatment. ACE inhibitory activity was quantified using ACE kit-WST, indicating a substantial inhibitory effect of 76.31% for the papain-digested NnV crude hydrolysate, which was validated by captopril as a positive control. The separation of the NnV-hydrolysate using DEAE sepharose weak-anion-exchange chromatography revealed nine peaks under a 0-1 M NaCl stepwise gradient, with peak no. 3 displaying the highest ACE inhibition of 96%. The further purification of peak no. 3 through ODS-C18 column reverse-phase high-performance liquid chromatography resulted in five sub-peaks (3.1, 3.2, 3.3, 3.4, and 3.5), among which 3.2 exhibited the most significant inhibitory activity of 95.74%. The subsequent analysis of the active peak (3.2) using MALDI-TOF/MS identified two peptides with distinct molecular weights of 896.48 and 1227.651. The peptide sequence determined by MS/MS analysis revealed them as IVGRPLANG and IGDEPRHQYL. The docking studies of the two ACE-inhibitory peptides for ACE molecule demonstrated a binding affinity of -51.4 ± 2.5 and -62.3 ± 3.3 using the HADDOCK scoring function.

This study aimed to test the hypothesis that bioactive peptides can exert multiple bioactivities at different sites in the gastrointestinal tract. Our previous research identified 33 gastric-resistant peptides derived from wheat germ with potential antiadhesive activity against Helicobacter pylori in the stomach. In this work, in silico digestion of these peptides with trypsin, thermolysin, and chymotrypsin produced 67 peptide fragments. Molecular docking was conducted to predict their ACE and DPP-IV inhibitory activities in the small intestine. Three peptides (VPIPNPSGDR, VPY, and AR) were selected and synthesized for in vitro validation. Their generation in the gastrointestinal tract was verified via in vitro digestion, followed by mass spectrometry analysis. The IC 50 values for ACE inhibition were 199.5 μM (VPIPNPSGDR), 316.3 μM (VPY), and 446.7 μM (AR). For DPP-IV inhibition, their IC 50 values were 0.5, 1.6, and 4.0 mM, respectively. This research pioneers new directions in the emerging field of multifunctional peptides, providing scientific evidence to support the utilization of wheat germ as value-added food ingredients.

This current study aims to analyze the potential bioactivities possessed by the enzymatic hydrolysates of commercial bovine, porcine, and tilapia gelatins using bioinformatics in combination with in vitro and in vivo studies. The hydrolysate with superior inhibition of angiotensin converting enzyme (ACE) activity was used to treat the D-galactose (DG)-induced amnesic mice. In silico digestion of the gelatins led to the identification of peptide sequences with potential antioxidant, ACE-inhibitory, and anti-amnestic properties. The results of in vitro digestion revealed that the <1 kDa peptide fraction of porcine gelatin hydrolysate obtained after 1 h digestion with papain (PP) (PP1, <1 kDa) potently inhibited ACE, acetylcholinesterase, and prolyl endopeptidase activities at 87.42%, 21.24%, and 48.07%, respectively. Administering the PP1 to DG-induced amnesic mice ameliorated the spatial cognitive impairment and Morris water maze learning abilities. The dentate area morphology in the PP1-treated mice was relatively similar to the control group. In addition, PP1 enhanced the antioxidant capacity in the DG-induced amnesic mice. This study suggests that PP1 could serve as a potential treatment tool against oxidative stress, hypertension, and neurodegenerative diseases.

This study investigates the characterization, mechanisms of action, structure-activity relationships, and in vivo antihypertensive effects of ACE inhibitory peptides derived from sufu hydrolysate following simulated gastrointestinal digestion. Sufu was enzymatically digested using pepsin, trypsin, and chymotrypsin to mimic gastrointestinal conditions, followed by ultrafiltration to fractionate the peptides based on molecular weight. The fraction under 1 kDa exhibited the highest ACE inhibitory activity. LC-MS/MS analysis identified 119 peptide fragments, with bioinformatics screening highlighting 41 peptides with potential ACE inhibitory properties. Among these, two peptides, AWR and LLR, were selected and synthesized for in vitro validation, displaying IC 50 values of 98.04 ± 2.56 μM and 94.01 ± 5.07 μM, respectively. Stability tests showed that both peptides maintained their ACE inhibitory activity across various temperatures and pH levels. Molecular docking and Highest Occupied Molecular Orbital analysis indicated strong binding interactions between these peptides and ACE, with the second-position tryptophan in AWR and the N-terminal leucine in LLR identified as key bioactive sites. These findings were further supported by molecular dynamics simulations, which confirmed the stability of the peptide-ACE complexes. In vivo studies using spontaneously hypertensive rats demonstrated significant reductions in both systolic and diastolic blood pressure, indicating that AWR and LLR have strong antihypertensive potential. This study illustrates that ultrafiltration, combined with LC-MS/MS and bioinformatics analysis, is an effective approach for the rapid screening of ACE inhibitory peptides. These results not only enhance our understanding of sufu-derived peptides but also offer promising implications for hypertension management.

Angiotensin-converting enzyme (ACE), consisting of N-domain and C-domain, is a key regulator of blood pressure. The use of cACE-specific inhibitors helps minimize side effects in clinical applications. Legumes are a good source of proteins containing ACE inhibitory peptides; however, no studies have reported the identification of cACE-specific inhibitory peptides from Fabaceae. In this study, thermal hydrolysates from seeds, sprouts, pods, seedlings, and flowers of legumes were analyzed. Flowers of legumes exhibited a C-domain-preference ACE inhibition and anti-hypertensive effect in rats. Screening the legume peptide library identified a novel cACE inhibitory peptide, SJ-1. This study reported the first identification of cACE inhibitory peptide from Fabaceae foods. SJ-1, identified from the legume flowers, interacted with active site residues of cACE, leading to the inhibition of ACE activity, downregulation of bradykinin levels, and reduction of blood pressure. These findings also suggested the potential of legume proteins as a source of cACE inhibitory peptides., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Heart failure (HF) is a complex syndrome that affects millions of people worldwide and leads to significant morbidity and mortality. Sacubitril/valsartan, a combination drug consisting of a neprilysin inhibitor and an angiotensin receptor blocker (ARB), has shown a greater improvement in the prognosis of HF than ACE inhibitors (ACEI) or ARB. Recent studies have found that ACEI/ARB or sacubitril/valsartan can increase flow-mediated dilation (FMD) and reduce pulse wave velocity (PWV), which are independent predictors of cardiovascular events and HF prognosis. The purpose of this study is to assess and compare the effect of sacubitril/valsartan and ACEI/ARB on FMD and PWV using meta-analysis and further provide a reference for the role of sacubitril/valsartan in the treatment of HF., Methods and Analysis: Clinical randomised controlled trials investigating the effect of sacubitril/valsartan and/or ACEI/ARB on FMD and PWV in patients with HF will be searched in the relevant database, including PubMed, Web of Science, Embase, Cochrane Library and China's National Knowledge Infrastructure up to January 2024. The outcomes of interest are changes in endothelial function assessed by FMD and changes in arterial stiffness assessed by PWV. The risk of bias was evaluated using the revised Cochrane risk of bias tool for randomised trials (RoB2.0). Review Manager V.5.3 software is used for meta-analysis data synthesis, sensitivity analysis, meta-regression analysis, subgroup analysis and risk of bias assessment. The reporting bias of studies will be evaluated using the funnel plot, in which symmetry will be assessed by Begg's and Egger's tests. The evidence quality of the included studies will be evaluated by the Grading of Recommendations Assessment, Development, and Evaluation., Ethics and Dissemination: This study only analyses research data from the published literature and therefore does not require ethical approval. We will submit the systematic review to a peer-reviewed journal., Prospero Registration Number: CRD42024538148., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Effects of the renin-angiotensin-aldosterone system (RAAS) inhibitors enalapril and telmisartan on circulating RAAS in dogs with proteinuric chronic kidney disease (pCKD) are undescribed., Objectives: To characterize the RAAS in untreated dogs with pCKD compared to healthy, life-stage- and sex-matched controls, and in dogs with pCKD after 30 days of treatment with enalapril or telmisartan., Animals: Dogs with pCKD (n = 36) and healthy controls (n = 20)., Methods: Retrospective study of banked samples and previously collected data. Day 0 serum equilibrium concentrations of angiotensin I, II, III, IV, 1-5, and 1-7, and aldosterone, and urinary aldosterone-to-creatinine ratio (UACR) from pCKD dogs were compared to values on day 30 of treatment with enalapril (0.5 mg/kg PO q12) or telmisartan (1 mg/kg PO q24h) and to those of healthy dogs. Data were analyzed using linear mixed models., Results: Compared with healthy dogs, pCKD dogs had significantly higher Ang I, III, 1-5, and 1-7 concentrations, and UACR. Relative to pretreatment values, day 30 Ang II concentrations were significantly increased and decreased in telmisartan- and enalapril-treated pCKD dogs, respectively (both P < .001). Mean (95% confidence interval) percentage change from pretreatment value in serum Ang 1-7 concentration was significantly greater in telmisartan- (753% [489%-1134%]) versus enalapril-treated (149% [69%-268%]) dogs (P < .001). Serum aldosterone decreased with treatment (P = .02 for enalapril, P < .001 for telmisartan), with no difference between groups at day 30., Conclusions and Clinical Importance: Circulating RAAS activity is higher in dogs with pCKD. Compared with enalapril, treatment with telmisartan caused significantly greater increases in the presumed beneficial peptide Ang 1-7., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Angiotensin converting enzyme (ACE) is not only a critical component in the renin-angiotensin system (RAS), but also suggested as an important mediator for immune response and activity, such as immune cell mobilization, metabolism, biogenesis of immunoregulatory molecules, etc. The chronic duration of cardiovascular diseases (CVD) has been increasingly considered to be triggered by uncontrolled pathologic immune reactions from myeloid cells and lymphocytes. Considering the potential anti-inflammatory effect of the traditional antihypertensive ACE inhibitor (ACEi), we attempt to elucidate whether ACE and its catalytically relevant substances as well as signaling pathways play a role in the immunity-related pathogenesis of common CVD, such as arterial hypertension, atherosclerosis and arrythmias. ACEi was also reported to benefit the prognoses of COVID-19-positive patients with CVD, and COVID-19 disease with preexisting CVD or subsequent cardiovascular damage is featured by a significant influx of immune cells and proinflammatory molecules, suggesting that ACE may also participate in COVID-19 induced cardiovascular injury, because COVID-19 disease basically triggers an overactive pathologic immune response. Hopefully, the ACE inhibition and manipulation of those associated bioactive signals could supplement the current medicinal management of various CVD and bring greater benefit to patients' cardiovascular health., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The binding affinities and interactions between eight drug candidates, both commercially available (candesartan; losartan; losartan carboxylic acid; nirmatrelvir; telmisartan) and newly synthesized benzimidazole-N-biphenyltetrazole (ACC519T), benzimidazole bis-N,N'-biphenyltetrazole (ACC519T(2) and 4-butyl-N,N-bis([2-(2H-tetrazol-5-yl)biphenyl-4-yl]) methyl (BV6), and the active site of angiotensin-converting enzyme-2 (ACE2) were evaluated for their potential as inhibitors against SARS-CoV-2 and regulators of ACE2 function through Density Functional Theory methodology and enzyme activity assays, respectively. Notably, telmisartan and ACC519T(2) exhibited pronounced binding affinities, forming strong interactions with ACE2's active center, favorably accepting proton from the guanidinium group of arginine273. The ordering of candidates by binding affinity and reactivity descriptors, emerged as telmisartan > ACC519T(2) > candesartan > ACC519T > losartan carboxylic acid > BV6 > losartan > nirmatrelvir. Proton transfers among the active center amino acids revealed their interconnectedness, highlighting a chain-like proton transfer involving tyrosine, phenylalanine, and histidine. Furthermore, these candidates revealed their potential antiviral abilities by influencing proton transfer within the ACE2 active site. Furthermore, through an in vitro pharmacological assays we determined that candesartan and the BV6 derivative, 4-butyl-N,N0-bis[20-2Htetrazol-5-yl)bipheyl-4-yl]methyl)imidazolium bromide (BV6(K + ) 2 ) also contain the capacity to increase ACE2 functional activity. This comprehensive analysis collectively underscores the promise of these compounds as potential therapeutic agents against SARS-CoV-2 by targeting crucial protein interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Although TRPV1 receptors play an essential role in the adverse effects on the airways following captopril treatment, there is no available evidence of their involvement in treatment regimens involving repeated doses of captopril. Comparing the difference in these two treatment regimens is essential since captopril is a continuous-use medication. Thus, this study explored the role of the transient receptor potential vanilloid 1 (TRPV1) in the effects of captopril on rat airways using two treatment regimens. Airway resistance, bronchoalveolar lavage (BAL), and histological and immunohistochemical analyses were conducted in rats administered with single or repeated doses of captopril. This study showed that the hyperresponsiveness to bradykinin and capsaicin in captopril-treated rats was acute. Treatment with the selective B 2 antagonist, HOE140 reduced bradykinin hyperresponsiveness and abolished capsaicin exacerbation in single-dose captopril-treated rats. Likewise, degeneration of TRPV1-positive neurones also reduced hyperresponsiveness to bradykinin. Single-dose captopril treatment increased leukocyte infiltration in the BAL when compared with the vehicle and this increase was reduced by TRPV1-positive neurone degeneration. However, when compared with the vehicle treatment, animals treated with repeated doses of captopril showed an increase in leukocyte influx as early as 1 h after the last captopril treatment, but this effect disappeared after 24 h. Additionally, an increase in TRPV1 expression occurred only in animals who received repeated captopril doses and the degeneration of TRPV1-positive neurones attenuated TRPV1 upregulation. In conclusion, these data strongly indicate that a treatment regimen involving multiple doses of captopril not only enhances sensitisation but also upregulates TRPV1 expression. Consequently, targeting TRPV1 could serve as a promising strategy to reduce the negative impact of captopril on the airways., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ulva prolifera , a type of green algae that can be consumed, was utilized in the production of an angiotensin-I converting enzyme (ACE) inhibitory peptide. The protein from the algae was isolated and subsequently hydrolyzed using a neutral protease. The resulting hydrolysate underwent several processes including Sephadex-G100 filtration chromatography, ultrafiltration, HPLC-Q-TOF-MS analysis, ADMET screening, UV spectrum detection test, molecular docking, and molecular dynamic simulation. Then, the ACE inhibitory peptide named KAF (IC 50 , 0.63 ± 0.26 µM) was identified. The effectiveness of this peptide in inhibiting ACE can be primarily attributed to two conventional hydrogen bonds. Additionally, it could activate endothelial nitric oxide synthase (eNOS) activity to promote the generation of nitric oxide (NO). Additionally, KAF primarily increased the intracellular calcium (Ca 2+ ) level by acting on L-type Ca 2+ channel (LTCC) and the ryanodine receptor (RyR) in the endoplasmic reticulum, and completed the activation of eNOS under the mediation of protein kinase B (Akt) signaling pathway. Our study has confirmed that KAF has the potential to be processed into pharmaceutical candidate functions on vasoconstriction.

Human somatic angiotensin-converting enzyme (ACE) is a key zinc metallopeptidase that plays a pivotal role in the renin-angiotensin-aldosterone system (RAAS) by regulating blood pressure and electrolyte balance. Inhibition of ACE is a cornerstone in the management of hypertension, cardiovascular diseases, and renal disorders. Recent advances in structural biology techniques have provided invaluable insights into the molecular mechanisms underlying ACE inhibition, facilitating the design and development of more effective therapeutic agents. This review focuses on the latest advancements in elucidating the structural basis for ACE inhibition. High-resolution crystallographic studies of minimally glycosylated individual domains of ACE have revealed intricate molecular details of the ACE catalytic N- and C-domains, and their detailed interactions with clinically relevant and newly designed domain-specific inhibitors. In addition, the recently elucidated structure of the glycosylated form of full-length ACE by cryo-electron microscopy (cryo-EM) has shed light on the mechanism of ACE dimerization and revealed continuous conformational changes which occur prior to ligand binding. In addition to these experimental techniques, computational approaches have also played a pivotal role in elucidating the structural basis for ACE inhibition. Molecular dynamics simulations and computational docking studies have provided atomic details of inhibitor binding kinetics and energetics, facilitating the rational design of novel ACE inhibitors with improved potency and selectivity. Furthermore, computational analysis of the motions observed by cryo-EM allowed the identification of allosteric binding sites on ACE. This affords new opportunities for the development of next-generation allosteric inhibitors with enhanced pharmacological properties. Overall, the insights highlighted in this review could enable the rational design of novel ACE inhibitors with improved efficacy and safety profiles, ultimately leading to better therapeutic outcomes for patients with hypertension and cardiovascular diseases., (© 2024 The Author(s).)

The average content of casein in yak milk is 40.2 g/L. Casein can be degraded by enzymatic digestion or food processing to produce abundant degradation peptides. International researchers have studied the degradation peptides of yak milk casein by using multiple techniques and methods, such as in vitro activity tests, cellular experiments, proteomics, bioinformatics, etc., and found that the degradation peptides have a wide range of functional activities that are beneficial to the human body, such as angiotensin-converting enzyme (ACE) inhibitory, antioxidant, anti-inflammatory, antidiabetic, antimicrobial, anticancer, and immunomodulatory activities, etc., and it has been proved that the types and strengths of functional activities are closely related to the structural characteristics of the peptides. This paper describes the characteristics of yak milk proteins, the functional activities, and mechanism of action of degraded peptides. Based on the types of functional activities of yak milk casein degradation peptides, we classified and elucidated the effects of structural factors, such as peptide molecular weight, peptide length, amino acid sequence, physicochemical properties, electrical charge, hydrophobicity, spatial conformation, chain length, and the type of enzyme on these activities. It reveals the great potential of yak milk casein degradation peptides as functional active peptide resources and as auxiliary treatments for diseases. It also provides important insights for analyzing yak casein degradation peptide activity and exploring high-value utilization.

A major and irreversible complication of diabetes is diabetic peripheral neuropathy (DPN), which can lead to significant disability and decreased quality of life. Prior work demonstrates the peptide hormone Angiotensin II (Ang II) is released locally in neuropathy and drives inflammation and impaired endoneurial blood flow. Therefore, we proposed that by utilizing a local thermoresponsive hydrogel injection, we could deliver inhibitors of angiotensin-converting enzyme (ACE) to suppress Ang II production and reduce nerve dysfunction in DPN through local drug release. The ACE inhibitor captopril was encapsulated into a micelle, which was then embedded into a reversibly thermoresponsive pluronics-based hydrogel matrix. Drug-free and captopril-loaded hydrogels demonstrated excellent product stability and sterility. Rheology testing confirmed sol properties with low viscosity at ambient temperature and increased viscosity and gelation at 37 °C. Captopril-loaded hydrogels significantly inhibited Ang II production in comparison to drug-free hydrogels. DPN mice treated with captopril-loaded hydrogels displayed normalized mechanical sensitivity and reduced inflammation, without side-effects associated with systemic exposure. Our data demonstrate the feasibility of repurposing ACE inhibitors as locally delivered anti-inflammatories for the treatment of sensory deficits in DPN. To the best of our knowledge, this is the first example of a locally delivered ACE inhibitor for the treatment of DPN., (© 2024. The Author(s).)

Rationale: Sarcoidosis is a granulomatous disorder of unclear cause notable for abnormal elevation of blood and tissue ACE1 (angiotensin converting enzyme 1) levels and activity. ACE1 regulates the renin-angiotensin-aldosterone system (RAAS), the terminal product of which is aldosterone, which selectively engages mineralocorticoid receptors to promote inflammation. Objectives: We sought to determine whether the RAAS promotes sarcoidosis granuloma formation and related inflammatory responses. Methods: Using an established ex vivo model, we first determined whether aldosterone was produced by sarcoidosis granulomas and verified the presence of CYP11B2, the enzyme required for its production. We then evaluated the effects of selective inhibitors of ACE1 (captopril), angiotensin type 1 receptor (losartan), and mineralocorticoid receptors (spironolactone, eplerenone) on granuloma formation, reflected by computer image analysis-generated granuloma area, and selected cytokines incriminated in sarcoidosis pathogenesis. Measurements and Main Results: Aldosterone was spontaneously produced by sarcoidosis peripheral blood mononuclear cells, and both intra- and extracellular levels steadily increased during granuloma formation. In parallel, peripheral blood mononuclear cells were shown to express more CYP11B2 during granuloma formation. Significant inhibition of sarcoidosis granulomas and related cytokines (TNFα, IL-1β, IFNγ, IL-10) was observed in response to pretreatments with captopril, losartan, spironolactone, or eplerenone, comparable to that of prednisone. Conclusions: The RAAS is intact in sarcoidosis granulomas and contributes significantly to early granuloma formation and to related inflammatory mediator responses, with important implications for clinical management.

Obesity has emerged as a worldwide health concern due to its increasing prevalence. Adipocytes have the ability to express angiotensin-converting enzyme 2 receptors (ACE2) and several adipocytokines. These expressions could lead to the activation of a cytokine storm, which in turn promotes the development of cardiovascular diseases. The aim of this study was to investigate the impact of perindopril and losartan exposure on the ACE2 and interleukin 6 (IL-6) levels in adipocyte cells. This study used an in vivo true experimental design utilizing a post-test-only control group. A total of 24 adult male albino rats were divided into four groups, one group served as the non-obese (negative control), while the other three groups were obese: (1) the positive control (untreated obese rats); (2) perindopril group (2 mg/kg BW/day orally for 4 weeks); and (3) losartan group (20 mg/kg BW/day for 4 weeks). Afterwards, the rats were euthanized, and the visceral fat tissue were obtained during dissection. The levels of ACE2 and IL-6 were measured using the enzyme-linked immunosorbent assay (ELISA). Losartan administration in obese rats resulted in a notable elevation in ACE2 levels compared to both the perindopril group (losartan vs perindopril, p =0.011) and the positive control ( p =0.004). In addition, the treatment of perindopril and losartan in obese rats resulted in a significant reduction in IL-6 levels when compared to the positive control (perindopril vs positive control, p= 0.020; losartan vs positive control, p= 0.002, respectively). This study provides insight into the administration of perindopril and losartan, which could suppress the pro-inflammatory (IL-6) but increase the ACE2 levels in adipose tissue., Competing Interests: All the authors declared that there is no conflict of interest., (© 2024 The Author(s).)

The expression of angiotensin-converting enzyme 2 (ACE2) in the adipose tissues of obese patients needs further study, as it may aid infection and serve as a viral reservoir. There has been controversy over whether to use ACE inhibitors to prevent coronavirus disease 2019 (COVID-19) severity. Perindopril, an ACE2 inhibitor, has been proposed; however, its relationship with COVID-19 has not yet been clear. The aim of this study was to investigate the effect of perindopril to reduce the expression of ACE2 and pro-inflammatory cytokine in adipocytes exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Enzymatic isolation of adipose tissues was performed from obese male donor patients aged 30-50 years, then exposed it with SARS-CoV-2 S1 spike protein. This study also included human recombinant ACE2 (hrsACE2) as a comparison to perindopril. The expression of ACE2 was evaluated using ELISA. Our data indicated that SARS-CoV-2 Spike protein exposure increased ACE2 expression significantly. Administration of perindopril decreased ACE2 expression (43.37 μg/mL) significantly compared to the positive group (80.31 μg/mL) ( p <0.001). Perindopril administration also decreased IL-6 levels significantly compared to positive group ( p <0.001). This study highlights that perindopril could reduce the ACE2 expression and pro-inflammatory cytokine levels in adipocytes exposed to SARS-CoV-2 S1 spike protein., Competing Interests: All the authors declare that there are no conflicts of interest., (© 2024 The Author(s).)

Aim: To prepare sweet tea extract microcapsules (STEMs) via a spray-drying by applying different wall material formulations with maltodextrin (MD), inulin (IN), and gum arabic (GA). Methods: The microcapsules were characterised by yield, encapsulation efficiency (EE), particle size, sensory evaluation, morphology, attenuated total reflectance-Fourier transform infra-red spectroscopy and in vitro digestion studies. Results: The encapsulation improved the physicochemical properties and bioactivity stability of sweet tea extract (STE). MD5IN5 had the highest yield (56.33 ± 0.06% w/w) and the best EE (e.g. 88.84 ± 0.36% w/w of total flavonoids). MD9GA1 obtained the smallest particle size (642.13 ± 4.12 nm). MD9GA1 exhibited the highest retention of bioactive components, inhibition of α-glucosidase (96.85 ± 0.55%), α-amylase (57.58 ± 0.99%), angiotensin-converting enzyme (56.88 ± 2.20%), and the best antioxidant activity during in vitro gastrointestinal digestion. Conclusion: The encapsulation of STE can be an appropriate way for the valorisation of STE with improved properties.

Objective: To examine the associations of renin-angiotensin system (RAS) inhibitor use with postmortem brain insulin signaling and neuropathology., Methods: Among Religious Orders Study participants, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had measurements of insulin receptor substrate-1 (IRS-1) and RAC-alpha serine/threonine protein kinase (AKT1) collected in the prefrontal cortex using ELISA and immunohistochemistry. Alzheimer's disease (AD), brain infarcts, and cerebral vessel pathology data were assessed by systematic neuropathologic evaluations. RAS inhibitor use was determined based on visual inspection of medication containers during study visits. The associations of RAS inhibitor use with brain insulin signaling measures and neuropathology were examined using adjusted regression analyses., Results: Of the 90 RAS inhibitor users (54 with diabetes), 65 had used only angiotensin-converting enzyme inhibitors, 11 only angiotensin II receptor blockers, and 14 used both. RAS inhibitor use was associated with lower pT 308 AKT1/total AKT1, but not with pS 307 IRS-1/total IRS-1 or the density of cells stained positive for pS 616 IRS-1. RAS inhibitor use was not associated with the level of global AD pathology or amyloid beta burden, but it was associated with a lower tau-neurofibrillary tangle density. Additionally, we found a significant interaction between diabetes and RAS inhibitors on tangle density. Furthermore, AKT1 phosphorylation partially mediated the association of RAS inhibitor use with tau tangle density. Lastly, RAS inhibitor use was associated with more atherosclerosis, but not with other cerebral blood vessel pathologies or cerebral infarcts., Interpretation: Late-life RAS inhibitor use may be associated with lower brain AKT1 phosphorylation and fewer neurofibrillary tangles., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

In the last decades, pharmaceuticals have emerged as a new class of environmental contaminants. Antihypertensives, including angiotensin-converting enzyme (ACE) inhibitors, are of special concern due to their increased consumption over the past years. However, the available data on their putative effects on the health of aquatic animals, as well as the possible interaction with biological systems are still poorly understood. This study analysed whether and to which extent the exposure to Enalapril, an ACE inhibitor commonly used for treating hypertension and heart failure, may induce morpho-functional alterations in the mussel Mytilus galloprovincialis, a sentinel organism of water pollution. By mainly focusing on the digestive gland (DG), a target tissue used for analysing the effects of xenobiotics in mussels, the effects of 10-days exposure to 0.6 ng/L (E1) and 600 ng/L (E2) of Enalapril were investigated in terms of cell viability and volume regulation, morphology, oxidative stress, and stress protein expression and localization. Results indicated that exposure to Enalapril compromised the capacity of DG cells from the E2 group to regulate volume by limiting the ability to return to the original volume after hypoosmotic stress. This occurred without significant effects on DG cell viability. Enalapril unaffected also haemocytes viability, although an increased infiltration of haemocytes was histologically observed in DG from both groups, suggestive of an immune response. No changes were observed in the two experimental groups on expression and tissue localization of heat shock proteins 70 (HSPs70) and HSP90, and on the levels of oxidative biomarkers. Our results showed that, in M. galloprovincialis the exposure to Enalapril did not influence the oxidative status, as well as the expression and localization of stress-related proteins, while it activated an immune response and compromised the cell ability to face osmotic changes, with potential consequences on animal performance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The study examined the antihypertensive effect of peptides derived from pepsin-hydrolyzed corn gluten meal, namely KQLLGY and PPYPW, and their in silico gastrointestinal tract digested fragments, KQL and PPY, respectively. KQLLGY and PPYPW showed higher angiotensin I-converting enzyme (ACE)-inhibitory activity and lower ACE inhibition constant (K i ) values when compared to KQL and PPY. Only KQL showed a mild antihypertensive effect in spontaneously hypertensive rats with -7.83 and - 5.71 mmHg systolic and diastolic blood pressure values, respectively, after 8 h oral administration. During passage through Caco-2 cells, KQL was further degraded to QL, which had reduced ACE inhibitory activity. In addition, molecular dynamics revealed that the QL-ACE complex was less stable compared to the KQL-ACE. This study reveals that structural transformation during peptide permeation plays a vital role in attenuating antihypertensive effect of the ACE inhibitor peptide., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Inhibitory activity against angiotensin-converting enzyme (IAACE) by chicken skin collagen hydrolysate (CSCH) and their peptide fractions before and after in-vitro gastrointestinal digestion, were evaluated; as well as their ability to modulate lipid accumulation in 3 T3-L1 adipocytes. Before digestion, peptide fraction <1 kDa (F4) showed the highest IAACE (p < 0.05) followed by CSCH. After these samples were digested, F4 presented an IAACE with IC 50 similar to its digest (DF4) (188.84 and 220.03 μg/mL, respectively), which was 2-fold lower (p < 0.05) than IC 50 of fraction <1 kDa from post-digested hydrolysate (FDH) (388.57 μg/mL). Nine peptides were identified as the potential ACE inhibitors in F4 and DF4. Addition of DF4 (800 μg/mL) reduced(p < 0.05) lipid accumulation by 83% within preadipocytes. A 45-60% reduction of lipid accumulation within differentiated adipocytes was obtained by adding FDH and DF4 (regardless the concentration). These results, digested CSCH and F4 with IAACE may be considered as potential adjuvants for obesity treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Angiotensin I-converting enzyme (ACE) regulates blood pressure through the renin-angiotensin system. Douchi, a traditional fermented soybean condiment, may have antihypertensive effects, but research on ACE inhibitory peptides from Douchi hydrolysates is limited. We hypothesized that enzymatic treatment could enhance ACE inhibitory peptide diversity and efficacy. We tested ten single enzymes and four combinations, finding pepsin-trypsin-chymotrypsin most effective. Hydrolysates were purified using Sephadex G-15 and reversed-phase HPLC, and peptides were identified via LC-MS/MS. Five peptides (LF, VVF, VGAW, GLFG, NGK) were identified, with VGAW as the most potent ACE inhibitor (IC 50 46.6 ± 5.2 μM) showing excellent thermal and pH stability. Lineweaver-Burk plots confirmed competitive inhibition, and molecular docking revealed eight hydrogen bonds between VGAW and ACE. In hypertensive rats, VGAW significantly reduced blood pressure at 12.5, 25, and 50 mg/kg. These findings highlight Douchi as a source of ACE inhibitory peptides and suggest VGAW as a promising functional food ingredient., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In this study, the purpose was to screen novel angiotensin converting enzyme inhibitory peptides (ACEIPs) from tuna muscle taking two-steps enzymatic hydrolysis (Neutrase and Alkaline). Following isolation and purification by ultrafiltration, the Sephadex G-15 gel chromatography and reversed-phase high-performance liquid chromatography based on active-guide, the amino acid sequence was identified using Q-Orbitrap-MS/MS. Five peptides were chose synthesized based on the in silico screening methods. Among these, the two novel ACEIPs LTGCP and YPKP showed better inhibitory ability, and their corresponding IC 50 values were 64.3 μM and 139.6 μM. Subsequently, the interaction mechanism of the best active peptide (LTGCP) against ACE was investigated by inhibitory pattern, molecular docking and molecular dynamic simulation. The result displayed that LTGCP was a mix-type inhibitor against ACE from the Lineweaver-Burk plots. LTGCP formed seven hydrogen bonds based on the molecular docking and the binding energy was -7.29 kcal/mol. LTGCP formed a stability complex with ACE based on the molecular dynamic simulation. Besides, LTGCP exhibited good stability in various temperature, pH and gastrointestinal digestion. Finally, the 0.125 mM ∼ 1.0 mM LTGCP exhibited no-toxic for Caco-2 cell. In summary, these findings showed that tuna was a good material to prepare ACEIPs and LTGCP may be the good potential antihypertensive drug or nutraceuticals., Competing Interests: Declaration of competing interest We declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. All authors of this manuscript have directly participated in the program execution and/or analysis of this study. The content of this manuscript has not been copyrighted or published before. The content of this manuscript is not currently considered for publication elsewhere., (Copyright © 2024. Published by Elsevier B.V.)

Hypertension and cancers are the most common causes of death in humans, as well as common co-diseases among elderly population. Studies have shown that hypertension is associated with carcinogenesis. The renin-angiotensin-aldosterone system (RAAS) is a crucial regulatory system of blood pressure, fluid, and electrolyte homeostasis, which plays an essential role in the pathogenesis of hypertension, whose mechanism is relatively clear. Studies have indicated that RAAS also widely exists in cancer tissues of different systems, which can affect the risk of cancers by stimulating cancer angiogenesis, participating in cancer-related oxidative stress, and regulating cancer-related immunity. Therefore, inhibiting RAAS activity seems beneficial to decreasing the risk of cancers. As one of the most commonly used antihypertensive drugs, RAAS inhibitors have been widely used in clinical practice. However, the conclusions of clinical studies on the relationship between RAAS inhibitors and cancers are not entirely consistent, which has been widely concerned by clinicians. The latest findings suggest that while RAAS inhibitors may reduce the risk of digestive cancers, respiratory cancers, urological cancers, gynecological cancers, and skin cancers, ACEIs may increase the risk of lung cancer, endometrial cancer, basal cell carcinoma, and squamous cell carcinoma. This article comprehensively reviews animal experiments, clinical studies, and meta-analyses on the relationship between RAAS inhibitors and cancers, to provide references for related studies in the future., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abnormal glucose metabolism is a common disease of the endocrine system. The effects of drugs on glucose metabolism have been reported frequently in recent years, and since abnormal glucose metabolism increases the risk of microvascular and macrovascular complications, metabolic disorders, and infection, clinicians need to pay close attention to these effects. A variety of common drugs can affect glucose metabolism and have different mechanisms of action. Hypertension is a common chronic cardiovascular disease that requires long-term medication. Studies have shown that various antihypertensive drugs also have an impact on glucose metabolism. Among them, α-receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers can improve insulin resistance, while β-receptor blockers, thiazides and loop diuretics can impair glucose metabolism. The aim of this review was to discuss the mechanisms underlying the effects of various antihypertensive drugs on glucose metabolism in order to provide reference information for rational clinical drug use., (© 2024 John Wiley & Sons Ltd.)

Gastrointestinal disorders dysregulate the biochemical environment of the gastrointestinal tract by altering pH conditions during the gastric phase of digestion or by reducing the secretion of pancreatin during the intestinal part of the process. Ingested functional food could therefore lose some of its health-promoting potential apart from its nutritional value. In this work, we aimed to manufacture bread marked by decreased gluten content, using a commercial or laboratory sourdough, that could be appropriate for patients afflicted with wheat allergy, hypertension and pancreatic malfunctions. A reference sample (no sourdough) was prepared alongside wheat and wheat-rye bread samples-produced with either commercial or laboratory sourdough ( L. plantarum BS, L. brevis 1269, L. sanfranciscensis 20663). We measured the QQQPP allergen content (ELISA) in bread extracts digested in vitro and determined how these extracted components affect the level of active angiotensin and alpha amylase (spectrophotometry). We then elucidated how these properties changed when physiological digestion conditions (pH and pancreatin activity) were disturbed to mimic gastric hyperacidity, hypochlorhydria or exocrine pancreatic insufficiency. The key finding was that every tested type of bread produced with laboratory sourdough exhibited pronounced angiotensin-converting enzyme inhibition. The effect was preserved even in dysregulated digestive conditions. The use of laboratory sourdough prevented an increase in allergenicity when pancreatin was restricted as opposed to the commercial sourdough, which surpassed the reference sample reading at 50% pancreatin. No statistically consistent link was reported when the inhibition of alpha amylase was assayed. In conclusion, functional bread manufactured with sourdough composed of L. plantarum BS, L. brevis 1269, and L. sanfranciscensis 20663 was shown to be potentially capable of contributing to the treatment against hypertension as evidenced by in vitro research. It was also moderately safer with regard to its allergenicity.

Renin-angiotensin system (RAS) modulators, including Angiotensin receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI), are effective medications for controlling blood pressure. Cognitive deficits, including lack of concentration, memory loss, and confusion, were reported after COVID-19 infection. ARBs or ACEI increase the expression of angiotensin-converting enzyme-2 (ACE-2), a functional receptor that allows binding of SARS-CoV-2 spike protein for cellular invasion. To date, the association between the use of RAS modulators and the severity of COVID-19 cognitive dysfunction is still controversial., Purpose: This study addressed the following questions: 1) Does prior treatment with RAS modulator worsen COVID-19-induced cerebrovascular and cognitive dysfunction? 2) Can post-treatment with RAS modulator improve cognitive performance and cerebrovascular function following COVID-19? We hypothesize that pre-treatment exacerbates COVID-19-induced detrimental effects while post-treatment displays protective effects., Methods: Clinical study: Patients diagnosed with COVID-19 between May 2020 and December 2022 were identified through the electronic medical record system. Inclusion criteria comprised a documented medical history of hypertension treated with at least one antihypertensive medication. Subsequently, patients were categorized into two groups: those who had been prescribed ACEIs or ARBs before admission and those who had not received such treatment before admission. Each patient was evaluated on admission for signs of neurologic dysfunction. Pre-clinical study: Humanized ACE-2 transgenic knock-in mice received the SARS-CoV-2 spike protein via jugular vein injection for 2 weeks. One group had received Losartan (10 mg/kg), an ARB, in their drinking water for two weeks before the injection, while the other group began Losartan treatment after the spike protein injection. Cognitive functions, cerebral blood flow, and cerebrovascular density were determined in all experimental groups. Moreover, vascular inflammation and cell death were assessed., Results: Signs of neurological dysfunction were observed in 97 out of 177 patients (51%) taking ACEIs/ARBs prior to admission, compared to 32 out of 118 patients (27%) not receiving ACEI or ARBs. In animal studies, spike protein injection increased vascular inflammation, increased endothelial cell apoptosis, and reduced cerebrovascular density. In parallel, spike protein decreased cerebral blood flow and cognitive function. Our results showed that pretreatment with Losartan exacerbated these effects. However, post-treatment with Losartan prevented spike protein-induced vascular and neurological dysfunctions., Conclusion: Our clinical data showed that the use of RAS modulators before encountering COVID-19 can initially exacerbate vascular and neurological dysfunctions. Similar findings were demonstrated in the in-vivo experiments; however, the protective effects of targeting the RAS become apparent in the animal model when the treatment is initiated after spike protein injection., Competing Interests: Some data were presented as an abstract at the International Stroke Conference 2023 and the MIDYEAR 2023 Clinical Meeting & Exhibition. The authors have declared that no competing interests exist. Funding:This study was supported by American Heart Association 23AIREA1045073 to MA., (Copyright: © 2024 Meier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The stability of bioactive peptides under various food processing conditions is the basis for their use in industrial manufacturing. This study aimed to identify natural ACE inhibitors with excellent stability and investigate their physicochemical properties and putative molecular mechanisms. Five novel ACE inhibitory peptides (QDPLFPL, FPGVSPF, SPAQLLPF, LVPYRP, and WYWPQ) were isolated and identified using RP-HPLC and Nano LC-MS/MS with foxtail millet protein hydrolysates as the raw material. These peptides are non-toxic and exhibit strong ACE inhibitory activity in vitro (IC 50 values between 0.13 mg mL -1 and 0.56 mg mL -1 ). In addition to QDPLFPL, FPGVSPF, SPAQLLPF, LVPYRP, and WYWPQ have excellent human intestinal absorption. Compared to FPGVSPF and SPAQLLPF, the stable helical structure of LVPYRP and WYWPQ allows them to maintain high stability under conditions that mimic gastrointestinal digestion and various food processing (temperatures, pH, sucrose, NaCl, citric acid, sodium benzoate, Cu 2+ , Zn 2+ , K + , Mg 2+ , Ca 2+ ). The results of molecular docking and molecular dynamics simulation suggest that LVPYRP has greater stability and binding capacity to ACE than WYWPQ. LVPYRP might attach to the active pockets (S1, S2, and S1') of ACE via hydrogen bonds and hydrophobic interactions, then compete with Zn 2+ in ACE to demonstrate its ACE inhibitory activity. The binding of LVPYRP to ACE enhances the rearrangement of ACE's active structural domains, with electrostatic and polar solvation energy contributing the most energy to the binding. Our findings suggested that LVPYRP derived from foxtail millet protein hydrolysates has the potential to be incorporated into functional foods to provide antihypertensive benefits.

Pinctada fucata meat is the main by-product of the pearl harvesting industry. It is rich in nutrition, containing a lot of protein and peptides, and holds significant value for both medicine and food. In this study, a new active protein was discovered and expressed heterogeneously through bioinformatics analysis. It was then identified using Western blot, molecular weight, and mass spectrometry. The antibacterial activity, hemolysis activity, antioxidant activity, and Angiotensin-Converting Enzyme II (ACE2) inhibitory activity were investigated. An unknown functional protein was screened through the Uniprot protein database, and its primary structure did not resemble existing proteins. It was an α-helical cationic polypeptide we named PFAP-1. The codon-optimized full-length PFAP-1 gene was synthesized and inserted into the prokaryotic expression vector pET-30a. The induced expression conditions were determined with a final isopropyl-β-d-thiogalactoside (IPTG) concentration of 0.2 mM, an induction temperature of 15 °C, and an induction time of 16 h. The recombinant PFAP-1 protein, with low endotoxin and sterility, was successfully prepared. The recombinant PFAP-1 protein exhibited strong antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) in vitro, and the diameter of the inhibition zone was 15.99 ± 0.02 mm. Its minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were 37.5 μg/mL and 150 μg/mL, respectively, and its hemolytic activity was low (11.21%) at the bactericidal concentration. The recombinant PFAP-1 protein significantly inhibited the formation of MRSA biofilm and eradicated MRSA biofilm. It also demonstrated potent 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH) scavenging activity with a half-maximal inhibitory concentration (IC 50 ) of 40.83 μg/mL. The IC 50 of ACE2 inhibition was 5.66 μg/mL. Molecular docking results revealed that the optimal docking fraction of PFAP-1 protein and ACE2 protein was -267.78 kcal/mol, with a confidence level of 0.913. The stable binding complex was primarily formed through nine groups of hydrogen bonds, three groups of salt bridges, and numerous hydrophobic interactions. In conclusion, recombinant PFAP-1 can serve as a promising active protein in food, cosmetics, or medicine.

Phenolic compounds are the main special metabolites of Cyperaceae species from phytochemical, pharmacological, and chemotaxonomical points of view. The present study focused on the isolation, structure determination, and pharmacological investigation of constituents from Carex praecox . Twenty-six compounds, including lignans, stilbenes, flavonoids, megastigmanes, chromenes, and phenylpropanoids, were identified from the methanol extract of the plant. Five of these compounds, namely, carexines A-E, are previously undescribed natural products. All compounds were isolated for the first time from C. praecox . The ACE-inhibitory activity of seven stilbenoid compounds was tested, and (-)-hopeaphenol proved to be the most active (IC 50 7.7 ± 0.9 μM). The enzyme-kinetic studies revealed a mixed-type inhibition; therefore, domain-specific studies were also conducted. The in silico docking of (-)-hopeaphenol to the ACE affirmed some favorable interactions. In addition, the antiproliferative and antibacterial effects of some compounds were also evaluated.

Recently, a mild elevation of the blood ketone levels was found to exert multifaceted cardioprotective effects. To investigate the effect of angiotensin receptor neprilysin inhibitors (ARNIs) on the blood ketone body levels, 46 stable pre-heart failure (HF)/HF patients were studied, including 23 who switched from angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to ARNIs (ARNI group) and 23 who continued treatment with ACE inhibitors or ARBs (control group). At baseline, there were no significant differences in the total ketone body (TKB) levels between the two groups. Three months later, the TKB levels in the ARNI group were higher than the baseline values (baseline to 3 months: 71 [51, 122] to 92 [61, 270] μmol/L, P < 0.01). In the control group, no significant change was observed between the baseline and 3 months later. A multiple regression analysis demonstrated that the initiation of ARNI and an increase in the blood non-esterified fatty acid (NEFA) levels at 3 months increased the percentage changes in the TKB levels from baseline to 3 months (%ΔTKB level) (initiation of ARNI: P = 0.017, NEFA level at 3 months: P < 0.001). These results indicate that ARNI administration induces a mild elevation of the blood TKB levels in pre-HF/HF patients., (© 2024. The Author(s).)

Bioactive peptides derived from food are promising health-promoting ingredients that can be used in functional foods and nutraceutical formulations. In addition to the potency towards the selected therapeutic target, the bioavailability of bioactive peptides is a major factor regarding clinical efficacy. We have previously shown that a low molecular weight peptide fraction (LMWPF) from poultry by-product hydrolysates possesses angiotensin-1-converting enzyme (ACE-1) and dipeptidyl-peptidase 4 (DPP4) inhibitory activities. The present study aimed to investigate the bioavailability of the bioactive peptides in the LMWPF. Prior to the investigation of bioavailability, a dipeptide YA was identified from this fraction as a dual inhibitor of ACE-1 and DPP4. Gastrointestinal (GI) stability and intestinal absorption of the bioactive peptides ( i.e. , YA as well as two previously reported bioactive dipeptides (VL and IY)) in the LMWPF were evaluated using the INFOGEST static in vitro digestion model and intestinal Caco-2 cell monolayer, respectively. Analysis of peptides after in vitro digestion confirmed that the dipeptides were resistant to the simulated GI conditions. After 4 hours of incubation, the concentration of the peptide from the apical side of the Caco-2 cell monolayer showed a significant decrease. However, the corresponding absorbed peptides were not detected on the basolateral side, suggesting that the peptides were not transported across the intestinal monolayer but rather taken up or metabolized by the Caco2 cells. Furthermore, when analyzing the gene expression of the Caco-2 cells upon peptide stimulation, a down-regulation of peptide transporters, the transcription factor CDX2 , and the tight junction protein-1 ( TJP1 ) was observed, suggesting the specific effects of the peptides on the Caco-2 cells. The study demonstrated that bioactive dipeptides found in the LMWPF were stable through in vitro GI digestion; however, the overall bioavailability may be hindered by inadequate uptake across the intestinal barrier.

Cardiovascular diseases, including heart failure, stroke, and hypertension, affect 608 million people worldwide and cause 32% of deaths. Combination therapy is required in 60% of patients, involving concurrent Renin-Angiotensin-Aldosterone-System (RAAS) and Neprilysin inhibition. This study introduces a novel multi-target in-silico modeling technique (mt-QSAR) to evaluate the inhibitory potential against Neprilysin and Angiotensin-converting enzymes. Using both linear (GA-LDA) and non-linear (RF) algorithms, mt-QSAR classification models were developed using 983 chemicals to predict inhibitory effects on Neprilysin and Angiotensin-converting enzymes. The Box-Jenkins method, feature selection method, and machine learning algorithms were employed to obtain the most predictive model with ~ 90% overall accuracy. Additionally, the study employed virtual screening of designed scaffolds (Chalcone and its analogues, 1,3-Thiazole, 1,3,4-Thiadiazole) applying developed mt-QSAR models and molecular docking. The identified virtual hits underwent successive filtration steps, incorporating assessments of drug-likeness, ADMET profiles, and synthetic accessibility tools. Finally, Molecular dynamic simulations were then used to identify and rank the most favourable compounds. The data acquired from this study may provide crucial direction for the identification of new multi-targeted cardiovascular inhibitors., (© 2024. The Author(s).)

Globalization and climate change are both contributing to an increase in the number of potentially invasive algae in coastal areas. In terms of biodiversity and financial losses, the invasiveness of algae has become a significant issue in Orbetello Lagoon. Indeed, studies from the Tuscany Regional Agency for Environmental Protection show that the reduction in dissolved oxygen caused by algal diffusion is detrimental to fisheries and biodiversity. Considering that wakame and numerous other potentially invasive seaweeds are consumed as food in Asia, we assess the nutritional and nutraceutical qualities of two potentially invasive seaweeds: Valonia aegagrophila and Chaetomorpha linum . We found that both algae are a valuable source of proteins and essential amino acids. Even if the fat content accounts for less than 2% of the dried weight, its quality is high, due to the presence of unsaturated fatty acids. Both algae are rich in antioxidants pigments and polyphenols, which can be exploited as nutraceuticals. Most importantly, human gastrointestinal digestion increased the quantity of polyphenols and originated secondary metabolites with ACE inhibitory activity. Taken together, our data strongly promote the use of Valonia aegagrophila and Chaetomorpha linum as functional foods, with possible application in the treatment of hypertension and cardiovascular diseases.

Hypertension is a major controllable risk factor associated with cardiovascular disease (CVD) and overall mortality worldwide. Most people with hypertension must take medications that are effective in blood pressure management but cause many side effects. Thus, it is important to explore safer antihypertensive alternatives to regulate blood pressure. In this study, peanut protein concentrate (PPC) was hydrolyzed with 3-5% Alcalase for 3-10 h. The in vitro angiotensin-converting enzyme (ACE) and renin-inhibitory activities of the resulting peanut protein hydrolysate (PPH) samples and their fractions of different molecular weight ranges were determined as two measures of their antihypertensive potentials. The results show that the crude PPH produced at 4% Alcalase for 6 h of hydrolysis had the highest ACE-inhibitory activity with IC 50 being 5.45 mg/mL. The PPH samples produced with 3-5% Alcalase hydrolysis for 6-8 h also displayed substantial renin-inhibitory activities, which is a great advantage over the animal protein-derived bioactive peptides or hydrolysate. Remarkably higher ACE- and renin-inhibitory activities were observed in fractions smaller than 5 kDa with IC 50 being 0.85 and 1.78 mg/mL. Hence, the PPH and its small molecular fraction produced under proper Alcalase hydrolysis conditions have great potential to serve as a cost-effective anti-hypertensive ingredient for blood pressure management.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)