MARRIAGE: A Randomized Trial of Moxonidine Versus Ramipril or in Combination With Ramipril in Overweight Patients With Hypertension and Impaired Fasting Glucose or Diabetes Mellitus. Impact on Blood Pressure, Heart Rate and Metabolic Parameters.

BACKGROUND: Moxonidine, an imidazoline I1 receptor agonist, is an effective antihypertensive drug that was shown to improve insulin sensitivity. RAAS-blockers are recommended as first-line therapy in patients with diabetes, alone or in combination with a calcium-channel antagonist or a diuretic. AIMS: This study compared the effects of moxonidine and ramipril on blood pressure (BP) and glucose metabolism in overweight patients with mild-to-moderate hypertension and impaired fasting glucose or type 2 diabetes. METHODS: Treatment-naïve patients for hypertension and dysglycemia were randomized to 12 weeks of double-blind moxonidine 0.4 mg or ramipril 5 mg once-daily treatment. At 12 weeks, for a further 12 weeks non-responders received combination of mox/ram, while responders continued blinded treatment. RESULTS: Moxonidine and ramipril were equivalent in lowering SiDBP and SiSBP at the end of the first 12 weeks. The responder rate was approximately 50% in both groups, with a mean SiDBP and SiSBP decrease of 10 and 15 mm Hg in the responders, respectively. The normalization rate (SiDBP < 85 mm Hg) was non significantly different between treatments groups. Moxonidine reduced heart rate (HR) (average -3.5 bpm, p = 0.017) during monotherapy, and when added to ramipril. HbA1c decreased significantly at Week 12 in both groups. Neither drug affected glucose or insulin response to the oral glucose tolerance test. In non-responders, moxonidine/ramipril combination further reduced BP without compromising metabolic parameters. CONCLUSION: Moxonidine 0.4 mg and ramipril 5 mg were equally effective on BP lowering and were well tolerated and mostly metabolically neutral either as monotherapies or in combination. HR was lowered on moxonidine treatment.

Effect of thermal pretreatment and gastrointestinal digestion on the bioactivity of dry-cured ham bone enzymatic hydrolyzates.

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.

Vicinal diaryl pyrazole with tetrazole/urea scaffolds as selective angiotensin converting enzyme-1/cyclooxygenase-2 inhibitors: Design, synthesis, anti-hypertensive, anti-fibrotic, and anti-inflammatory.

As a hybrid weapon, two novel series of pyrazoles, 16a-f and 17a-f, targeting both COX-2 and ACE-1-N-domain, were created and their anti-inflammatory, anti-hypertensive, and anti-fibrotic properties were evaluated. In vitro, 17b and 17f showed COX-2 selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and NF-κB (IC50 1.87 and 2.03 µM, respectively). 17b (IC50 0.078 µM) and 17 f (IC50 0.094 µM) inhibited ACE-1 comparable to perindopril (PER) (IC50 0.048 µM). In vivo, 17b decreased systolic blood pressure by 18.6%, 17b and 17f increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced NF-κB-p65 and P38-MAPK expression by -0.62, -0.22, -0.53, and -0.24 folds, respectively compared to  l-NAME (-0.34, -0.45 folds decline in NF-κB-p65 and P38-MAPK, respectively). 17b reduced ANG-II expression which significantly reversed the cardiac histological changes induced by L-NAME.

A novel ACE inhibitory peptide from Pelodiscus sinensis Wiegmann meat water-soluble protein hydrolysate.

Pelodiscus sinensis meat is a nutritional food and tonic with angiotensin-converting enzyme (ACE) inhibitory activities. To identify the bioactive substances responsible, several bioinformatics methods were integrated to enable a virtual screening for bioactive peptides in proteins identified within a water-soluble protein fraction of Pelodiscus sinensis meat by Shotgun proteomics. The peptides were generated from the identified proteins by in silico proteolysis using six proteases. A comparison of the numbers of proteins suitable for digestion with each enzyme and the iBAQ (intensity-based absolute quantification) values for these proteins revealed that bromelain and papain were the most suitable proteases for this sample. Next, the water solubility, toxicity, and ADMET (absorption/distribution/metabolism/excretion/toxicity) properties of these peptides were evaluated in silico. Finally, a novel ACE inhibitory peptide IEWEF with an IC50 value of 41.33 µM was identified. The activity of the synthesized peptide was verified in vitro, and it was shown to be a non-competitive ACE inhibitor. Molecular docking revealed that IEWEF could tightly bind to C-ACE, and N-ACE with energies less than 0 kJ mol-1, and the peptide IEWEF can form hydrogen bonds with C-ACE and N-ACE respectively. These results provide evidence that bioactive peptides in the water-soluble protein fraction account for (at least) some of the ACE inhibitory activities observed in Pelodiscus sinensis meat. Furthermore, our research provides a workflow for the efficient identification of novel ACE inhibitory peptides from complex protein mixtures.

Pharmacological Research Progress of Novel Antihypertensive Drugs.

Cardiovascular disease stands as the leading cause of death globally, with hypertension emerging as an independent risk factor for its development. The worldwide prevalence of hypertension hovers around 30%, encompassing a staggering 1.2 billion patients, and continues to escalate annually. Medication plays a pivotal role in managing hypertension, not only effectively regulating blood pressure (BP) but also substantially mitigating the occurrence of cardiovascular and cerebrovascular diseases. This review comprehensively outlines the categories, mechanisms, clinical applications, and drawbacks of conventional antihypertensive drugs. It delves into the five primary pharmacological classifications, namely ß-receptor blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and diuretics. The emphasis is placed on elucidating the mechanisms, advantages, and research progress of novel antihypertensive drugs targeting emerging areas. These include mineralocorticoid receptor antagonists (MRAs), atrial natriuretic peptides (ANPs), neutral endopeptidase inhibitors (NEPIs), sodium-dependent glucose transporter 2 inhibitors (SGLT-2Is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) agonists, brain aminopeptidase A inhibitors (APAIs), and small interfering ribonucleic acids (siRNAs) targeting hepatic angiotensinogen. Compared to conventional antihypertensive drugs, these novel alternatives exhibit favorable antihypertensive effects with minimal adverse reactions. This review serves as a valuable reference for future research and the clinical application of antihypertensive drugs.

Revealing the ACE receptor binding properties and interaction mechanisms of salty oligopeptides from Stropharia rugosoannulata mushroom by molecular simulation and antihypertensive evaluation.

The salty oligopeptides from Stropharia rugosoannulata have been proven to be potential ACE inhibitors. To investigate the ACE receptor binding properties and interaction mechanisms of salty oligopeptides, the molecular interaction, dynamics simulation, and antihypertensive evaluation cross-validation strategy were employed to reveal the oligopeptides' binding reactions and modes with the ACE receptor. Single oligopeptide (ESPERPFL, KSWDDFFTR) had exothermic and specific binding reactions with the ACE receptor, driven by hydrogen bonds and van der Waals forces. The coexistence of the multiple oligopeptide molecules did not produce the apparent ACE receptor competition binding reactions. The molecular dynamics simulation verified that the two oligopeptides disturbed the ACE receptor's different residue regions. Both oligopeptides could form stable complexes with the ACE receptor. Based on the classification of 50 oligopeptides' binding modes, ESPERPFL and KSWDDFFTR belonged to different classes, and their receptor binding modes and sites complemented, resulting in a potential synergistic effect on ACE inhibition. The antihypertensive effect of KSWDDFFTR and its distribution in the body were evaluated using SHR rats orally and ICR mice by tail vein injection, and KSWDDFFTR had antihypertensive effects within 8 h. The study provides a theoretical basis for understanding salty oligopeptides' ACE receptor binding mechanism and their antihypertensive effects.

Novel Angiotensin-Converting Enzyme-Inhibitory Peptides Obtained from Trichiurus lepturus: Preparation, Identification and Potential Antihypertensive Mechanism.

Peptides possessing antihypertensive attributes via inhibiting the angiotensin-converting enzyme (ACE) were derived through the enzymatic degradation of Trichiurus lepturus (ribbonfish) using alkaline protease. The resulting mixture underwent filtration using centrifugation, ultrafiltration tubes, and Sephadex G-25 gels. Peptides exhibiting ACE-inhibitory properties and DPPH free-radical-scavenging abilities were isolated and subsequently purified via LC/MS-MS, leading to the identification of over 100 peptide components. In silico screening yielded five ACE inhibitory peptides: FAGDDAPR, QGPIGPR, IFPRNPP, AGFAGDDAPR, and GPTGPAGPR. Among these, IFPRNPP and AGFAGDDAPR were found to be allergenic, while FAGDDAPRR, QGPIGPR, and GPTGPAGP showed good ACE-inhibitory effects. IC50 values for the latter peptides were obtained from HUVEC cells: FAGDDAPRR (IC50 = 262.98 µM), QGPIGPR (IC50 = 81.09 µM), and GPTGPAGP (IC50 = 168.11 µM). Peptide constituents derived from ribbonfish proteins effectively modulated ACE activity, thus underscoring their therapeutic potential. Molecular docking and modeling corroborated these findings, emphasizing the utility of functional foods as a promising avenue for the treatment and prevention of hypertension, with potential ancillary health benefits and applications as substitutes for synthetic drugs.

Screening and rational identification of a novel angiotensin-converting enzyme C-domain inhibitory peptide from Fabaceae food peptide library.

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.

Two Novel Angiotensin-Converting Enzyme (ACE) Inhibitory and ACE2 Upregulating Peptides from the Hydrolysate of Pumpkin (Cucurbita moschata) Seed Meal.

Pumpkin (Cucurbita moschata) seed meal (PSM), the major byproduct of pumpkin seed oil industry, was used to prepare angiotensin-converting enzyme (ACE) inhibitory and angiotensin-converting enzyme 2 (ACE2) upregulating peptides. These peptides were isolated and purified from the PSM hydrolysate prepared using Neutrase 5.0 BG by ultrafiltration, Sephadex G-15 column chromatography, and reversed-phase high-performance liquid chromatography. Two peptides with significant ACE inhibition activity were identified as SNHANQLDFHP and PVQVLASAYR with IC50 values of 172.07 and 90.69 µM, respectively. The C-terminal tripeptides of the two peptides contained Pro, Phe, and Tyr, respectively, and PVQVLASAYR also had Val in its N-terminal tripeptide, which was a favorable structure for ACE inhibition. Molecular docking results declared that the two peptides could interact with ACE through hydrogen bonds and hydrophobic interactions. Furthermore, the two peptides performed protective function on EA.hy926 cells by decreasing the secretion of endothelin-1, increasing the release of nitric oxide, and regulating the ACE2 activity. In vitro simulated gastrointestinal digestion showed the two peptides exhibited good stability against gastrointestinal enzyme digestion. In conclusion, PSM is a promising material for preparing antihypertensive peptides.

Exploring peptidomes of by-products generated during chhurpi production using Lactobacillus delbrueckii WS4 for identification of novel bioactive peptides.

The considerable value of whey is evident from its significant potential applications and contributions to the functional food and nutraceutical market. The by-products were individually obtained during functional chhurpi and novel soy chhurpi cheese production using defined lactic acid bacterial strains of Sikkim Himalaya's traditional chhurpi. Hydrolysis of substrate proteins by starter proteinases resulted in a comparable peptide content in whey and soy whey which was associated with antioxidant and ACE inhibition potential. Peptidome analysis of Lactobacillus delbrueckii WS4 whey and soy whey revealed the presence of several bioactive peptides including the multifunctional peptides PVVVPPFLQPE and YQEPVLGPVRGPFPIIV. In silico analyses predicted the antihypertensive potential of whey and soy whey peptides with strong binding affinity for ACE active sites. QSAR models predicted the highest ACE inhibition potential (IC50) for the ß-casein-derived decapeptide PVRGPFPIIV (0.95 µM) and the Kunitz trypsin inhibitor protein-derived nonapeptide KNKPLVVQF (16.64 µM). Chhurpi whey and soy whey can be explored as a valuable source of diverse and novel bioactive peptides for applications in designer functional foods development.

The Salutary Effects of Diminazene, Lisinopril or Valsartan on Cisplatin - Induced Acute Kidney Injury in Rats: A Comparative Study.

Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting enzyme 2 activator, exhibited renoprotective properties on rat models of kidney diseases. This research aims to investigate the salutary effect of diminazene in comparison with lisinopril or valsartan in CP-induced AKI. The first and second groups of rats received oral vehicle (distilled water) for 9 days, and saline injection or intraperitoneal CP (6 mg/kg) on day 6, respectively. Third, fourth, and fifth groups received intraperitoneal injections of CP on day 6 and diminazene (15 mg/kg/day, orally), lisinopril (10 mg/kg/day, orally), or valsartan (30 mg/kg/day, orally), for 9 days, respectively. 24h after the last day of treatment, blood and kidneys were removed under anesthesia for biochemical and histopathological examination. Urine during the last 24 h before sacrificing the rats was also collected. CP significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin, calcium, phosphorus, and uric acid. It also increased urinary albumin/creatinine ratio, N-Acetyl-beta-D-Glucosaminidase/creatinine ratio, and reduced creatinine clearance, as well the plasma concentrations of inflammatory cytokines [plasma tumor necrosis factor-alpha, and interleukin-1beta], and significantly reduced antioxidant indices [catalase, glutathione reductase , and superoxide dismutase]. Histopathologically, CP treatment caused necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. Diminazine, lisinopril, and valsartan ameliorated CP-induced biochemical and histopathological changes to a similar extent. The salutary effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Keywords: Cisplatin, Diminazene, ACE2 activator, Lisinopril, Valsartan, Acute kidney injury.

Dynamic digestion of a high protein beverage based on amaranth: Structural changes and antihypertensive activity.

An amaranth beverage (AB) was subjected to a simulated process of dynamic gastrointestinal digestion DIDGI®, a simple two-compartment in vitro dynamic gastrointestinal digestion system. The structural changes caused to the proteins during digestion and the digesta inhibitory capacity of the angiotensin converting enzyme (ACE) were investigated. In gastric compartment the degree of hydrolysis (DH) was 14.7 ± 1.5 % and in the intestinal compartment, proteins were digests in a greater extent (DH = 60.6 ± 8.4 %). Protein aggregation was detected during the gastric phase. The final digesta obtained both at the gastric and intestinal level, showed ACE inhibitory capacity (IC50 80 ± 10 and 140 ± 20 µg/mL, respectively). Purified fractions from these digesta showed even greater inhibitory capacity, being eluted 2 (E2) the most active fraction (IC50 60 ± 10 µg/mL). Twenty-six peptide sequences were identified. Six of them, with potential antihypertensive capacity, belong to A. hypochondriacus, 3 agglutinins and 3 encrypted sequences in the 11S globulin. Results obtained provide new and useful information on peptides released from the digestion of an amaranth based beverage and its ACE bioactivity.

Angiotensin-converting enzyme 2 and AMPK/mTOR pathway in the treatment of liver fibrosis: Should we consider further implications?

This editorial contains comments on the article by Zhao et al in print in the World Journal of Gastroenterology. The mechanisms responsible for hepatic fibrosis are also involved in cancerogenesis. Here, we recapitulated the complexity of the renin-angiotensin system, discussed the role of hepatic stellate cell (HSC) autophagy in liver fibrogenesis, and analyzed the possible implications in the development of hepatocarcinoma (HCC). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers definitively contribute to reducing hepatic fibrogenesis, whereas their involvement in HCC is more evident in experimental conditions than in human studies. Angiotensin-converting enzyme 2 (ACE2), and its product Angiotensin (Ang) 1-7, not only regulate HSC autophagy and liver fibrosis, but they also represent potential targets for unexplored applications in the field of HCC. Finally, ACE2 overexpression inhibits HSC autophagy through the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. In this case, Ang 1-7 acts binding to the MasR, and its agonists could modulate this pathway. However, since AMPK utilizes different targets to suppress the mTOR downstream complex mTOR complex 1 effectively, we still need to unravel the entire pathway to identify other potential targets for the therapy of fibrosis and liver cancer.

Ferroptosis, Inflammation, and Microbiome Alterations in the Intestine in the Göttingen Minipig Model of Hematopoietic-Acute Radiation Syndrome.

Hematopoietic acute radiation syndrome (H-ARS) involves injury to multiple organ systems following total body irradiation (TBI). Our laboratory demonstrated that captopril, an angiotensin-converting enzyme inhibitor, mitigates H-ARS in Göttingen minipigs, with improved survival and hematopoietic recovery, as well as the suppression of acute inflammation. However, the effects of captopril on the gastrointestinal (GI) system after TBI are not well known. We used a Göttingen minipig H-ARS model to investigate captopril's effects on the GI following TBI (60Co 1.79 or 1.80 Gy, 0.42-0.48 Gy/min), with endpoints at 6 or 35 days. The vehicle or captopril (0.96 mg/kg) was administered orally twice daily for 12 days, starting 4 h post-irradiation. Ilea were harvested for histological, protein, and RNA analyses. TBI increased congestion and mucosa erosion and hemorrhage, which were modulated by captopril. GPX-4 and SLC7A11 were downregulated post-irradiation, consistent with ferroptosis at 6 and 35 days post-irradiation in all groups. Interestingly, p21/waf1 increased at 6 days in vehicle-treated but not captopril-treated animals. An RT-qPCR analysis showed that radiation increased the gene expression of inflammatory cytokines IL1B, TNFA, CCL2, IL18, and CXCL8, and the inflammasome component NLRP3. Captopril suppressed radiation-induced IL1B and TNFA. Rectal microbiome analysis showed that 1 day of captopril treatment with radiation decreased overall diversity, with increased Proteobacteria phyla and Escherichia genera. By 6 days, captopril increased the relative abundance of Enterococcus, previously associated with improved H-ARS survival in mice. Our data suggest that captopril mitigates senescence, some inflammation, and microbiome alterations, but not ferroptosis markers in the intestine following TBI.

Obesity-induced skeletal muscle remodeling: A comparative analysis of exercise training and ACE-inhibitory drug in male mice.

Obesity over-activates the classical arm of the renin-angiotensin system (RAS), impairing skeletal muscle remodeling. We aimed to compare the effect of exercise training and enalapril, an angiotensin-converting enzyme inhibitor, on RAS modulation in the skeletal muscle of obese animals. Thus, we divided C57BL/6 mice into two groups: standard chow (SC) and high-fat (HF) diet for 16 weeks. At the eighth week, the HF-fed animals were divided into four subgroups-sedentary (HF), treated with enalapril (HF-E), exercise training protocol (HF-T), and combined interventions (HF-ET). After 8 weeks of treatment, we evaluated body mass and index (BMI), body composition, exercise capacity, muscle morphology, and skeletal muscle molecular markers. All interventions resulted in lower BMI and attenuation of overactivation in the classical arm, while favoring the B2R in the bradykinin receptors profile. This was associated with reduced apoptosis markers in obese skeletal muscles. The HF-T group showed an increase in muscle mass and expression of biosynthesis markers and a reduction in expression of degradation markers and muscle fiber atrophy due to obesity. These findings suggest that the combination intervention did not have a synergistic effect against obesity-induced muscle remodeling. Additionally, the use of enalapril impaired muscle's physiological adaptations to exercise training.

Production of Antioxidant, Angiotensin-Converting Enzyme Inhibitory and Osteogenic Gelatin Hydrolysate from Labeo rohita Swim Bladder.

Optimization of antioxidants and angiotensin-converting enzyme (ACE) inhibitory potential gelatin hydrolysate production from Labeo rohita (rohu) swim bladder (SBGH) by alcalase using central composite design (CCD) of response surface methodology (RSM) was investigated. The maximum degree of hydrolysis (DH), 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS), total antioxidants (TAO), and ACE inhibitory activity were achieved at 0.1:1.0 (w/w) enzyme to substrate ratio, 61 °C hydrolysis temperature, and 94-min hydrolysis time. The resulting SBGH obtained at 19.92% DH exhibited the DPPH (24.28 µM TE/mg protein), ABTS (34.47 µM TE/mg protein), TAO (12.01 µg AAE/mg protein), and ACE inhibitory (4.91 µg/mg protein) activity. Furthermore, SBGH at 100 µg/ml displayed osteogenic property without any toxic effects on MC3T3-E1 cells. Besides, the protein content of rohu swim bladder gelatin (SBG) and SBGH was 93.68% and 94.98%, respectively. Both SBG and SBGH were rich in glycine, proline, glutamic acid, alanine, arginine, and hydroxyproline amino acids. Therefore, SBGH could be an effective nutraceutical in functional food development.

Angiotensin-converting enzyme inhibition prevents l-dopa-induced dyskinesia in a 6-ohda-induced mouse model of Parkinson's disease.

Parkinson's disease (PD) is characterised by severe movement defects and the degeneration of dopaminergic neurones in the midbrain. The symptoms of PD can be managed with dopamine replacement therapy using L-3, 4-dihydroxyphenylalanine (L-dopa), which is the gold standard therapy for PD. However, long-term treatment with L-dopa can lead to motor complications. The central renin-angiotensin system (RAS) is associated with the development of neurodegenerative diseases in the brain. However, the role of the RAS in dopamine replacement therapy for PD remains unclear. Here, we tested the co-treatment of the angiotensin-converting enzyme inhibitor (ACEI) with L-dopa altered L-dopa-induced dyskinesia (LID) in a 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Perindopril, captopril, and enalapril were used as ACEIs. The co-treatment of ACEI with L-dopa significantly decreased LID development in 6-OHDA-lesioned mice. In addition, the astrocyte and microglial transcripts involving Ccl2, C3, Cd44, and Iigp1 were reduced by co-treatment with ACEI and L-dopa in the 6-OHDA-lesioned striatum. In conclusion, co-treatment with ACEIs and L-dopa, such as perindopril, captopril, and enalapril, may mitigate the severity of L-DOPA-induced dyskinesia in a mouse model of PD.

A combined in vitro and in silico study of the inhibitory mechanism of angiotensin-converting enzyme with peanut peptides.

Food-derived peptides with low molecular weight, high bioavailability, and good absorptivity have been exploited as angiotensin-converting enzyme (ACE) inhibitors. In the present study, in-vitro inhibition kinetics of peanut peptides, in silico screening, validation of ACE inhibitory activity, molecular dynamics (MD) simulations, and HUVEC cells were performed to systematically identify the inhibitory mechanism of ACE interacting with peanut peptides. The results indicate that FPHPP, FPHY, and FPHFD peptides have good thermal, pH, and digestive stability. MD trajectories elucidate the dynamic correlation between peptides and ACE and verify the specific binding interaction. Noteworthily, FPHPP is the best inhibitor with a strongest binding affinity and significantly increases NO, SOD production, and AT2R expression, and decreases ROS, MDA, ET-1 levels, ACE, and AT1R accumulation in Ang II-injury HUVEC cells.

Protein Hydrolysis as a Way to Valorise Squid-Processing Byproducts: Obtaining and Identification of ACE, DPP-IV and PEP Inhibitory Peptides.

The industrial processing of Argentine shortfin squid to obtain rings generates a significant amount of protein-rich waste, including the skin, which is rich in collagen and attached myofibrillar proteins. This waste is generally discarded. In this study, skin was used as a source of proteins that were hydrolysed using Trypsin, Esperase® or Alcalase®, which released peptides with antioxidant potential and, in particular, antihypertensive (ACE inhibition), hypoglycemic (DPP-IV inhibition) and/or nootropic (PEP inhibition) potential. Among the three enzymes tested, Esperase® and Alcalase produced hydrolysates with potent ACE-, DPP-IV- and PEP-inhibiting properties. These hydrolysates underwent chromatography fractionation, and the composition of the most bioactive fractions was analysed using HPLC-MS-MS. The fractions with the highest bioactivity exhibited very low IC50 values (16 and 66 µg/mL for ACE inhibition, 97 µg/mL for DPP-IV inhibition and 55 µg/mL for PEP inhibition) and were mainly derived from the hydrolysate obtained using Esperase®. The presence of Leu at the C-terminal appeared to be crucial for the ACE inhibitory activity of these fractions. The DPP-IV inhibitory activity of peptides seemed to be determined by the presence of Pro or Ala in the second position from the N-terminus, and Gly and/or Pro in the last C-terminal positions. Similarly, the presence of Pro in the peptides present in the best PEP inhibitory fraction seemed to be important in the inhibitory effect. These results demonstrate that the skin of the Argentine shortfin squid is a valuable source of bioactive peptides, suitable for incorporation into human nutrition as nutraceuticals and food supplements.

Renin-Angiotensin-Aldosterone System: From History to Practice of a Secular Topic.

Renin-angiotensin-aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS and pose the question of whether this survival trait is still necessary to humankind in the present age. We elucidate the benefits on cardiovascular health and kidney disease of RAAS inhibition and present promising novel medications. Furthermore, we address why more studies are needed to establish a new standard of care away from generally prescribing ACEi or ARB toward an improved approach to combine drugs tailored to the needs of individual patients.