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Archives of Endocrinology and Metabolism Jun 2023The incidence of diabetic nephropathy (DN) is gradually increasing worldwide. Podocyte injury, such as podocyte apoptosis and loss of the slit diaphragm (SD)-specific...
OBJECTIVE
The incidence of diabetic nephropathy (DN) is gradually increasing worldwide. Podocyte injury, such as podocyte apoptosis and loss of the slit diaphragm (SD)-specific markers are early pathogenic features of DN.
MATERIALS AND METHODS
The cultured mouse podocytes were separated into a high glucose-treated (HG, 30mM) group to mimic DN , a low glucose-treated (LG, 5mM) group as a control and HG+ angiotensin-(1-7)(Ang-(1-7)) and HG+Ang-(1-7) + D-Ala7-Ang-(1-7) (A779, Ang-(1-7)/Mas receptor antagonist) experimental groups. The Cell Counting Kit-8 (CCK-8) method and flow cytometry was used to detect podocyte activity and podocyte apoptosis respectively. The expression of angiotensin type 1 receptor (AT1R), Mas receptor (MasR) and podocyte-specific markers were examined by q-PCR and Western blot, respectively.
RESULTS
The results showed that the decrease in podocyte activity; the increase in podocyte apoptosis; the decreased mRNA and protein expression of nephrin, podocin, WT-1 and MasR; and the upregulated expression of AT1R induced by HG could be reversed by Ang-(1-7). However, these effects were blocked by A779. The possible mechanisms of the Ang-(1-7)-mediated effect depended on MasR. In addition, the protective effect of Ang-(1-7) on podocyte activity was dose-dependent and most obvious at 10 µM. A779 had the greatest antagonistic action against Ang-(1-7) at a concentration of 10 μM.
CONCLUSION
This study reveals that binding of Ang-(1-7) to its specific receptor MasR may counteract the effects of Ang II mediated by AT1R to significantly attenuate podocyte injury induced by high glucose. Ang-(1-7)/MasR targeting in podocytes may be a therapeutic approach to attenuate renal injury in DN.
Topics: Animals; Mice; Angiotensin II; Diabetic Nephropathies; Glucose; Podocytes
PubMed: 37364145
DOI: 10.20945/2359-3997000000643 -
Heliyon Jun 2023This study aimed to investigate the impact of the malolactic fermentation (MLF) carried out by on antihypertensive and antioxidant activities in cider. The MLF was...
This study aimed to investigate the impact of the malolactic fermentation (MLF) carried out by on antihypertensive and antioxidant activities in cider. The MLF was induced using three strains of . The modification in phenolic compounds (PCs) and nitrogen organic compounds, antioxidant, and antihypertensive activities were determined after MLF. Among the 17 PCs analyzed caffeic acid was the most abundant compound and phloretin, (-)-epicatechin, and myricetin were detected only in malolactic ciders, however, (-)-epigallocatechin was not detected after MLF. The evaluation of nitrogen organic compounds revealed a drop in total protein concentration (from 17.58 to 14.00 mg N/L) concomitantly with a significant release of peptide nitrogen (from 0.31 to a maximum value of 0.80 mg N/L) after MLF. In addition, an extracellular proteolytic activity was evidenced in all MLF supernatants. The FRAP activity increased reaching a maximum of 120.9 μmol FeSO/mL and the ABTS radical-scavenging activity increased until 6.8 mmol ascorbic acid/L. Moreover, the angiotensin I-converting enzyme inhibitory activity reached a maximum value of 39.8%. The MLF conducted by in ciders enables the increase of interesting biological activities and this finding could constitute a valuable tool to add value to final product.
PubMed: 37332959
DOI: 10.1016/j.heliyon.2023.e16806 -
Human Genomics Jun 2023Clinical severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outcomes could be influenced by genetic polymorphisms in angiotensin I-converting...
BACKGROUND
Clinical severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outcomes could be influenced by genetic polymorphisms in angiotensin I-converting enzyme (ACE1) and ACE2. This study aims to examine three polymorphisms (rs1978124, rs2285666, and rs2074192) on the ACE2 gene and ACE1 rs1799752 (I/D) in patients who have coronavirus disease 2019 (COVID-19) with various SARS-CoV-2 variants.
METHODS
Based on polymerase chain reaction-based genotyping, four polymorphisms in the ACE1 and ACE2 genes have been identified in 2023 deceased patients and 2307 recovered patients.
RESULTS
The ACE2 rs2074192 TT genotype was associated with the COVID-19 mortality in all three variants, whereas the CT genotype was associated with the Omicron BA.5 and Delta variants. ACE2 rs1978124 TC genotypes were related to COVID-19 mortality in the Omicron BA.5 and Alpha variants, but TT genotypes were related to COVID-19 mortality in the Delta variant. It was found that ACE2 rs2285666 CC genotypes were associated with COVID-19 mortality in Delta and Alpha variants, and CT genotypes in Delta variants. There was an association between ACE1 rs1799752 DD and ID genotypes in the Delta variant and COVID-19 mortality, whereas there was no association in the Alpha or Omicron BA.5 variants. In all variants of SARS-CoV-2, CDCT and TDCT haplotypes were more common. In Omicron BA.5 and Delta, CDCC and TDCC haplotypes were linked with COVID-19 mortality. In addition to COVID-19 mortality, the CICT, TICT, and TICC were significantly correlated.
CONCLUSION
The ACE1/ACE2 polymorphisms had an impact on COVID-19 infection, and these polymorphisms had different effects in various SARS-CoV-2 variants. To confirm these results, however, more research needs to be conducted.
Topics: Humans; Angiotensin-Converting Enzyme 2; COVID-19; Peptidyl-Dipeptidase A; Polymorphism, Genetic; SARS-CoV-2
PubMed: 37328914
DOI: 10.1186/s40246-023-00501-8 -
Food Science & Nutrition Jun 2023Lentil peptides have shown promising bioactive properties regarding the antioxidant activity and also inhibitory activity of angiotensin-I-converting enzyme (ACE)....
Lentil peptides have shown promising bioactive properties regarding the antioxidant activity and also inhibitory activity of angiotensin-I-converting enzyme (ACE). Sequential hydrolysis of proteins has shown a higher degree of hydrolysis with enhanced antioxidant and ACE-inhibitory activities. The lentil protein concentrate (LPC) was sequentially hydrolyzed using Alcalase and Flavourzyme at 2% w/w. The hydrolysate (LPH) was cross-linked (LPHC) or sonicated (LPHUS) and sequentially cross-linked (LPHUSC). Amino acid profile, molecular weight (MW) distribution, DPPH and ABTS radical scavenging activities (RSA; 7 mg/mL), ACE (0.1-2 mg/mL), α-glucosidase, and α-amylase inhibitory activities (10-500 μg/mL), and umami taste were determined. The highest DPPH RSA was obtained for LPH (68.75%), followed by LPHUSC (67.60%), and LPHUS (67.49%) while the highest ABTS RSA values were obtained for LPHC (97.28%) and LPHUSC (97.20%). Cross-linking and sonication led to the improvement of the ACE-inhibitory activity so that LPHUSC and LPHC had IC values of 0.23 and 0.27 mg/mL, respectively. LPHC and LPHUSC also indicated higher α-glucosidase inhibitory activity (IC50 of 1.2 and 1.23 mg/mL) compared to LPH (IC50 of 1.74 mg/mL) and LPHUS (IC50 of 1.75 mg/mL) while the IC50 value of acarbose indicated 0.51 mg/mL. Moreover, LPHC and LPHUSC exhibited higher α-amylase inhibitory activities (IC50 of 1.35 and 1.16 mg/mL) than LPHUS (IC50 of 1.95 mg/mL), and LPH (IC50 of 2.51 mg/mL) while acarbose had an IC50 value of 0.43 mg/mL. Umami taste analysis revealed that LPH and LPHC due to MW of 1.7 and 2.3 kDa and also high umami amino acids could be well considered as representative of meaty and umami analog flavors while indicating stronger antioxidant, antihypertension, and antidiabetic attributes.
PubMed: 37324857
DOI: 10.1002/fsn3.3279 -
Molecules (Basel, Switzerland) Jun 2023Despite many publications related to the identification of new angiotensin-I-converting enzyme (ACE) inhibitors, especially peptides from natural products, the actual... (Review)
Review
Is It Still Relevant to Discover New ACE Inhibitors from Natural Products? YES, but Only with Comprehensive Approaches to Address the Patients' Real Problems: Chronic Dry Cough and Angioedema.
Despite many publications related to the identification of new angiotensin-I-converting enzyme (ACE) inhibitors, especially peptides from natural products, the actual reason/s for why new ACE inhibitors need to be discovered are yet to be fully understood. New ACE inhibitors are pivotal to address serious side effects caused by commercially available ACE inhibitors in hypertensive patients. Despite the effectiveness of commercial ACE inhibitors, due to these side effects, doctors often prescribe angiotensin receptor blockers (ARBs). Recent evidence has shown the benefits of ACE inhibitors over ARBs in hypertensive patients and hypertensive-diabetes mellitus patients. In order to address these side effects, the somatic ACE's enzyme structures need to be revisited. The peptides isolated from the natural products need to be verified for their stability against ACE and several important gastrointestinal enzymes. The stable peptides sequence with the presence of favourable ACE inhibitory-related amino-acids, such as tryptophan (W), at the C-terminal need to be subjected to molecular docking and dynamics analyses for selecting ACE inhibitory peptide/s with C-domain-specific inhibition instead of both C- and N-domains' inhibition. This strategy will help to reduce the accumulation of bradykinin, the driving factor behind the formation of the side effects.
Topics: Humans; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Cough; Biological Products; Molecular Docking Simulation; Hypertension; Angioedema
PubMed: 37299008
DOI: 10.3390/molecules28114532 -
Foods (Basel, Switzerland) Jun 2023In this study, naked oat bran albumin hydrolysates (NOBAH) were subjected to gel chromatography with Sephadex G-15, reverse phase-high liquid performance separation, and...
Study on the In Silico Screening and Characterization, Inhibition Mechanisms, Zinc-Chelate Activity, and Stability of ACE-Inhibitory Peptides Identified in Naked Oat Bran Albumin Hydrolysates.
In this study, naked oat bran albumin hydrolysates (NOBAH) were subjected to gel chromatography with Sephadex G-15, reverse phase-high liquid performance separation, and UPLC-ESI-MS/MS identification. Six safe peptides including Gly-Thr-Thr-Gly-Gly-Met-Gly-Thr (GTTGGMGT), Gln-Tyr-Val-Pro-Phe (QYVPF), Gly-Ala-Ala-Ala-Ala-Leu-Val (GAAAALV), Gly-Tyr-His-Gly-His (GYHGH), Gly-Leu-Arg-Ala-Ala-Ala-Ala-Ala-Ala-Glu-Gly-Gly (GLRAAAAAAEGG), and Pro-Ser-Ser-Pro-Pro-Ser (PSSPPS) were identified. Next, in silico screening demonstrated that QYVPF and GYHGH had both angiotensin-I-converting enzyme (ACE) inhibition activity (IC: 243.36 and 321.94 μmol/L, respectively) and Zinc-chelating ability (14.85 and 0.32 mg/g, respectively). The inhibition kinetics demonstrated that QYVPF and GYHGH were both uncompetitive inhibitors of ACE. Molecular docking showed that QYVPF and GYHGH could bind, respectively, three and five active residues of ACE with short hydrogen bonds (but not belonging to any central pocket). QYVPF and GYHGH could bind, respectively, twenty-two and eleven residues through hydrophobic interactions. Moreover, GYHGH was able to affect zinc tetrahedral coordination in ACE by interacting with His383. The inhibition activities of QYVPF and GYHGH toward ACE were relatively resistant to gastrointestinal digestion. GYHGH improved zinc solubility in the intestines ( > 0.05) because its amino and carboxyl groups were chelating sites for zinc ions. These results suggest the potential applications of naked oat peptides for potential antihypertension or zinc fortification.
PubMed: 37297512
DOI: 10.3390/foods12112268 -
Clinical Science (London, England :... Jun 2023Compromised barrier function of colon epithelium with aging is largely due to gut microbial dysbiosis. Recent studies implicate an important role for angiotensin...
Compromised barrier function of colon epithelium with aging is largely due to gut microbial dysbiosis. Recent studies implicate an important role for angiotensin converting enzymes, ACE and ACE2, angiotensins, and the receptors, AT1 receptor (AT1R) and Mas receptor (MasR), in the regulation of colon functions. The present study tested the hypothesis that leaky gut in aging is associated with an imbalance in ACE2/ACE and that the treatment with angiotenisn-(1-7) (Ang-(1-7)) will restore gut barrier integrity and microbiome. Studies were carried out in Young (3-4 months) and old (20-24 months) male mice. Ang-(1-7) was administered by using osmotic pumps. Outcome measures included expressions of ACE, ACE2, AT1R, and MasR, intestinal permeability by using FITC-dextran, and immunohistochemistry of claudin 1 and occludin, and intestinal stem cells (ISCs). ACE2 protein and activity were decreased in Old group while that of ACE were unchanged. Increased intestinal permeability and plasma levels of zonulin-1 in the Old group were normalized by Ang-(1-7). Epithelial disintegrity, reduced number of goblet cells and ISCs in the old group were restored by Ang-(1-7). Expression of claudin 1 and occludin in the aging colon was increased by Ang-(1-7). Infiltration of CD11b+ or F4/80+ inflammatory cells in the old colons were decreased by Ang-(1-7). Gut microbial dysbiosis in aging was evident by decreased richness and altered beta diversity that were reversed by Ang-(1-7) with increased abundance of Lactobacillus or Lachnospiraceae. The present study shows that Ang-(1-7) restores gut barrier integrity and reduces inflammation in the aging colon by restoring the layer of ISCs and by restructuring the gut microbiome.
Topics: Mice; Male; Animals; Gastrointestinal Microbiome; Angiotensin-Converting Enzyme 2; Dysbiosis; Claudin-1; Occludin; Angiotensin I; Peptidyl-Dipeptidase A; Peptide Fragments; Aging; Angiotensin II
PubMed: 37254732
DOI: 10.1042/CS20220904 -
Food Research International (Ottawa,... Jul 2023Entomophagy is a sustainable alternative source of proteins for human nutrition. Acheta domesticus is one of the three insect species that complies with the European...
Entomophagy is a sustainable alternative source of proteins for human nutrition. Acheta domesticus is one of the three insect species that complies with the European Union Regulation on novel foods, but to date, there are no reports on their potential bioactive peptides. In this study, an in silico approach was applied to simulate the gastrointestinal (GI) digestion of six A. domesticus proteins and identify new peptides with potential anti-hypertensive and/or anti-diabetic properties, resulting from their capability to inhibit the somatic Angiotensin-I converting enzyme (sACE) and/or dipeptidyl peptidase 4 (DPP-4), respectively. A molecular docking protocol was applied to evaluate the binding interactions between the 43 peptides ranked with high probability of being bioactive and three drug targets: DPP-4 and two catalytic domains (N- and C-) of sACE. Five peptides (AVQPCF, CAIAW, IIIGW, DATW and QIVW) showed high docking scores for both enzymes, suggesting their potential to inhibit the DPP-4 and both catalytic domains of sACE, thus possessing multifunctional bioactive properties. Two peptides (PIVCF and DVW) showed higher docking scores for the N-domain of sACE, indicating a potential action as selective inhibitors and consequently with anti-cardiac and pulmonary fibrosis bioactivities. This is the first study identifying peptides originated from the simulated GI digestion of A. domesticus with potential activities against hypertension, diabetes, cardiac and pulmonary fibrosis.
Topics: Humans; Molecular Docking Simulation; Pulmonary Fibrosis; Dipeptidyl-Peptidase IV Inhibitors; Peptides; Diabetes Mellitus; Hypertension
PubMed: 37254421
DOI: 10.1016/j.foodres.2023.112847 -
Pathogens (Basel, Switzerland) Apr 2023Vaccination has drastically decreased mortality due to coronavirus disease 19 (COVID-19), but not the rate of acute respiratory syndrome coronavirus 2 (SARS-CoV-2)...
Vaccination has drastically decreased mortality due to coronavirus disease 19 (COVID-19), but not the rate of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Alternative strategies such as inhibition of virus entry by interference with angiotensin-I-converting enzyme 2 (ACE2) receptors could be warranted. Cyclodextrins (CDs) are cyclic oligosaccharides that are able to deplete cholesterol from membrane lipid rafts, causing ACE2 receptors to relocate to areas devoid of lipid rafts. To explore the possibility of reducing SARS-CoV-2 entry, we tested hydroxypropyl-β-cyclodextrin (HPβCD) in a HEK293T-ACE2 cell line stably overexpressing human ACE2 and Spike-pseudotyped SARS-CoV-2 lentiviral particles. We showed that HPβCD is not toxic to the cells at concentrations up to 5 mM, and that this concentration had no significant effect on cell cycle parameters in any experimental condition tested. Exposure of HEK293T-ACE cells to concentrations of HPβCD starting from 2.5 mM to 10 mM showed a concentration-dependent reduction of approximately 50% of the membrane cholesterol content. In addition, incubation of HEK293T-ACE cells with HIV-S-CoV-2 pseudotyped particles in the presence of increasing concentrations of HPβCD (from 0.1 to 10 mM) displayed a concentration-dependent effect on SARS-CoV-2 entry efficiency. Significant effects were detected at concentrations at least one order of magnitude lower than the lowest concentration showing toxic effects. These data indicate that HPβCD is a candidate for use as a SARS-CoV-2 prophylactic agent.
PubMed: 37242317
DOI: 10.3390/pathogens12050647 -
Scientific Reports May 2023Radiation pneumonitis (RP) affects both patients and physicians during radiation therapy for lung cancer. To date, there are no effective drugs for improving the...
Radiation pneumonitis (RP) affects both patients and physicians during radiation therapy for lung cancer. To date, there are no effective drugs for improving the clinical outcomes of RP. The activation of angiotensin-converting enzyme 2 (ACE2) improves experimental acute lung injury caused by severe acute respiratory syndrome coronavirus, acid inhalation, and sepsis. However, the effects and underlying mechanisms of ACE2 in RP remain unclear. Therefore, this study aimed to investigate the effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on RP and ACE2/angiotensin-(1-7)/Mas receptor pathway activation. We found that radiotherapy decreased the expression of ACE2 and that overexpression of ACE2 alleviated lung injury in an RP mouse model. Moreover, captopril and valsartan restored ACE2 activation; attenuated P38, ERK, and p65 phosphorylation; and effectively mitigated RP in the mouse model. Further systematic retrospective analysis illustrated that the incidence of RP in patients using renin-angiotensin system inhibitors (RASis) was lower than that in patients not using RASis (18.2% vs. 35.8% at 3 months, p = 0.0497). In conclusion, the current findings demonstrate that ACE2 plays a critical role in RP and suggest that RASis may be useful potential therapeutic drugs for RP.
Topics: Animals; Mice; NF-kappa B; Peptidyl-Dipeptidase A; Angiotensin-Converting Enzyme 2; Radiation Pneumonitis; Renin-Angiotensin System; Retrospective Studies; Antihypertensive Agents; Enzyme Inhibitors; Acute Lung Injury
PubMed: 37221286
DOI: 10.1038/s41598-023-35412-0