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1.
Medicine (Baltimore) ; 101(45): e31008, 2022 Nov 11.
Article in English | MEDLINE | ID: mdl-36397318

ABSTRACT

BACKGROUND: The aim of this meta-analysis is to investigate the association between Angiotensin II type 1 receptor (AT1R)-1166A/C, Angiotensin II type 2 receptor (AT2R)-1675A/G polymorphisms and susceptibility to preeclampsia (PE). METHODS: Online databases, including Web of Science, PubMed, EMBASE, CINAHL, CENTRAL, Scopus, Lilacs/SciELO, and Chinese National Knowledge Infrastructure, China Wan Fang, China Science and Technology Journal Database, were used to perform the literature search up to April 2022. The odds ratio (OR) and 95% confidence interval (CI) were used as effect size. The data was analyzed by Stata 15.0 software. RESULTS: According to the inclusion and exclusion criteria, a total of 22 case-control studies were identified, including 3524 cases and 6308 controls. Our meta-analysis showed that the AT1R -1166 A/C allele was significantly associated with susceptibility to PE (A vs C: OR = 0.82, 95% CI: 0.69-0.96, P = .013), and there was significant difference in recessive gene model (AA vs AC + CC: OR = 0.81, 95% CI: 0.67-0.97, P = .021). However, no association was found between AT2R-1675A/G polymorphism and susceptibility to PE. CONCLUSION: our meta-analysis suggested that AT1R-1166A/C polymorphism had an association with susceptibility to PE, but AT2R-1675A/G polymorphism had no association with susceptibility to PE.


Subject(s)
Pre-Eclampsia , Receptor, Angiotensin, Type 1 , Receptor, Angiotensin, Type 2 , Female , Humans , Pregnancy , Angiotensins/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Pre-Eclampsia/genetics , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 2/genetics
2.
World J Surg Oncol ; 20(1): 354, 2022 Nov 04.
Article in English | MEDLINE | ID: mdl-36329458

ABSTRACT

OBJECTIVE: This meta-analysis aims to explore the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and susceptibility to prostate cancer (PCa). METHODS: We searched studies related to ACE I/D polymorphism and susceptibility to PCa through PubMed, Web of Science, Embase, Cochrane Library, and Scopus databases from inception to June 1, 2022. Five gene models, including allelic, dominant, recessive, homozygote, and heterozygote models, were analyzed. The pooled odds ratio (OR) was calculated using Stata 15.0 software. Publication bias was judged by the funnel plot and Egger's test, with the robustness of the findings verified by sensitivity analysis. RESULTS: Eight published articles (including ten studies) were identified. The pooled results showed that ACE I/D locus polymorphism was significantly correlated with the risk of PCa under all gene models except for the heterozygous model (D vs. I: OR= 1.58, 95% CI: 1.14-2.21; DD vs. DI+II: OR=1.68, 95% CI: 1.11-2.54; DD+DI vs. II: OR=1.76, 95% CI: 1.11-2.80; DI vs. II: OR= 1.44, 95% CI: 0.99-2.10; DD vs. II: OR= 2.12, 95% CI: 1.15-3.93). Subgroup analysis based on genotype frequencies in the control group meeting Hardy-Weinberg equilibrium showed statistically significant differences in all gene models. The funnel plot and Egger's test indicated no publication bias. The sensitivity analysis verified the robustness of the conclusions obtained in this meta-analysis. CONCLUSION: ACE I/D locus polymorphism correlates to PCa risk. Allele D, genotype DD+DI, and DD at the ACE I/D locus increase susceptibility to PCa and can therefore serve as a potential diagnostic and screening molecular marker for PCa patients.


Subject(s)
Genetic Predisposition to Disease , Prostatic Neoplasms , Male , Humans , INDEL Mutation , Polymorphism, Genetic/genetics , Peptidyl-Dipeptidase A/genetics , Prostatic Neoplasms/genetics , Angiotensins/genetics
3.
Int J Mol Sci ; 23(20)2022 Oct 12.
Article in English | MEDLINE | ID: mdl-36293037

ABSTRACT

We investigated whether a functional insertion/deletion (I/D) polymorphism of angiotensin-converting enzyme (ACE) influenced antipsychotic treatment. At baseline, and after 8 weeks of treatment with various antipsychotic medications, we assessed patients' Positive and Negative Syndrome Scale (PANSS) scores, PANSS factors, and metabolic-syndrome-related parameters (fasting plasma lipid and glucose levels, and body mass index). A total of 186 antipsychotic-naïve first-episode psychosis patients or nonadherent chronic psychosis individuals (99 males and 87 females) were genotyped by polymerase chain reaction analysis. The ACE-I/D polymorphism was significantly associated with changes in PANSS psychopathology only (p < 0.05). Compared to ACE-II homozygous males, ACE-DD homozygous and ACE-ID heterozygous males manifested significantly greater decreases in PANSS positive score, PANSS excitement factor, and PANSS cognitive factor. ACE-DD homozygous females manifested higher decreases in PANSS depression factor compared to ACE-II homozygous and ACE-ID heterozygous females. The polymorphism's effect size was estimated as moderate to strong, while its contribution to the PANSS psychopathology ranged from ~5.4 to 8.7%, with the lowest contribution observed for PANSS positive score changes and the highest for PANSS depressive factor changes. Our results indicate that ACE-I/D polymorphism had a statistically significant but weak gender-specific impact on psychopathology data, and showed no association between ACE-I/D polymorphism and metabolic-syndrome-related parameters.


Subject(s)
Antipsychotic Agents , Metabolic Syndrome , Psychotic Disorders , Male , Female , Humans , Antipsychotic Agents/therapeutic use , Peptidyl-Dipeptidase A/genetics , Genotype , Psychotic Disorders/drug therapy , Psychotic Disorders/genetics , Angiotensins/genetics , Glucose , Lipids
4.
Int J Environ Res Public Health ; 19(19)2022 Oct 02.
Article in English | MEDLINE | ID: mdl-36231922

ABSTRACT

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2), has triggered an enormous scientific response. Many studies have focused on understanding the entry of the SARS-CoV-2 virus into the host cell. The angiotensin-converting enzyme-2 (ACE2) is recognized as the host receptor used by SARS-CoV-2 to enter its target cells. Recent studies suggest that ACE2 gene polymorphisms might be candidates for genetic susceptibility to SARS-CoV-2 infection. The aim of this study is to evaluate the influence of ACE2 polymorphisms on COVID-19 disease risk and severity. In our study, we confirmed that there is a statistically significant increased risk of a more severe disease course of SARS-CoV-2 infection associated with the need for hospitalization in intensive care for patients with specific polymorphisms of the ACE2 gene. The most significant correlation was found for variant ACE2 rs2285666 (AA allele, OR = 2.12, p = 0.0189) and ACE2 rs2074192 (TT allele, OR = 2.05, p = 0.0016), and for ACE2 rs4646174 (GG allele, OR = 1.93, p = 0.0016), ACE2 rs4646156 (TT allele OR = 1.71, p = 0.008) and ACE2 rs2158083 (TT allele OR = 1.84, p = 0.0025). In conclusion, our findings identify that certain ACE2 polymorphisms impact the severity of COVID-19 disease independently of other well-known risk factors.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19 , Angiotensins/genetics , COVID-19/epidemiology , COVID-19/genetics , Genetic Predisposition to Disease , Humans , Pandemics , Peptidyl-Dipeptidase A/genetics , SARS-CoV-2/genetics
5.
Methods Enzymol ; 675: 299-321, 2022.
Article in English | MEDLINE | ID: mdl-36220274

ABSTRACT

Mutations on the spike (S) protein of SARS-CoV-2 could induce structural changes that help increase viral transmissibility and enhance resistance to antibody neutralization. Here, we report a robust workflow to prepare recombinant S protein variants and its host receptor angiotensin-convert enzyme 2 (ACE2) by using a mammalian cell expression system. The functional states of the S protein variants are investigated by cryo-electron microscopy (cryo-EM) and negative staining electron microscopy (NSEM) to visualize their molecular structures in response to mutations, receptor binding, antibody binding, and environmental changes. The folding stabilities of the S protein variants can be deduced from morphological changes based on NSEM imaging analysis. Differential scanning calorimetry provides thermodynamic information to complement NSEM. Impacts of the mutations on host receptor binding and antibody neutralization are in vitro by kinetic binding analyses in addition to atomic insights gleaned from cryo-electron microscopy (cryo-EM). This experimental strategy is generally applicable to studying the molecular basis of host-pathogen interactions.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2/genetics , Angiotensins/genetics , Angiotensins/metabolism , Animals , COVID-19/genetics , Cryoelectron Microscopy , Humans , Mammals/metabolism , Models, Molecular , Mutation , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Receptors, Virus/chemistry , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship
6.
Clin Chim Acta ; 536: 39-44, 2022 Nov 01.
Article in English | MEDLINE | ID: mdl-36126762

ABSTRACT

BACKGROUND: Coronavirus disease 2019(COVID-19), the infectious respiratory disease caused by a newly discovered pathogen (severe acute respiratory syndrome coronavirus 2), is a pandemic that places a burden on the health care system. Recently, most research on COVID-19 has emphasized its profound impact on specific regions and ethnic groups. A possible explanation for these variations in disease presentation and severity might be differences in the gene pool of populations. This study therefore attempted to clarify possible involvements of genetic factors affecting COVID-19 pathogenesis with a focus on voltage-gated potassium channel-interacting protein 4 (KCNIP4) and angiotensin-converting enzyme 1 (ACE1) gene polymorphisms. MATERIALS AND METHODS: In this case-control study, the polymorphisms were genotyped using PCR in 194 COVID-19 patients and 194 healthy controls. RESULTS: COVID-19 susceptibility and severity appeared to be unaffected by these polymorphisms. However, this study supported the relevance of ACE1 II genotype frequency to a decreased number of deaths due to the infection. We found that COVID-19 patients with the ACE1 II genotype have a statistically significant better chance of survival (p = 0.008). CONCLUSION: This study strengthens the idea that the ACE1 I/D polymorphism can be a novel prognostic factor indicating the outcome of COVID-19.


Subject(s)
COVID-19 , Potassium Channels, Voltage-Gated , Angiotensin-Converting Enzyme 2 , Angiotensins/genetics , Angiotensins/metabolism , COVID-19/genetics , Case-Control Studies , Humans , Iran , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Polymorphism, Genetic , Potassium Channels, Voltage-Gated/genetics
7.
Mutat Res Rev Mutat Res ; 790: 108428, 2022.
Article in English | MEDLINE | ID: mdl-35905832

ABSTRACT

Whole-exome sequencing (WES) is useful for molecular diagnosis, family genetic counseling, and prognosis of intellectual disability (ID). However, ID molecular diagnosis ascertainment based on WES is highly dependent on de novo mutations (DNMs) and variants of uncertain significance (VUS). The quantification of DNM frequency in ID molecular diagnosis ascertainment and the biological mechanisms common to genes with VUS may provide objective information about WES use in ID diagnosis and etiology. We aimed to investigate and estimate the rate of ID molecular diagnostic assessment by WES, quantify the contribution of DNMs to this rate, and biologically and functionally characterize the genes whose mutations were identified through WES. A PubMed/Medline, Web of Science, Scopus, Science Direct, BIREME, and PsycINFO systematic review and meta-analysis was performed, including studies published between 2010 and 2022. Thirty-seven articles with data on ID molecular diagnostic yield using the WES approach were included in the review. WES testing accounted for an overall diagnostic rate of 42% (Confidence interval (CI): 35-50%), while the estimate restricted to DNMs was 11% (CI: 6-18%). Genetic information on mutations and genes was extracted and split into two groups: (1) genes whose mutation was used for positive molecular diagnosis, and (2) genes whose mutation led to uncertain molecular diagnosis. After functional enrichment analysis, in addition to their expected roles in neurodevelopment, genes from the first group were enriched in epigenetic regulatory mechanisms, immune system regulation, and circadian rhythm control. Genes from uncertain diagnosis cases were enriched in the renin angiotensin pathway. Taken together, our results support WES as an important approach to the molecular diagnosis of ID. The results also indicated relevant pathways that may underlie the pathogenesis of ID with the renin-angiotensin pathway being suggested to be a potential pathway underlying the pathogenesis of ID.


Subject(s)
Intellectual Disability , Humans , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Exome/genetics , Renin/genetics , Angiotensins/genetics
8.
Turk J Pediatr ; 64(3): 474-481, 2022.
Article in English | MEDLINE | ID: mdl-35899560

ABSTRACT

BACKGROUND: There was a contradiction in the previous literature on whether the D/D genotype of angiotensinconverting enzyme (ACE) is a protective or risk factor for respiratory distress syndrome (RDS) in premature neonates. To solve this debate, we intended to examine the association between ACE gene polymorphism and RDS in premature neonates. METHODS: We enrolled a total of 100 premature neonates with gestational age below 37 weeks. They were divided into 2 groups, the case group included 50 premature neonates diagnosed with RDS. While the control group included 50 premature neonates with no signs of RDS. We assessed ACE gene polymorphism using polymerase chain reaction. All neonates underwent chest x-ray, echocardiography, and routine laboratory investigations. RESULTS: D/D and D/I genotypes were higher in the control group (48% and 50%) than in the case group (26% and 40%). Whereas, I/I genotype was lower in the control group (2%) than in the case group (34%) (p < 0.001). By counting D alleles among members of both groups, D-alleles were significantly higher in the control group (73%) than in the case group (46%) (p < 0.001). CONCLUSIONS: In premature neonates, D/D and D/I genotypes and D-alleles are protective factors for RDS. Whereas, I/I genotype and I-alleles are associated with the incidence of RDS with complications.


Subject(s)
Infant, Premature , Respiratory Distress Syndrome, Newborn , Angiotensins/genetics , Case-Control Studies , Genetic Predisposition to Disease , Genotype , Humans , Infant , Infant, Newborn , Polymorphism, Genetic , Respiratory Distress Syndrome, Newborn/genetics
9.
Iran J Allergy Asthma Immunol ; 21(2): 104-111, 2022 Apr 11.
Article in English | MEDLINE | ID: mdl-35490264

ABSTRACT

Asthma is a complex disease caused by a combination of multiple genetic and environmental factors. Angiotensin-converting enzyme (ACE) is involved in the pathogenesis of asthma by inactivating bradykinin, substance P, and neurokinin A. It has been shown that the level of ACE variation in serum is associated with an insertion-deletion (I/D) polymorphism. So, this study aimed to investigate the association of these polymorphisms with asthma in western Iran. In this case-control study, 111 asthmatic patients as a case group and 80 healthy subjects as a control group were evaluated. The ACE gene polymorphism was determined by the PCR method. The relationship between genotypes done by the χ2 test and the relative risk of disease with genetic polymorphism (Odds Ratio) was performed using logistic regression. The frequency of I/D genotypes (included in II, ID, and DD) between patient and control groups had no significant difference. In addition, none of the genotypes in the patient and control groups show any significant differences between men and women. However, the frequency of ID and DD genotypes was considerably different between the male patient groups (over and under 40 years old). Hence, these genotypes are suggested to be a risk factor for asthma. The results of our study indicate that ACE gene polymorphism is not significantly associated with asthma in the west of Iran.


Subject(s)
Asthma , Peptidyl-Dipeptidase A/genetics , Polymorphism, Genetic , Adult , Angiotensins/genetics , Asthma/epidemiology , Asthma/genetics , Case-Control Studies , Female , Humans , Iran/epidemiology , Male
10.
J Cosmet Dermatol ; 21(6): 2629-2634, 2022 Jun.
Article in English | MEDLINE | ID: mdl-34499796

ABSTRACT

BACKGROUND: Androgenetic alopecia (AGA) is a prevalent condition with a complex etiopathogenesis. Angiotensin-converting enzyme (ACE) gene located on the chromosome 17q23 contains an insertion (I) and deletion (D) polymorphism in the intron 16. This gene polymorphism plays a role in multiple inflammatory disorders. However, there are no studies investigating its association with AGA susceptibility. OBJECTIVES: In this work, we aimed at exploring the association of ACE gene I/D polymorphism in AGA susceptibility in a group of Egyptian patients. METHODS: This study included 100 AGA patients, and 100 apparently healthy controls. The ACE gene I/D polymorphism was analyzed by polymerase chain reaction. RESULTS: The DD, ID genotypes, and D allele showed higher frequent distribution among studied AGA patients than controls (p < 0.05 each). Positive family history and ACE gene I/D polymorphism were considered AGA susceptibility predictors in both uni- and multivariable analyses [p < 0.05 each (OR (95% CI)] on applying logistic regression analysis for risk factors prediction. CONCLUSIONS: This study highlights the possible contribution of the suspected genetic polymorphism as a susceptibility indicator for AGA development in the examined group of patients.


Subject(s)
Genetic Predisposition to Disease , Peptidyl-Dipeptidase A , Alopecia/genetics , Angiotensins/genetics , Case-Control Studies , Egypt , Humans , Mutagenesis, Insertional , Peptidyl-Dipeptidase A/genetics , Polymorphism, Genetic
11.
Reprod Sci ; 29(9): 2536-2545, 2022 09.
Article in English | MEDLINE | ID: mdl-34773203

ABSTRACT

Rec ent studies have suggested a closer association between angiotensin-converting enzyme (ACE) gene polymorphisms and polycystic ovary syndrome (PCOS) risk, but the results were inconsistent. We conducted this meta-analysis to explore the precise associations between ACE gene I/D polymorphism and PCOS risk. Online electronic databases (PubMed, Embase, SCI index, CNKI, and Wanfang) were searched. Odds ratios (ORs) with 95% confidence interval (CIs) were calculated to assess the association between ACE gene I/D polymorphism and PCOS risk. In addition, heterogeneity, accumulative/sensitivity analysis, and publication bias were conducted to check the statistical power. Overall, 12 published case-control studies with 2248 patients and 1759 controls were included according to the criteria. Significant increased risk was found for PCOS susceptibility with I/D mutation (D vs. I: OR = 1.62, 95%CI = 1.24-2.11, P < 0.01, I2 = 86.1%; DD vs. II: OR = 2.10, 95%CI = 1.35-3.27, P < 0.01, I2 = 79.8%; ID + DD vs. II: OR = 1.57, 95%CI = 1.06-2.32, P = 0.02, I2 = 79.3%; DD vs. II + ID: OR = 1.91, 95%CI = 1.39-2.65, P < 0.01, I2 = 79.1%). Furthermore, some similar associations were also observed in subgroups. In summary, the current evidences indicated that ACE gene I/D polymorphism plays an important role in PCOS development, both in Asian and Caucasian descendants.


Subject(s)
Angiotensins , Polycystic Ovary Syndrome , Angiotensins/genetics , Female , Genetic Predisposition to Disease , Humans , Peptidyl-Dipeptidase A/genetics , Polycystic Ovary Syndrome/genetics , Polymorphism, Genetic
12.
Sci Rep ; 11(1): 5206, 2021 03 04.
Article in English | MEDLINE | ID: mdl-33664447

ABSTRACT

This study aimed to focus on the high-value utilization of raw wheat gluten by determining the potent antioxidant peptides and angiotensin I-converting enzyme (ACE) inhibitory peptides from wheat gluten oligopeptides (WOP). WOP were analyzed for in vitro antioxidant activity and inhibition of ACE, and the identification of active peptides was performed by reversed-phase high-performance liquid chromatography and mass spectrometry. Quantitative analysis was performed for highly active peptides. Five potent antioxidant peptides, Leu-Tyr, Pro-Tyr, Tyr-Gln, Ala-Pro-Ser-Tyr and Arg-Gly-Gly-Tyr (6.07 ± 0.38, 7.28 ± 0.29, 11.18 ± 1.02, 5.93 ± 0.20 and 9.04 ± 0.47 mmol 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) equivalent/g sample, respectively), and five potent ACE inhibitory peptides, Leu-Tyr, Leu-Val-Ser, Tyr-Gln, Ala-Pro-Ser-Tyr and Arg-Gly-Gly-Tyr (half maximal inhibitory concentration (IC50) values = 0.31 ± 0.02, 0.60 ± 0.03, 2.00 ± 0.13, 1.47 ± 0.08 and 1.48 ± 0.11 mmol/L, respectively), were observed. The contents of Leu-Tyr, Pro-Tyr, Tyr-Gln, Ala-Pro-Ser-Tyr, Arg-Gly-Gly-Tyr, and Leu-Val-Ser were 155.04 ± 8.36, 2.08 ± 0.12, 1.95 ± 0.06, 22.70 ± 1.35, 0.25 ± 0.01, and 53.01 ± 2.73 µg/g, respectively, in the WOP. Pro-Tyr, Tyr-Gln, Ala-Pro-Ser-Tyr, Arg-Gly-Gly-Tyr, and Leu-Val-Ser are novel antioxidative/ACE inhibitory peptides that have not been previously reported. The results suggest that WOP could potentially be applied in the food industry as a functional additive.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antioxidants/chemistry , Glutens/chemistry , Peptidyl-Dipeptidase A/genetics , Amino Acid Sequence , Angiotensin-Converting Enzyme Inhibitors/chemistry , Angiotensins/genetics , Antioxidants/pharmacology , Glutens/pharmacology , Mass Spectrometry , Peptide Fragments/chemistry , Peptide Fragments/pharmacology , Peptides/chemistry , Peptides/pharmacology , Peptidyl-Dipeptidase A/drug effects , Triticum/chemistry
13.
Peptides ; 137: 170477, 2021 03.
Article in English | MEDLINE | ID: mdl-33400951

ABSTRACT

After decades of notoriety for its adverse cardiovascular, proinflammatory and profibrotic actions, the renin-angiotensin system (RAS) began to be cast in a more favorable light with the discovery of angiotensin-converting enzyme-2 (ACE2) in 2000. This monocarboxypeptidase, best known for its ability to metabolize angiotensin (Ang) II to Ang 1-7, counteracts the adverse effects of Ang II mediated by the AT1 Ang II receptor. Ang peptides are classically considered to be metabolized by aminopeptidases, by which the nomenclature Ang III (des-Asp1Ang II, 2-8 heptapeptide) and Ang IV (des-Asp1des-Arg2Ang II, 3-8 hexapeptide) are derived. This report compares the ability of recombinant human ACE2 (rhACE2) to metabolize Ang III, Ang IV and Ang V, (4-8 pentapeptide) relative to Ang II to form corresponding des-omega-Phe metabolites. rhACE2 has highest affinity (lowest Km) for Ang III, followed by Ang II ∼ Ang V, followed by Ang IV. However, rhACE2 has the highest Kcat for metabolising Ang IV followed by Ang V, Ang III and Ang II. The enzymatic efficiency (Kcat/Km) is highest for Ang V and Ang III followed by Ang IV and is lowest for Ang II. As a gluzincin metallopeptidase, ACE2 requires a zinc molecule at its active site for catalysis. This report also documents inhibition of ACE2 activity by concentrations of zinc exceeding 10 µM. These observations extend the functional significance of ACE2 to include the metabolic inactivation of Ang III, Ang IV and Ang V, reemphasizing the importance of monitoring zinc intake to maintain metabolic homeostasis.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Angiotensins/metabolism , Peptides/metabolism , Recombinant Proteins/metabolism , Aminopeptidases/genetics , Aminopeptidases/metabolism , Angiotensin I/genetics , Angiotensin I/metabolism , Angiotensin II/analogs & derivatives , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensins/genetics , Humans , Peptide Fragments/genetics , Peptide Fragments/metabolism , Peptides/genetics , Peptidyl-Dipeptidase A/genetics , Recombinant Proteins/genetics , Renin-Angiotensin System/genetics , Zinc/pharmacology
14.
Biochem Genet ; 59(1): 335-345, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33136283

ABSTRACT

Uncontrolled diabetes mellitus may affect any part of the gastrointestinal tract (GIT) and impact negatively the quality of life. Angiotensin-converting enzyme (ACE) gene polymorphism can have direct effect on circulating level of ACE which further modifies the degradation of substance P and thus may influence the gut motility. Hence, it could be hypothesised that ACE gene polymorphism would influence the gut motility. An observational analytical study was conducted at PGIMER, Chandigarh. 300 Type2 diabetes mellitus (T2DM) and 200 age and sex matched healthy individuals were enrolled. After taking written consent, 5 ml blood sample was collected for measurement of substance P by ELISA method and for ACE gene polymorphism (insertion[I]/deletion[D]) by polymerase chain reaction. Orocecal transit time (OCTT) was measured using non-invasive lactulose breath test. Out of 300 diabetic patients, 32.7%, 44% and 23.3% belonged to II, ID and DD genotypes, respectively. The frequency of D allele (OR = 1.39) and DD genotype (OR = 2.17) was significantly higher in patients than in controls and was associated with increased risk. Moreover, more number of diabetes patients with constipation (90%) belonged to DD genotype and their OCTT was significantly delayed (166.7 ± 7.3 min) as compared to ID (143.5 ± 4.2 min) or II (121.8 ± 4.9 min) genotype. From this study, it could be concluded that ACE gene polymorphism could be an important contributing factor to influence the gut motility and thus giving rise to the GI symptoms for T2DM patients.


Subject(s)
Diabetes Mellitus, Type 2/genetics , Gastrointestinal Motility/genetics , Peptidyl-Dipeptidase A/genetics , Polymorphism, Genetic , Substance P/metabolism , Alleles , Angiotensins/genetics , Female , Gene Frequency , Genotype , Humans , Male , Middle Aged , Polymerase Chain Reaction
15.
Exp Mol Pathol ; 117: 104551, 2020 12.
Article in English | MEDLINE | ID: mdl-33010296

ABSTRACT

Cellular senescence is important for the maintenance of tissue homeostasis during normal development. In this study, we aimed to investigate the effect of renin angiotensin system (RAS) blockade on renal cell senescence in the developing rat kidney. Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle for seven days after birth. We investigated the intrarenal expressions of cell cycle regulators p21 and p16 with immunoblots and immunohistochemistry at postnatal day 8. For the determination of renal cellular senescence, immunostaining for senescence-associated ß-galactosidase (SA-ß-gal) and telomerase reverse transcriptase (TERT) was also performed. Enalapril treatment showed significant alterations in cellular senescence in neonatal rat kidneys. In the enalapril-treated group, intrarenal p16 and p21 protein expressions decreased compared to controls. The expressions of both p21 and p16 were reduced throughout the renal cortex and medulla of enalapril-treated rats. The immunoreactivity of TERT in enalapril-treated kidneys was also weaker than that in control kidneys. Control kidneys revealed a clear positive SA-ß-gal signal in the cortical tubules; however, SA-ß-gal activity was noticeably lower in the enalapril-treated kidneys than in control kidneys. Interruption of the RAS during postnatal nephrogenesis may disrupt physiologic renal cellular senescence in the developing rat kidney.


Subject(s)
Angiotensinogen/genetics , Cellular Senescence/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Kidney/metabolism , p21-Activated Kinases/genetics , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensins/antagonists & inhibitors , Angiotensins/genetics , Animals , Animals, Newborn/genetics , Animals, Newborn/growth & development , Embryonic Development/genetics , Enalapril/pharmacology , Gene Expression Regulation, Developmental/genetics , Humans , Kidney/growth & development , Kidney Tubules/drug effects , Kidney Tubules/growth & development , Rats , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/genetics , Telomerase/genetics
16.
Minerva Cardiol Angiol ; 70(1): 16-24, 2022 02.
Article in English | MEDLINE | ID: mdl-32989965

ABSTRACT

BACKGROUND: Genetic predisposition is an important risk factor in coronary artery disease (CAD).This study was conducted to determine the polymorphism frequencies of the plasminogen activator inhibitor-1(PAI-1) gene 4G/5G, angiotensin-converting enzyme (ACE) gene I/D, and angiotensin II type 1 receptor (AT1) gene A1166C genotypes and to examine the role of these polymorphisms in CAD. METHODS: Genomic DNAs obtained from 260 subjects (130 CAD patients and 130 control) were used in the study. ACE I/D and PAI-1 4G/5G polymorphism genotypes were determined using polymerase chain reaction (PCR) and electrophoresis. AT-1 A1166C polymorphism was determined using the PCR, restriction fragment length polymorphism (RFLP) and electrophoresis. The products amplified from AT1 gene by PCR were cut with HindIII restriction endonuclease and then analyzed by 2% agarose gel electrophoresis. The results were statistically analyzed with the chi-square test, Mann-Whitney U test, and independent two-sample t-test. RESULTS: Allele frequencies showed statistically significant differences between the patient and control groups. There was no statistically significant difference in ACEI/D genotype frequencies between the twogroups. Likewise, no statistically significant difference was found in the AT1 A1166C genotype frequencies; however, a statistically significant difference was found in allele frequencies. The PAI-1 4G/5G genotype frequency was significantly higher in the patient group. CONCLUSIONS: While there is a relationship between of PAI-1 gene 4G/5G polymorphism and CAD, ACE gene I/D and AT1 gene A1166C polymorphisms are not related. PAI-1 gene homozygous genotypes may be considered as a prognostic marker for CAD patients.


Subject(s)
Coronary Artery Disease , Renin , Angiotensins/genetics , Coronary Artery Disease/genetics , Genetics, Population , Humans , Peptidyl-Dipeptidase A/genetics , Plasminogen Activator Inhibitor 1/genetics , Polymorphism, Genetic/genetics , Receptor, Angiotensin, Type 1/genetics , Renin/genetics
17.
Int J Mol Sci ; 21(15)2020 Aug 04.
Article in English | MEDLINE | ID: mdl-32759852

ABSTRACT

The progression of nonalcoholic steatohepatitis (NASH) is complicated. The multiple parallel-hits theory is advocated, which includes adipocytokines, insulin resistance, endotoxins, and oxidative stress. Pathways involving the gut-liver axis also mediate the progression of NASH. Angiotensin-II receptor blockers (ARB) suppress hepatic fibrosis via the activation of hepatic stellate cells (HSCs). Rifaximin, a nonabsorbable antibacterial agent, is used for the treatment of hepatic encephalopathy and has been recently reported to improve intestinal permeability. We examined the inhibitory effects on and mechanism of hepatic fibrogenesis by combining ARB and rifaximin administration. Fischer 344 rats were fed a choline-deficient/l-amino acid-defined (CDAA) diet for 8 weeks to generate the NASH model. The therapeutic effect of combining an ARB and rifaximin was evaluated along with hepatic fibrogenesis, the lipopolysaccharide-Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. ARBs had a potent inhibitory effect on hepatic fibrogenesis by suppressing HSC activation and hepatic expression of transforming growth factor-ß and TLR4. Rifaximin reduced intestinal permeability by rescuing zonula occludens-1 (ZO-1) disruption induced by the CDAA diet and reduced portal endotoxin. Rifaximin directly affect to ZO-1 expression on intestinal epithelial cells. The combination of an ARB and rifaximin showed a stronger inhibitory effect compared to that conferred by a single agent. ARBs improve hepatic fibrosis by inhibiting HSCs, whereas rifaximin improves hepatic fibrosis by improving intestinal permeability through improving intestinal tight junction proteins (ZO-1). Therefore, the combination of ARBs and rifaximin may be a promising therapy for NASH fibrosis.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Liver Cirrhosis/drug therapy , Non-alcoholic Fatty Liver Disease/drug therapy , Rifaximin/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensins/genetics , Animals , Disease Models, Animal , Hepatic Stellate Cells/drug effects , Humans , Lipopolysaccharides/toxicity , Liver/drug effects , Liver/pathology , Liver Cirrhosis/chemically induced , Liver Cirrhosis/genetics , Liver Cirrhosis/pathology , Non-alcoholic Fatty Liver Disease/chemically induced , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/pathology , Oxidative Stress/drug effects , Rats , Signal Transduction/drug effects
18.
J Biol Chem ; 295(40): 13711-13723, 2020 10 02.
Article in English | MEDLINE | ID: mdl-32546481

ABSTRACT

Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent hydrolase involved in degrading oligopeptides with 4-12 amino acid residues. It has been associated with several pathophysiological processes, including blood pressure regulation, pain signaling, and cancer cell defense against oxidative stress. However, the physiological substrates and the cellular pathways that are potentially targeted by DPP3 to mediate these effects remain unknown. Here, we show that global DPP3 deficiency in mice (DPP3-/-) affects the renin-angiotensin system (RAS). LC-MS-based profiling of circulating angiotensin peptides revealed elevated levels of angiotensin II, III, IV, and 1-5 in DPP3-/- mice, whereas blood pressure, renin activity, and aldosterone levels remained unchanged. Activity assays using the purified enzyme confirmed that angiotensin peptides are substrates for DPP3. Aberrant angiotensin signaling was associated with substantially higher water intake and increased renal reactive oxygen species formation in the kidneys of DPP3-/- mice. The metabolic changes and altered angiotensin levels observed in male DPP3-/- mice were either absent or attenuated in female DPP3-/- mice, indicating sex-specific differences. Taken together, our observations suggest that DPP3 regulates the RAS pathway and water homeostasis by degrading circulating angiotensin peptides.


Subject(s)
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism , Kidney/enzymology , Renin-Angiotensin System , Sex Characteristics , Signal Transduction , Water-Electrolyte Balance , Angiotensins/genetics , Angiotensins/metabolism , Animals , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Female , Male , Mice , Mice, Knockout , Reactive Oxygen Species/metabolism
19.
Elife ; 92020 06 08.
Article in English | MEDLINE | ID: mdl-32510330

ABSTRACT

Trimethylamine-oxide (TMAO) is present in seafood which is considered to be beneficial for health. Deep-water animals accumulate TMAO to protect proteins, such as lactate dehydrogenase (LDH), against hydrostatic pressure stress (HPS). We hypothesized that TMAO exerts beneficial effects on the circulatory system and protects cardiac LDH exposed to HPS produced by the contracting heart. Male, Sprague-Dawley and Spontaneously-Hypertensive-Heart-Failure (SHHF) rats were treated orally with either water (control) or TMAO. In vitro, LDH with or without TMAO was exposed to HPS and was evaluated using fluorescence correlation spectroscopy. TMAO-treated rats showed higher diuresis and natriuresis, lower arterial pressure and plasma NT-proBNP. Survival in SHHF-control was 66% vs 100% in SHHF-TMAO. In vitro, exposure of LDH to HPS with or without TMAO did not affect protein structure. In conclusion, TMAO reduced mortality in SHHF, which was associated with diuretic, natriuretic and hypotensive effects. HPS and TMAO did not affect LDH protein structure.


Heart failure is a common cause of death in industrialized countries with aging populations. Japan, however, has lower rates of heart failure and fewer deaths linked to this disease than the United States or Europe, despite having the highest proportion of elderly people in the world. Dietary differences between these regions may explain the lower rate of heart failure in Japan. The Japanese diet is rich in seafood, which contains nutrients that promote heart health, such as omega-3 fatty acids. Seafood also contains other compounds, including trimethylamine oxide (TMAO). Fish that live in deep waters undergo high pressures, which can damage their proteins, but TMAO seems to protect the proteins from harm. In humans, eating seafood increases TMAO levels in the blood and urine, but it is unclear what effects this has on heart health. Increased levels of TMAO in the blood are associated with cardiovascular diseases, but scientists are not sure whether TMAO itself harms the heart. A toxic byproduct of gut bacteria called TMA is converted in TMAO in the body, so it is possible that TMA rather than TMAO is to blame. To assess the effects of dietary TMAO on heart failure, Gawrys-Kopczynska et al. fed the compound to healthy rats and rats with heart failure for one year. TMAO had no effects on the healthy rats. Of the rats with heart failure that were fed TMAO, all of them survived the year, while one third of rats with heart failure that were not fed TMAO died. TMAO-treated rats with heart failure had lower blood pressure and urinated more than untreated rats with the condition. The experiments suggest that dietary TMAO may mimic the effects of heart failure treatments, which remove excess water and salt and lower pressure on the heart. More studies are needed to confirm whether TMAO has this same effect on humans.


Subject(s)
Diuresis/drug effects , Heart Failure/drug therapy , Methylamines/chemistry , Methylamines/pharmacology , Seafood/analysis , Angiotensins/genetics , Angiotensins/metabolism , Animals , Gene Expression Regulation/drug effects , Kidney/drug effects , Male , Methylamines/administration & dosage , Microfluidic Analytical Techniques , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/physiology , Random Allocation , Rats , Rats, Sprague-Dawley , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2/genetics , Receptor, Angiotensin, Type 2/metabolism , Temperature
20.
Arch Physiol Biochem ; 128(5): 1165-1169, 2022 Oct.
Article in English | MEDLINE | ID: mdl-32401071

ABSTRACT

Background: The renin-angiotensin system (RAS), which is important for controlling haemostasis in the body, can increase the development of essential hypertension (HTN). Various surveys have shown that ACE I/D polymorphism that influences ACE activity, a key component of RAS, has been known to be associated with the risk of HTN. The goal of this study was to investigate the correlation between ACE (I/D) polymorphism and HTN.Methods: Blood samples were obtained from 102 patients and 104 healthy individuals. The two groups were matched by age and sex. Informed consent was prepared for the study. The demographic data were collected using a questionnaire. White blood cells (WBCs) and then DNA were extracted from whole blood. After this, the PCR test was performed using specific primers. PCR products were examined using 1% agarose gel. Individuals with genotype II having a band of 490 bp, ID two band of 490 bp and 190 bp, and individuals with DD genotype, have a band in region 190 bp.Results: The average age of the patients was 52.7 ± 7.5 years. A significant difference was seen in the distribution of DD, II and I/D genotypes of ACE polymorphism between the essential hypertensive patients (44.1, 10.8, and 45.1%) and their ethnically matched healthy control (61.5, 3.8, and 24.6%, respectively). Our study showed an increased risk of disease in people with II genotype in comparison to ID and DD genotypes (0.46 (0.1-1.75) and 0.26 (0.05-0.94), respectively).Conclusions: The present study demonstrated that ACEI/D polymorphism is characterised with greater risk of essential HTN in the Lorestan province. II genotype increased the relative risk of essential HTN in the population. In the future, more investigations with more samples size are recommended for the better study of genetic factors in hypertensive patients.


Subject(s)
Hypertension , Peptidyl-Dipeptidase A , Angiotensins/genetics , DNA , Genotype , Humans , Hypertension/genetics , Middle Aged , Mutagenesis, Insertional , Peptidyl-Dipeptidase A/genetics , Sepharose
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