-
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 -
Plant Foods For Human Nutrition... Jun 2023This study aims to isolate the active constituents of Pyrus pyrifolia Nakai fruits using a bioassay-guided fractionation approach, test their activity in vitro against...
This study aims to isolate the active constituents of Pyrus pyrifolia Nakai fruits using a bioassay-guided fractionation approach, test their activity in vitro against key enzymes for metabolic disorders, and support it with molecular docking simulations. The antioxidant potential of the methanolic extract (ME), its polar (PF), and non-polar fractions (NPF), along with the inhibitory activity against α-glucosidase, α-amylase, lipase, angiotensin I converting enzyme (ACE), renin, inducible nitric oxide synthase (iNOS), and xanthine oxidase (XO) were assessed. The PF exhibited the highest antioxidant and enzyme inhibitory activity. Purification of PF yielded rutin, isoquercitrin, isorhamnetin-3-O-β-D-glucoside, chlorogenic acid, quercetin, and cinnamic acid. HPLC-UV analysis of the PF allowed for the quantification of 15 phenolic compounds, including the isolated compounds. Cinnamic acid was the most powerful antioxidant in all assays and potent enzyme inhibitor against the tested enzymes (α-glucosidase, α-amylase, lipase, ACE, renin, iNOS, and XO). Additionally, it showed high affinity to target α-glucosidase and ACE active sites with high docking scores (calculated total binding free energy (ΔGbind) -23.11 kcal/mol and - 20.03 kcal/mol, respectively]. A 20-ns molecular dynamics simulation using MM-GBSA analysis revealed a stable conformation and binding patterns in a stimulating environment of cinnamic acid. Interestingly, the isolated compounds' dynamic investigations including RMSD, RMSF, and Rg demonstrated a stable ligand - protein complex to the active site of iNOS with ΔGbind ranging from - 68.85 kcal/mol to -13.47 kcal/mol. These findings support the notion that P. pyrifolia fruit is a functional food with multifactorial therapeutic agents against metabolic syndrome-associated diseases.
Topics: Antioxidants; Metabolic Syndrome; Fruit; Pyrus; alpha-Glucosidases; Molecular Docking Simulation; Renin; Chromatography, High Pressure Liquid; Plant Extracts; Phenols; Lipase; alpha-Amylases
PubMed: 37219720
DOI: 10.1007/s11130-023-01069-3 -
Clinical Epigenetics May 2023Adiponectin is a key protein produced in adipose tissue, with crucial involvement in multiple metabolic processes. Di-(2-ethylhexyl) phthalate (DEHP), one of the...
The role of angiotensin I-converting enzyme gene polymorphism and global DNA methylation in the negative associations between urine di-(2-ethylhexyl) phthalate metabolites and serum adiponectin in a young Taiwanese population.
BACKGROUND
Adiponectin is a key protein produced in adipose tissue, with crucial involvement in multiple metabolic processes. Di-(2-ethylhexyl) phthalate (DEHP), one of the phthalate compounds used as a plasticizer, has been shown to decrease adiponectin levels in vitro and in vivo studies. However, the role of angiotensin I-converting enzyme (ACE) gene polymorphism and epigenetic changes in the relationship between DEHP exposure and adiponectin levels is not well understood.
METHODS
This study examined the correlation between urine levels of DEHP metabolite, epigenetic marker 5mdC/dG, ACE gene phenotypes, and adiponectin levels in a sample of 699 individuals aged 12-30 from Taiwan.
RESULTS
Results showed a positive relationship between mono-2-ethylhexyl phthalate (MEHP) and 5mdC/dG, and a negative association between both MEHP and 5mdC/dG with adiponectin. The study found that the inverse relationship between MEHP and adiponectin was stronger when levels of 5mdC/dG were above the median. This was supported by differential unstandardized regression coefficients (- 0.095 vs. - 0.049, P value for interaction = 0.038)). Subgroup analysis also showed a negative correlation between MEHP and adiponectin in individuals with the I/I ACE genotype, but not in those with other genotypes, although the P value for interaction was borderline significant (0.06). The structural equation model analysis indicated that MEHP has a direct inverse effect on adiponectin and an indirect effect via 5mdC/dG.
CONCLUSIONS
In this young Taiwanese population, our findings suggest that urine MEHP levels are negatively correlated with serum adiponectin levels, and epigenetic modifications may play a role in this association. Further study is needed to validate these results and determine causality.
Topics: Adiponectin; Diethylhexyl Phthalate; DNA Methylation; Peptidyl-Dipeptidase A; Humans; Taiwan
PubMed: 37198693
DOI: 10.1186/s13148-023-01502-z -
Journal of Dairy Science Jul 2023Consumers' growing interest in fermented dairy foods necessitates research on a wide array of lactic acid bacterial strains to be explored and used. This study aimed to...
Differential behavior of Lactobacillus helveticus B1929 and ATCC 15009 on the hydrolysis and angiotensin-I-converting enzyme inhibition activity of fermented ultra-high-temperature milk and nonfat dried milk powder.
Consumers' growing interest in fermented dairy foods necessitates research on a wide array of lactic acid bacterial strains to be explored and used. This study aimed to investigate the differences in the proteolytic capacity of Lactobacillus helveticus strains B1929 and ATCC 15009 on the fermentation of commercial ultra-pasteurized (UHT) skim milk and reconstituted nonfat dried milk powder (at a comparable protein concentration, 4%). The antihypertensive properties of the fermented milk, measured by angiotensin-I-converting enzyme inhibitory (ACE-I) activity, were compared. The B1929 strain lowered the pH of the milk to 4.13 ± 0.09 at 37°C after 24 h, whereas ATCC 15009 needed 48 h to drop the pH to 4.70 ± 0.18 at 37°C. Two soluble protein fractions, one (CFS1) obtained after fermentation (acidic conditions) and the other (CFS2) after the neutralization (pH 6.70) of the pellet from CFS1 separation, were analyzed for d-/l-lactic acid production, protein concentration, the degree of protein hydrolysis, and ACE-I activity. The CFS1 fractions, dominated by whey proteins, demonstrated a greater degree of protein hydrolysis (7.9%) than CFS2. On the other hand, CFS2, mainly casein proteins, showed a higher level of ACE-I activity (33.8%) than CFS1. Significant differences were also found in the d- and l-lactic acid produced by the UHT milk between the 2 strains. These results attest that milk casein proteins possessed more detectable ACE-I activity than whey fractions, even without a measurable degree of hydrolysis. Findings from this study suggest that careful consideration must be given when selecting the bacterial strain and milk substrate for fermentation.
Topics: Animals; Milk; Lactobacillus helveticus; Hydrolysis; Powders; Caseins; Temperature; Angiotensin-Converting Enzyme Inhibitors; Milk Proteins; Fermentation; Whey Proteins; Angiotensins
PubMed: 37164857
DOI: 10.3168/jds.2022-22842 -
Molecules (Basel, Switzerland) Apr 2023One of the most striking aspects of the primary structure in the hydrophobic domains of the tropoelastin molecule is the occurrence of the VAPGVG repeating sequence....
One of the most striking aspects of the primary structure in the hydrophobic domains of the tropoelastin molecule is the occurrence of the VAPGVG repeating sequence. Since the N-terminal tripeptide VAP of VAPGVG showed a potent ACE inhibitory activity, the ACE inhibitory activity of various derivatives of VAP was examined in vitro. The results showed that VAP derivative peptides VLP, VGP, VSP, GAP, LSP, and TRP exhibited potent ACE inhibitory activities, while the non-derivative peptide APG showed only weak activity. In in silico studies, the docking score S value showed that VAP derivative peptides VLP, VGP, VSP, LSP, and TRP had stronger docking interactions than APG. Molecular docking in the ACE active pocket showed that TRP, the most potent ACE inhibitory peptide among the VAP derivatives, had a larger number of interactions with ACE residues in comparison with APG and that the TRP molecule appeared to spread widely in the ACE pocket, while the APG molecule appeared to spread closely. Differences in molecular spread may be a reason why TRP exhibits more potent ACE inhibitory activity than APG. The results suggest that the number and strength of interactions between the peptide and ACE are important for the ACE- inhibitory potency of the peptide.
Topics: Animals; Swine; Angiotensin-Converting Enzyme Inhibitors; Molecular Docking Simulation; Peptidyl-Dipeptidase A; Elastin; Peptides
PubMed: 37110571
DOI: 10.3390/molecules28083337 -
Arquivos Brasileiros de Cardiologia Mar 2023Although it has been reported that the intermittent fasting (IF) diet has positive effects on heart health and improvement in blood pressure, it has not been...
BACKGROUND
Although it has been reported that the intermittent fasting (IF) diet has positive effects on heart health and improvement in blood pressure, it has not been sufficiently clarified how it could have these positive effects yet.
OBJECTIVE
We aimed to evaluate the effects of IF on the autonomic nervous system (ANS) and renin-angiotensin system (RAS), which are closely related to blood pressure.
METHODS
Seventy-two hypertensive patients were included in the study, and the data of 58 patients were used. All the participants fasted for about 15-16 hours for 30 days. Participants were evaluated with 24-hour ambulatory blood pressure monitoring and Holter electrocardiography before and after IF; also, 5 ml venous blood samples were taken for assessment of Serum angiotensin I (Ang-I) and angiotensin II (Ang-II) levels and angiotensin-converting enzyme (ACE) activity. For data analysis, the p-value <0.05 was accepted as significant.
RESULTS
Compared to pre-IF, a significant decrease was observed in the patients' blood pressures in post-IF. An increase in high-frequency (HF) power and the mean root square of the sum of squares of differences between adjacent NN intervals (RMSSD) were observed after the IF protocol (p=0.039, p=0.043). Ang-II and ACE activity were lower in patients after IF (p=0.034, p=0.004), and decreasing Ang-II levels were determined as predictive factors for improvement of the blood pressure, like the increase in HF power and RMSSD.
CONCLUSION
The present findings of our study demonstrated an improvement in blood pressure and the relationship of blood pressure with positive outcomes, including HRV, ACE activity, and Ang-II levels after the IF protocol.
Topics: Humans; Renin-Angiotensin System; Blood Pressure; Intermittent Fasting; Blood Pressure Monitoring, Ambulatory; Angiotensin-Converting Enzyme Inhibitors; Hypertension; Angiotensin II; Autonomic Nervous System; Peptidyl-Dipeptidase A; Renin
PubMed: 37098959
DOI: 10.36660/abc.20220756 -
Journal of Physiology and Pharmacology... Dec 2022Renal cell carcinoma (RCC) is the most common kidney malignancy, accounting for 3% of all cancers. Despite significant advances in targeted therapies and immunotherapy,...
Renal cell carcinoma (RCC) is the most common kidney malignancy, accounting for 3% of all cancers. Despite significant advances in targeted therapies and immunotherapy, many patients with RCC develop resistance to available drugs. Angiotensin-(1-7) (Ang-(1-7)) is a heptapeptide and a member of the renin-angiotensin system which regulates the cardiovascular and the renal system. It has been proposed as a potential anticancer agent for the treatment of various types of cancers, but data regarding its efficiency against RCC are conflicting. The aim of our study was to evaluate the effects of Ang-(1-7) in RCC models in vitro and in vivo. We performed a series of in vitro experiments investigating the effects of Ang-(1-7) on cell viability and migration in Caki-1 and Caki-2 cell lines. In addition, we carried out an in vivo study in xenografts of Caki-1 cells in nude mice. In results: Ang-(1-7) or A779, an antagonist of its receptor MasR (Mas receptor), showed no effect on cell viability. Ang-(1-7) promoted cell migration in a dose-dependent manner by inducing the activation of MasR. It also promoted tumor growth in vivo, and this effect was not inhibited by the blockade of MasR. No effects on cell proliferation or tumor vessel density were observed. The results suggest that Ang-(1-7) can exert protumorigenic activity in RCC, however, further research on other RCC models is needed to better recapitulate the heterogeneity of the disease.
Topics: Mice; Animals; Humans; Carcinoma, Renal Cell; Proto-Oncogene Mas; Mice, Nude; Peptide Fragments; Angiotensin I; Kidney Neoplasms; Cell Movement; Cell Line, Tumor
PubMed: 37087563
DOI: 10.26402/jpp.2022.6.04 -
Animal Models and Experimental Medicine Apr 2023Busulfan (BU) is an alkylating agent used as a conditioning agent prior to hematopoietic stem cell (HSC) transplantation as it is known to be cytotoxic to host...
BACKGROUND
Busulfan (BU) is an alkylating agent used as a conditioning agent prior to hematopoietic stem cell (HSC) transplantation as it is known to be cytotoxic to host hematopoietic stem and progenitor cells. The susceptibility of HSCs to BU injury plays an important role in the myeloablative efficacy of BU. Different susceptibilities were demonstrated in genetically diverse (GD) mice in our preliminary research.
METHODS
Three strains of GD mice with different susceptibilities to BU-induced HSC injury were used for screening biological markers of HSC injury susceptibility in urine. The urine proteins were analyzed using liquid chromatography coupled with tandem mass spectrometry to screen for differentially expressed proteins. Screening for possible biomarkers based on differences in protein expression abundance was validated using enzyme-linked immunoassay (ELISA).
RESULTS
Functional analysis showed that the differential proteins were all involved in a series of biological pathways related to cellular senescence, apoptosis, and angiogenesis; whereas the differential proteins of the high-susceptible strain were enriched for the regulation of bone marrow microenvironment pathways, those of low-susceptible strain were enriched for the proapoptotic effect of GTPase pathways. Based on protein abundance differences, several urinary proteins that may be indicative of susceptibility were screened, and ELISA validation results showed that angiotensin-converting enzyme may be a potential biomarker predicting HSC susceptibility for BU conditioning.
CONCLUSIONS
This study indicates that urinary protein levels can reflect differences in susceptibility to BU-induced HSC injury. Using GD mice to construct genetic difference models will provide preclinical data for screening BU-related biological markers.
Topics: Mice; Animals; Busulfan; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Alkylating Agents; Tandem Mass Spectrometry
PubMed: 37062934
DOI: 10.1002/ame2.12320 -
JAMA Apr 2023Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II...
Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.
IMPORTANCE
Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology.
OBJECTIVE
To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II.
DESIGN, SETTING, AND PARTICIPANTS
Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022.
INTERVENTIONS
A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo.
MAIN OUTCOMES AND MEASURES
The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension.
RESULTS
Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo.
CONCLUSIONS AND RELEVANCE
In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04924660.
Topics: Adult; Female; Humans; Male; Middle Aged; Angiotensin II; Angiotensins; COVID-19; Hypoxia; Infusions, Intravenous; Ligands; Oligopeptides; Randomized Controlled Trials as Topic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; SARS-CoV-2; Vasodilator Agents
PubMed: 37039791
DOI: 10.1001/jama.2023.3546