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International Journal of Molecular... Dec 2023Pulmonary arterial hypertension (PAH) is a debilitating progressive disease characterized by excessive pulmonary vasoconstriction and abnormal vascular remodeling...
Pulmonary arterial hypertension (PAH) is a debilitating progressive disease characterized by excessive pulmonary vasoconstriction and abnormal vascular remodeling processes that lead to right-ventricular heart failure and, ultimately, death. Although our understanding of its pathophysiology has advanced and several treatment modalities are currently available for the management of PAH patients, none are curative and the prognosis remains poor. Therefore, further research is required to decipher the molecular mechanisms associated with PAH. Angiotensin-converting enzyme 2 (ACE2) plays an important role through its vasoprotective functions in cardiopulmonary homeostasis, and accumulating preclinical and clinical evidence shows that the upregulation of the ACE2/Angiotensin-(1-7)/MAS1 proto-oncogene, G protein-coupled receptor (Mas 1 receptor) signaling axis is implicated in the pathophysiology of PAH. Herein, we highlight the molecular mechanisms of ACE2 signaling in PAH and discuss its potential as a therapeutic target.
Topics: Humans; Pulmonary Arterial Hypertension; Angiotensin-Converting Enzyme 2; Hypertension, Pulmonary; Peptidyl-Dipeptidase A; Familial Primary Pulmonary Hypertension; Receptors, G-Protein-Coupled; Angiotensin I; Peptide Fragments; Renin-Angiotensin System
PubMed: 38139269
DOI: 10.3390/ijms242417441 -
Molecules (Basel, Switzerland) Mar 2024Food-derived angiotensin-I-converting enzyme (ACE)-inhibitory peptides have gained attention for their potent and safe treatment of hypertensive disorders. However,...
Food-derived angiotensin-I-converting enzyme (ACE)-inhibitory peptides have gained attention for their potent and safe treatment of hypertensive disorders. However, there are some limitations of conventional methods for preparing ACE-inhibitory peptides. In this study, in silico hydrolysis, the quantitative structure-activity relationship (QSAR) model, LC-MS/MS, inhibition kinetics, and molecular docking were used to investigate the stability, hydrolyzability, in vitro activity, and inhibition mechanism of bioactive peptides during the actual hydrolysis process. Six novel ACE-inhibitory peptides were screened from the protein (P) and had low IC values (from 0.63 ± 0.09 µM to 10.26 ± 0.21 µM), which were close to the results of the QSAR model. After in vitro gastrointestinal simulated digestion activity of IPYADFK, FYEPFM and NWPWMK were found to remain almost unchanged, whereas LYDHLGK, INEMLDTK, and IHFGTTGK were affected by gastrointestinal digestion. Meanwhile, the inhibition kinetics and molecular docking results were consistent in that ACE-inhibitory peptides of different inhibition forms could effectively bind to the active or non-central active centers of ACE through hydrogen bonding. Our proposed method has better reproducibility, accuracy, and higher directivity than previous methods. This study can provide new approaches for the deep processing, identification, and preparation of .
Topics: Angiotensin-Converting Enzyme Inhibitors; Molecular Docking Simulation; Peptidyl-Dipeptidase A; Chromatography, Liquid; Reproducibility of Results; Tandem Mass Spectrometry; Peptides; Angiotensins
PubMed: 38474646
DOI: 10.3390/molecules29051134 -
Bioscience Reports Nov 2023Abdominal aortic aneurysm (AAA) represents a debilitating vascular disease characterized by aortic dilatation and wall rupture if it remains untreated. We aimed to...
Abdominal aortic aneurysm (AAA) represents a debilitating vascular disease characterized by aortic dilatation and wall rupture if it remains untreated. We aimed to determine the effects of Ang 1-7 in a murine model of AAA and to investigate the molecular mechanisms involved. Eight- to 10-week-old apolipoprotein E-deficient mice (ApoEKO) were infused with Ang II (1.44 mg/kg/day, s.c.) and treated with Ang 1-7 (0.576 mg/kg/day, i.p.). Echocardiographic and histological analyses showed abdominal aortic dilatation and extracellular matrix remodeling in Ang II-infused mice. Treatment with Ang 1-7 led to suppression of Ang II-induced aortic dilatation in the abdominal aorta. The immunofluorescence imaging exhibited reduced smooth muscle cell (SMC) density in the abdominal aorta. The abdominal aortic SMCs from ApoEKO mice exhibited markedly increased apoptosis in response to Ang II. Ang 1-7 attenuated cell death, as evident by increased SMC density in the aorta and reduced annexin V/propidium iodide-positive cells in flow cytometric analysis. Gene expression analysis for contractile and synthetic phenotypes of abdominal SMCs showed preservation of contractile phenotype by Ang 1-7 treatment. Molecular analyses identified increased mitochondrial fission, elevated cellular and mitochondrial reactive oxygen species (ROS) levels, and apoptosis-associated proteins, including cytochrome c, in Ang II-treated aortic SMCs. Ang 1-7 mitigated Ang II-induced mitochondrial fission, ROS generation, and levels of pro-apoptotic proteins, resulting in decreased cell death of aortic SMCs. These results highlight a critical vasculo-protective role of Ang 1-7 in a degenerative aortic disease; increased Ang 1-7 activity may provide a promising therapeutic strategy against the progression of AAA.
Topics: Animals; Mice; Reactive Oxygen Species; Angiotensin II; Aortic Aneurysm, Abdominal; Aorta, Abdominal; Apoptosis Regulatory Proteins; Myocytes, Smooth Muscle; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 37947205
DOI: 10.1042/BSR20230718 -
Integrative Medicine Research Mar 2024Herbal medicine Oryeongsan (ORS), also known as Wulingsan in Chinesehas been used for the treatment of impaired body fluid balance. However, the mechanisms involved are...
BACKGROUND
Herbal medicine Oryeongsan (ORS), also known as Wulingsan in Chinesehas been used for the treatment of impaired body fluid balance. However, the mechanisms involved are not clearly defined. The purpose of the present study was to identify the actions of ORS on the renal excretory function and blood pressure (BP) and to define the mechanisms involved in association with renin-angiotensin system (RAS) and natriuretic peptide system (NPS) in spontaneously hypertensive rats (SHR), an animal model of human essential hypertension.
METHODS
Changes in urine volume (UV), excretion of electrolytes including Na (urinary excretion of Na (UV)) were measured. RT-PCR was performed to trace the changes in expression of RAS, NPS and sodium (Na)-hydrogen (H) exchanger 3 (NHE3) in the renal cortex.
RESULTS
In the SHR treated with vehicle (SHR-V) group, UV and UV were suppressed and the Na balance was maintained at the higher levels leading to an increase in BP compared to WKY-V group. These were accompanied by an increase in NHE3 expression with an accentuation of angiotensin I converting enzyme-angiotensin II type 1 (ACE-AT) receptor and concurrent suppression of angiotensin II type 2 (AT) receptor/ACE2-Mas receptor expression in the renal cortex. Chronic treatment with ORS increased UV and UV, and decreased the Na and water balance with a decrease in BP in the ORS-treated SHR-ORS group compared to SHR-V. These were accompanied by a decrease in NHE3 expression with a suppression of ACE-AT receptor and concurrent accentuation of AT/ACE2-Mas receptor.
CONCLUSION
The present study shows that ORS reduced BP with a decrease in Na and water retention by a suppression of NHE3 expression via modulation of RAS and NPS in SHR. The present study provides pharmacological rationale for the treatment of hypertension with ORS in SHR.
PubMed: 38298863
DOI: 10.1016/j.imr.2023.101007 -
Journal of Oral and Maxillofacial... 2023Inflammatory cells and cytokines in the chronically injured mucosa promote fibrosis in the oral submucous fibrosis (OSF) fibrotic milieu. Osteopontin (OPN) is a...
BACKGROUND
Inflammatory cells and cytokines in the chronically injured mucosa promote fibrosis in the oral submucous fibrosis (OSF) fibrotic milieu. Osteopontin (OPN) is a wound-healing mediator that upregulates the inflammatory response and is involved in the malignancy and fibrosis of multiple organ systems.
OBJECTIVES
We investigated the expression of OPN in oral potentially malignant disorders (OPMDs) and oral squamous cell carcinomas (OSCCs) to determine its role in the malignant transformation and fibrosis of oral tissues. The expression of OPN in OPMDs and OSCCs was compared and correlated, and the role of OPN as a fibrotic mediator in OSF was explained.
STUDY DESIGN
A total of 30 cases of normal mucosa and OPMDs (mild dysplasia, severe dysplasia, OSF and OSCCs) were studied by purposive sampling. In these groups, OPN immunoreactivity was examined and correlated with clinical findings.
RESULTS
In mild dysplasia, OPN expression was restricted to the basal cell layer with moderate staining intensity. In severe dysplasia, it was extremely intense and extended throughout the epithelium. In the OSF, OPN expression was moderate in the perinuclear areas of the basal cell layer. The expression of OPN was very strong in OSCC. A flow diagram explaining the profibrotic role of OPN in OSF has been provided.
CONCLUSION
A positive role of OPN in both pathogenesis and malignant transformation of OPMDs and OSCC has been demonstrated.
PubMed: 38304518
DOI: 10.4103/jomfp.jomfp_492_22 -
Nanoscale Advances Dec 2023This study demonstrates the copper nanocomposite-induced enzymatic inhibition of human angiotensin I-converting enzyme-2 (hACE-2) by complex stabilization through the...
This study demonstrates the copper nanocomposite-induced enzymatic inhibition of human angiotensin I-converting enzyme-2 (hACE-2) by complex stabilization through the formation of the enzyme nanocomposite. The immediate application of this work is related to ACE-2 as a mechanism of SARS-CoV-2 entry into cells. Moreover, ACE-2 enzyme regulation is a potential therapeutic strategy in hypertension and cardiovascular disease, diabetes, lung injury, and fibrotic disorders. Thus, inhibition of ACE-2 with nanocomposite therapy, may have pharmacologic application with regard to infectious and non-infectious diseases. Synthesized copper nanocomposites described here alone with a commercially available compound, were tested for their potential to inhibit hACE-2 activities. Following wet chemical synthesis, Cu/CuO nanoparticles and graphene-copper (GO-Cu) complexes were synthesized and characterized for their chemical integrity. Cu/CuO formed well-dispersed clusters of 390 ± 100 nm, that when complexed with the hACE-2 enzyme exhibited larger clusters of 506 ± 56 nm. The formation of the Cu/CuO and hACE-2 enzyme complex was monitored by analyzing the zeta potential, which reflected the surface charge distribution of the complex. A negatively charged Cu/CuO nanocomposite nearly becomes neutral when complexed with hACE-2 further assuring the complex formation. Formation of this complex and its inactivation of hACE-2 was evaluated using a standardized protocal for enzymatic activity. Similarly, carboxylate-functionalized graphene was complexed with copper, and its inhibitory effect was studied. Each step in the GO-Cu composite formation was monitored by characterizing its surface electrical properties, resulting in a decrease in its zeta potential and conductivity when complexed with copper. The interaction of the nanocomposites with hACE-2 was confirmed by 2D-FDS and gel electrophoresis analysis. GO-Cu was a rapid and efficacious inhibitor compared to Cu-CuO, especially at lower concentrations (2 μg ml). Considering the environmental friendliness of copper and graphene and their use in industries as surface coating materials, we anticipate that use of these composites once proven effective, may have future antimicrobial application. Utility of nanocomposites as antimicrobials, either as a surface antimicrobial or as an therapeutic, could be invisioned for use against current unknown and/or emergent pathogens.
PubMed: 38125590
DOI: 10.1039/d3na00468f -
Journal of Physiology and Pharmacology... Apr 2024We have previously described local aldosterone synthesis in mouse colon. In the renin-angiotensin-aldosterone system (RAAS), angiotensin II (Ang II) peptide is the...
We have previously described local aldosterone synthesis in mouse colon. In the renin-angiotensin-aldosterone system (RAAS), angiotensin II (Ang II) peptide is the physiological factor which stimulates aldosterone synthesis in the adrenal glands. We have recently demonstrated that Ang II stimulates aldosterone synthesis also in mouse colon. Here, we conducted a 75-min ex vivo incubation of murine colonic tissue and evaluated the effects of three other Ang peptides, Ang I (1 μM), Ang III (0.1 μM) and Ang (1-7) (0.1 μM) on aldosterone synthesis. As a possible mechanism, their effects on tissue levels of the rate-limiting enzyme, aldosterone synthase (CYP11B2) were measured by ELISA and Western blot. Ang III significantly elevated the amount of tissue CYP11B2 protein in colon. The values of released aldosterone in colon tissue incubation were increased over the control in the presence of Ang I, II or III, however, being statistically non-significant. In Western blot analysis, the values of tissue CYP11B2 protein content were elevated by Ang I and II. Ang (1-7) alone in colon did not influence CYP11B2 protein levels in the incubation experiment but showed higher aldosterone release without statistical significance. Ang (1-7) showed an antagonistic effect towards Ang II in release of aldosterone in adrenal gland. An overall estimation of a single peptide (three measured variables), the results were always in an increasing direction. The responses of aldosterone synthesis to high levels of glucose (44 mM) and potassium (18.8 mM) as physiological stimulators in vivo were investigated in the colon incubation. Glucose, equal to four times the concentration of the control buffer in the incubation, showed higher values of aldosterone release in colon than control without statistical significance similarly to the effect seen in adrenal glands. Increasing the concentration of potassium in the incubation buffer exerted no effect on colonic aldosterone production. Intriguingly, no correlation was found between aldosterone release and the tissue CYP11B2 protein content in colon. In summary, the response of colonic aldosterone synthesis to different Ang peptides resembles, but is not identical to, the situation in the adrenal glands.
Topics: Animals; Male; Mice; Aldosterone; Angiotensin I; Angiotensin II; Angiotensin III; Colon; Cytochrome P-450 CYP11B2; Glucose; Peptide Fragments; Potassium
PubMed: 38736265
DOI: 10.26402/jpp.2024.2.07 -
Frontiers in Endocrinology 2024The interaction between the renin-angiotensin system (RAS) and the acute ischemic stroke (AIS) is definite but not fully understood. This study aimed to analyze the risk...
PURPOSE
The interaction between the renin-angiotensin system (RAS) and the acute ischemic stroke (AIS) is definite but not fully understood. This study aimed to analyze the risk factors of AIS and explore the role of serum indicators such as angiotensin I (Ang I) in the prognosis of patients undergoing endovascular thrombectomy (EVT).
PATIENTS AND METHODS
Patients with AIS who underwent EVT and healthy controls were retrospectively enrolled in this study, and the patients were divided into a good or a poor prognosis group. We compared Ang I, blood routine indexes, biochemical indexes, electrolyte indexes, and coagulation indexes between patients and controls. We used univariate and multivariate logistic regression analyses to evaluate possible risk factors for AIS and the prognosis of patients undergoing EVT. Independent risk factors for the prognosis of patients undergoing EVT were identified through multifactorial logistic regression analyses to construct diagnostic nomograms, further assessed by receiver operating characteristic curves (ROC).
RESULTS
Consistent with previous studies, advanced age, high blood glucose, high D-dimer, and high prothrombin activity are risk factors for AIS. In addition, Ang I levels are lower in AIS compared to the controls. The level of Ang I was higher in the good prognosis group. Furthermore, we developed a nomogram to evaluate its ability to predict the prognosis of AIS after EVT. The AUC value of the combined ROC model (Ang I and albumin-globulin ratio (AGR)) was 0.859.
CONCLUSIONS
In conclusion, advanced age, high blood glucose, high D-dimer, and high prothrombin activity are risk factors for AIS. The combined Ang I and AGR model has a good predictive ability for the prognosis of AIS patients undergoing arterial thrombectomy.
Topics: Humans; Male; Female; Ischemic Stroke; Prognosis; Thrombectomy; Risk Factors; Middle Aged; Aged; Retrospective Studies; Endovascular Procedures; Fibrin Fibrinogen Degradation Products; Case-Control Studies; Biomarkers; ROC Curve
PubMed: 38919492
DOI: 10.3389/fendo.2024.1388871 -
Journal of Veterinary Internal Medicine 2024Systemic hypertension (SH) is a common cardiovascular disease in older cats that is treated primarily with the calcium channel blocker amlodipine besylate (AML). The...
BACKGROUND
Systemic hypertension (SH) is a common cardiovascular disease in older cats that is treated primarily with the calcium channel blocker amlodipine besylate (AML). The systemic effect of AML on the classical and alterative arms of the renin-angiotensin-aldosterone system (RAAS) in cats is incompletely characterized.
HYPOTHESIS/OBJECTIVES
To determine the effect of AML compared to placebo on circulating RAAS biomarkers in healthy cats using RAAS fingerprinting.
ANIMALS
Twenty healthy client-owned cats.
METHODS
Cats were administered amlodipine besylate (0.625 mg in toto) or placebo by mouth once daily for 14 days in a crossover design with a 4-week washout period. Plasma AML concentrations and RAAS biomarker concentrations were measured at multiple timepoints after the final dose in each treatment period. Time-weighted averages for RAAS biomarkers over 24 hours after dosing were compared between treatment groups using Wilcoxon rank-sum testing.
RESULTS
Compared to placebo, AML treatment was associated with increases in markers of plasma renin concentration (median 44% increase; interquartile range [IQR] 19%-86%; P = .009), angiotensin I (59% increase; IQR 27-101%; P = .006), angiotensin II (56% increase; IQR 5-70%; P = .023), angiotensin IV (42% increase; -19% to 89%; P = .013); and angiotensin 1-7 (38% increase; IQR 9-118%; P = .015).
CONCLUSIONS AND CLINICAL IMPORTANCE
In healthy cats, administration of AML resulted in nonspecific activation of both classical and alternative RAAS pathways.
Topics: Animals; Cats; Aldosterone; Amlodipine; Antihypertensive Agents; Biomarkers; Renin-Angiotensin System
PubMed: 38334012
DOI: 10.1111/jvim.17006 -
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