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Biomedicines Jan 2024We hypothesized that subjects with heterozygous loss-of-function (LoF) mutations are at risk for Alzheimer's disease because amyloid Aβ42, a primary component of the...
We hypothesized that subjects with heterozygous loss-of-function (LoF) mutations are at risk for Alzheimer's disease because amyloid Aβ42, a primary component of the protein aggregates that accumulate in the brains of AD patients, is cleaved by ACE (angiotensin I-converting enzyme). Thus, decreased ACE activity in the brain, either due to genetic mutation or the effects of ACE inhibitors, could be a risk factor for AD. To explore this hypothesis in the current study, existing SNP databases were analyzed for LoF mutations using four predicting tools, including PolyPhen-2, and compared with the topology of known mutations already associated with AD. The combined frequency of >400 of these LoF-damaging mutations in the general population is quite significant-up to 5%-comparable to the frequency of AD in the population > 70 y.o., which indicates that the contribution of low ACE in the development of AD could be under appreciated. Our analysis suggests several mechanisms by which ACE mutations may be associated with Alzheimer's disease. Systematic analysis of blood ACE levels in patients with all mutations is likely to have clinical significance because available sequencing data will help detect persons with increased risk of late-onset Alzheimer's disease. Patients with transport-deficient mutations (about 20% of damaging ACE mutations) may benefit from preventive or therapeutic treatment with a combination of chemical and pharmacological (e.g., centrally acting ACE inhibitors) chaperones and proteosome inhibitors to restore impaired surface ACE expression, as was shown previously by our group for another transport-deficient ACE mutation-Q1069R.
PubMed: 38255267
DOI: 10.3390/biomedicines12010162 -
Sheng Li Xue Bao : [Acta Physiologica... Aug 2023In this study, we used a rat model of pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) to investigate the role and mechanism of angiotensin...
In this study, we used a rat model of pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) to investigate the role and mechanism of angiotensin (Ang)-(1-7) in regulating pulmonary artery diastolic function. Three weeks after subcutaneous injection of MCT or normal saline, the right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) of rats were detected using a right heart catheter. Vascular endothelium-dependent relaxation was evaluated by acetylcholine (ACh)-induced vasodilation. The relaxation function of vascular smooth muscle was evaluated by sodium nitroprusside (SNP)-induced vasodilation. Human pulmonary artery endothelial cells (HPAECs) were incubated with Ang-(1-7) to measure nitric oxide (NO) release levels. The results showed that compared with control rats, RVSP and RVHI were significantly increased in the MCT-PAH rats, and both ACh or SNP-induced vasodilation were worsened. Incubation of pulmonary artery of MCT-PAH rats with Ang-(1-7) (1 × 10-1 × 10 mol/L) caused significant vaso-relaxation. Pre-incubation of Ang-(1-7) in the pulmonary artery of MCT-PAH rats significantly improved ACh-induced endothelium-dependent relaxation, but had no significant effect on SNP-induced endothelium-independent relaxation. In addition, Ang-(1-7) treatment significantly increased NO levels in HPAECs. The Mas receptor antagonist A-779 inhibited the effects of Ang-(1-7) on endothelium-dependent relaxation and NO release from endothelial cells. The above results demonstrate that Ang-(1-7) promotes the release of NO from endothelial cells by activating Mas receptor, thereby improving the endothelium-dependent relaxation function of PAH pulmonary arteries.
Topics: Rats; Humans; Animals; Vasodilation; Pulmonary Arterial Hypertension; Monocrotaline; Rats, Sprague-Dawley; Hypertension, Pulmonary; Endothelial Cells; Pulmonary Artery; Endothelium; Acetylcholine; Nitroprusside
PubMed: 37583036
DOI: No ID Found -
Foods (Basel, Switzerland) Mar 2024The angiotensin-I converting enzyme (ACE) plays a pivotal role in hypertension, and while ACE inhibitors are conventional in hypertension management, synthetic...
The angiotensin-I converting enzyme (ACE) plays a pivotal role in hypertension, and while ACE inhibitors are conventional in hypertension management, synthetic medications often carry undesirable side effects. This has spurred interest in alternative ACE inhibitors derived from natural sources, such as edible insects. The silkworm, recognized for its bioactive peptides with potent ACE-inhibitory properties, has emerged as a promising candidate. This study aims to evaluate the acute toxicity and assess the antihypertensive efficacy of crude mature silkworm hydrolysate powder (MSHP) obtained from mature Thai silkworms. Utilizing the commercial protease Alcalase2.4L, MSHP was administered at various doses, including 50, 100, and 200 mg kg, to hypertensive rats. The investigation spans a 14-day period to observe any potential acute toxic effects. Results indicate that MSHP exhibits LD50 values equal to or exceeding 2000 mg kg, signifying a low level of acute toxicity. Furthermore, the effective dose for blood pressure reduction in hypertensive rats surpasses 100 mg kg of rat body weight. These findings suggest that MSHP derived from Thai mature silkworms holds promise as a natural antihypertensive food source. The implications of this research extend to the development of functional foods, functional ingredients, and dietary supplements aimed at managing hypertension.
PubMed: 38540933
DOI: 10.3390/foods13060943 -
Pharmacological Research Oct 2023Engineered gut microbiota represents a new frontier in medicine, in part serving as a vehicle for the delivery of therapeutic biologics to treat a range of host...
Engineered gut microbiota represents a new frontier in medicine, in part serving as a vehicle for the delivery of therapeutic biologics to treat a range of host conditions. The gut microbiota plays a significant role in blood pressure regulation; thus, manipulation of gut microbiota is a promising avenue for hypertension treatment. In this study, we tested the potential of Lactobacillus paracasei, genetically engineered to produce and deliver human angiotensin converting enzyme 2 (Lacto-hACE2), to regulate blood pressure in a rat model of hypertension with genetic ablation of endogenous Ace2 (Ace2 and Ace2). Our findings reveal a sex-specific reduction in blood pressure in female (Ace2) but not male (Ace2) rats following colonization with the Lacto-hACE2. This beneficial effect of lowering blood pressure was aligned with a specific reduction in colonic angiotensin II, but not renal angiotensin II, suggesting the importance of colonic Ace2 in the regulation of blood pressure. We conclude that this approach of targeting the colon with engineered bacteria for delivery of ACE2 represents a promising new paradigm in the development of antihypertensive therapeutics.
Topics: Male; Rats; Animals; Female; Humans; Angiotensin-Converting Enzyme 2; Lacticaseibacillus paracasei; Angiotensin II; Peptidyl-Dipeptidase A; Hypertension; Blood Pressure; Angiotensin I
PubMed: 37716548
DOI: 10.1016/j.phrs.2023.106920 -
Plants (Basel, Switzerland) May 2024Kanehira (CO) is an endemic species of Taiwan. This study elucidated the composition of CO hydrosol, revealing -cinnamaldehyde (65.03%), -cinnamyl acetate (7.57%), and...
Kanehira (CO) is an endemic species of Taiwan. This study elucidated the composition of CO hydrosol, revealing -cinnamaldehyde (65.03%), -cinnamyl acetate (7.57%), and coumarin (4.31%) as the main volatile compounds. Seven compounds were identified in the water fraction of hydrosol, including a novel compound, 2-(2-hydroxyphenyl)oxetan-3-ol. This marks the first investigation into high-polarity compounds in hydrosol, extending beyond the volatile components. Notably, two compounds, -phenyloxetan-3-ol and -phenyloxetan-3-ol, demonstrated significant inhibition activity against phosphodiesterase type five (PDE5), with IC50 values of 4.37 µM and 3.40 µM, respectively, indicating their potential as novel PDE5 inhibitors. Furthermore, CO hydrosol was evaluated against enzymes associated with erectile dysfunction, namely acetylcholinesterase (AChE), angiotensin-I converting enzyme (ACE), and arginase type 2 (ARG2). These findings underscore the potential of CO hydrosol to modulate erectile function through diverse physiological pathways, hinting at its prospects for future development in a beverage or additive with enhanced effects on erectile function.
PubMed: 38891326
DOI: 10.3390/plants13111518 -
Frontiers in Microbiology 2023Like other coronaviruses, SARS-CoV-2 has ability to spread through human-to-human transmission and to circulate from humans to animals and from animals to humans. A high...
ACE2 receptor polymorphism in humans and animals increases the risk of the emergence of SARS-CoV-2 variants during repeated intra- and inter-species host-switching of the virus.
Like other coronaviruses, SARS-CoV-2 has ability to spread through human-to-human transmission and to circulate from humans to animals and from animals to humans. A high frequency of SARS-CoV-2 mutations has been observed in the viruses isolated from both humans and animals, suggesting a genetic fitness under positive selection in both ecological niches. The most documented positive selection force driving SARS-CoV-2 mutations is the host-specific immune response. However, after electrostatic interactions with lipid rafts, the first contact between the virus and host proteins is the viral spike-cellular receptor binding. Therefore, it is likely that the first level of selection pressure impacting viral fitness relates to the virus's affinity for its receptor, the angiotensin I converting enzyme 2 (ACE2). Although sufficiently conserved in a huge number of species to support binding of the viral spike with enough affinity to initiate fusion, ACE2 is highly polymorphic both among species and within a species. Here, we provide evidence suggesting that when the viral spike-ACE2 receptor interaction is not optimal, due to host-switching, mutations can be selected to improve the affinity of the spike for the ACE2 expressed by the new host. Notably, SARS-CoV-2 is mutation-prone in the spike receptor binding domain (RBD), allowing a better fit for ACE2 orthologs in animals. It is possibly that this may also be true for rare human alleles of ACE2 when the virus is spreading to billions of people. In this study, we present evidence that human subjects expressing the rare EG allele of ACE2 with higher allele frequencies in European populations exhibit a improved affinity for the SARS-CoV-2 spike NY variant of the virus. This may suggest that this viral NY variant emerged in the human population after SARS-CoV-2 had infected a human carrying the rare EG allele of ACE2. In addition, this viral evolution could impact viral replication as well as the ability of the adaptive humoral response to control infection with RBD-specific neutralizing antibodies. In a shifting landscape, this ACE2-driven genetic drift of SARS-CoV-2 which we have named the 'boomerang effect', could complicate the challenge of preventing COVID with a SARS-CoV-2 spike-derived vaccine.
PubMed: 37520374
DOI: 10.3389/fmicb.2023.1199561 -
BMJ Open Diabetes Research & Care May 2024ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing...
INTRODUCTION
ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing vasodilatation by acting on the Mas receptor. In diabetic kidney disease (DKD), it is still unclear whether plasma or urine ACE2 levels predict renal outcomes or not.
RESEARCH DESIGN AND METHODS
Among 777 participants with diabetes enrolled in the Urinary biomarker for Continuous And Rapid progression of diabetic nEphropathy study, the 296 patients followed up for 9 years were investigated. Plasma and urinary ACE2 levels were measured by the ELISA. The primary end point was a composite of a decrease of estimated glomerular filtration rate (eGFR) by at least 30% from baseline or initiation of hemodialysis or peritoneal dialysis. The secondary end points were a 30% increase or a 30% decrease in albumin-to-creatinine ratio from baseline to 1 year.
RESULTS
The cumulative incidence of the renal composite outcome was significantly higher in group 1 with lowest tertile of plasma ACE2 (p=0.040). Group 2 with middle and highest tertile was associated with better renal outcomes in the crude Cox regression model adjusted by age and sex (HR 0.56, 95% CI 0.31 to 0.99, p=0.047). Plasma ACE2 levels demonstrated a significant association with 30% decrease in ACR (OR 1.46, 95% CI 1.044 to 2.035, p=0.027) after adjusting for age, sex, systolic blood pressure, hemoglobin A1c, and eGFR.
CONCLUSIONS
Higher baseline plasma ACE2 levels in DKD were protective for development and progression of albuminuria and associated with fewer renal end points, suggesting plasma ACE2 may be used as a prognosis marker of DKD.
TRIAL REGISTRATION NUMBER
UMIN000011525.
Topics: Humans; Male; Female; Diabetic Nephropathies; Angiotensin-Converting Enzyme 2; Biomarkers; Middle Aged; Glomerular Filtration Rate; Peptidyl-Dipeptidase A; Aged; Prognosis; Disease Progression; Follow-Up Studies
PubMed: 38816205
DOI: 10.1136/bmjdrc-2024-004237 -
The International Journal of... Aug 2023
Corrigendum to: A Study in First-Episode Psychosis Patients: Does Angiotensin I-Converting Enzyme Activity Associated With Genotype Predict Symptom Severity Reductions After Treatment With Atypical Antipsychotic Risperidone?
PubMed: 37433025
DOI: 10.1093/ijnp/pyad038 -
Physiological Reports Mar 2024With climate change, selection for water efficiency and heat resilience are vitally important. We undertook this study to determine the effect of chronic cyclic heat...
With climate change, selection for water efficiency and heat resilience are vitally important. We undertook this study to determine the effect of chronic cyclic heat stress (HS) on the hypothalamic expression profile of water homeostasis-associated markers in high (HWE)- and low (LWE)-water efficient chicken lines. HS significantly elevated core body temperatures of both lines. However, the amplitude was higher by 0.5-1°C in HWE compared to their LWE counterparts. HWE line drank significantly less water than LWE during both thermoneutral (TN) and HS conditions, and HS increased water intake in both lines with pronounced magnitude in LWE birds. HWE had better feed conversion ratio (FCR), water conversion ratio (WCR), and water to feed intake ratio. At the molecular level, the overall hypothalamic expression of aquaporins (AQP8 and AQP12), arginine vasopressin (AVP) and its related receptor AVP2R, angiotensinogen (AGT), angiotensin II receptor type 1 (AT1), and calbindin 2 (CALB2) were significantly lower; however, CALB1 mRNA and AQP2 protein levels were higher in HWE compared to LWE line. Compared to TN conditions, HS exposure significantly increased mRNA abundances of AQPs (8, 12), AVPR1a, natriuretic peptide A (NPPA), angiotensin I-converting enzyme (ACE), CALB1 and 2, and transient receptor potential cation channel subfamily V member 1 and 4 (TRPV1 and TRPV4) as well as the protein levels of AQP2, however it decreased that of AQP4 gene expression. A significant line by environment interaction was observed in several hypothalamic genes. Heat stress significantly upregulated AQP2 and SCT at mRNA levels and AQP1 and AQP3 at both mRNA and protein levels, but it downregulated that of AQP4 protein only in LWE birds. In HWE broilers, however, HS upregulated the hypothalamic expression of renin (REN) and AVPR1b genes and AQP5 proteins, but it downregulated that of AQP3 protein. The hypothalamic expression of AQP (5, 7, 10, and 11) genes was increased by HS in both chicken lines. In summary, this is the first report showing improvement of growth performances in HWE birds. The hypothalamic expression of several genes was affected in a line- and/or environment-dependent manner, revealing potential molecular signatures for water efficiency and/or heat tolerance in chickens.
Topics: Animals; Chickens; Aquaporin 2; Water; Hot Temperature; Heat-Shock Response; RNA, Messenger
PubMed: 38467563
DOI: 10.14814/phy2.15972 -
Viruses Oct 2023Exacerbated inflammatory responses are a hallmark of severe coronavirus disease 2019 (COVID-19). Zileuton (Zi) is a selective inhibitor of 5-lipoxygenase, an enzyme...
Exacerbated inflammatory responses are a hallmark of severe coronavirus disease 2019 (COVID-19). Zileuton (Zi) is a selective inhibitor of 5-lipoxygenase, an enzyme involved in the production of several inflammatory/pro-resolving lipid mediators. Herein, we investigated the effect of Zi treatment in a severe acute respiratory syndrome (SARS) model. Mouse hepatitis virus (MHV)3-infected mice treated with Zi significantly improved the clinical score, weight loss, cardiopulmonary function, and survival rates compared with infected untreated animals. The protection observed in Zi-treated mice was associated with a lower inflammatory score, reduced dendritic cell-producing tumor necrosis factor (TNF), and increased neutrophil-producing interleukin (IL)-10 in the lungs three days after infection (dpi). At 5 dpi, the lungs of treated mice showed an increase in Th2-, Treg CD4-, and Treg CD8-producing IL-10 and reduced Th1 infiltrating cells. Furthermore, similar results were found upon Zi treatment after SARS-CoV-2 infection in transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2), significantly improving the clinical score, weight loss, and lung inflammatory score compared with untreated animals. Our data suggest that Zi protects against developing severe lung disease during SARS induced by betacoronavirus without affecting the host's capacity to deal with infection.
Topics: Humans; Mice; Animals; Lipoxygenase Inhibitors; SARS-CoV-2; COVID-19; Lung; Mice, Transgenic; Immunity, Innate; Weight Loss; Disease Models, Animal
PubMed: 37896826
DOI: 10.3390/v15102049