Angiotensin-converting Enzyme Type Research Articles

Polymorphism of RAAS genes in patients with COVID-19: comparison with frequency in population and relationship with severity of course

Evaluation of genes polymorphisms frequencies of angiotensinogen (AGT), angiotensin converting enzyme type 1 (ACE1) and angiotensin II receptors type 1 (AGTR1) and type 2 (AGTR2) in patients admitted with coronavirus disease (COVID-19) and its association the severity of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2). The study included 100 patients admitted to the hospital with a laboratory-confirmed diagnosis of COVID-19. All patients were identified with alleles and genotypes of polymorphic markers rs4762 of the AGT gene, rs1799752 of the ACE1 gene, rs5186 of the AGTR1 gene and rs1403543 of the AGTR2 gene. The frequencies of each polymorphisms were compared with population. Statistical processing was performed using the Statistica 8.0 software package. In evaluated cohort there was higher frequency of D-allele ACE1 rs1799752 compared to population. Depending on the availability of criteria for the severity of coronavirus infection, 44 (44%) patients were diagnosed with severe, 56 (56%) with moderate course. The groups did not significantly differ in age, gender, cardiovascular risk factors and comorbid pathology. In the groups with severe and moderate course, the same distribution of genotypes and alleles of AGT rs4762, AGTR2 rs1403543 and ACE1 rs1799752 was revealed. For the I/D alleles of the ACE1 rs1799752 gene, a significant deviation from the papulation was found in both the group of severe and moderate COVID-19. In the group with a severe course of the disease, a higher frequency of the mutant C-allele of the AGTR1 rs5186 gene was detected. In the same group, a deviation in the frequency ratio of A and C of the AGTR1 rs5186 alleles from Hardy-Weinberg Equilibrium was found. When calculating the risk of severe COVID-19 in the presence of the C-allele compared with the A-allele, an odds ratio 2.092 (95% confidence interval 1.066-4.108) was obtained. The data obtained suggest that the genes polymorphisms of the components of renin-angiotensin-aldosterone system, namely D-allele of ACE1 rs1799752 and C-allele of AGTR1 rs5186, may make it possible to identify groups of patients predisposed to the development of more severe COVID-19.

Renin-Angiotensin System Genes Polymorphisms in Patients With COVID-19 and Its Relation to Severe Cases of SARS-CoV-2 Infection.

Different variants of single nucleotide polymorphisms (SNPs) of angiotensinogen (AGT), angiotensin-converting enzyme type 1 (ACE1), and angiotensin II receptors type 1 (AGTR1) and 2 (AGTR2) genes determine different susceptibility to cardiovascular disease (CVD) and hypertension, which can be considered as risk factors for fatal outcomes among coronavirus disease 2019 (COVID-19) patients. The objective of our study was to assess the relation between the frequency of SNPs of the renin-angiotensin system (RAS) components, and the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The cross-sectional study included 100 patients with a laboratory-confirmed diagnosis of COVID-19 admitted to the hospital. Criteria for severe COVID-19 included respiratory rate (RR) > 30/min, blood oxygen saturation (SpO2) ≤ 93%, signs of unstable hemodynamics with systolic blood pressure (SBP) < 90 and/or diastolic blood pressure (DBP) < 60 mm Hg. All patients were identified with alleles and genotypes of the polymorphic markers rs4762 of the AGT gene, rs1799752 of the ACE1 gene, rs5186 of the AGTR1 gene and rs1403543 of the AGTR2 gene using the polymerase chain reaction method in human DNA preparations on real-time CFX96C1000 Touch, Bio-Rad equipment (Syntol, Russia). Statistical analysis was performed in R v.4.2. Patients were divided into groups with severe (n = 44) and moderate COVID-19 (n = 56). For ACE1 rs1799752, a significant deviation from the population distribution was detected in both studied subgroups. A higher frequency of the C allele SNP rs5186 AGTR1 gene was detected in the group with severe disease. More frequent A/A genotype of SNP rs1403543 AGTR2 was detected among females with severe COVID-19. Haplotype analysis revealed more common DCG haplotype among patients with severe COVID-19. The odds ratio for severe COVID-19 in the presence of the DCG haplotype was 3.996 (95% confidential interval: 1.080 -14.791, P < 0.05). Our data suggest that the SNP genes of the RAS components, may allow to identify groups of patients predisposed to a more severe course of COVID-19.

The angiotensin II/type 1 angiotensin II receptor pathway is implicated in the dysfunction of albumin endocytosis in renal proximal tubule epithelial cells induced by high glucose levels

It is well-established that dysfunction of megalin-mediated albumin endocytosis by proximal tubule epithelial cells (PTECs) and the activation of the Renin-Angiotensin System (RAS) play significant roles in the development of Diabetic Kidney Disease (DKD). However, the precise correlation between these factors still requires further investigation. In this study, we aimed to elucidate the potential role of angiotensin II (Ang II), a known effector of RAS, as the mediator of albumin endocytosis dysfunction induced by high glucose (HG) in PTECs. To achieve this, we utilized LLC-PK1 and HK-2 cells, which are well-established in vitro models of PTECs. Using albumin-FITC or DQ-albumin as tracers, we observed that incubation of LLC-PK1 and HK-2 cells with HG (25 mM for 48 h) significantly reduced canonical receptor-mediated albumin endocytosis, primarily due to the decrease in megalin expression. HG increased the concentration of Ang II in the LLC-PK1 cell supernatant, a phenomenon associated with an increase in angiotensin-converting enzyme (ACE) expression and a decrease in prolyl carboxypeptidase (PRCP) expression. ACE type 2 (ACE2) expression remained unchanged. To investigate the potential impact of Ang II on HG effects, the cells were co-incubated with angiotensin receptor inhibitors. Only co-incubation with 10−7 M losartan (an antagonist for type 1 angiotensin receptor, AT1R) attenuated the inhibitory effect of HG on albumin endocytosis, as well as megalin expression. Our findings contribute to understanding the genesis of tubular albuminuria observed in the early stages of DKD, which involves the activation of the Ang II/AT1R axis by HG.

ACE2 and a Traditional Chinese Medicine Formula NRICM101 Could Alleviate the Inflammation and Pathogenic Process of Acute Lung Injury

The coronavirus disease 2019 (COVID-19) is a highly transmittable respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and acute lung injury (ALI) is the major complication of COVID-19. The challenge in studying SARS-CoV-2 pathogenicity is the limited availability of animal model. Therefore, it is necessary to establish animal models that can reproduce multiple characteristics of ALI to study therapeutic application. The present study established a mouse model that has features of ALI that are similar to COVID-19 syndrome to investigate the role of human angiotensin-converting enzyme type II (ACE2) and the administration of the Chinese herbal prescription Chingguan Yihau (NRICM101) in ALI. The mice with ACE2 genetic modifications, including the overexpression of human ACE2 (K18-hACE2 TG) and the absence of ACE2 (mACE2 KO), were intratracheally instillated with hydrochloric acid to induce ALI. The acid intratracheal instillation induced the imbalance between angiotensin-converting enzyme (ACE) and ACE2 (i.e., ACE/ACE2), severe immune cell infiltration, cytokine storms, inflammatory effect, and pulmonary disease in the mice. Compared with K18-hACE2 TG mice, mACE2 KO mice exhibited dramatically increased levels of multiple inflammatory cytokines Interleukin-6 (IL-6) and Tumor necrosis factor alpha (TNF-α) in bronchoalveolar lavage fluid, histological evidence of lung injury, the production of the ACE expression, and the activation of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) expression. The results indicate that overproduction of ACE2 and induction of the ACE2-Ang-(1-7)/Mas axis could counteract the proinflammatory effect of acid-induced ALI and effectively alleviate the pathogenic process of acid-induced ALI by regulating MAPK, p-ERK1/2, and p-STAT3 pathways and dysregulation of MMP-2/MMP-9 activation. In addition, NRICM101, which is an effective TCM that has both antiviral and anti-inflammatory effects against COVID-19, shows potential for treating acid-induced ALI. NRICM101 could alleviate the disease progression of acid-induced ALI by suppressing IL-6 and TNF-α production in alveoli. In conclusion, the established mouse model provided an effective platform for researchers to investigate the role of ACE2 on pathological mechanisms and develop therapeutic strategies for ALI, including COVID-19-related pulmonary diseases. The effects of NRICM101 administration is a potential strategy for curing acid-induced ALI evaluated in the mouse model in this study. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Immunological aspects of COVID-19 in children

The authors present a review of the literature on the peculiarities of immunity in children, which may explain the differences in the symptoms of COVID-19 in childhood. In children, COVID-19 tends to occur more easily than in adults. However, as in the years of the pandemic, and in the post-pandemic period, there were quite a few cases of complicated course with the need for hospitalization, and sometimes with fatal outcomes. Infants under the age of 1 year account for the highest percentage of hospitalizations among children. Currently, the analysis of the results of comparing the clinical manifestations of the disease and laboratory data is continuing. Basically, the features of COVID-19 in children are explained by the immaturity of the immune system and the atrial fibrillation of the respiratory tract. It is known that in childhood there are fewer angiotensin converting enzyme type 2 receptors (ACE 2, ACE 2), with which the coronavirus enters the human body. The disease caused by SARS-CoV-2 in children is often accompanied by gastrointestinal manifestations. A small percentage of sick children may develop an intense inflammatory reaction called “multisystem inflammatory syndrome”, also known as MIS-C. In this condition, high titers of antibodies to RBD SARS-CoV-2 and autoantibodies to free interleukin (IL) -1Ra are detected. These data should be taken into account when clarifying the prevention and treatment regimens aimed at preventing complications in the pediatric population.

Chronic Intermittent Hypobaric Hypoxia Reduces Hypothalamic N-Methyl-d-Aspartate Receptor Activity and Sympathetic Outflow in Spontaneously Hypertensive Rats.

Guo, Xinqi, Hongyu Ma, Ziye Cui, Qiyue Zhao, Ying Zhang, Lu Jia, Liping Zhang, Hui Guo, Xiangjian Zhang, Yi Zhang, Yue Guan, and Huijie Ma. Chronic intermittent hypobaric hypoxia reduces hypothalamic N-Methyl-d-Aspartate Receptor activity and sympathetic outflow in spontaneously hypertensive rats. High Alt Med Biol. 25:77-88, 2024. Objective: This study aims to determine the role of hypothalamic renin-angiotensin system (RAS) in the antihypertensive effect of chronic intermittent hypobaric hypoxia (CIHH). Methods: Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) received 35 days of hypobaric hypoxia simulating an altitude of 4,000 m, 5 h/day. The levels of RAS, blood pressure, and N-methyl-d-aspartate receptor (NMDAR) activities of hypothalamic paraventricular nucleus (PVN) presympathetic neurons from each group of rats were determined. Results: The systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure (MAP) of SHRs significantly decreased from the third week of CIHH treatment. This blood pressure reduction effect could be maintained for at least 2 weeks after stopping the CIHH treatment. CIHH treatment also attenuated the decrease in MAP and renal sympathetic nerve activity induced by hexamethonium administration in SHRs, but not in WKY rats. Furthermore, CIHH reversed the increase in serum angiotensin (Ang)II concentration and the expression of PVN angiotensin-converting enzyme (ACE) and AngII type 1 (AT1) receptors, as well as the decrease in serum Ang1-7 concentration and the expression of PVN ACE2 and Mas receptors in SHRs. In addition, the administration of CIHH resulted in a reduction in the frequency of miniature excitatory postsynaptic currents and amplitude of NMDAR current in PVN presympathetic neurons of SHRs, which means that CIHH decreased the pre- and postsynaptic NMDAR activity of PVN presympathetic neurons in SHRs. However, pretreatment with A779 (a Mas receptor blocker) or AngII abrogated the above effects. Meanwhile, Ang1-7 pretreatment mimicked the CIHH effect on pre- and postsynaptic NMDAR activity of presympathetic neurons in SHRs. Conclusions: Our data indicate that CIHH reduces pre- and postsynaptic NMDAR activity of PVN presympathetic neurons, sympathetic outflow, and blood pressure by decreasing the activity of the ACE/AngII/AT1 axis and increasing the activity of ACE2/Ang1-7/Mas axis in the hypothalamus in hypertension.

PATHOMORPHOLOGICAL CHANGES OF THE PLACENTA IN THE ACUTE PERIOD OF COVID-19 IN PREGNANT WOMEN

Introduction. The barrier function of the mature placenta ensures the birth of PCR-negative infants in women during the acute period of coronavirus disease (COVID-19). This was explained by a decrease in the level of activity and concentration of angiotensin-converting enzyme type II protein (ACE2), which is a receptor for the coronavirus SARS-CoV-2 in the placenta. We conducted this study in order to detect compensatory changes in the placenta during COVID-19 in a pregnant woman. The aim of the study: To determine pathomorphological changes of the placenta in the acute period of COVID-19 in a pregnant woman. Materials and methods. The placentas of women with full-term pregnancy who were having COVID-19 confirmed by a positive PCR test (determination of SARS-CoV-2 RNA) during childbirth (n=32) were studied. The duration of the post-COVID interval (time from the diagnosis of COVID-19 to delivery) equaled 1–4 weeks. Macroscopic, organometric, microscopic, statistical, and immunohistochemical (with determination of CD34 monoclonal antibody expression) research methods were used. To determine the percentage of the studied structures that differed in color after histological staining, archival photos (×400) were uploaded to ONLINE JPG TOOLS. Results. Delivery dates: 37 to 42 weeks of gestation (median 40). COVID-19 occurred in the period 34 to 40 weeks of gestation (median 36). Course of coronavirus disease in pregnant women: 10 – mild, 18 – medium-severe, severe condition with bilateral polysegmental pneumonia – 4 women. Evaluation of newborns according to the Apgar score: 21 children (65.6%) – 8–9 points, 9 cases (28.1%) – 7–8 points, and one observation – 3–4 points and 6–7 points. No significant difference was found between the clinical manifestations of COVID-19 or the severity of the course of the disease in the pregnant woman and the morphological changes of the placenta. Microscopic examination of the placenta revealed placentitis: chorioamnionitis – 93.8% (95%CI: 82.4%–99.5%), basal deciduitis – 100% (95%CI: 94.2%–100%), villitis and intervillositis – 28.1% (95%CI: 13.7%–45.4%). The degree of manifestations of chorioamnionitis: (+) and (++) was in 34.4% (95% CI: 18.6%–52.1%), basal deciduitis (+) – 15.6% (95% CI: 5 %–30.6%), p1-2=0.08; and (++) in 28.1% (95% CI: 13.7%–45.4%). Manifestation of chorioamnionitis in (+++) and (++++) in 11.8% (95% CI: 3.2%–26.6%), basal deciduitis (+++) in 28.1% (95 % CI: 13.7%–45.4%) and (++++) in 15.6% (95% CI: 5%–30.6%). The expression of manifestations of basal deciduitis (+++++) was found in 11.8% (95% CI: 3.2%–26.6%), p1-2=0.04. The degree of severity of inflammatory changes of the maternal surface of the placenta from (+++) to (+++++) with minor similar changes in the amniotic membranes (+) and (++) confirmed the vertical route of infection. Edema of the stroma of the terminal villi was detected in 90.6% (95% CI: 77.7%–98.3%) and caused a narrowing of the lumen of the capillaries of the terminal villi of the chorion, and a decrease in the percentage of the intervillous space – 26.0 [20.7; 33.8] vs. 44.9 [40.5; 49.6] as a normal value; p = 0.0005. Percentages in a histological section of the terminal villus: stroma – 72.3 [65.8; 78.7], blood vessels – 29.0 [25.6; 34.2] vs. normal indicators: 32.1 [26.2; 39.6] and 67.8 [60.3; 73.7], respectively; p = 0.0039. Conclusions. Maternal pathomorphological changes in full-term pregnancy in the acute period of COVID-19 were caused by the exudation phase of the inflammatory process, which explained the manifestations of placentitis, swelling of the stroma of terminal villi with narrowing of the lumen of capillaries, dyscirculatory disorders. Live birth with high scores on the Apgar scale was ensured by compensatory changes of the mature placenta: an increase in the number of syncytial nodules, the locality of villitis and intervillositis, as mechanisms of increasing the intervillous space to ensure adequate perfusion.

COVID-19 on Oral Health: A New Bilateral Connection for the Pandemic.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and transmission are generally known to be produced by respiratory droplets and aerosols from the oral cavity (O.C.) of infected subjects, as stated by the World Health Organization. Saliva also retains the viral particles and aids in the spread of COVID-19. Angiotensin-converting enzyme Type 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are two of the numerous factors that promote SARS-CoV-2 infection, expressed by O.C. structures, various mucosa types, and the epithelia of salivary glands. A systemic SARS-CoV-2 infection might result from viral replication in O.C. cells. On the other hand, cellular damage of different subtypes in the O.C. might be associated with various clinical signs and symptoms. Factors interfering with SARS-CoV-2 infection potential might represent fertile ground for possible local pharmacotherapeutic interventions, which may confine SARS-CoV-2 virus entry and transmission in the O.C., finally representing a way to reduce COVID-19 incidence and severity.

Mechanisms of renal damage in patients with new coronavirus infection (literature review)

One in four people in the world currently has kidney problems to varying degrees. It is known that the new coronavirus infection (COVID-19) is primarily a respiratory disease, but the kidneys are the target organ. Coronavirus is tropic to renal tissue due to the presence in the organ of the angiotensin converting enzyme type 2 and transmembrane serine protease 2, which are considered the target of this virus. The presence of any stage of renal insufficiency is an independent adverse risk factor for coronavirus infection and results in high hospitalization rates in hospitals and a mortality rate. Kidney damage is caused by a variety of pathogenetic mechanisms: direct cytopathic effect of the virus on their structure (in the kidney body - podocytes, mesangial cells, in the vascular glomerulus - endothelium of capillaries, in the proximal tubules - epithelial cells); cytokine storm; damage to the renin-angiotensin-aldosterone system; immunothrombosis. In many patients with confirmed coronavirus infection, significant changes in urine analysis (hematuria, proteinuria) and an increase in serum creatinine levels have been observed in the laboratory since the first days of the disease. One of the main risk factors for mortality is the development of acute renal injury. More research is needed on the exact effects of SARS-CoV-2 on the kidneys. Understanding the main pathogenetic pathways of kidney damage in COVID-19 is necessary for the development of strategies and the development of effective treatment methods.

Diabetes-induced stimulation of the renin-angiotensin system in the rat brain cortex

Cerebrovascular disease is a threat to people with diabetes and hypertension. Diabetes can damage the brain by stimulating the renin-angiotensin system (RAS), leading to neurological deficits and brain strokes. Diabetes-induced components of the RAS, including angiotensin-converting enzyme (ACE), angiotensin-II (Ang-II), and angiotensin type 1 receptor (AT1R), have been linked to various neurological disorders in the brain. In this study, we investigated how diabetes and high blood pressure affected the regulation of these major RAS components in the frontal cortex of the rat brain. We dissected, homogenized, and processed the brain cortex tissues of control, streptozotocin-induced diabetic, spontaneously hypertensive (SHR), and streptozotocin-induced SHR rats for biochemical and Western blot analyses. We found that systolic blood pressure was elevated in SHR rats, but there was no significant difference between SHR and diabetic-SHR rats. In contrast to SHR rats, the heartbeat of diabetic SHR rats was low. Western blot analysis showed that the frontal cortexes of the brain expressed angiotensinogen, AT1R, and MAS receptor. There were no significant differences in angiotensinogen levels across the rat groups. However, the AT1R level was increased in diabetic and hypertensive rats compared to controls, whereas the MAS receptor was downregulated (p < 0.05). These findings suggest that RAS overactivation caused by diabetes may have negative consequences for the brain's cortex, leading to neurodegeneration and cognitive impairment.

Antimicrobial efficiency of chlorine dioxide and its potential use as anti-SARS-CoV-2 agent: mechanisms of action and interactions with gut microbiota.

Chlorine dioxide (ClO2) is a disinfectant gas with strong antifungal, antibacterial, and antiviral activities. Applied on hard non-porous surfaces as an aqueous solution or gas, the ClO2 exerts antimicrobial activity through its interaction and destabilization of cell membrane proteins, as well as through DNA/RNA oxidation, triggering cell death. As for viruses, the ClO2 promotes protein denaturalization mechanisms preventing the union between the human cells and the viral envelope. Currently, ClO2 has been pointed out as a potential anti-SARS-CoV-2 clinical treatment for use in humans with the ability to oxidize the cysteine residues in the spike protein of SARS-CoV-2, inhibiting the subsequent binding with the Angiotensin-converting enzyme type 2 receptor, located in the alveolus cells. Orally administered ClO2 reaches the gut tract and exacerbates the symptoms of COVID-19 generating a dysbiosis with gut inflammation and diarrhea as side effects, and once absorbed, produces toxic effects including methemoglobinemia and hemoglobinuria which can trigger respiratory diseases. These effects are dose-dependent and may not be entirely consistent between individuals since the gut microbiota composition is highly heterogeneous. However, to support the use of ClO2 as an anti-SARS-CoV-2 agent, further studies focused on its effectiveness and safety both in healthy and immunocompromised individuals, are needed.

Approaches towards menstrual cycle disorder therapy in reproductive-aged women with long COVID

Background. The mirror of a female’s reproductive health is the menstrual cycle. The SARS-CoV-2 pandemic itself acts as a significant stressor. This leads to women’s overall health and life quality disturbance. Moreover, patients struggle with long COVID effects, which is a prolongation of symptoms after recovery. Due to the expression of angiotensin-converting enzyme type 2 receptors in the intestinal mucosa and inflammation, the gastrointestinal (GI) tract is also triggered by the virus.Objectives. To assess the efficacy of the chosen treatment approach in women with changes in premenstrual syndrome and cyclicity due to long COVID with or without GI symptoms.Material and methods. A single-centre longitudinal interventional study was organized. Were studied data from the conducted tests (progesterone level, ultrasound follicle scan, etc.) and surveys. Then the effectiveness of the suggested treatment with the use of oral and vaginal forms of progesterone was evaluated. The study was held in the Kyiv City Center of Reproductive and Perinatal Medicine (Ukraine) from January to June 2021.Results. On average 78% patients without GI symptoms experienced relief after 3 months and 89% patients after 6 months of suggested treatment. 71% patients with GI symptoms experienced improvement after 3 and 87% of them after 6 months. The vaginal progesterone had better results compared to oral form. Averagely 6–8% experienced side effects (nausea, hypotension, less compliance) due to progesterone intake. The vaginal micronised progesterone also presented better results than oral with fewer side effects compared to the total number of participants.Conclusions. The proposed approach has shown particular correction of the menstrual cycle disturbances in women with long COVID. Vaginal micronized progesterone offers more promising outcomes in patients with GI symptoms and disrupted absorption, compared to the oral form.Further investigation is required for a more reasonable conclusion.

DO RENIN-ANGIOTENSIN SYSTEM INHIBITORS HAVE ANY EFFECT ON THE SEVERITY OF COVID-19 IN HYPERTENSIVE SUBJECTS?

Objective: An increase in angiotensin-converting enzyme (ACE) type 2 levels would stimulate the infection by SARS-Cov-2. On the other hand, the inhibition of the effect of angiotensin II could decrease the inflammatory and oxidative response related to the severity of the disease. Our purpose is to assess the effect of renin-angiotensin inhibitors (RASi) on the severity of COVID-19 in a primary care population of hypertensives. Design and method: Multicenter, observational, cross-sectional, retrospective and analytical study. The subjects were enrolled by a random sampling from 10 autonomous regions in Spain, among patients over 18 years-old with treated hypertension and COVID-19 (PCR positive), within the framework of primary health care (119 physicians). Patients were treated 6 months prior data collection (May 2021–February 2022) in the third wave. Multivariate logistic regression analysis adjusted by age, sex, smoking, and obesity was performed to assess the relationship of COVID-19 severity with anti-hypertensive therapy. Results: 1372 patients were enrolled, mean age 67.1±13.6 years, women 50.8%, smoking 12.5%, obesity 43.9%, diabetes 27.5%, controlled arterial hypertension 55.9% (office BP &lt;140 /90). The severity of COVID-19 was: mild-asymptomatic 971 (70.8%), hospital admission 401 (29.2%), ICU admission 74 (5.4%) and death 48 (Fatality rate, 4%). 64.3% of patients were treated with RASi alone or as add-on therapy during COVID-19. Comparing the progression of COVID-19 between those patients who required hospitalisation versus mild-asymptomatic, we found statistically significant differences (Figure 1): RASi vs Diuretics(D)+Calcium channel blockers(CCB)+RASi (OR = 0.36; 95%CI: 0.22-0.57; p&lt;0.001) and D+RASi vs D (OR = 0.49; 95%CI: 0.28-0.93; p&lt;0.05). RASi alone or in combination vs other anti-hypertensives only showed a non-significant trend for fewer hospitalizations (OR = 0.87; 95%CI: 0.68-1.12; p = 0.274). There were no differences between survivors vs non-survivors treated with RASi: 63.2% vs 58.3% (p = 0.496). Conclusions: RASi do not worsen the severity of COVID-19 among hypertensive patients. Regarding its possible protective effect on the progression of the disease, the results are not conclusive, although there could be a trend in this sense, especially when RASi are compared with some antihypertensive combinations.

Effect of the N501Y Mutation on Ligands Complexed with SARS-CoV-2 RBD: Insights on Potential Drug Candidates for COVID-19

Bioactive compounds against SARS-CoV-2 targets could be potential treatments for COVID-19. Inhibitors of the receptor-binding domain (RBD) on the viral spike protein can block its binding to the human angiotensin-converting enzyme type II (ACE2) receptor. This study presents ligands based on natural products and synthetic compounds, targeting multiple N501/Y501 RBDs, besides RBD-ACE2, over different regions. The selected compounds were evaluated by docking using consensus scoring, pharmacokinetics/toxicological analyses, and molecular dynamics. Additionally, N501/Y501 RBD-ACE2 interaction properties and RBD–ligand complexes were compared. We identified that coenzyme Q10, 1-stearoyl-2-arachidonoylglycerol, and palmitone showed the greatest RBD interactions. Targeting specific residues (in particular, tyrosine) in the C-, N-terminal, and central RBD sites promoted more stable protein–ligand interactions than in the N-terminal region only. Our results indicate that the molecules had more energetically favorable interactions with residues from distinct RBD regions rather than only interacting with residues in the N-terminal site. Moreover, the compounds might better interact with mutated N501Y than N501 RBDs. These hits can be optimized to leads and investigated through QSAR models and biological assays to comprehend mechanisms better. Altogether, such strategies may anticipate antiviral strategies if or when future variants and other CoVs arise.

NaHS restores the vascular alterations in the renin-angiotensin system induced by hyperglycemia in rats

Hyperglycemia (HG) impairs the renin-angiotensin system (RAS), which may contribute to vascular dysfunction. Besides, hydrogen sulfide (H2S) exerts beneficial cardiovascular effects in metabolic diseases. Therefore, our study aimed to determine the effects of chronic administration of sodium hydrosulfide (NaHS; inorganic H2S donor) and DL-Propargylglycine [DL-PAG; cystathionine-ץ-lyase (CSE) inhibitor] on the RAS-mediated vascular responses impairments observed in thoracic aortas from male diabetic Wistar rats. For that purpose, neonatal rats were divided into two groups that received: 1) citrate buffer (n = 12) or 2) streptozotocin (STZ, 70 mg/kg; n = 48) on the third postnatal day. After 12 weeks, diabetic animals were divided into 4 subgroups (n = 12 each) that received daily i.p. injections during 4 weeks of: 1) non-treatment; 2) vehicle (PBS, 1 mL/kg); 3) NaHS (5.6 mg/kg); and 4) DL-PAG (10 mg/kg). After treatments (16 weeks), blood glucose, angiotensin-(1−7) [Ang-(1−7)], and angiotensin II (Ang II) levels, vascular responses to Ang-(1−7) and Ang II, and the expression of angiotensin AT1, AT2, and Mas receptors, angiotensin converting enzyme (ACE) and ACE type 2 (ACE2) were determined. HG induced: 1) increased blood glucose levels and expression of angiotensin II AT1 receptor; 2) impaired Ang-(1−7) and Ang II mediated vascular responses; 3) decreased angiotensin levels and expression of angiotensin II AT2 and angiotensin-(1−7) Mas receptors, and ACE2; and 4) no changes in ACE expression. Interestingly, NaHS, but not DL-PAG, reversed HG-induced impairments, except for blood glucose level changes. These results suggest that NaHS restores vascular function in streptozotocin-induced HG through RAS modulation.

Chronic heart failure and COVID-19

The coronavirus pandemic has caused a rapid increase in the number of cases and high deaths worldwide. A new coronavirus infection in the presence of an initial cardiac pathology can provoke decompensation of chronic heart failure. The article shows current information on the pathogenesis of COVID-19 and organ-specific lesions that develop in this disease is presented. Data on inflammation and its biochemical markers, on the features of coagulopathy, endothelial damage and microthromboses has been reflected in detail in this article. Particular attention is paid to the role of type 2 angiotensin-converting enzyme receptors and type 2 transmembrane serine protease in the development of organ-specific lesions in COVID-19. The pathogenesis of damage to the cardiovascular system is considered in detail with the presentation of data from latest literature on changes in the myocardium in patients who underwent COVID-19.

Association of the ACE and AGT gene polymorphisms with global disparities in COVID-19-related deaths.

The aim of the study was to investigate the gene polymorphisms of angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and angiotensin type 1 receptor (AT1R) in association with coronavirus disease 2019 (COVID-19) mortality rates worldwide. The prevalence of ACE I/D, AGT M235T, and AT1R A1166C alleles' frequencies in different populations was assessed. Data on COVID-19-related cases and deaths were acquired from the European Center for Disease Prevention and Control, which included weekly reports by country and continent. An Excel tool was developed to visualize the acquired data of mortality and incidence by classifying them by continent/country across specific periods of time. Spearman's nonparametric correlation was used to evaluate the association between country-based frequencies in RAS gene polymorphisms and COVID-19-related deaths. While China constituted the initial reservoir of COVID-19, incidence/mortality rates in Europe and America outnumbered the figures in the former. A clear association was identified between death rates and ACE D/I ( r = 0.3659; P = 0.033), as well as AGT A/G variants ( r = 0.7576; P = 0.015). Data on AT1R polymorphisms suggested no correlation with mortality rates. Our results demonstrated a significant disparity in COVID-19-related susceptibility and mortality among different populations and corroborate the importance of gene polymorphisms in predicting and consequently improving patients' outcomes.

A histopathological view at the long-term effects of COVID-19 on the gastrointestinal system in children: a single center experience.

Subacute and chronic long-term effects of coronavirus disease 2019 (COVID-19) in different organ systems have been studied in post-COVID patients recently. COVID-19 may cause gastrointestinal (GI) system findings due to the presence of its receptor, angiotensin converting enzyme type 2 (ACE2), which is extensively expressed in the GI tract. In this study, we aimed to evaluate the post-infectious histopathological alterations of COVID-19 in pediatric patients who had GI symptoms. Fifty-six specimens of upper endoscopic biopsies (including esophagus, stomach, bulbus and duodenum) obtained from seven patients and 12 specimens of lower endoscopic biopsies obtained from one patient who had GI symptoms after having COVID-19 (proven by polymerase chain reaction [PCR]) were evaluated as the study group. Forty specimens from five patients presenting with similar complaints but without COVID-19 were selected as the control group. All biopsy materials were immunohistochemically stained with the anti-SARS-CoV-2S1 antibody. In all biopsies of the study group, anti-SARS-CoV-2S1 antibody was detected with moderate cytoplasmic positivity in epithelial cells and inflammatory cells in the lamina propria. No staining was observed in the control group. Epithelial damage, thrombus, or no other specific findings were detected in the GI tract biopsies of any of the patients. The virus antigen was detected immunohistochemically in the stomach and duodenum, but not in the esophagus, even months after infection and causes gastritis and duodenitis. No specific histopathological finding was observed from non-COVID-19 gastritis/duodenitis. Therefore, the post-COVID-19 GI system involvement should be kept in mind in patients presenting with dyspeptic symptoms even if several months have passed.

The Relationship Between COVID-19 and the Development of Depression: Implications on Mental Health.

Initially, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease-2019 (COVID-19), was predominantly considered to primarily affect the respiratory system. However, later studies revealed that it also affects brain function through its ability to bind to the angiotensin-converting enzyme type 2 (ACE2) receptors expressed on neural cells. Our study involved a comprehensive review of literature aiming to investigate the relationship between COVID-19 and the development of depression. Our analysis shows a connection between these 2 conditions, as a consequence of the inflammatory response in the nervous system to the COVID-19 virus and the psychophysiological effects of the pandemic. In COVID-19 patients, depression can arise either due to the direct viral infection of the brain or as a result of an indirect immune response triggering neuroinflammation after a cytokine storm. The resulting depression can be treated with non-pharmacological therapies such as psychotherapy, antidepressant medications, or a combination of these treatments depending on the severity of the symptoms.

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.

Renin-angiotensin system in the central nervous system: focus on Huntington's disease.