Angiotensin-converting Enzyme Type Research Articles

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.

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.

Preclinical studies of antiviral activity of the RPH-137 fusion protein and molnupiravir against COVID-19

Finding effective and safe medicines to fight SARS-CoV-2 infection is an urgent task. RPH-137 is an original trap fusion protein against SARS-CoV-2 virus. It comprises the angiotensin-converting enzyme type 2 extracellular domain and the human IgG1 Fc fragment.The aim of the study was to carry out a preclinical evaluation of the efficacy of RPH-137 and molnupiravir against SARS-CoV-2 infection.Materials and methods: the authors analysed RPH-137 expressed in a stable CHO cell line and molnupiravir used as an active pharmaceutical ingredient. Drug-mediated inhibition of virus-induced cytotoxicity was assessed in Vero cell culture. In vivo efficacy assessments were performed in Syrian hamsters. The animals were infected intranasally with SARS-CoV-2 (PIK35 clinical isolate) in the dose of 5 log TCID50. The authors evaluated body weight measurements, lung–body weight ratios, and lung histopathology findings and determined viral RNA levels in oropharyngeal swabs by RT-PCR using the amplification cycle threshold (Ct). The statistical analyses involved one- and two-way ANOVA, Student's t-test, and Mann–Whitney test.Results: RPH-137 and molnupiravir inhibited the cytopathic effect of SARS-CoV-2 in Vero cells; the EC50 values of RPH-137 amounted to 4.69 μg/mL (21.3 nM) and 16.24 μg/mL (73.8 nM) for 50 TCID50 and 200 TCID50, respectively, whereas the EC50 values of molnupiravir were 0.63 μg/mL (1900 nM) for both doses. Intramuscular RPH-137 (30 and 80 mg/kg) had no effect on the infection process in Syrian hamsters. The comparison with the challenge control group showed that intraperitoneal RPH-137 (100 mg/kg) had statistically significant effects on a number of parameters, including a 27% reduction in inflammation and a 30% reduction in the total lesion area of the lungs by Day 7. Intragastric molnupiravir (300 mg/kg twice daily) significantly inhibited SARS-CoV-2 infection.Conclusions: both RPH-137 and molnupiravir inhibited the cytopathic effect of SARS-CoV-2 in Vero cells. In Syrian hamsters, molnupiravir demonstrated a more pronounced inhibition of SARS-CoV-2 infection than RPH-137. However, RPH-137 had statistically significant effects on a range of parameters. This offers additional perspectives for further research.

Modified Levels of Renin Angiotensin Related Components in the Frontal Cortex and Hippocampus were Associated with Neuroinflammation and Lower Neuroprotective Effects of NGF During Acute Hepatic Encephalopathy in Mice

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that involves cognitive and motor dysfunctions due to hepatic failure. The clinical and experimental studies suggest that the angiotensin (Ang) converting enzyme (ACE), Ang II, and angiotensin type 1 receptor (AT1R), which compose the classical pathway of the renin-angiotensin system (RAS), exacerbate neuroinflammation in different neurologic diseases. Conversely, Ang-(1-7), ACE2, and Mas receptor, which integrate the alternative RAS axis, have been shown as promising therapeutic targets in neuropsychiatric disorders, leading to neuroprotection. This study aimed to investigate the potential participation of the RAS components in thioacetamide (TAA)-induced HE in mice. We also evaluated the levels of neurotrophic factors, pro-inflammatory cytokines, and chemokine in the central nervous system of TAA-induced HE in mice. Mice were submitted to acute liver failure induced by TAA administration by intraperitoneal route. Measurements of RAS components (ACE, Ang II, ACE2 and Ang1-7) and neurotrophic factors (BDNF, GDNF and NGF) were obtained by ELISA assay. Pro-inflammatory cytokines (TNF, IFN-γ, IL-6, IL-12p70) and the chemokine (CCL2) were quantified by cytometric bead array. The student's t-test was applied for statistical analysis. Mice presented increased cortical levels of ACE, while Ang-(1-7) levels were decreased in cortical and hippocampal samples compared to controls. Moreover, HE mice had an increase in the Ang II/Ang-(1-7) ratio along with reduced levels of neural growth factor (NGF) in the prefrontal cortex. They also showed elevated levels of IFN-γ and CCL2 in the prefrontal cortex and of TNF, IL-6, IL-12, and CCL2 in the hippocampus compared with controls. This study suggested that the reduction of components of the alternative RAS axis was associated with the deleterious effects of neuroinflammation and lower neuroprotective effects of NGF during TAA-induced HE.

The RAAS Axis and SARS-CoV-2: From Oral to Systemic Manifestations.

One of the essential regulators of arterial blood pressure, the renin-angiotensin-aldosterone system (RAAS) seems to be one of the most complex mechanisms in the human body. Since the discovery of its key components and their actions, new substances and functions are still being unraveled. The main pathway begins with the secretion of renin in the kidney and culminates with the synthesis of angiotensin II (Ang II)-a strong vasoconstrictor-thanks to the angiotensin-converting enzyme (ACE). Research conducted in 2000 identified another enzyme, named ACE2, that converts Ang II into Ang-(1-7), a heptapeptide with opposing effects to those of Ang II: vasodilation and anti-inflammatory properties. This particular enzyme became of paramount importance during the last two decades, as a result of the confrontation of the human race with life-threatening epidemics. Multiple studies have been performed in order to uncover the link between ACE2 and human coronaviruses, the results of which we systemized in order to create an overview of the pathogenic mechanism. Human coronaviruses, such as SARS-CoV and SARS-CoV-2, attach to ACE2 via their spike proteins (S), causing the destruction of the enzyme. Because ACE2 limits the production of Ang II (by converting it into Ang-(1-7)), its destruction leads to a dysregulated inflammatory response. The purpose of this review is to decipher the complex pathophysiological mechanisms underlying the multiorgan complications (oral, cardiac, pulmonary, systemic) that appear as a result of the interaction of the SARS CoV-2 virus with the angiotensin-converting enzyme type 2.

Orofacial and facial pain during the new coronavirus infection (COVID-19) pandemic. Choosing a non-steroid anti-inflammator – focus on nimesulide

Doctors of various specialties face orofacial and facial pain in their practice: dentists, maxillofacial surgeons, neurologists, neurosurgeons, otorhinolaryngologists, therapists, general practitioners, traumatologists, ophthalmologists, psychotherapists, physiotherapists, aesthetic medicine doctors, anesthesiologists, plastic surgeons and other specialists. The novel coronavirus infection (COVID-19) pandemic, spread by the SARS-CoV-2 virus, has become a challenge for all medical specialties and health care systems around the world. The respiratory system is the dominant target of SARS-CoV-2. The oral mucosa is also highly susceptible to SARS-CoV-2 infection, due to the wide distribution of angiotensin-converting enzyme type II receptors in the oral cavity. We searched the literature for the period from the beginning of the pandemic until August 22, 2022, on the study of the association of orofacial pain with a new coronavirus infection COVID-19 in the electronic search engines PubMed and Scopus. Analysis of the found sources indicates an increase in the frequency of various types of orofacial pain associated with 1) violation of dentoalveolar and related structures during the COVID-19 pandemic; 2) temporomandibular disorders; 3) with damage or disease of the cranial nerves; and 4) like manifestations of primary headache. This growth is due both directly to the infection caused by SARS-CoV-2, its complications, and to a complex of biopsychosocial factors directly related to the pandemic. In the second part of the article, as part of the review, the possibility of using nimesulide for the treatment of orofacial and facial pain during the COVID-19 pandemic is discussed. The choice of nimesulide is supported by 1) the likely coadjuvant effect of nimesulide in the treatment of COVID-19; 2) positive experience with the use of nimesulide in the treatment of facial and orofacial pain in the period preceding the COVID-19 pandemic; 3) the safety of using nimesulide in comorbid patients, who are the main risk group for the development and severe course of COVID-19.