Angiotensin and pain

The role of the renin-angiotensin system in human pain is a complicated and controversial field, partly due to the complexities of the system itself, but also because of the diverse ways in which pain functions. Here, we focus on what is known about the angiotensins in pathological pain and describe the ongoing attempts to identify candidate modulators of clinical significance. Systemic angiotensin agonists and antagonists have effects in a number of neuropathic ailments, including some of the most medically intractable conditions, such as endocrine disorders, cancer, myopathies, and viral infections (such as COVID-19), apart from direct damage to the nervous system. These arise due to multiple physiological processes involving both neural and nonneural pathways that could be overcome with future research. In summary, it is clear that the angiotensins acting through their different receptors exercise both algesic and analgesic effects, but less clear how this diversity of responses arises. © 2023 Elsevier Inc. All rights reserved.

Cumulative effects of air pollution and climate drivers on COVID-19 multiwaves in Bucharest, Romania.

Over more than two years of global health crisis due to ongoing COVID-19 pandemic, Romania experienced a five-wave pattern. This study aims to assess the potential impact of environmental drivers on COVID-19 transmission in Bucharest, capital of Romania during the analyzed epidemic period. Through descriptive statistics and cross-correlation tests applied to time series of daily observational and geospatial data of major outdoor inhalable particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5) or ≤ 10 µm (PM10), nitrogen dioxide (NO2), ozone (O3), sulfur dioxide (SO2), carbon monoxide (CO), Aerosol Optical Depth at 550 nm (AOD) and radon (222Rn), we investigated the COVID-19 waves patterns under different meteorological conditions. This study examined the contribution of individual climate variables on the ground level air pollutants concentrations and COVID-19 disease severity. As compared to the long-term average AOD over Bucharest from 2015 to 2019, for the same year periods, this study revealed major AOD level reduction by ~28 % during the spring lockdown of the first COVID-19 wave (15 March 2020-15 May 2020), and ~16 % during the third COVID-19 wave (1 February 2021-1 June 2021). This study found positive correlations between exposure to air pollutants PM2.5, PM10, NO2, SO2, CO and 222Rn, and significant negative correlations, especially for spring-summer periods between ground O3 levels, air temperature, Planetary Boundary Layer height, and surface solar irradiance with COVID-19 incidence and deaths. For the analyzed time period 1 January 2020-1 April 2022, before and during each COVID-19 wave were recorded stagnant synoptic anticyclonic conditions favorable for SARS-CoV-2 virus spreading, with positive Omega surface charts composite average (Pa/s) at 850 mb during fall- winter seasons, clearly evidenced for the second, the fourth and the fifth waves. These findings are relevant for viral infections controls and health safety strategies design in highly polluted urban environments.

Organoid technology and lung injury mouse models evaluating effects of hydroxychloroquine on lung epithelial regeneration.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) damages lung epithelial stem/progenitor cells. Ideal anti-SARS-CoV-2 drug candidates should be screened to prevent secondary injury to the lungs. Here, we propose that in vitro three-dimensional organoid and lung injury repair mouse models are powerful models for the screening antiviral drugs. Lung epithelial progenitor cells, including airway club cells and alveolar type 2 (AT2) cells, were co-cultured with supportive fibroblast cells in transwell inserts. The organoid model was used to evaluate the possible effects of hydroxychloroquine, which is administered as a symptomatic therapy to the coronavirus disease 2019 (COVID-19) patients, on the function of mouse lung stem/progenitor cells. Hydroxychloroquine was observed to promote the self-renewal of club cells and differentiation of ciliated and goblet cells in vitro. Additionally, it inhibited the self-renewal ability of AT2 cells in vitro. Naphthalene- or bleomycin-induced lung injury repair mouse models were used to investigate the in vivo effects of hydroxychloroquine on the regeneration of club and AT2 cells, respectively. The naphthalene model indicated that the proliferative ability and differentiation potential of club cells were unaffected in the presence of hydroxychloroquine. The bleomycin model suggested that hydroxychloroquine had a limited effect on the proliferation and differentiation abilities of AT2 cells. These findings suggest that hydroxychloroquine has limited effects on the regenerative ability of epithelial stem/progenitor cells. Thus, stem/progenitor cell-derived organoid technology and lung epithelial injury repair mouse models provide a powerful platform for drug screening, which could possibly help end the pandemic.

A New Immortalized Human Alveolar Epithelial Cell Model to Study Lung Injury and Toxicity on a Breathing Lung-On-Chip System.

The evaluation of inhalation toxicity, drug safety and efficacy assessment, as well as the investigation of complex disease pathomechanisms, are increasingly relying on in vitro lung models. This is due to the progressive shift towards human-based systems for more predictive and translational research. While several cellular models are currently available for the upper airways, modelling the distal alveolar region poses several constraints that make the standardization of reliable alveolar in vitro models relatively difficult. In this work, we present a new and reproducible alveolar in vitro model, that combines a human derived immortalized alveolar epithelial cell line (AXiAEC) and organ-on-chip technology mimicking the lung alveolar biophysical environment (AXlung-on-chip). The latter mimics key features of the in vivo alveolar milieu: breathing-like 3D cyclic stretch (10% linear strain, 0.2 Hz frequency) and an ultrathin, porous and elastic membrane. AXiAECs cultured on-chip were characterized for their alveolar epithelial cell markers by gene and protein expression. Cell barrier properties were examined by TER (Transbarrier Electrical Resistance) measurement and tight junction formation. To establish a physiological model for the distal lung, AXiAECs were cultured for long-term at air-liquid interface (ALI) on-chip. To this end, different stages of alveolar damage including inflammation (via exposure to bacterial lipopolysaccharide) and the response to a profibrotic mediator (via exposure to Transforming growth factor ß1) were analyzed. In addition, the expression of relevant host cell factors involved in SARS-CoV-2 infection was investigated to evaluate its potential application for COVID-19 studies. This study shows that AXiAECs cultured on the AXlung-on-chip exhibit an enhanced in vivo-like alveolar character which is reflected into: 1) Alveolar type 1 (AT1) and 2 (AT2) cell specific phenotypes, 2) tight barrier formation (with TER above 1,000 Ω cm2) and 3) reproducible long-term preservation of alveolar characteristics in nearly physiological conditions (co-culture, breathing, ALI). To the best of our knowledge, this is the first time that a primary derived alveolar epithelial cell line on-chip representing both AT1 and AT2 characteristics is reported. This distal lung model thereby represents a valuable in vitro tool to study inhalation toxicity, test safety and efficacy of drug compounds and characterization of xenobiotics.

Applying Advanced Wireless Network Cluster-Tree Topology to Optimize Covid-19 Sanitary Passport Blockchain-Based Security in a Constrained IoT Platform

Our work revolves around creating and developing a medical platform that acts on the citizen’s right to access a public space by differentiating between vaccinated and those who have done the PCR test to avoid the fast spread of the covid-19 virus. In this scope, three algorithms were applied to complete this platform: the first one serves to verify the citizens who are vaccinated, the second allows to see and check the validity of the PCR test for people who are not vaccinated, and, finally, the third algorithm serves to check the temperature and the identity of citizens. This last algorithm is applied when the citizen is not vaccinated or does not have the PCR test. For this project, we used four IoT nodes to run our platform in real time: a Passive infrared (PIR) client node, a temperature sensor, a RFID tag, and a camera client node. We also used artificial intelligence for facial recognition, which will allow us to verify the citizen’s identity. We applied the Constrained Application Protocol to ensure a fluid communication between the platform’s nodes, the integrity, and the confidentiality of the data shared. We secured payloads with two encryption algorithms which are Advanced Encryption Standard (AES)-Secure Hash Algorithm (SHA) 256-bit and Rivest Shamir Adleman (RSA)-SHA256. The security of the database’s information is also an important aspect;thus, the use of the AT2 blockchain will allow us to strengthen the security of the database against any network attack. As for the network topology, we have opted for the cluster-tree topology, and that is after a study that showed us it is the best in terms of execution time, memory occupation, and energy consumption and even for the reliability of the communication. © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.

Drugs Modulating Renin-Angiotensin System in COVID-19 Treatment.

A massive worldwide vaccination campaign constitutes the main tool against the COVID-19 pandemic. However, drug treatments are also necessary. Antivirals are the most frequently considered treatments. However, strategies targeting mechanisms involved in disease aggravation may also be effective. A major role of the tissue renin-angiotensin system (RAS) in the pathophysiology and severity of COVID-19 has been suggested. The main link between RAS and COVID-19 is angiotensin-converting enzyme 2 (ACE2), a central RAS component and the primary binding site for SARS-CoV-2 that facilitates the virus entry into host cells. An initial suggestion that the susceptibility to infection and disease severity may be enhanced by angiotensin type-1 receptor blockers (ARBs) and ACE inhibitors (ACEIs) because they increase ACE2 levels, led to the consideration of discontinuing treatments in thousands of patients. More recent experimental and clinical data indicate that ACEIs and, particularly, ARBs can be beneficial for COVID-19 outcome, both by reducing inflammatory responses and by triggering mechanisms (such as ADAM17 inhibition) counteracting viral entry. Strategies directly activating RAS anti-inflammatory components such as soluble ACE2, Angiotensin 1-7 analogues, and Mas or AT2 receptor agonists may also be beneficial. However, while ACEIs and ARBs are cheap and widely used, the second type of strategies are currently under study.

Non-invasive administration of AAV to target lung parenchymal cells and develop SARS-CoV-2-susceptible mice.

Adeno-associated virus (AAV)-mediated gene delivery holds great promise for gene therapy. However, the non-invasive delivery of AAV for lung tissues has not been adequately established. Here, we revealed that the intratracheal administration of an appropriate amount of AAV2/8 predominantly targets lung tissue. AAV-mediated gene delivery that we used in this study induced the expression of the desired protein in lung parenchymal cells, including alveolar type II cells. We harnessed the technique to develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-susceptible mice. Three kinds of immune function-relevant gene knockout (KO) mice were transduced with AAV encoding human angiotensin-converting enzyme 2 (hACE2) and then injected with SARS-CoV-2. Among these mice, type I interferon receptor (IFNAR) KO mice showed increased viral titer in the lungs compared to that in the other KO mice. Moreover, nucleocapsid protein of SARS-CoV-2 and multiple lesions in the trachea and lung were observed in AAV-hACE2-transduced, SARS-CoV-2-infected IFNAR KO mice, indicating the involvement of type I interferon signaling in the protection of SARS-CoV-2. In this study, we demonstrate the ease and rapidness of the intratracheal administration of AAV for targeting lung tissue in mice, and this can be used to study diverse pulmonary diseases.

Differentiation of immortalized human multi-lineage progenitor to alveolar type 2-like cells: angiotensin-converting enzyme 2 expression and binding of severe acute respiratory syndrome coronavirus 2 spike and spike 1 proteins.

Along with the nasal epithelium, the lung epithelium is a portal of entry for sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and many other respiratory viruses. In the case of SARS-CoV-2, the virus surface spike proteins bind to the angiotensin-converting enzyme 2 (ACE-2) receptor to facilitate entry into the respiratory epithelium. Alveolar type 2 (AT2) cells are committed respiratory progenitor cells responsible for the integrity and regeneration of the respiratory epithelium and production of respiratory surfactant proteins. AT2 cells express high levels of surface ACE-2 and thus are a leading target for primary infection by SARS-CoV-2. This study describes a method for directly differentiating telomerase reverse transcriptase-immortalized human cord blood-derived multi-lineage progenitor cells (MLPCs) to AT2-like cells for the purpose of generating an in vitro cellular platform for viral studies. Differentiation was confirmed with the acquisition of AT2 and absence of alveolar type 1 (AT1) specific markers by confocal microscopy. Expression of the ACE-2 receptor was confirmed by immunofluorescence antibody staining, quantitative reverse transcription polymerase chain reaction and binding of biotinylated SARS-CoV-2 spike and spike 1 proteins. The binding of biotinylated spike proteins was specifically blocked by unlabeled spike proteins and neutralizing antibodies. Additionally, it was demonstrated that the spike protein was internalized after binding to the surface membrane of the cells. The authors defined the culture conditions that enabled AT2-like cells to be repeatedly passaged and cryopreserved without further differentiation to AT1. The authors' method provides a stable and renewable source of AT2 cells for respiratory viral binding, blocking and uptake studies.

Adult stem cell-derived complete lung organoid models emulate lung disease in COVID-19.

Background: SARS-CoV-2, the virus responsible for COVID-19, causes widespread damage in the lungs in the setting of an overzealous immune response whose origin remains unclear. Methods: We present a scalable, propagable, personalized, cost-effective adult stem cell-derived human lung organoid model that is complete with both proximal and distal airway epithelia. Monolayers derived from adult lung organoids (ALOs), primary airway cells, or hiPSC-derived alveolar type II (AT2) pneumocytes were infected with SARS-CoV-2 to create in vitro lung models of COVID-19. Results: Infected ALO monolayers best recapitulated the transcriptomic signatures in diverse cohorts of COVID-19 patient-derived respiratory samples. The airway (proximal) cells were critical for sustained viral infection, whereas distal alveolar differentiation (AT2→AT1) was critical for mounting the overzealous host immune response in fatal disease; ALO monolayers with well-mixed proximodistal airway components recapitulated both. Conclusions: Findings validate a human lung model of COVID-19, which can be immediately utilized to investigate COVID-19 pathogenesis and vet new therapies and vaccines. Funding: This work was supported by the National Institutes for Health (NIH) grants 1R01DK107585-01A1, 3R01DK107585-05S1 (to SD); R01-AI141630, CA100768 and CA160911 (to PG) and R01-AI 155696 (to PG, DS and SD); R00-CA151673 and R01-GM138385 (to DS), R01- HL32225 (to PT), UCOP-R00RG2642 (to SD and PG), UCOP-R01RG3780 (to P.G. and D.S) and a pilot award from the Sanford Stem Cell Clinical Center at UC San Diego Health (P.G, S.D, D.S). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists. L.C.A's salary was supported in part by the VA San Diego Healthcare System. This manuscript includes data generated at the UC San Diego Institute of Genomic Medicine (IGC) using an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929).

Association of serum KL-6 levels on COVID-19 severity: A cross-sectional study design with purposive sampling.

BACKGROUND: The main target of SARS-CoV2 is the alveolar type II (AT2) cells of the lung. SARS-CoV2 evades the innate immune system resulting in the release of proinflammatory cytokines (IL-1ß, IL-6, TNF-α) which causes AT2 cell damage. Krebs von den Lungen (KL-6) is a specific biomarker of AT2 cell damage. KL-6 is produced in AT2 cells that are injured/regenerated. OBJECTIVE: Research that discusses the role of KL-6 in COVID-19 is still being debated and not much has been done in Indonesia. METHODS: This study was an analytical study with a prospective design on 75 COVID-19 patients who were treated. Subjects were divided into two large groups according to their degree of severity, 57 subjects with severe degrees and 18 subjects with non-severe degrees. The serum KL-6 levels were measured on days 0 and 6. Data were analyzed using paired t-test and independent t-test for data were normally distributed and Wilcoxon test and Mann Whitney test for data that were not normally distributed. RESULT: In this study, the mean serum KL-6 for day 0 in the severe group was higher than the non-severe group with values of 45.70 U/mL and 44.85 U/mL. On day 6, the mean serum KL-6 in the severe group was lower than that in the non-severe group with values of 41.3 U/mL and 41.95 U/mL. Serum KL-6 in the severe group experienced an even greater decrease than the non-severe group. CONCLUSION: There was no significant association between serum KL-6 values on 0 days in the severity of COVID-19.

RAAS, ACE2 and COVID-19; a mechanistic review.

The use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in coronavirus disease 2019 (COVID-19) patients has been claimed as associated with the risk of COVID-19 infection and its subsequent morbidities and mortalities. These claims were resulting from the possibility of upregulating the expression of angiotensin-converting enzyme 2 (ACE2), facilitation of SARS-CoV-2 entry, and increasing the susceptibility of infection in such treated cardiovascular patients. ACE2 and renin-angiotensin-aldosterone system (RAAS) products have a critical function in controlling the severity of lung injury, fibrosis, and failure following the initiation of the disease. This review is to clarify the mechanisms beyond the possible deleterious effects of angiotensin II (Ang II), and the potential protective role of angiotensin 1-7 (Ang 1-7) against pulmonary fibrosis, with a subsequent discussion of the latest updates on ACEIs/ARBs use and COVID-19 susceptibility in the light of these mechanisms and biochemical explanation.

Suppression of Inflammatory Cardiac Cytokine Network in Rats with Untreated Obesity and Pre-Diabetes by AT2 Receptor Agonist NP-6A4.

Obesity affects over 42% of the United States population and exacerbates heart disease, the leading cause of death in men and women. Obesity also increases pro-inflammatory cytokines that cause chronic tissue damage to vital organs. The standard-of-care does not sufficiently attenuate these inflammatory sequelae. Angiotensin II receptor AT2R is an anti-inflammatory and cardiovascular protective molecule; however, AT2R agonists are not used in the clinic to treat heart disease. NP-6A4 is a new AT2R peptide agonist with an FDA orphan drug designation for pediatric cardiomyopathy. NP-6A4 increases AT2R expression (mRNA and protein) and nitric oxide generation in human cardiovascular cells. AT2R-antagonist PD123319 and AT2RSiRNA suppress NP-6A4-effects indicating that NP-6A4 acts through AT2R. To determine whether NP-6A4 would mitigate cardiac damage from chronic inflammation induced by untreated obesity, we investigated the effects of 2-weeks NP-6A4 treatment (1.8 mg/kg delivered subcutaneously) on cardiac pathology of male Zucker obese (ZO) rats that display obesity, pre-diabetes and cardiac dysfunction. NP-6A4 attenuated cardiac diastolic and systolic dysfunction, cardiac fibrosis and cardiomyocyte hypertrophy, but increased myocardial capillary density. NP-6A4 treatment suppressed tubulointerstitial injury marker urinary ß-NAG, and liver injury marker alkaline phosphatase in serum. These protective effects of NP-6A4 occurred in the presence of obesity, hyperinsulinemia, hyperglycemia, and hyperlipidemia, and without modulating blood pressure. NP-6A4 increased expression of AT2R (consistent with human cells) and cardioprotective erythropoietin (EPO) and Notch1 in ZO rat heart, but suppressed nineteen inflammatory cytokines. Cardiac miRNA profiling and in silico analysis showed that NP-6A4 activated a unique miRNA network that may regulate expression of AT2R, EPO, Notch1 and inflammatory cytokines, and mitigate cardiac pathology. Seventeen pro-inflammatory and pro-fibrotic cytokines that increase during lethal cytokine storms caused by infections such as COVID-19 were among the cytokines suppressed by NP-6A4 treatment in ZO rat heart. Thus, NP-6A4 activates a novel anti-inflammatory network comprised of 21 proteins in the heart that was not reported previously. Since NP-6A4's unique mode of action suppresses pro-inflammatory cytokine network and attenuates myocardial damage, it can be an ideal adjuvant drug with other anti-glycemic, anti-hypertensive, standard-of-care drugs to protect the heart tissues from pro-inflammatory and pro-fibrotic cytokine attack induced by obesity.

Binding of the SARS-CoV-2 Spike Protein to the Asialoglycoprotein Receptor on Human Primary Hepatocytes and Immortalized Hepatocyte-Like Cells by Confocal Analysis.

BACKGROUND: The SARS-CoV-2 virus may have direct or indirect effects on other human organs beyond the respiratory system and including the liver, via binding of the spike protein. This study investigated the potential direct interactions with the liver by comparing the binding of SARS-CoV-2 spike proteins to human AT2-like cells, primary human hepatocytes and immortalized hepatocyte-like hybrid cells. Receptors with binding specificity for SARS-CoV-2 spike protein on AT2 cells and hepatocytes were identified. METHODS: The specific binding of biotinylated spike and spike 1 proteins to undifferentiated human E12 MLPC (E12), E12 differentiated alveolar type 2 (AT2) cells, primary human hepatocytes (PHH) and E12 human hepatocyte-like hybrid cells (HLC) was studied by confocal microscopy. We investigated the expression of ACE-2, binding of biotinylated spike protein, biotinylated spike 1 and inhibition of binding by unlabeled spike protein, two neutralizing antibodies and an antibody directed against the hepatocyte asialoglycoprotein receptor 1 (ASGr1). RESULTS: E12 MLPC did not express ACE-2 and did not bind either of spike or spike 1 proteins. AT2-like cells expressed ACE-2 and bound both spike and spike 1. Both PHH and HLC did not express ACE-2 and did not bind spike 1 protein. However, both PHH and HLC actively bound the spike protein. Biotinylated spike protein binding was inhibited by unlabeled spike but not spike 1 protein on PHH and HLC. Two commercial neutralizing antibodies blocked the binding of the spike to PHH and HLC but only one blocked binding to AT2. An antibody to the hepatocyte ASGr1 blocked the binding of the spike protein to PHH and HLC. CONCLUSION: The absence of ACE-2 receptors and inhibition of spike binding by an antibody to the ASGr1 on both PHH and HLC suggested that the spike protein interacts with the ASGr1. The differential antibody blocking of spike binding to AT2, PHH and HLC indicated that neutralizing activity of SARS-CoV-2 binding might involve additional mechanisms beyond RBD binding to ACE-2.

Strengthening CoViD-19 therapy via combinations of RAS modulators.

Evidence has accumulated that the pathology of CoViD-19 is strongly related to the renin-angiotensin system (RAS). The blockage of the angiotensin converting enzyme 2 (ACE2) by the SARS-CoV-2 virus leads to downstream consequences such as increased vascular tone, extensive fibrosis and pronounced immune reactions. Different approaches to tackle the adverse viral effects by compensating the lost ACE2 function have been suggested. Here, we use an unequal-arm lever model to describe a simplified version of the biased regulation exercised by the angiotensin II and angiotensin-(1-7) hormones, which are the substrate and the product of ACE2, respectively. We reason upon the lever dynamics and its disruptions caused by the virus, and propose that a combination of RAS modulators will most efficiently compensate the imbalance due to the excess of angiotensin II and the scarcity of angiotensin-(1-7). Specifically, we focus on the possible benefits of the simultaneous application of two agents, a MAS-receptor agonist and an angiotensin-II-type-2-receptor agonist. We conjecture that this combination has the potential to introduce a beneficial synergistic action that promotes anti-hypoxic, anti-fibrotic and anti-proliferative effects, thereby improving the clinical management of acute and chronic CoViD-19 pathologies.

Correcting the imbalanced protective RAS in COVID-19 with angiotensin AT2-receptor agonists.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is responsible for the global corona virus disease 2019 (COVID-19) pandemic enters host cells via a mechanism that includes binding to angiotensin converting enzyme (ACE) 2 (ACE2). Membrane-bound ACE2 is depleted as a result of this entry mechanism. The consequence is that the protective renin-angiotensin system (RAS), of which ACE2 is an essential component, is compromised through lack of production of the protective peptides angiotensin-(1-7) and angiotensin-(1-9), and therefore decreased stimulation of Mas (receptor Mas) and angiotensin AT2-receptors (AT2Rs), while angiotensin AT1-receptors (AT1Rs) are overstimulated due to less degradation of angiotensin II (Ang II) by ACE2. The protective RAS has numerous beneficial actions, including anti-inflammatory, anti-coagulative, anti-fibrotic effects along with endothelial and neural protection; opposite to the deleterious effects caused by heightened stimulation of angiotensin AT1R. Given that patients with severe COVID-19 exhibit an excessive immune response, endothelial dysfunction, increased clotting, thromboses and stroke, enhancing the activity of the protective RAS is likely beneficial. In this article, we discuss the evidence for a dysfunctional protective RAS in COVID and develop a rationale that the protective RAS imbalance in COVID-19 may be corrected by using AT2R agonists. We further review preclinical studies with AT2R agonists which suggest that AT2R stimulation may be therapeutically effective to treat COVID-19-induced disorders of various organ systems such as lung, vasculature, or the brain. Finally, we provide information on the design of a clinical trial in which patients with COVID-19 were treated with the AT2R agonist Compound 21 (C21). This trial has been completed, but results have not yet been reported.

Identifying potential anti-COVID-19 pharmacological components of traditional Chinese medicine Lianhuaqingwen capsule based on human exposure and ACE2 biochromatography screening.

Lianhuaqingwen (LHQW) capsule, a herb medicine product, has been clinically proved to be effective in coronavirus disease 2019 (COVID-19) pneumonia treatment. However, human exposure to LHQW components and their pharmacological effects remain largely unknown. Hence, this study aimed to determine human exposure to LHQW components and their anti-COVID-19 pharmacological activities. Analysis of LHQW component profiles in human plasma and urine after repeated therapeutic dosing was conducted using a combination of HRMS and an untargeted data-mining approach, leading to detection of 132 LHQW prototype and metabolite components, which were absorbed via the gastrointestinal tract and formed via biotransformation in human, respectively. Together with data from screening by comprehensive 2D angiotensin-converting enzyme 2 (ACE2) biochromatography, 8 components in LHQW that were exposed to human and had potential ACE2 targeting ability were identified for further pharmacodynamic evaluation. Results show that rhein, forsythoside A, forsythoside I, neochlorogenic acid and its isomers exhibited high inhibitory effect on ACE2. For the first time, this study provides chemical and biochemical evidence for exploring molecular mechanisms of therapeutic effects of LHQW capsule for the treatment of COVID-19 patients based on the components exposed to human. It also demonstrates the utility of the human exposure-based approach to identify pharmaceutically active components in Chinese herb medicines.

Does activation of the protective Renin-Angiotensin System have therapeutic potential in COVID-19?

Infection of lung cells by the corona virus results in a loss of the balance between, on the one hand, angiotensin II-mediated stimulation of the angiotensin II type 1 receptor and, on the other hand, stimulation of the angiotensin II type 2 receptor and/or the Mas receptor. The unbalanced enhanced stimulation of the angiotensin II type 1 receptor causes inflammation, edema and contributes to the pathogenesis of severe acute respiratory distress syndrome. Here we hypothesize that stable, receptor-specific agonists of the angiotensin II type 2 receptor and of the Mas receptor are molecular medicines to treat COVID-19 patients. These agonists have therapeutic potential in the acute disease but in addition may reduce COVID-19-associated long-term pulmonary dysfunction and overall end-organ damage of this disease.

Association of high level gene expression of ACE2 in adipose tissue with mortality of COVID-19 infection in obese patients.

INTRODUCTION: Obese patients have an increased risk of COVID-19 critical illness leading to ICU admission or death compared to normal weight individuals. SARS-CoV-2 binding to angiotensin-converting enzyme 2 (ACE2) receptor is a critical step mediate virus entry into target cells. Articles have alluded that the level of ACE2 gene expression in adipose tissue is higher than lung tissue, but a PubMed search found no results in articles to demonstrate this. The aim of this study was to investigate ACE2 gene expression in adipose tissue and lung tissue using a public database. MATERIAL AND METHODS: A search of a public gene expression database to investigate ACE2 gene expression in human tissues. RESULTS: ACE2 gene expression was present in both visceral and subcutaneous adipose tissues. The gene expression profile demonstrated that ACE2 gene expression was higher in human visceral and subcutaneous adipose tissues than human lung tissue. CONCLUSION: This study demonstrates that ACE2 gene expression is higher in visceral and subcutaneous adipose tissue than that in lung tissue, a major target tissue affected by SARS-CoV-2 infection. This suggests a mechanism by which excess adiposity may drive greater infection severity in patients with COVID-19.

Role of the Backbenchers of the Renin-Angiotensin System ACE2 and AT2 Receptors in COVID-19: Lessons From SARS.

The novel coronaviruses causing severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19) have been shown to utilize angiotensin-converting enzyme 2 (ACE2) as the receptor for entry into the host cells. The involvement of the renin-angiotensin system (RAS) in the evolution and pathogenesis of lung diseases has been implicated in recent years. The two enzymes of RAS, angiotensin-converting enzyme (ACE) and ACE2, serve a contrasting function. ACE helps in the formation of angiotensin II (AGII) from angiotensin I (AGI), and ACE2 cleaves AGI and AGII into AG (1-9) and AG (1-7) respectively. The ACE-induced AGII has vasoconstrictor and pro-inflammatory properties via AT1R, whereas ACE2 has been shown to protect against lung injury. The less spoken about AGII receptor, angiotensin receptor type 2 (AT2R), has anti-inflammatory and anti-fibrotic effects in lung tissue and may be of significance in light of the lung pathology presentation in COVID-19. A review of articles searched in PubMed and peer-reviewed journals of importance was done using search terms "ACE2," "AT2," "SARS," and COVID-19." Lung involvement in both SARS and COVID-19 has been very severe and suggestive of severe inflammatory and immune reactions. Animal studies have shown that ACE2 and AT2 receptors counter the pro-inflammatory and other effects mediated by angiotensin II by their vasodilator, anti-inflammatory, anti-fibrotic, and anti-proliferative effects. They have been shown to protect against and revert acute lung injuries. The instrumental role of recombinant ACE2, AT2 receptor agonists, and AT1 receptor blockers may be helpful in the treatment of COVID-19.

The Network of Angiotensin Receptors in Breast Cancer.

The renin-angiotensin system (RAS) is a network of proteins regulating many aspects of human physiology, including cardiovascular, pulmonary, and immune system physiology. The RAS is a complicated network of G-protein coupled receptors (GPCRs) (i.e., AT1R, AT2R, MASR, and MRGD) orchestrating the effects of several hormones (i.e., angiotensin II, angiotensin (1-7), and alamandine) produced by protease-based transmembrane receptors (ACE1 and ACE2). Two signaling axes have been identified in the RAS endocrine system that mediate the proliferative actions of angiotensin II (i.e., the AT1R-based pathway) or the anti-proliferative effects of RAS hormones (i.e., the AT2R-, MAS-, and MRGD-based pathways). Disruption of the balance between these two axes can cause different diseases (e.g., cardiovascular pathologies and the severe acute respiratory syndrome coronavirus 2- (SARS-CoV-2)-based COVID-19 disease). It is now accepted that all the components of the RAS endocrine system are expressed in cancer, including cancer of the breast. Breast cancer (BC) is a multifactorial pathology for which there is a continuous need to identify novel drugs. Here, I reviewed the possible roles of both axes of the RAS endocrine network as potential druggable pathways in BC. Remarkably, the analysis of the current knowledge of the different GPCRs of the RAS molecular system not only confirms that AT1R could be considered a drug target and that its inhibition by losartan and candesartan could be useful in the treatment of BC, but also identifies Mas-related GPCR member D (MRGD) as a druggable protein. Overall, the RAS of GPCRs offers multifaceted opportunities for the development of additional compounds for the treatment of BC.