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1.
BMC Infect Dis ; 24(1): 663, 2024 Jul 03.
Article in English | MEDLINE | ID: mdl-38956476

ABSTRACT

BACKGROUND: Severe COVID-19 is uncommon, restricted to 19% of the total population. In response to the first virus wave (alpha variant of SARS-CoV-2), we investigated whether a biomarker indicated severity of disease and, in particular, if variable expression of angiotensin converting enzyme 2 (ACE2) in blood might clarify this difference in risk and of post COVID -19 conditions (PCC). METHODS: The IRB-approved study compared patients hospitalized with severe COVID-19 to healthy controls. Severe infection was defined requiring oxygen or increased oxygen need from baseline at admission with positive COVID-19 PCR. A single blood sample was obtained from patients within a day of admission. ACE2 RNA expression in blood cells was measured by an RT-PCR assay. Plasma ACE1 and ACE2 enzyme activities were quantified by fluorescent peptides. Plasma TIMP-1, PIIINP and MMP-9 antigens were quantified by ELISA. Data were entered into REDCap and analyzed using STATA v 14 and GraphPad Prism v 10. RESULTS: Forty-eight patients and 72 healthy controls were recruited during the pandemic. ACE2 RNA expression in peripheral blood mononuclear cells (PBMC) was rarely detected acutely during severe COVID-19 but common in controls (OR for undetected ACE2: 12.4 [95% CI: 2.62-76.1]). ACE2 RNA expression in PBMC did not determine plasma ACE1 and ACE2 activity, suggesting alternative cell-signaling pathways. Markers of fibrosis (TIMP-1 and PIIINP) and vasculopathy (MMP-9) were additionally elevated. ACE2 RNA expression during severe COVID-19 often responded within hours to convalescent plasma. Analogous to oncogenesis, we speculate that potent, persistent, cryptic processes following COVID-19 (the renin-angiotensin system (RAS), fibrosis and vasculopathy) initiate or promote post-COVID-19 conditions (PCC) in susceptible individuals. CONCLUSIONS: This work elucidates biological and temporal plausibility for ACE2, TIMP1, PIIINP and MMP-9 in the pathogenesis of PCC. Intersection of these independent systems is uncommon and may in part explain the rarity of PCC.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Leukocytes, Mononuclear , SARS-CoV-2 , Humans , COVID-19/blood , Angiotensin-Converting Enzyme 2/blood , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Male , Female , Middle Aged , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/virology , Aged , Adult , Biomarkers/blood , Tissue Inhibitor of Metalloproteinase-1/blood , Tissue Inhibitor of Metalloproteinase-1/genetics , Matrix Metalloproteinase 9/blood , Matrix Metalloproteinase 9/genetics , Severity of Illness Index , Case-Control Studies , Peptidyl-Dipeptidase A/blood , Peptidyl-Dipeptidase A/genetics
3.
Life Sci ; : 122903, 2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38986897

ABSTRACT

Angiotensin converting enzyme (ACE) is not only a critical component in the renin-angiotensin system (RAS), but also suggested as an important mediator for immune response and activity, such as immune cell mobilization, metabolism, biogenesis of immunoregulatory molecules, etc. The chronic duration of cardiovascular diseases (CVD) has been increasingly considered to be triggered by uncontrolled pathologic immune reactions from myeloid cells and lymphocytes. Considering the potential anti-inflammatory effect of the traditional antihypertensive ACE inhibitor (ACEi), we attempt to elucidate whether ACE and its catalytically relevant substances as well as signaling pathways play a role in the immunity-related pathogenesis of common CVD, such as arterial hypertension, atherosclerosis and arrythmias. ACEi was also reported to benefit the prognoses of COVID-19-positive patients with CVD, and COVID-19 disease with preexisting CVD or subsequent cardiovascular damage is featured by a significant influx of immune cells and proinflammatory molecules, suggesting that ACE may also participate in COVID-19 induced cardiovascular injury, because COVID-19 disease basically triggers an overactive pathologic immune response. Hopefully, the ACE inhibition and manipulation of those associated bioactive signals could supplement the current medicinal management of various CVD and bring greater benefit to patients' cardiovascular health.

4.
Arch Physiol Biochem ; : 1-10, 2024 Jul 10.
Article in English | MEDLINE | ID: mdl-38988137

ABSTRACT

OBJECTIVE: Angiotensin-converting enzyme (ACE, EC 3.4.15.1) is a very important factor in the regulation of blood pressure. Also, the inhibition of ACE with natural compounds has been a very important research area in the treatment of high blood pressure. ACE was purified and characterized from sheep plasma. Molecular docking studies and the inhibition effect of thiamine, riboflavin, and captopril on ACE were investigated. METHODS: Herein, ACE was purified from sheep plasma by affinity chromatography. The effect of thiamine and riboflavin on ACE was researched. Molecular docking studies were performed to understand the molecular interactions between thiamine, riboflavin, and captopril with ACE. RESULTS: The purification coefficient was found to be 8636 fold. The binding energy of thiamine, riboflavin, and captopril was found to be -6.7 kcal/mol, -8.1 kcal/mol, and -5.5 kcal/mol, respectively. Thiamine conformed to three conventional hydrogen bonds with ASP:415, HIS:513, and LYS:454. Riboflavin formed four conventional hydrogen bonds with GLN:281, GLU:376, THR:282, and TYR:520. Captopril formed two conventional hydrogen bonds with ARG:124, one conventional hydrogen bond with TYR:62 and ASN:85, and one carbon-hydrogen bond with ASN:66. Molecular docking results showed that thiamine, riboflavin, and captopril interacted with ACE through hydrogen bonding and hydrophobic interactions. Thiamine and riboflavin indicated significant inhibition effects on ACE. The IC50 values of thiamine, riboflavin, and captopril were found as 960.56 µM, 11.02 µM, and 1.60 nM, respectively. Ki values for thiamine, riboflavin, and captopril were determined as 1352.04 µM, 12.30 µM, and 1.06 nM, respectively. CONCLUSION: In this work, it was concluded that thiamine and riboflavin may have preventive and therapeutical impacts against high blood pressure with their ACE inhibitor effect. Thiamine and riboflavin showed a lower inhibitory effect with a higher IC50 than captopril. However, when the inhibitory effect of thiamine and riboflavin vitamins is compared to captopril, it is concluded that they may be natural inhibitors with fewer side effects.

5.
Article in English | MEDLINE | ID: mdl-38967213

ABSTRACT

BACKGROUND AND AIM: Inflammatory bowel disease is challenging to diagnose. Fecal biomarkers offer noninvasive solutions. The renin-angiotensin-aldosterone system is implicated in intestinal inflammation. Angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) regulate its activity, but conflicting findings on these enzymes in colitis require further investigation. We aimed to assess ACE and ACE2 presence and activities in the feces, serum, and colon of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced rats. METHODS: Colitis was induced in male rats by rectal instillation of a 21% ethanolic TNBS solution. After rats' sacrifice, colonic portions, serum, and feces were collected. ACE and ACE2 presence in the feces was analyzed by western Blot, and colonic and serum enzymes' concentrations were quantified using ELISA kits. ACE activity was assessed using Hippuryl-His-Leu and Z-Phe-His-Leu as substrates. ACE2 activity was assessed using Mca-APK (Dnp) as a substrate in the presence and absence of DX600 (ACE2 inhibitor). RESULTS: An ACE isoform of ~70 kDa was found only in the feces of TNBS-induced rats. ACE concentration was higher than that of ACE2 in the serum and the inflamed colon. ACE N-domain activity was higher than that of the C-domain in all matrices. ACE2 activity was higher in the feces of TNBS-induced animals compared to controls. CONCLUSION: A 70 kDa ACE isoform only detected in the feces of TNBS-induced rats may have translational relevance. ACE N-domain seems to play a significant role in regulating colonic lesions. Further research using human samples is necessary to validate these findings.

6.
Cureus ; 16(6): e61732, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38975413

ABSTRACT

This case report details a rare presentation of diffuse scleroderma, where a 38-year-old female developed hypertensive encephalopathy due to scleroderma renal crisis (SRC). SRC, characterized by sudden severe hypertension and renal failure, poses a life-threatening emergency. The patient's clinical features, including skin changes and abnormalities on nailfold capillaroscopy, facilitated the diagnosis of diffuse scleroderma. Comprehensive diagnostic investigations revealed multisystem involvement. Management involved angiotensin-converting enzyme inhibitors, hydroxychloroquine, and packed red cell transfusions, highlighting a holistic therapeutic approach. This case underscores the importance of recognizing diverse scleroderma manifestations in hypertensive emergencies for timely intervention and improved outcomes.

7.
Article in English | MEDLINE | ID: mdl-38958827

ABSTRACT

The increasing aging of the population combined with improvements in cancer detection and care has significantly improved the survival and quality of life of cancer patients. These benefits are hampered by the increase of cardiovascular diseases being heart failure the most frequent manifestation of cardiotoxicity and becoming the major cause of morbidity and mortality among cancer survivor. Current strategies to prevent cardiotoxicity involves different approaches such as optimal management of CV risk factors, use of statins and/or neurohormonal medications, and, in some cases, even the use of chelating agents. As a class, SGLT2-i have revolutionized the therapeutic horizon of HF patients independently of their ejection fraction or glycemic status. There is an abundance of data from translational and observational clinical studies supporting a potential beneficial role of SGLT2-i in mitigating the cardiotoxic effects of cancer patients receiving anthracyclines. These findings underscore the need for more robust clinical trials to investigate the effect on cardiovascular outcomes of the prophylactic SGLT2-i treatment in patients undergoing cancer treatment.

8.
World J Gastroenterol ; 30(22): 2866-2880, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38947288

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by the highly pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily impacts the respiratory tract and can lead to severe outcomes such as acute respiratory distress syndrome, multiple organ failure, and death. Despite extensive studies on the pathogenicity of SARS-CoV-2, its impact on the hepatobiliary system remains unclear. While liver injury is commonly indicated by reduced albumin and elevated bilirubin and transaminase levels, the exact source of this damage is not fully understood. Proposed mechanisms for injury include direct cytotoxicity, collateral damage from inflammation, drug-induced liver injury, and ischemia/hypoxia. However, evidence often relies on blood tests with liver enzyme abnormalities. In this comprehensive review, we focused solely on the different histopathological manifestations of liver injury in COVID-19 patients, drawing from liver biopsies, complete autopsies, and in vitro liver analyses. We present evidence of the direct impact of SARS-CoV-2 on the liver, substantiated by in vitro observations of viral entry mechanisms and the actual presence of viral particles in liver samples resulting in a variety of cellular changes, including mitochondrial swelling, endoplasmic reticulum dilatation, and hepatocyte apoptosis. Additionally, we describe the diverse liver pathology observed during COVID-19 infection, encompassing necrosis, steatosis, cholestasis, and lobular inflammation. We also discuss the emergence of long-term complications, notably COVID-19-related secondary sclerosing cholangitis. Recognizing the histopathological liver changes occurring during COVID-19 infection is pivotal for improving patient recovery and guiding decision-making.


Subject(s)
COVID-19 , Liver , SARS-CoV-2 , Humans , COVID-19/complications , COVID-19/pathology , COVID-19/virology , Liver/pathology , Liver/virology , SARS-CoV-2/pathogenicity , Liver Diseases/pathology , Liver Diseases/virology , Liver Diseases/etiology , Hepatocytes/pathology , Hepatocytes/virology
9.
Ethiop J Health Sci ; 34(1): 85-100, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38957334

ABSTRACT

Background: Coronaviruses (CoVs) belong to the RNA viruses family. The viruses in this family are known to cause mild respiratory disease in humans. The origin of the novel SARS-COV2 virus that caused the coronavirus-19 disease (COVID-19) is the Wuhan city in China from where it disseminated to cause a global pandemic. Although lungs are the predominant target organ for Coronavirus Disease-19 (COVID-19), since its outbreak, the disease is known to affect heart, blood vessels, kidney, intestine, liver and brain. This review aimed to summarize the catastrophic impacts of Coronavirus disease-19 on heart and liver along with its mechanisms of pathogenesis. Methods: The information used in this review was obtained from relevant articles published on PubMed, Google Scholar, Google, WHO website, CDC and other sources. Key searching statements and phrases related to COVID-19 were used to retrieve information. Original research articles, review papers, research letters and case reports were used as a source of information. Results: Besides causing severe lung injury, COVID-19 has also been reported to affect and cause dysfunction of many other organs. COVID-19 infection can affect people by downregulating membrane-bound active angiotensin-converting enzyme (ACE). People who have deficient ACE2 expression are more vulnerable to COVID-19 infection. The patients' pre-existing co-morbidities are major risk factors that predispose individuals to severe COVID-19. Conclusion: The disease severity and its broad spectrum phenotype is a result of combined direct and indirect pathogenic factors. Therefore, protocols that harmonize many therapeutic preferences should be the best alternatives to de-escalate the disease and obviate deaths caused as a result of multiple organ damage and dysfunction induced by the disease.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/complications , COVID-19/epidemiology , Liver Diseases/etiology , Liver Diseases/virology , Heart Diseases/etiology , Heart Diseases/virology , Angiotensin-Converting Enzyme 2/metabolism , Liver/pathology , Liver/virology
10.
Bioorg Chem ; 150: 107602, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38959647

ABSTRACT

The binding affinities and interactions between eight drug candidates, both commercially available (candesartan; losartan; losartan carboxylic acid; nirmatrelvir; telmisartan) and newly synthesized benzimidazole-N-biphenyltetrazole (ACC519T), benzimidazole bis-N,N'-biphenyltetrazole (ACC519T(2) and 4-butyl-N,N-bis([2-(2H-tetrazol-5-yl)biphenyl-4-yl]) methyl (BV6), and the active site of angiotensin-converting enzyme-2 (ACE2) were evaluated for their potential as inhibitors against SARS-CoV-2 and regulators of ACE2 function through Density Functional Theory methodology and enzyme activity assays, respectively. Notably, telmisartan and ACC519T(2) exhibited pronounced binding affinities, forming strong interactions with ACE2's active center, favorably accepting proton from the guanidinium group of arginine273. The ordering of candidates by binding affinity and reactivity descriptors, emerged as telmisartan > ACC519T(2) > candesartan > ACC519T > losartan carboxylic acid > BV6 > losartan > nirmatrelvir. Proton transfers among the active center amino acids revealed their interconnectedness, highlighting a chain-like proton transfer involving tyrosine, phenylalanine, and histidine. Furthermore, these candidates revealed their potential antiviral abilities by influencing proton transfer within the ACE2 active site. Furthermore, through an in vitro pharmacological assays we determined that candesartan and the BV6 derivative, 4-butyl-N,N0-bis[20-2Htetrazol-5-yl)bipheyl-4-yl]methyl)imidazolium bromide (BV6(K+)2) also contain the capacity to increase ACE2 functional activity. This comprehensive analysis collectively underscores the promise of these compounds as potential therapeutic agents against SARS-CoV-2 by targeting crucial protein interactions.

11.
Int J Mol Sci ; 25(11)2024 May 21.
Article in English | MEDLINE | ID: mdl-38891786

ABSTRACT

Inflammatory bowel disease (IBD) is a nonspecific chronic inflammatory disease resulting from an immune disorder in the intestine that is prone to relapse and incurable. The understanding of the pathogenesis of IBD remains unclear. In this study, we found that ace (angiotensin-converting enzyme), expressed abundantly in the intestine, plays an important role in IBD. The deletion of ace in zebrafish caused intestinal inflammation with increased expression of the inflammatory marker genes interleukin 1 beta (il1b), matrix metallopeptidase 9 (mmp9), myeloid-specific peroxidase (mpx), leukocyte cell-derived chemotaxin-2-like (lect2l), and chemokine (C-X-C motif) ligand 8b (cxcl8b). Moreover, the secretion of mucus in the ace-/- mutants was significantly higher than that in the wild-type zebrafish, validating the phenotype of intestinal inflammation. This was further confirmed by the IBD model constructed using dextran sodium sulfate (DSS), in which the mutant zebrafish had a higher susceptibility to enteritis. Our study reveals the role of ace in intestinal homeostasis, providing a new target for potential therapeutic interventions.


Subject(s)
Peptidyl-Dipeptidase A , Zebrafish , Animals , Zebrafish/genetics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Disease Models, Animal , Dextran Sulfate , Inflammation/genetics , Inflammation/metabolism , Inflammation/pathology , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolism , Intestines/pathology , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/pathology , Interleukin-1beta/metabolism , Interleukin-1beta/genetics , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology
12.
J Am Heart Assoc ; 13(12): e035215, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38842283

ABSTRACT

BACKGROUND: The effect of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs) on major adverse cardiovascular events (MACE) in patients who undergo coronary artery bypass graft surgery is equivocal. This retrospective, population-based cohort study evaluated effect of exposure to an ACEI/ARB on MACE using linked administrative databases that included all cardiac revascularization procedures, hospitalizations, and prescriptions for the population of British Columbia, Canada. METHODS AND RESULTS: All adults who underwent coronary artery bypass graft surgery between 2002 and 2020 were eligible. The primary outcome was time to MACE, defined as a composite of all-cause death, myocardial infarction, and ischemic stroke using Cox proportional hazards models with inverse probability treatment weighting. Included were 15 439 patients and 6191 (40%) were prescribed an ACEI/ARB. Mean age was 66 years, 83% were men, and 16% had heart failure (HF). Median exposure time was 40 months. Over the 5-year follow-up, 1623 MACE occurred. Impact of exposure was different for patients with and without HF (P <0.0001 for interaction). After probability-weighting and adjustment for relevant covariates, exposure to ACEI/ARBs was associated with a lower hazard of MACE in patients with HF at 1 year (hazard ratio, 0.13 [95% CI, 0.09-0.19]) and 5 years (hazard ratio, 0.36 [95% CI, 0.30-0.44]). In patients without HF, ACEI/ARBs had a lower hazard of MACE at 1 year (hazard ratio, 0.35 [95% CI, 0.27-0.46]) and 5 years (hazard ratio, 0.66 [95% CI, 0.58-0.76]). CONCLUSIONS: In this population-based study, ACEI/ARBs were associated with a lower hazard of MACE in a cohort of patients post-coronary artery bypass graft surgery irrespective of HF status.


Subject(s)
Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , Coronary Artery Bypass , Humans , Coronary Artery Bypass/adverse effects , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Male , Female , Aged , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin Receptor Antagonists/adverse effects , Retrospective Studies , British Columbia/epidemiology , Middle Aged , Coronary Artery Disease/surgery , Coronary Artery Disease/mortality , Treatment Outcome , Risk Factors , Myocardial Infarction/epidemiology , Time Factors , Postoperative Complications/epidemiology
13.
Sci Rep ; 14(1): 13171, 2024 06 07.
Article in English | MEDLINE | ID: mdl-38849492

ABSTRACT

Angiotensin-converting enzyme (ACE) is closely related to cardiometabolic risk factors and atherosclerosis. This study aims to investigate whether the insertion/deletion (I/D) variant of ACE gene impacts cardiometabolic risk factors, premature coronary artery disease (PCAD), and severity of coronary lesions. PubMed, Cochrane Library, Central, CINAHL, and ClinicalTrials.gov were searched until December 22, 2023. 94,270 individuals were included for the analysis. Carriers of DD genotype had higher levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), and waist circumference (WC) than carriers of II or ID genotypes. In addition, carriers of DD genotype were at high risk of PCAD and multiple vessel lesions. The impacts of ACE I/D variant on lipid levels were significant in American individuals but stronger in male individuals. In contrast, the impacts of ACE I/D variant on PCAD and severity of coronary lesions were primarily significant in Caucasian individuals. This study indicates that the ACE I/D variant has a slight but significant impact on cardiometabolic risk factors, PCAD, and severity of coronary lesions. Angiotensin-converting enzyme inhibitors (ACEI) may benefit high-risk populations with ACE DD genotype to prevent PCAD and multiple vessel lesions.PROSPERO registration number: CRD42023426732.


Subject(s)
Cardiometabolic Risk Factors , Coronary Artery Disease , INDEL Mutation , Peptidyl-Dipeptidase A , Humans , Peptidyl-Dipeptidase A/genetics , Coronary Artery Disease/genetics , Male , Female , Blood Pressure , Genetic Predisposition to Disease , Severity of Illness Index , Middle Aged , Genotype , Body Mass Index , Risk Factors , Triglycerides/blood , Adult
14.
Ann Intensive Care ; 14(1): 89, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38877367

ABSTRACT

Recent years have seen a resurgence of interest for the renin-angiotensin-aldosterone system in critically ill patients. Emerging data suggest that this vital homeostatic system, which plays a crucial role in maintaining systemic and renal hemodynamics during stressful conditions, is altered in septic shock, ultimately leading to impaired angiotensin II-angiotensin II type 1 receptor signaling. Indeed, available evidence from both experimental models and human studies indicates that alterations in the renin-angiotensin-aldosterone system during septic shock can occur at three distinct levels: 1. Impaired generation of angiotensin II, possibly attributable to defects in angiotensin-converting enzyme activity; 2. Enhanced degradation of angiotensin II by peptidases; and/or 3. Unavailability of angiotensin II type 1 receptor due to internalization or reduced synthesis. These alterations can occur either independently or in combination, ultimately leading to an uncoupling between the renin-angiotensin-aldosterone system input and downstream angiotensin II type 1 receptor signaling. It remains unclear whether exogenous angiotensin II infusion can adequately address all these mechanisms, and additional interventions may be required. These observations open a new avenue of research and offer the potential for novel therapeutic strategies to improve patient prognosis. In the near future, a deeper understanding of renin-angiotensin-aldosterone system alterations in septic shock should help to decipher patients' phenotypes and to implement targeted interventions.

15.
Virology ; 597: 110149, 2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38917689

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a significant socioeconomic burden, and combating COVID-19 is imperative. Blocking the SARS-CoV-2 RBD-ACE2 interaction is a promising therapeutic approach for viral infections, as SARS-CoV-2 binds to the ACE2 receptors of host cells via the RBD of spike proteins to infiltrate these cells. We used computer-aided drug design technology and cellular experiments to screen for peptide S4 with high affinity and specificity for the human ACE2 receptor through structural analysis of SARS-CoV-2 and ACE2 interactions. Cellular experiments revealed that peptide S4 effectively inhibited SARS-CoV-2 and HCoV-NL63 viruses from infecting host cells and was safe for cells at effective concentrations. Based on these findings, peptide S4 may be a potential pharmaceutical agent for clinical application in the treatment of the ongoing SARS-CoV-2 pandemic.

16.
Article in English | MEDLINE | ID: mdl-38909634

ABSTRACT

BACKGROUND: The Spike protein mutation of SARS-CoV-2 led to decreased protective effect of various vaccines and monoclonal antibodies, suggesting that blocking SARS-CoV-2 infection by targeting host factors would make the therapy more resilient against virus mutations. Angiotensin converting enzyme 2 (ACE2) is the host receptor of SARS-CoV-2 and its variants, as well as many other coronaviruses. Down-regulation of ACE2 expression in the respiratory tract may prevent viral infection. Antisense oligonucleotides (ASOs) can be rationally designed based on sequence data, require no delivery system, and can be administered locally. OBJECTIVE: We sought to design ASOs that can block SARS-CoV-2 by down-regulating ACE2 in human airway. METHODS: ACE2-targeting ASOs were designed using a bioinformatic method and screened in cell lines. Human primary nasal epithelial cells cultured at the air-liquid interface and humanized ACE2 mice were used to detect the ACE2 reduction levels and the safety of ASOs. ASOs pretreated nasal epithelial cells and mice were infected and then used to detect the viral infection levels. RESULTS: ASOs reduced ACE2 expression on mRNA and protein level in cell lines and in human nasal epithelial cells. Furthermore they efficiently suppressed virus replication of three different SARS-CoV-2 variants in human nasal epithelial cells. In vivo, ASOs also down-regulated human ACE2 in humanized ACE2 mice and thereby reduced viral load, histopathological changes in lungs, and they increased survival of mice. CONCLUSION: ACE2-targeting ASOs can effectively block SARS-COV-2 infection. Our study provides a new approach for blocking SARS-CoV-2 and other ACE2-targeting virus in high-risk populations.

17.
ACS Sens ; 9(6): 3158-3169, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38843447

ABSTRACT

An integrated approach combining surface-enhanced Raman spectroscopy (SERS) with a specialized deep learning algorithm to rapidly and accurately detect and quantify SARS-CoV-2 variants is developed based on an angiotensin-converting enzyme 2 (ACE2)-functionalized AgNR@SiO2 array SERS sensor. SERS spectra with concentrations of different variants were collected using a portable Raman system. After appropriate spectral preprocessing, a deep learning algorithm, CoVari, is developed to predict both the viral variant species and concentrations. Using a 10-fold cross-validation strategy, the model achieves an average accuracy of 99.9% in discriminating between different virus variants and R2 values larger than 0.98 for quantifying viral concentrations of the three viruses, demonstrating the high quality of the detection. The limit of detection of the ACE2 SERS sensor is determined to be 10.472, 11.882, and 21.591 PFU/mL for SARS-CoV-2, SARS-CoV-2 B1, and CoV-NL63, respectively. The feature importance of virus classification and concentration regression in the CoVari algorithm are calculated based on a permutation algorithm, which showed a clear correlation to the biochemical origins of the spectra or spectral changes. In an unknown specimen test, classification accuracy can achieve >90% for concentrations larger than 781 PFU/mL, and the predicted concentrations consistently align with actual values, highlighting the robustness of the proposed algorithm. Based on the CoVari architecture and the output vector, this algorithm can be generalized to predict both viral variant species and concentrations simultaneously for a broader range of viruses. These results demonstrate that the SERS + CoVari strategy has the potential for rapid and quantitative detection of virus variants and potentially point-of-care diagnostic platforms.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Deep Learning , SARS-CoV-2 , Spectrum Analysis, Raman , Spectrum Analysis, Raman/methods , SARS-CoV-2/isolation & purification , Humans , COVID-19/diagnosis , COVID-19/virology , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Metal Nanoparticles/chemistry , Silver/chemistry , Biosensing Techniques/methods , Silicon Dioxide/chemistry , Algorithms , Limit of Detection
18.
Chem Pharm Bull (Tokyo) ; 72(6): 574-583, 2024 Jun 26.
Article in English | MEDLINE | ID: mdl-38866495

ABSTRACT

In Vietnam, the stems and roots of the Rutaceous plant Paramignya trimera (Oliv.) Burkill (known locally as "Xáo tam phân") are widely used to treat liver diseases such as viral hepatitis and acute and chronic cirrhosis. In an effort to search for Vietnamese natural compounds capable of inhibiting coronavirus based on molecular docking screening, two new dimeric coumarin glycosides, namely cis-paratrimerin B (1) and cis-paratrimerin A (2), and two previously identified coumarins, the trans-isomers paratrimerin B (3) and paratrimerin A (4), were isolated from the roots of P. trimera and tested for their anti-angiotensin-converting enzyme 2 (ACE-2) inhibitory properties in vitro. It was discovered that ACE-2 enzyme was inhibited by cis-paratrimerin B (1), cis-paratrimerin A (2), and trans-paratrimerin B (3), with IC50 values of 28.9, 68, and 77 µM, respectively. Docking simulations revealed that four biscoumarin glycosides had good binding energies (∆G values ranging from -10.6 to -14.7 kcal/mol) and mostly bound to the S1' subsite of the ACE-2 protein. The key interactions of these natural ligands include metal chelation with zinc ions and multiple H-bonds with Ser128, Glu145, His345, Lys363, Thr371, Glu406, and Tyr803. Our findings demonstrated that biscoumarin glycosides from P. trimera roots occur naturally in both cis- and trans-diastereomeric forms. The biscoumarin glycosides Lys363, Thr371, Glu406, and Tyr803. Our findings demonstrated that biscoumarin glycosides from P. trimera roots hold potential for further studies as natural ACE-2 inhibitors for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.


Subject(s)
Angiotensin-Converting Enzyme 2 , Coumarins , Glycosides , Molecular Docking Simulation , SARS-CoV-2 , Glycosides/chemistry , Glycosides/pharmacology , Glycosides/isolation & purification , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/chemistry , Humans , Coumarins/chemistry , Coumarins/pharmacology , Coumarins/isolation & purification , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , COVID-19/virology , Rutaceae/chemistry , COVID-19 Drug Treatment , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Plant Roots/chemistry , Angiotensin-Converting Enzyme Inhibitors/chemistry , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/isolation & purification
19.
Hypertens Res ; 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38942815

ABSTRACT

There is insufficient evidence that angiotensin-converting enzyme inhibitors (ACEIs) can reduce pneumonia by inducing a dry cough that confers a protective effect on the airway. To increase the evidence base on the clinical use of ACEIs for pneumonia prevention, this retrospective cohort study aimed to comparatively examine the risk of pneumonia-related hospitalization between ACEI initiators and angiotensin II receptor blocker (ARB) initiators using claims data from two Japanese municipalities. We identified persons who were newly prescribed any ACEI or ARB as their first antihypertensive agent between April 2016 and March 2020. The Fine-Gray method was applied to a Cox proportional hazards model to estimate the subdistribution hazard ratio (HR) of ACEI use (reference: ARB use) for pneumonia-related hospitalization, with death treated as a competing risk. Sex, age, comorbidities, medications, and pneumococcal immunization were included as covariates. The analysis was conducted on 1421 ACEI initiators and 9040 ARB initiators, and the adjusted subdistribution HR of ACEI use was estimated to be 1.21 (95% confidence interval: 0.89-1.65; P = 0.22). ACEI initiation did not demonstrate any significant preventive effect against pneumonia-related hospitalization relative to ARB initiation. There remains a lack of strong evidence on the protective effects of ACEIs, and further research is needed to ascertain the benefits of their use in preventing pneumonia. We conducted a large-scale retrospective cohort study using real-world healthcare data from a Japanese population. In this study, ACEI initiation did not indicate a significant preventive effect against pneumonia-related hospitalization.

20.
Int J Mol Sci ; 25(11)2024 May 29.
Article in English | MEDLINE | ID: mdl-38892098

ABSTRACT

There is a lack of studies aiming to assess cellular a disintegrin and metalloproteinase-17 (ADAM-17) activity in COVID-19 patients and the eventual associations with the shedding of membrane-bound angiotensin-converting enzyme 2 (mACE2). In addition, studies that investigate the relationship between ACE2 and ADAM-17 gene expressions in organs infected by SARS-CoV-2 are lacking. We used data from the Massachusetts general hospital COVID-19 study (306 COVID-19 patients and 78 symptomatic controls) to investigate the association between plasma levels of 33 different ADAM-17 substrates and COVID-19 severity and mortality. As a surrogate of cellular ADAM-17 activity, an ADAM-17 substrate score was calculated. The associations between soluble ACE2 (sACE2) and the ADAM-17 substrate score, renin, key inflammatory markers, and lung injury markers were investigated. Furthermore, we used data from the Genotype-Tissue Expression (GTEx) database to evaluate ADAM-17 and ACE2 gene expressions by age and sex in ages between 20-80 years. We found that increased ADAM-17 activity, as estimated by the ADAM-17 substrates score, was associated with COVID-19 severity (p = 0.001). ADAM-17 activity was also associated with increased mortality but did not reach statistical significance (p = 0.06). Soluble ACE2 showed the strongest positive correlation with the ADAM-17 substrate score, follow by renin, interleukin-6, and lung injury biomarkers. The ratio of ADAM-17 to ACE2 gene expression was highest in the lung. This study indicates that increased ADAM-17 activity is associated with severe COVID-19. Our findings also indicate that there may a bidirectional relationship between membrane-bound ACE2 shedding via increased ADAM-17 activity, dysregulated renin-angiotensin system (RAS) and immune signaling. Additionally, differences in ACE2 and ADAM-17 gene expressions between different tissues may be of importance in explaining why the lung is the organ most severely affected by COVID-19, but this requires further evaluation in prospective studies.


Subject(s)
ADAM17 Protein , Angiotensin-Converting Enzyme 2 , COVID-19 , SARS-CoV-2 , Severity of Illness Index , Humans , COVID-19/virology , COVID-19/metabolism , COVID-19/genetics , COVID-19/pathology , ADAM17 Protein/metabolism , ADAM17 Protein/genetics , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Middle Aged , Female , Male , Aged , Adult , Aged, 80 and over , Young Adult , Biomarkers/blood
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