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The animal origin of SARS-CoV-2 remains elusive, lacking a plausible evolutionary narrative that may account for its emergence. Its spike protein resembles certain segments of BANAL-236 and RaTG13, two bat coronaviruses considered possible progenitors of SARS-CoV-2. Additionally, its spike contains a furin motif, a common feature of rodent coronaviruses. To explore the possible involvement of rodents in the emergence of SARS-CoV-2 spike, we examined the crystal structures of the spike receptor-binding domains (RBDs) of BANAL-236 and RaTG13 each complexed with mouse receptor ACE2. Both RBDs have residues at positions 493 and 498 that align well with two virus-binding hotspots on mouse ACE2. Our biochemical evidence supports that both BANAL-236 and RaTG13 spikes can use mouse ACE2 as their entry receptor. These findings point to a scenario in which these bat coronaviruses may have coinfected rodents, leading to a recombination of their spike genes and a subsequent acquisition of a furin motif in rodents, culminating in the emergence of SARS-CoV-2.
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Enzima de Conversão de Angiotensina 2 , Quirópteros , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Animais , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/química , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Quirópteros/virologia , Camundongos , SARS-CoV-2/metabolismo , SARS-CoV-2/química , Humanos , Receptores Virais/metabolismo , Receptores Virais/química , COVID-19/virologia , COVID-19/metabolismo , Cristalografia por Raios X , Ligação Proteica , Coronavirus/metabolismo , Coronavirus/genética , Modelos MolecularesRESUMO
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Obesity is a major risk factor for the development of COVID-19. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2. The receptor-binding domain of the S1 subunit (S1-RBD protein) in the SARS-CoV-2 spike glycoprotein binds to ACE2 on host cells, through which the virus enters several organs, including the lungs. Considering these findings, recombinant ACE2 might be utilized as a decoy protein to attenuate SARS-CoV-2 infection. Here, we examined whether obesity increases ACE2 expression in the lungs and whether recombinant ACE2 administration diminishes the entry of S1-RBD protein into lung cells. We observed that high-fat diet-induced obesity promoted ACE2 expression in the lungs by increasing serum levels of LPS derived from the intestine. S1-RBD protein entered the lungs specifically through ACE2 expressed in host lungs and that the administration of recombinant ACE2 attenuated this entry. We conclude that obesity makes hosts susceptible to recombinant SARS-CoV-2 spike proteins due to elevated ACE2 expression in lungs, and this model of administering S1-RBD protein can be applied to new COVID-19 treatments.
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COVID-19 , Dieta Hiperlipídica , Pulmão , Obesidade , Proteínas Recombinantes , Glicoproteína da Espícula de Coronavírus , Animais , Humanos , Masculino , Camundongos , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , COVID-19/metabolismo , COVID-19/virologia , Dieta Hiperlipídica/efeitos adversos , Pulmão/metabolismo , Pulmão/virologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Proteínas Recombinantes/metabolismo , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Internalização do VírusRESUMO
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.
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Blocking the interaction between the SARS-CoV-2 spike protein and the human angiotensin-converting enzyme II (hACE2) protein serves as a therapeutic strategy for treating COVID-19. Traditional Chinese medicine (TCM) treatments containing bioactive products could alleviate the symptoms of severe COVID-19. However, the emergence of SARS-CoV-2 variants has complicated the process of developing broad-spectrum drugs. As such, the aim of this study was to explore the efficacy of TCM treatments against SARS-CoV-2 variants through targeting the interaction of the viral spike protein with the hACE2 receptor. Antiviral activity was systematically evaluated using a pseudovirus system. Scutellaria baicalensis (S. baicalensis) was found to be effective against SARS-CoV-2 infection, as it mediated the interaction between the viral spike protein and the hACE2 protein. Moreover, the active molecules of S. baicalensis were identified and analyzed. Baicalein and baicalin, a flavone and a flavone glycoside found in S. baicalensis, respectively, exhibited strong inhibitory activities targeting the viral spike protein and the hACE2 protein, respectively. Under optimized conditions, virus infection was inhibited by 98% via baicalein-treated pseudovirus and baicalin-treated hACE2. In summary, we identified the potential SARS-CoV-2 inhibitors from S. baicalensis that mediate the interaction between the Omicron spike protein and the hACE2 receptor. Future studies on the therapeutic application of baicalein and baicalin against SARS-CoV-2 variants are needed.
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COVID-19 , Flavonas , Humanos , SARS-CoV-2 , Scutellaria baicalensis , Glicoproteína da Espícula de Coronavírus , Angiotensinas , Ligação ProteicaRESUMO
Angiotensin-converting enzyme-2 (ACE2) has been recognized as the binding receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Flow cytometry demonstrated that there was little to no expression of ACE2 on most of the human peripheral blood-derived immune cells including CD4+ T, CD8+ T, activated CD4+ /CD8+ T, Tregs, Th17, NKT, B, NK cells, monocytes, dendritic cells, and granulocytes. There was no ACE2 expression on platelets and very low level of ACE2 protein expression on the surface of human primary pulmonary alveolar epithelial cells. The ACE2 expression was markedly upregulated on the activated type 1 macrophages (M1). Immunohistochemistry demonstrated high expressions of ACE2 on human tissue macrophages, such as alveolar macrophages, Kupffer cells within livers, and microglial cells in brain at steady state. The data suggest that alveolar macrophages, as the frontline immune cells, may be directly targeted by the SARS-CoV-2 infection and therefore need to be considered for the prevention and treatment of COVID-19.
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COVID-19 , Humanos , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2 , Peptidil Dipeptidase A/metabolismo , Macrófagos Alveolares , AngiotensinasRESUMO
Alleviating vascular barrier injury improves colitis. Angiotensin converting enzyme 2/angiotensin 1-7/Mas receptor (ACE2/Ang1-7/MasR) axis-related drugs have various biological properties, such as inhibition of inflammation and fibrosis, but their role in improving the gut-vascular barrier (GVB) has rarely been reported. This study aims to investigate the effects of diminazene aceturate (DIZE), an ACE2 activator, on vascular barrier damage in colitis. Mice were randomly divided into three groups: control, dextran sulfate sodium salt (DSS), and DIZE+DSS. Mice in the DSS group drank DSS for 8 days starting on day 4. Mice in the DIZE+DSS group were pregavaged with DIZE for 3 days and then drank DSS for 8 days while continuing to be gavaged with DIZE for 4 days. Mice were euthanized and samples were collected on the last day. Injury to colonic structure and colonic microvasculature was assessed by visual observation and appropriate staining. DSS-induced colonic and microvascular pathological damage in mice was substantially reversed by DIZE treatment. Molecular pathways were investigated by Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), and enzyme linked immunosorbent assay (ELISA). DSS treatment upregulated angiotensin converting enzyme (ACE), angiotensin type 1 receptor (AT1R) protein, pro-inflammatory cytokines and inhibited tight junction-related protein expression. DIZE treatment activated ACE2/MasR protein expression and reversed epithelial barrier damage and inflammatory infiltration during DSS injury. In addition, DIZE treatment inhibited vascular endothelial growth factor A/vascular endothelial growth factor receptor 2/proto-oncogene tyrosine-protein kinase Src (VEGFA/VEGFR2/Src) pathway activation and restored vascular adhesion-linker protein vascular endothelial cadherin (VE-cadherin) expression during DSS injury. In conclusion, DIZE treatment ameliorated colitis, which was associated with balancing the two axes of the renin-angiotensin system (RAS) and repairing the GVB injury.
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Enzima de Conversão de Angiotensina 2 , Colite , Animais , Camundongos , Enzima de Conversão de Angiotensina 2/metabolismo , Sistema Renina-Angiotensina/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Human angiotensin-converting enzyme 2 (ACE2), a type I transmembrane receptor physiologically acting as a carboxypeptidase enzyme within the renin-angiotensin system (RAS), is a critical mediator of infection by several severe acute respiratory syndrome (SARS) corona viruses. For instance, it has been demonstrated that ACE2 is the primary receptor for the SARS-CoV-2 entry to many human cells through binding to the viral spike S protein. Consequently, genetic variability in ACE2 gene has been suggested to contribute to the variable clinical manifestations in COVID-19. Many of those genetic variations result in missense variants within the amino acid sequence of ACE2. The potential effects of those variations on binding to the spike protein have been speculated and, in some cases, demonstrated experimentally. However, their effects on ACE2 protein folding, trafficking and subcellular targeting have not been established. RESULTS: In this study we aimed to examine the potential effects of 28 missense variants (V801G, D785N, R768W, I753T, L731F, L731I, I727V, N720D, R710H, R708W, S692P, E668K, V658I, N638S, A627V, F592L, G575V, A501T, I468V, M383I, G173S, N159S, N149S, D38E, N33D, K26R, I21T, and S19P) distributed across the ACE2 receptor domains on its subcellular trafficking and targeting through combinatorial approach involving in silico analysis and experimental subcellular localization analysis. Our data show that none of the studied missense variants (including 3 variants predicted to be deleterious R768W, G575V, and G173S) has a significant effect on ACE2 intracellular trafficking and subcellular targeting to the plasma membrane. CONCLUSION: Although the selected missense variants display no significant change in ACE2 trafficking and subcellular localization, this does not rule out their effect on viral susceptibility and severity. Further studies are required to investigate the effect of ACE2 variants on its expression, binding, and internalization which might explain the variable clinical manifestations associated with the infection.
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Enzima de Conversão de Angiotensina 2/genética , COVID-19 , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/genética , Humanos , Peptidil Dipeptidase A/genética , Ligação Proteica , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genéticaRESUMO
The clinical manifestations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection responsible for coronavirus disease 2019 (COVID-19) commonly include dyspnoea and fatigue, and they primarily involve the lungs. However, extra-pulmonary organ dysfunctions, particularly affecting the cardiovascular system, have also been observed following COVID-19 infection. In this context, several cardiac complications have been reported, including hypertension, thromboembolism, arrythmia and heart failure, with myocardial injury and myocarditis being the most frequent. These secondary myocardial inflammatory responses appear to be associated with a poorer disease course and increased mortality in patients with severe COVID-19. In addition, numerous episodes of myocarditis have been reported as a complication of COVID-19 mRNA vaccinations, especially in young adult males. Changes in the cell surface expression of angiotensin-converting enzyme 2 (ACE2) and direct injury to cardiomyocytes resulting from exaggerated immune responses to COVID-19 are just some of the mechanisms that may explain the pathogenesis of COVID-19-induced myocarditis. Here, we review the pathophysiological mechanisms underlying myocarditis associated with COVID-19 infection, with a particular focus on the involvement of ACE2 and Toll-like receptors (TLRs).
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COVID-19 , Miocardite , Humanos , COVID-19/complicações , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2 , Miocardite/etiologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Receptores Toll-LikeRESUMO
This study aimed to (1) determine whether the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 is increased in tobacco smokers, which potentially increases their susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and (2) assess whether eye rinsing can reduce susceptibility. This prospective study included 20 eyes of 10 smokers and 18 eyes of nine healthy non-smokers (control) for reverse-transcription polymerase chain reaction. This study also included 28 eyes of 14 smokers and 16 eyes of eight healthy non-smokers (control) for enzyme-linked immunosorbent assay. Tear and impression cytology samples were collected from the right eye of each patient. The left eye was then rinsed for 30 s, and after 5 min, the tear and impression cytology samples were collected in the same manner. The expression of the ACE2 gene was significantly higher in the conjunctiva of smokers (n = 17; median 3.07 copies/ng of total RNA) than in those of non-smokers (n = 17; median 1.92 copies/ng of total RNA, p = 0.003). Further, mRNA expression and protein levels of ACE2 were weakly correlated in smokers (r = 0.49). ACE2 protein levels in Schirmer's strip samples were significantly reduced from 5051 to 3202 pg/mL after eye washing (n = 10; p = 0.001). Ocular surface cells are susceptible to SARS-CoV-2 infection. Smoking may be a risk factor for SARS-CoV-2 infection, and eye rinsing may reduce the risk of infection.
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Enzima de Conversão de Angiotensina 2 , COVID-19 , Humanos , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Túnica Conjuntiva/metabolismo , COVID-19/metabolismo , COVID-19/prevenção & controle , Estudos Prospectivos , RNA/metabolismo , SARS-CoV-2/metabolismo , Fumantes , Olho/metabolismoRESUMO
Coronavirus disease-19 (COVID-19) is caused by the infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The virus enters host cells through receptor-mediated endocytosis of angiotensin-converting enzyme-2 (ACE2), leading to systemic inflammation, also known as a "cytokine storm", and neuroinflammation. COVID-19's upstream regulator, interferon-gamma (IFNG), is downregulated upon the infection of SARS-CoV-2, which leads to the downregulation of ACE2. The neuroinflammation signaling pathway (NISP) can lead to neurodegenerative diseases, such as Parkinson's disease (PD), which is characterized by the formation of Lewy bodies made primarily of the α-synuclein protein encoded by the synuclein alpha (SNCA) gene. We hypothesize that COVID-19 may modulate PD progression through neuroinflammation induced by cytokine storms. This study aimed to elucidate the possible mechanisms and signaling pathways involved in COVID-19-triggered pathology associated with neurodegenerative diseases like PD. This study presents the analysis of the pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. Through QIAGEN's Ingenuity Pathway Analysis (IPA), the study identified the NISP as a top-five canonical pathway/signaling pathway and SNCA as a top-five upstream regulator. Core Analysis was also conducted on the associated molecules between COVID-19 and SNCA to construct a network connectivity map. The Molecule Activity Predictor tool was used to simulate the infection of SARS-CoV-2 by downregulating IFNG, which leads to the predicted activation of SNCA, and subsequently PD, through a dataset of intermediary molecules. Downstream effect analysis was further used to quantify the downregulation of ACE2 on SNCA activation.
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COVID-19 , Doença de Parkinson , Humanos , Doença de Parkinson/genética , Enzima de Conversão de Angiotensina 2/genética , Doenças Neuroinflamatórias , SARS-CoV-2 , Síndrome da Liberação de Citocina , Interferon gamaRESUMO
In 2019-2020, the novel "severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)" had emerged as the biggest challenge for humanity, causing "coronavirus disease 19 (COVID-19)". Scientists around the world have been putting continuous efforts to unfold potential inhibitors of SARS-CoV-2. We have performed computational studies that help us to identify cyanobacterial photoprotective compounds as potential inhibitors against SARS-CoV-2 druggable target human angiotensin-converting enzyme (ACE2), which plays a vital role in the attachment and entry of the virus into the cell. Blocking the receptor-binding domain of ACE2 can prevent the access of the virus into the compartment. A molecular docking study was performed between photoprotective compounds mycosporine-like amino acids, scytonemins and ACE2 protein using AutoDock tools. Among sixteen molecularly docked metabolites, seven compounds were selected with binding energy < 6.8 kcal/mol. Afterwards, drug-likeness and toxicity of the top candidate were predicted using Swiss ADME and Pro Tox-II online servers. All top hits show desirable drug-likeness properties, but toxicity pattern analysis discloses the toxic effect of scytonemin and its derivatives, resulting in the elimination from the screening pipeline. Further molecular interaction study of the rest two ligands, mycosporine-glycine-valine and shinorine with ACE2 was performed using PyMol, Biovia Discovery studio and LigPlot+. Lastly biological activity of both the ligands was predicted by using the PASS online server. Combining the docking score and other studied properties, we believe that mycosporine-glycine-valine and shinorine have potential to be potent inhibitors of ACE2 and can be explored further to use against COVID-19.
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BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system and a well-known functional receptor for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells. The COVID-19 pandemic has brought ACE2 into the spotlight, and ACE2 expression in tumors and its relationship with SARS-COV-2 infection and prognosis of cancer patients have received extensive attention. However, the association between ACE2 expression and tumor therapy and prognosis, especially in breast cancer, remains ambiguous and requires further investigation. We have previously reported that ACE2 is elevated in drug-resistant breast cancer cells, but the exact function of ACE2 in drug resistance and progression of this malignant disease has not been explored. METHODS: The expression of ACE2 and HIF-1α in parental and drug-resistant breast cancer cells under normoxic and hypoxic conditions was analyzed by Western blot and qRT-PCR methods. The protein levels of ACE2 in plasma samples from breast cancer patients were examined by ELISA. The relationship between ACE2 expression and breast cancer treatment and prognosis was analyzed using clinical specimens and public databases. The reactive oxygen species (ROS) levels in breast cancer cells were measured by using a fluorescent probe. Small interfering RNAs (siRNAs) or lentivirus-mediated shRNA was used to silence ACE2 and HIF-1α expression in cellular models. The effect of ACE2 knockdown on drug resistance in breast cancer was determined by Cell Counting Kit 8 (CCK-8)-based assay, colony formation assay, apoptosis and EdU assay. RESULTS: ACE2 expression is relatively low in breast cancer cells, but increases rapidly and specifically after exposure to anticancer drugs, and remains high after resistance is acquired. Mechanistically, chemotherapeutic agents increase ACE2 expression in breast cancer cells by inducing intracellular ROS production, and increased ROS levels enhance AKT phosphorylation and subsequently increase HIF-1α expression, which in turn upregulates ACE2 expression. Although ACE2 levels in plasma and cancer tissues are lower in breast cancer patients compared with healthy controls, elevated ACE2 in patients after chemotherapy is a predictor of poor treatment response and an unfavorable prognostic factor for survival in breast cancer patients. CONCLUSION: ACE2 is a gene in breast cancer cells that responds rapidly to chemotherapeutic agents through the ROS-AKT-HIF-1α axis. Elevated ACE2 modulates the sensitivity of breast cancer cells to anticancer drugs by optimizing the balance of intracellular ROS. Moreover, increased ACE2 is not only a predictor of poor response to chemotherapy, but is also associated with a worse prognosis in breast cancer patients. Thus, our findings provide novel insights into the spatiotemporal differences in the function of ACE2 in the initiation and progression of breast cancer.
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Neoplasias da Mama , COVID-19 , Humanos , Feminino , Enzima de Conversão de Angiotensina 2 , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , SARS-CoV-2 , Pandemias , Prognóstico , Transdução de Sinais , RNA Interferente Pequeno , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismoRESUMO
With the emergence of the novel coronavirus SARS-CoV-2 since December 2019, more than 65 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some cases, leading to over 1.5 million deaths globally. Despite the collaborative and concerted research efforts that have been made, no effective medication for COVID-19 (coronavirus disease-2019) is currently available. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as an initial mediator for viral attachment and host cell invasion. ACE2 is widely distributed in the human tissues including the cell surface of lung cells which represent the primary site of the infection. Inhibiting or reducing cell surface availability of ACE2 represents a promising therapy for tackling COVID-19. In this context, most ACE2-based therapeutic strategies have aimed to tackle the virus through the use of angiotensin-converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2, which does not directly aim to reduce its membrane availability. However, through this review, we present a different perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, and shedding and cellular trafficking pathways including the internalization are not well elucidated in literature. Therefore, we hereby present an overview of the fate of newly synthesized ACE2, its post translational modifications, and what is known of its trafficking pathways. In addition, we highlight the possibility that some of the identified ACE2 missense variants might affect its trafficking efficiency and localization and hence may explain some of the observed variable severity of SARS-CoV-2 infections. Moreover, an extensive understanding of these processes is necessarily required to evaluate the potential use of ACE2 as a credible therapeutic target.
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Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/prevenção & controle , Mutação , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , COVID-19/epidemiologia , COVID-19/virologia , Humanos , Pandemias , Receptores Virais/genética , Receptores Virais/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Virulência/genética , Internalização do VírusRESUMO
The gateway for invasion by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into human host cells is via the angiotensin-converting enzyme 2 (ACE2) transmembrane receptor expressed in multiple immune and nonimmune cell types. SARS-CoV-2, that causes coronavirus disease 2019 (COVID-19; CoV-19) has the unusual capacity to attack many different types of human host cells simultaneously via novel clathrin- and caveolae-independent endocytic pathways, becoming injurious to diverse cells, tissues and organ systems and exploiting any immune weakness in the host. The elicitation of this multipronged attack explains in part the severity and extensive variety of signs and symptoms observed in CoV-19 patients. To further our understanding of the mechanism and pathways of SARS-CoV-2 infection and susceptibility of specific cell- and tissue-types and organ systems to SARS-CoV-2 attack in this communication we analyzed ACE2 expression in 85 human tissues including 21 different brain regions, 7 fetal tissues and 8 controls. Besides strong ACE2 expression in respiratory, digestive, renal-excretory and reproductive cells, high ACE2 expression was also found in the amygdala, cerebral cortex and brainstem. The highest ACE2 expression level was found in the pons and medulla oblongata in the human brainstem, containing the medullary respiratory centers of the brain, and may in part explain the susceptibility of many CoV-19 patients to severe respiratory distress.
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Encéfalo/patologia , Encéfalo/virologia , COVID-19/virologia , SARS-CoV-2/patogenicidade , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/genética , Regulação Enzimológica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Especificidade de ÓrgãosRESUMO
Angiotensin-converting enzyme 2 (ACE2) is closely related to tumor formation. We developed the radiolabeled peptide pair 68Ga/177Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated DX600 (68Ga/177Lu-HZ20), for the targeting and mapping of ACE2-overexpressing tumors. 68Ga/177Lu-HZ20 was prepared with a routine labeling method. HepG2ACE2+/HepG2WT cell lines were used to evaluate the specificity of 68Ga/177Lu-HZ20. Pharmacokinetics, biodistribution, and micro-PET/CT and -SPECT/CT imaging were performed, and radiation dosimetry was estimated. Immunohistochemistry (IHC) staining was performed to assess the expression of ACE2 in tumors. The radiolabeling yields of 68Ga/177Lu-HZ20 were 88.49 ± 8.57% (n > 10) and 84.71 ± 9.75% (n > 10), with specific activities of (18.74 ± 3.72) × 106 and (17.85 ± 1.62) × 106 GBq/mol, respectively. 68Ga/177Lu-HZ20 showed significant differences in the cellular uptake of HepG2ACE2+/HepG2WT cells and fast clearance in KM mice. Moreover, HepG2ACE2+ tumors were clearly visualized in 68Ga/177Lu-HZ20 micro-PET/SPECT images. Based on micro-PET/CT, the standard uptake value (SUVmax) of HepG2ACE2+ tumors was 0.66 ± 0.02 at 30 min postinjection, IHC confirmed the high expression of ACE2 in HepG2ACE2+ tumors. In PET/CT images, the SUVmean of volunteer 1 was higher than the 18F-FDG value in the same lesion. 68Ga/177Lu-HZ20 was successfully obtained and showed high and specific uptake in tumors overexpressing ACE2. They may serve as paired probes for ACE2-targeting theranostics.
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Radioisótopos de Gálio , Neoplasias , Animais , Camundongos , Enzima de Conversão de Angiotensina 2 , Linhagem Celular Tumoral , Peptídeos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
The novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a global pandemic which is primarily considered a respiratory illness. However, emerging reports show that the virus exhibits both pulmonary and extra-pulmonary manifestations in humans, with the kidney as a major extra-pulmonary target due to its abundant expression of angiotensin-converting enzyme 2 and transmembrane protease serine 2, which facilitate entry of the virus into cells. Acute kidney injury has become prevalent in COVID-19 patients without prior any history of kidney dysfunction. In addition, the virus also worsens kidney conditions and increases mortality of COVID-19 patients with pre-existing chronic kidney disease, renal cancer, diabetic nephropathy, end-stage kidney disease as well as dialysis and kidney transplant patients. In the search for antiviral agents for the treatment of COVID-19, hydrogen sulfide (H2S), the third established member of gasotransmitter family, is emerging as a potential candidate, possessing important therapeutic properties including antiviral, anti-inflammatory, anti-thrombotic and antioxidant properties. A recent clinical study revealed higher serum H2S levels in survivors of COVID-19 pneumonia with reduced interleukin-6 levels compared to fatal cases. In this review, we summarize the global impact of COVID-19 on kidney conditions and discuss the emerging role of H2S as a potential COVID-19 therapy.
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Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Sulfeto de Hidrogênio/farmacologia , Nefropatias/tratamento farmacológico , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , COVID-19/virologia , Humanos , Sulfeto de Hidrogênio/química , Nefropatias/virologiaRESUMO
Patients with chronic kidney disease (CKD) are at higher risk for severe coronavirus disease 2019 (COVID-19). Such patients are more likely to develop "COVID-19-induced acute kidney injury (AKI)", which exacerbates the pre-existing CKD and increases the mortality rate of the patients. COVID-19-induced AKI is pathologically characterized by acute tubular necrosis and the interstitial infiltration of proinflammatory leukocytes. In our rat model with advanced CKD, immunohistochemistry for angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) demonstrated their strong expression in the cytoplasm of damaged proximal tubular cells and the infiltrating leukocytes within the cortical interstitium, which overlapped with the lesions of COVID-19-induced AKI. Since ACE2 and TMPRSS2 are enzymes that facilitate the viral entry into the cells and trigger the onset of cytokine storm, the renal distribution of these proteins in advanced CKD was thought to be responsible for the development of COVID-19-induced AKI. Concerning such mechanisms, the pharmacological blockade of ACE2 or the use of soluble forms of the ACE2 protein may halt the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells. This would protect against the COVID-19-induced exacerbation of pre-existing CKD by preventing the development of AKI.
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Injúria Renal Aguda , COVID-19 , Insuficiência Renal Crônica , Ratos , Animais , Enzima de Conversão de Angiotensina 2 , COVID-19/complicações , SARS-CoV-2 , Insuficiência Renal Crônica/prevenção & controle , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controleRESUMO
PURPOSE OF REVIEW: This review summarises the literature data and provides an overview of the role and impact of the use of renin-angiotensin-aldosterone system (RAAS) inhibitors in patients with coronavirus disease 2019 (COVID-19) infection. RECENT FINDINGS: The angiotensin-converting enzyme 2 (ACE2) has a key role in the regulation of the RAAS pathway, downregulating angiotensin II and attenuating inflammation, vasoconstriction and oxidative stress. Additionally, it plays an instrumental part in COVID-19 infection as it facilitates the cell entry of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and enables its replication. The use and role of RAAS inhibitors therefore during the COVID-19 pandemic have been intensively investigated. Although it was initially assumed that RAAS inhibitors may relate to worse clinical outcomes and severe disease, data from large studies and meta-analyses demonstrated that they do not have an adverse impact on clinical outcomes or prognosis. On the contrary, some experimental and retrospective observational cohort studies showed a potential protective mechanism, although this effect remains to be seen in large clinical trials.
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Tratamento Farmacológico da COVID-19 , Hipertensão , Aldosterona/metabolismo , Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Enzima de Conversão de Angiotensina 2 , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Humanos , Hipertensão/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Pandemias , Peptidil Dipeptidase A/metabolismo , Renina/metabolismo , Sistema Renina-Angiotensina/fisiologia , Estudos Retrospectivos , SARS-CoV-2RESUMO
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread globally despite the worldwide implementation of preventive measures to combat the disease. Although most COVID-19 cases are characterised by a mild, self-limiting disease course, a considerable subset of patients develop a more severe condition, varying from pneumonia and acute respiratory distress syndrome (ARDS) to multi-organ failure (MOF). Progression of COVID-19 is thought to occur as a result of a complex interplay between multiple pathophysiological mechanisms, all of which may orchestrate SARS-CoV-2 infection and contribute to organ-specific tissue damage. In this respect, dissecting currently available knowledge of COVID-19 immunopathogenesis is crucially important, not only to improve our understanding of its pathophysiology but also to fuel the rationale of both novel and repurposed treatment modalities. Various immune-mediated pathways during SARS-CoV-2 infection are relevant in this context, which relate to innate immunity, adaptive immunity, and autoimmunity. Pathological findings in tissue specimens of patients with COVID-19 provide valuable information with regard to our understanding of pathophysiology as well as the development of evidence-based treatment regimens. This review provides an updated overview of the main pathological changes observed in COVID-19 within the most commonly affected organ systems, with special emphasis on immunopathology. Current management strategies for COVID-19 include supportive care and the use of repurposed or symptomatic drugs, such as dexamethasone, remdesivir, and anticoagulants. Ultimately, prevention is key to combat COVID-19, and this requires appropriate measures to attenuate its spread and, above all, the development and implementation of effective vaccines. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Imunidade Adaptativa/imunologia , Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , COVID-19 , SARS-CoV-2/patogenicidade , Imunidade Adaptativa/efeitos dos fármacos , COVID-19/patologia , COVID-19/virologia , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Reino UnidoRESUMO
The 2021 Annual Review Issue of The Journal of Pathology contains 14 invited reviews on current research areas of particular importance in pathology. The subjects included here reflect the broad range of interests covered by the journal, including both basic and applied research fields but always with the aim of improving our understanding of human disease. This year, our reviews encompass the huge impact of the COVID-19 pandemic, the development and application of biomarkers for immune checkpoint inhibitors, recent advances in multiplexing antigen/nucleic acid detection in situ, the use of genomics to aid drug discovery, organoid methodologies in research, the microbiome in cancer, the role of macrophage-stroma interactions in fibrosis, and TGF-ß as a driver of fibrosis in multiple pathologies. Other reviews revisit the p53 field and its lack of clinical impact to date, dissect the genetics of mitochondrial diseases, summarise the cells of origin and genetics of sarcomagenesis, provide new data on the role of TRIM28 in tumour predisposition, review our current understanding of cancer stem cell niches, and the function and regulation of p63. The reviews are authored by experts in their field from academia and industry, and provide comprehensive updates of the chosen areas, in which there has been considerable recent progress. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.