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1.
J Chromatogr A ; 1693: 463903, 2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-36870232

RESUMO

Patients have different responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and these may be life-threatening for critically ill patients. Screening components that act on host cell receptors, especially multi-receptor components, is challenging. The in-line combination of dual-targeted cell membrane chromatography and a liquid chromatography-mass spectroscopy (LC-MS) system for analyzing angiotensin-converting enzyme 2 (ACE2) and cluster of differentiation 147 (CD147) receptors based on SNAP-tag technology provides a comprehensive solution for screening multiple components in complex samples acting on the two receptors. The selectivity and applicability of the system were validated with encouraging results. Under the optimized conditions, this method was used to screen for antiviral components in Citrus aurantium extracts. The results showed that 25 µmol /L of the active ingredient could inhibit virus entry into cells. Hesperidin, neohesperidin, nobiletin, and tangeretin were identified as antiviral components. In vitro pseudovirus assays and macromolecular cell membrane chromatography further verified the interaction of these four components with host-virus receptors, showing good effects on some or all of the pseudoviruses and host receptors. In conclusion, the in-line dual-targeted cell membrane chromatography LC-MS system developed in this study can be used for the comprehensive screening of antiviral components in complex samples. It also provides new insight into small-molecule drug-receptor and macromolecular-protein-receptor interactions.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2 , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Membrana Celular/metabolismo , Antivirais/farmacologia
2.
Artigo em Inglês | MEDLINE | ID: mdl-36901403

RESUMO

Particulate matter (PM) is a harmful component of urban air pollution and PM2.5, in particular, can settle in the deep airways. The RAS system plays a crucial role in the pathogenesis of pollution-induced inflammatory diseases: the ACE/AngII/AT1 axis activates a pro-inflammatory pathway counteracted by the ACE2/Ang(1-7)/MAS axis, which in turn triggers an anti-inflammatory and protective pathway. However, ACE2 acts also as a receptor through which SARS-CoV-2 penetrates host cells to replicate. COX-2, HO-1, and iNOS are other crucial proteins involved in ultrafine particles (UFP)-induced inflammation and oxidative stress, but closely related to the course of the COVID-19 disease. BALB/c male mice were subjected to PM2.5 sub-acute exposure to study its effects on ACE2 and ACE, COX-2, HO-1 and iNOS proteins levels, in the main organs concerned with the pathogenesis of COVID-19. The results obtained show that sub-acute exposure to PM2.5 induces organ-specific modifications which might predispose to greater susceptibility to severe symptomatology in the case of SARS-CoV-2 infection. The novelty of this work consists in using a molecular study, carried out in the lung but also in the main organs involved in the disease, to analyze the close relationship between exposure to pollution and the pathogenesis of COVID-19.


Assuntos
COVID-19 , Animais , Humanos , Masculino , Camundongos , Enzima de Conversão de Angiotensina 2 , Ciclo-Oxigenase 2 , Pandemias , Material Particulado , Peptidil Dipeptidase A/metabolismo , SARS-CoV-2
3.
Nutrients ; 15(4)2023 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-36839305

RESUMO

Abalone viscera, which accounts for more than 20% of the total weight of abalone, is generally regarded as waste in the food industry, and effective methods are required to utilize it productively. In this study, the viscera were fermented with Aspergillus oryzae 001 to add functionality. Fermented abalone viscera exhibited increased angiotensin I-converting enzyme (ACE) inhibitory activity and enhanced inhibition of blood pressure elevation in spontaneously hypertensive rats (SHRs). Abalone viscera administration had no significant effect on body weight, food intake, liver and kidney weights, or serum components in SHRs. ACE inhibitors specific to fermented abalone viscera were identified through extraction, fractionation, purification, and analysis. The identified substance was L-m-tyrosine, which non-competitively inhibited ACE and, in a single oral administration, significantly reduced blood pressure in SHRs compared to that in the control. This study identified that abalone viscera fermented by A. oryzae 001 has an inhibitory effect on blood pressure elevation, suggesting its potential use as a functional food. In addition, L-m-tyrosine, a unique substance in fermented abalone viscera, was isolated for the first time as a single ACE-inhibitory amino acid.


Assuntos
Aspergillus oryzae , Gastrópodes , Hipertensão , Animais , Ratos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Aspergillus oryzae/metabolismo , Pressão Sanguínea , Peptidil Dipeptidase A/metabolismo , Ratos Endogâmicos SHR , Vísceras/metabolismo , Fermentação
4.
Int J Mol Sci ; 24(4)2023 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-36834705

RESUMO

In early 2020, the novel pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, and rapidly propagated worldwide causing a global health emergency. SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) protein for cell entry, followed by proteolytic cleavage of the Spike (S) protein by the transmembrane serine protease 2 (TMPRSS2), allowing fusion of the viral and cellular membranes. Interestingly, TMPRSS2 is a key regulator in prostate cancer (PCa) progression which is regulated by androgen receptor (AR) signaling. Our hypothesis is that the AR signaling may regulate the expression of TMPRSS2 in human respiratory cells and thus influence the membrane fusion entry pathway of SARS-CoV-2. We show here that TMPRSS2 and AR are expressed in Calu-3 lung cells. In this cell line, TMPRSS2 expression is regulated by androgens. Finally, pre-treatment with anti-androgen drugs such as apalutamide significantly reduced SARS-CoV-2 entry and infection in Calu-3 lung cells but also in primary human nasal epithelial cells. Altogether, these data provide strong evidence to support the use of apalutamide as a treatment option for the PCa population vulnerable to severe COVID-19.


Assuntos
COVID-19 , Masculino , Humanos , COVID-19/metabolismo , SARS-CoV-2/metabolismo , Peptidil Dipeptidase A/metabolismo , Pulmão/metabolismo , Células Epiteliais/metabolismo , Internalização do Vírus
5.
Curr Opin Allergy Clin Immunol ; 23(2): 193-198, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-36752375

RESUMO

PURPOSE OF REVIEW: The relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the most severe forms of asthma has been an object of discussion. Indeed, it is not clear whether asthma is among the risk factors for the occurrence of severe coronavirus disease 2019 (COVID-19) disease, or rather it plays a protective role against the worsening of the respiratory involvement in the SARS-CoV-2 infection. On the other hand, the extent to which coronavirus infection may trigger asthma attacks is still partly unknown. The current investigation aims at reviewing the available literature on the topic to address factors influencing this relationship. RECENT FINDINGS: Based on recent observations, it is likely that type 2 inflammation plays a protective role against SARS-CoV-2 infection and disease. In particular, asthmatics show different expression of angiotensin-converting enzyme2 (ACE2) and Transmembrane protease, serine 2 (TMPRSS2) that are responsible for a reduced risk of infection as well as lower risk of hospitalization. Interestingly, studies showed a safe profile of inhaled corticosteroids and biological drugs in SARS-CoV-2 infection. In addition, inhaled corticosteroid could play a protective role against worsening of asthma. SUMMARY: The current findings suggest that current treatment for asthma should be maintained to avoid severe exacerbations. Severe asthmatics under biological treatment should continue their medications, and be encouraged to receive COVID-19 vaccines.


Assuntos
Asma , COVID-19 , Humanos , SARS-CoV-2 , Vacinas contra COVID-19 , Peptidil Dipeptidase A/metabolismo
6.
PLoS One ; 18(2): e0281281, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36735698

RESUMO

Although the COVID-19 pandemic began over three years ago, the virus responsible for the disease, SARS-CoV-2, continues to infect people across the globe. As such, there remains a critical need for development of novel therapeutics against SARS-CoV-2. One technology that has remained relatively unexplored in COVID-19 is the use of antisense oligonucleotides (ASOs)-short single-stranded nucleic acids that bind to target RNA transcripts to modulate their expression. In this study, ASOs targeted against the SARS-CoV-2 genome and host entry factors, ACE2 and TMPRSS2, were designed and tested for their ability to inhibit cellular infection by SARS-CoV-2. Using our previously developed SARS-CoV-2 bioassay platform, we screened 180 total ASOs targeting various regions of the SARS-CoV-2 genome and validated several ASOs that potently blocked SARS-CoV-2 infection in vitro. Notably, select ASOs retained activity against both the WA1 and B.1.1.7 (commonly known as alpha) variants. Screening of ACE2 and TMPRSS2 ASOs showed that targeting of ACE2 also potently prevented infection by the WA1 and B.1.1.7 SARS-CoV-2 viruses in the tested cell lines. Combined with the demonstrated success of ASOs in other disease indications, these results support further research into the development of ASOs targeting SARS-CoV-2 and host entry factors as potential COVID-19 therapeutics.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Pandemias , Peptidil Dipeptidase A/metabolismo , Internalização do Vírus
7.
Physiol Rep ; 11(3): e15598, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36750199

RESUMO

Hypertensive individuals taking anti-hypertensive drugs from renin-angiotensin system inhibitors may exhibit a more severe evolution of the disease when contracting the SARS-CoV-2 virus (COVID-19 disease) due to potential increases in ACE2 expression. The study investigated ACE1 and ACE2 axes and hydroxychloroquine in the lungs and adipose tissue of male and female normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHRs). SHRs were treated with losartan (10 mg/kg/day) or captopril (10 mg/kg/day) for 14 days or 7 days with hydroxychloroquine (200 mg/kg/day) in drinking water. WKY rats were also treated for 7 days with hydroxychloroquine. Blood pressure (BP), protein, and mRNA expression of ACE1 and ACE2 were analyzed in serum, adipose, and lung tissues. Losartan and captopril reduced BP in both sexes in SHR, whereas hydroxychloroquine increased BP in WKY rats. Losartan reduced ACE2 in serum and lungs in both sexes and in adipose tissue of male SHRs. Captopril decreased ACE2 protein in the lung of females and in adipose tissue in both sexes of SHRs. Hydroxychloroquine decreased ACE1 and ACE2 proteins in the lungs in both sexes and adipose tissue in male SHRs. In female WKY rats, ACE2 protein was lower only in the lungs and adipose tissue. Losartan effectively inhibited ACE2 in male and captopril in female SHRs. Hydroxychloroquine inhibited ACE2 in male SHRs and female WKY rats. These results further our understanding of the ACE2 mechanism in patients under renin-angiotensin anti-hypertensive therapy and in many trials using hydroxychloroquine for COVID-19 treatment and potential sex differences in response to drug treatment.


Assuntos
COVID-19 , Hipertensão , Animais , Feminino , Humanos , Masculino , Ratos , Tecido Adiposo/metabolismo , Enzima de Conversão de Angiotensina 2 , Anti-Hipertensivos/farmacologia , Pressão Sanguínea , Captopril/uso terapêutico , Tratamento Farmacológico da COVID-19 , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Losartan/farmacologia , Pulmão/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , SARS-CoV-2 , Peptidil Dipeptidase A/metabolismo
8.
Acta Biomed ; 94(1): e2023030, 2023 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-36786264

RESUMO

BACKGROUND AND AIM: Angiotensin-converting enzyme 2 (ACE2), transmembrane serine 2 and serine 11A proteases (TMPRSS2, TMPRSS11A), and a cell surface cluster of differentiation 147 (CD147) might be a gene candidate that exerts the susceptibility to and mortality from coronavirus disease 19 (COVID-19). The aim of this study was to investigate the associations between ace2, tmprss2, tmprss11a, and cd147 polymorphic variants and the severity of COVID-19 in the Ukrainian population. METHODS: The study population consisted of the Ukrainian population with COVID-19: patients without oxygen therapy (n=62), with non-invasive (n=92) and invasive (n=35) oxygen therapy, as well as control subjects (n=92). Allelic polymorphisms of ace2 rs4240157, tmprss2 rs12329760, and tmprss11a rs353163 were determined by real-time PCR, and cd147 rs8259 polymorphism was detected by PCR with subsequent restrictase analysis. We compared investigated polymorphisms distribution with other populations by meta-analysis. RESULTS: Our study is the first to obtain data about the distribution of investigated gene polymorphisms in the Ukrainian population: tmprss2 rs12329760 - CC 60.9%, CT 35.9%, TT 3.2%; tmprss11a rs353163 - CC 46.7%, CT 40.2%, TT 13.1%; ace2 rs4240157 - CC 7.6%, C 18.5%, CT 22.8%, TT 19.6%, T 31.5%; cd147 rs8259 - TT 60.9%, AT 32.6%, AA 6.5%. This distribution was similar to the Northern, Western and Southern European populations. There was a statistically significant difference in the frequency of tmprss2 polymorphic genotypes CC 57.1%, CT 28.6%, and TT 14.3% (P<0.05) in COVID-19 patients with invasive oxygen therapy in comparison with non-invasive oxygen therapy. This tmprss2 mutation occurs in the scavenger receptor cysteine-rich (SRCR) domain and might be important for protein-protein interaction in a calcium-dependent manner. CONCLUSIONS: Our study indicated the presence of an association between the tmprss2 rs12329760 polymorphism and the severity of COVID-19 in the Ukrainian population.


Assuntos
COVID-19 , Humanos , COVID-19/genética , Enzima de Conversão de Angiotensina 2/genética , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Polimorfismo Genético , Serina/genética , Oxigênio , Proteínas de Membrana/genética , Serina Proteases/genética , Serina Endopeptidases/genética
9.
Cell ; 186(5): 906-922, 2023 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-36787743

RESUMO

ACE2 is the indispensable entry receptor for SARS-CoV and SARS-CoV-2. Because of the COVID-19 pandemic, it has become one of the most therapeutically targeted human molecules in biomedicine. ACE2 serves two fundamental physiological roles: as an enzyme, it alters peptide cascade balance; as a chaperone, it controls intestinal amino acid uptake. ACE2's tissue distribution, affected by co-morbidities and sex, explains the broad tropism of coronaviruses and the clinical manifestations of SARS and COVID-19. ACE2-based therapeutics provide a universal strategy to prevent and treat SARS-CoV-2 infections, applicable to all SARS-CoV-2 variants and other emerging zoonotic coronaviruses exploiting ACE2 as their cellular receptor.


Assuntos
COVID-19 , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , Humanos , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2 , Peptidil Dipeptidase A/metabolismo , Pandemias
10.
J Transl Med ; 21(1): 103, 2023 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-36759834

RESUMO

BACKGROUND: Recent numerous epidemiology and clinical association studies reported that ApoE polymorphism might be associated with the risk and severity of coronavirus disease 2019 (COVID-19), and yielded inconsistent results. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptor expressed on host cell membranes. METHODS: A meta-analysis was conducted to clarify the association between ApoE polymorphism and the risk and severity of COVID-19. Multiple protein interaction assays were utilized to investigate the potential molecular link between ApoE and the SARS-CoV-2 primary receptor ACE2, ApoE and spike protein. Immunoblotting and immunofluorescence staining methods were used to access the regulatory effect of different ApoE isoform on ACE2 protein expression. RESULTS: ApoE gene polymorphism (ε4 carrier genotypes VS non-ε4 carrier genotypes) is associated with the increased risk (P = 0.0003, OR = 1.44, 95% CI 1.18-1.76) and progression (P < 0.00001, OR = 1.85, 95% CI 1.50-2.28) of COVID-19. ApoE interacts with both ACE2 and the spike protein but did not show isoform-dependent binding effects. ApoE4 significantly downregulates ACE2 protein expression in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1-7. CONCLUSIONS: ApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Instead, ApoE4 downregulates ACE2 protein expression and subsequently the dysregulation of renin-angiotensin system (RAS) may provide explanation by which ApoE4 exacerbates COVID-19 disease.


Assuntos
COVID-19 , Humanos , Sistema Renina-Angiotensina/fisiologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/farmacologia , SARS-CoV-2 , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteína E4/farmacologia , Regulação para Baixo/genética , Glicoproteína da Espícula de Coronavírus/genética , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo
11.
Sci Rep ; 13(1): 2351, 2023 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-36759535

RESUMO

The high magnitude zoonotic event has caused by Severe Acute Respitarory Syndrome CoronaVirus-2 (SARS-CoV-2) is Coronavirus Disease-2019 (COVID-19) epidemics. This disease has high rate of spreading than mortality in humans. The human receptor, Angiotensin-Converting Enzyme 2 (ACE2), is the leading target site for viral Spike-protein (S-protein) that function as binding ligands and are responsible for their entry in humans. The patients infected with COVID-19 with comorbidities, particularly cancer patients, have a severe effect or high mortality rate because of the suppressed immune system. Nevertheless, there might be a chance wherein cancer patients cannot be infected with SARS-CoV-2 because of mutations in the ACE2, which may be resistant to the spillover between species. This study aimed to determine the mutations in the sequence of the human ACE2 protein and its dissociation with SARS-CoV-2 that might be rejecting viral transmission. The in silico approaches were performed to identify the impact of SARS-CoV-2 S-protein with ACE2 mutations, validated experimentally, occurred in the patient, and reported in cell lines. The identified changes significantly affect SARS-CoV-2 S-protein interaction with ACE2, demonstrating the reduction in the binding affinity compared to SARS-CoV. The data presented in this study suggest ACE2 mutants have a higher and lower affinity with SARS-Cov-2 S-protein to the wild-type human ACE2 receptor. This study would likely be used to report SARS-CoV-2 resistant ACE2 mutations and can be used to design active peptide development to inactivate the viral spread of SARS-CoV-2 in humans.


Assuntos
COVID-19 , Humanos , COVID-19/genética , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Ligação Proteica/genética , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Mutação , Proteínas de Transporte/metabolismo
12.
PLoS Biol ; 21(2): e3001989, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36745682

RESUMO

Angiotensin-converting enzyme 2 (ACE2) is the cell-surface receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). While its central role in Coronavirus Disease 2019 (COVID-19) pathogenesis is indisputable, there remains significant debate regarding the role of this transmembrane carboxypeptidase in the disease course. These include the role of soluble versus membrane-bound ACE2, as well as ACE2-independent mechanisms that may contribute to viral spread. Testing these roles requires in vivo models. Here, we report humanized ACE2-floxed mice in which hACE2 is expressed from the mouse Ace2 locus in a manner that confers lethal disease and permits cell-specific, Cre-mediated loss of function, and LSL-hACE2 mice in which hACE2 is expressed from the Rosa26 locus enabling cell-specific, Cre-mediated gain of function. Following exposure to SARS-CoV-2, hACE2-floxed mice experienced lethal cachexia, pulmonary infiltrates, intravascular thrombosis and hypoxemia-hallmarks of severe COVID-19. Cre-mediated loss and gain of hACE2 demonstrate that neuronal infection confers lethal cachexia, hypoxemia, and respiratory failure in the absence of lung epithelial infection. In this series of genetic experiments, we demonstrate that ACE2 is absolutely and cell-autonomously required for SARS-CoV-2 infection in the olfactory epithelium, brain, and lung across diverse cell types. Therapies inhibiting or blocking ACE2 at these different sites are likely to be an effective strategy towards preventing severe COVID-19.


Assuntos
COVID-19 , Camundongos , Animais , Enzima de Conversão de Angiotensina 2/genética , SARS-CoV-2/metabolismo , Caquexia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Hipóxia
13.
J Med Virol ; 95(2): e28470, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36606602

RESUMO

Due to the COVID-19 pandemic, a series of sequelae, such as fatigue, tachypnea, and ageusia, appeared in long COVID patients, but the pathological basis was still uncertain. The targeted radiopharmaceuticals were of potential to systemically and dynamically trace the pathological changes. For the key ACE2 protein in the virus-host interaction, 68 Ga-cyc-DX600 was developed on the basis of DX600 as a PET tracer of ACE2 fluctuation and maintained the ability in differentiating ACE and ACE2. In the temporary infection model inhaled with the radio-traceable pseudovirus in the upper respiratory tract of male humanized ACE2 (hACE2) mice, organ-specific ACE2 dysfunction in acute period and the following ACE2 recovery in a relatively long period was visualized and quantified by ACE2 PET, revealing a complex pattern of virus concentration-dependent degree and time period-dependent tendency of ACE2 recovery, mainly a sudden decrease of apparent ACE2 in the heart, liver, kidneys, lungs, and so on, but the liver was of a quick functional compensation on ACE2 expression after a temporary decrease. ACE2 expression of most organs has recovered to a normal level at 15 days post inhalation, with brain and genitals still of a decreased SUVACE2 ;  meanwhile, kidneys were of an increased SUVACE2 . These findings on ACE2 PET were further verified by western blot. When compared with high-resolution computed tomography on structural changes and FDG PET on glycometabolism, ACE2 PET was superior in an earlier diagnostic window during infection and more comprehensive understanding of functional dysfunction post-infection. In the respective ACE2 PET/CT and ACE2 PET/MR scans of a volunteer, the repeatability of SUVACE2 and the ACE2 specificity were further confirmed. In conclusion, 68 Ga-cyc-DX600 was developed as an ACE2-specific tracer, and the corresponding ACE2 PET revealed the dynamic patterns of functional ACE2 recovery and provided a reference and approach to explore the ACE2-related pathological basis of sequelae in long COVID.


Assuntos
COVID-19 , Masculino , Humanos , Camundongos , Animais , Peptidil Dipeptidase A/metabolismo , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2 , Síndrome Pós-COVID-19 Aguda , Pandemias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
14.
Toxicology ; 486: 153442, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36706861

RESUMO

Previous studies suggest some link between formaldehyde exposure and harmful cardiovascular effects. But whether exposure to formaldehyde can cause blood pressure to rise, and if so, what the underlying mechanism is, remains unclear. In this study, C57BL/6 male mice were exposed to 0.1, 0.5, 2.5 mg/m3 of gaseous formaldehyde for 4 h daily over a three-week period. The systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP) and heart rate (HR) of the mice were measured by tail-cuff plethysmography, and any histopathological changes in the target organs of hypertension were investigated. The results showed that exposure to formaldehyde did cause a significant increase in blood pressure and heart rate, and resulted in varying degrees of damage to the heart, aortic vessels and kidneys. To explore the underlying mechanism, a specific inhibitor of angiotensin converting enzyme (ACE) was used to block the ACE/AT1R axis. We observed the levels of ACE and angiotensin II type 1 receptor (AT1R), as well as the bradykinin (BK) in cardiac cytoplasm. The data suggest that exposure to formaldehyde induced an increase in the expression of ACE and AT1R, and decreased the levels of BK. Strikingly, treatment with 5 mg/kg/d ACE inhibitor can attenuate the increase in blood pressure and the pathological changes caused by formaldehyde exposure. This result has improved our understanding of whether, and how, formaldehyde exposure affects the development of hypertension.


Assuntos
Hipertensão , Peptidil Dipeptidase A , Animais , Masculino , Camundongos , Pressão Sanguínea , Bradicinina/metabolismo , Formaldeído/toxicidade , Hipertensão/induzido quimicamente , Camundongos Endogâmicos C57BL , Peptidil Dipeptidase A/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo
15.
Chemosphere ; 318: 137911, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36669534

RESUMO

It is now well-established that arsenic exposure induces hypertension in humans. Although arsenic-induced hypertension is reported in many epidemiological studies, the underlying molecular mechanism of arsenic-induced hypertension is not fully characterized. In the human body, blood pressure is primarily regulated by a well-known physiological system known as the renin-angiotensin system (RAS). Hence, we explored the potential molecular mechanisms of arsenic-induced hypertension by investigating the regulatory roles of the RAS. Adult C57BL/6JJcl male mice were divided into four groups according to the concentration of arsenic in drinking water (0, 8, 80, and 800 ppb) provided for 8 weeks. Arsenic significantly raised blood pressure in arsenic-exposed mice compared to the control group, and significantly raised plasma MDA and Ang II and reduced Ang (1-7) levels. RT-PCR results showed that arsenic significantly downregulated ACE2 and MasR in mice aortas. In vitro studies of endothelial HUVEC cells treated with arsenic showed increased level of MDA and Ang II and lower levels of Ang (1-7), compared with the control. Arsenic significantly downregulated ACE2 and MasR expression, as well as those of Sp1 and SIRT1; transcriptional activators of ACE2, in HUVECs. Arsenic also upregulated markers of endothelial dysfunction (MCP-1, ICAM-1) and inflammatory cytokines (IL-6, TNF-α) in HUVECs. Our findings suggest that arsenic-induced hypertension is mediated, at least in part, by oxidative stress-mediated inhibition of ACE2 as well as by suppressing the vasoprotective axes of RAS, in addition to the activation of the classical axis.


Assuntos
Arsênio , Hipertensão , Animais , Humanos , Masculino , Camundongos , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Arsênio/toxicidade , Hipertensão/metabolismo , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina/fisiologia
16.
Nat Microbiol ; 8(1): 121-134, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36604514

RESUMO

The coronavirus SARS-CoV-2 causes the severe disease COVID-19. SARS-CoV-2 infection is initiated by interaction of the viral spike protein and host receptor angiotensin-converting enzyme 2 (ACE2). We report an improved bright and reversible fluorogenic reporter, named SURF (split UnaG-based reversible and fluorogenic protein-protein interaction reporter), that we apply to monitor real-time interactions between spike and ACE2 in living cells. SURF has a large dynamic range with a dark-to-bright fluorescence signal that requires no exogenous cofactors. Utilizing this reporter, we carried out a high-throughput screening of small-molecule libraries. We identified three natural compounds that block replication of SARS-CoV-2 in both Vero cells and human primary nasal and bronchial epithelial cells. Cell biological and biochemical experiments validated all three compounds and showed that they block the early stages of viral infection. Two of the inhibitors, bruceine A and gamabufotalin, were also found to block replication of the Delta and Omicron variants of SARS-CoV-2. Both bruceine A and gamabufotalin exhibited potent antiviral activity in K18-hACE2 and wild-type C57BL6/J mice, as evidenced by reduced viral titres in the lung and brain, and protection from alveolar and peribronchial inflammation in the lung, thereby limiting disease progression. We propose that our fluorescent assay can be applied to identify antiviral compounds with potential as therapeutic treatment for COVID-19 and other respiratory diseases.


Assuntos
COVID-19 , SARS-CoV-2 , Chlorocebus aethiops , Camundongos , Humanos , Animais , SARS-CoV-2/metabolismo , Células Vero , Enzima de Conversão de Angiotensina 2 , Peptidil Dipeptidase A/metabolismo , Antivirais/farmacologia
17.
Int J Biol Macromol ; 230: 123138, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36610577

RESUMO

The moth bean is a high-protein food legume. Enzymatic hydrolysates of food proteins demostrate health benefits. Search for diet related food protein hydrolysates is therefore within the scope of functional foods. Present study asertains to produce, screen and identify natural ACE-I inhibitory peptides derived from moth bean seed protein hydrolysates. The extracted protein was hydrolysed using alcalase, chymotrypsin, flavourzyme, papain, pepsin and trypsin respectively. Alcalase achieved the greatest degree of hydrolysis and ACE inhibition. The highest ACE-I inhibitory activity was exhibited by the peptide with the lowest molecular weight i.e. <3 kDa (IC50 11.19 ± 0.15 µg/mL). This was further separated by FPLC, followed by mass spectrometry. Molecular docking analysis showed the peptides IAWDFR and ADLPGLK bind to active sites whereas DKPWWPK and AVIPNAPNLR to non-active sites of the ACE molecule. In vivo administration of MBP hydrolysate to dexamethasone-induced hypertensive rats reduced their systolic blood pressure (125 ± 0.76 mmHg) compared with positive control (155 ± 3.13 mmHg). Moth bean protein peptides exhibit functional nutraceutical properties with adequate antihypertensive activity.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Vigna , Animais , Ratos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/química , Angiotensinas , Anti-Hipertensivos/química , Hidrólise , Simulação de Acoplamento Molecular , Peptídeos/química , Peptidil Dipeptidase A/metabolismo , Hidrolisados de Proteína/química , Subtilisinas/metabolismo , Tripsina/metabolismo , Vigna/metabolismo , Sementes/química
18.
Sci Rep ; 13(1): 953, 2023 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-36653504

RESUMO

We aimed to assess the systemic and hepatic renin-angiotensin-system (RAS) fingerprint in advanced chronic liver disease (ACLD). This prospective study included 13 compensated (cACLD) and 12 decompensated ACLD (dACLD) patients undergoing hepatic venous pressure gradient (HVPG) measurement. Plasma components (all patients) and liver-local enzymes (n = 5) of the RAS were analyzed using liquid chromatography-tandem mass spectrometry. Patients with dACLD had significantly higher angiotensin (Ang) I, Ang II and aldosterone plasma levels. Ang 1-7, a major mediator of the alternative RAS, was almost exclusively detectable in dACLD (n = 12/13; vs. n = 1/13 in cACLD). Also, dACLD patients had higher Ang 1-5 (33.5 pmol/L versus cACLD: 6.6 pmol/L, p < 0.001) and numerically higher Ang III and Ang IV levels. Ang 1-7 correlated with HVPG (ρ = 0.655; p < 0.001), von Willebrand Factor (ρ = 0.681; p < 0.001), MELD (ρ = 0.593; p = 0.002) and interleukin-6 (ρ = 0.418; p = 0.047). Considerable activity of ACE, chymase, ACE2, and neprilysin was detectable in all liver biopsies, with highest chymase and ACE2 activity in cACLD patients. While liver-local classical and alternative RAS activity was already observed in cACLD, systemic activation of alternative RAS components occurred only in dACLD. Increased Ang 1-7 was linked to severe liver disease, portal hypertension, endothelial dysfunction and inflammation.


Assuntos
Hipertensão Portal , Doenças Vasculares , Humanos , Sistema Renina-Angiotensina/fisiologia , Quimases , Enzima de Conversão de Angiotensina 2 , Estudos Prospectivos , Cirrose Hepática , Angiotensina II/metabolismo , Inflamação , Peptidil Dipeptidase A/metabolismo
19.
PLoS One ; 18(1): e0279578, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36595529

RESUMO

The SARS-CoV-2 virus is currently causing a global pandemic. Infection may result in a systemic disease called COVID-19, affecting primarily the respiratory tract. Often the gastrointestinal tract and kidneys also become involved. Angiotensin converting enzyme 2 (ACE2) serves as the receptor for SARS-CoV-2. The membrane proteins, Transmembrane serine protease 2 (TMPRSS2) and Neuropilin 1 (NRP1) are accessory proteins facilitating the virus entry. In this study we show that the human proximal kidney tubules, express these factors. We hypothesized that cancers derived from proximal tubules as clear cell (CCRCC) and papillary renal cell carcinoma (PRCC), retain the expression of the SARS-CoV-2 entry factors making these cancers susceptible to SARS-CoV-2 infection. We used bioinformatics, western blotting, and assessment of tissue micro arrays (TMA) including 263 cases of CCRCC, 139 cases of PRCC and 18 cases of chromophobe RCC to demonstrate that the majority of CCRCC and PRCC cases retained the RNA and protein expression of the entry factors for SARS-CoV-2. We furthermore show that SARS-CoV-2 virus propagated robustly in primary cultures of CCRCC and PRCC cells with a visible virus cytopathogenic effect correlating with viral RNA expression levels. We also noted that the delta-variant of SARS-CoV-2 causes cancer cells to form syncytia in-vitro. This phenomenon was also identified histologically in CCRCC tissue from a patient that had been hospitalized for COVID-19, twelve months prior to nephrectomy. Our data provide insights into SARS-CoV-2 infectivity in renal cell carcinoma and that the virus causes a distinct cytopathogenic effect.


Assuntos
COVID-19 , Carcinoma de Células Renais , Neoplasias Renais , Humanos , SARS-CoV-2/metabolismo , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/metabolismo , Peptidil Dipeptidase A/metabolismo , Neoplasias Renais/metabolismo , Internalização do Vírus
20.
Semin Respir Crit Care Med ; 44(1): 21-34, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36646083

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has caused a devastating impact on morbidity and mortality around the world. Severe acute respiratory syndrome-coronavirus-2 has a characteristic tropism for the cardiovascular system by entering the host cells and binding to angiotensin-converting enzyme 2 receptors, which are expressed in different cells, particularly endothelial cells. This endothelial injury is linked by a direct intracellular viral invasion leading to inflammation, microthrombosis, and angiogenesis. COVID-19 has been associated with acute myocarditis, cardiac arrhythmias, new onset or worsening heart failure, ischemic heart disease, stroke, and thromboembolic disease. This review summarizes key relevant literature regarding the epidemiology, diagnosis, treatment, and preventive measures related to cardiovascular complications in the setting of COVID-19.


Assuntos
COVID-19 , Doenças Cardiovasculares , Humanos , COVID-19/complicações , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Peptidil Dipeptidase A/metabolismo , SARS-CoV-2 , Inflamação/complicações , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/complicações
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