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1.
J Virol ; 98(3): e0180223, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38334329

RESUMO

With a high incidence of acute kidney injury among hospitalized COVID-19 patients, considerable attention has been focussed on whether SARS-CoV-2 specifically targets kidney cells to directly impact renal function, or whether renal damage is primarily an indirect outcome. To date, several studies have utilized kidney organoids to understand the pathogenesis of COVID-19, revealing the ability for SARS-CoV-2 to predominantly infect cells of the proximal tubule (PT), with reduced infectivity following administration of soluble ACE2. However, the immaturity of standard human kidney organoids represents a significant hurdle, leaving the preferred SARS-CoV-2 processing pathway, existence of alternate viral receptors, and the effect of common hypertensive medications on the expression of ACE2 in the context of SARS-CoV-2 exposure incompletely understood. Utilizing a novel kidney organoid model with enhanced PT maturity, genetic- and drug-mediated inhibition of viral entry and processing factors confirmed the requirement for ACE2 for SARS-CoV-2 entry but showed that the virus can utilize dual viral spike protein processing pathways downstream of ACE2 receptor binding. These include TMPRSS- and CTSL/CTSB-mediated non-endosomal and endocytic pathways, with TMPRSS10 likely playing a more significant role in the non-endosomal pathway in renal cells than TMPRSS2. Finally, treatment with the antihypertensive ACE inhibitor, lisinopril, showed negligible impact on receptor expression or susceptibility of renal cells to infection. This study represents the first in-depth characterization of viral entry in stem cell-derived human kidney organoids with enhanced PTs, providing deeper insight into the renal implications of the ongoing COVID-19 pandemic. IMPORTANCE: Utilizing a human iPSC-derived kidney organoid model with improved proximal tubule (PT) maturity, we identified the mechanism of SARS-CoV-2 entry in renal cells, confirming ACE2 as the sole receptor and revealing redundancy in downstream cell surface TMPRSS- and endocytic Cathepsin-mediated pathways. In addition, these data address the implications of SARS-CoV-2 exposure in the setting of the commonly prescribed ACE-inhibitor, lisinopril, confirming its negligible impact on infection of kidney cells. Taken together, these results provide valuable insight into the mechanism of viral infection in the human kidney.


Assuntos
Enzima de Conversão de Angiotensina 2 , Rim , Organoides , SARS-CoV-2 , Internalização do Vírus , Humanos , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/complicações , COVID-19/virologia , Rim/citologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/virologia , Lisinopril/farmacologia , Lisinopril/metabolismo , Organoides/citologia , Organoides/efeitos dos fármacos , Organoides/metabolismo , Organoides/virologia , Pandemias , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/virologia , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/virologia , Receptores de Coronavírus/metabolismo , Modelos Biológicos , Serina Endopeptidases/metabolismo , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Endossomos/virologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células-Tronco/citologia
2.
Environ Sci Pollut Res Int ; 30(9): 23263-23275, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36319925

RESUMO

Sodium fluoride (NaF) is one of the neglected environmental toxicants that has continued to silently cause toxicity to both humans and animals. NaF is universally present in water, soil, and atmosphere. The persistent and alarming rate of increase in cardiovascular and renal diseases caused by chemicals such as NaF in mammalian tissues has led to the use of various drugs for the treatment of these diseases. The present study aimed at evaluating the renoprotective and antihypertensive effects of L-arginine against NaF-induced nephrotoxicity. Thirty male Wistar rats (150-180 g) were used in this study. The rats were randomly divided into five groups of six rats each as follows: Control, NaF (300 ppm), NaF + L-arginine (100 mg/kg), NaF + L-arginine (200 mg/kg), and NaF + lisinopril (10 mg/kg). Histopathological examination and immunohistochemistry of renal angiotensin-converting enzyme (ACE) and mineralocorticoid receptor (MCR) were performed. Markers of renal damage, oxidative stress, antioxidant defense system, and blood pressure parameters were determined. L-arginine and lisinopril significantly (P < 0.05) ameliorated the hypertensive effects of NaF. The systolic, diastolic, and mean arterial blood pressure of the treated groups were significantly (P < 0.05) reduced compared with the hypertensive group. This finding was concurrent with significantly increased serum bioavailability of nitric oxide in the hypertensive rats treated with L-arginine and lisinopril. Also, there was a significant reduction in the level of blood urea nitrogen and creatinine of hypertensive rats treated with L-arginine and lisinopril. There was a significant (P < 0.05) reduction in markers of oxidative stress such as malondialdehyde and protein carbonyl and concurrent increase in the levels of antioxidant enzymes in the kidney of hypertensive rats treated with L-arginine and lisinopril. The results of this study suggest that L-arginine and lisinopril normalized blood pressure, reduced oxidative stress, and the expression of renal ACE and mineralocorticoid receptor, and improved nitric oxide production. Thus, L-arginine holds promise as a potential therapy against hypertension and renal damage.


Assuntos
Hipertensão , Lisinopril , Humanos , Ratos , Masculino , Animais , Lisinopril/metabolismo , Lisinopril/farmacologia , Lisinopril/uso terapêutico , Fluoreto de Sódio/toxicidade , Antioxidantes/metabolismo , Óxido Nítrico/metabolismo , Receptores de Mineralocorticoides/metabolismo , Receptores de Mineralocorticoides/uso terapêutico , Ratos Wistar , Hipertensão/induzido quimicamente , Rim , Pressão Sanguínea , Estresse Oxidativo , Arginina/metabolismo , Arginina/farmacologia , Arginina/uso terapêutico , Suplementos Nutricionais , Angiotensinas/metabolismo , Angiotensinas/farmacologia , Angiotensinas/uso terapêutico , Mamíferos
3.
Biopharm Drug Dispos ; 43(6): 233-246, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36299167

RESUMO

Lisinopril is an antihypertensive drug with poor intestinal permeability. Enhancement of intestinal absorption depends on a clear understanding of the permeation pathways and absorption mechanisms. Unfortunately, these are not fully elucidated for lisinopril. Accordingly, the aim was to determine lisinopril permeation pathways and obstacles limiting membrane transport with subsequent nomination of appropriate permeation enhancers. This employed an in situ rabbit intestinal perfusion technique, which revealed site-dependent absorptive clearance (PeA/L) from a lisinopril simple solution (5 µg/ml), with paracellular absorption playing a role. Regional drug permeability ranked as colon> duodenum> jejunum> ileum opposing intestinal expression rank of P-glycoprotein (P-gp) efflux transporters. Duodenal and jejunal perfusion of a higher lisinopril concentration (50 µg/ml) reflected saturable absorption, suggesting carrier-mediated transport. The effect of piperine and verapamil as P-gp inhibitors on intestinal absorption of lisinopril was investigated. Coperfusion with either piperine or verapamil significantly enhanced lisinopril absorption, with enhancement being dominant in the ileum segment. This supported the contribution of P-gp transporters to poor lisinopril permeability. On the other hand, coperfusion of lisinopril with zinc acetate dihydrate significantly multiplied lisinopril PeA/L by 2.3- and 6.6-fold in duodenum and ileum segments, respectively, through magnifying intestinal water flux. The study explored the barriers limiting lisinopril intestinal absorption. Moreover, the study exposed clinically relevant lisinopril interactions with common coadministered cargos that should be considered for an appropriate lisinopril regimen. However, this requires further in vivo verification.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Lisinopril , Animais , Coelhos , Lisinopril/farmacologia , Lisinopril/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Absorção Intestinal , Verapamil/farmacologia , Permeabilidade , Mucosa Intestinal/metabolismo
4.
Fundam Clin Pharmacol ; 36(6): 992-1004, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35697514

RESUMO

Low serum concentrations of the amino acid homoarginine (HA) are associated with increased cardiovascular mortality by incompletely understood mechanisms. This study sought to assess the influence of HA on cardiac remodeling in rats undergoing either transaortic banding or inhibition of nitric oxide synthesis by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). Male Wistar rats (n = 136) underwent sham operation (SH) or aortic banding (AB). Both groups were equally divided into 14 subgroups, receiving different doses of HA alone or in combination with lisinopril, spironolactone, or L-NAME for 4 weeks. HA treatment in AB animals resulted in a dose-dependent improvement of cardiac function up to a concentration of 800 mg·kg-1 ·day-1 . Combining 800 mg·kg-1 ·day-1 HA with spironolactone or lisinopril yielded additional effects, showing a positive correlation with LV ejection fraction (+33%, p = 0.0002) and fractional shortening (+41%, p = 0.0014). An inverse association was observed with collagen area fraction (-41%, p < 0.0001), myocyte cross-sectional area (-22%, p < 0.0001) and the molecular markers atrial natriuretic factor (-74%, p = 0.0091), brain natriuretic peptide (-42%, p = 0.0298), beta-myosin heavy chain (-46%, p = 0.0411), and collagen type V alpha 1 chain (-73%, p = 0.0257) compared to placebo-treated AB animals. Co-administration of HA and L-NAME was found to attenuate cardiac remodeling and prevent NO-deficient hypertension following AB. HA treatment has led to a dose-dependent improvement of myocardial function and marked histological and molecular changes in cardiac remodeling following AB. Combining HA with standard heart failure medication resulted in additional beneficial effects boosting its direct impact on heart failure pathophysiology.


Assuntos
Insuficiência Cardíaca , Hipertensão , Ratos , Masculino , Animais , NG-Nitroarginina Metil Éster/farmacologia , Espironolactona/metabolismo , Espironolactona/farmacologia , Espironolactona/uso terapêutico , Homoarginina/metabolismo , Homoarginina/farmacologia , Homoarginina/uso terapêutico , Lisinopril/metabolismo , Lisinopril/farmacologia , Lisinopril/uso terapêutico , Remodelação Ventricular , Hipertensão/tratamento farmacológico , Ratos Wistar , Miocárdio/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Pressão Sanguínea
5.
Inflammopharmacology ; 30(5): 1909-1926, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35764864

RESUMO

BACKGROUND: Cardiovascular disorders are major complications of rheumatoid arthritis (RA). Hence, finding effective agents that can target RA progression and its cardiovascular consequences is demanding. The present work aimed to explore the potential of lisinopril, an angiotensin-converting enzyme inhibitor, to mitigate adjuvant's-induced arthritis with emphasis on the pro-inflammatory signals, articular degradation cues, and angiogenesis alongside JAK-2/STAT-3 and Nrf2/HO-1 pathways. METHODS: Lisinopril (10 mg/kg/day) was administered by oral gavage for 3 weeks and the target signals were examined by biochemical assays, ELISA, histopathology, immunoblotting, and immunohistochemistry. RESULTS: Lisinopril attenuated the progression of arthritis as proven by lowering paw edema, arthritic index, and gait scores alongside diminishing the immune-cell infiltration/aberrant histopathology in the dorsal pouch lining. These favorable actions were associated with curtailing the production of inflammatory cytokines (TNF-α, IL-6, IL-1ß, and IL-17) and the pro-inflammatory angiotensin II alongside upregulating the anti-inflammatory angiotensin-(1-7) in the hind paw of arthritic rats. At the molecular level, lisinopril inhibited the upstream JAK-2/STAT-3 pathway by downregulating the protein expression of p-JAK-2/total JAK-2 and p-STAT-3/total STAT-3 ratio and the nuclear levels of NF-κBp65. Meanwhile, lisinopril curbed the downstream cartilage degradation signals matrix metalloproteinases (MMP-3 and MMP-9) and the bone erosion cue RANKL. Equally important, the protein expression of the angiogenesis signal VEGF was downregulated in the hind paw/dorsal lining. With respect to oxidative stress, lisinopril suppressed the paw lipid peroxides and boosted GSH and Nrf-2/HO-1 pathway. CONCLUSION: Lisinopril attenuated adjuvant-induced arthritis via inhibition of inflammation, articular degradation cues, and angiogenesis.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Artrite Experimental , Artrite Reumatoide , Lisinopril , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Citocinas/metabolismo , Adjuvante de Freund , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Peróxidos Lipídicos , Lisinopril/metabolismo , Lisinopril/uso terapêutico , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Oxirredução , Ratos , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
Phys Chem Chem Phys ; 22(48): 28434-28439, 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33305304

RESUMO

The sudden arrival of novel coronavirus disease 2019 (COVID-19) has stunned the world with its rapidly spreading virus. Remdesivir, a broad spectrum anti-viral drug, is now under in vitro and in vivo investigation as a potential agent against SARS-CoV-2. However, the results of this therapy were recently equivocal due to no significant benefit in the clinical trial. Herein, combination molecular docking with dissipative particle dynamics (DPD) simulations is used to theoretically design angiotensin-converting enzyme inhibitor (ACEI)-containing remdesivir-loaded PLGA nanoparticles (NPs) for anti-SARS-CoV-2 therapy. Based on the therapeutic and lung protective effect of ACEI, the classical lisinopril molecule covalently grafted onto PLGA (L-PLGA) has been used to encapsulate remdesivir. A binding model is used to confirm the interactions between lisinopril and ACE on the surface of cells, as well as remdesivir and its intracellular targeting protein (RNA-dependent RNA polymerase (RdRp)). Furthermore, DPD simulations are applied to study the nano-aggregation of drug-free L-PLGA, and remdesivir loaded in L-PLGA. The lisinopril molecules were directly demonstrated to be on the surface of L-PLGA NPs. Molecular docking proved that hydrogen bonding was decisive for the encapsulation of remdesivir. With an increase in concentration, remdesivir loaded L-PLGA formed spherical NPs, and then underwent precipitation. Similar to the above conditions, high remdesivir loading was also observed to cause precipitation formation. Thus, the optimized remdesivir NPs in our study give insights into a rational platform for formulation design against this global pandemic.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Antivirais/metabolismo , Portadores de Fármacos/química , Lisinopril/metabolismo , Nanopartículas/química , Monofosfato de Adenosina/química , Monofosfato de Adenosina/metabolismo , Alanina/química , Alanina/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Inibidores da Enzima Conversora de Angiotensina/química , Antivirais/química , Sinergismo Farmacológico , Humanos , Lisinopril/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ligação Proteica , SARS-CoV-2/efeitos dos fármacos , Tratamento Farmacológico da COVID-19
7.
Metabolomics ; 15(10): 133, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31583478

RESUMO

INTRODUCTION: Only ~ 50% of hypertensive patients will respond to treatment. OBJECTIVE: This pilot study aims to identify clinical and metabolite markers that predict response to lisinopril. METHODS: Hypertensive patients (n = 45) received lisinopril (10 mg) at their baseline visit. Blood pressures were reevaluated one week later. Responders to lisinopril (n = 19) were defined by a 10% decline in systolic blood pressure. Plasma metabolites were evaluated with mass spectrometry. RESULTS: BMI (p = 0.009), GFR (p = 0.015) and 2-oxoglutarate were included in a logistic regression model to predict response to lisinopril. CONCLUSIONS: Further validation cohorts are needed to confirm the predictive values of these clinical and metabolic markers.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Lisinopril/farmacologia , Anti-Hipertensivos/sangue , Anti-Hipertensivos/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Humanos , Hipertensão/sangue , Hipertensão/metabolismo , Lisinopril/sangue , Lisinopril/metabolismo , Espectrometria de Massas , Metabolômica , Projetos Piloto , Análise de Regressão
8.
Cell Biochem Biophys ; 76(3): 357-376, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29687225

RESUMO

The Influenza A virus is one of the principle causes of respiratory illness in human. The surface glycoprotein of the influenza virus, neuraminidase (NA), has a vital role in the release of new viral particle and spreads infection in the respiratory tract. It has been long recognized as a valid drug target for influenza A virus infection. Oseltamivir is used as a standard drug of choice for the treatment of influenza. However, the emergence of mutants with novel mutations has increased the resistance to potent NA inhibitor. In the present investigation, we have employed computer-assisted combinatorial techniques in the screening of 8621 molecules from Drug Bank to find potent NA inhibitors. A three-dimensional pharmacophore model was generated from the previously reported 28 carbocylic influenza NA inhibitors along with oseltamivir using PHASE module of Schrödinger Suite. The model generated consists of one hydrogen bond acceptor (A), one hydrogen bond donors (D), one hydrophobic group (H), and one positively charged group (P), ADHP. The hypothesis was further validated for its integrity and significance using enrichment analysis. Subsequently, an atom-based 3D-QSAR model was built using the common pharmacophore hypothesis (CPH). The developed 3D-QSAR model was found to be statistically significant with R2 value of 0.9866 and Q2 value of 0.7629. Further screening was accomplished using three-stage docking process using the Glide algorithm. The resultant lead molecules were examined for its drug-like properties using the Qikprop algorithm. Finally, the calculated pIC50 values of the lead compounds were validated by the AutoQSAR algorithm. Overall, the results from our analysis highlights that lisinopril (DB00722) is predicted to bind better with NA than currently approved drug. In addition, it has the best match in binding geometry conformations with the existing NA inhibitor. Note that the antiviral activity of lisinopril is reported in the literature. However, our paper is the first report on lisinopril activity against influenza A virus infection. These results are envisioned to help design the novel NA inhibitors with an increased antiviral efficacy.


Assuntos
Reposicionamento de Medicamentos/métodos , Inibidores Enzimáticos/metabolismo , Neuraminidase/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Antivirais/uso terapêutico , Sítios de Ligação , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Humanos , Ligação de Hidrogênio , Influenza Humana/tratamento farmacológico , Ligantes , Lisinopril/química , Lisinopril/metabolismo , Lisinopril/uso terapêutico , Conformação Molecular , Neuraminidase/metabolismo , Oseltamivir/química , Oseltamivir/metabolismo , Oseltamivir/uso terapêutico
9.
Drug Metab Dispos ; 44(4): 485-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26758854

RESUMO

Resveratrol undergoes extensive metabolism to form biologically active glucuronides in humans. However, the transport mechanisms for resveratrol glucuronides are not fully established. Here, we aimed to characterize the efflux transport of resveratrol glucuronides using UGT1A1-overexpressing HeLa cells (HeLa1A1 cells), and to determine the contribution of multidrug resistance-associated protein (MRP) 4 to cellular excretion of the glucuronides. Two glucuronide isomers [i.e., resveratrol 3-O-glucuronide (R3G) and resveratrol 4'-O-glucuronide (R4'G)] were excreted into the extracellular compartment after incubation of resveratrol (1-100 µM) with HeLa1A1 cells. The excretion rate was linearly related to the level of intracellular glucuronide, indicating that glucuronide efflux was a nonsaturable process. MK-571 (a dual inhibitor of UGT1A1 and MRPs) significantly decreased the excretion rates of R3G and R4'G while increasing their intracellular levels. Likewise, short-hairpin RNA (shRNA)-mediated silencing of MRP4 caused a significant reduction in glucuronide excretion but an elevation in glucuronide accumulation. Furthermore, ß-glucuronidase expressed in the cells catalyzed the hydrolysis of the glucuronides back to the parent compound. A cellular pharmacokinetic model integrating resveratrol transport/metabolism with glucuronide hydrolysis/excretion was well fitted to the experimental data, allowing derivation of the efflux rate constant values in the absence or presence of shRNA targeting MRP4. It was found that a large percentage of glucuronide excretion (43%-46%) was attributed to MRP4. In conclusion, MRP4 participated in cellular excretion of R3G and R4'G. Integration of mechanistic pharmacokinetic modeling with transporter knockdown was a useful method to derive the contribution percentage of an exporter to overall glucuronide excretion.


Assuntos
Líquido Extracelular/metabolismo , Glucuronídeos/metabolismo , Glucuronosiltransferase/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Estilbenos/metabolismo , Transfecção , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Relação Dose-Resposta a Droga , Líquido Extracelular/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/genética , Células HeLa , Humanos , Lisinopril/metabolismo , Lisinopril/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Transfecção/métodos
10.
Protein J ; 32(5): 356-64, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23660814

RESUMO

Angiotensin converting enzyme (ACE) cleaves amyloid beta peptide. So far this cleavage mechanism has not been studied in detail at atomic level. Keeping this view in mind, we performed molecular dynamics simulation of crystal structure complex of testis truncated version of ACE (tACE) and its inhibitor lisinopril along with Zn(2+) to understand the dynamic behavior of active site residues of tACE. Root mean square deviation results revealed the stability of tACE throughout simulation. The residues Ala 354, Glu 376, Asp 377, Glu 384, His 513, Tyr 520 and Tyr 523 of tACE stabilized lisinopril by hydrogen bonding interactions. Using this information in subsequent part of study, molecular docking of tACE crystal structure with Aß-peptide has been made to investigate the interactions of Aß-peptide with enzyme tACE. The residues Asp 7 and Ser 8 of Aß-peptide were found in close contact with Glu 384 of tACE along with Zn(2+). This study has demonstrated that the residue Glu 384 of tACE might play key role in the degradation of Aß-peptide by cleaving peptide bond between Asp 7 and Ser 8 residues. Molecular basis generated by this attempt could provide valuable information towards designing of new therapies to control Aß concentration in Alzheimer's patient.


Assuntos
Peptídeos beta-Amiloides/química , Inibidores da Enzima Conversora de Angiotensina/química , Lisinopril/química , Peptidil Dipeptidase A/química , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Domínio Catalítico , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lisinopril/metabolismo , Masculino , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptidil Dipeptidase A/metabolismo , Testículo/enzimologia , Zinco/química , Zinco/metabolismo
11.
Kardiologiia ; 53(2): 38-42, 2013.
Artigo em Russo | MEDLINE | ID: mdl-23548389

RESUMO

We assessed effect of lisinopril on structural-functional state of vascular bed in 82 premenopausal women with hypoestrogenia and arterial hypertension (AH). Test with postocclusion reactive hyperemia showed that at the background of significant lowering of endothelial vasomotor function before treatment 47.5% of women had inertial type of vasomotor reaction. This evidenced for considerable role of dyshormonal states in progression of AH first of all at the account of increase of vascular stiffness and development of endothelial dysfunction. Lisinopril improved structural-functional state of vascular wall of common carotid arteries, affected positively dysfunction of endothelium, lowered stiffness of arterial vascular wall.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Hipertensão , Lisinopril , Pré-Menopausa , Inibidores da Enzima Conversora de Angiotensina , Monitoramento de Medicamentos , Endotélio/metabolismo , Endotélio/fisiopatologia , Feminino , Humanos , Hiperemia/etiologia , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/etiologia , Lisinopril/administração & dosagem , Lisinopril/metabolismo , Pessoa de Meia-Idade , Pré-Menopausa/efeitos dos fármacos , Pré-Menopausa/metabolismo , Resultado do Tratamento , Rigidez Vascular/efeitos dos fármacos
12.
J Am Soc Hypertens ; 7(2): 128-36, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23312967

RESUMO

Identification of angiotensin-(1-12) [Ang-(1-12)] in forming angiotensin II (Ang II) by a non-renin dependent mechanism has increased knowledge on the paracrine/autocrine mechanisms regulating cardiac expression of Ang peptides. This study now describes in humans the identity of the enzyme accounting for Ang-(1-12) metabolism in the left ventricular (LV) tissue of normal subjects. Reverse phase HPLC characterized the products of (125)I-Ang-(1-12) metabolism in plasma membranes (PMs) from human LV in the absence and presence of inhibitors for chymase (chymostatin), angiotensin-converting enzyme (ACE) 1 (lisinopril) and 2 (MLN-4760), and neprilysin (SHC39370). In the presence of the inhibitor cocktail, ≥ 98% ± 2% of cardiac (125)I-Ang-(1-12) remained intact, whereas exclusion of chymostatin from the inhibitor cocktail led to significant conversion of Ang-(1-12) into Ang II. In addition, chymase-mediated hydrolysis of (125)I-Ang I was higher compared with Ang-(1-12). Negligible Ang-(1-12) hydrolysis occurred by ACE, ACE2, and neprilysin. A high chymase activity was detected for both (125)I-Ang-(1-12) and (125)I-Ang I substrates. Chymase accounts for the conversion of Ang-(1-12) and Ang I to Ang II in normal human LV. These novel findings expand knowledge of the alternate mechanism by which Ang-(1-12) contributes to the production of cardiac angiotensin peptides.


Assuntos
Angiotensinas/metabolismo , Quimases/metabolismo , Ventrículos do Coração/metabolismo , Adulto , Análise de Variância , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Western Blotting , Membrana Celular/metabolismo , Cromatografia Líquida de Alta Pressão , Feminino , Regulação Enzimológica da Expressão Gênica , Ventrículos do Coração/citologia , Ventrículos do Coração/enzimologia , Humanos , Hidrólise , Imidazóis/metabolismo , Imuno-Histoquímica , Radioisótopos do Iodo , Leucina/análogos & derivados , Leucina/metabolismo , Lisinopril/metabolismo , Masculino , Pessoa de Meia-Idade , Neprilisina/metabolismo
13.
Peptides ; 34(2): 395-403, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22369721

RESUMO

The purpose of this study was to construct stably transfected HeLa cells with human peptide transporters (hPEPT1/hPEPT2) and to identify the function of the transfected cells using the substrate JBP485 (a dipeptide) and a typical substrate for PEPTs, glycylsarcosine (Gly-Sar). An efficient and rapid method was established for the preparation and transformation of competent cells of Escherichia coli. After extraction and purification, hPEPT1/hPEPT2-pcDNA3 was transfected into HeLa cells by the liposome transfection method, respectively. HeLa-hPEPT1/hPEPT2 cells were selected by measuring the protein expression and the uptake activities of JBP485 and Gly-Sar. A simple and rapid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of JBP485 and Gly-Sar in biological samples. The Michaelis-Menten constant (K(m)) values of Gly-Sar uptake by the hPEPT1 and hPEPT2-expressing transfectants were 1.03 mM and 0.0965 mM, respectively, and the K(m) values of JBP485 uptake were 1.33 mM for PEPT1 and 0.144 mM for PEPT2. The uptake of Gly-Sar was significantly inhibited by JBP485 with a K(i) value of 8.11 mM (for PEPT1) and 1.05 mM (for PEPT2). Maximal uptake of Gly-Sar were detected at pH 5.8 (for PEPT1) and pH 6.5 (for PEPT2), suggesting that both HeLa-hPEPT1 and HeLa-hPEPT2 were H(+) dependent transporters. Stably transfected HeLa-hPEPT1/HeLa-hPEPT2 cells were constructed successfully, and the functions of hPEPT1/hPEPT2 were identified using their substrates, JBP485 and Gly-Sar. The transfected cells with transporters were used to investigate drug-drug interactions (DDIs) between JBP485 and other substrates (cephalexin or lisinopril) of PEPT1 and PEPT2.


Assuntos
Engenharia Celular/métodos , Simportadores/metabolismo , Transporte Biológico/efeitos dos fármacos , Cefalexina/metabolismo , Cefalexina/farmacologia , Cromatografia Líquida , Dipeptídeos/metabolismo , Dipeptídeos/farmacologia , Interações Medicamentosas , Escherichia coli , Expressão Gênica , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Cinética , Lipossomos/química , Lisinopril/metabolismo , Lisinopril/farmacologia , Transportador 1 de Peptídeos , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacologia , Plasmídeos/genética , Simportadores/genética , Espectrometria de Massas em Tandem , Transfecção
14.
Drug Metab Pharmacokinet ; 27(2): 232-41, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22123131

RESUMO

The purpose of this study was to clarify the pharmacokinetic mechanism of interaction between JBP485 (cyclo-trans-4-L-hydroxyprolyl-L-serine, a dipeptide with antihepatitis activity) and lisinopril (an angiotensin-converting enzyme inhibitor) in vitro and in vivo. When JBP485 and lisinopril were administered orally simultaneously, the plasma concentrations of the two drugs were decreased significantly, but few changes were observed after simultaneous intravenous administration of the two drugs. The uptake of JBP485 and lisinopril in everted intestinal sacs and in HeLa cells transfected with human peptide cotransporter 1 (PEPT1), as well as absorption of JBP485 and lisinopril after jejunal perfusion were reduced after simultaneous drug administration, which suggested that the first target of drug interaction was PEPT1 in the intestine during the absorption process. The cumulative urinary excretions and renal clearance of the two drugs were decreased after intravenous co-administration, while uptakes of the two drugs in kidney slices and hOAT1/hOAT3-transfected HEK293 cells were decreased. These results indicated that the second target of drug-drug interaction was located in the kidney. These findings confirmed that the pharmacokinetic mechanism of interaction between JBP485 and lisinopril could be explained by their inhibition of the same transporters in the intestinal mucosa (PEPT1) and kidneys (OATs).


Assuntos
Mucosa Intestinal/metabolismo , Rim/metabolismo , Lisinopril/metabolismo , Proteína 1 Transportadora de Ânions Orgânicos , Transportadores de Ânions Orgânicos/metabolismo , Peptídeos Cíclicos/metabolismo , Simportadores/metabolismo , Animais , Sistemas de Liberação de Medicamentos/métodos , Interações Medicamentosas/fisiologia , Células HEK293 , Células HeLa , Humanos , Mucosa Intestinal/efeitos dos fármacos , Rim/efeitos dos fármacos , Lisinopril/administração & dosagem , Masculino , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Transportador 1 de Peptídeos , Peptídeos Cíclicos/administração & dosagem , Ratos , Ratos Sprague-Dawley
15.
PLoS Negl Trop Dis ; 4(12): e918, 2010 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-21179504

RESUMO

Leptospirosis is a widespread zoonotic infection that primarily affects residents of tropical regions, but causes infections in animals and humans in temperate regions as well. The agents of leptospirosis comprise several members of the genus Leptospira, which also includes non-pathogenic, saprophytic species. Leptospirosis can vary in severity from a mild, non-specific illness to severe disease that includes multi-organ failure and widespread endothelial damage and hemorrhage. To begin to investigate how pathogenic leptospires affect endothelial cells, we compared the responses of two endothelial cell lines to infection by pathogenic versus non-pathogenic leptospires. Microarray analyses suggested that pathogenic L. interrogans and non-pathogenic L. biflexa triggered changes in expression of genes whose products are involved in cellular architecture and interactions with the matrix, but that the changes were in opposite directions, with infection by L. biflexa primarily predicted to increase or maintain cell layer integrity, while L. interrogans lead primarily to changes predicted to disrupt cell layer integrity. Neither bacterial strain caused necrosis or apoptosis of the cells even after prolonged incubation. The pathogenic L. interrogans, however, did result in significant disruption of endothelial cell layers as assessed by microscopy and the ability of the bacteria to cross the cell layers. This disruption of endothelial layer integrity was abrogated by addition of the endothelial protective drug lisinopril at physiologically relevant concentrations. These results suggest that, through adhesion of L. interrogans to endothelial cells, the bacteria may disrupt endothelial barrier function, promoting dissemination of the bacteria and contributing to severe disease manifestations. In addition, supplementing antibiotic therapy with lisinopril or derivatives with endothelial protective activities may decrease the severity of leptospirosis.


Assuntos
Células Endoteliais/microbiologia , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno , Leptospira/patogenicidade , Aderência Bacteriana , Translocação Bacteriana , Humanos , Lisinopril/metabolismo , Análise em Microsséries
16.
Eur J Clin Invest ; 38(11): 820-6, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19021699

RESUMO

BACKGROUND: Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) exhibit beneficial antidiabetic effects in patients with type 2 diabetes independent of their blood pressure-lowering effects. Some antidiabetic properties of ARB and ACE-I might by exerted by activation of peroxisome proliferator-activated receptor gamma (PPARgamma). However, it is not clear whether this action is drug specific. MATERIALS AND METHODS: The binding affinity of telmisartan, valsartan, lisinopril, rosiglitazone and angiotensin II to PPARgamma was assessed in a cell-free assay system. PPARgamma signalling was studied in isolated skeletal muscle cells using Western blot analysis of phosphorylated protein kinase B (pAKT) and phosphorylated insulin like growth factor-1 receptor (pILGF-1R). Further, the ability of the drugs under study to stimulate the release of the adipocytokine visfatin was investigated in isolated human adipocytes, skeletal muscle cells, and umbilical vein endothelial cells (HUVEC). RESULTS: The binding affinity to PPARgamma was highest for telmisartan with a half-maximal effective concentration of 463 nM, followed by lisinopril (2.9 microM) and valsartan (6.2 microM). In skeletal muscle cells phosphorylation of ILGF-1R was 2-fold increased after incubation with telmisartan or valsartan and 1.7-fold with lisinopril. pAKT expression was enhanced after incubation with telmisartan, valsartan and with lisinopril. The release of visfatin from adipocytes was 1.6-fold increased after treatment with lisinopril and about 2.0-fold increased with telmisartan and valsartan. Similar results were obtained in skeletal muscle cells and HUVEC. CONCLUSIONS: Our data confirm agonism of telmisartan, valsartan and lisinopril on PPARgamma. Pharmacokinetic differences may explain different potencies of PPARgamma stimulation by drugs acting on the renin-angiotensin system in clinical settings.


Assuntos
Adipócitos/metabolismo , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Células Endoteliais/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , PPAR gama/metabolismo , Adipócitos/efeitos dos fármacos , Angiotensina II , Benzimidazóis/metabolismo , Benzoatos/metabolismo , Western Blotting , Células Endoteliais/efeitos dos fármacos , Humanos , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Lisinopril/metabolismo , Músculo Esquelético/metabolismo , Nicotinamida Fosforribosiltransferase/efeitos dos fármacos , Receptor IGF Tipo 1/efeitos dos fármacos , Receptor IGF Tipo 1/metabolismo , Rosiglitazona , Telmisartan , Tetrazóis/metabolismo , Tetrazóis/farmacologia , Tiazolidinedionas/metabolismo , Tiazolidinedionas/farmacologia , Veias Umbilicais/efeitos dos fármacos , Veias Umbilicais/metabolismo , Valina/análogos & derivados , Valina/metabolismo , Valina/farmacologia , Valsartana
17.
Kidney Int ; 74(4): 407-9, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18670403

RESUMO

Zhao et al. demonstrated that chronic renal failure was associated with lipid redistribution in the kidney and other organs. We discuss three types of lipid redistribution in the context of inflammatory stress, which might help to explain many conflicting clinical observations in relation to lipid-mediated renal and vascular injury. An assessment of lipid redistribution may provide a new target for therapeutic intervention.


Assuntos
Rim/fisiopatologia , Metabolismo dos Lipídeos , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Modelos Animais de Doenças , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Falência Renal Crônica/fisiopatologia , Lisinopril/metabolismo , Lisinopril/farmacologia , Nefrectomia , Ratos , Ratos Sprague-Dawley , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/metabolismo , Fatores de Tempo
18.
Kidney Int ; 74(4): 467-77, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18496513

RESUMO

Dyslipidemia complicates renal function leading to disturbances of major homeostatic organs in the body. Here we examined the effect of chronic renal dysfunction induced by uninephrectomy on fat redistribution and lipid peroxidation in rats treated with an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) for up to 10 months. Uninephrectomized rats developed fat redistribution and hypercholesterolemia typical of chronic renal failure when compared with sham-operated rats or lisinopril-treated uninephrectomized rats. The weight of the peri-renal fat was significantly less in the untreated compared to the lisinopril-treated uninephrectomized rats or those rats with a sham operation. We also found that there was a shift of heat-protecting unilocular adipocytes to heat-producing multilocular fat cells in the untreated uninephrectomized rats. Similarly in these rats we found a shift of subcutaneous and visceral fat to ectopic fat with excessive lipid accumulation and lipofuscin pigmentation. Lisinopril treatment prevented fat redistribution or transformation and lipid peroxidation. This study shows that ACE inhibition may prevent the fat anomalies associated with chronic renal dysfunction.


Assuntos
Adipócitos/metabolismo , Rim/efeitos dos fármacos , Metabolismo dos Lipídeos , Adipócitos/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Hipercolesterolemia/etiologia , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Rim/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipofuscina/biossíntese , Lisinopril/metabolismo , Lisinopril/farmacologia , Masculino , Nefrectomia , Ratos , Ratos Sprague-Dawley , Receptores de Angiotensina/análise , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/metabolismo , Fatores de Tempo
19.
Br J Pharmacol ; 152(6): 903-14, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17906684

RESUMO

BACKGROUND AND PURPOSE: In Dahl S rats, high salt increases activity of the tissue renin-angiotensin-aldosterone system (RAAS) in the CNS, heart and kidneys. Here, we assessed the effects of chronic angiotensin converting enzyme (ACE) inhibition on salt-induced hypertension and cardiovascular and renal hypertrophy and fibrosis, relative to the extent of ACE blockade. EXPERIMENTAL APPROACH: From 4.5 weeks of age, Dahl S rats received either the lipophilic ACE inhibitor trandolapril (1 or 5 mg kg(-1) day(-1)) or the hydrophilic ACE inhibitor lisinopril (10 or 50 mg kg(-1) day(-1)) and a high salt diet was started 0.5 week later. Treatments ended at 9 weeks of age. KEY RESULTS: High salt diet markedly increased blood pressure (BP), decreased plasma angiotensin II and increased ACE binding densities in brain, heart, aorta and kidneys. Trandolapril and lisinopril prevented 50% of the increase in BP in light and dark period of the day. After the last doses, trandolapril decreased ACE densities by approximately 80% in brain nuclei and heart and lisinopril by approximately 60% in the brain and by approximately 70% in the heart. The two ACE inhibitors prevented right ventricular hypertrophy and attenuated left ventricular hypertrophy but did not affect renal hypertrophy caused by high salt. Both drugs prevented high salt-induced fibrosis in heart, kidney and aorta. CONCLUSION AND IMPLICATION: As the ACE inhibitors could completely prevent tissue fibrosis and partially prevent tissue hypertrophy and hypertension, the tissue RAAS may play a critical role in salt-induced fibrosis, but a lesser role in the hypertrophy.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/prevenção & controle , Hipertensão/induzido quimicamente , Hipertensão/prevenção & controle , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Doenças Cardiovasculares/patologia , Ingestão de Líquidos/efeitos dos fármacos , Ecocardiografia , Fibrose , Frequência Cardíaca/efeitos dos fármacos , Hipertrofia , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Injeções Subcutâneas , Rim/patologia , Nefropatias/patologia , Lisinopril/química , Lisinopril/metabolismo , Lisinopril/farmacologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Endogâmicos Dahl , Receptor Tipo 1 de Angiotensina/metabolismo , Sódio na Dieta/toxicidade , Telemetria
20.
Curr Cardiol Rep ; 9(2): 150-8, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17430683

RESUMO

Congestive heart failure is a pathologic condition characterized by progressive decrease in left ventricular contractility and consequent decline of cardiac output. There is convincing clinical and experimental evidence that the renin-angiotensin system (RAS) and its primary effector peptide, angiotensin II, are linked to the pathophysiology of interstitial fibrosis, cardiac remodeling, and heart failure. In addition to the traditional endocrine or circulating RAS, an active tissue RAS has been characterized. Tissue angiotensin-converting enzyme and locally synthesized angiotensin II, for example, by chymase, exert local trophic effects that modulate gene expression, which regulates growth and proliferation in both myocytes and nonmyocytes. The existence of the tissue RAS offers an opportunity for targeted imaging, which may be of considerable value for guiding medical therapy.


Assuntos
Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/enzimologia , Miocárdio/enzimologia , Peptidil Dipeptidase A/metabolismo , Animais , Diagnóstico por Imagem , Regulação Enzimológica da Expressão Gênica , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Lisinopril/análogos & derivados , Lisinopril/metabolismo , Miocárdio/metabolismo , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/genética , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/enzimologia , Disfunção Ventricular Esquerda/fisiopatologia
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