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1.
Int J Mol Sci ; 22(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34576169

RESUMO

Autotaxin (ATX; ENPP2) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling phospholipid. Genetic and pharmacologic studies have previously established a pathologic role for ATX and LPA signaling in pulmonary injury, inflammation, and fibrosis. Here, increased ENPP2 mRNA levels were detected in immune cells from nasopharyngeal swab samples of COVID-19 patients, and increased ATX serum levels were found in severe COVID-19 patients. ATX serum levels correlated with the corresponding increased serum levels of IL-6 and endothelial damage biomarkers, suggesting an interplay of the ATX/LPA axis with hyperinflammation and the associated vascular dysfunction in COVID-19. Accordingly, dexamethasone (Dex) treatment of mechanically ventilated patients reduced ATX levels, as shown in two independent cohorts, indicating that the therapeutic benefits of Dex include the suppression of ATX. Moreover, large scale analysis of multiple single cell RNA sequencing datasets revealed the expression landscape of ENPP2 in COVID-19 and further suggested a role for ATX in the homeostasis of dendritic cells, which exhibit both numerical and functional deficits in COVID-19. Therefore, ATX has likely a multifunctional role in COVID-19 pathogenesis, suggesting that its pharmacological targeting might represent an additional therapeutic option, both during and after hospitalization.


Assuntos
COVID-19/diagnóstico , Células Dendríticas/imunologia , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/sangue , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , COVID-19/sangue , COVID-19/imunologia , COVID-19/terapia , Estudos de Coortes , Conjuntos de Dados como Assunto , Células Dendríticas/efeitos dos fármacos , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Feminino , Humanos , Interleucina-6/sangue , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , RNA-Seq , Respiração Artificial , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Análise de Célula Única
2.
Biomolecules ; 11(7)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34356597

RESUMO

Usnic acid (UA) is a secondary metabolite of lichens that exhibits a wide range of biological activities. Previously, we found that UA derivatives are effective inhibitors of tyrosyl-DNA phosphodiesterase 1 (TDP1). It can remove covalent complex DNA-topoisomerase 1 (TOP1) stabilized by the TOP1 inhibitor topotecan, neutralizing the effect of the drugs. TDP1 removes damage at the 3' end of DNA caused by other anticancer agents. Thus, TDP1 is a promising therapeutic target for the development of drug combinations with topotecan, as well as other drugs for cancer treatment. Ten new UA enamino derivatives with variation in the terpene fragment and substituent of the UA backbone were synthesized and tested as TDP1 inhibitors. Four compounds, 11a-d, had IC50 values in the 0.23-0.40 µM range. Molecular modelling showed that 11a-d, with relatively short aliphatic chains, fit to the important binding domains. The intrinsic cytotoxicity of 11a-d was tested on two human cell lines. The compounds had low cytotoxicity with CC50 ≥ 60 µM for both cell lines. 11a and 11c had high inhibition efficacy and low cytotoxicity, and they enhanced topotecan's cytotoxicity in cancerous HeLa cells but reduced it in the non-cancerous HEK293A cells. This "protective" effect from topotecan on non-cancerous cells requires further investigation.


Assuntos
Benzofuranos/química , Monoterpenos/química , Inibidores de Fosfodiesterase , Diester Fosfórico Hidrolases/metabolismo , Benzofuranos/farmacologia , Células HEK293 , Humanos , Monoterpenos/farmacologia , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia
3.
Phytother Res ; 35(9): 5282-5289, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34314073

RESUMO

Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a recently discovered DNA repair enzyme that can repair topoisomerase 2-mediated DNA damage, resulting in cancer cell resistance. In this study, two compounds, robustadial A and B, were isolated from a fraction of the ethyl acetate extract of Eucalyptus globulus Labill. fruits based on TDP2 inhibition screening. The biological experiments indicated that robustadial A and B have TDP2 inhibitory activity with EC50 values of 17 and 42 µM, respectively, but no tyrosyl-DNA phosphodiesterase 1 inhibition at 100 µM. Robustadial A showed significant synergistic effects with the anticancer drug etoposide in four human cancer cell lines, non-small cell lung cancer cell line (A549), prostate cancer cell line (DU145), breast cancer cell line (MCF-7), colorectal adenocarcinoma cell line (HCT-116), and chicken lymphoma cell line (DT40), and chicken lymphoma cell line complementation with human TDP2 (DT40 hTDP2) with combination index values ranging from 0.21 to 0.74. This work will facilitate future efforts for the development of robustadial A-based TDP2 selective inhibitors.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Eucalyptus , Neoplasias , Inibidores de Fosfodiesterase , Animais , Linhagem Celular Tumoral , Galinhas , Proteínas de Ligação a DNA , Eucalyptus/química , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases
4.
Sensors (Basel) ; 21(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34300575

RESUMO

DNA sensors can be used as robust tools for high-throughput drug screening of small molecules with the potential to inhibit specific enzymes. As enzymes work in complex biological pathways, it is important to screen for both desired and undesired inhibitory effects. We here report a screening system utilizing specific sensors for tyrosyl-DNA phosphodiesterase 1 (TDP1) and topoisomerase 1 (TOP1) activity to screen in vitro for drugs inhibiting TDP1 without affecting TOP1. As the main function of TDP1 is repair of TOP1 cleavage-induced DNA damage, inhibition of TOP1 cleavage could thus reduce the biological effect of the TDP1 drugs. We identified three new drug candidates of the 1,5-naphthyridine and 1,2,3,4-tetrahydroquinolinylphosphine sulfide families. All three TDP1 inhibitors had no effect on TOP1 activity and acted synergistically with the TOP1 poison SN-38 to increase the amount of TOP1 cleavage-induced DNA damage. Further, they promoted cell death even with low dose SN-38, thereby establishing two new classes of TDP1 inhibitors with clinical potential. Thus, we here report a dual-sensor screening approach for in vitro selection of TDP1 drugs and three new TDP1 drug candidates that act synergistically with TOP1 poisons.


Assuntos
DNA Topoisomerases Tipo I , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases , DNA , Dano ao DNA , DNA Topoisomerases Tipo I/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo
5.
Molecules ; 26(12)2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198510

RESUMO

Antimicrobial resistance is a major healthcare threat globally. Xanthines, including caffeine and pentoxifylline, are attractive candidates for drug repurposing, given their well-established safety and pharmacological profiles. This study aimed to analyze potential interactions between xanthines and aromatic antibiotics (i.e., tetracycline and ciprofloxacin), and their impact on antibiotic antibacterial activity. UV-vis spectroscopy, statistical-thermodynamical modeling, and isothermal titration calorimetry were used to quantitatively evaluate xanthine-antibiotic interactions. The antibacterial profiles of xanthines, and xanthine-antibiotic mixtures, towards important human pathogens Staphylococcus aureus, Enterococcus faecium, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, and Enterobacter cloacae were examined. Caffeine and pentoxifylline directly interact with ciprofloxacin and tetracycline, with neighborhood association constant values of 15.8-45.6 M-1 and enthalpy change values up to -4 kJ·M-1. Caffeine, used in mixtures with tested antibiotics, enhanced their antibacterial activity in most pathogens tested. However, antagonistic effects of caffeine were also observed, but only with ciprofloxacin toward Gram-positive pathogens. Xanthines interact with aromatic antibiotics at the molecular and in vitro antibacterial activity level. Given considerable exposure to caffeine and pentoxifylline, these interactions might be relevant for the effectiveness of antibacterial pharmacotherapy, and may help to identify optimal treatment regimens in the era of multidrug resistance.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Cafeína/farmacologia , Compostos Heterocíclicos/química , Pentoxifilina/farmacologia , Antibacterianos/química , Bactérias/crescimento & desenvolvimento , Cafeína/química , Estimulantes do Sistema Nervoso Central/química , Estimulantes do Sistema Nervoso Central/farmacologia , Interações Medicamentosas , Testes de Sensibilidade Microbiana , Pentoxifilina/química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia
6.
J Med Chem ; 64(13): 9537-9549, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34142552

RESUMO

Hepatic fibrosis commonly exists in chronic liver disease and would eventually develop to cirrhosis and liver cancer with high fatality. Phosphodiesterase-9 (PDE9) has attracted profound attention as a drug target because of its highest binding affinity among phosphodiesterases (PDEs) with cyclic guanosine monophosphate. However, no published study has reported PDE9 inhibitors as potential agents against hepatic fibrosis yet. Herein, structural modification from a starting hit LL01 led to lead 4a, which exhibited an IC50 value of 7.3 nM against PDE9, excellent selectivity against other PDE subfamilies, and remarkable microsomal stability. The cocrystal structure of PDE9 with 4a revealed an important residue, Phe441, capable of improving the selectivity of PDE9 inhibitors. Administration of 4a exerted a significant antifibrotic effect in bile duct-ligation-induced rats with hepatic fibrosis and transforming growth factor-ß-induced fibrogenesis. This therapeutic effect was indeed achieved by selectively inhibiting PDE9 rather than other PDE isoforms, identifying PDE9 inhibitors as potential agents against hepatic fibrosis.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Descoberta de Drogas , Fibrose/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Animais , Ductos Biliares/metabolismo , Ductos Biliares/cirurgia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fibrose/metabolismo , Humanos , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Ratos , Relação Estrutura-Atividade
7.
Biomolecules ; 11(5)2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068780

RESUMO

PDE9 inhibitors have been studied to validate their potential to treat diabetes, neurodegenerative disorders, cardiovascular diseases, and erectile dysfunction. In this report, we have selected highly potent previously reported selective PDE9 inhibitors BAY73-6691R, BAY73-6691S, 28r, 28s, 3r, 3s, PF-0447943, PF-4181366, and 4r to elucidate the differences in their interaction patterns in the presence of different metal systems such as Zn/Mg, Mg/Mg, and Zn/Zn. The initial complexes were generated by molecular docking followed by molecular dynamics simulation for 100 ns in triplicate for each system to understand the interactions' stability. The results were carefully analyzed, focusing on the ligands' non-bonded interactions with PDE9 in different metal systems.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/química , Magnésio/química , Inibidores de Fosfodiesterase/farmacologia , Zinco/química , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Química Computacional , Cristalografia por Raios X , Humanos , Ligantes , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
8.
Sci Rep ; 11(1): 12293, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112881

RESUMO

Phosphodiesterase (PDE) inhibitors, such as pentoxifylline (PTX), are used as pharmacological agents to enhance sperm motility in assisted reproductive technology (ART), mainly to aid the selection of viable sperm in asthenozoospermic ejaculates and testicular spermatozoa, prior to intracytoplasmic sperm injection (ICSI). However, PTX is reported to induce premature acrosome reaction (AR) and, exert toxic effects on oocyte function and early embryo development. Additionally, in vitro binding studies as well as computational binding free energy (ΔGbind) suggest that PTX exhibits weak binding to sperm PDEs, indicating room for improvement. Aiming to reduce the adverse effects and to enhance the sperm motility, we designed and studied PTX analogues. Using structure-guided in silico approach and by considering the physico-chemical properties of the binding pocket of the PDEs, designed analogues of PTX. In silico assessments indicated that PTX analogues bind more tightly to PDEs and form stable complexes. Particularly, ex vivo evaluation of sperm treated with one of the PTX analogues (PTXm-1), showed comparable beneficial effect at much lower concentration-slower AR, higher DNA integrity and extended longevity of  spermatozoa and  superior embryo quality. PTXm-1 is proposed to be a better pharmacological agent for ART than PTX for sperm function enhancement.


Assuntos
Astenozoospermia/tratamento farmacológico , Pentoxifilina/química , Diester Fosfórico Hidrolases/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Acrossomo/efeitos dos fármacos , Astenozoospermia/patologia , Humanos , Masculino , Estrutura Molecular , Pentoxifilina/análogos & derivados , Pentoxifilina/farmacologia , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/química , Técnicas de Reprodução Assistida/tendências , Injeções de Esperma Intracitoplásmicas/métodos , Espermatozoides/crescimento & desenvolvimento , Testículo/efeitos dos fármacos , Testículo/patologia
9.
Int J Mol Sci ; 22(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067243

RESUMO

The COVID-19 pandemic has established an unparalleled necessity to rapidly find effective treatments for the illness; unfortunately, no specific treatment has been found yet. As this is a new emerging chaotic situation, already existing drugs have been suggested to ameliorate the infection of SARS-CoV-2. The consumption of caffeine has been suggested primarily because it improves exercise performance, reduces fatigue, and increases wakefulness and awareness. Caffeine has been proven to be an effective anti-inflammatory and immunomodulator. In airway smooth muscle, it has bronchodilator effects mainly due to its activity as a phosphodiesterase inhibitor and adenosine receptor antagonist. In addition, a recent published document has suggested the potential antiviral activity of this drug using in silico molecular dynamics and molecular docking; in this regard, caffeine might block the viral entrance into host cells by inhibiting the formation of a receptor-binding domain and the angiotensin-converting enzyme complex and, additionally, might reduce viral replication by the inhibition of the activity of 3-chymotrypsin-like proteases. Here, we discuss how caffeine through certain mechanisms of action could be beneficial in SARS-CoV-2. Nevertheless, further studies are required for validation through in vitro and in vivo models.


Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , COVID-19/dietoterapia , Cafeína/farmacologia , Reposicionamento de Medicamentos/métodos , Músculo Liso/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , COVID-19/metabolismo , COVID-19/fisiopatologia , Humanos , Fatores Imunológicos/farmacologia , Simulação de Dinâmica Molecular , Músculo Liso/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo
10.
Int J Mol Sci ; 22(10)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063491

RESUMO

Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides to modulate multiple signaling events in cells. PDEs are recognized to actively associate with cyclic nucleotide receptors (protein kinases, PKs) in larger macromolecular assemblies referred to as signalosomes. Complexation of PDEs with PKs generates an expanded active site that enhances PDE activity. This facilitates signalosome-associated PDEs to preferentially catalyze active hydrolysis of cyclic nucleotides bound to PKs and aid in signal termination. PDEs are important drug targets, and current strategies for inhibitor discovery are based entirely on targeting conserved PDE catalytic domains. This often results in inhibitors with cross-reactivity amongst closely related PDEs and attendant unwanted side effects. Here, our approach targeted PDE-PK complexes as they would occur in signalosomes, thereby offering greater specificity. Our developed fluorescence polarization assay was adapted to identify inhibitors that block cyclic nucleotide pockets in PDE-PK complexes in one mode and disrupt protein-protein interactions between PDEs and PKs in a second mode. We tested this approach with three different systems-cAMP-specific PDE8-PKAR, cGMP-specific PDE5-PKG, and dual-specificity RegA-RD complexes-and ranked inhibitors according to their inhibition potency. Targeting PDE-PK complexes offers biochemical tools for describing the exquisite specificity of cyclic nucleotide signaling networks in cells.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores de Fosfodiesterase/farmacologia , Extratos Vegetais/farmacologia , Proteínas Quinases/metabolismo , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Domínio Catalítico , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Polarização de Fluorescência , Terapia de Alvo Molecular , Complexos Multiproteicos/metabolismo , Nucleotídeos Cíclicos/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Especificidade por Substrato
11.
Molecules ; 26(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069639

RESUMO

Phosphodiesterase 2 (PDE2) has been regarded as a novel target for the treatment of Alzheimer's disease (AD). In this study, we obtained (R)-LZ77 as a hit compound with moderate PDE2 inhibitory activity (IC50 = 261.3 nM) using a high-throughput virtual screening method based on molecular dynamics. Then, we designed and synthesized 28 dihydropyranopyrazole derivatives as PDE2 inhibitors. Among them, compound (+)-11h was the most potent PDE2 inhibitor, with an IC50 value of 41.5 nM. The molecular docking of PDE2-(+)-11h reveals that the 4-(trifluoromethyl)benzyl)oxyl side chain of the compound enters the H-pocket and forms strong hydrophobic interactions with L770/L809/F862, which improves inhibitory activity. The above results may provide insight for further structural optimization of highly potent PDE2 inhibitors and may lay the foundation for their use in the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/uso terapêutico , Pirazóis/síntese química , Análise Espectral/métodos
12.
J Med Chem ; 64(11): 7617-7629, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34008967

RESUMO

As a recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1) removes topoisomerase IB (TOP1)-mediated DNA protein cross-links. Inhibiting TDP1 can potentiate the cytotoxicity of TOP1 inhibitors and overcome cancer cell resistance to TOP1 inhibitors. On the basis of our previous study, herein we report the synthesis of benzophenanthridinone derivatives as TOP1 and TDP1 inhibitors. Seven compounds (C2, C4, C5, C7, C8, C12, and C14) showed a robust TOP1 inhibitory activity (+++ or ++++), and four compounds (A13, C12, C13, and C26) showed a TDP1 inhibition (half-maximal inhibitory concentration values of 15 or 19 µM). We also show that the dual TOP1 and TDP1 inhibitor C12 induces both cellular TOP1cc, TDP1cc formation and DNA damage, resulting in cancer cell apoptosis at a sub-micromolar concentration. In addition, C12 showed an enhanced activity in drug-resistant MCF-7/TDP1 cancer cells and was synergistic with topotecan in both MCF-7 and MCF-7/TDP1 cells.


Assuntos
Benzofenantridinas/química , DNA Topoisomerases Tipo I/metabolismo , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/metabolismo , Inibidores da Topoisomerase I/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzofenantridinas/metabolismo , Benzofenantridinas/farmacologia , Benzofenantridinas/uso terapêutico , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Inibidores de Fosfodiesterase/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/metabolismo , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico
13.
Bioorg Chem ; 111: 104881, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33839584

RESUMO

Based on our previous study on the development of the furoquinolinedione and isoxazoloquinolinedione TDP2 inhibitors, the further structure-activity relationship (SAR) was studied in this work. A series of furoquinolinedione and isoxazoloquinolinedione derivatives were synthesized and tested for enzyme inhibitions. Enzyme-based assays indicated that isoxazoloquinolinedione derivatives selectively showed high TDP2 inhibitory activity at sub-micromolar range, as well as furoquinolinedione derivatives at low micromolar range. The most potent 3-(3,4-dimethoxyphenyl)isoxazolo[4,5-g]quinoline-4,9-dione (70) showed TDP2 inhibitory activity with IC50 of 0.46 ± 0.15 µM. This work will facilitate future efforts for the discovery of isoxazoloquinolinedione TDP2 selective inhibitors.


Assuntos
Proteínas de Ligação a DNA/antagonistas & inibidores , Inibidores de Fosfodiesterase/farmacologia , Quinolonas/farmacologia , Animais , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta a Droga , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/metabolismo , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade
14.
Eur J Pharmacol ; 901: 174077, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33798601

RESUMO

This study investigated the hemodynamic effect of Bay 60-7550, a phosphodiesterase type 2 (PDE2) inhibitor, in healthy rat hearts both in vivo and ex vivo and its underlying mechanisms. In vivo rat left ventricular pressure-volume loop, Langendorff isolated rat heart, Ca2+ transient of left ventricular myocyte and Western blot experiments were used in this study. The results demonstrated that Bay 60-7550 (1.5 mg/kg, i. p.) increased the in vivo rat heart contractility by enhancing stroke work, cardiac output, stroke volume, end-diastolic volume, heart rate, and ejection fraction. The simultaneous aortic pressure recording indicated that the systolic blood pressure was increased and diastolic blood pressure was decreased by Bay 60-7550. Also, the arterial elastance which is proportional to the peripheral vessel resistance was significantly decreased. Bay 60-7550 (0.001, 0.01, 0.1, 1 µmol/l) also enhanced the left ventricular development pressure in non-paced and paced modes with a decrease of heart rate in non-paced model. Bay 60-7550 (1 µmol/l) increased SERCA2a activity and SR Ca2+ content and reduced SR Ca2+ leak rate. Furthermore, Bay 60-7550 (0.1 µmol/l) increased the phosphorylation of phospholamban at 16-serine without significantly changing the phosphorylation levels of phospholamban at 17-threonine and RyR2. Bay 60-7550 increased the rat heart contractility and reduced peripheral arterial resistance may be mediated by increasing the phosphorylation of phospholamban and dilating peripheral vessels. PDE2 inhibitors which result in a positive inotropic effect and a decrease in peripheral resistance might serve as a target for developing agents for the treatment of heart failure in clinical settings.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Cardiotônicos/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Imidazóis/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Triazinas/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Cálcio/metabolismo , Hemodinâmica/efeitos dos fármacos , Técnicas In Vitro , Masculino , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fosforilação , Ratos , Ratos Sprague-Dawley , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/efeitos dos fármacos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Resistência Vascular/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
15.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807511

RESUMO

3'-5' cyclic nucleotide phosphodiesterases (PDEs) are a large family of enzymes playing a fundamental role in the control of intracellular levels of cAMP and cGMP. Emerging evidence suggested an important role of phosphodiesterases in heart formation, but little is known about the expression of phosphodiesterases during cardiac development. In the present study, the pattern of expression and enzymatic activity of phosphodiesterases was investigated at different stages of heart formation. C57BL/6 mice were mated and embryos were collected from 14.5 to 18.5 days of development. Data obtained by qRT-PCR and Western blot analysis showed that seven different isoforms are expressed during heart development, and PDE1C, PDE2A, PDE4D, PDE5A and PDE8A are modulated from E14.5 to E18.5. In heart homogenates, the total cAMP and cGMP hydrolytic activity is constant at the evaluated times, and PDE4 accounts for the majority of the cAMP hydrolyzing ability and PDE2A accounts for cGMP hydrolysis. This study showed that a subset of PDEs is expressed in developing mice heart and some of them are modulated to maintain constant nucleotide phosphodiesterase activity in embryonic and fetal heart.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Coração Fetal/metabolismo , Diester Fosfórico Hidrolases/metabolismo , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Animais , AMP Cíclico , GMP Cíclico/metabolismo , Feminino , Coração Fetal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Fosfodiesterase/farmacologia
16.
Life Sci ; 277: 119506, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33865881

RESUMO

Diclofenac, one of the most commonly used non-steroidal anti-inflammatory drugs, leads to severe adverse effects on the kidneys. The aim of the present study was to investigate the potential pretreatment effect of phosphodiesterase (1, 3 & 5) inhibitors on diclofenac-induced acute renal failure in rats. Rats orally received pentoxifylline (100 mg/kg), vinpocetine (20 mg/kg), cilostazol (50 mg/kg), or sildenafil (5 mg/kg) once per day for 6 consecutive days. Diclofenac (15 mg/kg) was injected on day-4, -5 and -6 in all groups except normal control group. The used phosphodiesterase inhibitors significantly reduced the diclofenac-induced elevation in the serum levels of blood urea nitrogen, creatinine and cystatin C. Moreover, the renal tissue contents of tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB as well as the protein expression of toll-like receptor (TLR) 4 and high mobility group box (HMGB) 1 were markedly reduced by the used phosphodiesterase inhibitors, as compared to the diclofenac control. This was reflected on the marked improvement in histopathological changes induced by diclofenac. Sildenafil showed the best protection regarding TNF-α and NF-κB, while cilostazol showed the best results regarding TLR4, HMGB1 and histopathological examination. This study revealed the good protective effect of these phosphodiesterase inhibitors against diclofenac-induced acute renal failure.


Assuntos
Injúria Renal Aguda/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/patologia , Animais , Nitrogênio da Ureia Sanguínea , Cilostazol/farmacologia , Creatinina/metabolismo , Diclofenaco/efeitos adversos , Diclofenaco/farmacologia , Rim/patologia , Masculino , NF-kappa B/metabolismo , Pentoxifilina/farmacologia , Inibidores de Fosfodiesterase/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Ratos , Ratos Wistar , Citrato de Sildenafila/farmacologia , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Alcaloides de Vinca/farmacologia
17.
Bioorg Med Chem Lett ; 41: 128016, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33838306

RESUMO

The multi-target-directed-ligand (MTDL) strategy has been widely applied in the discovery of novel drugs for the treatment of Alzheimer's disease (AD) because of the multifactorial pathological mechanisms of AD. Phosphodiesterase-2 (PDE2) has been identified to be a novel and promising target for AD. However, MTDL combining with the inhibitory activity against PDE2A and other anti-AD factors such as antioxidants has not been developed yet. Herein, a novel series of PDE2 inhibitors with antioxidant capacities were designed, synthesized, and evaluated. Most compounds showed remarkable inhibitory activities against PDE2A as well as antioxidant activities. Compound 6d was selected, which showed good IC50 of 6.1 nM against PDE2A, good antioxidant activity (ORAC (Trolox) = 8.4 eq.) and no cytotoxicity to SH-SY5Y cells. Molecular docking and dynamics simulations were applied for the rational design and explanation of structure-activity relationship (SAR) of lead compounds.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Descoberta de Drogas , Inibidores de Fosfodiesterase/farmacologia , Doença de Alzheimer/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2 , Relação Dose-Resposta a Droga , Fluoresceínas/análise , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
18.
BMC Urol ; 21(1): 38, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33711972

RESUMO

BACKGROUND: Prostate cancer is one of the most frequently diagnosed types of cancers worldwide. In its initial period, the tumor is hormone-sensitive, but in advanced states, it evolves into a metastatic castration-resistant tumor. In this state, chemotherapy with taxanes such as Docetaxel (DTX) comprises the first line of treatment. However, the response is poor due to chemoresistance and toxicity. On the other hand, Pentoxifylline (PTX) is an unspecific inhibitor of phosphodiesterases; experimental, and clinically it has been described as sensitizing tumor cells to chemotherapy, increasing apoptosis and decreasing senescence. We study whether the PTX sensitizes prostate cancer cells to DTX for greater effectiveness. METHODS: PC3 human prostate cancer cells were treated in vitro at different doses and times with PTX, DTX, or their combination. Viability was determined by the WST-1 assay by spectrophotometry, cell cycle progression, apoptosis, generic caspase activation and senescence by flow cytometry, DNA fragmentation and caspases-3, -8, and -9 activity by ELISA. RESULTS: We found that PTX in PC3 human prostate cancer cells induces significant apoptosis per se and increases that generated by DTX, while at the same time it reduces the senescence caused by the chemotherapy and increases caspases-3,-8, and -9 activity in PTX + DTX-treated cells. Both treatments blocked the PC3 cell in the G1 phase. CONCLUSIONS: Our results show that PTX sensitizes prostate tumor cells to apoptosis induced by DTX. Taken together, the results support the concept of chemotherapy with rational molecular bases.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Pentoxifilina/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Neoplasias da Próstata/patologia , Humanos , Masculino , Células PC-3/efeitos dos fármacos
19.
Biol Pharm Bull ; 44(3): 404-409, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33642548

RESUMO

Mucus hypersecretion is a hallmark of respiratory diseases, and excess airway mucus can worsen these conditions. Therefore, it is important to control the production of airway mucus in the treatment of respiratory diseases. The phosphodiesterase inhibitor ibudilast has been reported to be effective in treating sputum and postnasal drip in patients with chronic airway inflammation. On the basis of the hypothesis that ibudilast could inhibit mucus production in the airway, in the present study, we examined the effects of ibudilast on the production of MUC5AC, a major protein component of mucus. In in vitro studies using NCI-H292 cells, ibudilast suppressed MUC5AC production induced by various stimuli. In addition, ibudilast inhibited extracellular signal-regulated kinase (ERK)1/2 phosphorylation and MUC5AC gene transcription. Furthermore, it attenuated MUC5AC production and Muc5ac mRNA expression in lipopolysaccharide-treated mice in vivo. Collectively, these findings demonstrate that ibudilast has an inhibitory effect on mucus production, which could at least partly be attributed to the inhibition of ERK1/2 phosphorylation and the repression of MUC5AC gene transcription.


Assuntos
Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Mucina-5AC/antagonistas & inibidores , Muco/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Piridinas/farmacologia , Animais , Linhagem Celular , Humanos , Peróxido de Hidrogênio/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos ICR , Mucina-5AC/genética , Mucina-5AC/metabolismo , Fosforilação/efeitos dos fármacos , Fumaça , Tabaco
20.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669167

RESUMO

Despite progress in understanding the pathophysiology of acute lung damage, currently approved treatment possibilities are limited to lung-protective ventilation, prone positioning, and supportive interventions. Various pharmacological approaches have also been tested, with neuromuscular blockers and corticosteroids considered as the most promising. However, inhibitors of phosphodiesterases (PDEs) also exert a broad spectrum of favorable effects potentially beneficial in acute lung damage. This article reviews pharmacological action and therapeutical potential of nonselective and selective PDE inhibitors and summarizes the results from available studies focused on the use of PDE inhibitors in animal models and clinical studies, including their adverse effects. The data suggest that xanthines as representatives of nonselective PDE inhibitors may reduce acute lung damage, and decrease mortality and length of hospital stay. Various (selective) PDE3, PDE4, and PDE5 inhibitors have also demonstrated stabilization of the pulmonary epithelial-endothelial barrier and reduction the sepsis- and inflammation-increased microvascular permeability, and suppression of the production of inflammatory mediators, which finally resulted in improved oxygenation and ventilatory parameters. However, the current lack of sufficient clinical evidence limits their recommendation for a broader use. A separate chapter focuses on involvement of cyclic adenosine monophosphate (cAMP) and PDE-related changes in its metabolism in association with coronavirus disease 2019 (COVID-19). The chapter illuminates perspectives of the use of PDE inhibitors as an add-on treatment based on actual experimental and clinical trials with preliminary data suggesting their potential benefit.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/fisiopatologia , Animais , COVID-19/tratamento farmacológico , COVID-19/metabolismo , COVID-19/fisiopatologia , AMP Cíclico/metabolismo , Modelos Animais de Doenças , Humanos , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/fisiopatologia , Sepse/tratamento farmacológico , Sepse/metabolismo , Sepse/fisiopatologia
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