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1.
Pharmaceuticals (Basel) ; 17(6)2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38931419

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal form of pancreatic cancer characterized by therapy resistance and early metastasis, resulting in a low survival rate. Histone deacetylase (HDAC) inhibitors showed potential for the treatment of hematological malignancies. In PDAC, the overexpression of HDAC 2 is associated with the epithelial-mesenchymal transition (EMT), principally accompanied by the downregulation of the epithelial marker E-cadherin and increased metastatic capacity. The effector cytokine transforming growth factor-ß (TGF ß) is known to be a major inducer of the EMT in PDAC, leading to high metastatic and invasive potential. In addition, the overexpression of HDAC 6 in PDAC is associated with reduced apoptosis. Here, we have demonstrated that a novel HDAC 2/6 inhibitor not only significantly increased E-cadherin expression in PANC-1 cells (5.5-fold) and in 3D PDAC co-culture spheroids (2.5-fold) but was also able to reverse the TGF-ß-induced downregulation of E-cadherin expression. Moreover, our study indicates that the HDAC inhibitor mediated re-differentiation resulting in a significant inhibition of tumor cell invasion by approximately 60% compared to control. In particular, we have shown that the HDAC inhibitor induces both apoptosis (2-fold) and cell cycle arrest. In conclusion, the HDAC 2/6 inhibitor acts by suppressing invasion via upregulating E-cadherin mediated by HDAC 2 blockade and by inducing cell cycle arrest leading to apoptosis via HDAC 6 inhibition. These results suggest that the HDAC 2/6 inhibitor might represent a novel therapeutic strategy for the treatment of PDAC tumorigenesis and metastasis.

2.
ACS Infect Dis ; 8(2): 271-279, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-34994538

RESUMO

Acanthamoeba is a ubiquitous and free-living protozoan pathogen responsible for causing Acanthamoeba keratitis (AK), a severe corneal infection inflicting immense pain that can result in permanent blindness. A drug-based treatment of AK has remained arduous because Acanthamoeba trophozoites undergo encystment to become highly drug-resistant cysts upon exposure to harsh environmental conditions such as amoebicidal agents (e.g., polyhexanide, chloroquine, and chlorohexidine). As such, drugs that block the Acanthamoeba encystation process could result in a successful AK treatment. Histone deacetylase inhibitors (HDACi) have recently emerged as novel therapeutic options for treating various protozoan and parasitic diseases. Here, we investigated whether novel HDACi suppress the proliferation and encystation of Acanthamoeba. Synthetic class II HDACi FFK29 (IIa selective) and MPK576 (IIb selective) dose-dependently decreased the viability of Acanthamoeba trophozoites. While these HDACi demonstrated a negligible effect on the viability of mature cysts, Acanthamoeba encystation was significantly inhibited by these HDACi. Apoptosis was slightly increased in trophozoites after a treatment with these HDACi, whereas cysts were unaffected by the HDACi exposure. The viability of human corneal cells was not affected by HDACi concentrations up to 10 µmol/L. In conclusion, these synthetic HDACi demonstrated potent amoebicidal effects and inhibited the growth and encystation of Acanthamoeba, thus highlighting their enormous potential for further development.


Assuntos
Ceratite por Acanthamoeba , Acanthamoeba castellanii , Amebicidas , Ceratite por Acanthamoeba/tratamento farmacológico , Ceratite por Acanthamoeba/parasitologia , Amebicidas/farmacologia , Animais , Inibidores de Histona Desacetilases/farmacologia , Humanos , Trofozoítos
3.
ACS Infect Dis ; 8(1): 106-117, 2022 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-34985259

RESUMO

Malaria, caused by Plasmodium parasites, results in >400,000 deaths annually. There is no effective vaccine, and new drugs with novel modes of action are needed because of increasing parasite resistance to current antimalarials. Histone deacetylases (HDACs) are epigenetic regulatory enzymes that catalyze post-translational protein deacetylation and are promising malaria drug targets. Here, we describe quantitative structure-activity relationship models to predict the antiplasmodial activity of hydroxamate-based HDAC inhibitors. The models incorporate P. falciparum in vitro activity data for 385 compounds containing a hydroxamic acid and were subject to internal and external validation. When used to screen 22 new hydroxamate-based HDAC inhibitors for antiplasmodial activity, model A7 (external accuracy 91%) identified three hits that were subsequently verified as having potent in vitro activity against P. falciparum parasites (IC50 = 6, 71, and 84 nM), with 8 to 51-fold selectivity for P. falciparum versus human cells.


Assuntos
Malária , Parasitos , Animais , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Plasmodium falciparum , Relação Quantitativa Estrutura-Atividade
4.
Molecules ; 26(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068691

RESUMO

Due to widespread multi-drug resistance in parasitic nematodes of livestock animals, there is an urgent need to discover new anthelmintics with distinct mechanisms of action. Extending previous work, here we screened a panel of 245 chemically-diverse small molecules for anti-parasitic activity against Haemonchus contortus-an economically important parasitic nematode of livestock. This panel was screened in vitro against exsheathed third-stage larvae (xL3) of H. contortus using an established phenotypic assay, and the potency of select compounds to inhibit larval motility and development assessed in dose-response assays. Of the 245 compounds screened, three-designated MPK18, MPK334 and YAK308-induced non-wildtype larval phenotypes and repeatedly inhibited xL3-motility, with IC50 values of 45.2 µM, 17.1 µM and 52.7 µM, respectively; two also inhibited larval development, with IC50 values of 12.3 µM (MPK334) and 6.5 µM (YAK308), and none of the three was toxic to human liver cells (HepG2). These findings suggest that these compounds deserve further evaluation as nematocidal candidates. Future work should focus on structure-activity relationship (SAR) studies of these chemical scaffolds, and assess the in vitro and in vivo efficacies and safety of optimised compounds against adults of H. contortus.


Assuntos
Haemonchus/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Haemonchus/crescimento & desenvolvimento , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Fenótipo , Bibliotecas de Moléculas Pequenas/química
5.
ChemMedChem ; 16(11): 1798-1803, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33629513

RESUMO

The acetylome is important for maintaining the homeostasis of cells. Abnormal changes can result in the pathogenesis of immunological or neurological diseases, and degeneration can promote the manifestation of cancer. In particular, pharmacological intervention in the acetylome with pan-histone deacetylase (HDAC) inhibitors is clinically validated. However, these drugs exhibit an undesirable risk-benefit profile due to severe side effects. Selective HDAC inhibitors might promote patient compliance and represent a valuable opportunity in personalised medicine. Therefore, we envisioned the development of HDAC6-selective inhibitors. During our lead structure identification, we demonstrated that an alkoxyurea-based connecting unit proves to be beneficial for HDAC6 selectivity and established the synthesis of alkoxyurea-based hydroxamic acids. Herein, we report highly potent N-alkoxyurea-based hydroxamic acids with improved HDAC6 preference compared to nexturastat A. We further validated the biological activity of these oxa analogues of nexturastat A in a broad subset of leukaemia cell lines and demonstrated their superior anti-proliferative properties compared to nexturastat A.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Compostos de Fenilureia/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/química , Relação Estrutura-Atividade
6.
J Virol ; 94(23)2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-32907979

RESUMO

Pandemic human immunodeficiency virus type 1 (HIV-1) is the result of the zoonotic transmission of simian immunodeficiency virus (SIV) from the chimpanzee subspecies Pan troglodytestroglodytes (SIVcpzPtt). The related subspecies Pan troglodytesschweinfurthii is the host of a similar virus, SIVcpzPts, which did not spread to humans. We tested these viruses with small-molecule capsid inhibitors (PF57, PF74, and GS-CA1) that interact with a binding groove in the capsid that is also used by CPSF6. While HIV-1 was sensitive to capsid inhibitors in cell lines, human macrophages, and peripheral blood mononuclear cells (PBMCs), SIVcpzPtt was resistant in rhesus FRhL-2 cells and human PBMCs but was sensitive to PF74 in human HOS and HeLa cells. SIVcpzPts was insensitive to PF74 in FRhL-2 cells, HeLa cells, PBMCs, and macrophages but was inhibited by PF74 in HOS cells. A truncated version of CPSF6 (CPSF6-358) inhibited SIVcpzPtt and HIV-1, while in contrast, SIVcpzPts was resistant to CPSF6-358. Homology modeling of HIV-1, SIVcpzPtt, and SIVcpzPts capsids and binding energy estimates suggest that these three viruses bind similarly to the host proteins cyclophilin A (CYPA) and CPSF6 as well as the capsid inhibitor PF74. Cyclosporine treatment, mutation of the CYPA-binding loop in the capsid, or CYPA knockout eliminated the resistance of SIVcpzPts to PF74 in HeLa cells. These experiments revealed that the antiviral capacity of PF74 is controlled by CYPA in a virus- and cell type-specific manner. Our data indicate that SIVcpz viruses can use infection pathways that escape the antiviral activity of PF74. We further suggest that the antiviral activity of PF74 capsid inhibitors depends on cellular cofactors.IMPORTANCE HIV-1 originated from SIVcpzPtt but not from the related virus SIVcpzPts, and thus, it is important to describe molecular infection by SIVcpzPts in human cells to understand the zoonosis of SIVs. Pharmacological HIV-1 capsid inhibitors (e.g., PF74) bind a capsid groove that is also a binding site for the cellular protein CPSF6. SIVcpzPts was resistant to PF74 in HeLa cells but sensitive in HOS cells, thus indicating cell line-specific resistance. Both SIVcpz viruses showed resistance to PF74 in human PBMCs. Modulating the presence of cyclophilin A or its binding to capsid in HeLa cells overcame SIVcpzPts resistance to PF74. These results indicate that early cytoplasmic infection events of SIVcpzPts may differ between cell types and affect, in an unknown manner, the antiviral activity of capsid inhibitors. Thus, capsid inhibitors depend on the activity or interaction of currently uncharacterized cellular factors.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteínas do Capsídeo/química , Proteínas do Capsídeo/efeitos dos fármacos , Proteínas do Capsídeo/metabolismo , Capsídeo/efeitos dos fármacos , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Fatores de Poliadenilação e Clivagem de mRNA/química , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Animais , Sítios de Ligação , Proteínas do Capsídeo/genética , Linhagem Celular , Ciclofilina A/genética , Ciclofilina A/metabolismo , Técnicas de Inativação de Genes , Células HEK293 , HIV-1 , Células HeLa , Humanos , Indazóis/farmacologia , Indóis/farmacologia , Leucócitos Mononucleares/virologia , Macrófagos/virologia , Modelos Moleculares , Pan troglodytes/virologia , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Piridinas/farmacologia , Alinhamento de Sequência , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/química , Vírus da Imunodeficiência Símia/genética , Zoonoses , Fatores de Poliadenilação e Clivagem de mRNA/genética
7.
Antimicrob Agents Chemother ; 64(12)2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-32928736

RESUMO

Treatment of Acanthamoeba keratitis (AK) is difficult because Acanthamoeba cysts are resistant to drugs, and as such, successful treatment requires an effective approach that inhibits cyst formation. Histone deacetylase inhibitors (HDACis) are involved in cell proliferation, differentiation, and apoptotic cell death. In this study, the effects of HDACis such as MPK472 and KSK64 on Acanthamoeba castellanii trophozoites and cysts were observed. MPK472 and KSK64 showed at least 60% amoebicidal activity against Acanthamoeba trophozoites at a concentration of 10 µM upon 8 h of treatment. Neither of the two HDACis affected mature cysts, but significant amoebicidal activities (36.4 and 33.9%) were observed against encysting Acanthamoeba following treatment with 5 and 10 µM HDACis for 24 h. Light microscopy and transmission electron microscopy results confirmed that the encystation of Acanthamoeba was inhibited by the two HDACis. In addition to this, low cytopathic effects on human corneal epithelial (HCE) cells were observed following treatment with MPK472 and KSK64 for 24 h. Our results indicate that the HDACis MPK472 and KSK64 could be used as new candidates for the development of an optimal therapeutic option for AK.


Assuntos
Ceratite por Acanthamoeba , Acanthamoeba castellanii , Amebicidas , Ceratite por Acanthamoeba/tratamento farmacológico , Amebicidas/farmacologia , Animais , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Trofozoítos
8.
Int J Mol Sci ; 21(13)2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32635356

RESUMO

Histone deacetylase inhibitors (HDACi) are already approved for the therapy of leukemias. Since they are also emerging candidate compounds for the treatment of non-malignant diseases, HDACi with a wide therapeutic window and low hazard potential are desirable. Here, we investigated a panel of 12 novel hydroxamic acid- and benzamide-type HDACi employing non-malignant V79 hamster cells as toxicology guideline-conform in vitro model. HDACi causing a ≥10-fold preferential cytotoxicity in malignant neuroblastoma over non-malignant V79 cells were selected for further genotoxic hazard analysis, including vorinostat and entinostat for control. All HDACi selected, (i.e., KSK64, TOK77, DDK137 and MPK77) were clastogenic and evoked DNA strand breaks in non-malignant V79 cells as demonstrated by micronucleus and comet assays, histone H2AX foci formation analyses (γH2AX), DNA damage response (DDR) assays as well as employing DNA double-strand break (DSB) repair-defective VC8 hamster cells. Genetic instability induced by hydroxamic acid-type HDACi seems to be independent of bulky DNA adduct formation as concluded from the analysis of nucleotide excision repair (NER) deficient mutants. Summarizing, KSK64 revealed the highest genotoxic hazard and DDR stimulating potential, while TOK77 and MPK77 showed the lowest DNA damaging capacity. Therefore, these compounds are suggested as the most promising novel candidate HDACi for subsequent pre-clinical in vivo studies.


Assuntos
Benzamidas/toxicidade , Inibidores de Histona Desacetilases/toxicidade , Ácidos Hidroxâmicos/toxicidade , Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Ensaio Cometa , Cricetinae , Quebras de DNA de Cadeia Dupla , Quebras de DNA de Cadeia Simples , Histonas/química , Histonas/metabolismo , Humanos , Testes para Micronúcleos , Fosforilação , Vorinostat/toxicidade
9.
Bioorg Med Chem ; 27(22): 115087, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31561937

RESUMO

Epigenetic control plays an important role in gene regulation through chemical modifications of DNA and post-translational modifications of histones. An essential post-translational modification is the histone acetylation/deacetylation-process which is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The mammalian zinc dependent HDAC family is subdivided into three classes: class I (HDACs 1-3, 8), class II (IIa: HDACs 4, 5, 7, 9; IIb: HDACs 6, 10) and class IV (HDAC 11). In this review, recent studies on the biological role and regulation of class IIa HDACs as well as their contribution in neurodegenerative diseases, immune disorders and cancer will be presented. Furthermore, the development, synthesis, and future perspectives of selective class IIa inhibitors will be highlighted.


Assuntos
Epigenômica/métodos , Histona Desacetilases/metabolismo , Humanos
10.
Bioorg Med Chem ; 27(19): 115036, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31431326

RESUMO

A series of α,ß-unsaturated hydroxamic acid derivatives as novel HDAC inhibitors (HDACi) with structural modifications of the connecting unit and the CAP group was synthesized. The in vitro evaluation against the human cancer cell lines A2780 and Cal27 identified 6e and 7j as the most potent compounds regarding HDAC inhibitory activity and inhibition of proliferation. Isoform profiling against HDAC2, 4, 6 and 8 revealed a preference for HDAC2 and 6 for both compounds in contrast to the pan HDACi panobinostat. 6e and 7j enhanced significantly cisplatin-induced cytotoxicity in a combination treatment mediated by increased apoptosis induction and caspase-3/7 activation. The interaction between 6e or 7j and cisplatin was highly synergistic and more pronounced for the cisplatin resistant subline Cal27CisR. IC50 values of cisplatin were even lower in Cal27CisR pretreated with 6e or 7j than for the parental cell line Cal27. Based on our findings, the novel dual class I/HDAC6 inhibitors could serve as an option to overcome cisplatin resistance with fewer side effects in comparison to panobinostat.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Inibidores de Histona Desacetilases/síntese química , Humanos , Ácidos Hidroxâmicos/síntese química , Panobinostat/farmacologia , Vorinostat/farmacologia
11.
PLoS One ; 14(3): e0213186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30830950

RESUMO

OBJECTIVE: Non-selective histone deacetylase (HDAC) inhibitors are known to improve hypertension. Here, we investigated the therapeutic effect and regulatory mechanism of the class I HDAC selective inhibitors, MS-275 and RGFP966, in angiotensin (Ang) II-induced hypertensive mice. METHODS AND RESULTS: MS-275 inhibited the activity of HDAC1, HDAC2, and HDAC3, while RGFP966 weakly inhibited that of HDAC3 in a cell-free system. MS-275 and RGFP966 treatment reduced systolic blood pressure and thickness of the aorta wall in Ang II-induced hypertensive mice. MS-275 treatment reduced aorta collagen deposition, as determined by Masson's trichrome staining. MS-275 decreased the components of the renin angiotensin system and increased vascular relaxation of rat aortic rings via the nitric oxide (NO) pathway. NO levels reduced by Ang II were restored by MS-275 treatment in vascular smooth muscle cells (VSMCs). However, MS-275 dose (3 mg·kg-1·day-1) was not enough to induce NO production in vivo. In addition, MS-275 did not prevent endothelial nitric oxide synthase (eNOS) uncoupling in the aorta of Ang II-induced mice. Treatment with MS-275 failed to inhibit Ang II-induced expression of NADPH oxidase (Nox)1, Nox2, and p47phox. MS-275 treatment reduced proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and monocyte chemoattractant protein (MCP)-1, as well as adhesion molecules. Histological analysis showed that Ang II-induced macrophage infiltration was reduced by MS-275 and RGFP966 administration. CONCLUSIONS: Our results indicate that class I HDAC selective inhibitors may be good therapeutic agents for the treatment of hypertension through the regulation of vascular remodeling and vasoconstriction, as well as inflammation.


Assuntos
Angiotensina II/farmacologia , Benzamidas/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Hipertensão/patologia , Piridinas/farmacologia , Vasoconstrição/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Benzamidas/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Moléculas de Adesão Celular/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Inflamação/prevenção & controle , Macrófagos/imunologia , Masculino , Camundongos , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , NADPH Oxidase 1/metabolismo , Óxido Nítrico/metabolismo , Piridinas/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
12.
J Cell Mol Med ; 23(4): 2801-2812, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30734467

RESUMO

Here, we report that LMK235, a class I and histone deacetylase (HDAC6)-preferential HDAC inhibitor, reduces hypertension via inhibition of vascular contraction and vessel hypertrophy. Angiotensin II-infusion mice and spontaneously hypertensive rats (SHRs) were used to test the anti-hypertensive effect of LMK235. Daily injection of LMK235 lowered angiotensin II-induced systolic blood pressure (BP). A reduction in systolic BP in SHRs was observed on the second day when SHRs were treated with 3 mg/kg LMK235 every 3 days. However, LMK235 treatment did not affect angiotensin-converting enzyme 1 and angiotensin II receptor mRNA expression in either hypertensive model. LMK235, acting via the nitric oxide pathway, facilitated the relaxing of vascular contractions induced by a thromboxane A2 agonist in the rat aortic and mesenteric artery ring test. In addition, LMK235 increased nitric oxide production in HUVECs and inhibited the increasing of aortic wall thickness in both animal hypertensive models. LMK235 decreased the enhanced cell cycle-related genes cyclin D1 and E2F3 in angiotensin II-infusion mice and restored the decreased p21 expression. In addition, LMK235 suppressed calcium calmodulin-dependent protein kinase II (CaMKII) α, which is related to vascular smooth muscle cell proliferation. Inhibition or knockdown of HDAC5 blocked the CaMKIIα-induced cell cycle gene expression. Immunoprecipitation demonstrated that class I HDACs were involved in the inhibition of CaMKII α-induced HDAC4/5 by LMK235. We suggest that LMK235 should be further investigated for its use in the development of new therapeutic options to treat hypertension via reducing vascular hyperplasia or vasoconstriction.


Assuntos
Anti-Hipertensivos/farmacologia , Doenças da Aorta/tratamento farmacológico , Benzamidas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertensão/complicações , Vasoconstrição/efeitos dos fármacos , Angiotensina II/toxicidade , Animais , Doenças da Aorta/etiologia , Doenças da Aorta/patologia , Inibidores de Histona Desacetilases/farmacologia , Hipertensão/induzido quimicamente , Hipertensão/patologia , Masculino , Camundongos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley
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