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1.
Acta Pharmacol Sin ; 45(9): 1964-1977, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38698214

RESUMO

The retinoic acid receptor-related orphan receptor γ (RORγ) is regarded as an attractive therapeutic target for the treatment of prostate cancer. Herein, we report the identification, optimization, and evaluation of 1,2,3,4-tetrahydroquinoline derivatives as novel RORγ inverse agonists, starting from high throughput screening using a thermal stability shift assay (TSA). The representative compounds 13e (designated as XY039) and 14a (designated as XY077) effectively inhibited the RORγ transcriptional activity and exhibited excellent selectivity against other nuclear receptor subtypes. The structural basis for their inhibitory potency was elucidated through the crystallographic study of RORγ LBD complex with 13e. Both 13e and 14a demonstrated reasonable antiproliferative activity, potently inhibited colony formation and the expression of AR, AR regulated genes, and other oncogene in AR positive prostate cancer cell lines. Moreover, 13e and 14a effectively suppressed tumor growth in a 22Rv1 xenograft tumor model in mice. This work provides new and valuable lead compounds for further development of drugs against prostate cancer.


Assuntos
Antineoplásicos , Proliferação de Células , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Neoplasias da Próstata , Quinolinas , Masculino , Animais , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Quinolinas/farmacologia , Quinolinas/química , Quinolinas/uso terapêutico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Agonismo Inverso de Drogas , Camundongos , Camundongos Nus , Descoberta de Drogas , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C
2.
Mol Ther ; 30(8): 2844-2855, 2022 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-35450818

RESUMO

The roles of micropeptides in cell cycle regulation and cancer development remain largely unknown. Here we found that a micropeptide STMP1 (small transmembrane protein 1) was up-regulated in multiple malignancies including hepatocellular carcinoma (HCC), and its high level was associated with short recurrence-free survival of HCC patients. Gain- and loss-of-function analyses revealed that STMP1 accelerated cell proliferation and clonogenicity in vitro and tumor growth in vivo, and silencing STMP1 blocked G1/S transition. Mechanistically, STMP1 promoted the mRNA and protein levels of CCNE2, CDK2, and E2F1. STMP1 was localized in the inner membrane of mitochondria and interacted with mitochondrial complex IV and then enhanced its activity. Moreover, treatment with the mitochondrial complex IV inhibitor tetrathiomolybdate dramatically abrogated the promoting effect of STMP1 on cell proliferation and the expression of cyclin E2, CDK2, and E2F1. These results suggest that STMP1 may promote G1/S transition and cell proliferation by enhancing mitochondrial complex IV activity, which highlights STMP1 as a new regulator of the cell cycle and a potential target for anti-cancer therapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , RNA Mensageiro/metabolismo
3.
Acta Pharmacol Sin ; 43(10): 2735-2748, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35264812

RESUMO

BRD4 plays a key role in the regulation of gene transcription and has been identified as an attractive target for cancer treatment. In this study, we designed 26 new compounds by modifying 3-ethyl-benzo[d]isoxazole core with sulfonamides. Most compounds exhibited potent BRD4 binding activities with ΔTm values exceeding 6 °C. Two crystal structures of 11h and 11r in complex with BRD4(1) were obtained to characterize the binding patterns. Compounds 11h and 11r were effective for BRD4(1) binding and showed remarkable anti-proliferative activity against MV4-11 cells with IC50 values of 0.78 and 0.87 µM. Furthermore, 11r (0.5-10 µM) concentration-dependently inhibited the expression levels of oncogenes including c-Myc and CDK6 in MV4-11 cells. Moreover, 11r (0.5-10 µM) concentration-dependently blocked cell cycle in MV4-11 cells at G0/G1 phase and induced cell apoptosis. Compound 11r may serve as a new lead compound for further drug development.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Androstenóis , Antineoplásicos/química , Apoptose , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Nucleares/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Fatores de Transcrição
4.
Opt Express ; 24(3): 2360-9, 2016 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-26906811

RESUMO

We investigate theoretically four-wave mixing (FWM) response and optical bistability (OB) in a hybrid nanosystem composed of a metal nanoparticle (MNP) and a semiconductor quantum dot (SQD) coupled to a nanomechanical resonator (NR). It is shown that the FWM signal is enhanced by more than three orders of magnitude as compared to that of the system without exciton-phonon interaction, and the FWM signal can also be suppressed significantly and broadened due to the exciton-plasmon interaction. As the MNP couples strongly with the SQD, the bistable FWM response can be achieved by adjusting the SQD-MNP distance and the pumping intensity. For a given pumping constant and a fixed SQD-MNP distance, the enhanced exciton-phonon interaction can promote the occurrence of bistability. Our findings not only present a feasible way to detect the spacing between two nanoparticles, but also hold promise for developing quantum switches and nanoscale rulers.

5.
Acta Pharmacol Sin ; 37(11): 1516-1524, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27374490

RESUMO

AIM: Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design. METHODS: Based on the structure of compound 8, a previously described agonist of RORa, a series of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives were designed and synthesized. The interaction between the compounds and RORc was detected at molecular level using AlphaScreen assay. The compounds were further examined in 293T cells transfected with RORc and luciferase reporter gene. Thermal stability shift assay was used to evaluate the effects of the compounds on protein stability. RESULTS: A total of 27 derivatives were designed and synthesized. Among them, the compound 22b was identified as the most potent RORc inverse agonist. Its IC50 values were 2.39 µmol/L in AlphaScreen assay, and 0.82 µmol/L in inhibition of the cell-based luciferase reporter activity. Furthermore, the compound 22b displayed a 120-fold selectivity for RORc over other nuclear receptors. Moreover, a molecular docking study showed that the structure-activity relationship was consistent with the binding mode of compound 22b in RORc. CONCLUSION: 4-(4-(Benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives are promising candidates for the treatment of Th17-mediated autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis.


Assuntos
Derivados de Benzeno/química , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Pirimidinonas/química , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Derivados de Benzeno/síntese química , Derivados de Benzeno/farmacologia , Agonismo Inverso de Drogas , Genes Reporter , Células HEK293 , Humanos , Luciferases de Renilla/genética , Simulação de Acoplamento Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Relação Estrutura-Atividade , Células Th17/imunologia
6.
Acta Pharmacol Sin ; 36(1): 71-87, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25500868

RESUMO

Nuclear receptors (NRs) are ligand-regulated transcription factors that regulate metabolism, development and immunity. The NR superfamily is one of the major classes of drug targets for human diseases. Retinoic acid receptor-related orphan receptor (ROR) α, ß and γ belong to the NR superfamily, and these receptors are still considered as 'orphan' receptors because the identification of their endogenous ligands has been controversial. Recent studies have demonstrated that these receptors are regulated by synthetic ligands, thus emerge as important drug targets for the treatment of multiple sclerosis, rheumatoid arthritis, psoriasis, etc. Studying the structural basis and ligand development of RORs will pave the way for a better understanding of the roles of these receptors in human diseases. Here, we review the structural basis, disease relevance, strategies for ligand identification, and current status of development of therapeutic ligands for RORs.


Assuntos
Receptores Nucleares Órfãos/metabolismo , Animais , Descoberta de Drogas/métodos , Humanos , Ligantes
7.
Am J Physiol Gastrointest Liver Physiol ; 305(12): G891-9, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24136786

RESUMO

Cytokines play important roles in all stages of steatohepatitis, including hepatocyte injury, the inflammatory response, and the altered function of sinusoidal cells. This study examined the involvement of a major inflammatory cytokine, interferon-γ (IFN-γ), in the progression of steatohepatitis. In a steatohepatitis model by feeding a methionine- and choline-deficient high-fat (MCDHF) diet to both wild-type and IFN-γ-deficient mice, the liver histology, expression of genes encoding inflammatory cytokines, and fibrosis-related markers were examined. To analyze the effects of IFN-γ on Kupffer cells in vitro, we examined the tumor necrosis factor-α (TNF-α) production by a mouse macrophage cell line. Forty two days of MCDHF diet resulted in weight loss, elevated aminotransferases, liver steatosis, and inflammation in wild-type mice. However, the IFN-γ-deficient mice exhibited less extensive changes. RT-PCR revealed that the expression of tumor necrosis factor-α (TNF-α), transforming growth factor-ß, inducible nitric oxide synthase, interleukin-4 and osteopontin were increased in wild-type mice, although they were suppressed in IFN-γ-deficient mice. Seventy days of MCDHF diet induced much more liver fibrosis in wild-type mice than in IFN-γ-deficient mice. The expression levels of fibrosis-related genes, α-smooth muscle actin, type I collagen, tissue inhibitor of matrix metalloproteinase-1, and matrix metalloproteinase-2, were dramatically increased in wild-type mice, whereas they were significantly suppressed in IFN-γ-deficient mice. Moreover, in vitro experiments showed that, when RAW 264.7 macrophages were treated with IFN-γ, they produced TNF-α in a dose-dependent manner. The present study showed that IFN-γ deficiency might inhibit the inflammatory response of macrophages cells and subsequently suppress stellate cell activation and liver fibrosis. These findings highlight the critical role of IFN-γ in the progression of steatohepatitis.


Assuntos
Fígado Gorduroso , Células Estreladas do Fígado , Interferon gama , Células de Kupffer , Cirrose Hepática , Animais , Linhagem Celular , Deficiência de Colina/metabolismo , Deficiência de Colina/patologia , Dieta Hiperlipídica/métodos , Modelos Animais de Doenças , Fígado Gorduroso/complicações , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Perfilação da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Inflamação/metabolismo , Inflamação/patologia , Interferon gama/deficiência , Interferon gama/metabolismo , Células de Kupffer/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Metionina/deficiência , Metionina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
8.
PhytoKeys ; 234: 145-165, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37901134

RESUMO

Five taxa of Delphiniumsubg.Anthriscifolium have been karyologically studied through chromosome counting, chromosomal measurement, and karyotype symmetry. Each taxon that we investigated has a basic chromosome number of x = 8, D.anthriscifoliumvar.savatieri, D.anthriscifoliumvar.majus, D.ecalcaratum, and D.callichromum were diploid with 2n = 16, while D.anthriscifoliumvar.anthriscifolium was tetraploid with 2n = 32. Monoploid chromosome sets of the investigated diploid taxa contained 1 metacentric chromosome, 3 submetacentric chromosomes, and 4 subtelocentric chromosomes. Higher interchromosomal asymmetry (CVCL) was present in D.ecalcaratum and D.callichromum than in other taxa. The highest levels of intrachromosomal asymmetry (MCA) and heterogeneity in centromere position (CVCI) were found in D.anthriscifoliumvar.majus. Diploid and tetraploid genome sizes varied by 3.02-3.92 pg and 6.04-6.60 pg, respectively. Karyotype and genome size of D.anthriscifoliumvar.savatieri, D.anthriscifoliumvar.majus, D.callichromum, and D.ecalcaratum were reported for the first time. Finally, based on cytological and morphological data, the classification of Delphiniumanthriscifolium was revised.

9.
Mol Oncol ; 17(5): 901-916, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36495128

RESUMO

The biological functions of short open reading frame (sORF)-encoded micropeptides remain largely unknown. Here, we report that LINC00998, a previously annotated lncRNA, was upregulated in multiple cancer types and the sORF on LINC00998 encoded a micropeptide named SMIM30. SMIM30 was localized in the membranes of the endoplasmic reticulum (ER) and mitochondria. Silencing SMIM30 inhibited the proliferation of hepatoma cells in vitro and suppressed the growth of tumor xenografts and N-nitrosodiethylamine-induced hepatoma. Overexpression of the 5'UTR-sORF sequence of LINC00998, encoding wild-type SMIM30, enhanced tumor cell growth, but this was abolished when a premature stop codon was introduced into the sORF via single-base deletion. Gain- and loss-of-function studies revealed that SMIM30 peptide but not LINC00998 reduced cytosolic calcium level, increased CDK4, cyclin E2, phosphorylated-Rb and E2F1, and promoted the G1/S phase transition and cell proliferation. The effect of SMIM30 silencing was attenuated by a calcium chelator or the agonist of sarco/endoplasmic reticulum calcium ATPase (SERCA) pump. These findings suggest a novel function of micropeptide SMIM30 in promoting G1/S transition and cell proliferation by enhancing SERCA activity and reducing cytosolic calcium level.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Humanos , Cálcio/metabolismo , ATPases Transportadoras de Cálcio/metabolismo , Ciclo Celular , Micropeptídeos
10.
Biochem Biophys Res Commun ; 417(1): 287-93, 2012 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-22155236

RESUMO

The incidence of non-alcoholic fatty liver disease (NAFLD) has been increasing, and there is a shortage of liver donors, which has led to the acceptance of steatotic livers for transplantation. However, steatotic livers are known to experience more severe acute ischemia-reperfusion (I/R) injury than normal livers upon transplantation. In the present study, we investigated the role of theaflavin, a polyphenol substance extracted from black tea, in attenuating acute I/R injury in a fatty liver model. We induced I/R in normal and steatotic livers treated with or without theaflavin. We also separated primary hepatocytes from the normal and steatotic livers, and applied RAW264.7 cells, a mouse macrophage cell line, that was pretreated with theaflavin. We observed that liver steatosis, oxidative stress, inflammation and hepatocyte apoptosis were increased in the steatotic liver compared to the normal liver, however, these changes were significantly decreased by theaflavin treatment. In addition, theaflavin significantly diminished the ROS production of steatotic hepatocytes and TNF-α production by LPS-stimulated RAW264.7 cells. We concluded that theaflavin has protective effects against I/R injury in fatty livers by anti-oxidant, anti-inflammatory, and anti-apoptotic mechanisms.


Assuntos
Antioxidantes/administração & dosagem , Biflavonoides/administração & dosagem , Catequina/administração & dosagem , Fígado Gorduroso/fisiopatologia , Transplante de Fígado , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/fisiopatologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/patologia , Hepatócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/biossíntese , Traumatismo por Reperfusão/patologia , Doadores de Tecidos , Fator de Necrose Tumoral alfa/metabolismo
11.
Stem Cell Res Ther ; 10(1): 16, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635047

RESUMO

BACKGROUND: Liver fibrosis is a key phase that will progress to further injuries such as liver cirrhosis or carcinoma. This study aimed to investigate whether transplantation of bone marrow mesenchymal stromal cells (BM-MSCs) can attenuate liver fibrosis in mice and the underlying mechanisms based on the regulation of macrophage subtypes. METHODS: A liver fibrosis model was induced by intraperitoneal (i.p.) injection of CCl4 twice per week for 70 days, and BM-MSCs were intravenously transplanted twice on the 60th and 70th days. Immunohistology and gene expression of liver fibrosis and macrophage subtypes were analyzed. Mouse RAW264.7 cells and JS1 cells (hepatic stellate cell strain) were also used to explore the underlying mechanisms of the effects of BM-MSCs on liver fibrosis. RESULTS: After transplantation of BM-MSCs, F4/80+CD206+-activated M2 macrophages and matrix metalloproteinase 13 (MMP 13) expression were significantly increased while F4/80+iNOS+-activated M1 macrophages were inhibited in liver tissue. Gene expression of IL-10 was elevated while IL12b, IFN-γ, TNF-α, and IL-6 gene expression were decreased. ΤGF-ß1 and collagen-1 secretions were reduced while caspase-3 was increased in JS1 cells treated with BM-MSC-conditioned media. BM-MSCs effectively suppressed the expression of α-SMA, Sirius red, and collagen-1 in the liver, which are positively correlated with fibrosis and induced by CCl4 injection. CONCLUSIONS: Taken together, we have provided the first demonstration that BM-MSC transplantation can promote the activation of M2 macrophages expressing MMP13 and inhibition of M1 macrophages to further inhibit hepatic stellate cells (HSCs), which play synergistic roles in attenuating liver fibrosis.


Assuntos
Cirrose Hepática/terapia , Metaloproteinase 13 da Matriz/genética , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Animais , Células da Medula Óssea/citologia , Proteínas de Ligação ao Cálcio/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/metabolismo , Humanos , Subunidade p40 da Interleucina-12/genética , Cirrose Hepática/genética , Cirrose Hepática/patologia , Macrófagos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Óxido Nítrico Sintase Tipo II/genética , Células RAW 264.7 , Receptores Acoplados a Proteínas G/genética
12.
Med Biol Eng Comput ; 48(9): 903-10, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20556662

RESUMO

Physical modelling of phonation requires a mechanical description of the vocal fold coupled to a description of the flow within the glottis. In this study, an in-vitro set-up, allowing to reproduce flow conditions comparable to those of human glottal flow is used to systematically verify and discuss the relevance of the pressure and flow-rate predictions of several laminar flow models. The obtained results show that all the considered flow models underestimate the measured flow-rates and that flow-rates predicted with the one-dimensional model are most accurate. On the contrary, flow models based on boundary-layer theory and on the two-dimensional numerical resolution of Navier-Stokes equations yield most accurate pressure predictions. The influence of flow separation on the predictions is discussed since these two models can estimate relevant flow separation positions whereas this phenomenon is treated in a simplified ad-hoc way in the one-dimensional flow modelling. Laminar flow models appear to be unsuitable to describe the flow downstream of the glottal constriction. Therefore, the use of flow models taking into account three-dimensional effects as well as turbulence is motivated.


Assuntos
Glote/fisiologia , Modelos Biológicos , Fonação/fisiologia , Fenômenos Biomecânicos/fisiologia , Humanos , Prega Vocal/fisiologia
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