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1.
Mol Divers ; 27(3): 1123-1140, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35767128

RESUMEN

3D-QSAR models were established by collecting 46 multivariate-substituted 4-oxyquinazoline HDAC6 inhibitors. The relationship of molecular structure and inhibitory activity was studied by comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). The results showed the models established by CoMFA (q2 = 0.590, r2 = 0.965) and CoMSIA (q2 = 0.594, r2 = 0.931) had good prediction ability. At the same time, 3D-QSAR models met the internal verification, external verification and AD test. Ten new compounds were designed based on CoMFA and CoMSIA contour maps and their pharmacokinetic/toxic properties (ADME/T) were evaluated. It was found that most compounds have well safety profile and pharmacokinetic property. Then, we explored the interaction between HDAC6 and compounds by molecular docking. The results showed that the binding mode of the new compounds with HDAC6 was the same as the template compound 46, and the hydrogen bond and hydrophobic bond played a vital role in the binding process. Molecular dynamics simulation results showed that residues Ser531, His574 and Tyr745 played key roles in the binding process. All newly designed compounds had lower energy gap and binding energy than compound 46 according to DFT analysis and free energy analysis. This study provided a theoretical reference for designing compounds of higher activity and a new idea for the development of novel HDAC6 inhibitors.


Asunto(s)
Simulación de Dinámica Molecular , Relación Estructura-Actividad Cuantitativa , Simulación del Acoplamiento Molecular , Estructura Molecular
2.
Mikrochim Acta ; 190(8): 341, 2023 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-37530902

RESUMEN

A novel stimulus-responsive surface-enhanced Raman scattering (SERS) nanoprobe has been developed for sensitive glutathione (GSH) detection based on manganese dioxide (MnO2) core and silver/gold nanoparticles (Ag/Au NPs). The MnO2 core is not only capable to act as a scaffold to amplify the SERS signal via producing "hot spots", but also can be degraded in the presence of the target and thus greatly enhance the nanoprobe sensitivity for sensing of GSH. This approach enables a wide linear range from 1 to 100 µM with a 2.95 µM (3σ/m) detection limit. Moreover, the developed SERS nanoprobe represents great possibility in both sensitive detection of intracellular GSH and even can monitor the change of intracellular GSH level when the stimulant occurs. This sensing system not merely offers a novel strategy for sensitive sensing of GSH, but also provides a new avenue for other biomolecules detection.


Asunto(s)
Nanopartículas del Metal , Oro , Compuestos de Manganeso , Plata , Óxidos , Glutatión
3.
Hepatology ; 71(3): 929-942, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31692012

RESUMEN

BACKGROUND AND AIMS: Aristolochic acid (AA) exposure has been statistically associated with human liver cancers. However, direct evidence of AA exposure-induced liver cancer is absent. This study aims to establish a direct causal relationship between AA exposure and liver cancers based on a mouse model and then explores the AA-mediated genomic alterations that could be implicated in human cancers with AA-associated mutational signature. APPROACH AND RESULTS: We subjected mice, including phosphatase and tensin homolog (Pten)-deficient ones, to aristolochic acid I (AAI) alone or a combination of AAI and CCl4 . Significantly, AAI exposure induced mouse liver cancers, including hepatocellular carcinoma (HCC) and combined HCC and intrahepatic cholangiocarcinoma, in a dose-dependent manner. Moreover, AAI exposure also enhanced tumorigenesis in these CCl4 -treated or Pten-deficient mice. AAI led to DNA damage and AAI-DNA adduct that could initiate liver cancers through characteristic adenine-to-thymine transversions, as indicated by comprehensive genomic analysis, which revealed recurrent mutations in Harvey rat sarcoma virus oncogene. Interestingly, an AA-associated mutational signature was mainly implicated in human liver cancers, especially from China. Moreover, we detected the AAI-DNA adduct in 25.8% (16/62) of paratumor liver tissues from randomly selected Chinese patients with HCC. Furthermore, based on phylogenetic analysis, the characteristic mutations were found in the initiating malignant clones in the AA-implicated mouse and human liver cancers where the mutations of tumor protein p53 and Janus kinase 1 were prone to be significantly enriched in the AA-affected human tumors. CONCLUSIONS: This study provides evidence for AA-induced liver cancer with the featured mutational processes during malignant clonal evolution, laying a solid foundation for the prevention and diagnosis of AA-associated human cancers, especially liver cancers.


Asunto(s)
Ácidos Aristolóquicos/toxicidad , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/genética , Mutación , Animales , Neoplasias de los Conductos Biliares/inducido químicamente , Neoplasias de los Conductos Biliares/genética , Tetracloruro de Carbono/toxicidad , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/genética , Colangiocarcinoma/inducido químicamente , Colangiocarcinoma/genética , Daño del ADN , Relación Dosis-Respuesta a Droga , Humanos , Janus Quinasa 1/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína p53 Supresora de Tumor/genética , Quinasas raf/fisiología
4.
Molecules ; 26(22)2021 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-34834088

RESUMEN

Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin in the human body. Overproduction of melanin can lead to a variety of skin disorders. Calycosin is an isoflavone from Astragali Radix, which is a traditional Chinese medicine that exhibits several pharmacological activities including skin whitening. In our study, the inhibitory effect of calycosin on melanin production is confirmed in a zebrafish in vivo model by comparing with hydroquinone, kojic acid, and arbutin, known as tyrosinase inhibitors. Moreover, the inhibitory kinetics of calycosin on tyrosinase and their binding mechanisms are determined using molecular docking techniques, molecular dynamic simulations, and free energy analysis. The results indicate that calycosin has an obvious inhibitory effect on zebrafish pigmentation at the concentration of 7.5 µM, 15 µM, and 30 µM. The IC50 of calycosin is 30.35 µM, which is lower than hydroquinone (37.35 µM), kojic acid (6.51 × 103 µM), and arbutin (3.67 × 104 µM). Furthermore, all the results of molecular docking, molecular dynamics simulations, and free energy analysis suggest that calycosin can directly bind to the active site of tyrosinase with very good binding affinity. The study indicates that the combination of computer molecular modeling and zebrafish in vivo assay would be feasible in confirming the result of the in vitro test and illustrating the target-binding information.


Asunto(s)
Melaninas , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Monofenol Monooxigenasa , Proteínas de Pez Cebra , Pez Cebra/metabolismo , Animales , Humanos , Isoflavonas/química , Isoflavonas/farmacología , Melaninas/antagonistas & inhibidores , Melaninas/química , Melaninas/metabolismo , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/química , Monofenol Monooxigenasa/metabolismo , Proteínas de Pez Cebra/antagonistas & inhibidores , Proteínas de Pez Cebra/química , Proteínas de Pez Cebra/farmacología
5.
Prostate ; 80(6): 508-517, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32119131

RESUMEN

BACKGROUND: As a rare subtype of prostate carcinoma, basal cell carcinoma (BCC) has not been studied extensively and thus lacks systematic molecular characterization. METHODS: Here, we applied single-cell genomic amplification and RNA-Seq to a specimen of human prostate BCC (CK34ßE12+ /P63+ /PAP- /PSA- ). The mutational landscape was obtained via whole exome sequencing of the amplification mixture of 49 single cells, and the transcriptomes of 69 single cells were also obtained. RESULTS: The five putative driver genes mutated in BCC are CASC5, NUTM1, PTPRC, KMT2C, and TBX3, and the top three nucleotide substitutions are C>T, T>C, and C>A, similar to common prostate cancer. The distribution of the variant allele frequency values indicated that these single cells are from the same tumor clone. The 69 single cells were clustered into tumor, stromal, and immune cells based on their global transcriptomic profiles. The tumor cells specifically express basal cell markers like KRT5, KRT14, and KRT23 and epithelial markers EPCAM, CDH1, and CD24. The transcription factor covariance network analysis showed that the BCC tumor cells have distinct regulatory networks. By comparison with current prostate cancer datasets, we found that some of the bulk samples exhibit basal cell signatures. Interestingly, at single-cell resolution the gene expression patterns of prostate BCC tumor cells show uniqueness compared with that of common prostate cancer-derived circulating tumor cells. CONCLUSIONS: This study, for the first time, discloses the comprehensive mutational and transcriptomic landscapes of prostate BCC, which lays a foundation for the understanding of its tumorigenesis mechanism and provides new insights into prostate cancers in general.


Asunto(s)
Carcinoma Basocelular/genética , Neoplasias de la Próstata/genética , Biopsia con Aguja , Carcinoma Basocelular/patología , Amplificación de Genes , Perfilación de la Expresión Génica/métodos , Frecuencia de los Genes , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mutación , Neoplasias de la Próstata/patología , Análisis de la Célula Individual/métodos , Células del Estroma/patología , Transcriptoma , Secuenciación del Exoma
6.
Development ; 144(3): 441-451, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-28003215

RESUMEN

Sirt1 is a member of the sirtuin family of proteins and has important roles in numerous biological processes. Sirt1-/- mice display an increased frequency of abnormal spermatozoa, but the mechanism of Sirt1 in spermiogenesis remains largely unknown. Here, we report that Sirt1 might be directly involved in spermiogenesis in germ cells but not in steroidogenic cells. Germ cell-specific Sirt1 knockout mice were almost completely infertile; the early mitotic and meiotic progression of germ cells in spermatogenesis were not obviously affected after Sirt1 depletion, but subsequent spermiogenesis was disrupted by a defect in acrosome biogenesis, which resulted in a phenotype similar to that observed in human globozoospermia. In addition, LC3 and Atg7 deacetylation was disrupted in spermatids after knocking out Sirt1, which affected the redistribution of LC3 from the nucleus to the cytoplasm and the activation of autophagy. Furthermore, Sirt1 depletion resulted in the failure of LC3 to be recruited to Golgi apparatus-derived vesicles and in the failure of GOPC and PICK1 to be recruited to nucleus-associated acrosomal vesicles. Taken together, these findings reveal that Sirt1 has a novel physiological function in acrosome biogenesis.


Asunto(s)
Acrosoma/fisiología , Sirtuina 1/fisiología , Espermatogénesis/fisiología , Acrosoma/patología , Proteínas Adaptadoras Transductoras de Señales , Animales , Autofagia/genética , Autofagia/fisiología , Proteínas Portadoras/metabolismo , Proteínas de Ciclo Celular , Modelos Animales de Enfermedad , Proteínas de la Matriz de Golgi , Humanos , Infertilidad Masculina/etiología , Infertilidad Masculina/genética , Infertilidad Masculina/patología , Péptidos y Proteínas de Señalización Intracelular , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Microscopía Electrónica de Transmisión , Modelos Biológicos , Proteínas Nucleares/metabolismo , Fenotipo , Sirtuina 1/deficiencia , Sirtuina 1/genética , Espermatogénesis/genética , Espermatozoides/patología , Espermatozoides/fisiología , Esteroides/biosíntesis , Teratozoospermia/etiología , Teratozoospermia/patología
7.
Fish Shellfish Immunol ; 82: 573-578, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30176336

RESUMEN

Receptor interacting protein kinase 3 (RIP3) has emerged as an essential molecular regulator in human inflammation with accumulating evidence in vertebrates. However, the structure and functions of RIP3 in teleosts remains elusive. Here we identified one RIP3 homologue from half-smooth tongue sole Cynoglossus semilaevis, designated CsRIP3. The open reading frame (ORF) of CsRIP3 contained 1491 nucleotides and encoded a protein with 496 amino acids (Mw = 55.44 kDa). CsRIP3 expression was detected in various tissues in half-smooth tongue soles. CsRIP3 expression was up-regulated after pathogens i.e. Vibrio and poly (i:c) treatment in vivo, indicating its possible role in teleost immune response. Further analysis using human cells demonstrated that CsRIP3 exhibited highly conserved pro-apoptotic and pro-necroptotic functions in comparison with human RIP3. In conclusion, for the first time we reported the homologous structure and functions of CsRIP3 in inflammatory cell death, which provides novel perspectives on fish immunity studies in future.


Asunto(s)
Enfermedades de los Peces/inmunología , Peces Planos/genética , Peces Planos/inmunología , Regulación de la Expresión Génica/inmunología , Inmunidad Innata/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/inmunología , Secuencia de Aminoácidos , Animales , Proteínas de Peces/química , Proteínas de Peces/genética , Proteínas de Peces/inmunología , Perfilación de la Expresión Génica/veterinaria , Filogenia , Poli I-C/farmacología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/química , Alineación de Secuencia/veterinaria , Vibrio/fisiología , Vibriosis/inmunología
8.
Integr Cancer Ther ; 23: 15347354241233258, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38369762

RESUMEN

BACKGROUND: Soothing the liver (called Shu Gan Jie Yu in Chinese, SGJY) is a significant therapeutic method for breast cancer in TCM. In this study, 3 liver-soothing herbs, including Cyperus rotundus L., Citrus medica L. var. sarcodactylis Swingle and Rosa rugosa Thunb. were selected and combined to form a SGJY herbal combinatory. THE AIM OF THE STUDY: To investigate the inhibiting effect of SGJY on breast cancer in vivo and vitro, and to explore the potential mechanisms. MATERIALS AND METHODS: SGJY herbal combination was extracted using water. A breast cancer rat model was developed by chemical DMBA by gavage, then treated with SGJY for 11 weeks. The tumor tissue was preserved for RNA sequencing and analyzed by IPA software. The inhibition effects of SGJY on MCF-7 and T47D breast cancer cells were investigated by SRB assay and cell apoptosis analysis, and the protein expression levels of SNCG, ER-α, p-AKT and p-ERK were measured by western blotting. RESULTS: SGJY significantly reduced the tumor weight and volume, and the level of estradiol in serum. The results of IPA analysis reveal SGJY upregulated 7 canonical pathways and downregulated 16 canonical pathways. Estrogen receptor signaling was the key canonical pathway with 9 genes downregulated. The results of upstream regulator analysis reveal beta-estradiol was the central target; the upstream regulator network scheme showed that 86 genes could affect the expression of the beta-estradiol, including SNCG, CCL21 and MB. Additionally, SGJY was verified to significantly alter the expression of SNCG mRNA, CCL21 mRNA and MB mRNA which was consistent with the data of RNA-Seq. The inhibition effects of SGJY exhibited a dose-dependent response. The apoptosis rates of MCF7 and T47D cells were upregulated. The protein expression of SNCG, ER-α, p-AKT and p-ERK were all significantly decreased by SGJY on MCF-7 and T47D cells. CONCLUSION: The results demonstrate that SGJY may inhibit the growth of breast cancer. The mechanism might involve downregulating the level of serum estradiol, and suppressing the protein expression in the SNCG/ER-α/AKT-ERK pathway.


Asunto(s)
Neoplasias de la Mama , Sistema de Señalización de MAP Quinasas , Animales , Femenino , Humanos , Ratas , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Estradiol , gamma-Sinucleína/genética , gamma-Sinucleína/metabolismo , Células MCF-7 , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Estrógenos/metabolismo , ARN Mensajero/metabolismo , RNA-Seq
9.
J Biomol Struct Dyn ; : 1-12, 2023 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-37464874

RESUMEN

Colorectal cancer is a serious threat to people's life due to its high incidence and high mortality. Quercetin can effectively treat colorectal carcinoma (CRC), but its exact mechanism of action is still unclear. Then quercetin-related target genes were obtained from Swiss Target Prediction database and Similarity Ensemble Approach (SEA) database, and CRC-related target genes were obtained from GeneCards database, respectively. Common target genes were obtained by FunRich software. String software was used to construct a protein-protein interaction (PPI) network. R package was used for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Molecular docking, molecular dynamics (MD) simulation and post-dynamics simulation were used to explore the binding stability of quercetin to key targets. In total, 103 and 141 target information of quercetin were obtained from the Swiss Target Prediction database and SEA database, respectively. 1,649 CRC-related genes were obtained from GeneCards database. FunRich software was used to draw venny map and obtain 36 intersection targets of quercetin and CRC. String software was used to construct the PPI network. The core genes were AKT1, EGFR, MMP9, KDR, MET and PTK2. There were 532 items related to biological processes, 14 items related to cellular components, and 43 items related to molecular functions among the key target GO enrichment items. KEGG enrichment pathways of key targets involved cancer pathways, PI3K-Akt signal pathway, etc. The results of molecular docking, MD simulation and post-dynamics simulation showed they had a good affinity and formed a stable effect. So quercetin may play an important role in the treatment of CRC by acting on AKT1, EGFR, MMP9, KDR, MET and PTK2 to affect the development of CRC.Communicated by Ramaswamy H. Sarma.

10.
Ann N Y Acad Sci ; 1517(1): 213-224, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36081327

RESUMEN

Tumor clonal structure is closely related to future progression, which has been mainly investigated as mutation abundance clustering in bulk samples. With relatively limited studies at single-cell resolution, a systematic comparison of the two approaches is still lacking. Here, using bulk and single-cell mutational data from the liver and colorectal cancers, we checked whether co-mutations determined by single-cell analysis had corresponding bulk variant allele frequency (VAF) peaks. While bulk analysis suggested the absence of subclonal peaks and, possibly, neutral evolution in some cases, the single-cell analysis identified coexisting subclones. The overlaps of bulk VAF ranges for co-mutations from different subclones made it difficult to separate them. Complex subclonal structures and dynamic evolution could be hidden under the seemingly clonal neutral pattern at the bulk level, suggesting single-cell analysis is necessary to avoid underestimation of tumor heterogeneity.


Asunto(s)
Neoplasias , Análisis de la Célula Individual , Humanos , Neoplasias/genética , Mutación
11.
Front Pharmacol ; 12: 775602, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34925034

RESUMEN

Glioblastoma multiforme (GBM) is the most common and malignant brain tumor, and almost half of the patients carrying EGFR-driven tumor with PTEN deficiency are resistant to EGFR-targeted therapy. EGFR amplification and/or mutation is reported in various epithelial tumors. This series of studies aimed to identify a potent compound against EGFR-driven tumor. We screened a chemical library containing over 600 individual compounds purified from Traditional Chinese Medicine against GBM cells with EGFR amplification and found that cinobufagin, the major active ingredient of Chansu, inhibited the proliferation of EGFR amplified GBM cells and PTEN deficiency enhanced its anti-proliferation effects. Cinobufagin also strongly inhibited the proliferation of carcinoma cell lines with wild-type or mutant EGFR expression. In contrast, the compound only weakly inhibited the proliferation of cancer cells with low or without EGFR expression. Cinobufagin blocked EGFR phosphorylation and its downstream signaling, which additionally induced apoptosis and cytotoxicity in EGFR amplified cancer cells. In vivo, cinobufagin blocked EGFR signaling, inhibited cell proliferation, and elicited apoptosis, thereby suppressing tumor growth in both subcutaneous and intracranial U87MG-EGFR xenograft mouse models and increasing the median survival of nude mice bearing intracranial U87MG-EGFR tumors. Cinobufagin is a potential therapeutic agent for treating malignant glioma and other human cancers expressing EGFR.

12.
J Hematol Oncol ; 14(1): 22, 2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33531041

RESUMEN

Genetic heterogeneity of tumor is closely related to its clonal evolution, phenotypic diversity and treatment resistance, and such heterogeneity has only been characterized at single-cell sub-chromosomal scale in liver cancer. Here we reconstructed the single-variant resolution clonal evolution in human liver cancer based on single-cell mutational profiles. The results indicated that key genetic events occurred early during tumorigenesis, and an early metastasis followed by independent evolution was observed in primary liver tumor and intrahepatic metastatic portal vein tumor thrombus. By parallel single-cell RNA-Seq, the transcriptomic phenotype of HCC was found to be related with genetic heterogeneity. For the first time we reconstructed the single-cell and single-variant clonal evolution in human liver cancer, and dissection of both genetic and phenotypic heterogeneity will facilitate better understanding of their relationship.


Asunto(s)
Carcinoma Hepatocelular/genética , Evolución Clonal , Neoplasias Hepáticas/genética , Humanos , Mutación , Análisis de la Célula Individual , Células Tumorales Cultivadas
13.
Food Funct ; 9(2): 1058-1069, 2018 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-29355275

RESUMEN

In this study, the inhibitory effects of volatile oil from ginger on melanogenesis and its antioxidant characteristics were investigated. The effects of volatile oil from ginger on cell proliferation, melanin content and tyrosinase activity were determined using a microplate reader. In addition, the expression of melanogenesis-related protein was determined by western blotting. The results indicate that the tested concentrates of volatile oil from ginger showed inhibitory effects on cell proliferation and melanogenesis. This revealed that volatile oil from ginger exhibited apparent capacities for scavenging ROS and lipid peroxidation. Furthermore, volatile oil from ginger improved the activities of GSH, SOD and CAT in B16 melanoma cells. These results demonstrated that volatile oil from ginger suppressed melanin synthesis through its antioxidant properties and the inhibitory effects on tyrosinase activity and melanogensis-related proteins. Hence, volatile oil from ginger could be used as an effective skin-whitening agent applied in food industry.


Asunto(s)
Melanoma Experimental/tratamiento farmacológico , Aceites Volátiles/farmacología , Aceites de Plantas/farmacología , Zingiber officinale/química , Animales , Antioxidantes/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Glutatión/metabolismo , Humanos , Melanoma Experimental/fisiopatología , Ratones , Estrés Oxidativo/efectos de los fármacos
14.
Neurosci Lett ; 612: 104-109, 2016 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-26655464

RESUMEN

Our recent study demonstrated that pinocembrin (PB), the most abundant flavonoid in propolis, has neuroprotective effect against 1-methyl-4-phenylpyridinium (MPP(+))-induced SH-SY5Y neurotoxicity. However, the mechanism as how PB can induce neuroprotection is not known. In the present study, we demonstrate here that PB increased heme oxygenase-1 (HO-1) expression, which conferred protection against MPP(+)-induced cytotoxicity, because the inhibitor of HO-1 zinc protoporphyrin-IX attenuated the neuroprotection of PB. PB induced the phosphorylation of ERK1/2, and its cytoprotective effect was abolished by ERK1/2 inhibitors. Meanwhile, we have shown that MPP(+) induce the expression in a concentration-dependent manner in SH-SY5Y cells, which was further enhanced by PB. Taken together, the results suggest that PB enhances HO-1 expression to suppress MPP(+)-induced oxidative damage via ERK1/2 signaling pathways. These results revealed the mechanisms of PB enhances HO-1 expression, and contribute to shed some light on the mechanisms whereby PB inhibits the MPP(+)-induced neurotoxicity. These data indicated that PB might provide a valuable therapeutic strategy for the treatment of PD.


Asunto(s)
1-Metil-4-fenilpiridinio/toxicidad , Flavanonas/farmacología , Hemo-Oxigenasa 1/biosíntesis , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fármacos Neuroprotectores/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Transducción de Señal , Regulación hacia Arriba
15.
J Neurol Sci ; 368: 223-30, 2016 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-27538638

RESUMEN

Amyloid beta peptide (Aß) can cause neurotoxicity in Alzheimer's disease (AD). It evokes a cascade of oxidative damage to neurons. Pinocembrin (PCB), the most abundant flavonoid in propolis, has been proven to have neuroprotective effects in vivo and in vitro. In the present study, we investigated the neuroprotective effects of PCB on Aß25-35-induced neurotoxicity. Exposure of SH-SY5Y cells to 25µM Aß25-35 for 24h caused viability loss, apoptotic increase and reactive oxygen species (ROS) increase, pre-treatment with PCB for 4h significantly reduced the viability loss, apoptotic rate and attenuated Aß-mediated ROS production. PCB strikingly inhibited Aß25-35-induced mitochondrial dysfunctions, including lowered membrane potential, decreased Bcl-2/Bax ratio. In addition, PCB suppressed the release of cytochrome c and the cleavage of caspase-3. PCB treatment also resulted in an increase in Nrf2 protein levels and subsequent induction of heme oxygenase-1(HO-1) expression in SH-SY5Y cells. RNA interference-mediated knockdown of Nrf2 expression suppressed the PCB-induced HO-1 expression. Notably, we found that the HO-1 inhibitor zinc protoporphyrin IX (ZnPP) markedly diminished the neuroprotective effect of PCB against Aß-mediated neurotoxicity. Taken together, these results indicated that PCB protects SH-SY5Y cells from Aß25-35-induced neurotoxicity through activation of Nrf2/HO-1 pathways. Thus, activation of Nrf2/HO-1 pathways and inhibition of mitochondria-dependent apoptosis together may protect cells from Aß25-35-induceded neurotoxicity.


Asunto(s)
Péptidos beta-Amiloides/toxicidad , Apoptosis/efectos de los fármacos , Flavanonas/farmacología , Fármacos Neuroprotectores/farmacología , Fragmentos de Péptidos/toxicidad , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Citocromos c/metabolismo , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Neuroblastoma/patología , ARN Interferente Pequeño/genética , Especies Reactivas de Oxígeno/metabolismo , Factores de Tiempo , Transfección
16.
Mol Med Rep ; 10(6): 3169-76, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25310235

RESUMEN

Prostate cancer is the most commonly diagnosed type of cancer and the second leading cause of cancer­associated mortality in males. The efficacy of prostate cancer chemotherapy is frequently impaired by drug resistance; however, the underlying mechanisms of this resistance remain elusive. Sex determining region Y-box 2 (Sox2) is of vital importance in the regulation of stem cell proliferation and carcinogenesis. In the present study, using MTT, clone formation, cell cycle and apoptosis assays, over-expression of Sox2 was demonstrated to enhance the paclitaxel (Pac) resistance of the PC-3 prostate cancer cell line, promoting cell proliferation and exhibiting an anti­apoptotic effect. Western blot analysis revealed that the phosphoinositide 3-kinase/Akt signaling pathway was activated in cells overexpressing Sox2, and by targeting cyclin E and survivin, Sox2 promoted G1/S phase transition and prevented apoptosis under Pac treatment. The present study provided an understanding of Pac resistance in prostate cancer and may indicate novel therapeutic methods for chemoresistant prostate cancer.


Asunto(s)
Resistencia a Antineoplásicos/genética , Paclitaxel/farmacología , Fosfatidilinositol 3-Quinasas/genética , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Proteínas Proto-Oncogénicas c-akt/genética , Factores de Transcripción SOXB1/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Ciclina E/genética , Fase G1/efectos de los fármacos , Fase G1/genética , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Masculino , Fase S/efectos de los fármacos , Fase S/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Survivin
17.
J Genet ; 92(3): 413-21, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24371163

RESUMEN

Testing linkage heterogeneity between two loci is an important issue in genetics. Currently, there are four methods (K-test, A-test, B-test and D-test) for testing linkage heterogeneity in linkage analysis, which are based on the likelihood-ratio test. Among them, the commonly used methods are the K-test and A-test. In this paper, we present a novel test method which is different from the above four tests, called G-test. The new test statistic is based on estimating function, possessing a theoretic asymptotic distribution, and therefore demonstrates its own advantages. The proposed test is applied to analyse a real pedigree dataset. Our simulation results also indicate that the G-test performs well in terms of power of testing linkage heterogeneity and outperforms the current methods to some degree.


Asunto(s)
Heterogeneidad Genética , Ligamiento Genético , Modelos Genéticos , Algoritmos , Simulación por Computador , Frecuencia de los Genes , Estudios de Asociación Genética , Sitios Genéticos , Marcadores Genéticos , Humanos , Funciones de Verosimilitud , Linaje
18.
Int J Oncol ; 41(5): 1827-36, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22941344

RESUMEN

The unique CX3C chemokine CX3CL1 and its cognate receptor CX3CR1 have been implicated in organ-specific metastasis of various types of tumors. Hypoxia, a common phenomenon in solid tumors, is associated with a malignant cancer phenotype. Previous studies have proved that hypoxia facilitates cancer cell metastasis through upregulation of specific chemokine receptors. We hypothesized that hypoxia could upregulate CX3CR1 expression and lead to an increased chemotactic response to CX3CL1 in prostate cancer cells. In the present study, we found that CX3CR1 expression was significantly increased in androgen-independent prostate cancer cells, including DU145, PC-3 and PC-3M, following exposure to hypoxia. This upregulation of CX3CR1 corresponded to a significant increase in migration and invasion of prostate cancer cells under hypoxic conditions, which was attenuated after knocking down CX3CR1 expression. In addition, we examined the possible role of HIF-1 and NF-κB in the process of hypoxia-induced CX3CR1 expression and hypoxia-mediated metastasis. Attenuation of HIF-1 and NF-κB transcriptional activity by siRNAs or pharmacological inhibitors, abrogated hypoxia-induced upregulation of CX3CR1, and also prevented the migration and invasion of DU145 cells under a hypoxic environment. In summary, our study demonstrated that HIF-1 and NF-κB are essential for hypoxia-regulated CX3CR1 expression, which is associated with increased migratory and invasive potential of prostate cancer cells. CX3CR1 signaling is a potential therapeutic target in the adjuvant treatment of prostate cancer.


Asunto(s)
Andrógenos/metabolismo , Factor 1 Inducible por Hipoxia/metabolismo , Hipoxia , FN-kappa B/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Receptores de Quimiocina/genética , Receptor 1 de Quimiocinas CX3C , Línea Celular Tumoral , Movimiento Celular/genética , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Metástasis de la Neoplasia , Neoplasias de la Próstata/patología
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