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1.
Bioorg Med Chem Lett ; 71: 128825, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35644299

RESUMEN

The synergistic anti-tumor effect by simultaneous inhibitions of PI3K and HDAC has been verified to provide the rationality of PI3K/HDAC dual inhibitors for cancer treatment. Notably, the outstanding effect of PI3K/HDAC dual inhibitors against DLBCL has been paid much attention, especially for RR-DLBCL. Our previously reported 4-methylquinazoine scaffold based PI3K/HDAC dual inhibitors could suppress the growth of solid tumors and hematologic malignancies both in vitro and in vivo, validating the potential as new therapeutic agents for cancer. In this research, we further investigated the anti-tumor activity of one of our compounds against DLBCL cell lines and in vivo zebrafish xenograft model as well as the underlying mechanism, hoping to provide a novel therapeutic agent for treating DLBCL.


Asunto(s)
Inhibidores de Histona Desacetilasas , Linfoma de Células B Grandes Difuso , Animales , Apoptosis , Línea Celular Tumoral , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Pez Cebra
2.
Int J Mol Sci ; 23(10)2022 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-35628341

RESUMEN

The extracellular heat shock protein 90α (eHSP90α) has been reported to promote cancer cell motility. However, whether pancreatic cancer (PC) cells expressed membrane-bound or secreted HSP90α, as well as its underlying mechanism for PC progression, were still unclear. Our study demonstrated that the amounts of secreted HSP90α proteins were discrepant in multiple PC cells. In addition, highly invasive Capan-2 cells have a higher level of secreted HSP90α compared with those of less invasive PL45 cells. The conditioned medium of Capan-2 cells or recombinant HSP90α treatment stimulated the migration and invasion of PC cells, which could be prevented with a neutralizing anti-HSP90α antibody. Furthermore, secreted HSP90α promoted elements of epithelial-mesenchymal transition in PL45 cells, including increases in vimentin and Snail expressions, decreases in E-cadherin expression, and changes in cell shape towards a mesenchymal phenotype, but these phenomena were reversed by the anti-HSP90α antibody in Capan-2 cells. In addition, high levels of low-density lipoprotein receptor-related protein 1 (LRP1) were associated with worsened patient survival in pancreatic adenocarcinoma. We demonstrated LRP1 as a receptor of eHSP90α for its stimulatory role in metastasis, by activating the AKT pathway. In addition, silencing LRP1 enhanced the chemosensitivity to gemcitabine and doxorubicin in Capan-2 cells. Therefore, our study indicated that blocking secreted HSP90α underlies an aspect of metastasis and chemoresistance in PC.


Asunto(s)
Adenocarcinoma , Neoplasias Pancreáticas , Receptores de Lipoproteína , Resistencia a Antineoplásicos , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas
3.
Prostate ; 81(10): 667-682, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33956349

RESUMEN

The surface expression of Na/K-ATPase α1 (NKA) is significantly reduced in primary prostate tumors and further decreased in bone metastatic lesions. Here, we show that the loss of cell surface expression of NKA induces epithelial-mesenchymal transition (EMT) and promotes metastatic potential and tumor growth of prostate cancer (PCa) by decreasing the expression of E-cadherin and increasing c-Myc expression via the activation of Src/FAK pathways. Mechanistically, reduced surface expression of NKA in PCa is due to increased endocytosis through the activation of NKA/Src receptor complex. Using a high-throughput NKA ligand-screening platform, we have discovered MB5 as an inverse agonist of the NKA/Src receptor complex, capable of blocking the endocytosis of NKA. MB5 treatment increased NKA expression and E-cadherin in PCa cells, which reversed EMT and consequently decreased the invasion and growth of spheroid models and tumor xenografts. Thus, we have identified a hitherto unrecognized mechanism that regulates EMT and invasiveness of PCa and demonstrated for the first time the feasibility of identifying inverse agonists of receptor NKA/Src complex and their potential utility as anticancer drugs. We, therefore, conclude that cell surface expression of α1 NKA can be targeted for the development of new therapeutics against aggressive PCa and that MB5 may serve as a prototype for drug development against EMT in metastatic PCa.


Asunto(s)
Agonismo Inverso de Drogas , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/fisiología , Neoplasias de la Próstata/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/biosíntesis , Animales , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ouabaína/farmacología , Tiamina/análogos & derivados , Tiamina/farmacología , Tiamina/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
4.
J Assist Reprod Genet ; 38(10): 2697-2706, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34403017

RESUMEN

PURPOSE: The precise timing of insemination after oocyte retrieval is sometimes challenging. In this study, we have assessed the effect of the variation in insemination timing on reproductive outcome for both conventional insemination (CI) and intracytoplasmic sperm injection (ICSI) cycles. METHODS: A single-center retrospective cohort data analysis was performed on 6559 patients (9575 oocyte retrievals) from January 2017 to July 2019. The main outcome measured was live birth rates. Secondary outcomes included fertilization rate per all oocytes retrieved, blastocyst utilization, clinical pregnancy, and miscarriage rates. The time interval between oocyte retrieval and insemination was analyzed in eight categories: 0 (0- < 0.5 h), 1 (0.5- < 1.5 h), 2 (1.5- < 2.5 h), 3 (2.5- < 3.5 h), 4 (3.5- < 4.5), 5 (4.5- < 5.5), 6 (5.5-6.5), and 7 (6.5- < 8 h). The number of retrievals in each group (0-7) was 586, 1594, 1644, 1796, 1836, 1351, 641, and 127 respectively. RESULTS: The mean fertilization rate for CI ranged from 54.1 to 64.9% with a significant difference between time categories 0 and 5 (p < 0.001) and 1 and 5 (p < 0.0.001). The mean fertilization rate for ICSI ranged from 52.8 to 67.3% with no significant difference between time categories. Blastocyst rate for CI and ICSI was not significantly different. Miscarriage and clinical pregnancy rates in CI and ICSI were not significantly different. Live birth rates differed significantly (p < 0.05) in CI with time categories 0 and 7 representing the lowest rates, but not in the ICSI group. CONCLUSION: If performing CI or ICSI before 1.5 h and > 6.5 h, any detrimental effects are moderate on fertilization but do not affect blastocyst usage and birth rates. TRIAL REGISTRATION: Institutional Review Board Approval from the Beth Israel Deaconess Medical Centre [IRB Protocol #: 2015P000122].


Asunto(s)
Fertilización In Vitro/métodos , Infertilidad/terapia , Inseminación , Nacimiento Vivo/epidemiología , Inyecciones de Esperma Intracitoplasmáticas/métodos , Adulto , Tasa de Natalidad , Femenino , Humanos , Embarazo , Índice de Embarazo , Estudios Retrospectivos , Estados Unidos/epidemiología
5.
J Asian Nat Prod Res ; 23(5): 436-451, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33844614

RESUMEN

Based on the interaction modes of the natural 20S proteasome inhibitors TMC-95A, we have previously discovered a dipeptide 1. To explore the SAR around compound 1, we designed and synthesized a series of dipeptides (8-38) with a fragment-based strategy. Among them, nine compounds showed significant inhibitory activities against the chymotrypsin-like activity of human 20S proteasome with IC50 values at the submicromolar level, which were comparable or even superior to the parent compound 1. Meanwhile, they displayed no significant inhibition against trypsin-like and caspase-like activities of 20S proteasome. The results suggested the feasibility to design dipeptides as novel and potent 20S proteasome inhibitors.[Formula: see text].


Asunto(s)
Dipéptidos , Inhibidores de Proteasoma , Dipéptidos/farmacología , Estructura Molecular , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología
6.
J Gene Med ; 22(12): e3262, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32840014

RESUMEN

BACKGROUND: Long non-coding RNA (lncRNA) small nucleolar RNA host gene 6 (SNHG6) exerts a regulatory role in cancer biology, although its detailed functions and mechanisms in colorectal cancer (CRC) still remain unclear. METHODS: A quantitative reverse transcriptase-polymerase chain reaction was implemented to investigate the expression of SNHG6, miR-181 family and Janus kinase 2 (JAK2) in CRC tissues and cell lines. The proliferation of CRC cells was detected by a cell counting kit-8 assay, and the apoptosis of CRC cells was determined by flow cytometry analysis. The interaction of the miR-181 family with SNHG6 or with the 3'-untranslated region of JAK2 was validated by the luciferase reporter gene method. The effects of SNHG6 and the miR-181 family on JAK2 expression were analyzed by western blotting. RESULTS: SNHG6 was significantly up-regulated in CRC samples. The knockdown of SNHG6 reduced the proliferation of CRC cells and promoted the apoptosis, whereas the over-expression of SNHG6 had the opposite effect. SNHG6 could bind with all the four members of the miR-181 family, and expression in miR-181 family members was significantly down-regulated in CRC samples. SNHG6 expression was negatively correlated with the miR-181 family member expression in CRC samples. Moreover, over-expressed SNHG6 significantly counteracted the inhibitory effect of miR-181 mimics on CRC cell proliferation, as well as the promoting effect on apoptosis. Furthermore, SNHG6 over-expression and knockdown can promote and inhibit JAK2 expression, respectively, and miR-181 family member function is opposite to that of SNHG6 by repressing JAK2. CONCLUSIONS: SNHG6 can exert a cancer-promoting effect in CRC by targeting miR-181 family members and up-regulating JAK2.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Proliferación Celular , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Janus Quinasa 2/metabolismo , MicroARNs/genética , ARN Largo no Codificante/genética , Adulto , Anciano , Apoptosis , Biomarcadores de Tumor/genética , Movimiento Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Femenino , Humanos , Janus Quinasa 2/genética , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas
7.
Mol Cell Biochem ; 472(1-2): 1-8, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32632609

RESUMEN

Hypoxic-ischemic (HI) brain damage (HIBD) leads to high neonatal mortality and severe neurologic morbidity. Autophagy is involved in the pathogenesis of HIBD. This study aims to investigate the effect of long non-coding RNA colorectal neoplasia differentially expressed (CRNDE) on HIBD and to validate whether autophagy is involved in this process. A HIBD model in rat pups and a HI model in rat primary cerebrocortical neurons were established. Autophagy was evaluated by western blot. The HIBD in rats was evaluated by hematoxylin and eosin staining, TUNEL staining, triphenyl tetrazolium chloride staining, and morris water maze test. The HI injury in vitro was evaluated by determining cell viability and apoptosis. The results showed that CRNDE expression was time-dependently increased in the brain after HIBD. Administration with CRNDE shRNA-expressing lentiviruses alleviated pathological injury and apoptosis in rat hippocampus, decreased infarct volume, and improved behavior performance of rats subjected to HIBD. Furthermore, CRNDE silencing promoted cell viability and inhibited cell apoptosis in neurons exposed to HI. Moreover, CRNDE silencing promoted autophagy and the autophagy inhibitor 3-methyladenine counteracted the neuroprotective effect of CRNDE silencing on HI-induced neuronal injury both in vivo and in vitro. Collectively, CRNDE silencing alleviates HIBD, at least partially, through promoting autophagy.


Asunto(s)
Autofagia , Encéfalo/metabolismo , Hipoxia-Isquemia Encefálica/prevención & control , Neuronas/metabolismo , Fármacos Neuroprotectores , ARN Largo no Codificante/antagonistas & inhibidores , Animales , Animales Recién Nacidos , Conducta Animal , Encéfalo/patología , Hipoxia-Isquemia Encefálica/etiología , Hipoxia-Isquemia Encefálica/patología , Neuronas/patología , ARN Largo no Codificante/genética , Ratas , Ratas Sprague-Dawley
8.
Bioorg Med Chem Lett ; 30(21): 127508, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-32853683

RESUMEN

Thirty novel triaryl compounds were designed and synthesized based on the known proteasome inhibitor PI-1840. Most of them showed significant inhibition against the ß5c subunit of human 20S proteasome, and five of them exhibited IC50 values at the sub-micromolar level, which were comparable to or even more potent than PI-1840. The most active two (1c and 1d) showed IC50 values of 0.12 and 0.18 µM against the ß5c subunit, respectively, while they displayed no obvious inhibition against the ß2c, ß1c and ß5i subunits. Molecular docking provided informative clues for the subunit selectivity. The potent and subunit selective proteasome inhibitors identified herein represent new chemical templates for further molecular optimization.


Asunto(s)
Amidas/farmacología , Diseño de Fármacos , Oxadiazoles/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología , Amidas/química , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxadiazoles/química , Inhibidores de Proteasoma/síntesis química , Inhibidores de Proteasoma/química , Relación Estructura-Actividad
9.
Mol Cell Probes ; 52: 101565, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32234564

RESUMEN

BACKGROUND: This study aimed to test the hypothesis that long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) could exacerbate brain injury caused by intrauterine infection in neonatal rats. METHODS: Intrauterine infection was induced in pregnant rats by lipopolysaccharide (LPS). After delivery, newborn rats with brain injury caused by intrauterine infection were randomly divided into control, control shRNA, and CRNDE shRNA groups. CRNDE expression in serum and amniotic fluid of pregnant rats and neonatal brain tissues were determined by quantitative real-time PCR (qRT-PCR). Morris water maze (MWM) task was used to test the spatial learning and memory ability. Histological examination and apoptosis detection were performed by hematoxylin and eosin (H&E) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, respectively. Immunohistochemistry was conducted to evaluate the activation of astrocytes and microglia. RESULTS: LncRNA CRNDE was highly expressed in serum and amniotic fluid of maternal rats and in brain tissues of offspring rats. Furthermore, shRNA-mediated CRNDE downregulation could rescue the spatial learning and memory ability, improve brain histopathological changes and cell death, and inhibit the activation of astrocytes and microglia caused by LPS. CONCLUSION: CRNDE silencing possessed a cerebral protective effect in neonatal rats with brain injury caused by interauterine infection.


Asunto(s)
Lesiones Encefálicas/etiología , Lesiones Encefálicas/genética , ARN Largo no Codificante/metabolismo , Útero/microbiología , Útero/patología , Animales , Animales Recién Nacidos , Astrocitos/patología , Encéfalo/patología , Lesiones Encefálicas/fisiopatología , Muerte Celular , Citocinas/biosíntesis , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Lipopolisacáridos , Masculino , Memoria , Microglía/patología , Embarazo , ARN Largo no Codificante/genética , Ratas , Aprendizaje Espacial , Regulación hacia Arriba/genética
10.
Cell Mol Life Sci ; 76(17): 3433-3447, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30980109

RESUMEN

Enhancement of insulin-like growth factor 1 receptor (IGF-IR) degradation by heat shock protein 90 (HSP90) inhibitor is a potential antitumor therapeutic strategy. However, very little is known about how IGF-IR protein levels are degraded by HSP90 inhibitors in pancreatic cancer (PC). We found that the HSP90α inhibitor NVP-AUY922 (922) effectively downregulated and destabilized the IGF-1Rß protein, substantially reduced the levels of downstream signaling molecules (p-AKT, AKT and p-ERK1/2), and resulted in growth inhibition and apoptosis in IGF-1Rß-overexpressing PC cells. Preincubation with a proteasome or lysosome inhibitor (MG132, 3 MA or CQ) mainly led to IGF-1Rß degradation via the lysosome degradation pathway, rather than the proteasome-dependent pathway, after PC cells were treated with 922 for 24 h. These results might be associated with the inhibition of pancreatic cellular chymotrypsin-peptidase activity by 922 for 24 h. Interestingly, 922 induced autophagic flux by increasing LC3II expression and puncta formation. However, knockdown of the crucial autophagy component AGT5 and the chemical inhibitor 3 MA-blocked 922-induced autophagy did not abrogate 922-triggered IGF-1Rß degradation. Furthermore, 922 could enhance chaperone-mediated autophagy (CMA) activity and promote the association between HSP/HSC70 and IGF-1Rß or LAMP2A in coimmunoprecipitation and immunofluorescence analyses. Silencing of LAMP2A to inhibit CMA activity reversed 922-induced IGF-1Rß degradation, suggesting that IGF-1Rß degradation by 922 was partially dependent on the CMA pathway rather than macroautophagy. This finding is mirrored by the identification of the KFERQ-like motif in IGF-1Rß. These observations support the potential application of 922 for IGF-1Rß-overexpressing PC therapy and first identify the role of the CMA pathway in IGF-1Rß degradation by an HSP90 inhibitor.


Asunto(s)
Autofagia/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/metabolismo , Isoxazoles/farmacología , Receptor IGF Tipo 1/metabolismo , Resorcinoles/farmacología , Adenina/análogos & derivados , Adenina/farmacología , Secuencia de Aminoácidos , Proteína 5 Relacionada con la Autofagia/metabolismo , Línea Celular Tumoral , Regulación hacia Abajo/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Humanos , Proteína 2 de la Membrana Asociada a los Lisosomas/antagonistas & inhibidores , Proteína 2 de la Membrana Asociada a los Lisosomas/genética , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismo , Lisosomas/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/parasitología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptor IGF Tipo 1/química , Receptor IGF Tipo 1/genética , Alineación de Secuencia , Transducción de Señal/efectos de los fármacos
11.
Molecules ; 25(6)2020 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-32210078

RESUMEN

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing intracellular enzyme that catalyzes the first and rate-determining step of tryptophan metabolism and is an important immunotherapeutic target for the treatment of cancer. In this study, we designed and synthesized a new series of compounds as potential IDO1 inhibitors. These compounds were then evaluated for inhibitory activity against IDO1 and tryptophan 2,3-dioxygenase (TDO). Among them, the three phenyl urea derivatives i12, i23, i24 as showed potent IDO1 inhibition, with IC50 values of 0.1-0.6 µM and no compound exhibited TDO inhibitory activity. Using molecular docking, we predicted the binding mode of compound i12 within IDO1. Compound i12 was further investigated by determining its in vivo pharmacokinetic profile and anti-tumor efficacy. The pharmacokinetic study revealed that compound i12 had satisfactory properties in mice, with moderate plasma clearance (22.45 mL/min/kg), acceptable half-life (11.2 h) and high oral bioavailability (87.4%). Compound i12 orally administered at 15 mg/kg daily showed tumor growth inhibition (TGI) of 40.5% in a B16F10 subcutaneous xenograft model and 30 mg/kg daily showed TGI of 34.3% in a PAN02 subcutaneous xenograft model. In addition, the body weight of i12-treated mice showed no obvious reduction compared with the control group. Overall, compound i12 is a potent lead compound for developing IDO1 inhibitors and anti-tumor agents.


Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos , Indolamina-Pirrol 2,3,-Dioxigenasa , Melanoma Experimental , Proteínas de Neoplasias , Compuestos de Fenilurea , Animales , Línea Celular Tumoral , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/enzimología , Melanoma Experimental/patología , Ratones , Simulación del Acoplamiento Molecular , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Relación Estructura-Actividad
12.
J Med Virol ; 91(10): 1788-1796, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31241179

RESUMEN

Human group A rotavirus (RVA) is the leading cause of acute viral gastroenteritis in children under 5 years old worldwide. The aim of this study was to investigate the genotype distribution of RVA in the Midwest of China. Sentinel-based surveillance of acute diarrhea was conducted at Children's Hospital of Chongqing Medical University from 2011 to 2015. RVA was tested by using enzyme-linked immunosorbent assays. The partial VP4 genes and VP7 genes of rotavirus were amplified and sequenced, and genotyping and phylogenetic analyses were performed. Among the 2236 stool specimens collected from children with acute gastroenteritis, 681 (30.46%) were positive for RVA. The majority of children (89.28%) who tested positive for RVA were children aged ≤2 years. The seasonal peak of RVA was in the winter. As for genotype, four strain combinations, G9P[8], G3P[8], G1P[8], and G2P[4] contributed to 75.62% (515/681) of the RVA-associated diarrhea cases. After a marked increase in G9P[8] (30.77%) in 2013, G9P[8] became the predominant genotype in 2014 and 2015, whilst the prevalence of G1P[8] was decreased to 2.72% in 2015. Unusual G-P combinations (eg, G1P[4], G9P[4], G4P[6], G3P[4], G2P[8]) were also detected sporadically over the study period. Phylogenetic tree analysis results showed that the VP7 sequences of G9 strains were clustered into two main lineages, and 77.34% of them were clustered into lineage VI, with the highest nucleotide similarity to the strain JS12-17(China). VP4 gene sequences of P[8] strains were almost P[8]-lineage 3. Substantial temporal variation in the circulation of various genotypes of rotavirus in Chongqing was observed during 2011-2015, and highlights the need for continuous surveillance of RVA infection for better understanding and control of RVA infection.


Asunto(s)
Diarrea/virología , Epidemiología Molecular , Infecciones por Rotavirus/epidemiología , Infecciones por Rotavirus/virología , Rotavirus/genética , Antígenos Virales/genética , Proteínas de la Cápside/genética , Preescolar , China/epidemiología , Diarrea/epidemiología , Heces/virología , Femenino , Regulación Viral de la Expresión Génica , Genoma Viral , Humanos , Masculino , Pacientes Ambulatorios , Filogenia , ARN Viral/genética , Rotavirus/clasificación
13.
Molecules ; 24(11)2019 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-31195673

RESUMEN

Indoleamine 2,3-dioxygenase (IDO) 1 is the key enzyme for regulating tryptophan metabolism and is an important target for interrupting tumor immune escape. In this study, we designed four series of compounds as potential IDO1 inhibitors by attaching various fragments or ligands to indole or phenylimidazole scaffolds to improve binding to IDO1. The compounds were synthesized and their inhibitory activities against IDO1 and tryptophan 2,3-dioxygenase were evaluated. The cytotoxicities of the compounds against two tumor cell lines were also determined. Two compounds with a phenylimidazole scaffold (DX-03-12 and DX-03-13) showed potent IDO1 inhibition with IC50 values of 0.3-0.5 µM. These two IDO1 inhibitors showed low cell cytotoxicity, which indicated that they may exert their anti-tumor effect via immune modulation. Compound DX-03-12 was investigated further by determining the in vivo pharmacokinetic profile and anti-tumor efficacy. The pharmacokinetic study revealed that DX-03-12 had satisfactory properties in mice, with rapid absorption, moderate plasma clearance (∼36% of hepatic blood flow), acceptable half-life (∼4.6 h), and high oral bioavailability (∼96%). Daily oral administration of 60 mg/kg of compound DX-03-12 decreased tumor growth by 72.2% after 19 days in a mouse melanoma cell B16-F10 xenograft model compared with the untreated control. Moreover, there was no obvious weight loss in DX-03-12-treated mice. In conclusion, compound DX-03-12 is a potent lead compound for developing IDO1 inhibitors and anti-tumor agents.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Inyecciones Intravenosas , Masculino , Ratones Endogámicos ICR , Modelos Moleculares , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Analyst ; 143(5): 1224-1233, 2018 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-29431786

RESUMEN

The 5-bromo-2'-deoxyuridine (BrdU) incorporation cell proliferation assay is the most commonly used method for assessing DNA replication. The current detection of BrdU in cells relies on antibody immunostaining, but has various limitations including low antibody specificity and poor tissue penetration. In this study, we utilised a Suzuki-Miyaura reaction to develop a chemical method to label cellular BrdU with fluorescent boronic acid probes. The coupling conditions were optimised for complex cellular environments, and the key observation was the need to use oxygen scavengers and zerovalent palladium to prevent side reactions and increase the rate of coupling. The reliability and specificity of the BrdU Suzuki-Miyaura labelling method were verified under various biological conditions. The applicability of the BrdU Suzuki-Miyaura labelling methodology was also investigated, and we show that labelling cellular BrdU is highly sensitive and reliable, which is comparable to the ideal performance of BrdU immunostaining. Moreover, the Suzuki-Miyaura reaction protocol provides high BrdU recognition specificity. Taken together, the BrdU Suzuki-Miyaura labelling protocol provides an attractive alternative to the more traditional cell proliferation assay.


Asunto(s)
Bromodesoxiuridina/química , Proliferación Celular , Replicación del ADN , Coloración y Etiquetado/métodos , Anticuerpos , Línea Celular Tumoral , Fluorescencia , Colorantes Fluorescentes , Humanos , Paladio , Reproducibilidad de los Resultados
15.
Biol Pharm Bull ; 41(4): 592-596, 2018 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-29415945

RESUMEN

Psoriasis is a chronic inflammatory skin disease characterized by red, scaly and raised plaques. Thus far, T-cell infiltration is one of the most prominent pathogenic triggers, however, the exact molecular mechanisms underlying psoriasis have not been clearly established. Sphingolipid sphingosine-1-phosphate (S1P) is a lysophospholipid regulator modulating a variety of immune cell trafficking via interactions with its cognate receptors, S1P1-5. Activation of S1P signaling has recently emerged as a novel therapeutic avenue for psoriasis treatment. Here, we test a newly developed selective S1P1 modulator, Syl930, in four different psoriasis animal models. Our data reveals that oral administration of Syl930 can induce strong anti-proliferative and anti-inflammatory effects. Specifically, Syl930 decreases the pathological thickening of back skin induced by sodium lauryl sulfate (SLS), inhibits the proliferation of basal cells in a vaginal epithelium model and increases the granular layer scales in a mouse tail assay. Moreover, Syl930 can ameliorate the parakeratosis and acanthosis as well as improve granular layer composition and decrease the thickening of epidermis in a propranolol-induced guinea pig psoriasis model. Therefore, we demonstrate that Syl930 is a promising candidate for psoriasis therapy in clinical.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Modelos Animales de Enfermedad , Oxazoles/uso terapéutico , Propanolaminas/uso terapéutico , Psoriasis/tratamiento farmacológico , Receptores de Lisoesfingolípidos/agonistas , Piel/efectos de los fármacos , Administración Oral , Animales , Animales no Consanguíneos , Antiinflamatorios no Esteroideos/administración & dosificación , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Clorhidrato de Fingolimod/administración & dosificación , Clorhidrato de Fingolimod/uso terapéutico , Cobayas , Ratones , Índice Mitótico , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/inmunología , Membrana Mucosa/metabolismo , Membrana Mucosa/patología , Oxazoles/administración & dosificación , Propanolaminas/administración & dosificación , Psoriasis/inmunología , Psoriasis/metabolismo , Psoriasis/patología , Distribución Aleatoria , Receptores de Lisoesfingolípidos/metabolismo , Reproducibilidad de los Resultados , Piel/inmunología , Piel/metabolismo , Piel/patología , Organismos Libres de Patógenos Específicos , Receptores de Esfingosina-1-Fosfato , Vagina/efectos de los fármacos , Vagina/inmunología , Vagina/metabolismo , Vagina/patología
16.
Biochem Biophys Res Commun ; 482(2): 257-263, 2017 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-27845044

RESUMEN

Cell cytotoxicity assays include cell activity assays and morphological identification assays. Currently, all frequently used cytotoxicity assays belong to cell activity assays but suffer from detection limitations. Morphological identification of cell death remains as the gold standard, although the method is difficult to scale up. At present there is no generally accepted morphological identification based cell cytotoxicity assay. In this study, we applied previous developed cell cytoplasm-localized fluorescent probe (CLFP) to display cell morphologies. Under fluorescence microscopy, the fluorescence morphology and intensity of living cells are distinct from dead cells. Based on these characters we extracted the images of living cells from series of samples via computational analysis. Thus, a novel cell morphological identification cytotoxicity assay (CLFP assay) is developed. The performance of the CLFP assay was similar to cell activity assay (MTT assay), but the accuracy of the CLFP assay was superior when measuring the cytotoxicity of active compounds.


Asunto(s)
Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citotoxinas/administración & dosificación , Colorantes Fluorescentes/química , Microscopía Fluorescente/métodos , Pruebas de Toxicidad/métodos , Apoptosis/fisiología , Bioensayo/métodos , Tamaño de la Célula/efectos de los fármacos , Supervivencia Celular/fisiología , Citoplasma/química
17.
Bioorg Med Chem Lett ; 27(15): 3326-3331, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28625363

RESUMEN

The indolin-2-one core is a privileged structure for antitumor agents, especially kinase inhibitors. Twenty-three novel indolin-2-ones were designed by molecular dissection of the anticancer drug indirubin. Seventeen of them exhibited significant inhibition against the tested cell lines, and two of them (1c and 1h) showed IC50 values at the submicromolar level against HCT-116 cells. Compounds 1c and 2c were also potent inhibitors of the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Flow cytometry was utilized to explore the antitumor mechanism of 1c and 2c with MDA-MB-231 cells, and distinct effects were observed on 2c. Furthermore, immunocytochemical examination of 1c suggested a destabilization of microtubules, which was significantly different from the effect of IM, an indirubin derivative.


Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Indoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Inmunohistoquímica , Indoles/síntesis química , Indoles/química , Estructura Molecular , Relación Estructura-Actividad
18.
Bioorg Med Chem ; 25(15): 4045-4054, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28622906

RESUMEN

The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50=467nM, PARP-2 IC50=11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program.


Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Poli(ADP-Ribosa) Polimerasas/efectos de los fármacos , Quinazolinas/química , Quinazolinas/farmacología , Espectroscopía de Resonancia Magnética con Carbono-13 , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Espectroscopía de Protones por Resonancia Magnética , Espectrometría de Masa por Ionización de Electrospray
19.
Development ; 140(11): 2334-44, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23615278

RESUMEN

Vertebrate axis specification is an evolutionarily conserved developmental process that relies on asymmetric activation of Wnt signaling and subsequent organizer formation on the future dorsal side of the embryo. Although roles of Wnt signaling during organizer formation have been studied extensively, it is unclear how the Wnt pathway is asymmetrically activated. In Xenopus and zebrafish, the Wnt pathway is triggered by dorsal determinants, which are translocated from the vegetal pole to the future dorsal side of the embryo shortly after fertilization. The transport of dorsal determinants requires a unique microtubule network formed in the vegetal cortex shortly after fertilization. However, molecular mechanisms governing the formation of vegetal cortical microtubule arrays are not fully understood. Here we report that Dead-End 1 (Dnd1), an RNA-binding protein required for primordial germ cell development during later stages of embryogenesis, is essential for Xenopus axis specification. We show that knockdown of maternal Dnd1 specifically interferes with the formation of vegetal cortical microtubules. This, in turn, impairs translocation of dorsal determinants, the initiation of Wnt signaling, organizer formation, and ultimately results in ventralized embryos. Furthermore, we found that Dnd1 binds to a uridine-rich sequence in the 3'-UTR of trim36, a vegetally localized maternal RNA essential for vegetal cortical microtubule assembly. Dnd1 anchors trim36 to the vegetal cortex in the egg, promoting high concentrations of Trim36 protein there. Our work thus demonstrates a novel and surprising function for Dnd1 during early development and provides an important link between Dnd1, mRNA localization, the microtubule cytoskeleton and axis specification.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Microtúbulos/fisiología , Proteínas de Unión al ARN/genética , Proteínas de Xenopus/metabolismo , Xenopus/embriología , Regiones no Traducidas 3' , Animales , Tipificación del Cuerpo , Proteínas Portadoras/metabolismo , Citoesqueleto/fisiología , Embrión no Mamífero/fisiología , Femenino , Péptidos y Proteínas de Señalización Intracelular , Microscopía Confocal , Regiones Promotoras Genéticas , Transducción de Señal , Proteínas Wnt/metabolismo , Xenopus/genética , Proteínas de Xenopus/genética
20.
J Med Virol ; 88(3): 408-16, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26255857

RESUMEN

Hand, foot, and mouth disease (HFMD) has become very common in children, with widespread occurrence across China. The aim of this study was to investigate the epidemiologic and etiologic characteristics of HFMD, including etiologic variations in Chongqing, China. An epidemiologic investigation was based on 3,472 patients who presented with HFMD manifestations and were admitted at the Children's Hospital of Chongqing Medical University between 2010 and 2013. Fecal specimens from 830 patients were analyzed by nested RT-PCR to identify the enterovirus pathogens, and the molecular characterization of HFMD was illustrated by phylogenetic tree analysis. The results of this study indicate that the peak of the HFMD epidemic in Chongqing between 2010 and 2013 occurred between April and July each year. The median age of onset was 2.24 years old, and children under the age of five accounted for 96.4% of all the HFMD cases; the male-to-female ratio was 1.89:1. Enterovirus 71 accounted for a major proportion of the isolated strains every year, including the majority (74%) of severe cases. However, the proportion of Coxsackie A (CV-A) 6 infections increased from 2.11% in 2010 to 16.36% in 2013, while the proportion of CV-A16 infections decreased from 31.23% in 2010 to 4.67% in 2013. Molecular epidemiologic study showed that all enterovirus 71 strains belonged to subgenotype C4a, whereas all CV-A16 strains belonged to genotype B1, including subgenotype B1a and subgenotype B1b.


Asunto(s)
Enterovirus Humano A/genética , Enterovirus Humano A/aislamiento & purificación , Enterovirus/genética , Enterovirus/aislamiento & purificación , Enfermedad de Boca, Mano y Pie/epidemiología , Enfermedad de Boca, Mano y Pie/virología , Niño , Preescolar , China/epidemiología , Brotes de Enfermedades , Enterovirus/clasificación , Enterovirus/patogenicidad , Enterovirus Humano A/clasificación , Enterovirus Humano A/patogenicidad , Infecciones por Enterovirus/epidemiología , Infecciones por Enterovirus/virología , Epidemias , Heces/virología , Femenino , Genotipo , Humanos , Lactante , Masculino , Filogenia , Reacción en Cadena de la Polimerasa , ARN Viral/genética , Factores de Tiempo
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