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1.
Org Lett ; 23(16): 6423-6428, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34351160

RESUMO

A novel method to synthesize 4-alkylpyrimidines by the mechanochemical magnesium-mediated Minisci reaction of pyrimidine derivatives and alkyl halides has been reported. The reaction process operates with a broad substrate scope and excellent regioselectivity under mild conditions with no requirement of transition-metal catalysts, solvents, and inert gas protection. The practicality of this protocol has been demonstrated by the up-scale synthesis, mechanochemical product derivatization, and antimalarial drug pyrimethamine preparation.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34353269

RESUMO

BACKGROUND: Despite emerging research on new treatment strategies, chemotherapy remains one of the most important therapeutic modalities for cancers. Imidazopyridines are important targets in organic chemistry and are worthy of attention given their numerous applications. OBJECTIVE: To design and synthesize a novel series of imidazo[1,2-a]pyridine-derived compounds and investigate their antitumor effects and the underlying mechanisms. METHODS: Imidazo[1,2-a]pyridine-derived compounds were synthesized with new strategies and conventional methods. The antitumor activities of the new compounds were evaluated by MTT assay. Flow cytometry and immunofluorescence were performed to examine the effects of the most effective antiproliferative compound on cell apoptosis. Western blot analysis was used to assess the expression of apoptotic proteins. RESULTS: Fifty-two new imidazo[1,2-a]pyridine compounds were designed and successfully synthesized. The compound, 1-(imidazo[1,2-a]pyridin-3-yl)-2-(naphthalen-2-yl)ethane-1,2-dione, named La23, showed high potential for suppressing the viability of HeLa cells (IC50 15.32 µM). La23 inhibited cell proliferation by inducing cell apoptosis, and it reduced the mitochondrial membrane potential of HeLa cells. Moreover, treatment with La23 appeared to increase the expression of apoptotic-related protein P53, Bax, cleaved caspase-3, and cytochrome c at a low concentration range. CONCLUSION: The novel imidazo[1,2-a]pyridine compound, La23, was synthesized and suppressed cell growth by inducing cell apoptosis via the p53/Bax mitochondrial apoptotic pathway.

3.
Mol Cell Biol ; 41(8): e0006521, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34001648

RESUMO

Cerebral ischemia/reperfusion (I/R) can lead to serious brain function impairments. Long noncoding RNA (lncRNA) CCAAT enhancer binding protein α antisense RNA 1 (CEBPA-AS1) was shown to be upregulated in human ischemic stroke. This study investigated the function and mechanism of CEBPA-AS1 in I/R. An oxygen-glucose deprivation/reperfusion (OGD/R) model was used to induce I/R injury in SH-SY5Y cells in vitro. RT-qPCR examined the expression of CEBPA-AS1, microRNA 24-3p (miR-24-3p), and Bcl-2-related ovarian killer (Bok). The cell viability, apoptosis, oxidative stress in OGD/R-treated cells were detected using CCK-8, flow cytometry, Western blotting, and enzyme-linked immunosorbent assays. The relationship among genes was tested by RNA pulldown and luciferase reporter assays. We found that OGD/R upregulated CEBPA-AS1 expression in SH-SY5Y cells. Functionally, CEBPA-AS1 depletion ameliorated OGD/R-induced apoptosis and oxidative stress in SH-SY5Y cells by reducing reactive oxygen species production and superoxide dismutase and glutathione. Mechanistic investigations indicated that CEBPA-AS1 acts as a sponge for miR-24-3p, and miR-24-3p binds to BOK. Moreover, miR-24-3p upregulation or BOK downregulation antagonized the protective role of CEBPA-AS1 depletion in SH-SY5Y cells exposed to OGD/R. Overall, downregulation of CEBPA-AS1 exerts protective functions against OGD/R-induced injury by targeting the miR-24-3p/BOK axis.


Assuntos
Isquemia Encefálica/genética , Proteínas Estimuladoras de Ligação a CCAAT/genética , Glucose/metabolismo , MicroRNAs/genética , Oxigênio/metabolismo , Isquemia Encefálica/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Longo não Codificante/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo
4.
Front Oncol ; 11: 643199, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33842353

RESUMO

Purpose: Circulating cell-free DNA (cfDNA) level has been demonstrated to be associated with efficacy in first generation EGFR TKIs in non-small cell lung cancer (NSCLC). However, the role of dynamic cfDNA analysis using next-generation sequencing (NGS) in patients with subsequent third-generation EGFR TKIs remains unclear. Methods: From 2016 to 2019, 81 NSCLC patients with EGFR T790M mutation either in tissue or plasma who received third-generation EGFR TKIs treatment were enrolled. CfDNA were sequenced by NGS with a 425-gene panel. The association of clinical characteristics, pretreatment, dynamic cfDNA and T790M level with outcomes in patients treated with the third-generation TKIs were analyzed. Results: In univariate analysis, the median PFS of patients with undetectable cfDNA level during treatment was significantly longer than those with detectable cfDNA (16.97 vs. 6.10 months; HR 0.2109; P < 0.0001). The median PFS of patients with undetectable T790M level during treatment was significantly longer than those with detectable T790M (14.1 vs. 4.4 months; HR 0.2192; P < 0.001). Cox hazard proportion model showed that cfDNA clearance was an independent predictor for longer PFS (HR 0.3085; P < 0.001) and longer OS (HR 0.499; P = 0.034). The most common resistant mutations of the third-generation TKIs were EGFR C797S (24%). CDK6 CNV, GRIN2A, BRCA2, EGFR D761N, EGFR Q791H, EGFR V843I, and ERBB4 mutation genes may possibly be new resistant mechanisms. Conclusions: Patients with undetectable cfDNA during the third-generation EGFR TKI treatment have superior clinical outcomes, and dynamic cfDNA analysis by NGS is valuable to explore potential resistant mechanisms.

5.
Zhongguo Fei Ai Za Zhi ; 24(2): 78-87, 2021 Feb 20.
Artigo em Chinês | MEDLINE | ID: mdl-33478196

RESUMO

BACKGROUND: Targeted therapy for patients with driver genes positive and immunotherapy for patients with driver gene-negative but high programmed death ligand 1 (PD-L1) expression are the standards of first-line treatment for patients with advanced non-small cell lung cancer (NSCLC). The treatment options for patients with driver gene positive and high PD-L1 expression are still worth exploring. METHODS: The characteristics of 315 patients with NSCLC were identified to analyze the clinicopathological characteristics of patients with driver gene positive and high PD-L1 expression, and the efficacy of targeted therapy. RESULTS: Among the 315 patients, the total positive rate of driver genes was 62.2%, and the high PD-L1 expression rate (≥50.0%) was 11.2%. The proportion of patients with driver gene positive and high PD-L1 expression was 10.7%. PD-L1 was highly expressed in patients with epidermal growth factor receptor (EGFR) mutation, KRAS mutation, ALK fusion, BRAF mutation, and MET 14 exon skip mutation, the proportions were 7.8% (11/141), 18.2% (4/22), and 23.1%, (3/13), 50.0% (2/4) and 100.0% (1/1) respectively. EGFR mutation positive with PD-L1 high expression was mainly in patients with stage IV lung adenocarcinoma. KRAS mutation positive with PD-L1 high expression was mainly in patients with a history of smoking. Among them, two patients were followed in detail for targeted therapy, who with ALK fusion-positive and PD-L1 high expression (90.0%), EGFR L858R mutation and PD-L1 high expression (70.0%) respectively. The total OS of the patients was 5 months, 2 months. CONCLUSIONS: The high PD-L1 expression rate in NSCLC patients with different driver gene mutations was variable, which maybe correlated with distinct clinicopathological characteristics. Patients with sensitive mutations and high PD-L1 expression may be less benefit from targeted therapy and have poor prognosis.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Adulto , Idoso , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Estudos Retrospectivos
6.
Nat Prod Res ; 35(7): 1159-1166, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31322441

RESUMO

A new coprostanol glycoside, 26-trihydroxy-16, 22-dioxo-3ß-[(α-L-rhamnopyranosyl)oxy]-5ß-cholestan-1ß-yl O-α-L-rhamnopyranosyl-(1→2)-ß-D-fucopyranoside (1) (25S)-5ß-spirostan-1ß,2ß,3ß, 4ß,5ß, 6ß-hexol (2), a new C-22 steroidal lactone saponin, (20 R)-16ß-trihydroxy-3ß-[(α-L-rhamnopyranosyl)oxy]-1ß-[(O-α-L-rhamnopyranosyl-(1→2)-ß-D-xylopyranosyl)oxy]-5ß-pregnane-20-oic acid γ-lactone (3) along with two known pregnane glycosides (4 and 5) were obtained from the roots of Reineckia carnea. Their structures were determined by 1 D, 2 D NMR, IR and MS data analysis. In addition, the cytotoxic activities in HT-29, HCT116, H1299 and A549 tumor cells of the isolated compounds (1 - 5) were determined by the MTT method. The results showed that only compound 1 exhibited weak effect against these cells with IC50 values ranging from 63.36 µM to 105.01 µM.


Assuntos
Asparagaceae/química , Raízes de Plantas/química , Esteroides/isolamento & purificação , Antineoplásicos/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Hidrólise , Concentração Inibidora 50 , Espectroscopia de Prótons por Ressonância Magnética , Esteroides/química , Esteroides/farmacologia , Açúcares/análise
7.
Ear Nose Throat J ; : 145561320962584, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023340

RESUMO

OBJECTIVE: A case of primary first bite syndrome (FBS), diagnosed in a patient with nonspecific adenocarcinoma of the deep lobe of the parotid gland. DATA SOURCES: A Medline literature search was conducted on PubMed, using the keywords "first bite syndrome." REVIEW METHODS: Using primary FBS and existence of a definite etiology as inclusion criteria. RESULTS: We report on an unusual case of primary FBS, which had no surgical history. After multiple examinations, the pain was localized to a mass in the deep lobe of the parotid gland. After tumorectomy, the FBS pain was significantly relieved. The postoperative pathological examination determined that the excised mass was a nonspecific adenocarcinoma. Reviewing the literature, we found that primary FBS was mostly caused by malignant tumors in the inferior temporal fossa, the deep lobe of the parotid gland, and (or) the parapharyngeal space. Surgery was reported to be an effective treatment. CONCLUSION: The case highlights the critical importance of identifying the etiology of primary FBS. When manifested with a primary FBS, malignant tumors must be high on the differential diagnosis list, especially those in the region of the inferior temporal fossa, the deep lobe of the parotid gland, and the parapharyngeal space.

8.
Medicine (Baltimore) ; 99(30): e20703, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791664

RESUMO

Few models regarding to the individualized prognosis assessment of oropharyngeal squamous cell carcinoma (OPSCC) patients were documented. The purpose of this study was to establish nomogram model to predict the long-term overall survival (OS) and cancer-specific survival (CSS) of OPSCC patients. The detailed clinical data for the 10,980 OPSCC patients were collected from the surveillance, epidemiology and end results (SEER) database. Furthermore, we applied a popular and reasonable random split-sample method to divide the total 10,980 patients into 2 groups, including 9881 (90%) patients in the modeling cohort and 1099 (10%) patients in the external validation cohort. Among the modeling cohort, 3084 (31.2%) patients were deceased at the last follow-up date. Of those patients, 2188 (22.1%) patients died due to OPSCC. In addition, 896 (9.1%) patients died due to other causes. The median follow-up period was 45 months (1-119 months). We developed 2 nomograms to predict 5- and 8- year OS and CSS using Cox Proportional Hazards model. The nomograms' accuracy was evaluated through the concordance index (C-index) and calibration curves by internal and external validation. The C-indexes of internal validation on the 5- and 8-year OS and CSS were 0.742 and 0.765, respectively. Moreover, the C-indexes of external validation were 0.740 and 0.759, accordingly. Based on a retrospective cohort from the SEER database, we succeeded in constructing 2 nomograms to predict long-term OS and CSS for OPSCC patients, which provides reference for surgeons to develop a treatment plan and individual prognostic evaluations.


Assuntos
Carcinoma de Células Escamosas/mortalidade , Nomogramas , Neoplasias Orofaríngeas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Programa de SEER , Análise de Sobrevida , Estados Unidos/epidemiologia , Adulto Jovem
9.
Front Oncol ; 10: 1162, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32850330

RESUMO

HER2 mutations have emerged as oncogenic driver gene mutations in non-small cell lung cancer (NSCLC), which have not been described in detail like other driver gene mutations. Here, 295 patients with advanced lung adenocarcinoma were retrospectively screened for HER2 mutations using next-generation sequencing (NGS), and the positive cases were validated by Sanger sequencing. We identified five cases with HER2 exon 20 insertions, representing 1.7% of 295 lung adenocarcinomas. Among them, four different subtypes of HER2 exon 20 insertions were identified, including a rare subtype G778_S779insCPG never reported before with a partial response (PR) to pyrotinib and progression-free survival (PFS) of 12.8 months. Our findings reveal that HER2 exon 20 insertion mutations were detected in a small subset of lung adenocarcinomas. Given the different drug sensitivities, determining the mutation subtype by next-generation sequencing at the time of diagnosis might make sense.

10.
Artigo em Inglês | MEDLINE | ID: mdl-32493683

RESUMO

OBJECTIVE: The objectives of this study were to document the results of using fibrin glue (FG) combined with pingyangmycin (PYM) for the embolism and sclerotherapy of maxillofacial arteriovenous malformations (AVMs). STUDY DESIGN: We reviewed the associated clinical data from December 2012 to June 2017 for 25 patients with maxillofacial AVMs. The major treatment method was direct percutaneous puncture and injection of FG combined with PYM. Treatment outcomes were assessed through physical examination, Doppler ultrasonography, computed tomography, and 3-dimensional computed tomography angiography scans. Follow-up time ranged from 12 months to 3 years after the last treatment (mean 21 months). RESULTS: Of the 25 lesions, 80% showed greater than 90% reduction, 12% showed greater than 75% reduction, and 8% showed greater than 50% reduction. Superficial skin necrosis or mucous ulcer occurred in 3 patients and healed without intervention. Regrowth was observed in 3 patients with extensive lesions involving multiple anatomic regions. CONCLUSIONS: These data suggest that embolization and sclerotherapy with the use of FG combined with PYM are safe and effective for the treatment of small- to medium-sized, locally dilated maxillofacial AVMs. For AVMs involving multiple anatomic regions, combined application of this approach with other options should be considered.


Assuntos
Malformações Arteriovenosas/terapia , Embolização Terapêutica , Bleomicina/análogos & derivados , Adesivo Tecidual de Fibrina , Humanos , Soluções Esclerosantes/uso terapêutico , Escleroterapia , Resultado do Tratamento
11.
Zhongguo Fei Ai Za Zhi ; 23(5): 337-342, 2020 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-32336065

RESUMO

BACKGROUND: New treatment methods such as targeted therapy and immune checkpoint inhibitors have been applied to lung cancer patients. It is necessary to further understand the patients with lung cancer combined with pulmonary tuberculosis with the development of lung cancer research. The purpose of this study was to analyze the clinical characteristics of lung cancer patients with pulmonary tuberculosis, the status of driver genes, and their relationships. METHODS: A retrospective analysis was performed on 405 patients with lung cancer and pulmonary tuberculosis hospitalized in our hospital from January 2014 to December 2019. The relationship between clinical characteristics and driver genes status was analyzed. RESULTS: Among the 405 patients with lung cancer combined with pulmonary tuberculosis, 77.3% were male and 85.3% were patients with a history of smoking. The pathological type was mainly lung adenocarcinoma. When there were cavities in chest computed tomography (CT) , squamous cell carcinoma was the main type. 214 patients underwent driver genes testing. The epidermal growth factor receptor (EGFR) gene mutation rate was 35.9%, of which 41.8% were exon 19 deletion mutations and 50.9% were exon 21 L858R mutations. When there were cavities in the chest CT, the EGFR mutation rate was significantly reduced (16.1%). The positive rate of anaplastic lymphoma kinase (ALK) fusion gene detection was 2.5%, the mutation rate of c-ros oncogene 1 receptor kinase (ROS1) gene was 1.9%, the mutation rate of V-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene was 1.1%, and the mutation rate of Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene was 10.1%. The genetic mutation rate of female patients with lung cancer and pulmonary tuberculosis was 50.0%, and that of men was 27.9%. CONCLUSIONS: Patients with lung cancer and pulmonary tuberculosis are predominantly male with smoking history. Adenocarcinoma is the most common pathological type. The positive rate of gene mutation was not significantly different from that of simple lung cancer, but when there were cavities in the chest image, the genetic mutation rate was significantly reduced.


Assuntos
Neoplasias Pulmonares/genética , Tuberculose/genética , Idoso , Quinase do Linfoma Anaplásico/genética , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Proteínas Oncogênicas v-raf/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Estudos Retrospectivos , Tuberculose/complicações
12.
Histochem Cell Biol ; 153(5): 307-321, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32078038

RESUMO

Serine-52 (Ser52) is the major physiologic site of keratin 18 (K18) phosphorylation. Here, we report that serine-52 phosphorylated K18 (phospho-Ser52 K18) accumulated on centrosomes in a cell cycle-dependent manner. Moreover, we found that phospho-Ser52 K18 was located at the proximal end of the mother centriole. Transfection with the K18 Ser52 → Ala (K18 S52A) mutant prevented centriole localization of phospho-Ser52 K18 and resulted in separation of the mother-daughter centrioles. Inhibition of microtubule polymerization led to the disappearance of aggregated phospho-Ser52 K18 on the centrosome; removal of inhibitors resulted in reaccumulation of phospho-Ser52 K18 in microtubule-organizing centers. Transfection with a K18 S52A mutant inhibited microtubule nucleation. These results reveal a cell cycle-dependent change in centrosome localization of phospho-Ser52 k18 and strongly suggest that the phosphorylation status of Ser52 K18 of mother centrioles plays a critical role in maintaining a tight engagement between mother and daughter centrioles and also contributes to microtubule nucleation.


Assuntos
Ciclo Celular , Centríolos/metabolismo , Queratina-18/metabolismo , Microtúbulos/metabolismo , Serina/metabolismo , Animais , Células Cultivadas , Células HeLa , Humanos , Camundongos , Células NIH 3T3 , Fosforilação
13.
Zhongguo Fei Ai Za Zhi ; 23(2): 84-90, 2020 Feb 20.
Artigo em Chinês | MEDLINE | ID: mdl-32093452

RESUMO

BACKGROUND: The patients with advanced lung adenocarcinoma should select targeted drugs based on the type of tumor epidermal growth factor receptor (EGFR) gene mutation. However, it is difficult to collect tumor tissue of advanced lung adenocarcinoma, and some experts agree that peripheral blood can be used as a substitute for tumor tissue as a test specimen. This paper aimed to investigate the clinical value of ddPCR and super-amplification refractory mutation system (ARMS) in detecting EGFR gene mutation in peripheral blood of patients with advanced lung adenocarcinoma. METHODS: A total of 119 patients diagnosed in Beijing Chest Hospital Affiliated to Capital Medical University from February 2016 to February 2019 were collected, and the sensitivity and specificity of plasma ctDNA EGFR gene mutation detected by ddPCR and super-arms were compared. Some patients with positive EGFR gene mutations received oral treatment with first-line EGFR tyrosine kinase inhibitors (EGFR-TKI). The patients were divided into subgroups according to the test results. In group 1, both ddPCR and super-arms showed positive EGFR gene mutation results, with 21 cases. In group 2, ddPCR and super-arms detection of EGFR gene mutation were all negative, with 16 cases. In group 3, the ddPCR test was positive and the super-arms test was negative, with 5 cases. In group 4, the ddPCR test result was negative while the super-arms test result was positive. Since the number of patients in group 4 was 0, no statistics were included. Objective response rate (ORR) and disease control rate (DCR) were used to evaluate the short-term outcome, and progression-free survival (PFS) was compared with survival analysis to evaluate the long-term outcome. RESULTS: EGFR mutations were detected in 58 (48.7%) of 119 patients with advanced lung adenocarcinoma. The coincidence rate between ddPCR and EGFR gene mutation in tumor tissues was 82.4% (Kappa=0.647, P<0.001), the sensitivity was 74.1%, and the specificity was 90.2%. However, the coincidence degree of super-arms test and tissue test was 71.4%, the sensitivity was only 58.6%, and the specificity was 83.6%. The ORR and DCR values in group 3 were lower than those in group 1 and 2, but there was no significant difference in ORR between groups (P>0.05). Survival analysis showed that the PFS of the three groups was compared. The difference was not statistically significant (χ²=2.221, P=0.329). CONCLUSIONS: ddPCR, as a high sensitivity and specificity liquid gene detection method, can be used as a reliable method to detect the mutation of plasma ctDNA EGFR gene in patients with advanced lung adenocarcinoma. The results of plasma genetic testing can also be used as the basis for predicting the efficacy of EGFR-TKIs in patients.


Assuntos
Adenocarcinoma de Pulmão/genética , DNA Tumoral Circulante/genética , Neoplasias Pulmonares/genética , Reação em Cadeia da Polimerase/métodos , Adenocarcinoma de Pulmão/sangue , Idoso , Idoso de 80 Anos ou mais , DNA Tumoral Circulante/sangue , Receptores ErbB/sangue , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Mutação
14.
J Org Chem ; 85(2): 1009-1021, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31822061

RESUMO

C3-alkenylated and C3-(hetero)arylated 1H-indazoles are privileged structural motifs in numerous pharmaceuticals. Direct C3-alkenylation and C3-(hetero)arylation of 1H-indazoles have been significantly challenging because of the inert nature of this carbon center. Herein, we present an efficient mechanochemical strategy for palladium-catalyzed C-H/C-H cross-coupling to construct C3-alkenylated and C3-heteroarylated 1H-indazoles using low-cost copper oxidants with satisfactory product yields and broad functional group tolerance. The robustness of the developed protocols was further demonstrated by the unprecedented total mechanosynthesis of the intermediate of PLK4 inhibitor CFI-400945 and HIF-1α inhibitor YC-1.

15.
Front Neurosci ; 14: 616559, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33613176

RESUMO

Introduction: S100 calcium-binding protein A8 (S100A8) is also known as macrophage-related protein 8, which is involved in various pathological processes in the central nervous system post-traumatic brain injury (TBI), and plays a critical role in inducing inflammatory cytokines. Accumulating evidences have indicated that toll-like receptor 4 (TLR4) is considered to be involved in inflammatory responses post TBI. The present study was designed to analyze the hypothesis that S100A8 is the key molecule that induces inflammation via TLR4 in TBI. Methods: The weight-drop TBI model was used and randomly implemented on mice that were categorized into six groups: Sham, NS, S100A8, S100A8+TAK-242, TBI, and TBI+TAK-242 groups. In the S100A8+TAK-242 and TBI+TAK-242 groups, at half an hour prior to the intracerebroventricular administration of S100A8 or TBI, mice were intraperitoneally treated with TAK-242 that acts as a selective antagonist and inhibitor of TLR4. Furthermore, the protein recombinant of S100A8 was injected into the lateral ventricle of the brain of mice in the S100A8 and S100A8+TAK-242 groups. Sterile normal saline was injected into the lateral ventricle in the NS group. To evaluate the association between S100A8 and TLR4, Western blot, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and Nissl staining were employed. Simultaneously, the neurological score and brain water content were assessed. In the in vitro analysis, BV-2 microglial cells were stimulated with lipopolysaccharide LPS or S100A8 recombinant protein, with or without TAK-242. The expression of the related proteins was subsequently detected by Western blot or enzyme-linked immunosorbent assay. Results: The levels of S100A8 protein and pro-inflammatory cytokines were significantly elevated after TBI. There was a reduction in the neurological scores of non-TBI animals with remarkable severe brain edema after the intracerebroventricular administration of S100A8. Furthermore, the TLR4, p-p65, and myeloid differentiation factor 88 (MyD88) levels were elevated after the administration of S100A8 or TBI, which could be restored by TAK-242. Meanwhile, in the in vitro analysis, due to the stimulation of S100A8 or LPS, there was an upregulation of p-p65 and MyD88, which could also be suppressed by TAK-242. Conclusion: The present study demonstrated that the TLR4-MyD88 pathway was activated by S100A8, which is essential for the development of inflammation in the brain after TBI.

16.
J Cancer ; 10(24): 6065-6073, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31762816

RESUMO

The present study was aimed to investigate the role and mechanism of neurotrophin-3 (NT-3) and its specific receptor tropomyosin receptor kinase C (TrkC) in the perineural invasion (PNI) process of the salivary adenoid cystic carcinoma (SACC). The co-cultured system between SACC cells and Schwann cells (SCs) was employed to detect the expression of NT-3 and TrkC. The results of ELISA, qRT-PCR and western blot showed that NT-3 was noticeably elevated in the co-cultured SACC-83 cells, while TrkC was increased in the co-cultured SCs. The results of scratch wound healing, migration, and 3D co-culture assays showed that the directional migration abilities of the co-cultured SACC-83 cells and SCs were significantly increased. Under the stimulation of NT-3, the directional motor ability of SACC-83 cells and SCs was significantly improved, and the apoptosis of SACC-83 cells and SCs were obviously inhibited. In addition, blocking TrkC by its specific inhibitor AZD7451 could significantly inhibit these effects. Immunohistochemistry staining showed that the positive expression of NT-3 (88.5%) and TrkC (92.3%) was significantly correlated with the PNI in SACC specimens (P < 0.05). Additionally, the high expression of NT-3 was significantly associated with the poor prognosis of SACC patients (P < 0.05). The present study indicated that NT-3/TrkC axis contributed to the PNI progression and the poor prognosis of SACC via regulating the interaction between SACC cells and SCs. Interruption of the interaction between SACC cells and SCs by blocking the NT-3/TrkC axis might be an effective strategy for anti-PNI therapy in SACC.

17.
Interdiscip Sci ; 11(2): 287-291, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31187431

RESUMO

BACKGROUND: Nivolumab, a fully human IgG4 programmed cell death-1 checkpoint inhibitor, demonstrated its benefit of prolonged survival in advanced non-small cell lung cancer (NSCLC). However, nivolumab generated unique immune-related adverse events such as thyroid dysfunctions. Herein we assessed nivolumab-induced thyroid dysfunctions in patients with previously treated advanced NSCLC in our hospital. METHODS: The medical records of 11 patients with advanced NSCLC who were initiated with nivolumab treatment between June 28, 2018, and January 15, 2019, in our hospital were reviewed. Serological tests of thyroid-stimulating hormone and free tetraiodothyronine were measured at baseline and every 8 weeks. RESULTS: Three out of 11 patients developed new-onset hypothyroidism during the treatment, and two of three patients had transient hyperthyroidism first. Two patients were diagnosed with Grade 2 hypothyroidism and received levothyroxine therapy. The other one was Grade 1 hypothyroidism and asymptomatic. All these three patients continued nivolumab therapy. CONCLUSION: Nivolumab-induced thyroid dysfunctions in advanced NSCLC were mostly mild and controlled. Thyroid function needs to be monitored for early prediction and appropriate managements of thyroid dysfunctions.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/fisiopatologia , Nivolumabe/uso terapêutico , Glândula Tireoide/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Glândula Tireoide/efeitos dos fármacos , Tireotropina/metabolismo , Tiroxina/metabolismo
18.
Interdiscip Sci ; 11(2): 266-272, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31098955

RESUMO

BACKGROUND: The mechanism of regulation of PD-L1 expression by ALK translocation remains unclear. We detected PD-L1 protein expression and its regulation in lung adenocarcinoma patients with EML4-ALK fusion gene. METHODS: PD-L1 and ALK expression at protein level in human lung adenocarcinoma cell lines and tumor tissue specimens was evaluated by immunohistochemistry analysis and Western blotting. The expression at DNA level and RNA level was indicated by quantitative real-time PCR analysis. The signal pathway was indicated at protein level by western blotting. RESULTS: The PD-L1 protein expression was higher in human lung adenocarcinoma cell lines with EML4-ALK fusion gene than that without this fusion gene. Induced expression of EML4-ALK in A549 cells significantly increased PD-L1 protein expression, whereas PD-L1 protein expression was downregulated after crizotinib and pembrolizumab successively. Significant positive correlations between PD-L1 and p-ERK, p-STAT3 or p-AKT expression were observed in ALK-translocated tumors. PD-L1 overexpression was significantly associated with shorter progressive survival and overall survival after crizotinib in ALK-translocated patients. CONCLUSIONS: We demonstrate that ALK translocation can upregulate PD-L1 expression by activating ERK, STAT3 and AKT pathways. ALK inhibitor combined with a PD-L1-targeted therapy may be a potential strategy in ALK-translocated lung adenocarcinoma patients.


Assuntos
Adenocarcinoma de Pulmão/genética , Quinase do Linfoma Anaplásico/genética , Antígeno B7-H1/metabolismo , Translocação Genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Prognóstico , Transdução de Sinais , Regulação para Cima
19.
Org Biomol Chem ; 17(18): 4446-4451, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-30985843

RESUMO

A facile decarboxylative acylation of N-free indoles with α-ketonates via liquid-assisted grinding was reported. The reaction requires only a catalytic amount of Cu(OAc)2·H2O in combination with O2 as the terminal oxidant to give various 3-acylindoles with high efficiency. Additionally, this new methodology was applicable to a gram-scale synthesis.

20.
Front Oncol ; 9: 231, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31024838

RESUMO

Objective: The present study investigated the roles and underlying mechanism of CCL2/CCR2 axis in the interactions between tumor cells and tumor-associated macrophages (TAMs) during the progression of salivary adenoid cystic carcinoma (SACC). Methods: Immunohistochemical staining and survival analysis were performed to study the correlation and clinical value of CD68, CD163, CCL2, and CCR2 expression in SACC cases. CCL2 silencing by RNA interference and CCR2 blocking by CCR2 specific antagonist (RS504393) were performed. ELISA, qRT-PCR, western blot, immunofluorescence, flow cytometry, CCK8, scratch wound healing, and transwell assays were used to explore the functional roles and possible mechanism of CCL2/CCR2 axis in the interactions between SACC cells and TAMs. The effects of targeting TAMs by blocking the CCL2/CCR2 axis were investigated in a xenograft mice model with SACC cells. Results: The high infiltration of TAMs marked by CD68 and high infiltration of M2 TAMs marked by CD163 were significantly correlated with the expression of CCL2 and CCR2 in SACC tissues. Notably, the high infiltration of TAMs and the overexpression of CCL2 were obviously associated with the clinical progression and poor prognosis of SACC. SACC cells derived CCL2 could activate its receptor CCR2 expression in TAMs in vitro. The in vitro results further indicated that the SACC cells derived CCL2 was involved in the recruitment, M2 polarization, and GDNF expression of TAMs through the CCL2/CCR2 axis. Meanwhile, TAMs derived GDNF promoted the proliferation, migration, and invasion of SACC cells through the GDNF/p-RET pathway. Treating immunodeficient mice with the CCR2 antagonist (RS504393) greatly inhibited the infiltration of TAMs and the tumorigenicity of SACC cells. Conclusion: These new findings indicated that the CCL2/CCR2 axis promoted the progression of SACC cells via recruiting and reprogramming TAMs. Targeting TAMs by blocking the CCL2/CCR2 axis might be a prospective strategy for SACC therapy.

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