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1.
Drug Dev Res ; 84(5): 975-987, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37089026

RESUMO

A novel series of 5-substituted/unsubstituted [1,2,4]triazolo[3,4-b][1,3,4] thiadiazine compounds has been achieved successfully through chemoselective reduction of the C = N bond, based on our prior work. Initial biological evaluation illustrated that the most active derivative 7j exhibited significant cell growth inhibitory activity toward MCF-7, A549, HCT116, and A2780 with the IC50 values of 0.75, 0.94, 2.90, and 4.15 µM, respectively. Most importantly, all the representative analogs did not demonstrate obvious cytotoxic activity against the non-tumoural cell line HEK-293 (IC50 > 100 µM). The mechanism study revealed that 7j caused the G2 /M phase arrest, induced cell apoptosis in HeLa cells in a concentration-dependent manner, and also showed potent tubulin polymerization inhibitory effect. Meanwhile, 7j exerted significant antivascular activity in the wound-healing and tube formation assays. These observations indicate that 5-unsubstituted 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine scaffold might be considered as a potential lead for antitubulin inhibitors to develop highly efficient anticancer agents with potent selectivity over normal human cells.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Tiadiazinas , Feminino , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Tubulina (Proteína)/metabolismo , Linhagem Celular Tumoral , Células HeLa , Tiadiazinas/farmacologia , Tiadiazinas/química , Células HEK293 , Ensaios de Seleção de Medicamentos Antitumorais , Desenho de Fármacos , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/química , Proliferação de Células , Antineoplásicos/química , Apoptose
2.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-993590

RESUMO

Objective:To study the value of myocardial perfusion imaging (MPI) and coronary flow reserve (CFR) combined with coronary artery calcium score (CACS) in the diagnosis of obstructive coronary artery disease (CAD).Methods:From January 2019 to December 2020, 96 confirmed or suspective CAD patients (65 males, 31 females; age: 30-81 years) who completed rest/stress MPI, CFR and CACS defection in Fuwai Central China Cardiovascular Hospital were retrospectively analyzed. Coronary angiography (CAG) was used as the diagnostic standard to calculate the sensitivity and accuracy of MPI, CFR and MPI/CFR combined with CACS in the diagnosis of CAD. The χ2 test was used to compare the diagnostic efficiency of different methods. Results:The diagnostic sensitivity of MPI was 76.06%(54/71), and the accuracy was 75.00%(72/96), while the sensitivity increased to 97.18%(69/71; χ2=13.67, P<0.001) and the accuracy increased to 87.50%(84/96; χ2=4.92, P=0.020) with significant differences after combined with CACS. The sensitivity and accuracy of CFR were 91.55%(65/71)and 87.50%(84/96), which increased to 97.18%(69/71; χ2=2.12, P=0.137) and 89.58%(86/96; χ2=0.21, P=0.411) with no significant differences after combined with CACS. The sensitivity of MPI in the diagnosis of three-vessel CAD was 70.00%(21/30), which increased to 100%(30/30; χ2=7.75, P=0.004) after combined with CACS; while the sensitivity of MPI combined with CACS in the diagnosis of single-vessel and double-vessel CAD were not significantly improved ( χ2 values: 3.29, 1.51, P values: 0.114, 0.416). Conclusion:The combination of MPI and CACS can significantly improve the diagnostic efficiency of CAD, contributed by the improvement of the diagnostic sensitivity in three-vessel disease; whereas the diagnostic efficiency of CFR for CAD is not significantly improved after combined with CACS.

3.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-965139

RESUMO

@#Abstract: Objective To analyze the occupational hazards of enterprises in Pingshan district of Shenzhen in 2017. Methods Occupational hazards were analyzed in 200 enterprises in Pingshan district of Shenzhen City selected using stratified Results random sampling method. A total of 24 industries were involved in the 200 enterprises. The declaration rate of , occupational hazards was 91.5% and the exposure rate of occupational hazards among workers was 49.2%. The regular monitoring rate of occupational hazard factors in workplaces of the enterprises was 79.5%. There were 129 kinds of occupational , , hazard factors of which 19 factors exceeded the national occupational exposure limit accounting for 14.7%. The over standard , , , , , , , , rates of noise silica dust cotton dust methanol toluene and other dust were 28.7% 13.6% 11.8% 5.86% 0.5% and , , 0.4% respectively. There were 13 kinds of occupational hazard factors in the workplace of metal products industry all of which ( ) exceeded the occupational exposure limit. The exposure rate 56.7% of occupational hazard factors in workers was the highest. Conclusion , , The main occupational hazard factors were noise dust and chemical factor and the major occupational hazard industry was metal manufacturing in Pingshan district of Shenzhen City.

4.
Chinese Journal of Stomatology ; (12): 258-265, 2022.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-935859

RESUMO

Objective: To evaluate the risk factors of inferior alveolar nerve injury (IANI) after surgical removal of the mandibular third molars (M3) and present a new risk scoring system to predict the probability of IANI. Methods: Patients who underwent extraction of M3 in the Stomatology Hospital, Zhejiang University School of Medicine from April 2017 to December 2019 were involved. The investigators enrolled a sample composed of 949 mandibular third molars. Prediction model was used for univariate and multivariate analysis of gender, age, M3, inferior alveolar canal (IAC), and the contact between M3 and IAC, to assess the risk factors of IANI. Combined with the risk factors determined by the outcomes of prediction model, the risk scoring system was constructed. The diagnostic performance of each cut-off score was examined to conduct a risk stratification of IANI risk scores. The predictive ability and reliability of the model were evaluated. Results: In prediction model, twenty nine cases (4.4%, 29/664) experienced postoperative IANI. Number of root (P<0.01), depth of impaction (P<0.05), contact between M3 and IAC (P<0.01) and their contact position (P<0.05) were statistically significant as contributing risk factors of IANI. Specifically, the incidence of temporary IANI was higher in those who aged under 25 years (P<0.001), while female suffer more permanent injury (P<0.05). Based on the IANI risk scoring system, patients were stratified into low-risk, middle-risk and high-risk groups at cutoff scores of 3 and 4. The area under the receiver operator characteristic curve of the risk scoring system were 0.81 [95%CI (0.70-0.90), P=0.002] and 0.80 [95%CI (0.68-0.92), P=0.007] towards good discrimination. Conclusions: Age, gender, number of root, depth of impaction, and contact between M3 and IAC were risk factors of IANI. IANI risk scoring system might help in preoperative assessment, recognition of high-risk cases and decision-making to reduce IANI.


Assuntos
Idoso , Feminino , Humanos , Mandíbula/cirurgia , Nervo Mandibular , Dente Serotino/cirurgia , Reprodutibilidade dos Testes , Fatores de Risco , Extração Dentária/efeitos adversos , Traumatismos do Nervo Trigêmeo/etiologia
5.
Bioorg Chem ; 116: 105324, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34509794

RESUMO

CDK4/6 have been validated as the cancer therapeutic targets. Here, we describe a series of pteridin-7(8H)-one analogues as potent CDK4/6 inhibitors. Among them, the most promising compound 7s demonstrated remarkable and broad-spectrum antiproliferative activities toward HCT116, HeLa, MDA-MB-231, and HT-29 cells with IC50 values of 0.65, 0.70, 0.39, and 2.53 µM, respectively, which were more potent than that of the anticancer drug Palbociclib. Interestingly, 7s also manifested the greatest inhibitory activities toward both CDK4/cyclin D3 and CDK6/cyclin D3 (IC50 = 34.0 and 65.1 nM, respectively), which was comparable with Palbociclib. Additionally, molecular simulation indicated that 7s bound efficiently at the ATPbindingsitesofCDK4 and CDK6. Further mechanistic studies revealed that compound 7s could concentration-dependently induce cell cycle arrest and apoptosis in HeLa cells. Takentogether, 7s represents a promising novel CDK4/6 inhibitor for the potential treatment of cancer.


Assuntos
Antineoplásicos/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Desenvolvimento de Medicamentos , Inibidores de Proteínas Quinases/farmacologia , Pteridinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pteridinas/síntese química , Pteridinas/química , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 47: 128213, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34157389

RESUMO

In order to discover new anticancer agents, 25 novel 2,4-diamino-5-methyleneaminopyrimidine derivatives were designed and synthesized based on our previous work via a ring-opening strategy. Among them, compared with 5-FU, compound 7i exhibited 4.9-, 2.9-, 2.1-, and 3.0-fold improvement in inhibiting HCT116, HT-29, MCF-7, and HeLa cells proliferation with IC50 values of 4.93, 5.57, 8.84, and 14.16 µM, respectively. Moreover, further mechanistic studies indicated that compound 7i could concentration-dependently induce cell cycle arrest and apoptosis in HCT116 cells. These findings revealed that 2,4-diamino-5-methyleneaminopyrimidine scaffold has potential for further investigation to explore novel anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Pirimidinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 220: 113449, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33895499

RESUMO

By removing 5-methyl and 6-acetyl groups in our previously reported compound 3, we designed a series of novel 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidine derivatives as potential tubulin polymerization inhibitors. Among them, compound 5e displayed low nanomolar antiproliferative efficacy on HeLa cells which was 166-fold higher than the lead analogue 3. Interestingly, 5e displayed significant selectivity in inhibiting cancer cells over HEK-293 (normal human embryonic kidney cells). In addition, 5e dose-dependently arrested HeLa in G2/M phase through the alterations of the expression levels of p-cdc2 and cyclin B1, and caused HeLa cells apoptosis by regulation of expressions of cleaved PARP. Further evidence demonstrated that 5e effectively inhibited tubulin polymerization and was 3-fold more powerful than positive control CA-4. Moreover, molecular docking analysis indicated that 5e overlapped well with CA-4 in the colchicine-binding site. These studies demonstrated that 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidine skeleton might be used as the leading unit to develop novel tubulin polymerization inhibitors as potential anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Pirimidinas/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Polimerização/efeitos dos fármacos , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
8.
Bioorg Med Chem Lett ; 38: 127880, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33636303

RESUMO

Based on our previous research, thirty new 5-amino-1H-1,2,4-triazoles possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities. Among them, compounds IIa, IIIh, and IIIm demonstrated significant antiproliferative activities against a panel of tumor cell lines, and the promising compound IIIm dose-dependently caused G2/M phase arrest in HeLa cells. Furthermore, analogue IIa exhibited the most potent tubulinpolymerization inhibitory activity with an IC50 value of 9.4 µM, and molecular modeling studies revealed that IIa formed stable interactions in the colchicine-binding site of tubulin, suggesting that 5-amino-1H-1,2,4-triazole scaffold has potential for further investigation to develop novel tubulin polymerization inhibitors with anticancer activity.


Assuntos
Antineoplásicos/farmacologia , Triazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
9.
Bioorg Med Chem Lett ; 31: 127684, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33197548

RESUMO

Based on our previous work, a novel class of 8-cyclopentyl-7,8-dihydropteridin-6(5H)-one derivatives were synthesized and evaluated as antiproliferative agents. Structure-activity relationship analysis revealed that the greatest activities were achieved with a 4-(4-methylpiperazin-1-yl)aniline group at C-2 position of dihydropteridin-6(5H)-one core, and the most promising compound 6k demonstrated comparable antiproliferative activity with Palbociclib and more potent than our parent derivative 4 toward four cell lines including HCT-116, HeLa, HT-29, and MDA-MB-231 with IC50 values of 3.29, 6.75, 7.56, and 10.30 µM, respectively. Moreover, the mechanism studies revealed that compound 6k could induce cell cycle arrest at G2/M phase via a concentration-dependent manner. In general, these preliminary observations suggested that these compounds could serve as promising scaffolds for further modification to develop novel and highly potent cancer therapy agents.


Assuntos
Antineoplásicos/farmacologia , Pteridinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Pteridinas/síntese química , Pteridinas/química , Relação Estrutura-Atividade
10.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-847086

RESUMO

BACKGROUND: Tissue engineering technology relies on biomaterial scaffolds as supporting structures for tissue repair and regeneration. Among these biological scaffolds, electrospun fiber scaffolds have been widely applied in regenerative medicine owing to their mimicry of the natural structure of extracellular matrix. OBJECTIVE: To summarize the current application of electrospun aligned nanofibers in the field of tissue engineering. METHODS: Relevant articles included in PubMed from January 2010 to March 2020 were searched by the first author, with key words of “electrospinning; aligned nanofibers; tissue engineering; regenerative medicine; bioactive materials” in English. Relevant articles included in CNKI and Wanfang database from January 2010 to March 2020 were searched with key words of “electrospinning; aligned nanofibers; oriented fiber; tissue engineering; tissue regeneration” in Chinese. Finally, 67 articles were included for review. RESULTS AND CONCLUSION: Electrospinning is a simple and effective technology for the preparation of nanomaterials. In recent years, many kinds of natural materials or polyester materials with good biocompatibility and biodegradability have been prepared into electrospun nanofiber scaffolds with different structures by electrospinning technology, which are widely used in tissue engineering, regenerative medicine and other fields. Among them, the electrospun oriented nanofiber scaffolds, inspired by the highly directional characteristics of natural extracellular matrix, have highly consistent fiber arrangement direction, which can promote cell adhesion and migration through contact guidance, and the combination with cells or growth factors can further promote cell proliferation and differentiation, and ultimately achieve tissue regeneration in nerve, myocardium, tendon and bone tissue. In the field of regeneration and wound healing, it has great potential and wide application prospect.

11.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-887885

RESUMO

Minute pulmonary meningothelial-like nodule(MPMN)is a rare respiratory disease with no specific clinical manifestations and requires bronchial or percutaneous lung biopsy for diagnosis.Here we report a case of an old male patient with recurrent cough and sputum as the main manifestations,which failed to be cured by antibiotic.His chest computed tomography showed a mass-like tumorous lesion located in the posterior segment of the right upper lobe,and the pathological diagnosis by percutaneous lung biopsy confirmed MPMN with lung infection.At the same time,we reviewed 34 cases to summarize the clinical data,pathological manifestation,diagnosis,treatment,and prognosis of MPMN.


Assuntos
Humanos , Masculino , Pulmão , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia Computadorizada por Raios X
12.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-887138

RESUMO

Objective:To investigate epidemiological characteristics and trends of five sexually transmitted diseases (STDs) in Gongshu District of Hangzhou City, and to provide evidence for the development of control strategies. Methods:Data of five STDs from 2012 to 2019 in Gongshu District were collected and then analyzed by descriptive epidemiological methods. Results:In 2012-2019, a total of 9 767 STD cases were reported in Gongshu, with an average incidence rate of 218.35 per 100 000. The overall incidence rate of STD tended to decline over years (χ2=82.60,P<0.001).The areas with high incidence were mainly Xiangfu sub-district, Shangtang sub-district and Daguan sub-district with a total of 4 136 cases, accounting for 42.34%.The occupations with the highest proportion were business service (35.89%), worker (19.03%), household work and unemployment (15.94%). Latent syphilis was the main stage of syphilis, which increased at an average annual rate of 14.08%. The proportion of primary syphilis and secondary syphilis decreased over years, with the average annual reduction rate of 36.86% and 18.77%, respectively. The average annual incidence of genital chlamydia trachomatis infection in females (100.03 per 100 000) was higher than that in males (31.88 per 100 000).The average annual incidence of condyloma acuminatum in males (24.68 per 100 000) was higher than that in females (16.80 per 100 000).The average annual incidence of gonorrhea in males (75.41 per 100 000) was higher than that in females (13.06 per 100 000). Conclusion:The incidence of five STDs in Gongshu District is effectively controlled. It warrants health education, behavioral intervention, STD screening, and standardized diagnosis and treatment services for high-risk groups in high-risk areas to control the epidemic of STDs. Gender differences in reported incidence of condyloma acuminatum, gonorrhea and genital chlamydia trachomatis infection may be reduced by strengthening outpatient health education and optimizing laboratory examinations.

13.
Eur J Med Chem ; 204: 112625, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32717486

RESUMO

On the basis of our previous work, twenty-nine novel [1,2,4]triazolo[4,3-a]pyridines possessing 3,4,5-trimethoxylphenyl groups were designed, synthesized, and evaluated as tubulin polymerization inhibitors. The bioassay results revealed that some of the compounds displayed excellent antiproliferative efficacies in the nanomolar range against HeLa cells, and the most promising derivative 7i demonstrated almost comparable activity to that of the reference CA-4 and sixty-two fold more potent than the parent compound 6 with an IC50 value of 12 nM. Importantly, 7i exhibited high selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 µM). Further mechanism studies revealed that 7i significantly arrested cell cycle at G2/M phase, induced apoptosis with a dose-dependent manner, and disrupted microtubule networks. Additionally, the most active compound 7i effectively inhibited tubulin polymerization with a value similar to that of CA-4 (3.4 and 4.2 µM, respectively). Furthermore, molecular docking analysis suggested that 7i well occupied the colchicine binding pocket of tubulin. The present study highlights that compound 7i is a novel potential tubulin polymerization inhibitor and deserves further investigation for the treatment of cancers.


Assuntos
Piridinas/química , Triazóis/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Concentração Inibidora 50 , Análise Espectral/métodos
14.
Trans Am Clin Climatol Assoc ; 131: 140-146, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32675854

RESUMO

WNK [with-no-lysine (K)] kinases are a family of four members of serine and threonine kinases that regulate renal Na+ and K+ transport. Mutations of WNK1 and WNK4 cause a hereditary hypertensive and hyperkalemic disease known as pseudohypoaldosteronism type II (PHA2). Unlike other WNK isoforms, WNK1 is ubiquitously expressed and regulates many other cellular processes outside the kidney. Oxidative stress response kinase (OSR1) and related STE 20/SPS1-related proline alanine-rich kinase (SPAK) are downstream kinases of WNK kinases. To examine the role of WNK kinase cascade in vivo, we generated global Wnk1-deleted mice and found that Wnk1-ablated mice die in utero from embryonic angiogenesis and cardiac developmental defects. Endothelial-specific Wnk1 deletion reveals that angiogenesis defect is due to WNK1 requirement in endothelium. We further showed that global and endothelial-deletion of Osr1 phenocopies Wnk1 deletion. Furthermore, expression of a catalytic constitutively active Osr1 transgene rescues angiogenesis defects and embryonic lethality of Wnk1-ablated mice. In zebrafish, Wnk1 knockdown causes similar angiogenesis defects to Vegf2 (Flk1) knockdown and that expression of WNK1 partially rescues Flk1 angiogenesis defects. The results indicate that WNK1 is downstream of VEGF signaling cascade. T-lymphocytes isolated from Wnk1-null mice exhibit migration defects. Inhibition of WNK1-OSR1 downstream target Na-K-2Cl cotransporter NKCC1 mimics migration defect of WNK1-deficient T-lymphocytes. Thus, WNK1-OSR1/SPAK cascade is important for angiogenesis. Regulation of ion homeostasis and cell volume may underlie the mechanism for WNK1 regulation of endothelial cell migration and angiogenesis.

15.
Bioorg Chem ; 102: 104076, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32683180

RESUMO

A new series of derivatives characterized by the presence of the 3,4,5-trimethoxylbenzamide substituted benzofurans were synthesized and evaluated for antiproliferative activity against four cancer cell lines and one normal human cell line. Among them, derivative 6g with greatest cytotoxicity significantly inhibited the growth of MDA-MB-231, HCT-116, HT-29 and HeLa cell lines with IC50 values of 3.01, 5.20, 9.13, and 11.09 µM, respectively. Importantly, 6g possessed excellent selectivity over non-tumoral cell lines HEK-293 (IC50 > 30 µM). Moreover, mechanistic studies revealed that 6g induced HeLa cells arrested in G2/M phase in a concentration-dependent manner, and inhibited polymerization of tubulin via a consistent way with CA-4. In general, these observations suggest that 6g is a promising anti-cancer lead and is worth further investigation to generate potential antitumor agents.


Assuntos
Benzamidas/síntese química , Benzamidas/uso terapêutico , Polimerização/efeitos dos fármacos , Moduladores de Tubulina/uso terapêutico , Tubulina (Proteína)/química , Benzamidas/farmacologia , Desenho de Fármacos , Células HeLa , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Moduladores de Tubulina/farmacologia
16.
Bioorg Med Chem Lett ; 30(8): 127025, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32063430

RESUMO

Twenty-six novel pyrazolo[3,4-b]pyridine-bridged analogues of combretastatin A-4 possessing 3,4,5-trimethoxylphenyl groups, were synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. Preliminary biological evaluation demonstrated that some of the target compounds displayed significant antiproliferative effectagainst four different cell lines including MCF-7, MDA-MB-231, HeLa and Kyse150. The most active analogue 6n was found to induce HeLa cells arrest in the G2/M phase in a dose-dependent manner. Molecular modeling studies indicated that derivative 6n most likely occupies the colchicine site of tubulin. The initial results suggest that the 3,4,5-trimethoxyphenyl substituted pyrazolo[3,4-b]pyridine could serve as a promising scaffold for development of potent tubulin inhibitors as anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Estilbenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Estilbenos/química , Relação Estrutura-Atividade
17.
Bioorg Med Chem Lett ; 30(2): 126816, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31753698

RESUMO

A series of novel indole-based oxalamide and aminoacetamide derivatives were designed, synthesized, and evaluated for antiproliferative activities. Preliminary results revealed that compound 8g exhibited significant antiproliferative effect against PC-3, HeLa and HCT-116 cell lines. Flow cytometric analysis of the cell cycle demonstrated the compound 8g induced the cell cycle arrest at G2/M phase in HeLa cell lines. Immunocytochemistry revealed loss of intact microtubule structure in cells treated with 8g andinhibition of tubulinpolymerization. Additionally, molecular docking analysis suggested that 8g formed stable interactions in the colchicine-binding site of tubulin. These preliminary results demonstrated that a new class of novel indole-based oxalamide and aminoacetamide derivatives described in the investigation could be developed as potential scaffolds to new anticancer agents.


Assuntos
Indóis/síntese química , Moduladores de Tubulina/antagonistas & inibidores , Humanos , Indóis/química , Estrutura Molecular , Relação Estrutura-Atividade
18.
Arch Dermatol Res ; 312(5): 353-359, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31797034

RESUMO

The main pathology involved in chronic idiopathic urticaria (CIU) is immunological dysfunction which mainly adapts to the immune system of body. Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PA) is an inactivated Pseudomonas aeruginosa biological product which displays a broad immune regulatory effect. The current study was designed to explore the protective nature of PA as an immune regulator in CIU. The participants were randomly divided into CIU + PA, CIU, control + PA and control group. lg E, anti FcεRI, anti IgE antibody, IL-4, IL-17, TGF-ß1 and interferon-γ in the sera were assayed by ELISA. Then CD4+ T cells and CD19+ B cells were isolated from peripheral blood of patients with CIU (n = 10) and healthy control (n = 10). CD4+ T cells and CD19+ B proliferation and apoptosis were analyzed through CCK-8 and flow cytometry respectively. T helper cells differentiations were assessed by real-time PCR. The results revealed that compared with the control group, the curative effect of CIU + PA group was more effective than that of the CIU control group. There was a hyper proliferation of CD19+ B cells in the CIU patients. Moreover, it was also discovered that presence of Th1 decreased while Th2 cells increased in CIU patients. PA significantly inhibited the proliferation of CD19+ B and Th2 cells but at the same time promoted the proliferation of Th1 compared to healthy control. The conclusion arrived at from this study is that the PA displayed a remarkable regulatory effect in CD4+ T cells and CD19+ B cells function by promoting Th1 but inhibited Th2 and the hyperfunction of B cells of CIU patients.


Assuntos
Linfócitos B/imunologia , Urticária Crônica/microbiologia , Proteínas de Fímbrias/metabolismo , Pseudomonas aeruginosa/metabolismo , Células Th1/imunologia , Células Th2/imunologia , Adolescente , Adulto , Antígenos CD19/metabolismo , Proliferação de Células , Células Cultivadas , Urticária Crônica/imunologia , Citocinas/metabolismo , Feminino , Proteínas de Fímbrias/química , Humanos , Imunomodulação , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Equilíbrio Th1-Th2 , Adulto Jovem
19.
Chinese Journal of School Health ; (12): 1657-1660, 2020.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-837585

RESUMO

Objective@#To investigate the influencing factors of smoking tendency of adolescents and to analyze the influence of e-cigarette on smoking tendency of teenagers and the possible interaction, to provide evidence for tobacco control measures.@*Methods@#Stratified multistage cluster probability sampling method was used to select 6 178 students from junior middle school, high school and vocational high school students in Shanghai for questionnaire survey from September to October 2019. Students with smoking tendency were taken as case group, adolescents with same sex and similar age(within 1 year) were mathed in 1∶3 ratio. A total of 631 adolescents with smoking tendency and 1 870 non-smoking tendency were included in the study. Conditional Logistic regression was used to analyze the influencing factors and possible interactions.@*Results@#After adjusting gender, age and other covariates, conditional Logistic analysis results showed that the smoking tendency of middle school students was associated with factors such as their friends smoking, trying cigarettes and trying e-cigarettes. The OR value and 95%CI were 3.26(2.47-4.29), 5.90(3.76-9.24), and 3.28(2.11-5.10), respectively. The interaction analysis results showed that the OR value and 95%CI of the multiplying interaction between friends smoking and trying e-cigarettes, trying smoking and trying e-cigarettes were 8.62(4.90-15.17) and 12.01(6.02-23.95), respectively. There was no additive interaction.@*Conclusion@#Tobacco control interventions, such as e-cigarette harm publicity and peer education, can help to change teenagers smoking tendency and further reduce their tobacco use rate.

20.
Chinese Journal of School Health ; (12): 1646-1649, 2020.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-837580

RESUMO

Objective@#To investigate risk perception, emergency preparedness and emergency literacy among medical students under COVID-19 epidemic.@*Methods@#An online survey was conducted by using the self designed COVID-19 questionnaire on risk perception, emergency preparedness and emergency literacy from March 27 to March 30, 2020. The convenience sampling method was used to investigate 4 864 medical students from 2 colleges and technical secondary schools in Sichuan Province.@*Results@#The scores of risk perception, emergency preparedness and emergency literacy associated with COVID-19 were(35.18±4.33)(28.30±4.16) and(25.23±2.97) respectively. Risk perception of medical students was positively correlated with emergency preparedness and emergency literacy(r=0.35, 0.40), emergency preparedness was positively correlated with emergency literacy(r=0.51)(P<0.05).@*Conclusion@#Considering interrelationships among risk perception, emergency preparedness and emergency literacy associated with COVID-19, medical students should be given targeted prevention and control training.

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