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1.
Front Aging Neurosci ; 16: 1390324, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38586827

RESUMO

Phosphatase and tensin homologue deleted on chromosome ten (PTEN) was initially recognized as a significant regulator of cancer suppression and could impede cancer cell survival, proliferation, and energy metabolism. PTEN is highly expressed in neurons and performs crucial functions in neurogenesis, synaptogenesis, and neuronal survival. Disruption of PTEN activity may also result in abnormal neuronal function and is associated with various neurological disorders, including stroke, seizures, and autism. Although several studies have shown that PTEN is involved in the development and degenerative processes of the nervous system, there is still a lack of in-depth studies that summarize and analyse patterns of cooperation between authors, institutions, countries, and journals, as well as research hotspots and trends in this important field. To identify and further visualize the cooperation and comprehend the development and trends of PTEN in the nervous system, especially in neural development and neurological diseases, we used a bibliometric analysis to identify relevant publications on this topic. We first found that the number of publications displayed a growing trend with time, but this was not stable. Universities, institutions, and authors from the United States are leading in this area of research. In addition, many cutting-edge research results have been discovered, such as key regulatory molecules and cellular mechanisms of PTEN in the nervous system, which may provide novel intervention targets and precise therapeutic strategies for related pathological injuries and diseases. Finally, the literature published within the last 5 years is discussed to identify future research trends regarding PTEN in the nervous system. Taken together, our findings, analysed using bibliometrics, may reflect research hotspots and trends, providing a reference for studying PTEN in the nervous system, especially in neural development and neurological diseases. These findings can assist new researchers in developing their research interests and gaining basic information. Moreover, our findings also may provide precise clinical guidelines and strategies for treating nervous system injuries and diseases caused by PTEN dysfunction.

2.
Front Surg ; 10: 1180624, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37151861

RESUMO

Background: Skin regeneration is a challenging issue worldwide. Increasing research has highlighted the role of immune cells in healing and the underlying regulatory mechanism. The purpose of this study was to identify the hotspots and trends in skin regeneration and inflammation research through bibliometrics and to provide insights into the future development of fundamental research and disease treatment. Methods: Publications were collected from the Web of Science Core Collection on March 1, 2022. Articles and reviews published in English from January 1, 1999, to December 31, 2022, were selected, and statistical analyses of countries, institutions, authors, references, and keywords were performed using VOSviewer 1.6.18 and CiteSpace 5.8. Results: A total of 3,894 articles and reviews were selected. The number of publications on skin inflammation and regeneration showed an increasing trend over time. Additionally, authors and institutions in the United States, United Kingdom, Canada, and China appeared to be at the forefront of research in the field of skin inflammation and regeneration. Werner Sabine published some of the most cited papers. Wound Repair and Regeneration was the most productive journal, while Journal of Investigative Dermatology was the most cited journal. Angiogenesis, diamonds, collagen, cytokine, and keratinocytes were the five most commonly used keywords. Conclusion: The number of publications on skin inflammation and regeneration show an increasing trend. Moreover, a series of advanced technologies and treatments for skin regeneration, such as exosomes, hydrogels, and wound dressings, are emerging, which will provide precise information for the treatment of skin wounds. This study can enhance our understanding of current hotspots and future trends in skin inflammation and regeneration research, as well as provide guidelines for fundamental research and clinical treatment.

3.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(1): 91-97, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33476544

RESUMO

OBJECTIVE: To explore the clinical characteristics and genetic findings of patients with infantile intrahepatic cholestasis. METHODS: The clinical data were collected in children who were admitted to the Department of Gastroenterology in Children's Hospital, Capital Institute of Pediatrics from June 2017 to June 2019 and were suspected of inherited metabolic diseases. Next generation sequencing based on target gene panel was used for gene analysis in these children. Sanger sequencing technology was used to verify the genes of the members in this family. RESULTS: Forty patients were enrolled. Pathogenic gene variants were identified in 13 patients (32%), including SLC25A13 gene variation in 3 patients who were diagnosed with citrin deficiency, JAG1 gene variation in 3 patients who were diagnosed with Alagille syndrome, ABCB11 gene variation in 3 patients who were diagnosed with progressive familial intrahepatic cholestasis type 2, HSD3B7 gene variation in 1 patient who was diagnosed with congenital bile acid synthesis defect type 1, AKR1D1 gene variation in 1 patient who was diagnosed with congenital bile acid synthesis defect type 1, NPC1 gene variation in 1 patient who was diagnosed with Niemann-Pick disease, and CFTR gene variation in 1 patient who was diagnosed with cystic fibrosis. CONCLUSIONS: The etiology of infantile intrahepatic cholestasis is complex. Next generation sequencing is helpful in the diagnosis of infantile intrahepatic cholestasis.


Assuntos
Colestase Intra-Hepática , Citrulinemia , Síndrome de Alagille/genética , Criança , Colestase Intra-Hepática/genética , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas de Transporte da Membrana Mitocondrial , Mutação
4.
Complement Ther Clin Pract ; 40: 101210, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32891286

RESUMO

BACKGROUND: and purpose: We investigated the effectiveness of cupping therapy with three different pressures in patients with chronic fatigue syndrome (CFS). MATERIALS AND METHODS: The participants were randomly assigned to three groups, as follows: cupping pressure of -0.02 mpa (n = 38), -0.03 mpa (n = 38), or -0.05 mpa (n = 36). Each group received cupping treatment that consisted of 10 sessions over 5 weeks (2 sessions per week). The primary outcomes were Fatigue Scale (FS-14) score and Fatigue Assessment Instrument (FAI) score after 5 and 10 sessions. The secondary outcomes were the Self-Rating Anxiety Scale (SAS) score, the Self-Rating Depression Scale (SDS) score, and the Pittsburgh Sleep Quality Index (PSQI) score. RESULTS: There were 91 participants who completed the trial. After five sessions of treatment, the primary outcome of FS-14 score decreased by 3.20 (2.19, 4.21) in the -0.02 mpa group, by 2.39 (1.51, 3.27) in the -0.03 mpa group, and by 3.40 (2.28, 4.52) in the -0.05 mpa group (P = 0.667). After 10 sessions of treatment, the outcome of FS-14 score decreased by 5.00 (3.79, 6.21) in the -0.02 mpa group, by 4.06 (3.07, 5.05) in the -0.03 mpa group, and by 4.77 (3.52, 5.94) in the -0.05 mpa group (P = 0.929). And, the results were statistically different between 5 sessions and 10 sessions of treatment (P < 0.01). However, there were no statistical differences in FAI, SAS, SDS, and PSQI scores between the three groups after 5 sessions and 10 sessions of treatment. CONCLUSIONS: In conclusion, cupping therapy has significantly relieved fatigue symptoms and improved emotion and sleep condition of CFS patients, and 10 sessions of treatment had superior results compared with 5 sessions in each group. Moreover, in 5 sessions of treatment, cupping with high pressure showed better improvement in fatigue syndromes and sleep condition according to effective rates. TRIAL REGISTRATION: Chinese clinical trial registry (ChiCTR1800017590); Ethical approval number: ChiECRCT-20180085.


Assuntos
Ventosaterapia/métodos , Síndrome de Fadiga Crônica/terapia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Transtornos do Sono-Vigília/terapia , Adulto Jovem
5.
Eur J Med Chem ; 187: 111971, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881457

RESUMO

For the purpose of advancing our research on diverse C-20 decorated derivatives of camptothecin (CPT), 46 new CPT acylthiourea derivatives were synthesized and evaluated in vitro for their cytotoxicity. All the compounds showed promising in vitro cytotoxicity against six tumor cell lines (Hep3B, MCF7, A549, MDA-MB-231, KB and KB-vin). Out of them, compound c20 possesses remarkable in vitro cytotoxic activity and is more potent than topotecan. Mechanistically, c20 not only induces cell cycle arrest and cell apoptosis in A549 cells, but also inhibits Topo I activity in the cell and cell-free system in a manner similar to that of topotecan. In both xenograft and primary HCC mouse models, c20 displays significant in vivo anti-cancer activity and is more potent than topotecan. In addition, the acute toxicity assay showed that c20 has no apparent toxicity to mouse liver, kidney and hemopoietic system of the FVB/N mice. Take together, these results indicated that compound c20 could be a potential anti-cancer candidate for further clinical trial.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Desenho de Fármacos , Ureia/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Camptotecina/síntese química , Camptotecina/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ureia/análogos & derivados , Ureia/química
6.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(6): 505-510, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31208500

RESUMO

OBJECTIVE: To investigate the viral etiology and allergen distribution in infants and young children at high risk of asthma during a wheezing episode. METHODS: A total of 135 infants and young children at high risk of asthma were enrolled who were admitted due to asthmatic bronchitis or asthmatic bronchopneumonia between April 2016 and August 2017. Fluorescent probe PCR was used to measure influenza A (Flu A), respiratory syncytium virus (RSV), adenovirus (ADV), parainfluenza virus (PinF), human rhinovirus (HRV), human partial lung virus (hMPV) and human bocavirus (HBoV) in nasopharyngeal aspirates. ImmunoCAP was used to measure inhaled allergens, food allergens, and total IgE concentration. RESULTS: Among the 135 patients, the overall virus detection rate of nasopharyngeal aspirates was 49.6%, and HRV had the highest detection rate of 25.2%, followed by HBoV (9.6%), RSV (8.1%), PinF (5.9%), Flu-A (3.7%), ADV (1.5%) and hMPV (0.7%). The 1-3 years group had a significantly higher detection rate of HRV than the <1 year group (P<0.05). The positive rate of allergen screening was 59.3%, with 44% for inhaled allergens and 89% for food allergens. Among the inhaled allergens, dust mites had the highest positive rate of 77%, followed by mould (37%), pollen (26%) and animal dander (9%). Among the food allergens, egg white had a positive rate of 73% and milk had a positive rate of 68%. The <1 year group had a significantly higher positive rate of inhaled allergens than the 1-3 years group (P<0.05). The 1-3 years age group had a significantly higher level of T-IgE than the <1 year group (P<0.05). The positive virus group had a significantly higher positive rate of inhaled allergens than the non-virus group (P<0.05). The children with the second wheezing episode had significantly higher positive rates of inhaled allergens and food allergens and level of T-IgE than those with the first wheezing episode (P<0.05). The children with the second wheezing episode also had significantly higher positive rates of dust mites and mould than those with the first wheezing episode (P<0.05). CONCLUSIONS: Early HRV infection and inhaled allergen sensitization are closely associated with the development of wheezing in infants and young children at high risk of asthma.


Assuntos
Asma , Hipersensibilidade a Ovo , Alérgenos , Animais , Criança , Pré-Escolar , Humanos , Lactente , Pyroglyphidae , Sons Respiratórios
7.
Oncotarget ; 8(61): 102880-102887, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29262530

RESUMO

The prognostic effect of chemoradiotherapy in gastric cancer has been evaluated for decades while the results are still in debate and heterogeneous. We thus comprehensively updated the evidence through systematic review and meta-analysis to evaluate chemoradiotherapy in gastric cancer to determine its effect. Pubmed, EMBASE, and Cochrane Library from the earliest possible year to April 2017 were searched. Randomised controlled trials (RCTs) that assessed the effects of combined chemoradiotherapy for patients with gastric cancer compared with that of single chemotherapy were included. The main outcome measure was 5-year overall survival (OS) and the second was disease-free survival (DFS) or recurrence-free survival (RFS). Fifteen RCTs involving 3347 patients were included into this meta-analysis. Compared with single chemotherapy, the relative risk (RR) for 5-year OS for chemoradiotherapy was 1.05 (95% CI 0.88 to 1.25), with moderate heterogeneity across eligible trials (I2 = 55.7%, p = 0.016). Subgroup analyses and sensitivity analyses confirmed the consistent findings. We found that significant survival benefit for 5-year DFS/RFS for chemoradiotherapy over single chemotherapy (RR 0.89 95% CI 0.81 to 0.98) for patients with gastric cancer. This updated meta-analysis does not provide strong evidence for a 5-year survival benefit of chemoradiotherapy over chemotherapy alone in patients with gastric cancer. A clear advantage of chemoradiotherapy over chemotherapy has not been established. Further larger RCTs should be conducted to determine its true effect.

8.
Bioorg Med Chem Lett ; 27(20): 4694-4697, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28927790

RESUMO

Fluorination is a well-known strategy for improving the bioavailability of bioactive molecules in the lead optimization phase of drug discovery projects. In an attempt to improve the antitumor activity of camptothecins (CPTs), novel 10-fluoro-CPT derivatives were designed, synthesized and evaluated for cytotoxicity against five human cancer cell lines (A-549, MDA-MB-231, KB, KB-VIN and MCF-7). All of the derivatives showed more potent in vitro cytotoxic activity than the clinical CPT-derived drug irinotecan against the tumor cell lines tested, and most of them showed comparable or superior potency to topotecan. Remarkably, compounds 16b (IC50, 67.0nM) and 19b (IC50, 99.2nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that incorporation of a fluorine atom into position 10 of CPT is an effective method for discovering new potent CPT derivatives.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Desenho de Fármacos , Antineoplásicos/química , Camptotecina/síntese química , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Flúor/química , Humanos , Relação Estrutura-Atividade , Topotecan/farmacologia
9.
Acta Pharmacol Sin ; 37(6): 814-24, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27133304

RESUMO

AIM: Jungermannenone A and B (JA, JB) are new ent-kaurane diterpenoids isolated from Chinese liverwort Jungermannia fauriana, which show anti-proliferation activities in cancer cells. In this study we investigated the mechanisms underlying the anticancer action of JA and JB in PC3 human prostate cancer cells in vitro. METHODS: A panel of 9 human cancer cell lines was tested. Cell proliferation was assessed with a real-time cell analyzer and MTT assay. Cell apoptosis, cell cycle distribution and ROS levels were measured using cytometry. Mitochondrial damage was examined by transmission electron microscopy. DNA damage was detected with comet assay. Apoptotic, DNA damage- and cell cycle-related proteins were analyzed using Western blotting. The expression of DNA repair genes was measured with qRT-PCR. RESULTS: Both JA and JB exerted potent anti-proliferative action against the 9 cancer cell lines, and PC3 cells were more sensitive with IC50 values of 1.34±0.09 and 4.93±0.20 µmol/L, respectively. JA (1.5 µmol/L) and JB (5 µmol/L) induced PC3 cell apoptosis, which was attenuated by the caspase inhibitor Z-VAD. Furthermore, both JA and JB caused mitochondrial damage and ROS accumulation in PC3 cells, whereas vitamin C blocked the ROS accumulation and attenuated the cytotoxicity of JA and JB. Moreover, both JA and JB induced DNA damage, accompanied by downregulated DNA repair proteins Ku70/Ku80 and RDA51. JA induced marked cell cycle arrest at the G0/G1 phase, which was related to c-Myc suppression, whereas JB enforced the cell cycle blockade in the G2/M phase, which associated with activation of the JNK signaling. CONCLUSION: Both JA and JB induce prostate cancer apoptosis via ROS accumulation and induction of cell cycle arrest.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular Tumoral , Hepatófitas/química , Humanos , Masculino , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Espécies Reativas de Oxigênio/metabolismo
10.
Eur J Med Chem ; 115: 109-20, 2016 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-26994847

RESUMO

In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure-activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π-π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Desenho de Fármacos , Simulação de Acoplamento Molecular , Antineoplásicos/síntese química , Antineoplásicos/química , Camptotecina/síntese química , Camptotecina/química , Camptotecina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 25(13): 2690-3, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-25987370

RESUMO

In our continuing search for camptothecin (CPT)-derived antitumor drugs, novel structurally diverse PEG-based 20(S)-CPT sulfonylamidine derivatives were designed, synthesized via a Cu-multicomponent reaction (MCR), and evaluated for cytotoxicity against four human tumor cell lines (A-549, MDA-MB-231, KB, and KBvin). All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, and were more potent than irinotecan. Significantly, these derivatives exhibited comparable cytotoxicity against KBvin, while irinotecan was less active against this cell line. With a concise efficient synthesis and potent cytotoxic profiles, especially significant activity towards KBvin, these compounds merit further development as a new generation of CPT-derived PEG-conjugated drug candidates.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Antineoplásicos/química , Camptotecina/síntese química , Camptotecina/química , Camptotecina/farmacologia , Catálise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cobre , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Irinotecano , Células KB , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Relação Estrutura-Atividade
12.
Bioorg Med Chem ; 22(22): 6453-8, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25438769

RESUMO

In our continuing search for natural product-based spin-labeled antitumor drugs, 20 novel spin-labeled camptothecin derivatives were synthesized via a Cu-catalyzed one pot reaction and evaluated for cytotoxicity against four human tumor cell lines (A-549, MDA-MB-231, KB, and KBvin). Eighteen of the target compounds (9a, 9b, 9d-9k, 9m-9t) exhibited significant in vitro antiproliferative activity against these four tested tumor cell lines. Compounds 9e and 9j (IC50 0.057 and 0.072µM, respectively) displayed the greatest cytotoxicity against the multidrug-resistant (MDR) KBvin cell line and merit further development into preclinical and clinical drug candidates for treating cancer including MDR phenotype.


Assuntos
Antineoplásicos/síntese química , Camptotecina/química , Desenho de Fármacos , Antineoplásicos/toxicidade , Camptotecina/síntese química , Camptotecina/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células KB , Marcadores de Spin , Relação Estrutura-Atividade
14.
J Med Chem ; 57(14): 6008-18, 2014 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-25003995

RESUMO

Twelve novel 20-sulfonylamidine derivatives (9a-9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.


Assuntos
Amidinas/química , Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , DNA Topoisomerases Tipo I/metabolismo , Desenho de Fármacos , Neoplasias Experimentais/tratamento farmacológico , Sulfonamidas/química , Inibidores da Topoisomerase I/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Camptotecina/química , 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 , Feminino , Células HCT116 , Humanos , Células KB , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Conformação Molecular , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química
15.
Eur J Med Chem ; 75: 282-8, 2014 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-24553146

RESUMO

Spin-labeled podophyllotoxins have elicited widespread interest due to their far superior antitumor activity compared to podophyllotoxin. To extend our prior studies in this research area, we synthesized a new generation of spin-labeled podophyllotoxin analogs via isocyanide multicomponent reactions and evaluated their cytotoxicity against four human cancer cell lines (A-549, DU-145, KB and KBvin). Most of the compounds exhibited potent cytotoxic activity against all four cell lines, notably against the drug resistant KBvin cancer cell line. Among the new analogs, compounds 12e (IC50: 0.60-0.75 µM) and 12h (IC50: 1.12-2.03 µM) showed superior potency to etoposide (IC50: 2.03 to >20 µM), a clinically available anticancer drug. With a concise efficient synthesis and potent cytotoxic profiles, compounds 12e and 12h merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Marcadores de Spin/síntese química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Cianetos/síntese química , Cianetos/química , Ensaios de Seleção de Medicamentos Antitumorais , Etoposídeo/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Podofilotoxina/síntese química , Podofilotoxina/química , Relação Estrutura-Atividade
16.
Med Chem Res ; 23(11): 4926-4931, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25709376

RESUMO

A series of novel spin-labeled 4ß-[(4-substituted)-1,2,3-triazol-1-yl]podophyllotoxin derivatives (17a-h) were firstly designed and synthesized with significant regioselectivity by employing Cu(I) catalyzed click approach, and evaluated for cytotoxicity against four human tumor cell lines (A-549, DU145, KB, and KBvin). Among them, compound 17h displayed the highest cytotoxic activity against the tumor cell lines tested. Significantly, compound 17h showed superior cytotoxic activity compared with etoposide (IC50 6.30 to>10 µM), a clinically available anticancer drug. Significant activity toward the drug resistant KBvin cell line revealed promising future for compound 17h as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidate.

17.
Bioorg Med Chem ; 22(1): 204-10, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24332656

RESUMO

Three series of novel sulfonylurea podophyllotoxin derivatives were designed, synthesized, and evaluated for in vitro cytotoxicity against four tumor cell lines (A-549, DU-145, KB and KBvin). Compounds 14c (IC50: 1.41-1.76 µM) and 14e (IC50: 1.72-2.01 µM) showed superior cytotoxic activity compared with etoposide (IC50: 2.03 to >20 µM), a clinically available anticancer drug. Significantly, most of the compounds exhibited comparable cytotoxicity against the drug-resistant tumor cell line KBvin, while etoposide lost activity completely. Preliminary structure-activity relationship (SAR) correlations indicated that the 4'-O-methyl functionality in podophyllotoxin analogues may be essential to maintain cytotoxic activity, while an arylsulfonylurea side chain at podophyllotoxin's 4ß position can significantly improve cytotoxic activity.


Assuntos
Podofilotoxina/síntese química , Compostos de Sulfonilureia/síntese química , Antineoplásicos , Linhagem Celular Tumoral , Humanos , Podofilotoxina/análogos & derivados , Podofilotoxina/química , Relação Estrutura-Atividade , Compostos de Sulfonilureia/química
18.
Med Chem Res ; 23(7): 3269-3273, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25722628

RESUMO

Chemotherapy is a general treatment option for various cancers, including lung cancer. In order to find compounds with superior bioactivity and less toxicity against lung cancer, novel spin-labeled 5-fluorouracil (5-FU) derivatives (3a-f) were synthesized and evaluated against four human tumor cell lines (A-549, DU-145, KB, and KBvin). Two promising compounds 3d and 3f exhibited IC50 values of 2.76 and 2.38 µM, respectively, against non-small cell lung carcinoma cell line A-549. These compounds were twofold more cytotoxic than 5-FU and less toxic against other tested cell lines. Compound 3f exhibited seven times more selective cytotoxicity against A-549 than 5-FU. Our results suggest that compounds 3d and 3f merit further investigation for development into clinical trial candidates for non-small cell lung cancer.

19.
Cell Immunol ; 274(1-2): 1-11, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22480874

RESUMO

CD59 is a complement regulatory protein known to prevent the membrane attack complex (MAC) from assembling. To investigate the role of CD59 molecules in human T cell activation in response to exogenous antigens, gene silencing via small interfering RNAs (siRNAs) was carried out. Subsequent T cell activation in response to both autologous dendritic cells (DCs) loaded with tumor lysate and beads coated with anti-CD3, anti-CD28 and anti-CD59 antibodies was investigated. The findings demonstrated that decreased CD59 expression on T cells significantly enhanced activation and proliferation of CD4(+) T cells and CD8(+) T cells while the expansion of CD4(+) CD25(+) regulatory T cells (Tregs) was not affected, and CD59 mediated inhibition of T cell activation requires the binding of CD59 with its ligand on antigen-presenting cells (APCs). The data support that CD59 down-regulates antigen-specific activation of human T lymphocytes in a ligand-dependent manner.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígenos CD59/genética , Antígenos CD59/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Neoplasias/imunologia , Interferência de RNA , Animais , Anticorpos Monoclonais/imunologia , Antígenos CD28/imunologia , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD59/biossíntese , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Células Dendríticas/metabolismo , Humanos , Ativação Linfocitária , Camundongos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
20.
Zhonghua Yu Fang Yi Xue Za Zhi ; 45(3): 205-10, 2011 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-21624230

RESUMO

OBJECTIVE: To study the epidemiological characteristics of respiratory virus infection and its relations to climatic factors in Suzhou. METHODS: From 2006 to 2009, viral etiology surveillance was conducted among 6655 children hospitalized with acute respiratory tract infections (ARIs). Direct immunofluorescence method was used to test respiratory secretion samples for respiratory syncytial virus (RSV), influenza viruses A and B (Inf-A, Inf-B), parainfluenza virus types I, II, and III (Pinf-I, Pinf-II, Pinf-III) and adenovirus. Samples were tested for human metapneumovirus (hMPV) with reverse transcription polymerase chain reaction (RT-PCR). Samples from Jan 2006 to Dec 2009 were also tested for human bocavirus (HBoV). Climatic factors, including mean temperature, relative humidity, rainfall amount, sum of sunshine and mean wind velocity were collected monthly. The relationship between activity of each virus and climatic factors were analyzed by linear regression and stepwise regression analysis. RESULTS: From 2006 to 2009, in the total virus detection rate was 32.2% (2142/6655) in Suzhou. RSV was the most common virus and the average detection rate was 15.7% (1048/6655), followed by hMPV 8.9% (596/6655), HBoV 7.8% (148/1883), Pinf-III 2.7% (183/6655), Inf-A 2.4% (161/6655), ADV 1.3% (89/6655), Pinf-I 0.4% (29/6655), Inf-B 0.37% (25/6655) and Pinf-II 0.16% (11/6655). The positive rates of RSV, hMPV and ADV were significantly different in four years (χ(2) = 17.71, 33.23, 8.42, all P values < 0.05). Different virus has different epidemiological characteristics and distinct seasonality. The detection rate of RSV, hMPV, Inf-A were higher in Winter as 37.2%, 13.2%, 4.4%, respectively. ADV and Pinf-III were higher in summer as 2.3% and 4.6% respectively. The peak of HBoV existed in Autumn as 3.3%. The total virus detection rate showed significant inverse correlation with month average temperature (r = -0.732, P < 0.001) and a weak inverse correlation with average wind velocity was also found (r = -0.36, 0.01 < P < 0.05). The highest month total virus detection rate was from 47.6% to 84.4% when average temperature was from 3.2°C to 9.4°C and mean wind velocity was from 1.2 - 1.9 m/s. The associations of average temperature, sum of sunshine and wind velocity with RSV activity were statistical significant (r = -0.88, P < 0.001; r = -0.43, P < 0.01; r = -0.47, P < 0.01). The highest rate was from 24.3% to 58.2%, when mean temperature was from 5.3°C to 19.9°C, mean wind velocity was from 1.3 - 2.4 m/s and sum of sunshine was 61.0 to 153.4 hours. hMPV detection rate was inversely correlated with mean temperature and rain account (r = -0.43, P < 0.01; r = -0.29, P < 0.05). The rate was highest from 11.7% to 31.6% when mean temperature was from 5.3°C to 21.9°C and rain account was from 27.5 millimeter to 150.9 millimeter. Only mean temperature was positively correlated with Pinf-III (r = 0.53, P < 0.001). The rate was from 2.8% to 7.2% when mean temperature was between 11.9°C and 30.4°C. ADV detection rate was positively correlated with mean temperature and sum of sunshine, but negatively correlated with wind velocity (r = 0.35, P < 0.05; r = 0.30, P < 0.05; r = -0.32, P < 0.05). The rate was from 2.2% to 6.6% when mean temperature was between 15.9°C and 30.4°C, and sum of sunshine between 93 hours to 240.7 hours and mean wind velocity was from 1.1 - 2.8 m/s. Average temperature and relative humidity showed interactions on the detection rate of ADV (r = 0.36, P = 0.0093; r = -0.34, P = 0.016), but temperature showed higher effect on ADV detection rate. ADV detection rate was high at higher temperature (15.9 - 30.4°C) and low humidity (56% - 71%). CONCLUSION: RSV was one of the most common viruses among hospitalized children in Suzhou, and hMPV and HBoV also played an important role in respiratory tract infection of children. Different virus has different cycle and seasonality. Climatic factors, especially mean temperature, was the main factor affecting the virus prevalence.


Assuntos
Criança Hospitalizada , Clima , Infecções por Vírus Respiratório Sincicial/epidemiologia , Criança , Pré-Escolar , China/epidemiologia , Feminino , Bocavirus Humano , Humanos , Lactente , Masculino , Metapneumovirus , Prevalência , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia
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