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1.
ISME J ; 17(10): 1564-1577, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37340074

RESUMO

Proteobacteria primarily utilize acyl-homoserine lactones (AHLs) as quorum-sensing signals for intra-/interspecies communication to control pathogen infections. Enzymatic degradation of AHL represents the major quorum-quenching mechanism that has been developed as a promising approach to prevent bacterial infections. Here we identified a novel quorum-quenching mechanism revealed by an effector of the type IVA secretion system (T4ASS) in bacterial interspecies competition. We found that the soil antifungal bacterium Lysobacter enzymogenes OH11 (OH11) could use T4ASS to deliver the effector protein Le1288 into the cytoplasm of another soil microbiome bacterium Pseudomonas fluorescens 2P24 (2P24). Le1288 did not degrade AHL, whereas its delivery to strain 2P24 significantly impaired AHL production through binding to the AHL synthase PcoI. Therefore, we defined Le1288 as LqqE1 (Lysobacter quorum-quenching effector 1). Formation of the LqqE1-PcoI complex enabled LqqE1 to block the ability of PcoI to recognize/bind S-adenosy-L-methionine, a substrate required for AHL synthesis. This LqqE1-triggered interspecies quorum-quenching in bacteria seemed to be of key ecological significance, as it conferred strain OH11 a better competitive advantage in killing strain 2P24 via cell-to-cell contact. This novel quorum-quenching also appeared to be adopted by other T4ASS-production bacteria. Our findings suggest a novel quorum-quenching that occurred naturally in bacterial interspecies interactions within the soil microbiome by effector translocation. Finally, we presented two case studies showing the application potential of LqqE1 to block AHL signaling in the human pathogen Pseudomonas aeruginosa and the plant pathogen Ralstonia solanacearum.


Assuntos
Pseudomonas fluorescens , Percepção de Quorum , Humanos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Pseudomonas/metabolismo , Pseudomonas aeruginosa/metabolismo , Acil-Butirolactonas/metabolismo
2.
J Dig Dis ; 24(2): 70-84, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37220999

RESUMO

With the development and generalization of endoscopic technology and screening, clinical application of magnetically controlled capsule gastroscopy (MCCG) has been increasing. In recent years, various types of MCCG are used globally. Therefore, establishing relevant guidelines on MCCG is of great significance. The current guidelines containing 23 statements were established based on clinical evidence and expert opinions, mainly focus on aspects including definition and diagnostic accuracy, application population, technical optimization, inspection process, and quality control of MCCG. The level of evidence and strength of recommendations were evaluated. The guidelines are expected to guide the standardized application and scientific innovation of MCCG for the reference of clinicians.


Assuntos
Gastroscopia , Humanos , Gastroscopia/métodos , Magnetismo
3.
Pest Manag Sci ; 79(10): 3666-3675, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37184259

RESUMO

BACKGROUND: Cruciferous black rot is caused by Xanthomonas campestris pv. campestris (Xcc) infection and is a widespread disease worldwide. Excessive and repeated use of bactericide is an important cause of the development of bacterial resistance. It is imperative to take new approaches to screening compounds that target virulence factors rather than kill bacterial pathogens. The type III secretion system (T3SS) invades a variety of cells by transporting virulence effector factors into the cytoplasm and is an attractive antitoxic target. Toward the search of new T3SS inhibitors, an alternative series of novel pyrimidin-4-one derivatives were designed and synthesized and assessed for their effect in blocking the virulence. RESULTS: All of the target compounds were characterized by proton (1 H) nuclear magnetic resonance (NMR), carbon-13 (13 C) NMR, fluorine-19 (19 F) NMR and high-resolution mass spectrometry (HRMS). All compounds were evaluated using high-throughput screening systems against Xcc. The results of the biological activity test revealed that the compound SPF-9 could highly inhibit the activity of xopN gene promoter and the hypersensitivity (HR) of tobacco without affecting bacterial growth. Moreover, messenger RNA (mRNA) level measurements showed that compound SPF-9 inhibited the expression of some representative genes (hrp/hrc genes). Compound SPF-9 weakened the pathogenicity of Xcc to Raphanus sativus L. CONCLUSION: Compound SPF-9 has good potential for further development as a novel T3SS inhibitor against Xcc. © 2023 Society of Chemical Industry.


Assuntos
Xanthomonas campestris , Xanthomonas campestris/genética , Xanthomonas campestris/metabolismo , Proteínas de Bactérias/genética , Sistemas de Secreção Tipo III/genética , Sistemas de Secreção Tipo III/metabolismo , Virulência/genética , Fatores de Virulência/metabolismo
4.
Orthop Surg ; 14(10): 2563-2570, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36056786

RESUMO

OBJECTIVE: To compare the clinical results of the direct anterior approach (DAA) and posterolateral approach (PLA) in total hip arthroplasty (THA) patients. METHODS: From January 2017 to September 2019, 80 patients who received primary THA in our hospital were retrospectively selected based on the propensity score matching (PSM) method. Baseline characteristics of patients who underwent the DAA and PLA were collected. Moreover, the incision length, intraoperative blood loss, operative time, length of stay, and Harris hip score were compared between patients in the two groups. The CK level was used to assess muscle damage between patients in the DAA and PLA groups. The complications of these two approaches were also evaluated at patients' 12-month follow-up evaluation. RESULTS: There was no significant difference in baseline characteristics between patients in the two groups (p > 0.05). The patients in the DAA group had a shorter incision length (9.2 ± 0.2 vs 14.7 ± 0.5, respectively; p < 0.05) and shorter length of hospital stay (9.5 ± 0.7 vs 12.9 ± 0.8, respectively, p < 0.05) than patients in the PLA group. Moreover, the DAA was associated with a decrease in intraoperative blood loss compared with the PLA (109.1 ± 12.6 vs 305.1 ± 14.1 ml, respectively, p < 0.05). However, the operation time was longer in patients in the DAA group (130.7 ± 1.7) than in patients in the PLA group (112.6 ± 1.3 min, p < 0.05). The CK level of patients in the DAA group was lower than that of patients in the PLA group (p < 0.05). The CK level at 48 h post-surgery was negatively correlated with the Harris hip scores at 6 months after THA (r = -0.538, p = 0.000). Compared with patients in the PLA group, the muscle strength of patients in the DAA group was significantly higher than that of patients in the DAA group at 4 days (p < 0.05) and 7 days (p < 0.05) after THA. The Harris hip scores of patients in the DAA group and PLA group were 81.0 ± 0.8 vs 70.8 ± 0.7 at 6 weeks, 93.4 ± 0.9 vs 86.4 ± 0.6 at 3 months, and 96.8 ± 1.1 vs 93.4 ± 0.8 at 6 months, respectively, both p < 0.05. There was no significant difference in the incidence of complications between patients in the DAA and PLA groups (p > 0.05). CONCLUSION: DAA was superior to the PLA in improving hip function after THA. Compared with the PLA, the DAA could reduce muscle damage, which is negatively correlated with hip function. Further multi-institution studies are required with longer follow-up durations, and larger patient populations are needed to provide more definitive conclusions.


Assuntos
Artroplastia de Quadril , Artroplastia de Quadril/métodos , Perda Sanguínea Cirúrgica , Humanos , Estudos Retrospectivos , Resultado do Tratamento
5.
World J Clin Cases ; 10(18): 5946-5956, 2022 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-35949828

RESUMO

Patients with varicose veins can be treated with conservative or surgical approaches based on the clinical conditions and patient preferences. In the recent decade, the recommendations for managing symptomatic varicose veins have changed dramatically due to the rise of minimally invasive endovascular techniques. The literature was systematically searched on Medline without language restrictions. All papers on the treatment of varicose veins and venous insufficiency with different procedures were included and reviewed. Endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) both are same safe and effective in terms of occlusion rate, and time to return to normal activity. In comparison with RFA or EVLT, Cure conservatrice et Hemodynamique de l'Insufficience Veineuse en Ambulatoire (CHIVA) may cause more bruising and make little or no difference to rates of limb infection, superficial vein thrombosis, nerve injury, or hematoma. In terms of recurrence of varicose veins, there is little or no difference between CHIVA and stripping, RFA, or EVLT. Great saphenous vein recanalization is highest in the ultrasound-guided foam sclerotherapy (FS) group (51%) during 1 year of follow-up. The 2013 National Institute for Health and Care Excellence clinical guidelines recommend surgery as a third-line therapeutic option after EVLA or RFA and sclerotherapy. Although the mechanochemical endovenous ablation (MOCA) is a non-thermal, non-tumescent option and appears to be of similar efficacy to stab avulsion with no potential risk of nerve damage, the overall success rate of MOCA is lower than those of other procedures such as EVLA, RFA, or high ligation and stripping. EVLA is the most cost-effective therapeutic option, with RFA being a close second for the treatment of patients with varicose veins. Endovenous thermal ablation (EVLA or RFA) is recommended as a first-line treatment for varicose veins and has substituted the high ligation of saphenofemoral junctional reflux and stripping of varicose veins. Ultrasound-guided FS is associated with a high recurrence rate and can be used in conjunction with other procedures. MOCA and cyanoacrylate embolization appear promising, but evidence of their effectiveness is required.

6.
iScience ; 25(6): 104471, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35712081

RESUMO

Reversing chemotherapy resistance in small cell lung cancer (SCLC) is crucial to improve patient prognosis. The present study aims to investigate the underlying mechanisms in SCLC chemoresistance. We see that nuclear receptor binding factor 2 (NRBF2) is a poor prognostic factor in SCLC. The effects of NRBF2 on chemoresistance were determined in SCLC. The underlying molecular mechanisms of NRBF2 in the autophagy process in SCLC were examined. NRBF2 positively regulated autophagy, leading to drug resistance in SCLC. The MIT domain of NRBF2 directly interacted with the PB1 domain of P62. This interaction increased autophagic P62 body formation, revealing the regulatory role of NRBF2 in autophagy. Notably, NRBF2 was directly modulated by the transcription factor XRCC6. The MIT domain of NRBF2 interacts with the PB1 domain of P62 to regulate the autophagy process, resulting in SCLC chemoresistance. NRBF2 is likely a useful chemotherapy response marker and therapeutic target in SCLC.

7.
Neoplasma ; 69(3): 538-549, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35188401

RESUMO

Gallbladder cancer is a malignant tumor with a high mortality rate. Accumulating evidence supports that lncRNA MEG3 may halt the progression of gallbladder cancer, while the downstream mechanism is rarely studied. Thus, we aim to investigate the molecular basis of the tumor-suppressing role of lncRNA MEG3 in gallbladder cancer. The expression of lncRNA MEG3 and CXCL3 was measured in patient serum and cell lines of gallbladder cancer. The viability, apoptosis, migration, and invasion of gallbladder cancer cells were assessed following ectopic MEG3 expression, as detected by CCK-8, flow cytometry, and Transwell assays. The interaction among lncRNA MEG3, EZH2, and CXCL3 was explored through ChIP, RNA pull-down, and RIP assays. The effects of lncRNA MEG3 and CXCL3 on tumor growth were evaluated by a mouse xenograft model. lncRNA MEG3 was expressed at a low level in gallbladder cancer patient serum and cell lines, while CXCL3 was highly expressed. MEG3 overexpression repressed the malignant behaviors of gallbladder cancer cells and promoted their apoptosis. MEG3 was mainly localized in the nucleus. MEG3 bound to EZH2, and EZH2 catalyzed the H3K27 trimethylation of the CXCL3 promoter region. MEG3 downregulated CXCL3 by activating EZH2-mediated H3K27 trimethylation of CXCL3; MEG3 overexpression attenuated cancer cell malignant behaviors in vitro and suppressed tumor growth in vivo in gallbladder cancer by inhibiting CXCL3 expression. Altogether, our results indicate that lncRNA MEG3 impedes gallbladder cancer development via the EZH2-CXCL3 axis, offering potential biomarkers for gallbladder cancer management.


Assuntos
Quimiocinas CXC , Proteína Potenciadora do Homólogo 2 de Zeste , Neoplasias da Vesícula Biliar , RNA Longo não Codificante , Animais , Apoptose/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Xenoenxertos , Humanos , Metilação , Camundongos , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
8.
Cell Death Differ ; 26(11): 2430-2446, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30824836

RESUMO

TAMM41, located within the congenital heart diseases (CHD) sensitive region of 3p25 deletion syndrome, is a mitochondrial membrane maintenance protein critical for yeast survival, but its function in higher vertebrates remains unknown. Via in vivo zebrafish model, we found that tamm41 is highly expressed in the developing heart and deficiency of which led to heart valve abnormalities. Molecular mechanistic studies revealed that TAMM41 interacts and modulates the PINK1-PARK2 dependent mitophagy pathway, thereby implicating TAMM41 in heart valve development during zebrafish embryonic cardiogenesis. Furthermore, through screening of the congenital heart diseases (CHD) sensitive region of 3p25 deletion syndrome among 118 sporadic atrioventricular septal defect (AVSD) patients, we identified three cases carrying heterozygous pathogenic intronic variants of TAMM41. All three cases lacked normal full-length TAMM41 transcripts, most likely due to specific expression of the mutant allele. Collectively, our studies highlight essential roles for TAMM41-dependent mitophagy in development of the heart and provide novel insights into the etiology of AVSD.


Assuntos
Valvas Cardíacas/embriologia , Mitocôndrias/metabolismo , Mitofagia/fisiologia , Nucleotidiltransferases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Adolescente , Animais , Animais Geneticamente Modificados , Diferenciação Celular , Linhagem Celular , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Proteínas Mitocondriais/metabolismo , Miócitos Cardíacos/patologia , Nucleotidiltransferases/genética , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , Adulto Jovem , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genética
9.
J Orthop Surg Res ; 13(1): 229, 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30189881

RESUMO

BACKGROUND: This meta-analysis aimed to evaluate the postoperative clinical outcomes and safety of the direct anterior approach (DAA) versus posterior approach (PA) in total hip arthroplasty (THA). METHODS: We searched PubMed, Embase, Web of Science, the Cochrane Library, and Google databases from inception to June 2018 to select studies that compared the DAA and PA for THA. Only randomized controlled trials (RCTs) were included. Outcomes included Harris hip score at 2 weeks, 6 weeks, 12 weeks, and 1 year; VAS at 24 h, 48 h, and 72 h; incision length, operation time, postoperative blood loss, length of hospital stay, and complications (intraoperative fracture, postoperative dislocation, heterotopic ossification (HO), and groin pain). RESULTS: Nine RCTs totaling 754 THAs (DAA group = 377, PA group = 377) met the criteria to be included in this meta-analysis. The present meta-analysis indicated that, compared with PA group, DAA group was associated with an increase of the Harris hip score at the 2-week and 4-week time points. No significant difference was found between DAA and PA groups of the Harris hip scores at 12 weeks, 1 year length of hospital stay (p > 0.05). DAA group was associated with a reduction of the VAS at 24 h, 48 h, and 72 h with statistical significance (p < 0.05). What is more, DAA was associated with a reduction of the incision length and postoperative blood loss (p < 0.05). There was no significant difference between the operation time and complications (intraoperative fracture, postoperative dislocation, HO, and groin pain). CONCLUSION: In THA patients, compared with PA, DAA was associated with an early functional recovery and less pain scores. What is more, DAA was associated with shorter incision length and blood loss.


Assuntos
Artroplastia de Quadril , Idoso , Artroplastia de Quadril/métodos , Feminino , Humanos , Tempo de Internação , Pessoa de Meia-Idade , Duração da Cirurgia , Complicações Pós-Operatórias , Período Pós-Operatório , Resultado do Tratamento
10.
Gene Expr Patterns ; 28: 34-41, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29454044

RESUMO

Transcriptional cofactor Vestigial-like 4 (VGLL4) was considered to take part in the early stage of development. Different from human, three paralogs of vgll4 were found in zebrafish, which were vgll4a, vgll4b and vgll4l. However, the expression patterns of the three paralogs during zebrafish development remains unknown. In this study, we used in situ hybridization to elucidate the temporal and spatial expression of zebrafish vgll4 paralogs during normal embryonic and larval development. Similar expression was shown in certain areas at similar stages for the three paralogs. Expression of vgll4a, vgll4b and vgll4l were all found in pectoral fins and otic vesicles during the early developmental stages. On the other hand, a few differences of the three paralogs expression were found in eyes, pharynx, pharyngeal arches and brain tissues. The expression of vgll4a was weak and ubiquitous, while vgll4b was obviously expressed in brain tissues and vgll4l was clearly restricted to each pair of pharyngeal pouches. What's more, vgll4b and vgll4l had unique expression at mature lateral line neuromasts and forerunner cells respectively. Despite the conservativeness of functional domains, the three paralogs of zebrafish vgll4 shared several similarities and displayed some distinctions in the expression patterns, indicating that they may still have different and exclusive functions, which need to be further explored.


Assuntos
Embrião não Mamífero/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Fatores de Transcrição/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Sequência de Aminoácidos , Animais , Embrião não Mamífero/citologia , Desenvolvimento Embrionário/genética , Hibridização In Situ , Homologia de Sequência , Peixe-Zebra/metabolismo
11.
Mol Neurobiol ; 55(1): 696-706, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-27995573

RESUMO

Abnormally hyperphosphorylated tau is the major protein constituent of neurofibrillary tangles (NFTs) in the brain of Alzheimer disease (AD) patients. Cell cycle reactivation is considered an important neuropathological feature of AD, and re-expression and activation of cell cycle regulators are known to occur in neurons containing NFTs. The aim of the present study was to investigate cell cycle reactivation during tau hyperphosphorylation in primary hippocampal neurons. We used forskolin, a specific activator of PKA, to induce tau hyperphosphorylation in cultured primary hippocampal neurons, and then measured levels of cyclin D1 and cyclin B1. We found that forskolin induced hyperphosphorylation of tau at Ser214, Ser396, and Ser202/Thr205 sites, attaining peak levels at 6, 12, and 12 h, respectively, while returning to normal levels at 24 h. Forskolin also induced a sustained cAMP elevation and PKA activation, which peaked at 6 h, in association with activation and overexpression of protein phosphatase-2A (PP-2A) at 24 h. The tau hyperphosphorylation was accompanied by increases in cyclin D1 and cyclin B1 levels; immunostaining showed overlapping distribution of hyperphosphorylated tau and cyclin D1 and cyclin B1 in primary hippocampal neurons. Forskolin induced hyperphosphorylation of tau and increased cyclin D1 and cyclin B1 protein levels in HEK293/tau441 cells, but not in the HEK293/vector cells, whereas the PKA inhibitor H89 inhibited the effects of forskolin on tau hyperphosphorylation and cyclin D1 and cyclin B1 protein levels. These findings suggest that forskolin induces tau hyperphosphorylation, which is itself necessary for the subsequent increases of cyclin D1 and cyclin B1 levels.


Assuntos
Ciclo Celular/efeitos dos fármacos , Colforsina/farmacologia , Hipocampo/citologia , Neurônios/citologia , Neurônios/metabolismo , Proteínas tau/metabolismo , Animais , Animais Recém-Nascidos , Células Cultivadas , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ciclina B1/metabolismo , Ciclina D1/metabolismo , Células HEK293 , Humanos , Isoquinolinas/farmacologia , Neurônios/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteína Fosfatase 2/metabolismo , Ratos Sprague-Dawley , Sulfonamidas/farmacologia
12.
World J Gastroenterol ; 22(19): 4707-15, 2016 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-27217702

RESUMO

AIM: To explore the feasibility and safety of laparoscopic colonic anastomosis using a degradable stent in a porcine model. METHODS: Twenty Bama mini-pigs were randomly assigned to a stent group (n = 10) and control group (hand-sewn anastomosis, n = 10). The anastomotic completion and operation times were recorded, along with histological examination, postoperative general condition, complications, mortality, bursting pressure, and the average anastomotic circumference (AC). RESULTS: All pigs survived postoperatively except for one in the stent group that died from ileus at 11 wk postoperatively. The operation and anastomotic completion times of the stent group were significantly shorter than those of the control group (P = 0.004 and P = 0.001, respectively). There were no significant differences in bursting pressure between the groups (P = 0.751). No obvious difference was found between the AC and normal circumference in the stent group, but AC was significantly less than normal circumference in the control group (P = 0.047, P < 0.05). No intestinal leakage and luminal stenosis occurred in the stent group. Histological examination revealed that the stent group presented with lower general inflammation and better healing. CONCLUSION: Laparoscopic colonic anastomosis with a degradable stent is a simple, rapid, and safe procedure in this porcine model.


Assuntos
Implantes Absorvíveis , Colo/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório/instrumentação , Laparoscopia/instrumentação , Stents , Anastomose Cirúrgica , Animais , Colo/patologia , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Estudos de Viabilidade , Feminino , Laparoscopia/efeitos adversos , Masculino , Modelos Animais , Duração da Cirurgia , Complicações Pós-Operatórias/etiologia , Desenho de Prótese , Suínos , Porco Miniatura , Fatores de Tempo , Cicatrização
14.
World J Gastroenterol ; 20(31): 10886-94, 2014 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-25152590

RESUMO

AIM: To investigate whether cold water intake into the stomach affects colonic motility and the involvement of the oxytocin-oxytocin receptor pathway in rats. METHODS: Female Sprague Dawley rats were used and some of them were ovariectomized. The rats were subjected to gastric instillation with cold (0-4 °C, cold group) or room temperature (20-25 °C, control group) saline for 14 consecutive days. Colon transit was determined with a bead inserted into the colon. Colonic longitudinal muscle strips were prepared to investigate the response to oxytocin in vitro. Plasma concentration of oxytocin was detected by ELISA. Oxytocin receptor expression was investigated by Western blot analysis. Immunohistochemistry was used to locate oxytocin receptors. RESULTS: Colon transit was slower in the cold group than in the control group (P < 0.05). Colonic smooth muscle contractile response to oxytocin decreased, and the inhibitory effect of oxytocin on muscle contractility was enhanced by cold water intake (0.69 ± 0.08 vs 0.88 ± 0.16, P < 0.05). Atosiban and tetrodotoxin inhibited the effect of oxytocin on colonic motility. Oxytocin receptors were located in the myenteric plexus, and their expression was up-regulated in the cold group (P < 0.05). Cold water intake increased blood concentration of oxytocin, but this effect was attenuated in ovariectomized rats (286.99 ± 83.72 pg/mL vs 100.56 ± 92.71 pg/mL, P < 0.05). However, in ovariectomized rats, estradiol treatment increased blood oxytocin, and the response of colonic muscle strips to oxytocin was attenuated. CONCLUSION: Cold water intake inhibits colonic motility partially through oxytocin-oxytocin receptor signaling in the myenteric nervous system pathway, which is estrogen dependent.


Assuntos
Temperatura Baixa , Colo/inervação , Motilidade Gastrointestinal/efeitos dos fármacos , Músculo Liso/inervação , Plexo Mientérico/efeitos dos fármacos , Ocitocina/farmacologia , Receptores de Ocitocina/agonistas , Estresse Psicológico/tratamento farmacológico , Água , Animais , Relação Dose-Resposta a Droga , Ingestão de Líquidos , Estradiol/farmacologia , Terapia de Reposição de Estrogênios , Feminino , Antagonistas de Hormônios/farmacologia , Plexo Mientérico/metabolismo , Plexo Mientérico/fisiopatologia , Ovariectomia , Ocitocina/sangue , Ratos Sprague-Dawley , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/sangue , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Fatores de Tempo
16.
Bioorg Med Chem ; 21(2): 448-55, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23245802

RESUMO

A series of novel thiazolyl-pyrazoline derivatives containing benzodioxole (C1-C20) have been designed and synthesized. Among of the synthesized compounds, 2-(5-(benzo[d][1,3]dioxol-5-yl)-3-(4-bromophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-(4-bromophenyl)thiazole (C6) displayed the most potent inhibitory activity for HER-2 (IC(50) = 0.18 µM for HER-2). Antiproliferative assay results indicated that compound C6 owned high antiproliferative activity against MCF-7 and B16-F10 in vitro, with IC(50) value of 0.09 and 0.12 µM, respectively, being comparable with the positive control Erlotinib. Docking simulation was further performed to determine the probable binding model. Based on the preliminary results, compound C6 with potent inhibitory activity in tumor growth would be a potential anticancer agent.


Assuntos
Antineoplásicos/síntese química , Benzodioxóis/química , Pirazóis/química , Tiazóis/química , Antineoplásicos/química , Antineoplásicos/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/toxicidade , Estrutura Terciária de Proteína , Pirazóis/síntese química , Pirazóis/toxicidade , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade
17.
Bioorg Med Chem ; 20(6): 2010-8, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22361272

RESUMO

A series of pyrazolyl-thiazolinone derivatives (E1-E36) have been designed and synthesized and their biological activities were also evaluated as potential EGFR and HER-2 kinase inhibitors. Thirty-four of the 36 compounds were reported for the first time. Among them, compound 2-(5-(4-bromophenyl)-3-p-tolyl-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (E28) displayed the most potent inhibitory activity (IC(50)=0.24µM for EGFR and IC(50)=1.07µM for HER-2). Antiproliferative assay results indicated that compound E28 owned high antiproliferative activity against MCF-7, B16-F10 and HCT-116 in vitro, with IC(50) value of 0.30, 0.54, and 0.70µM, respectively. Docking simulation was further performed to position compound E28 into the EGFR active site to determine the probable binding model. Based on the preliminary results, compound E28 with potent inhibitory activity in tumor growth would be a potential anticancer agent.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Receptor ErbB-2/metabolismo
18.
J Alzheimers Dis ; 21(1): 167-79, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20413892

RESUMO

The formation of neurofibrillary tangles, mainly composed of hyperphosphorylated tau protein, is a hallmark in the brain of human tauopathies, including Alzheimer's disease (AD). Although neurons bearing neurofibrillary tangles are constantly exposed to various apoptotic stimuli, they do not appear to preferentially die by apoptosis. The underlying mechanism for such resistance to apoptosis remains elusive. Previously, we studied the role of tau phosphorylation in apoptosis and found that tau hyperphosphorylation by glycogen synthase kinase-3 (GSK-3) rendered cells more resistant to apoptosis. In this study, we show that the overexpression of tau without any exogenous activation of kinases also confers increased resistance to apoptosis in both N2a cells and in a tau transgenic mouse model. Mechanistically, the overexpression of tau was associated with a reduced p53 level, decreased release of cytochrome C from mitochondria, and inhibition of caspases-9/-3. Additionally, a decreased phosphorylation and increased nuclear translocation of beta-catenin were also detected in N2a/tau cells, and knockdown of beta-catenin eliminated the anti-apoptotic effect of tau. Furthermore, tau was spontaneously hyperphosphorylated upon overexpression and by staurosporine treatment. The phosphorylation level of p53 decreased upon tau overexpression, and a more profound reduction of the phosphorylated p53 was detected when the cells were treated with lithium and roscovitine, inhibitors of GSK-3 and cyclin-dependent kinase-5 (Cdk-5). These results suggest that the overexpression of tau, which may be hyperphosphorylated by endogenous GSK-3 and Cdk-5, is anti-apoptotic by mechanisms involving modulation of multiple anti-apoptotic factors, including beta-catenin and p53-mitochondria-caspase-mediated apoptotic pathways.


Assuntos
Apoptose/fisiologia , Citocromos c/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Quinase 3 da Glicogênio Sintase/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas tau/metabolismo , Animais , Anexina A5/metabolismo , Apoptose/efeitos dos fármacos , Camptotecina/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/efeitos adversos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Maitansina/análogos & derivados , Maitansina/metabolismo , Camundongos , Camundongos Transgênicos , Mutação/genética , Neuroblastoma/patologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Estaurosporina/efeitos adversos , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo , Fatores de Tempo , Transfecção/métodos , beta Catenina/metabolismo , Proteínas tau/genética
19.
J Alzheimers Dis ; 19(3): 953-62, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20157251

RESUMO

Phosphorylation of tau, a major microtubule-associated protein, has been recently discovered to affect cell apoptosis. While the phosphorylation of tau is dynamically regulated, the role of tau dephosphorylation in cell viability is elusive. Here, we observed that the cells bearing high level of the dephosphorylated tau at Tau-1 epitope were more vulnerable to the apoptosis induced by staurosporine, camptothecin, and hydrogen peroxide, though the general outcome of tau expression was still anti-apoptotic. Further studies demonstrate that co-expression of tau and protein phosphatase 2A catalytic subunit (PP2Ac), the most active tau phosphatase, potentiates cell apoptosis with a correlatively increased dephosphorylation of tau and phosphorylation of Bcl-2 at Ser87 (pS87-Bcl2, the inactive form of the anti-apoptotic factor), whereas expression of PP2Ac alone in the absence of tau decreases the levels of pS87-Bcl2 and cleaved PARP, markers of early apoptosis. Finally, both tau and Bcl-2 were co-immunoprecipitated with PP2Ac, but the binding level of Bcl-2 with PP2Ac decreased prominently when tau was co-expressed. These data suggest that tau dephosphorylation by PP2Ac facilitates cell apoptosis with the mechanisms involving a failed dephosphorylation/activation of Bcl-2.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Apoptose/fisiologia , Genes bcl-2/genética , Fosforilação/fisiologia , Proteínas tau/fisiologia , Animais , Anticorpos Monoclonais , Western Blotting , Linhagem Celular Tumoral , Modelos Animais de Doenças , Hipocampo/patologia , Humanos , Imunoprecipitação , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Neuroblastoma/patologia , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/genética
20.
Zhonghua Wai Ke Za Zhi ; 47(1): 48-50, 2009 Jan 01.
Artigo em Chinês | MEDLINE | ID: mdl-19484951

RESUMO

OBJECTIVE: To compare multiple organ dysfunction score (MODS), the sequential organ failure assessment (SOFA) and the logistic organ dysfunction score (LODS) in predicting hospital mortality in severe sepsis. METHODS: Four hundred and three patients admitted to the ICU from December 2004 to November 2007 with a diagnosis of severe sepsis were enrolled in this study. Their MODS, SOFA, LODS and Acute Physiology and Chronic Health Evaluation (APACHE) II at admission and the highest score during hospitalization were respectively recorded and collected in regard to mortality. The discrimination of three multiple organ dysfunction score systems were assessed by the areas under the receiver operating characteristic curves (AUC). RESULTS: The AUC of admission scores was 0.811 for LODS, 0.787 for SOFA, 0.725 for MODS, and 0.770 for APACHE II in predicting hospital mortality. All maximum scores had better power of discrimination than the admission scores (P < 0.01). The power of discrimination of LODS and SOFA were better than the MODS, either the admission or the highest, respectively (P < 0.01). However, no significant difference was observed between the LODS and the SOFA regarding mortality prediction (P > 0.05). The AUC value for the APACHE II score was much lower compared to LODS (P < 0.01). However, there was no difference in AUC value among APACHE II, SOFA and MODS (P > 0.05). CONCLUSION: LODS, SOFA and MODS show a good discrimination power, while maximum LODS is of the highest discrimination power to predict the outcome of patient with severe sepsis.


Assuntos
Unidades de Terapia Intensiva , Sepse/mortalidade , Índice de Gravidade de Doença , APACHE , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/patologia , Prognóstico
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