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The penetration ability of visible light (<2 mm) and near-infrared (NIR) light (â¼1 cm) remarkably impairs the therapeutic efficacy and clinical applications of photodynamic therapy (PDT). To address the limitation of light penetration depth, a novel self-luminescent bacterium, teLuc.FP-EcN, has been engineered through transfection of a fusion expression plasmid containing the luciferase gene teLuc and bright red fluorescent protein mScarlet-I into Escherichia coli Nissle 1917 (EcN). The engineered teLuc.FP-EcN can specifically target and colonize tumors without significant toxicity to the host. Acting as a continuous internal light source, teLuc.FP-EcN can activate the photosensitizer chlorin e6 (Ce6) to generate reactive oxygen species (ROS) and then effectively destroy tumor tissue from the inside. As a result, a significant reduction in tumor proliferation and extension of the overall survival in mouse tumor models has been observed. Furthermore, teLuc.FP-EcN-boosted PDT amplified its therapeutic effect by activating antitumor immune response, including the conversion of M2 macrophages into pro-inflammatory M1 macrophages, as well as an increase in the proportion of CD3+ T cells and a decrease in T-cell exhaustion. In conclusion, teLuc.FP-EcN can be used as an implantable light source for tumor phototherapy, which simultaneously possesses ROS generation and immune regulation.
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Neoplasias da Mama , Fotoquimioterapia , Fármacos Fotossensibilizantes , Fotoquimioterapia/métodos , Animais , Feminino , Camundongos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Humanos , Espécies Reativas de Oxigênio/metabolismo , Clorofilídeos , Camundongos Endogâmicos BALB C , Porfirinas/química , Porfirinas/farmacologia , Porfirinas/uso terapêutico , Linhagem Celular Tumoral , Escherichia coli/efeitos dos fármacosRESUMO
BACKGROUND/AIMS: Cardiac fibrosis after myocardial infarction (MI) has been identified as a key factor in the development of heart failure, but the mechanisms undelying cardiac fibrosis remained unknown. microRNAs (miRNAs) are novel mechanisms leading to fibrotic diseases, including cardiac fibrosis. Previous studies revealed that miR-22 might be a potential target. However, the roles and mechanisms of miR-22 in cardiac fibrosis remained ill defined. The present study thus addressed the impact of miR-22 in cardiac fibrosis. METHODS: After seven days following coronary artery occlusion in mice, tissues used for histology were collected and processed for Masson's Trichrome staining. In addition, cardiac fibroblasts were transfected with mimics and inhibitors of miR-22 using Lipofectamin 2000, and luciferase activity was measured in cell lysates using a luciferase assay kit. Western blotting was used to detect the expression of collagen1, α-SMA and TGFßRI proteins levels, and real time-PCR was employed to measure the Col1α1, Col3α1, miR-22 and TGFßRI mRNA levels. RESULTS: In this study, we found that miR-22 was dynamically downregulated following MI induced by permanent ligation of the left anterior descending coronary artery for 7 days, an effect paralleled by significant collagen deposition. Inhibition of miR-22 with AMO-22 resulted in increased expression of Col1α1, Col3α1 and fibrogenesis in cultured cardiac fibroblasts. Conversely, overexpression of miR-22 in cultured cardiac fibroblasts significantly abrogated angiotensin II-induced collagen formation and fibrogenesis. Furthermore, we found that TGFßRI is a direct target for miR-22, and downregulation of TGFßR may have mediated the antifibrotic effect of miR-22. CONCLUSION: Our data clearly demonstrate that miR-22 acts as a novel negative regulator of angiotensin II-induced cardiac fibrosis by suppressing the expression of TGFßRI in the heart and may represent a new potential therapeutic target for treating cardiac fibrosis.
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Fibroblastos/metabolismo , Fibroblastos/patologia , MicroRNAs/metabolismo , Miocárdio/patologia , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Angiotensina II/farmacologia , Animais , Sequência de Bases , Células Cultivadas , Colágeno/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Fibrose , Inativação Gênica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Ratos Sprague-Dawley , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismoRESUMO
OBJECTIVE: To study the chemical constituents from the rhizome of Valeriana jatamansi. METHODS: The chemical constituents were separated and purified by silica gel, medium pressure column chromatography, and preparative HPLC. Their structures were determined by physicochemical properties and spectral data. RESULTS: Six compounds were isolated from the dibromochloromethane extract in the rhizome of Valeriana jatamansi, and identified as decursidin (1), decursitin B (2), decursitin A (3), 3'(S)-acetoxy-4'(R)-angeloyloxy-3',4'-dihydroxanthyletin (4), 8-acetoxyl-pathchouli alcohol (5) and dibutyl phthalate (6). CONCLUSION: Compounds 1-4 are coumarins which are isolated from this genus for the first time,and compound 6 is isolated from this genus for the first time.
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Compostos Fitoquímicos/análise , Rizoma/química , Valeriana/química , Cromatografia Líquida de Alta Pressão , Cumarínicos/análise , Nardostachys/químicaRESUMO
AIM: To review and evaluate the efficacy of kidney-tonifying traditional Chinese medicine prescriptions (KT-TCMP) in hypoplastic uterus (HU) treatment. METHODS: We searched MEDLINE, the Cochrane Library, CNKI (China National Knowledge Infrastructure), WANFANG and VIP databases until 14 December 2013 independently with two investigators. Randomized controlled trials (RCT) involving KT-TCMP as a combined or monotherapy in the treatment of HU were reviewed and analyzed. Meta-analysis was performed by Review Manager (version 5.2). RESULTS: Nine RCT of 1745 patients were eligible for this review and meta-analysis, of which eight RCT described the primary outcome of clinical efficacy and three RCT drew the secondary outcome of uterine size. Meta-analyzed 'recovery' clinical efficacy of KT-TCMP in seven RCT was conducted which considered diethylstilbestrol therapy alone as control, as well as three RCT that meta-analyzed the effect of KT-TCMP on uterine diameter enlargement. As a result, KT-TCMP therapy had a significantly improved difference in increasing 'recovery' clinical efficacy (risk ratio, 2.34; 95% confidence interval [CI], 1.90-2.89) and enlarging the uterine diameter (standardized mean difference, 1.62; 95% CI, 1.39-1.84). One study reported adverse reactions as an important outcome and found it was safe during KT-TCMP therapy. CONCLUSION: The therapy of applying KT-TCMP as a combined or monotherapy in the treatment of HU may be more efficacious. However, these RCT were of moderate methodological quality and small sample size; thus, the results should be confirmed with more rigorously controlled further studies.
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Transtornos do Desenvolvimento Sexual/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Fitoterapia , Doenças Uterinas/tratamento farmacológico , Útero/efeitos dos fármacos , Transtornos do Desenvolvimento Sexual/patologia , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Humanos , Tamanho do Órgão/efeitos dos fármacos , Fitoterapia/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Doenças Uterinas/congênito , Doenças Uterinas/patologia , Útero/anormalidades , Útero/patologiaRESUMO
Purpose: The increasing multi-drug resistance (MDR) is a serious threat to human health. The appropriate use of antibiotics can control the progression of MDR and clinical pharmacists play an important role in the rational use of antibiotics. There are many factors that influence the effectiveness of multi-drug resistant organisms (MDRO) infection consultations. The study aimed to establish a model to predict the outcome of consultation and explore ways to improve clinical pharmacy services. Patients and methods: Patients diagnosed with MDRO infection and consulted by clinical pharmacists were included. Univariate analysis and multivariate logistic regression analysis were used to identify independent risk factors for MDRO infection consultation effectiveness, and then a nomogram was constructed and validated. Results: 198 patients were finally included. The number of underlying diseases (OR=1.720, 95% CI: 1.260-2.348), whether surgery was performed prior to infection (OR=8.853, 95% CI: 2.668-29.373), ALB level (OR=0.885, 95% CI: 0.805~0.974), pharmacist title (OR=3.463, 95% CI: 1.277~9.396) and whether the recommendation was taken up (OR=0.117, 95% CI: 0.030~0.462) were identified as independent influences on the effectiveness of the consultation. The nomogram prediction model was successfully constructed and the AUC of the training set and the verification set were 0.849 (95% CI: 0.780-0.917) and 0.761 (95% CI: 0.616-0.907) respectively. The calibration curves exhibited good overlap between the data predicted by the model and the actual data. Conclusion: A nomogram model was developed to predict the risk of consultation failure and was shown to be good accuracy and good prediction efficiency, which can provide proactive interventions to improve outcomes for potentially treatment ineffective patients.
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Annonaceous acetogenins (ACGs) have potent anti-tumor activity, and the problems of their low solubility, hemolysis, and in vivo delivery have been solved by encapsulation into nanoparticles. However, the high toxicity still limits their application in clinic. In this paper, the co-delivery strategy was tried to enhance the in vivo anti-tumor efficacy and reduce the toxic effects of ACGs. Ginsenoside Rh2, a naturally derived biologically active compound, which was reported to have synergistic effect with paclitaxel, was selected to co-deliver with ACGs. And due to its similarity with cholesterol in chemical structure, the co-loading liposomes, (ACGs + Rh2)-Lipo, were successfully constructed using Rh2 instead of cholesterol as the membrane material. The obtained (ACGs + Rh2)-Lipo and ACGs-Lipo had similar mean particle size (about 80 nm), similar encapsulation efficiency (EE, about 97%) and good stability. The MTS assay indicated that (ACGs + Rh2)-Lipo had stronger toxicity in vitro. In the in vivo study, in contrast to ACGs-Lipo, (ACGs + Rh2)-Lipo demonstrated an improved tumor targetability (3.3-fold in relative tumor targeting index) and significantly enhanced the antitumor efficacy (tumor inhibition rate, 72.9 ± 5.4% vs. 60.5 ± 5.4%, p < .05). The body weight change, liver index, and spleen index of tumor-bearing mice showed that Rh2 can attenuate the side effects of ACGs themselves. In conclusion, (ACGs + Rh2)-Lipo not only alleviated the toxicity of ACGs to the organism, but also enhanced their anti-tumor activity, which is expected to break through their bottleneck.
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Acetogeninas , Ginsenosídeos , Glioma , Camundongos , Animais , Acetogeninas/farmacologia , Acetogeninas/química , Lipossomos , Glioma/tratamento farmacológico , ColesterolRESUMO
Objectives: This study aims to characterize the population pharmacokinetics of polymyxin B in lung transplant recipients and optimize its dosage regimens. Patients and methods: This prospective study involved carbapenem-resistant organisms-infected patients treated with polymyxin B. The population pharmacokinetic model was developed using the NONMEM program. The clinical outcomes including clinical treatment efficacy, microbiological efficacy, nephrotoxicity, and hyperpigmentation were assessed. Monte Carlo simulation was performed to calculate the probability of target attainment in patients with normal or decreased renal function. Results: A total of 34 hospitalized adult patients were included. 29 (85.29%) patients were considered of clinical cure or improvement; 14 (41.18%) patients had successful bacteria elimination at the end of the treatment. Meanwhile, 5 (14.71%) patients developed polymyxin B-induced nephrotoxicity; 19 (55.88%) patients developed skin hyperpigmentation. A total of 164 concentrations with a range of 0.56-11.66 mg/L were obtained for pharmacokinetic modeling. The pharmacokinetic characteristic of polymyxin B was well described by a 1-compartment model with linear elimination, and only creatinine clearance was identified as a covariate on the clearance of polymyxin B. Monte Carlo simulations indicated an adjusted dosage regimen might be needed in patients with renal insufficiency and the currently recommended dose regimens by the label sheet of polymyxin B may likely generate a subtherapeutic exposure for MIC = 2 mg/L. Conclusion: Renal function has a significant effect on the clearance of polymyxin B in lung transplant recipients, and an adjustment of dosage was needed in patients with renal impairments.
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BACKGROUND: Germline mutations play an important role in the pathogenesis of lung cancer. Nonetheless, research on malignant ground glass opacity (GGO) nodules is limited. METHODS: A total of 13 participants with malignant GGO nodules were recruited in this study. Peripheral blood was used for exome sequencing, and germline mutations were analyzed using InterVar. The whole exome sequencing dataset was analyzed using a filtering strategy. KOBAS 3.0 was used to analyze KEGG pathway to further identify possible deleterious mutations. RESULTS: There were seven potentially deleterious germline mutations. NM_001184790:exon8: c.C1070T in PARD3, NM_001170721:exon4:c.C392T in BCAR1 and NM_001127221:exon46: c.G6587A in CACNA1A were present in three cases each; rs756875895 frameshift in MAX, NM_005732: exon13:c.2165_2166insT in RAD50 and NM_001142316:exon2:c.G203C in LMO2, were present in two cases each; one variant was present in NOTCH3. CONCLUSIONS: Our results expand the germline mutation spectrum in malignant GGO nodules. Importantly, these findings will potentially help screen the high-risk population, guide their health management, and contribute to their clinical treatment and determination of prognosis.
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BACKGROUND: Valtrate is a novel epoxy iridoid ester isolated from Chinese herbal medicine Valeriana jatamansi Jones with anti-proliferative activity against various human cancer cell lines. However, its efficacy and molecular mechanisms against pancreatic cancer (PC) cells are largely unclear. PURPOSE: To investigate the anti-cancer effects of valtrate on PC cell lines and its underlying mechanisms. METHODS: MTT assay was first performed to detect the effect of valtrate on cell viability in human PC cell lines and normal pancreatic epithelial cells HPDE. Cell apoptosis and cycle phase assay were detected by flow cytometry. The relative mRNA expressions of Bax, Bcl-2, c-Myc, and CyclinB1 were tested by quantitative PCR (qPCR) assay. The expression of relative proteins was detected by Western blotting (WB). A PANC-1luc cells xenograft mouse model in nu/nu female mice was used to elucidate the effect of valtrate on tumor growth in vivo. RESULTS: Valtrate significantly inhibited the growth of PC cells without affecting the growth of normal pancreatic epithelial cells HPDE, induced significant apoptosis and cell cycle arrest in G2/M phase. Moreover, valtrate inhibited the tumor growth of PC cell PANC-1 in xenograft mice by 61%. Further mechanism study demonstrated that valtrate could increase the expression level of Bax, suppress Bcl-2 as well as c-Myc and Cyclin B1, inhibit the transcriptional activity of Stat3, while valtrate decreased the expression level of Stat3 and phosphated-Stat3 (Tyr705) and induced the high molecular aggregation of Stat3. Molecular docking analysis predicted that valtrate might interact with Cys712 of Stat3 protein. Valtrate could also induce a transient depleted intracellular glutathione (GSH) level and increased reactive oxygen species (ROS). NAC (N-acetylcysteine), a reducer reversed valtrate-induced the depletion of Stat3, p-Stat3, c-Myc, and Cyclin B1. CONCLUSION: Valtrate exerts anti-cancer activity against PC cells by directly targeting Stat3 through a covalent linkage to inhibit Stat3 activity, which causes apoptosis and cell cycle arrest.
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Iridoides/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina B1/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Valeriana/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: Inflammation-driven markers play a crucial role in tumorigenesis and tumor progression. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in blood are systemic inflammatory response markers. Some reports have showed that NLR and PLR are related to a poor prognosis in patients with lung cancer. However, little studies have reported whether NLR and PLR can be diagnostic markers for lung cancer. The aim of the current study is to investigate the roles of NLR and PLR in diagnosing lung cancer. METHODS: This study analyzed data from lung cancer patients and healthy individuals in Wuxi People's Hospital Affiliated with Nanjing Medical University. The Mann-Whitney U test was performed to compare differences between the lung cancer group and the control group. Based on white blood cell (WBC) counts, both lung cancer patients and healthy individuals were divided into the low-level group, moderate-level group, and high-level group. The Kruskal-Wallis test was applied to compare differences of NLR and PLR among those groups with different WBC counts. Spearman correlation analysis was used to assess correlations. Receiver operating characteristic (ROC) curves were performed to determine diagnostic accuracy. RESULTS: 210 patients diagnosed with lung cancer and 261 healthy subjects were enrolled in this study. Levels of NLR and PLR increased in the lung cancer group compared with the control group (P < 0.001). For the lung cancer group, NLR levels could rise with the increasing of WBC levels (P < 0.001) while PLR levels had no significant variation with the increasing of WBC levels (P = 0.206). For the control group, NLR levels could rise with the increasing of WBC levels (P < 0.001) while PLR levels would decline with the increasing of WBC levels (P < 0.001). In the lung cancer group, both NLR and PLR had no significant correlations with aspartate transaminase, urea, and glucose. The area under the curve (AUC) with 95% confidence interval (95% CI) of NLR and PLR to distinguish lung cancer patients from healthy subjects was, respectively, 0.684 (0.634-0.735) and 0.623 (0.571-0.674). When NLR and PLR were combined, AUC (95% CI) increased to 0.691 (0.642-0.740). CONCLUSIONS: NLR and PLR alone have moderate ability to distinguish lung cancer patients from healthy subjects. Furthermore, combination forms of NLR and PLR can improve diagnostic ability.
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Contagem de Leucócitos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Neutrófilos , Contagem de Plaquetas , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-IdadeRESUMO
We aimed to (i) develop a population pharmacokinetic model of tacrolimus in Chinese lung transplant recipients and (ii) propose model-based dosing regimens for individualized treatment. We obtained 807 tacrolimus steady-state whole blood concentrations from 52 lung transplant patients and genotyped CYP3A5*3. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Monte Carlo simulations were employed to determine the initial dosing regimens. Tacrolimus pharmacokinetics was described by a one-compartment model with first-order absorption and elimination processes. In CYP3A5*3/*3 70-kg patients with 30% hematocrit and voriconazole-free therapy, the mean estimated apparent clearance was 13.1 l h-1 with 20.1% between-subject variability, which was lower than that in Caucasian lung transplant patients (17.5-36.5 l h-1). Hematocrit, postoperative days, tacrolimus daily dose, voriconazole concomitant therapy, and CYP3A5*3 genotype were identified as significant covariates for tacrolimus clearance. To achieve target trough concentration (10-15 ng ml-1) on the 8th day post-transplant, a higher initial dosage than the current regimen of 0.04 mg kg-1 every 12 h is recommended for CYP3A5*1/*3 patients without voriconazole concomitant therapy. Given the nonlinear kinetics of tacrolimus and large variability, population pharmacokinetic model should be combined with therapeutic drug monitoring to optimize individualized therapy.
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Transplante de Rim , Tacrolimo , China , Citocromo P-450 CYP3A/genética , Genótipo , Humanos , Imunossupressores , Pulmão , Modelos Biológicos , TransplantadosRESUMO
BACKGROUND: Glucagon-like peptide 1 receptor (GLP-1R) is an important biomarker for diagnosis and therapy of the endocrine cancers due to overexpression. Recently, in human prostate cancer cell lines the receptor was also observed, therefore it may be a potential target for the disease. 18F-Al-NOTA-MAL-Cys39- exendin-4 holds great promise for GLP-1R. Therefore, the feasibility of the 18F-labeled exendin-4 analog for prostate cancer imaging was investigated. METHODS: New probe 18F-Al-NOTA-MAL-Cys39-exendin-4 was made through one-step fluorination. Prostate cancer PC3 cell xenograft model mice were established to primarily evaluate the imaging properties of the tracer via small animal PET studies in vivo. Pathological studies and Western Blots were also performed. RESULTS: PC-3 prostate xenografts were clearly imaged under baseline conditions. At 30 and 60 min postinjection, the tumor uptakes were 2.90±0.41%ID/g and 2.26±0.32 %ID/g respectively. The presence of cys39-exendin-4 significantly reduced the tumor uptake to 0.82±0.10 %ID/g at 60 min p.i. Findings of ex vivo biodistribution studies were similar to those of in vivo PET imaging. The tumors to blood and muscles were significantly improved with the increase of time due to rapid clearance of the tracer from normal organs. Low levels of radioactivity were also detected in the GLP-1R positive tumor and normal organs after coinjection with excessive unlabeled peptides. Immunohistochemistry and Western Blots results confirmed that GLP-1R was widely expressed in PC-3 prostate cancers. CONCLUSION: 18F-Al labeled exendin-4 analog might be a promising tracer for in vivo detecting GLP-1R positive prostate cancer with the advantage of facile synthesis and favorable pharmacokinetics. It may be useful in differential diagnosis, molecularly targeted therapy and prognosis of the cancers.
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Exenatida/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/diagnóstico por imagem , Animais , Exenatida/farmacocinética , Xenoenxertos , Humanos , Ligantes , Masculino , Camundongos , Neoplasias da Próstata/metabolismo , Distribuição TecidualRESUMO
Myasthenia gravis (MG) is an acquired autoimmune disease affecting the postsynaptic membrane of neuromuscular junctions and characterized by antibody-mediated T cell dependence and complement involvement. Cholinesterase inhibitors (e.g., pyridostigmine bromide), glucocorticoids, and azathioprine are currently recommended as first-line treatments for MG, though they have limitations, including potential toxicity and ineffectiveness in patients with refractory MG. In recent years, owing to an increasing understanding of MG pathogenesis the development and execution of clinical trials with novel biologics, including monoclonal antibodies (mAbs) that have demonstrated higher safety and more specificity, provide new opportunities for the treatment of MG. In this article, we review recent advances in MG pathogenesis and the mAbs that have been used for target-specific MG therapy.
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Anticorpos Monoclonais/uso terapêutico , Imunoterapia/métodos , Miastenia Gravis/tratamento farmacológico , Azatioprina/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Miastenia Gravis/imunologia , Brometo de Piridostigmina/uso terapêutico , Resultado do TratamentoRESUMO
5d, a novel analogue of the racemic 3-n-butylphthalide (NBP), has been reported for its free radical scavenging activity in vitro and preventive neuroprotection in vivo. Nevertheless, the mechanism by which 5d attenuated ischemia/reperfusion (I/R) injury is still unknown. Our results showed that 5d significantly increased CK2 activity as well as CK2α and 2α' protein levels after I/R injury. Besides, 5d suppressed the translocation of cytosolic p47phox and Rac1 to the membrane, decreased NOX4 expression and ROS generation. Furthermore, 5d blocked the dissociation between CK2α and Rac1 so as to decrease NADPH oxidase activity. Based on these findings, we propose that the neuroprotective effect of 5d is due to an increase of CK2 activity, which blocks I/R-induced dissociation between CK2α and Rac1, decreases NADPH oxidase activity, inhibits ROS production and finally realizes the neuroprotection of I/R. These findings point to that 5d might be considered an attractive candidate for further studies in ischemic stroke.
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Benzofuranos/farmacologia , Regulação Enzimológica da Expressão Gênica , NADPH Oxidases/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Encéfalo/metabolismo , Caseína Quinase II/metabolismo , Membrana Celular/metabolismo , Sobrevivência Celular , Citosol/metabolismo , Infarto da Artéria Cerebral Média , Masculino , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Interferência de RNA , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
Wnt/ß-catenin signaling is essential for melanogenesis in melanocytes. Neurokinin-1 receptor (NK-1R) has recently been demonstrated to be involved in melanin production. However, the cross talk between NK-1R and Wnt/ß-catenin is poorly understood. Here, [Sar9, Met(O2)11] substance P (SMSP) was used to activate NK-1R, while L-733060 was used to inhibit it. The effects of NK-1R activation and inhibition on Wnt and its inhibitors were analyzed using western blot and real-time quantitative PCR. The results showed that SMSP positively regulated Wnt/ß-catenin signaling by increasing the expression of ß-catenin and p-GSK3ß protein, which resulted from the weakened expression of the Wnt inhibitor Dickkopf-1 (DKK1). On the contrary, L-733060 lowered the expression of ß-catenin and p-GSK3ß protein through the up-regulation of DKK1 expression. Furthermore, in L-733060-treated mice, it was found that the pigmentation level as well as the melanogenic proteins and ß-catenin protein expression were down-regulated, while the expression of DKK1 was up-regulated. These results showed the interaction between NK-1R and Wnt in human melanocytes in vitro and C57BL/6J mice in vivo, indicating that NK-1R may positively regulate melanogenesis through Wnt/ß-catenin signaling pathway.
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Melaninas/biossíntese , Melanócitos/metabolismo , Receptores da Neurocinina-1/metabolismo , Pigmentação da Pele , Pele/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Melanócitos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Fosforilação , Piperidinas/farmacologia , Receptores da Neurocinina-1/efeitos dos fármacos , Pele/citologia , Pele/efeitos dos fármacos , Pigmentação da Pele/efeitos dos fármacos , Substância P/análogos & derivados , Substância P/farmacologia , Fatores de Tempo , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genéticaRESUMO
BACKGROUND: Nasopharyngeal carcinoma (NPC) is a squamous-cell carcinoma especially prevailing among the natives of southern China. The regimen of concurrent chemoradiotherapy (CCRT) that include platinum and 5-fluorouracil (5-FU) is considered to be the standard treatment for NPC. However, its clinical use is limited by its toxicity. Our purpose was to evaluate the efficacy and safety of the regimen of CCRT with taxanes and platinum versus the regimen of CCRT with 5-FU and platinum in NPC treatment. METHODS: Medline, the Cochrane library, and the Chinese medical literature database were searched for eligible studies. Meta-analysis was performed using Review Manager (Version 5.2). RESULTS: Six random controlled trials (RCTs) including 514 patients met our criteria. Meta-analysis showed that the regimen of CCRT with taxanes and platinum had an improved significant difference in complete remission (CR) and less incidence rate in adverse reactions such as gastrointestinal impairment grades III-IV, liver and kidney impairment grades I-II, and radiodermatitis grades III-IV versus the conventional regimen of CCRT with 5-FU and platinum, while the longterm effectiveness rate of overall survival, locoregional failure-free survival, or distant metastasis failure-free survival between the two groups was therapeutic equivalence. CONCLUSIONS: The regimen of CCRT with taxanes and platinum in NPC therapy may be more efficient and safe compared to the conventional modality of 5-FU and platinum in CCRT. However, we need more high-quality studies of multi-center and randomized double-blind clinical trials to further compare, analyze, and confirm the findings.
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Fluoruracila/uso terapêutico , Neoplasias Nasofaríngeas/tratamento farmacológico , Platina/uso terapêutico , Taxoides/uso terapêutico , Carcinoma , Quimiorradioterapia , Fluoruracila/administração & dosagem , Humanos , Carcinoma Nasofaríngeo , Platina/administração & dosagem , Taxoides/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: The amelioration of insulin resistance by bilobetin is closely related to its hypolipidaemic effect. The aim of the present study was to determine the insulin-sensitizing mechanism of bilobetin by elucidating its effect on lipid metabolism. EXPERIMENTAL APPROACH: Rats fed a high-fat diet were treated with bilobetin for either 4 or 14 days before applying a hyperinsulinaemic-euglycaemic clamp. Triglyceride and fatty acids labelled with radioactive isotopes were used to track the transportation and the fate of lipids in tissues. The activity of lipid metabolism-related enzymes and ß-oxidation rate were measured. Western blot was used to investigate the phosphorylation, translocation and expression of PPARα in several tissues and cultured cells. The location of amino acid residues subjected to phosphorylation in PPARα was also studied. KEY RESULTS: Bilobetin ameliorated insulin resistance, increased the hepatic uptake and oxidation of lipids, reduced very-low-density lipoprotein triglyceride secretion and blood triglyceride levels, enhanced the expression and activity of enzymes involved in ß-oxidation and attenuated the accumulation of triglycerides and their metabolites in tissues. Bilobetin also increased the phosphorylation, nuclear translocation and activity of PPARα accompanied by elevated cAMP level and PKA activity. Threonine-129-alanine and/or serine-163-alanine mutations on the PPARα genes and PKA inhibitors prevented the effects of bilobetin on PPARα. However, cells overexpressing PKA appeared to stimulate the phosphorylation, nuclear translocation and activity of PPARα. CONCLUSIONS AND IMPLICATIONS: Bilobetin treatment ameliorates hyperlipidaemia, lipotoxicity and insulin resistance in rats by stimulating PPARα-mediated lipid catabolism. PKA activation is crucial for this process.