RESUMO
We conducted a 12-week randomized double-blind placebo-controlled clinical trial to investigate the potential impact of Bifidobacterium bifidum (Bf-688) supplementation on attention-deficit/hyperactivity disorder (ADHD). Children with ADHD who were already receiving a stable dose of methylphenidate (MPH) treatment were enrolled and were randomly assigned to two groups: one receiving add-on Bf-688 (daily bacterial count of 5 × 109 CFUs) (n = 51) and the other receiving a placebo (n = 51). All participants underwent assessments using Conners' Continuous Performance Test (CPT) and Conners' Continuous Auditory Test of Attention (CATA). Additionally, fecal samples were collected at the beginning of the trial (week 0) and at the endpoint (week 12). Remarkably, the group receiving Bf-688 supplementation, but not the placebo group, exhibited significant improvements in omission errors in CPT as well as Hit reaction time in both CPT and CATA. Gut microbiome analysis revealed a significant increase in the Firmicutes to Bacteroidetes ratio (F/B ratio) only in the Bf-688 group. Furthermore, we identified significant negative correlations between N-Glycan biosynthesis and Hit reaction time in both CPT and CATA. Our results demonstrate that the probiotic Bf-688 supplement can enhance neuropsychological performance in children with ADHD, possibly by altering the composition of the gut microbiota, ultimately leading to reduced N-Glycan biosynthesis.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Bifidobacterium bifidum , Suplementos Nutricionais , Fezes , Microbioma Gastrointestinal , Probióticos , Humanos , Método Duplo-Cego , Masculino , Probióticos/administração & dosagem , Feminino , Criança , Microbioma Gastrointestinal/efeitos dos fármacos , Fezes/microbiologia , Metilfenidato/administração & dosagem , Resultado do Tratamento , Atenção/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacosRESUMO
The effects of gut microbiota on the association between carbohydrate intake during pregnancy and neonatal low birth weight (LBW) were investigated. A prospective cohort study was conducted with 257 singleton-born mother-child pairs in Taiwan, and maternal dietary intake was estimated using a questionnaire, with each macronutrient being classified as low, medium, or high. Maternal fecal samples were collected between 24 and 28 weeks of gestation, and gut microbiota composition and diversity were profiled using 16S rRNA amplicon gene sequencing. Carbohydrates were the major source of total energy (56.61%), followed by fat (27.92%) and protein (15.46%). The rate of infant LBW was 7.8%, which was positively correlated with maternal carbohydrate intake. In the pregnancy gut microbiota, Bacteroides ovatus and Dorea spp. were indirectly and directly negatively associated with fetal growth, respectively; Rosenburia faecis was directly positively associated with neonatal birth weight. Maternal hypertension during pregnancy altered the microbiota features and was associated with poor fetal growth. Microbiota-accessible carbohydrates can modify the composition and function of the pregnancy gut microbiota, thus providing a potential marker to modulate deviations from dietary patterns, particularly in women at risk of hypertension during pregnancy, to prevent neonatal LBW.
Assuntos
Carboidratos da Dieta , Fezes , Microbioma Gastrointestinal , Recém-Nascido de Baixo Peso , Humanos , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Gravidez , Recém-Nascido , Adulto , Estudos Prospectivos , Fezes/microbiologia , Fenômenos Fisiológicos da Nutrição Materna , Taiwan , RNA Ribossômico 16S/genética , Desenvolvimento FetalRESUMO
Biochanin A is a major isoflavone in red clover and a potent chemopreventive agent against cancer. However, the effects of biochanin A on human osteosarcoma cells have never been clarified. This study investigated the anti-proliferative potential of biochanin A in osteosarcoma cells. The results indicate that biochanin A inhibited cell growth and colony formation in a dose-dependent manner with a minimal toxicity to normal cells. The combination of doxorubicin and biochanin A could synergistically inhibit osteosarcoma cell growth. The cytotoxic effect of biochanin A via the induction of apoptosis as evidenced by formation of apoptotic bodies, externalization of phosphatidylserine, accumulation of sub-G1 phase cells, caspase 3 activation, and cleavage of PARP. Apoptosis was associated with loss of the mitochondrial membrane potential, release of cytochrome c, caspase 9 activation, increased Bax expression, and reduced Bcl-2 and Bcl-XL expression. Pre-treatment with a caspase-9 specific inhibitor (Z-LEHD-FMK) partially attenuated cell death, suggesting involvement of the intrinsic mitochondrial apoptotic cascade. However, pre-treatment with the JNK inhibitor SP600125, the MEK inhibitor PD-98059, and the p38 MAPK inhibitor SB203580 or the antioxidants vitamin E, N-acetylcysteine, and glutathione failed to prevent biochanin A-induced cell death. Our results suggest that biochanin A inhibits cell growth and induces apoptosis in osteosarcoma cells by triggering activation of the intrinsic mitochondrial pathway and caspase-9 and -3 and increasing the Bax: Bcl-2/Bcl-XL ratio.
Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Genisteína/farmacologia , Mitocôndrias/efeitos dos fármacos , Osteossarcoma/fisiopatologia , Extratos Vegetais/farmacologia , Linhagem Celular Tumoral , Humanos , Mitocôndrias/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Trifolium/química , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismoAssuntos
Extubação , Displasia Broncopulmonar/terapia , Tempo de Internação/estatística & dados numéricos , Esteroides/administração & dosagem , Displasia Broncopulmonar/mortalidade , Feminino , Humanos , Lactente , Lactente Extremamente Prematuro , Recém-Nascido , Modelos Logísticos , Masculino , Missouri , Estudos Retrospectivos , Traqueostomia , Falha de TratamentoRESUMO
Histone deacetylase 6 (HDAC6) is a unique member of the histone deacetylase family. Although HDAC6 is mainly localized in the cytoplasm, it can regulate the activities of the transcription factors in the nucleus. However, a correlation of intracellular distribution of HDAC6 with tumor progression is lacking. In this study, we found that a low frequency of nuclear HDAC6-positive cells in tumors was associated with distant metastasis and a worse overall survival in 134 patients with non-small cell lung cancer (NSCLC). Ectopic expression of wild-type HDAC6 promoted migration and invasion of A549 and H661 cells. However, the enforced expression of nuclear export signal-deleted HDAC6 inhibited the invasion but not the migration of both cell lines. The inhibitory effect of nuclear HDAC6 on invasion was mediated by the deacetylation of the p65 subunit of nuclear factor-κB, which decreased its DNA-binding activity to the MMP2 promoter, leading to the downregulation of MMP2 expression. Our findings indicated that the loss of nuclear HDAC6 may be a potential biomarker for predicting metastasis in patients with NSCLC.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Movimento Celular , Núcleo Celular/enzimologia , Histona Desacetilases/metabolismo , Neoplasias Pulmonares/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , NF-kappa B/metabolismo , Acetilação , Idoso , Sítios de Ligação , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/terapia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Desacetilase 6 de Histona , Histona Desacetilases/genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Metaloproteinase 2 da Matriz/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais , Transdução de Sinais , Fatores de Tempo , Fator de Transcrição RelA/metabolismo , TransfecçãoRESUMO
Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer mortality worldwide. It is noted that metastasis is a fundamental biological behavior of HCC and the main cause of treatment failure. The identification of somatic alterations and their specific inhibitors may contribute to reduce side effects and prolong patient survival in HCC. Chromosomal copy number alterations (CNAs) are important subclasses of somatic mutations and can be used as an effective method of identifying driver genes with causal roles in carcinogenesis. Jia et al. identified a novel recurrent focal amplicon, 1q24.1-24.2, targets the MPZL1 gene in HCC. They also found that MPZL1 may recruit the SHP-2 and subsequently activate/phosphorylate Src kinase at Tyr426, promoting phosphorylation of cortactin and migration of HCC cells. It is noted that phosphorylation of Tyr416 in the activation loop of the kinase domain up-regulates enzyme activity of Src. In addition, the active state of c-Src, p-Tyr416-c-Src, is an independent prognostic marker of poor patient survival in HCC. Therefore, c-Src signaling may be a druggable target and c-Src targeted therapy may improve patient outcome in this specific subtype of HCC patient with a gain of the recurrent focal amplicon, 1q24.1-24.2.
RESUMO
BACKGROUND: The nuclear factor-κB (NF-κB) pathway activates many of the target genes that are critical to the initiation and establishment of endometriosis. We sought to examine the potential application of pyrrolidine dithiocarbamate (PDTC), a potent NF-κB inhibitor, in the treatment of endometriosis. METHODS: The phosphorylation of IκB, expression of nuclear p65 protein and NF-κB DNA binding in endometriotic epithelial cells (EECs), endometriotic eutopic epithelial cells (EuECs) and normal epithelial cells (NECs) were detected by Western blot analysis and electrophoretic mobility shift assay. Cyclooxgenase-2 (COX-2) gene and protein expressions in EECs were measured by RT-PCR and Western blot analysis. Prostaglandin E(2) (PGE(2)) production of EECs was measured by ELISA. RESULTS: PDTC in the absence or presence of tumor necrosing factor-α (TNF-α) showed stronger inhibitory effects on IκB phosphorylation, expression of nuclear p65 protein and NF-κB DNA-binding activity in EECs than in EuECs or NECs. Pretreatment of EECs with PDTC resulted in a dose-dependent reduction in the TNF-α-induced expressions of COX-2 at gene and protein levels, as well as a reduction of PGE(2) synthesis. CONCLUSION: PDTC may represent a novel therapeutic strategy for treatment of endometriosis.
Assuntos
Antioxidantes/farmacologia , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , NF-kappa B/antagonistas & inibidores , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Western Blotting , Ciclo-Oxigenase 2/genética , Primers do DNA/química , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Expressão Gênica , Humanos , Proteínas I-kappa B/metabolismo , Técnicas In Vitro , Sondas de Oligonucleotídeos , Fosforilação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição RelA/metabolismoRESUMO
The activation of nuclear factor-κB (NF-κB) has been implicated in the development and progression of endometriosis. The aim of this study is to investigate the potential application of pyrrolidine dithiocarbamate (PDTC), a potent NF-κB inhibitor, in the treatment of endometriosis. NF-κB-DNA-binding activity, IκB phosphorylation and expression of nuclear p65 protein in endometriotic ectopic stromal cells (EcSCs), endometriotic eutopic stromal cells (EuSCs) and normal endometrial stromal cells (NESCs) were detected by electrophoretic mobility shift assay and western blot analysis. Adhesion, migration, invasion and apoptosis of EcSCs were observed by means of adhesion, migration, invasion and terminal deoxynucleotidyl transferase-mediated dUDP nick-end labeling assay, respectively. Gene and protein expressions of CD44s, matrix metalloproteinase (MMP)-2, MMP-9 and survivin in EcSCs were measured by RT-PCR and western blot analysis. The results showed that PDTC in the absence or presence of interleukin (IL)-1ß showed stronger inhibitory effects on NF-κB-DNA-binding activity, IκB phosphorylation and expression of nuclear p65 protein in EcSCs than those in EuSCs or NESCs. PDTC enhanced apoptosis, and suppressed IL-1ß-induced cellular adhesion, migration and invasion of EcSCs. Pretreatment of EcSCs with PDTC attenuated IL-1ß-induced expressions of CD44s, MMP-2, MMP-9 and survivin at gene and protein levels. All these findings suggest that PDTC induces apoptosis and down-regulates adhesion, migration and invasion of EcSCs through the suppression of various molecules. Therefore, PDTC could be used as a therapeutic agent for the treatment of endometriosis.
Assuntos
Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Endométrio/efeitos dos fármacos , NF-kappa B/metabolismo , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Endométrio/patologia , Ativação Enzimática/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Células Estromais/efeitos dos fármacos , Células Estromais/patologiaRESUMO
This study demonstrated that pyrrolidine dithiocarbamate (PDTC), a potent nuclear factor-κB inhibitor, showed stronger inhibitory effects on nuclear factor-κB activation in endometriotic stromal cells than in normal endometrial stromal cells as determined by electrophoretic mobility shift assay and Western blot analysis. Pretreatment of endometriotic stromal cells with PDTC attenuated tumor necrosis factor-α-induced expressions of CD44s, matrix metalloproteinase-9, and vascular endothelial growth factor whereas reversed tumor necrosis factor-α-reduced expressions of tissue inhibitor of metalloproteinase-1 revealed by reverse transcriptase polymerase chain reaction and Western blot analysis, suggesting that PDTC may represent a novel therapeutic strategy for treatment of endometriosis.
Assuntos
Endometriose/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Doenças Peritoneais/tratamento farmacológico , Pirrolidinas/uso terapêutico , Tiocarbamatos/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Estudos de Casos e Controles , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Endometriose/genética , Endometriose/metabolismo , Endometriose/patologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/metabolismo , Cistos Ovarianos/patologia , Doenças Peritoneais/genética , Doenças Peritoneais/metabolismo , Doenças Peritoneais/patologia , Pirrolidinas/farmacologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , Tiocarbamatos/farmacologia , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismoRESUMO
OBJECTIVE: To investigate the relationship between -344T polymorphism in aldosterone synthetase (CYP11B2) gene promoter region and the pathogenesis of polycystic ovary syndrome (PCOS). METHODS: Ninety two patients with PCOS and controls were genotyped according to the fragment length (273 bp and or 202 bp) of CYP11B2 gene promoter by the technique of polymerase chain reaction-restriction fragment length polymorphism. The levels of luteinizing hormone, follicular stimulating hormone, estrodiol, progesterone, prolactin, testosterone, plasma renin activity (PRA), plasma angiotensin II (PANG II) and aldosterone in the basal state were also determined. Different genotypes between PCOS were compared about their levels of PRA, PANG II, aldosterone and testosterone. RESULTS: (1) The C allele frequencies of CYP11B2 gene in control and PCOS was 22% and 36%, respectively. (2) The frequency of variants (TC, CC) of CYP11B2 gene -344T polymorphism site in PCOS (57%) was significantly higher than that of control subjects (37%). (3) The level of PRA, PANG II, aldosterone, testosterone were all significantly higher in the genotype of -344CC than in that of -344TT in PCOS and normal women (P < 0.01). CONCLUSIONS: (1) The variants (T-->C) of -344T polymorphism site of CYP11B2 gene predisposes increased risk of PCOS. (2) The genotype of -344CC, -344TC may be susceptible genotype of PCOS and has related to the enhanced functional activity of ovarian renin angiotensin system in PCOS.