RESUMO
Autism spectrum disorders (ASD) have heterogeneous etiologies involving dysfunction of central nervous systems, for which no effective pan-specific treatments are available. Ilex kudingcha (IK) C.J. Tseng is a nootropic botanical used in Asia for neuroprotection and improvement of cognition. This study establishes that a chemically characterized extract from IK (IKE) mitigates behavioral traits in the Drosophila melanogaster rugose mutant, whose traits resemble human ASD, and examines possible mechanisms. IKE treatment significantly ameliorated deficits in social interaction, short-term memory, and locomotor activity in Drosophila rugose, and significantly increased synaptic bouton number of size more than 2 µm2 in the neuromuscular junctions (NMJs) of Drosophila rugose. To clarify mechanism(s) of IKE action, methylphenidate (MPH), a dopamine transporter inhibitor, was included as a reference drug in the behavioral assays: MPH significantly improved social interaction and short-term memory deficit in Drosophila rugose; administration of the dopamine D1 receptor antagonist SCH23390 and dopamine D2 receptor antagonist sulpiride reversed the ameliorative effects of both MPH and IKE on the social interaction deficits of Drosophila rugose. To extend analysis of IKE treatment to the vertebrate central nervous system, ASD-associated gene expression in mouse hippocampus was studied by RNA-seq: IKE treatment altered the expression of genes coding phosphoinositide 3-kinases/protein kinase B (PI3K-Akt), proteins in glutamatergic, dopaminergic, serotonergic, and GABAergic synapses, cAMP response element-binding protein (CREB), and RNA transporter proteins. These results provide a foundation for further analysis of IKE as a candidate for treatment of some forms of ASD.
Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Nootrópicos/uso terapêutico , Extratos Vegetais/uso terapêutico , Animais , Transtorno do Espectro Autista/metabolismo , Ritmo Circadiano/efeitos dos fármacos , Drosophila melanogaster/genética , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Ilex/química , Locomoção/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Metilfenidato/uso terapêutico , Fenótipo , Folhas de Planta/química , Terminações Pré-Sinápticas/efeitos dos fármacos , Interação Social/efeitos dos fármacos , VietnãRESUMO
BACKGROUND: Mutations in the human Ubiquilin 2 gene are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD), the fatal neurodegenerative disease that progressively affected neuronal cells in both brain and spinal cord. There is currently no effective therapy for these diseases. Over the last decade, researchers have focused on the potential use of natural products especially in neurodegenerative studies. Insect products have been used as traditional medicines, however, scientific information is still lacking. Fruit fly is recently used as a model organism to investigate degenerative diseases related to the nervous system because it has a short life span and produces a large number of offspring. METHODS: The present study investigated the effects of honeybee products and edible insect powders on the locomotive and learning abilities, neuromuscular junctions (NMJs) structure, and reactive oxygen species (ROS) in larval brains of Ubiquilin- knockdown Drosophila. RESULTS: dUbqn knockdown flies showed defects in locomotive and learning abilities accompanied with structural defects in NMJs. The results obtained revealed that the recovery of locomotive defects was significantly greater in dUbqn knockdown flies fed with coffee honey from Apis cerana (1% v/v) or Apis dorsata melittin (0.5 µg/ml) or wasp powder (2 mg/ml) than that of in untreated dUbqn knockdown flies. Furthermore, dUbqn knockdown flies fed with coffee honey showed the partial rescue of structural defects in NMJs, improved learning ability, and reduced the accumulation of ROS caused by dUbqn depletion in the brain over the untreated group. CONCLUSION: These results suggest that coffee honey from Apis cerana contains a neuroprotective agent that will contribute to the development of a novel treatment for ALS/FTD.
Assuntos
Apiterapia/métodos , Insetos Comestíveis , Locomoção/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Animais , Abelhas , Drosophila , Feminino , Pós , TailândiaRESUMO
CONTEXT: Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is an autosomal recessive disease caused by biallelic mutations in the vitamin D receptor (VDR) gene. No patients have been reported with uniparental disomy (UPD). OBJECTIVE: Using genome-wide single nucleotide polymorphism (SNP) array to confirm whether HVDRR was caused by UPD of chromosome 12. MATERIALS AND METHODS: A 2-year-old girl with alopecia and short stature and without any family history of consanguinity was diagnosed with HVDRR by typical laboratory data findings and clinical features of rickets. Sequence analysis of VDR was performed, and the origin of the homozygous mutation was investigated by target SNP sequencing, short tandem repeat analysis, and genome-wide SNP array. RESULTS: The patient had a homozygous p.Arg73Ter nonsense mutation. Her mother was heterozygous for the mutation, but her father was negative. We excluded gross deletion of the father's allele or paternal discordance. Genome-wide SNP array of the family (the patient and her parents) showed complete maternal isodisomy of chromosome 12. She was successfully treated with high-dose oral calcium. CONCLUSIONS: This is the first report of HVDRR caused by UPD, and the third case of complete UPD of chromosome 12, in the published literature. Genome-wide SNP array was useful for detecting isodisomy and the parental origin of the allele. Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders. Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.
Assuntos
Cromossomos Humanos Par 12 , Polimorfismo de Nucleotídeo Único , Raquitismo Hipofosfatêmico/diagnóstico , Raquitismo Hipofosfatêmico/genética , Dissomia Uniparental/genética , Vitamina D/análogos & derivados , Administração Oral , Alelos , Alopecia/genética , Estatura , Cálcio/administração & dosagem , Pré-Escolar , Suplementos Nutricionais , Feminino , Genoma Humano , Transtornos do Crescimento/genética , Heterozigoto , Homozigoto , Humanos , Hidroxicolecalciferóis/administração & dosagem , Mutação , Vitamina D/metabolismoRESUMO
This study investigated whether surface topography affects the retentive strength of cemented full crowns, comparing the effects of standard machined, sandblasted, and grooved implant abutments. Five metallic crowns per abutment type were cast and cemented with zinc phosphate. After 24 hours, the specimens were submitted to a tensile test. The retentive strength of the cemented crowns was affected by abutment surface topography. The sandblasted and grooved surface groups had approximately 2.4 times greater mean uniaxial retentive strength than the machined surface group (P < .001). The retentive strength of the sandblasted and grooved abutments was similar, despite marked differences in surface profiles and roughness parameters.
Assuntos
Cimentação/métodos , Coroas , Dente Suporte , Implantes Dentários para Um Único Dente , Planejamento de Prótese Dentária , Retenção em Prótese Dentária , Óxido de Alumínio/química , Corrosão Dentária/métodos , Materiais Dentários/química , Análise do Estresse Dentário/instrumentação , Humanos , Umidade , Teste de Materiais , Estresse Mecânico , Propriedades de Superfície , Temperatura , Resistência à Tração , Fatores de Tempo , Titânio/química , Cimento de Fosfato de Zinco/químicaRESUMO
Prostaglandin endoperoxide H synthase (PGHS) is a key enzyme for the synthesis of prostaglandins (PGs) which play important roles in inflammation and carcinogenesis. Because the extract from Psidium guajava is known to have a variety of beneficial effects on our body including the anti-inflammatory, antioxidative and antiproliferative activities, we investigated whether the extract inhibited the catalytic activity of the two PGHS isoforms using linoleic acid as an alternative substrate. The guava leaf extract inhibited the cyclooxygenase reaction of recombinant human PGHS-1 and PGHS-2 as assessed by conversion of linoleic acid to 9- and 13-hydroxyoctadecadienoic acids (HODEs). The guava leaf extract also inhibited the PG hydroperoxidase activity of PGHS-1, which was not affected by nonsteroidal anti-inflammatory drugs (NSAIDs). Quercetin which was one of the major components not only inhibited the cyclooxygenase activity of both isoforms but also partially inhibited the PG hydroperoxidase activity. Overexpression of human PGHS-1 and PGHS-2 in the human colon carcinoma cells increased the DNA synthesis rate as compared with mock-transfected cells which did not express any isoforms. The guava leaf extract not only inhibited the PGE(2) synthesis but also suppressed the DNA synthesis rate in the PGHS-1- and PGHS-2-expressing cells to the same level as mock-transfected cells. These results demonstrate the antiproliferative activity of the guava leaf extract which is at least in part caused by inhibition of the catalytic activity of PGHS isoforms.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Folhas de Planta/química , Linhagem Celular Tumoral , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Ácido Linoleico/metabolismo , Ácidos Linoleicos/metabolismo , Ácidos Linoleicos Conjugados/metabolismo , Extratos Vegetais/farmacologia , Psidium , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
BACKGROUND: Immunotherapy with bacillus Calmette-Guérin (BCG) for bladder cancer is successful, although the precise mechanism is unclear. Natural killer (NK) cells are a candidate for BCG-activated killer cells, but the roles of other T lymphocytes, such as NKT cells and gammadeltaT cells, are not fully understood. Mycobacterium tuberculosis is a potent activator of both NKT cells and gammadeltaT cells. However, it is known that the patient's prognosis is good if there are increased numbers of dendritic cells (DCs) in the urine after BCG therapy. Therefore, we investigated whether DCs are matured by BCG and whether BCG-pulsed DCs stimulate NKT cells and gammadeltaT cells. METHODS: Naïve Pan T cells were isolated form peripheral blood mononuclear cells (PBMCs) and DCs were obtained by culturing CD14(+) monocytes with granulocyte-macrophage colony-stimulating factor and interleukin-4. The DCs were pulsed with BCG and their maturation was measured by fluorescence-activated cell sorter analysis using the CD86 antibody. Naïve T lymphocytes were stimulated by coculture with BCG-pulsed DCs in vitro, followed by FACS analysis to estimate the ratio and activation of NKT cells and the ratio of gammadeltaT cells. The (51)Cr (chromium) release assay was used to estimate the cytotoxic activity of the stimulated T cells. Cytolytic proteins in the patient's PBMCs were measured during BCG therapy using semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS: The DCs were matured by BCG stimulation and the number of NKT cells and gammadeltaT cells increased after culturing with BCG-pulsed DCs. The BCG-pulsed DCs also activated the NKT cells and gammadeltaT cells. Also, the lymphocytes that were cocultured with the BCG-pulsed DCs showed unspecific cytotoxic activity against a bladder cancer cell line. CONCLUSION: Sensitization of NKT cells and gammadeltaT cells by BCG-pulsed DCs might be one of the mechanisms of BCG immunotherapy.
Assuntos
Adjuvantes Imunológicos/farmacologia , Vacina BCG/farmacologia , Células Dendríticas/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Linfócitos T Citotóxicos/imunologia , Neoplasias da Bexiga Urinária/imunologia , Vacina BCG/imunologia , Células Dendríticas/imunologia , Citometria de Fluxo , Humanos , Imunoterapia/métodos , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T Citotóxicos/metabolismo , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/terapiaRESUMO
Antithrombotic activities of odorless garlic powder were demonstrated in blood fibrinolytic and coagulation systems. Though the odorless garlic preparation did not influence tissue-type plasminogen activator (t-PA) or its inhibitor secretions from human umbilical vein endothelial cells, it enhanced plasmin generation by t-PA on fibrin film and in chromogenic assays by 1.8-fold and 8.7-fold respectively. The coagulation system was considerably reduced after the administration of the garlic in a rat in situ loop model, indicating that increased levels of thrombin-antithrombin III (TAT) complex in the control group were significantly reduced to normal (sham) in the garlic group (p<0.05), which was associated with decreasing tendencies towards prolonged or increased values of coagulation parameters in the control group. These findings suggest that odorless garlic not only activates fibrinolytic activity by accelerating t-PA-mediated plasminogen activation, but also suppresses the coagulation system by downregulating thrombin formation, suggesting a beneficial role in preventing pathological thrombus formation in such cardiovascular disorders.
Assuntos
Fibrinolíticos/farmacologia , Alho , Odorantes , Ração Animal , Animais , Peso Corporal/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fibrinolíticos/uso terapêutico , Humanos , Cinética , Masculino , Plasminogênio/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ratos , Trombose/tratamento farmacológico , Trombose/patologia , Ativador de Plasminogênio Tecidual/metabolismo , Cordão Umbilical/efeitos dos fármacos , Cordão Umbilical/metabolismoRESUMO
PURPOSE: We described the temporarily increase phenomenon in prostate-specific antigen level (PSA bounce) after transperineal interstitial permanent prostate brachytherapy (TIPPB) for localized prostate cancer. MATERIALS AND METHODS: From December 1998 to May 2003, 500 consecutive patients with localized prostate cancer were treated with TIPPB using iodine-125 or palladium-103. We examined 200 patients who have more than 2-year PSA follow-up. Median follow-up length was 1,069 days (range, 712-1,411 days). No patient received neoadjuvant or adjuvant hormone therapy. PSA determinations were performed every 3 months for the first 2 years after procedure, and every 6 months hereafter. PSA bounce was defined as an increase of 0.1 ng/ml or greater above the preceding PSA level after implant followed by a subsequent decrease below that level. The American Society for Therapeutic Radiology and Oncology (ASTRO) consensus panel criteria 1996 were used to define biochemical failure. RESULTS: PSA bounce was observed in 40% (80/200) of the cases receiving TIPPB. The median time to PSA bounce was 13 months from the day of implant. The median magnitude of the PSA bounce was 0.3 ng/ml from the pre-bounce level. Twelve cases demonstrated biochemical failure according to the ASTRO consensus guidelines of three consecutive rises in PSA. Ten of these subsequently showed a drop in PSA, consistent with biologic control of their disease. Two cases remain classified as apparent biochemical failures. CONCLUSIONS: A transient rise in the PSA following TIPPB, the so-called "bounce" is a common occurrence. The apparent PSA control of ten of twelve cases failing by the ASTRO criteria raises some concern. Further observation will be necessary to determine ways to discriminate these from true disease progression.
Assuntos
Biomarcadores Tumorais/sangue , Braquiterapia/efeitos adversos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/radioterapia , Idoso , Braquiterapia/métodos , Seguimentos , Humanos , Radioisótopos do Iodo/uso terapêutico , Masculino , Paládio/uso terapêutico , Radioisótopos/uso terapêutico , Fatores de TempoRESUMO
PURPOSE: The long-term results were studied in patients who underwent transcatheter arterial embolization (TAE) for the spontaneous rupture of renal angiomyolipoma (AML). MATERIAL AND METHODS: Five cases (1 male, 4 females) who underwent TAE for spontaneous AML rupture between November, 1996 and February 2000 were studied. Spontaneous rupture of AML was diagnosed with CT. TAE were carried out by injection of ethanol and lipiodol and application of either a metal coil or gelform. RESULT: In 4 cases, after performing TAE only one time, the tumor size was reduced and there has been no re-rupture or re-bleeding during the ongoing follow-up. In the other case, an enucleation operation was carried out 11 days after TAE in accordance with the patient's request. DISCUSSION: Recently, there have been a few reports on the long-term effectiveness of TAE, a conservative treatment for renal AML rupture. Our study indicated that TAE might be recommended for patients with renal AML rupture not only for stanching and pre-operative treatment but also for a conservative treatment with regular follow-up.