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1.
Artigo em Inglês | MEDLINE | ID: mdl-34200176

RESUMO

Prenatal exposure to bisphenol A (BPA) may increase the risk of abnormal birth outcomes, and DNA methylation might mediate these adverse effects. This study aimed to investigate the effects of maternal BPA exposure on maternal and fetal DNA methylation levels and explore whether epigenetic changes are related to the associations between BPA and low birth weight. We collected urine and blood samples originating from 162 mother-infant pairs in a Taiwanese cohort study. We measured DNA methylation using the Illumina Infinium HumanMethylation 450 BeadChip in 34 maternal blood samples with high and low BPA levels based on the 75th percentile level (9.5 µg/g creatinine). Eighty-seven CpGs with the most differentially methylated probes possibly interacting with BPA exposure or birth weight were selected using two multiple regression models. Ingenuity pathway analysis (IPA) was utilized to narrow down 18 candidate CpGs related to disease categories, including developmental disorders, skeletal and muscular disorders, skeletal and muscular system development, metabolic diseases, and lipid metabolism. We then validated these genes by pyrosequencing, and 8 CpGs met the primer design score requirements in 82 cord blood samples. The associations among low birth weight, BPA exposure, and DNA methylation were analyzed. Exposure to BPA was associated with low birth weight. Analysis of the epigenome-wide findings did not show significant associations between BPA and DNA methylation in cord blood of the 8 CpGs. However, the adjusted odds ratio for the dehydrogenase/reductase member 9 (DHRS9) gene, at the 2nd CG site, in the hypermethylated group was significantly associated with low birth weight. These results support a role of BPA, and possibly DHRS9 methylation, in fetal growth. However, additional studies with larger sample sizes are warranted.


Assuntos
Metilação de DNA , Efeitos Tardios da Exposição Pré-Natal , Compostos Benzidrílicos/toxicidade , Peso ao Nascer , Estudos de Coortes , Feminino , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Exposição Materna/efeitos adversos , Fenóis , Projetos Piloto , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Taiwan/epidemiologia
2.
Biochemistry ; 59(40): 3796-3801, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33006472

RESUMO

Ubiquitination and SUMOylation of protein are crucial for various biological responses. The recent unraveling of cross-talk between SUMO and ubiquitin (Ub) has shown the pressing needs to develop the platform for the synthesis of Ub tagged SUMO2 dimers to decipher its biological functions. Still, the platforms for facile synthesis of dimers under native condition are less explored and remain major challenges. Here, we have developed the platform that can expeditiously synthesize all eight Ub tagged SUMO2 and SUMOylated proteins under native condition. Expanding genetic code (EGC) method was employed to incorporate Se-alkylselenocysteine at lysine positions. Oxidative selenoxide elimination generates the electrophilic center, dehydroalanine, which upon Michael addition with C-terminal modified ubiquitin, a nucleophile, yield Ub tagged SUMO2. The dimers were further interrogated with USP7, a SUMO2 deubiquitinase, which is involved in DNA repair, to understand specificity toward the Ub tagged SUMO2 dimer. Our results have shown that the C-terminal domain of USP7 is crucial for USP7 efficiency and selectivity for the Ub tagged SUMO2 dimer.


Assuntos
Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Peptidase 7 Específica de Ubiquitina/metabolismo , Ubiquitina/metabolismo , Humanos , Modelos Moleculares , Domínios Proteicos , Multimerização Proteica , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/química , Especificidade por Substrato , Sumoilação , Ubiquitina/química , Peptidase 7 Específica de Ubiquitina/química , Ubiquitinação
3.
Biochemistry ; 59(24): 2205-2209, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32484330

RESUMO

Methanosarcina mazei pyrrolysyl-tRNA synthetase (PylRS) and its cognate tRNA have been evolved to generate genetically encoded noncanonical amino acids (ncAAs). Use of tryptophan (Trp) analogues with pyrrole ring modification for their spatial and polarity tuning in enzyme activity and substrate specificity is still limited. Herein, we report the application of an evolved PylRS, FOWRS2, for efficient incorporation of five Trp analogues into the deubiquitinase USP30 to decipher the role of W475 for diubiquitin selectivity. Structures of the five FOWRS-C/Trp analogue complexes at 1.7-2.5 Å resolution showed multiple ncAA binding modes. The W475 near the USP30 active site was replaced with Trp analogues, and the effect on the activity as well as the selectivity toward diubiquitin linkage types was examined. It was found that the Trp analogue with a formyl group attached to the nitrogen atom of the indole ring led to an improved activity of USP30 likely due to enhanced polar interactions and that another Trp analogue, 3-benzothienyl-l-alanine, induced a unique K6-specificity. Collectively, genetically encoded noncanonical Trp analogues by evolved PylRS·tRNACUAPyl pair unravel the spatial role of USP30-W475 in its diubiquitin selectivity.


Assuntos
Proteínas Mitocondriais/química , Tioléster Hidrolases/química , Triptofano/análogos & derivados , Triptofano/química , Aminoacil-tRNA Sintetases/química , Proteínas Arqueais/química , Domínio Catalítico , Humanos , Methanosarcina/enzimologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Tioléster Hidrolases/genética , Tioléster Hidrolases/metabolismo , Triptofano/metabolismo
4.
Int J Geriatr Psychiatry ; 34(10): 1465-1472, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31111978

RESUMO

OBJECTIVE: To examine the association between benzodiazepines (BZDs) and Z-drugs treatment and risk of burn injury in elders. METHODS: We designed a nested case-control study. All subjects were aged 65 and older and enrolled in the National Health Insurance program in Taiwan, 2003 to 2012; 813 cases were identified with burn injury for the first time in their inpatient claims, and they were individually matched to 4879 controls based on age, gender, and index year. Benzodiazepines and Z-drugs usage (doses, duration, half-life) and the other covariates including comorbidities, health care utilization, and psychotropic medications used in the 365 days before index events were examined. RESULTS: A significant increased risk of burn injury hospitalization in elders was observed among current Z-drugs users compared with nonusers (adjusted odds ratio [AOR] = 1.59, 95% confidence interval [CI] [1.23, 2.07]). BZDs at high (AOR = 1.81, 95% CI [1.12, 2.94] and medium dosage (AOR = 1.53, 95% CI [1.15, 2.04] and Z-drugs at medium dosage (AOR = 1.60, 95% CI [1.20, 2.12]) were all significantly increased the burn-related injury requiring hospitalization. Polypharmacy of anxiolytic and hypnotic BZDs, long- and short-acting BZDs, and more than one BZD with or without Z-drugs also increased the risk. CONCLUSIONS: BZDs and Z-drugs prescriptions in elders may be associated with increased risk of burn injury hospitalization. When prescribing BZDs and Z-drugs, clinicians should exercise caution with the elderly to minimize risks.


Assuntos
Benzodiazepinas/efeitos adversos , Queimaduras/epidemiologia , Hospitalização/estatística & dados numéricos , Hipnóticos e Sedativos/efeitos adversos , Psicotrópicos/efeitos adversos , Idoso , Ansiolíticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Estudos de Casos e Controles , Feminino , Humanos , Hipnóticos e Sedativos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Razão de Chances , Psicotrópicos/uso terapêutico , Taiwan/epidemiologia
5.
Psychiatry Clin Neurosci ; 73(8): 501-507, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31077503

RESUMO

AIM: Antipsychotics off-label use is common in clinical practice but information is limited in regards to the trends of antipsychotic use in specific mental disorders in Taiwan. This study aimed to examine the trends and associated factors of antipsychotic use among outpatients with anxiety disorders in Taiwan during 2005-2013. METHODS: We assessed the annual prescriptions of antipsychotic use in nine consecutive years (2005-2013) using the National Health Insurance Research Database among adults (aged ≥18 years) with anxiety disorders in outpatient visits in Taiwan. We applied logistic regression to examine the trends and associated factors of antipsychotic use. RESULTS: The proportion of antipsychotic medication use for anxiety disorder increased from 8.4% in 2005 to 9.1% in 2013. First-generation antipsychotics (FGA) use was more than that of second-generation antipsychotics (SGA) use in patients with anxiety disorder through the 9-year period. Sulpiride and flupentixol were the two most common FGA in the treatment of anxiety disorder. Patients with specific anxiety disorder (post-traumatic stress disorder, panic disorder/agoraphobia, generalized anxiety disorder, and obsessive-compulsive disorder), female sex, younger age (age < 65 years), comorbidity with major depression or minor depression, antidepressants concurrent use, and visits to psychiatrists, medical centers and primary care were significantly more likely to take prescribed antipsychotics. CONCLUSION: Antipsychotic off-label use significantly increased among patients with anxiety disorder in this national representative cohort. Such increased use of antipsychotics could be driven by augmentation of their prescription for major depression. As their efficacy and safety remain uncertain, further study is warranted.


Assuntos
Antipsicóticos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Uso de Medicamentos/estatística & dados numéricos , Uso Off-Label/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Idoso , Bases de Dados Factuais/estatística & dados numéricos , Uso de Medicamentos/tendências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais/estatística & dados numéricos , Fatores Sexuais , Taiwan , Adulto Jovem
6.
BMC Geriatr ; 17(1): 140, 2017 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-28693443

RESUMO

BACKGROUND: Non-benzodiazepine hypnotics (Z-drugs) are advocated to be safer than benzodiazepines (BZDs). This study comprehensively investigated the association of BZD and Z-drug usage with the risk of hospitalisation for fall-related injuries in older people. METHODS: This study used the Taiwan National Health Insurance Database with a nested matched case-control design. We identified 2238 elderly patients who had been hospitalised for fall-related injuries between 2003 and 2012. They were individually matched (1:4) with a comparison group by age, sex, and index year. Conditional logistic regression was used to determine independent effects of drug characteristics (type of exposure, dosage, half-life, and polypharmacy) on older people. RESULTS: Older people hospitalisation for fall-related injuries were significantly associated with current use of BZDs (adjusted odds ratio [AOR] = 1.32, 95% confidential interval [CI] = 1.17-1.50) and Z-drugs (AOR = 1.24, 95%CI = 1.05-1.48). At all dose levels of BZDs, high dose levels of Z-drugs, long-acting BZD, and short-acting BZD use were all significantly increased the risk of fall-related injuries requiring hospitalisation. Polypharmacy, the use of two or more kinds of BZDs, one kind of BZD plus Z-drugs and two or more kinds of BZDs plus Z-drugs, also significantly increased the risk (AOR = 1.61, 95% CI = 1.38-1.89; AOR = 1.65, 95% CI = 1.08-2.50, and AOR = 1.58, 95% CI = 1.21-2.07). CONCLUSIONS: Different dose levels and half-lives of BZDs, a high dose of Z-drugs, and polypharmacy with BZDs and Z-drugs were associated with an increased risk of fall-related injury requiring hospitalisation in older people. Physicians should balance the risks and benefits when prescribing these drug regimens to older people considering the risk of falls.


Assuntos
Acidentes por Quedas , Benzodiazepinas/efeitos adversos , Hospitalização/tendências , Hipnóticos e Sedativos/efeitos adversos , Acidentes por Quedas/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Benzodiazepinas/administração & dosagem , Estudos de Casos e Controles , Bases de Dados Factuais/tendências , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Masculino , Polimedicação , Fatores de Risco , Taiwan/epidemiologia , Ferimentos e Lesões/induzido quimicamente , Ferimentos e Lesões/diagnóstico , Ferimentos e Lesões/epidemiologia
7.
Sci Total Environ ; 607-608: 1126-1135, 2017 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-28724251

RESUMO

Prenatal exposure to phenols, phthalates (PAEs), and organophosphate (OP) pesticides may increase the risk of abnormal birth outcomes. However, many previous studies have examined exposure to a limited number of chemical classes or exposure profiles limited to a specific stage of pregnancy. This study aims to characterize the concurrent exposure scenario throughout pregnancy by simultaneously monitoring internal doses of several endocrine-disrupting compounds (EDCs), including 2 phenols (nonylphenol (NP) and bisphenol A (BPA)), 9 PAEs, and 6 OP pesticide metabolites and to assess the relationships between concurrent exposure to EDCs and infant birth weight, length, and head and chest circumference. One hundred and sixty two women provided three spot urine samples at approximately 11 and 26weeks gestation and at delivery. We applied multivariable linear regression and ridge regression models to estimate the effects of separate and correlated exposures. Multivariable linear regression models revealed that women with short birth-length infants had significantly higher urinary second-trimester NP levels (50th percentile, 5.03µg/g creatinine) (ß=-0.47cm; 95% CI=-0.93 to -0.01). Similarly significant relationships were observed between second-trimester mono-methyl phthalate (MMP) exposure and short birth length, second-trimester ΣPAEs and short birth length, second-trimester ΣPAEs exposure and reduced head and chest circumference, second-trimester diethylphosphate (DEP) exposure and reduced birth weight and length, and second-trimester ΣDEPs exposure and short birth length. Women with urinary BPA above the 75th percentile or ΣPAEs levels above the 50th percentile in the third trimester had infants with significantly reduced head circumference. These observations suggest that the second trimester may be the critical stage of susceptibility for fetal development. In ridge regression models, for which women with fewer measures for exposure to NP, BPA, MMP, ΣPAEs, DEP and ΣDEPs simultaneously were available, no relationships were found with infant size at birth. Additional studies with larger sample sizes are warranted.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Exposição Materna/efeitos adversos , Organofosfatos/efeitos adversos , Fenóis/efeitos adversos , Ácidos Ftálicos/efeitos adversos , Peso ao Nascer , Estatura , Estudos de Coortes , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Humanos , Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Taiwan
8.
Int Clin Psychopharmacol ; 32(5): 262-270, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28542035

RESUMO

This study aimed to examine the trends and factors associated with antipsychotic prescriptions for elderly outpatients with dementia in Taiwan from 2005 to 2013. We assessed the annual prescription patterns of antipsychotic medications among elderly patients attending outpatient visits for dementia between 2005 and 2013 using the National Health Insurance Research Database in Taiwan. We also carried out logistic regression analyses to test the trends and associated factors. We found that any antipsychotic prescriptions for elderly patients making visits for dementia increased slightly, from 25.5 to 26.5%, over the 9-year period. From 2005 to 2013, prescriptions for first-generation antipsychotics only decreased from 7.8 to 3.3%, whereas second-generation antipsychotic prescriptions only increased from 17.0 to 22.2%. Elderly dementia patients who were female, older, concomitantly using other psychotropic drugs (antidepressants, benzodiazepines, and Z-drugs), and treated by psychiatrists and at regional/local hospitals were prescribed significantly more antipsychotics, whereas patients with comorbid hypertension, hyperlipidemia, diabetes, and stroke used antipsychotics significantly less. Although physicians seemed to avoid prescribing antipsychotics for elderly outpatients with dementia and certain comorbid physical disorders, second-generation antipsychotic use increased during the study period. Physicians should balance the benefits and risks of antipsychotic use to ensure the safety of dementia patients.


Assuntos
Antipsicóticos/uso terapêutico , Demência/tratamento farmacológico , Uso de Medicamentos/tendências , Padrões de Prática Médica/tendências , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Humanos , Masculino , Fatores de Risco , Fatores Sexuais , Taiwan
9.
Acta Neuropsychiatr ; 27(6): 380-5, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26503496

RESUMO

OBJECTIVE: Heat stroke is a medical emergency. Psychiatric patients are particularly susceptible to heat stroke. Therefore, awareness and preventive measures of heat stroke are important for both clinicians and patients. Case description A 49-year-old man with schizophrenia, who was under maintenance treatment with olanzapine 20 mg/day, trihexyphenidyl 4 mg/day, and trazodone 50 mg/day, suffered from heat stroke in a heat wave and required intensive care. He recovered with the medical treatment provided. Discussion Several factors could have contributed to the impaired thermoregulation and the occurrence of heat stroke in this case: schizophrenia, the psychotropic regimen, and lack of preventive measures. Possible differential diagnoses of heat stroke in this case include infection, neuroleptic malignant syndrome, and serotonin syndrome. CONCLUSION: Heat stroke can occur during the maintenance treatment of olanzapine, trihexyphenidyl, and trazodone for schizophrenia. Clinicians should be proactive to reduce the risk of heat stroke in psychiatric patients.


Assuntos
Antiparkinsonianos/administração & dosagem , Antipsicóticos/administração & dosagem , Golpe de Calor/etiologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Inibidores de Captação de Serotonina/administração & dosagem , Amissulprida , Antiparkinsonianos/efeitos adversos , Antipsicóticos/efeitos adversos , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Regulação da Temperatura Corporal/efeitos dos fármacos , Cuidados Críticos , Diagnóstico Diferencial , Interações Medicamentosas , Golpe de Calor/induzido quimicamente , Golpe de Calor/prevenção & controle , Golpe de Calor/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Olanzapina , Esquizofrenia/diagnóstico , Inibidores de Captação de Serotonina/efeitos adversos , Tentativa de Suicídio , Sulpirida/administração & dosagem , Sulpirida/efeitos adversos , Sulpirida/análogos & derivados , Trazodona/administração & dosagem , Trazodona/efeitos adversos , Triexifenidil/administração & dosagem , Triexifenidil/efeitos adversos
10.
Onco Targets Ther ; 8: 2345-60, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26366090

RESUMO

BACKGROUND: Chemotherapy is not limited to a single treatment, and the evidence demonstrates that different drug combinations can have positive results in patients. In this study, we sought to determine whether cordycepin combined with cisplatin and/or paclitaxel would have an additive effective on inducing apoptosis in mouse Leydig tumor cells, and the mechanisms were also briefly examined. METHODS: The additive effects of cordycepin combined with cisplatin and/or paclitaxel on apoptosis in MA-10 cells were investigated by monitoring changes in morphological characteristics and examining cell viability, flow cytometry assays, and Western blot analyses. RESULTS: Combination of cordycepin plus cisplatin and/or paclitaxel for 12 and 24 hours induced apoptotic features in MA-10 cells. The MTT assay showed that the combination treatment reduced the viability of MA-10 cells in a dose-dependent manner, with additive effects. Cell cycle analysis showed that combination treatment significantly increased subG1 phase cell numbers in MA-10 cells, indicating apoptosis. Moreover, cordycepin plus cisplatin and/or paclitaxel significantly induced cleavage of caspase-8, caspase-9, caspase-3, and poly ADP-ribose polymerase, and phosphorylation of c-Jun NH2-terminal kinase, extracellular signal-regulated kinase, p38, and p53 proteins in MA-10 cells. CONCLUSION: Cordycepin plus cisplatin and/or paclitaxel can have an additive effect on apoptosis in MA-10 cells, with activation of caspase, mitogen-activated protein kinase, and p53 signal pathways.

11.
Lancet Respir Med ; 1(10): 771-8, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24461756

RESUMO

BACKGROUND: Avian influenza A H6N1 virus is one of the most common viruses isolated from wild and domestic avian species, but human infection with this virus has not been previously reported. We report the clinical presentation, contact, and environmental investigations of a patient infected with this virus, and assess the origin and genetic characteristics of the isolated virus. METHODS: A 20-year-old woman with an influenza-like illness presented to a hospital with shortness of breath in May, 2013. An unsubtyped influenza A virus was isolated from her throat-swab specimen and was transferred to the Taiwan Centres for Disease Control (CDC) for identification. The medical records were reviewed to assess the clinical presentation. We did a contact and environmental investigation and collected clinical specimens from the case and symptomatic contacts to test for influenza virus. The genomic sequences of the isolated virus were determined and characterised. FINDINGS: The unsubtyped influenza A virus was identified as the H6N1 subtype, based on sequences of the genes encoding haemagglutinin and neuraminidase. The source of infection was not established. Sequence analyses showed that this human isolate was highly homologous to chicken H6N1 viruses in Taiwan and had been generated through interclade reassortment. Notably, the virus had a G228S substitution in the haemagglutinin protein that might increase its affinity for the human α2-6 linked sialic acid receptor. INTERPRETATION: This is the first report of human infection with a wild avian influenza A H6N1 virus. A unique clade of H6N1 viruses with a G228S substitution of haemagglutinin have circulated persistently in poultry in Taiwan. These viruses continue to evolve and accumulate changes, increasing the potential risk of human-to-human transmission. Our report highlights the continuous need for preparedness for a pandemic of unpredictable and complex avian influenza. FUNDING: Taiwan Centres for Disease Control.


Assuntos
DNA Viral/análise , Vírus da Influenza A/genética , Influenza Aviária/virologia , Influenza Humana/virologia , Animais , Feminino , Humanos , Influenza Aviária/epidemiologia , Influenza Humana/epidemiologia , Pandemias , Aves Domésticas , Reação em Cadeia da Polimerase em Tempo Real , Taiwan/epidemiologia , Adulto Jovem
12.
Clin Cancer Res ; 16(23): 5770-80, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-20971808

RESUMO

PURPOSE: Recent evidence indicates that a tumor suppressor gene CEBPD (CCAAT/enhancer-binding protein delta) is downregulated in many cancers including cervical cancer, which provides a therapeutic potential associated with its reactivation. However, little is known for CEBPD activators and the effect of reactivation of CEBPD transcription upon anticancer drug treatment. In this study, we identified a novel CEBPD activator, 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB). The purpose of this study is to characterize the mechanism of HMDB-induced CEBPD activation and its potential effect in cancer therapy. EXPERIMENTAL DESIGN: Methylation-specific PCR assay, reporter assay, and chromatin immunoprecipitation (ChIP) assay were performed to dissect the signaling pathway of HMDB-induced CEBPD transcription. Furthermore, a consequence of HMDB-induced CEBPD expression was linked with E2F1 and retinoblastoma (RB), which discloses the scenario of CEBPD, E2F1, and RB bindings and transcriptional regulation on the promoters of proapoptotic genes, PPARG2 and GADD153. Finally, the anticancer effect of HMDB was examined in xenograft mice. RESULTS: We demonstrate that CEBPD plays an essential role in HMDB-mediated apoptosis of cancer cells. HMDB up-regulates CEBPD transcription through the p38/CREB pathway, thus leading to transcriptional activation of PPARG2 and GADD153. Furthermore, increased level of CEBPD attenuates E2F1-induced cancer cell proliferation and partially rescues RB/E2F1-mediated repression of PPARG2 and GADD153 transcription. Moreover, HMDB treatment attenuates the growth of A431 xenografts in severe combined immunodeficient mice mice. CONCLUSIONS: These results clearly demonstrate that HMDB kills cancer cells through activation of CEBPD pathways and suggest that HMDB can serve as a superior chemotherapeutic agent with limited potential for adverse side effects.


Assuntos
Apoptose/efeitos dos fármacos , Proteína delta de Ligação ao Facilitador CCAAT/fisiologia , Fator de Transcrição E2F1/fisiologia , Cetonas/farmacologia , Neoplasias/genética , Neoplasias/patologia , Propano/análogos & derivados , Proteína do Retinoblastoma/fisiologia , Animais , Apoptose/genética , Proteína delta de Ligação ao Facilitador CCAAT/genética , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Células Cultivadas , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica/fisiologia , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Propano/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Biochemistry (Mosc) ; 75(11): 1388-92, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21314607

RESUMO

Delonix regia trypsin inhibitor (DrTI) consists of a single-polypeptide chain with a molecular mass of 22 kDa and containing two disulfide bonds (Cys44-Cys89 and Cys139-Cys149). Sequence comparison with other plant trypsin inhibitors of the Kunitz family reveals that DrTI contains a negatively charged residue (Glu68) at the reactive site rather than the conserved Arg or Lys found in other Kunitz-type trypsin inhibitors. Site-directed mutagenesis yielded five mutants containing substitutions at the reactive site and at one of the disulfide bonds. Assay of the recombinant proteins showed mutant Glu68Leu and Glu68Lys to have only 4-5% of the wild-type activity. These provide evidence that the Glu68 residue is the reactive site for DrTI and various other Kunitz-type trypsin inhibitors. The Cys139Gly mutant lost its inhibitory activity, whereas the Cys44Gly mutant did not, indicating that the second disulfide bond (Cys139-Cys149) is critical to DrTI inhibitory activity, while the first disulfide bond (Cys44-Cys89) is not required.


Assuntos
Caesalpinia , Proteínas Recombinantes de Fusão/genética , Inibidores da Tripsina/genética , Sequência de Aminoácidos , Sequência Conservada , Ensaios Enzimáticos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Proteínas Recombinantes de Fusão/química , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Tripsina/química , Inibidores da Tripsina/química
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