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1.
Foods ; 12(22)2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-38002142

RESUMO

The typical Korean diet contains a significant quantity of doenjang owing to its unique taste and health benefits. However, the presence of anti-nutritional and toxic substances, such as biogenic amines and microbial pathogens, in doenjang has resulted in a loss of revenue and poor consumer health. The present study focused on the identification and quantification of different biogenic amines, pathogenic Bacillus cereus, and yeast counts in 36 doenjang products (designated as De-1 to De-36, 500 g each) procured from the different cottage industries situated in different parts of the Republic of Korea. The results indicated, only three samples were contaminated with B. cereus, exceeding the recommended limit (4 log CFU/g) suggested by the national standards of Korea. A total of six distinct yeasts were identified in different doenjang samples, whose comprehensive enzymatic profiling suggested the absence of harmful enzymes such as N-acetyl-ß-glucosaminidase, α-chymotrypsin, and ß-glucuronidase. The biogenic amines were detected in the range of 67.68 mg/kg to 2556.68 mg/kg and classified into six major groups based on hierarchical cluster analysis. All doenjang samples contained tryptamine, putrescine, cadaverine, histamine, and tyramine, while 94.44% were positive for spermidine and spermine. The results documented the analysis of traditional cottage industry doenjang and suggest the need for constant monitoring to ensure the safety of food for the consumer.

2.
Int J Food Microbiol ; 387: 110046, 2023 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-36521240

RESUMO

Gochujang (fermented hot pepper paste) products are well known for their distinct, spicy flavor. However, frequent pack burst spoilage of gochujang products occurs during transportation and storage because of microbial aerogenesis, resulting in considerable economic losses. The present study aimed to prevent pack burst spoilage of gochujang products by supplementing them with garlic ethanol extract. A simulated pack burst experiment revealed that 42.86 % of normal gochujang products were spoiled. Garlic ethanol extract significantly inhibited the growth of Zygosaccharomyces rouxii in gochujang products, with low minimum inhibitory concentration values (12.5-25 mg/mL). Gochujang products supplemented with various concentrations (1 % and 2.5 %) of garlic ethanol extract exhibited marked inhibition of microbial growth, particularly Z. rouxii, and pack burst spoilage. Microbiome analysis revealed that the pack burst samples harbored a high abundance of Z. rouxii. Supplementation of gochujang with 1 % garlic ethanol extract drastically reduced Z. rouxii abundance and prevented pack burst. Moreover, gochujang products supplemented with 1 % garlic ethanol extract exhibited a high hedonic score in the sensory analysis. Based on the results of this study, we concluded that supplementation of gochujang products with 1 % garlic ethanol extract before packaging could be effective in preventing pack burst spoilage of gochujang.


Assuntos
Capsicum , Alho , Etanol , Antioxidantes , Suplementos Nutricionais , Extratos Vegetais
3.
Nat Commun ; 13(1): 2572, 2022 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-35546148

RESUMO

Recent development of the chemical inhibitors specific to oncogenic KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog) mutants revives much interest to control KRAS-driven cancers. Here, we report that AIMP2-DX2, a variant of the tumor suppressor AIMP2 (aminoacyl-tRNA synthetase-interacting multi-functional protein 2), acts as a cancer-specific regulator of KRAS stability, augmenting KRAS-driven tumorigenesis. AIMP2-DX2 specifically binds to the hypervariable region and G-domain of KRAS in the cytosol prior to farnesylation. Then, AIMP2-DX2 competitively blocks the access of Smurf2 (SMAD Ubiquitination Regulatory Factor 2) to KRAS, thus preventing ubiquitin-mediated degradation. Moreover, AIMP2-DX2 levels are positively correlated with KRAS levels in colon and lung cancer cell lines and tissues. We also identified a small molecule that specifically bound to the KRAS-binding region of AIMP2-DX2 and inhibited the interaction between these two factors. Treatment with this compound reduces the cellular levels of KRAS, leading to the suppression of KRAS-dependent cancer cell growth in vitro and in vivo. These results suggest the interface of AIMP2-DX2 and KRAS as a route to control KRAS-driven cancers.


Assuntos
Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Transformação Celular Neoplásica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
4.
J Korean Acad Nurs ; 52(1): 80-91, 2022 Feb.
Artigo em Coreano | MEDLINE | ID: mdl-35274622

RESUMO

PURPOSE: This study developed an instrument to evaluate the health empowerment of North Korean women refugees and examined its validity and reliability. METHODS: Through literature review and focused group interviews, 66 preliminary items with three constructs, including perceived control, perceived competence, and goal internalization were selected based on Menon's psychological health empowerment model. A questionnaire survey was conducted with 239 North Korean women refugees in the community from August 31 to September 4, 2020. Content, construct, convergent, and discriminative validity were evaluated. Cronbach's α was used to evaluate the reliability of scale. RESULTS: The final instrument consisted of 31 items with three factors that were identified through confirmatory factor analysis. The convergent validity showed that the correlation coefficient was .52 (p < .001), which confirmed the validity of the developed measurement tool. Cronbach's α for all the items was .94, and Cronbach's α for the factors was .76~.91. CONCLUSION: This health empowerment scale has been developed to include aspects of health empowerment, provide a conceptual framework, and offer objective indicators to evaluate the effectiveness of a health education program.


Assuntos
Povo Asiático , Análise Fatorial , Feminino , Humanos , Reprodutibilidade dos Testes , República da Coreia , Inquéritos e Questionários
5.
Foods ; 11(3)2022 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-35159525

RESUMO

Gochujang, fermented red pepper paste, is a grain-based Korean traditional food. The quality of gochujang produced by cottage industries is not well-documented. Thus, the present study aimed to analyze the quality of gochujang from 35 traditional cottage industries for physicochemical and microbial characteristics, along with volatile compound contents. In addition to microbial characteristics, salinity, pH, free amino nitrogen, and alcohol content were evaluated. Ethanol was detected as the predominant alcohol and 57% of tested gochujang products harbored >1% of total alcohol content, which was above the recommended level for halal products. Gochujang products contained hexadecanoic and linoleic acids predominantly and several volatile compounds belonging to the classes of alcohols, aldehydes, alkanes, nitrogen-containing compounds, and terpenes. A wide range of aerobic mesophilic bacteria (2.79-8.73 log CFU/g) and yeast counts (1.56-7.15 log CFU/g) was observed. Five distinct yeast species were identified, including Zygosaccharomyces rouxii. Eight gochujang products were found to be contaminated with Bacillus cereus (>4 log CFU/g). This study suggests that there is a need to limit B. cereus contamination in cottage industry products and reduce alcohol content to comply with halal food guidelines.

6.
Foods ; 10(10)2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34681419

RESUMO

Traditional gochujang is well known for its distinguished flavor and taste. However, the safety of cottage industry gochujang products is uncertain, particularly, in terms of biogenic amine (BA) content which is not yet documented. The present study aimed to determine the level of BAs present in 35 traditional gochujang products nationwide. All gochujang products had considerable amounts of total BAs ranging from 52.95 mg/kg to 176.24 mg/kg. Individually, histamine and tyramine were either not detected or detected up to 16.94 mg/kg and 2.15-52.34 mg/kg, respectively. In all the tested gochujang products, putrescine, spermidine, and spermine were detected in the range of 7.60-56.72 mg/kg, 14.96-36.93 mg/kg, and 4.68-16.31 mg/kg, respectively. A total of 22 and 19 gochujang products had less than 1 mg/kg of cadaverine and histamine, respectively. The findings indicate that all the gochujang products tested herein had BA levels below the suggested toxicity limits recommended by the various regulatory authorities, which reveal that they are safe for human consumption.

7.
J Pharmacol Exp Ther ; 379(3): 358-371, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34503993

RESUMO

Although protein-protein interactions (PPIs) have emerged as an attractive therapeutic target space, the identification of chemicals that effectively inhibit PPIs remains challenging. Here, we identified through library screening a chemical probe (compound 1) that can inhibit the tumor-promoting interaction between the oncogenic factor exon 2-depleted splice variant of aminoacyl-transfer RNA synthetase-interacting multifunctional protein 2 (AIMP2-DX2) and heat shock protein 70 (HSP70). We found that compound 1 binds to the N-terminal subdomain of glutathione S-transferase (GST-N) of AIMP2-DX2, causing a direct steric clash with HSP70 and an intramolecular interaction between the N-terminal flexible region and the GST-N of AIMP2-DX2, which induces masking of the HSP70 binding region during molecular dynamics and mutation studies. Compound 1 thus interferes with the AIMP2-DX2 and HSP70 interaction and suppresses the growth of cancer cells that express high levels of AIMP2-DX2 in vitro and in preliminary in vivo experiment. This work provides an example showing that allosteric conformational changes induced by chemicals can be a way to control pathologic PPIs. SIGNIFICANCE STATEMENT: Compound 1 is a promising protein-protein interaction inhibitor between AIMP2-DX2 and HSP70 for cancer therapy by the mechanism with allosteric modulation as well as competitive binding. It seems to induce allosteric conformational change of AIMP2-DX2 proteins and direct binding clash between AIMP2-DX2 and HSP70. The compound reduced the level of AIMP2-DX2 in ubiquitin-dependent manner via suppression of binding between AIMP2-DX2 and HSP70 and suppressed the growth of cancer cells highly expressing AIMP2-DX2 in vitro and in preliminary in vivo experiment.


Assuntos
Antineoplásicos/farmacologia , Éxons/fisiologia , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Células A549 , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Células CHO , Sobrevivência Celular , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Éxons/efeitos dos fármacos , Feminino , Células HEK293 , Proteínas de Choque Térmico HSP70/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Nucleares/química , Ligação Proteica/fisiologia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
Molecules ; 25(12)2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32549310

RESUMO

While aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) is a tumor suppressor, its exon 2-depleted splice variant (AIMP2-DX2 or shortly DX2) is highly expressed in human lung cancer, and the ratio of DX2 to AIMP2 increases according to the progression of lung cancer. In this study, pyrimethamine inhibited the level of DX2 (IC50 = 0.73 µM) in A549 cells expressing nanoluciferase-tagged DX2. In a panel of 5 lung cancer cell lines with various DX2 levels, pyrimethamine most potently suppressed the growth of H460 cells, which express high levels of DX2 (GI50 = 0.01 µM). An immunoblot assay in H460 cells showed that pyrimethamine decreased the DX2 level dose-dependently but did not affect the AIMP2 level. Further experiments confirmed that pyrimethamine resulted in ubiquitination-mediated DX2 degradation. In an in vivo mouse xenograft assay using H460 cells, intraperitoneal administration of pyrimethamine significantly reduced the tumor size and weight, comparable with the effects of taxol, without affecting body weight. Analysis of tumor tissue showed a considerably high concentration of pyrimethamine with a decreased levels of DX2. These results suggest that pyrimethamine, currently used as anti-parasite drug, could be repurposed to treat lung cancer patients expressing high level of DX2.


Assuntos
Proteínas Nucleares/metabolismo , Pirimetamina/química , Pirimetamina/farmacologia , Células A549 , Aminoacil-tRNA Sintetases/metabolismo , Animais , Linhagem Celular Tumoral , Éxons , Feminino , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Nucleares/fisiologia , Ubiquitina/genética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Biomolecules ; 10(6)2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32471182

RESUMO

AIMP2-DX2, an exon 2-deleted splice variant of AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein 2), is highly expressed in lung cancer and involved in tumor progression in vivo. Oncogenic function of AIMP2-DX2 and its correlation with poor prognosis of cancer patients have been well established; however, the application of this potentially important biomarker to cancer research and diagnosis has been hampered by a lack of antibodies specific for the splice variant, possibly due to the poor immunogenicity and/or stability of AIMP2-DX2. In this study a monoclonal antibody, H5, that specifically recognizes AIMP2-DX2 and its isoforms was generated via rabbit immunization and phage display techniques, using a short peptide corresponding to the exon 1/3 junction sequence as an antigen. Furthermore, based on mutagenesis, limited cleavage, and mass spectrometry studies, it is also suggested that the endogenous isoform of AIMP2-DX2 recognized by H5 is produced by proteolytic cleavage of 33 amino acids from N-terminus and is capable of inducing cell proliferation similarly to the uncleaved protein. H5 monoclonal antibody is applicable to enzyme-linked immunosorbent assay, immunoblot, immunofluorescence, and immunohistochemistry, and expected to be a valuable tool for detecting AIMP2-DX2 with high sensitivity and specificity for research and diagnostic purposes.


Assuntos
Anticorpos Monoclonais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteínas Nucleares/genética , Isoformas de Proteínas/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Células Cultivadas , Cricetulus , Humanos , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/isolamento & purificação , Proteínas Nucleares/metabolismo , Coelhos
10.
J Med Chem ; 63(10): 5139-5158, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32315177

RESUMO

AIMP2-DX2, a splicing variant of AIMP2, is up-regulated in lung cancer, possesses oncogenic activity, and results in tumorigenesis. Specifically inhibiting the interaction between AIMP2-DX2 and HSP70 to suppress AIMP2-DX2-dependent cancers with small molecules is considered a promising avenue for cancer therapeutics. Optimization of hit BC-DXI-04 (IC50 = 40.1 µM) provided new potent sulfonamide based AIMP2-DX2 inhibitors. Among these, BC-DXI-843 showed improved inhibition against AIMP2-DX2 (IC50 = 0.92 µM) with more than 100-fold selectivity over AIMP2 in a luciferase assay. Several binding assays indicated that this compound effectively induces cancer cell apoptosis by specifically interrupting the interaction between DX2 and HSP70, which leads to the degradation of DX2 via Siah1-mediated ubiquitination. More importantly, BC-DXI-843 demonstrated in vivo efficacy in a tumor xenograft mouse model (H460 cells) at a dosage of 50 mg/kg, suggesting it as a promising lead for development of novel therapeutics targeting AIMP2-DX2 in lung cancer.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Desenvolvimento de Medicamentos/métodos , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Células A549 , Animais , Antineoplásicos/farmacologia , Sulfonatos de Arila/síntese química , Sulfonatos de Arila/metabolismo , Sulfonatos de Arila/farmacologia , Células CHO , Cricetinae , Cricetulus , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
11.
J Med Chem ; 63(8): 3908-3914, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32208684

RESUMO

Aminoacyl-tRNA synthetase interacting multifunctional proteins (AIMPs) have recently been considered novel therapeutic targets in several cancers. In this publication we report the development of novel 2-aminophenylpyrimidines as new AIMP2-DX2 inhibitors. In particular, aminophenylpyrimidine 3 not only exhibited promising in vitro and in vivo potency but also exerted selective inhibition of H460 and A549 cells and AIMP2-DX2 rather than WI-26 cells and AIMP2. Aminophenylpyrimidine 3 offers possible therapeutic potential in the treatment of lung cancer.


Assuntos
Aminoacil-tRNA Sintetases/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Células A549 , Aminoacil-tRNA Sintetases/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Nucleares/metabolismo , Pirimidinas/química , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
12.
Nat Chem Biol ; 16(1): 31-41, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31792442

RESUMO

A tumorigenic factor, AIMP2 lacking exon 2 (AIMP2-DX2), is often upregulated in many cancers. However, how its cellular level is determined is not understood. Here, we report heat-shock protein HSP70 as a critical determinant for the level of AIMP2-DX2. Interaction of the two factors was identified by interactome analysis and structurally determined by X-ray crystallography and NMR analyses. HSP70 recognizes the amino (N)-terminal flexible region, as well as the glutathione S-transferase domain of AIMP2-DX2, via its substrate-binding domain, thus blocking the Siah1-dependent ubiquitination of AIMP2-DX2. AIMP2-DX2-induced cell transformation and cancer progression in vivo was further augmented by HSP70. A positive correlation between HSP70 and AIMP2-DX2 levels was shown in various lung cancer cell lines and patient tissues. Chemical intervention in the AIMP2-DX2-HSP70 interaction suppressed cancer cell growth in vitro and in vivo. Thus, this work demonstrates the importance of the interaction between AIMP2-DX2 and HSP70 on tumor progression and its therapeutic potential against cancer.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/metabolismo , Processamento Alternativo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Cristalografia por Raios X , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Ligação Proteica , Mapeamento de Interação de Proteínas , Multimerização Proteica , Ressonância de Plasmônio de Superfície , Ubiquitina/química
13.
Exp Mol Med ; 51(9): 1-14, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31558706

RESUMO

The enhanced productive folding of translated polypeptides by heat shock protein 70 (HSP70) is often required for the survival of cancer cells. Although the folding activity of HSP70 is considered a significant determinant of the progression of cancer cells, it is still unknown how this activity could be regulated. Here, we report that the phosphorylation of HSP70 facilitates its folding activity, enhancing cell proliferation. Mass spectrometry identified the serine residues at positions 385 and 400 in the linker and substrate-binding domains of HSP70, respectively, as sites of phosphorylation mediated by EGF signaling, and this result was further confirmed by site-directed mutagenesis. ERK is known to be a specific kinase. The phosphorylation of the two sites induces the extended conformation of HSP70 via the regulation of the binding of the linker to the nucleotide- and substrate-binding domains, augmenting the binding affinity of HSP70 to substrates and enhancing its folding activity; this ultimately results in pro-proliferative effects. Cell lines harboring activated ERK showed increased phosphorylation of HSP70, and a positive correlation between the phosphorylation of HSP70 and the activity of ERK was observed. Thus, this study demonstrated that the ERK-dependent phosphorylation of HSP70 facilitated its folding activity and cellular proliferative function.


Assuntos
Proliferação de Células/genética , Proteínas de Choque Térmico HSP70/genética , Chaperonas Moleculares/genética , Neoplasias/genética , Animais , Linhagem Celular Tumoral , Fator de Crescimento Epidérmico/genética , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Mutagênese Sítio-Dirigida , Neoplasias/patologia , Fosforilação , Dobramento de Proteína
14.
Mol Nutr Food Res ; 60(5): 1068-78, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26918318

RESUMO

SCOPE: Cruciferous vegetables harbor a number of isothiocyanates that have been recognized for their cancer-related properties. Out of these, sulforaphene (a naturally occurring derivative of sulforaphane) has received little attention in studies of colon cancer and its mechanism of action remains to be elucidated. METHODS AND RESULTS: We observed that sulforaphene inhibited growth of human colon cancer cell lines HCT116, HT-29, KM12, SNU-1040, and DLD-1, while exhibiting negligible toxicity toward nonmalignant cells. Sulforaphene induced G2/M phase cell cycle arrest and apoptosis of colon cancer cells analyzed by flow cytometry, concomitant with phosphorylation of CDK1 and CDC25B at inhibitory sites, and upregulation of the p38 and JNK pathways. It was further determined that sulforaphene is a potent inhibitor of microtubule polymerization while generating reactive oxygen species via the depletion of glutathione. These observations further extended into inhibitory effects against colon tumor growth in a mouse xenograft model. CONCLUSION: These findings demonstrate that sulforaphene may contribute to the anti-tumor effects of cruciferous vegetables that contain sulforaphene and other isothiocyanates.


Assuntos
Antineoplásicos/farmacologia , Neoplasias do Colo/patologia , Glutationa/metabolismo , Isotiocianatos/farmacologia , Microtúbulos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteína Quinase CDC2/genética , Proteína Quinase CDC2/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HCT116 , Células HT29 , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Nus , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Fosfatases cdc25/genética , Fosfatases cdc25/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
PLoS One ; 10(11): e0142624, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26555441

RESUMO

Despite the growing attention given to Traditional Medicine (TM) worldwide, there is no well-known, publicly available, integrated bio-pharmacological Traditional Korean Medicine (TKM) database for researchers in drug discovery. In this study, we have constructed PharmDB-K, which offers comprehensive information relating to TKM-associated drugs (compound), disease indication, and protein relationships. To explore the underlying molecular interaction of TKM, we integrated fourteen different databases, six Pharmacopoeias, and literature, and established a massive bio-pharmacological network for TKM and experimentally validated some cases predicted from the PharmDB-K analyses. Currently, PharmDB-K contains information about 262 TKMs, 7,815 drugs, 3,721 diseases, 32,373 proteins, and 1,887 side effects. One of the unique sets of information in PharmDB-K includes 400 indicator compounds used for standardization of herbal medicine. Furthermore, we are operating PharmDB-K via phExplorer (a network visualization software) and BioMart (a data federation framework) for convenient search and analysis of the TKM network. Database URL: http://pharmdb-k.org, http://biomart.i-pharm.org.


Assuntos
Sistemas de Gerenciamento de Base de Dados , Medicina Tradicional , Integração de Sistemas , República da Coreia
16.
J Biol Chem ; 290(39): 23553-62, 2015 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-26242912

RESUMO

Bioactive phytochemicals can suppress the growth of malignant cells, and investigation of the mechanisms responsible can assist in the identification of novel therapeutic strategies for cancer therapy. Ginger has been reported to exhibit potent anti-cancer effects, although previous reports have often focused on a narrow range of specific compounds. Through a direct comparison of various ginger compounds, we determined that gingerenone A selectively kills cancer cells while exhibiting minimal toxicity toward normal cells. Kinase array screening revealed JAK2 and S6K1 as the molecular targets primarily responsible for gingerenone A-induced cancer cell death. The effect of gingerenone A was strongly associated with relative phosphorylation levels of JAK2 and S6K1, and administration of gingerenone A significantly suppressed tumor growth in vivo. More importantly, the combined inhibition of JAK2 and S6K1 by commercial inhibitors selectively induced apoptosis in cancer cells, whereas treatment with either agent alone did not. These findings provide rationale for dual targeting of JAK2 and S6K1 in cancer for a combinatorial therapeutic approach.


Assuntos
Apoptose/efeitos dos fármacos , Diarileptanoides/farmacologia , Inibidores Enzimáticos/farmacologia , Janus Quinase 2/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Janus Quinase 2/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
17.
J Biol Chem ; 288(33): 23740-50, 2013 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-23833193

RESUMO

Resistance to cisplatin (CDDP) in ovarian cancer (OVCA) arises from the dysregulation of tumor suppressors and survival signals. During genotoxic challenge, these factors can be influenced by secondary agents that facilitate the induction of apoptosis. Piceatannol is a natural metabolite of the stilbene resveratrol found in grapes and is converted from its parent compound by the enzyme CYP1BA1 p450. It has been hypothesized to exert specific effects against various cellular targets; however, its ability to influence CDDP resistance in cancer cells has not been investigated to date. Here, we show that piceatannol is a potent enhancer of CDDP sensitivity in OVCA, and this effect is achieved through the modulation of several major determinants of chemoresistance. Piceatannol enhances p53-mediated expression of the pro-apoptotic protein NOXA, increases XIAP degradation via the ubiquitin-proteasome pathway, and enhances caspase-3 activation. This response is associated with an increase in Drp1-dependent mitochondrial fission, leading to more effective induction of apoptosis. In vivo studies using a mouse model of OVCA reveal that a number of these changes occur in association with a greater overall reduction in tumor weight when mice are treated with both piceatannol and CDDP, in comparison to treatment with either agent alone. Taken together, these findings demonstrate the potential application of piceatannol to enhance CDDP sensitivity in OVCA, and it acts on p53, XIAP, and mitochondrial fission.


Assuntos
Cisplatino/uso terapêutico , Dinâmica Mitocondrial , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Estilbenos/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Dinaminas/metabolismo , Feminino , Humanos , Camundongos , Dinâmica Mitocondrial/efeitos dos fármacos , Modelos Biológicos , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Ubiquitinação/efeitos dos fármacos
18.
Clin Cancer Res ; 19(14): 3894-904, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23748694

RESUMO

PURPOSE: Common treatment modalities for non-small cell lung cancer (NSCLC) involve the EGF receptor-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib. However, the vast majority of treated patients acquire resistance to EGFR-TKIs, due, in large part, to secondary mutations in EGFR or amplification of the MET gene. Our purpose was to test ubiquitin-specific peptidase 8 (USP8) as a potential therapeutic target for gefitinib-resistant and -sensitive non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Testing the effect of knockdown of USP8 and use of a synthetic USP8 inhibitor to selectively kill gefitinib-resistant (or -sensitive) NSCLCs with little effect on normal cells in cell culture and a xenograft mouse model. RESULTS: Knockdown of ubiquitin-specific peptidase 8 (USP8) selectively kills gefitinib-resistant NSCLCs while having little toxicity toward normal cells. Genetic silencing of USP8 led to the downregulation of several receptor tyrosine kinases (RTK) including EGFR, ERBB2, ERBB3, and MET. We also determined that a synthetic USP8 inhibitor markedly decreased the viability of gefitinib-resistant and -sensitive NSCLC cells by decreasing RTK expression while having no effect on normal cells. Moreover, treatment with a USP8 inhibitor led to significant reductions in tumor size in a mouse xenograft model using gefitinib-resistant and -sensitive NSCLC cells. CONCLUSIONS: Our results show for the first time that the inhibition of USP8 activity or reduction in USP8 expression can selectively kill NSCLC cells. We propose USP8 as a potential therapeutic target for gefitinib-resistant and -sensitive NSCLC cells.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Endopeptidases/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/farmacologia , Ubiquitina Tiolesterase/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Linhagem Celular Tumoral , Sobrevivência Celular , Endopeptidases/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/antagonistas & inibidores , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Gefitinibe , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/enzimologia , Masculino , Camundongos , Camundongos Nus , Inibidores de Proteases/farmacologia , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/genética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Nutr Biochem ; 24(6): 1096-104, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23318138

RESUMO

Abnormal regulation of Ca(2+) mediates tumorigenesis and Ca(2+) channels are reportedly deregulated in cancers, indicating that regulating Ca(2+) signaling in cancer cells is considered as a promising strategy to treat cancer. However, little is known regarding the mechanism by which Ca(2+) affects cancer cell death. Here, we show that 20-O-ß-d-glucopyranosyl-20(S)-protopanaxadiol (20-GPPD), a metabolite of ginseng saponin, causes apoptosis of colon cancer cells through the induction of cytoplasmic Ca(2+). 20-GPPD decreased cell viability, increased annexin V-positive early apoptosis and induced sub-G1 accumulation and nuclear condensation of CT-26 murine colon cancer cells. Although 20-GPPD-induced activation of AMP-activated protein kinase (AMPK) played a key role in the apoptotic death of CT-26 cells, LKB1, a well-known upstream kinase of AMPK, was not involved in this activation. To identify the upstream target of 20-GPPD for activating AMPK, we examined the effect of Ca(2+) on apoptosis of CT-26 cells. A calcium chelator recovered 20-GPPD-induced AMPK phosphorylation and CT-26 cell death. Confocal microscopy showed that 20-GPPD increased Ca(2+) entry into CT-26 cells, whereas a transient receptor potential canonical (TRPC) blocker suppressed Ca(2+) entry. When cells were treated with a TRPC blocker plus an endoplasmic reticulum (ER) calcium blocker, 20-GPPD-induced calcium influx was completely inhibited, suggesting that the ER calcium store, as well as TRPC, was involved. In vivo mouse CT-26 allografts showed that 20-GPPD significantly suppressed tumor growth, volume and weight in a dose-dependent manner. Collectively, 20-GPPD exerts potent anticarcinogenic effects on colon carcinogenesis by increasing Ca(2+) influx, mainly through TRPC channels, and by targeting AMPK.


Assuntos
Antineoplásicos/farmacologia , Cálcio/metabolismo , Neoplasias do Colo/tratamento farmacológico , Ginsenosídeos/farmacologia , Panax/química , Canais de Cátion TRPC/metabolismo , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose , Morte Celular , Sobrevivência Celular , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação , Transdução de Sinais , Canais de Cátion TRPC/antagonistas & inibidores
20.
Carcinogenesis ; 34(2): 397-405, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23161610

RESUMO

Apigenin, a flavonoid abundant in various vegetables and fruits, including parsley and onions, has been reported to possess anticarcinogenic effects. However, the direct molecular target of apigenin and its chemopreventive effect on ultraviolet (UV)-induced skin inflammation are not understood fully. Herein, we examined the anti-inflammatory effect of apigenin and its associated mechanisms in JB6 P+ cell line and SKH-1 hairless mouse model. Apigenin inhibited UVB-induced cyclooxygenase-2 (COX-2) expression, which is a well-known key mediator of inflammation and cancer, and restored the upstream stimulatory factor level in JB6 P+ cells. Immunoblot and kinase assay data demonstrate that Src activity was attenuated by apigenin, and this led to subsequent inhibition of UVB-induced phosphorylation of epidermal growth factor receptor, mitogen-activated protein kinases and Akt signaling. Inhibitory effects of apigenin on UVB-induced signaling were also confirmed in HaCaT human keratinocytes. In addition, in vitro pull-down assays revealed that apigenin binds Src in an adenosine triphosphate-competitive manner. Results using in vivo skin model indicate apigenin significantly inhibits UVB-induced ear edema development, COX-2 expression and Src kinase activity in SKH-1 hairless mice. Collectively, these findings suggest that apigenin exerts potent chemopreventive activity against UVB-induced skin inflammation primarily by targeting Src.


Assuntos
Apigenina/farmacologia , Dermatite/prevenção & controle , Neoplasias Induzidas por Radiação/prevenção & controle , Neoplasias Cutâneas/prevenção & controle , Raios Ultravioleta/efeitos adversos , Quinases da Família src/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Células Cultivadas , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Dermatite/etiologia , Dermatite/patologia , Receptores ErbB/metabolismo , Feminino , Humanos , Immunoblotting , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Luciferases/genética , Luciferases/metabolismo , Camundongos , Camundongos Pelados , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Induzidas por Radiação/etiologia , Neoplasias Induzidas por Radiação/patologia , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Regiões Promotoras Genéticas/genética , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologia , Quinases da Família src/metabolismo
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