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1.
Medicine (Baltimore) ; 100(32): e26880, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397904

RESUMO

ABSTRACT: Poor oral hygiene can be potentially life-threatening in inpatients. However, no basic protocol on oral hygiene customized for inpatients exists, and lack of oral care related knowledge, attitude, and skills among caregivers could be detrimental to the general health of patients. This study sought to identify the oral care practices and oral health status of inpatients with varying physical activity limitations in a rehabilitation ward.Sixty-one inpatients in a rehabilitation ward were evaluated for their medical and physical conditions and oral health status. These were assessed using the bedside oral exam, decayed, missing, filled teeth index, plaque index, gingival index, and caries activity test.In total, 40 men and 21 women (mean age, 56.6 years) were included in this study. Among them, 50.8% of the patients could brush their teeth unassisted, whereas 49.2% required assistance from an assistant for oral care. The proportion of patients receiving nasogastric tube feeding was higher in the group that could not provide oral self-care; 36.7% and 33.3% of these patients showed moderate and severe dysfunction, respectively, based on bedside oral exam. Scores for the swallowing, tongue, and total domains of bedside oral exam were poorer for patients who could not provide oral self-care (P < .01). The caries activity test indicated a moderate risk for both groups.Our findings suggest that an oral care protocol that considers the physical activity limitations in inpatients in rehabilitation wards is necessary to minimize negative influences on the systemic health of these patients.


Assuntos
Atividades Cotidianas , Cárie Dentária , Saúde Bucal/normas , Higiene Bucal , Autocuidado , Cuidadores/educação , Cárie Dentária/diagnóstico , Cárie Dentária/prevenção & controle , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Pacientes Internados/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Determinação de Necessidades de Cuidados de Saúde , Higiene Bucal/educação , Higiene Bucal/métodos , Índice Periodontal , Desempenho Físico Funcional , Centros de Reabilitação/estatística & dados numéricos , República da Coreia/epidemiologia , Autocuidado/métodos , Autocuidado/estatística & dados numéricos
2.
Int J Dent Hyg ; 19(3): 340-349, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34092027

RESUMO

OBJECTIVE: This study aimed to develop and assess a tool for measuring violence experienced by clinical dental hygienists in the workplace. METHODS: The basic questionnaire used in this study was created by referring to previous studies, the Negative Acts Questionnaire-Revised (NAQ-R) and the Workplace Bullying in Nursing-Type Inventory (WPBN-TI). The content feasibility was verified by ten experts in the field, and irrelevant questions were deleted, based on a content validity index value of 0.8. This study surveyed 205 clinical dental hygienists to test the tool's validity and reliability. Frequency analysis was conducted on items related to general characteristics and workplace violence. RESULTS: The questionnaire set was 31 questions, which, comprised five domains, were finalized through reliability verification. These domains were verbal attacks and alienation (9 questions), inappropriate work experiences (6 questions), physical threats (4 questions), workplace sexual harassment (6 questions) and verbal violence (6 questions) from patients and their family members. Among the study participants, 47.3% said they received rude signals from others, 17.9% said they were subjected to sexual evaluations regarding their appearance, and 29.4% said their abilities were ignored by patients and family members of patients. CONCLUSIONS: Clinical dental hygienists have been exposed to various types of violence in their workplaces, such as sexual and verbal harassment, by patients and their family members. This tool can be used in the dental setting to conduct surveys on workplace violence and establish a monitoring and support system.


Assuntos
Bullying , Violência no Trabalho , Higienistas Dentários , Humanos , Reprodutibilidade dos Testes , Inquéritos e Questionários , Local de Trabalho
3.
Pharmaceuticals (Basel) ; 14(1)2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33419162

RESUMO

Rearranged during transfection (RET), a receptor tyrosine kinase, is activated by glial cell line-derived neurotrophic factor family ligands. Chromosomal rearrangement or point mutations in RET are observed in patients with papillary thyroid and medullary thyroid carcinomas. Oncogenic alteration of RET results in constitutive activation of RET activity. Therefore, inhibiting RET activity has become a target in thyroid cancer therapy. Here, the anti-tumor activity of a novel RET inhibitor was characterized in medullary thyroid carcinoma cells. The indirubin derivative LDD-2633 was tested for RET kinase inhibitory activity. In vitro, LDD-2633 showed potent inhibition of RET kinase activity, with an IC50 of 4.42 nM. The growth of TT thyroid carcinoma cells harboring an RET mutation was suppressed by LDD-2633 treatment via the proliferation suppression and the induction of apoptosis. The effects of LDD-2633 on the RET signaling pathway were examined; LDD-2633 inhibited the phosphorylation of the RET protein and the downstream molecules Shc and ERK1/2. Oral administration of 20 or 40 mg/kg of LDD-2633 induced dose-dependent suppression of TT cell xenograft tumor growth. The in vivo and in vitro experimental results supported the potential use of LDD-2633 as an anticancer drug for thyroid cancers.

4.
Eur J Med Chem ; 195: 112205, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32272419

RESUMO

FMS-like receptor tyrosine kinase-3 (FLT3) is expressed on acute leukemia cells and is implicated in the survival, proliferation and differentiation of hematopoietic cells in most acute myeloid leukemia (AML) patients. Despite recent achievements in the development of FLT3-targeted small-molecule drugs, there are still unmet medical needs related to kinase selectivity and the progression of some mutant forms of FLT3. Herein, we describe the discovery of novel orally available type 1 FLT3 inhibitors from structure-activity relationship (SAR) studies for the optimization of indirubin derivatives with biological and pharmacokinetic profiles as potential therapeutic agents for AML. The SAR exploration provided important structural insights into the key substituents for potent inhibitory activities of FLT3 and in MV4-11 cells. The profile of the most optimized inhibitor (36) showed IC50 values of 0.87 and 0.32 nM against FLT3 and FLT3/D835Y, respectively, along with potent inhibition against MV4-11 and FLT3/D835Y expressed MOLM14 cells with a GI50 value of 1.0 and 1.87 nM, respectively. With the high oral bioavailability of 42.6%, compound 36 displayed significant in vivo antitumor activity by oral administration of 20 mg/kg once daily dosing schedule for 21 days in a mouse xenograft model. The molecular docking study of 36 in the homology model of the DFG-in conformation of FLT3 resulted in a reasonable binding mode in type 1 kinases similar to the reported type 1 FLT3 inhibitors Crenolanib and Gilteritinib.


Assuntos
Desenho de Fármacos , Indóis/química , Indóis/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Oximas/química , Oximas/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Indóis/administração & dosagem , Indóis/metabolismo , Leucemia Mieloide Aguda/patologia , Camundongos , Simulação de Acoplamento Molecular , Oximas/administração & dosagem , Oximas/metabolismo , Fosforilação/efeitos dos fármacos , Conformação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/química , Tirosina Quinase 3 Semelhante a fms/metabolismo
5.
Int J Dent Hyg ; 17(4): 336-342, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31344752

RESUMO

OBJECTIVES: To investigate registered nurses' awareness and implementation of oral health care in patients who are hospitalized in general wards or intensive care units (ICUs) in South Korea. METHODS: This research was performed as a descriptive survey of 149 nurses working in nine general hospitals with at least 100 beds in major Korean cities. RESULTS: Approximately half (40.9%) of the survey respondents reported providing oral health care for hospitalized patients but that relevant protocols were not available at most hospitals or wards (89.5%). Nurses working in an ICU were significantly more likely to provide oral health care than those working in general wards (83.9% vs 15.1%; P < .001). Most respondents (83.2%) were aware of the importance of providing oral health care for hospitalized patients; however, the proportion considering that such care should be provided by dental hygienists was greater than that considering it should be provided by nurses (36.4% vs 26.0%; P < .001). Agreement that oral health care should be provided for hospitalized patients by dental hygienists was highest in nurses working in ICUs (53.3%; P < .001). CONCLUSIONS: According to this survey, oral healthcare provision is generally low in hospitalized patients and differs between ICUs and general wards. Most respondents considered that dental hygienists should provide oral health care for hospitalized patients. There is an opportunity for nurses and dental hygienists to work collaboratively towards development of an evidence-based protocol for oral health care in hospitalized patients.


Assuntos
Higienistas Dentários , Saúde Bucal , Atenção à Saúde , Humanos , República da Coreia , Inquéritos e Questionários
6.
Oncol Lett ; 17(5): 4735-4741, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30944659

RESUMO

Fms-like tyrosine kinase 3 (FLT3) is a valuable pharmacological target in the treatment of acute myeloid leukemia (AML). LDD-1075 and LDD-1076 are indirubin derivatives, and LDD-1075 is the ester form of LDD-1076. LDD-1076 exhibited a potent in vitro FLT3 kinase activity inhibition with an IC50 of 7.89 nM, whereas, LDD-1075 demonstrated a relatively weak activity against FLT3 (IC50 of 3.19 µM). In contrast with the results of the FLT3 kinase activity inhibition assay, the LDD-1076 did not affect the growth of the MV4-11 cell line, which harbors the constitutively activated form of the FLT3 mutation. Notably, LDD-1075 exhibited a strong cytotoxic effect against the MV4-11 cells. When LDD-1075 was incubated with the MV4-11 cell lysate, the formation of LDD-1076 was observed. Treatment with LDD-1075 inhibited the FLT3 phosphorylation along with the phosphorylation of the signal transducer and activator of transcription 5 protein, which is a downstream signal transducer of FLT3. Treatment with LDD-1075 induced apoptosis and cell cycle arrest at the G1 phase. The present study demonstrated that the LDD-1076 formed by the bioconversion of LDD-1075 is a potent FLT3 inhibitor with anti-leukemic activity.

7.
Biomol Ther (Seoul) ; 27(2): 216-221, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30060294

RESUMO

The c-Met protein is a receptor tyrosine kinase involved in cell growth, proliferation, survival, and angiogenesis of several human tumors. Overexpression of c-Met has been found in gastric cancers and correlated with a poor prognosis. Indirubin is the active component of Danggui Longhui Wan, which is a traditional Chinese antileukemic recipe. In the present study, we tested the anti-cancer effects of an indirubin derivative, LDD-1937, on human gastric cancer cells SNU-638. When we performed the in vitro kinase assay against the c-Met activity, LDD-1937 inhibited the activity of c-Met. This result was confirmed by immunoblot and immunofluorescence of phosphorylated c-Met. Immunoblot analysis showed that LDD-1937 decreased the expression of the Erk1/2, STAT3, STAT5, and Akt, downstream proteins of c-Met. In addition, LDD-1937 reduced the cell viability and suppressed colony formation and migration of SNU-638 cells. Furthermore, LDD-1937 induced G2/M phase arrest in the SNU-638 cells by decreasing the expression levels of cyclin B1 and CDC2. Cleaved-PARP, an apoptosis-related protein, was up-regulated in cells treated with LDD-1937. Overall, this study suggests that LDD-1937 may be a novel small-molecule with therapeutic potential for selectively inhibiting c-Met and c-Met downstream pathways in human gastric cancers overexpressing c-Met.

9.
J Phys Ther Sci ; 30(3): 398-399, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29581658

RESUMO

[Purpose] The purpose of this study was to examine the effects of interferential current therapy on the shoulder muscles of subjects with forward head posture. [Subjects and Methods] Thirty volunteers (15 forward head posture, 15 control) participated in this study. Interferential current therapy treatment was conducted for 10 min, three times per week, for 3 weeks on both the upper trapezius and levator scapulae. Subjects were measured anterior both acromion distance and posterior both acromial distance using a ruler, and the forward head posture angle using an electronic application. [Results] Both groups showed significant increases in anterior acromial distance, and decreases in posterior acromial distance and forward head posture angle. [Conclusion] Subjects were concluded that electrical therapy could improve structural alignment; therefore, the implementation of interferential current therapy is expected to be effective for the treatment of forward head posture.

10.
Oncotarget ; 9(1): 924-936, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29416667

RESUMO

FMS-like receptor tyrosine kinase-3 (FLT3) belongs to the family of receptor tyrosine kinase (RTK), and the FLT3 mutation is observed in 1/3 of all acute myeloid leukemia (AML) patients. Potential FLT3 inhibitors have been investigated as potential therapeutic agents of AML. In this study, we identified a potent FLT3 inhibitor LDD1937 containing an indirubin skeleton. The potent inhibitory activity of LDD1937 against FLT3 was shown with an in vitro kinase assay (IC50 = 3 nM). The LDD1937 compound selectively inhibited the growth of MV-4-11 cells (GI50 = 1 nM) and induced apoptotic cell death. LDD1937 caused cell cycle arrest at the G2/M phase and increased the cell population at the sub-G1 phase. Phosphorylation of STAT5, which is the downstream signaling of FLT3, was significantly reduced by LDD1937 in a dose-dependent manner. The pharmacokinetic properties of LDD1937 were investigated in mice. Then, the in vivo anti-tumor effect was investigated using a MV-4-11 xenograft. With the intravenous administration of 5 and 10 mg/kg in nu/nu mice, the tumor volume and weight were significantly reduced compared to the control. LDD1937 is a promising therapeutic candidate to treat AML patients because of its ability to suppress tumor cell growth in vitro and in vivo.

11.
Invest New Drugs ; 35(6): 733-741, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28905188

RESUMO

Lysine (K)-specific demethylase 4A (KDM4A) is a histone demethylase that removes methyl residues from trimethylated or dimethylated histone 3 at lysines 9 and 36. Overexpression of KDM4A is found in various cancer types. To identify KDM4A inhibitors with anti-tumor functions, screening with an in vitro KDM4A enzyme activity assay was carried out. The benzylidenehydrazine analogue LDD2269 was selected, with an IC50 of 6.56 µM of KDM4A enzyme inhibition, and the binding mode was investigated using in silico molecular docking. Demethylation inhibition by LDD2269 was confirmed with a cell-based assay using antibodies against methylated histone at lysines 9 and 36. HCT-116 colon cancer cell line proliferation was suppressed by LDD2269, which also interfered with soft-agar growth and migration of HCT-116 cells. AnnexinV staining and PARP cleavage experiments showed apoptosis induction by LDD2269. Derivatives of LDD2269 were synthesized and the structure-activity relationship was explored. LDD2269 is reported here as a strong inhibitor of KDM4A in in vitro and cell-based systems, with anti-tumor functions.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos de Benzil/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Inibidores Enzimáticos/farmacologia , Hidrazinas/farmacologia , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Antineoplásicos/química , Compostos de Benzil/química , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/enzimologia , Inibidores Enzimáticos/química , Humanos , Hidrazinas/química , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
12.
Drug Des Devel Ther ; 11: 2605-2619, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28919711

RESUMO

Manganese (Mn) is an important mineral element required in trace amounts for development of the human body, while over- or chronic-exposure can cause serious organ toxicity. The current study was designed to evaluate the protective role of quercetin (Qct) against Mn-induced toxicity in the liver, kidney, lung, and hematological parameters in acute and subchronic rat models. Male Sprague Dawley rats were divided into control, Mn (100 mg/kg for acute model and 15 mg/kg for subchronic model), and Mn + Qct (25 and 50 mg/kg) groups in both acute and subchronic models. Our result revealed that Mn + Qct groups effectively reduced Mn-induced ALT, AST, and creatinine levels. However, Mn + Qct groups had effectively reversed Mn-induced alteration of complete blood count, including red blood cells, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets, and white blood cells. Meanwhile, the Mn + Qct groups had significantly decreased neutrophil and eosinophil and increased lymphocyte levels relative to the Mn group. Additionally, Mn + Qct groups showed a beneficial effect against Mn-induced macrophages and neutrophils. Our result demonstrated that Mn + Qct groups exhibited protective effects on Mn-induced alteration of GRP78, CHOP, and caspase-3 activities. Furthermore, histopathological observation showed that Mn + Qct groups effectively counteracted Mn-induced morphological change in the liver, kidney, and lung. Moreover, immunohistochemically Mn + Qct groups had significantly attenuated Mn-induced 8-oxo-2'-deoxyguanosine immunoreactivity. Our study suggests that Qct could be a substantially promising organ-protective agent against toxic Mn effects and perhaps against other toxic metal chemicals or drugs.


Assuntos
Antioxidantes/toxicidade , Manganês/toxicidade , Quercetina/farmacologia , Animais , Modelos Animais de Doenças , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Manganês/administração & dosagem , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley
13.
Oncol Lett ; 14(2): 1347-1354, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28789350

RESUMO

Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase that regulates the signal transducer and activator of transcription (STAT) signaling pathway. Deregulation of JAK2 signaling has previously been observed in hematologic malignancies, including erythroleukemia. In the present study, an aminopyridine derivative compound, KRC-180, exhibited direct inhibition of the JAK2 protein at the catalytic site, as demonstrated using in vitro kinase activity assays and docking analyses. In addition, KRC-180 reduced the phosphorylation of STAT3 and STAT5, downstream signaling molecules of JAK2. The growth of HEL92.1.7 erythroleukemia cells harboring a constitutively activated form of JAK2 was suppressed by KRC-180 treatment; KRC-180 induced apoptotic cell death and cell cycle arrest. The results of the present study indicate that KRC-180 is a JAK2 inhibitor with anti-leukemic properties.

14.
Molecules ; 22(9)2017 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-28841181

RESUMO

Recently, more than 30 small molecules and eight monoclonal antibodies that modulate kinase signaling have been approved for the treatment of several pathological conditions, including cancer, idiopathic pulmonary fibrosis, and rheumatoid arthritis. Among them, kinase modulators have been a primary focus for use in cancer treatment. Cellular senescence is believed to protect cells from tumorigenesis by irreversibly halting cell cycle progression and avoiding the growth of damaged cells and tissues. Senescence can also contribute to tumor suppression and be utilized as a mechanism by anti-cancer agents. Although the role of kinase modulators in cancer treatment and their effects on senescence in tumor development have been extensively studied, the relationship between kinase modulators for cancer treatment and senescence has not been fully discussed. In this review, we discuss the pro- and anti-tumorigenesis functions of senescence and summarize the key roles of kinase modulators in the regulation of senescence against tumors.


Assuntos
Antineoplásicos/uso terapêutico , Senescência Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Fosfotransferases/metabolismo , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias/irrigação sanguínea , Neoplasias/enzimologia , Neoplasias/patologia , Estresse Oxidativo , Fosfotransferases/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/metabolismo
15.
Immune Netw ; 17(2): 110-115, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28458622

RESUMO

Aurora kinase A plays an essential role in mitosis including chromosome separation and cytokinesis. Aberrant expression and activity of Aurora kinase A is associated with numerous malignancies including colorectal cancer followed by poor prognosis. The aim of this study is to determine the inhibitory effects of LDD970, an indirubin derivative, on Aurora kinase A in HT29 colorectal cancer cells. In vitro kinase assay revealed that, LDD970 inhibited levels of activated Aurora kinase A (IC50=0.37 mM). The inhibitory effects of LDD970 on Aurora kinase A, autophosphorylation and phosphorylation of histone H3 (Ser10), were confirmed by immunoblot analysis. Moreover, LDD970 inhibited migration of HT29 cells and upregulated apoptosis-related protein cleaved PARP. In cell viability assay, LDD970 was observed to suppress HT29 cell growth (GI50=4.22 µM). Although further studies are required, results of the present study suggest that LDD970 provide a valuable insight into small molecule indirubin derivative for therapeutic potential in human colorectal cancer.

16.
Angew Chem Int Ed Engl ; 55(38): 11495-8, 2016 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-27513827

RESUMO

The preparation of bicontinuous nanoporous covalent frameworks, which are promising for caging active enzymes, is demonstrated. The frameworks have three- dimensionally continuous, hydrophilic pores with widths varying between 5 and 30 nm. Enzymes were infiltrated into the bicontinuous pore by applying a pressured enzyme solution. The new materials and methods allowed the amount of caged proteins to be controlled precisely. The resulting enzyme-loaded framework films could be recycled many times with nearly no loss of catalytic activity. Entropic trapping of proteins by a bicontinuous pore with the right size distribution is an unprecedented strategy toward facile in vitro utilization of biocatalysts.


Assuntos
Enzimas/química , Nanoporos , Biocatálise , Enzimas/metabolismo , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Lipase/química , Lipase/metabolismo , Ácido Oleico/metabolismo , Polietilenoglicóis/química , Fatores de Tempo
17.
Bioorg Med Chem ; 24(21): 5036-5046, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27555284

RESUMO

Members of the Janus kinase (JAK) family are potential therapeutic targets. Abnormal signaling by mutant JAK2 is related to hematological malignancy, such as myeloproliferative neoplasms (MPNs), and tyrosine kinase inhibitor (TKI)-resistance in non-small cell lung cancer (NSCLC). We discovered a potent and highly selective inhibitor of JAK2 over JAK1 and -3 based on the structure of 4-(2,5-triazole)-pyrrolopyrimidine. Among all triazole compounds tested, 2,5-triazole regioisomers more effectively inhibited JAK2 kinase activity than isomers with substitutions of various alkyl groups at the R2 position, except for methyl-substituted 1,5-triazole, which was more potent than the corresponding 1,4- and 2,5-triazoles. None of the synthesized 1,4-isomers inhibited all three JAK family members. Compounds with phenyl or tolyl group substituents at the R1 position were completely inactive compared with the corresponding analogues with a methyl substituted at the R1 position. As a result of this structure-activity relationship, 54, which is substituted with a cyclopropylmethyl moiety, exhibited significant inhibitory activity and selectivity (IC50=41.9nM, fold selectivity JAK1/2 10.6 and JAK3/2 58.1). Compound 54 also exhibited an equivalent inhibition of wild type JAK2 and the V617F mutant. Moreover, 54 inhibited the proliferation of HEL 92.1.7 cells, which carry JAK2 V617F, and gefitinib-resistant HCC827 cells. Compound 54 also suppressed STAT3 phosphorylation at Y705.


Assuntos
Descoberta de Drogas , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 3/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Triazóis/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo , Janus Quinase 3/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Pirróis/química , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/química
18.
Immune Netw ; 16(3): 183-8, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27340387

RESUMO

Sirtuin family members with lysine deacetylase activity are known to play an important role in anti-aging and longevity. Cellular senescence is one of the hallmarks of aging, and downregulation of sirtuin is reported to induce premature senescence. In this study, we investigated the effects of small-molecule sirtuin inhibitors on cellular senescence. Various small molecules such as tenovin-1 and EX527 were employed for direct sirtuin activity inhibition. U251, SNB-75, and U87MG glioblastoma cells treated with sirtuin inhibitors exhibited phenotypes with nuclear enlargement. Furthermore, treatment of rat primary astrocytes with tenovin-1 also increased the size of the nucleus. The activity of senescence-associated ß-galactosidase, a marker of cellular senescence, was induced by tenovin-1 and EX527 treatment in U87MG glioblastoma cells. Consistent with the senescent phenotype, treatment with tenovin-1 increased p53 expression in U87MG cells. This study demonstrated the senescence-inducing effect of sirtuin inhibitors, which are potentially useful tools for senescence research.

19.
Oncol Lett ; 11(2): 991-997, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26893681

RESUMO

Investigation of the mechanisms of resistance to targeted therapies is essential as resistance acquired during treatment may lead to relapse or refractoriness to the therapy. Our previous study identified the small molecule KRC-108 as a result of efforts to find an anticancer agent with c-Met-inhibitory activity. In the present study, the changes accompanying resistance to KRC-108 were investigated in the gastric cancer cell line MKN-45 and its KRC-108-resistant clones by western blot and immunofluorescence analyses. Increased expression of the c-Met protein was observed in KRC-108-resistant cells compared with that of the parental cells, and the phosphorylation of c-Met also increased in cell lines resistant to KRC-108. Resistance to the c-Met inhibitor was associated with cell morphological changes: MKN-45 parental cells, which had a round and poorly differentiated morphology, were altered to exhibit an epithelial cell-like phenotype in KRC-108-resistant clones. Consistent with the transition to an epithelial morphology, the expression of E-cadherin was increased in resistant cells. Using immunoprecipitation, an interaction between E-cadherin and the c-Met protein was observed in the KRC-108-resistant cells. Immunohistochemical analysis of human gastric carcinoma tissues revealed the co-expression of E-cadherin and c-Met. These results suggest that the epithelial transition in KRC-108-resistant cells is mediated by recruiting E-cadherin to c-Met protein. Thus, the present study identified a mechanism used by cancer cells to confer resistance to anticancer agents.

20.
Oncol Lett ; 11(2): 998-1006, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26893682

RESUMO

Myoferlin is a protein that is associated with cellular repair following injury. The expression of myoferlin in breast cancer and pancreatic adenocarcinoma has been reported to correlate with tumor invasiveness, epithelial to mesenchymal transition and an adverse prognosis. In the present study, myoferlin expression was investigated in non-small cell lung carcinoma (NSCLC), along with its association with patient prognosis and the expression of a number of other proteins. A total of 148 patients exhibiting NSCLC were enrolled in the present study. The survival data of all patients was examined, and myoferlin, vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor, E-cadherin, ß-catenin, thyroid transcription factor-1 and tumor protein p63 expression was investigated via immunohistochemical staining of tissue microarrays. Myoferlin expression was detected in the cytoplasm of 75/148 (50.7%) of the NSCLC cases. In the adenocarcinoma cases, myoferlin-positive patients possessed a poorer prognosis (odds ratio, 2.94; P=0.339). In the squamous cell carcinoma cases, myoferlin expression was significantly associated with VEGFR-2 expression (P=0.001). Immunohistochemical staining for VEGFR-2 and myoferlin expression indicated similar features and cytoplasmic staining in tumor cells. As VEGFR-2 is a significant target for novel anticancer therapies, it is anticipated that myoferlin may also possess the potential to become a novel clinical target for the treatment of NSCLC.

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