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1.
Medicine (Baltimore) ; 100(34): e26681, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449453

RESUMO

RATIONALE: Recently, the number of osteosarcomas has been increasing in elderly patients due to human longevity. Lung metastases are the primary cause of death from osteosarcomas. Complete resection of lung metastases can prolong the survival. However, complete resection in elderly patients is often difficult due to high risk of operative complications. Computed tomography (CT) guided radiofrequency ablation (RFA) is a minimally invasive technique to destroy tumor nodules using heat. In this report, we present the first case older than 65 years applying RFA for lung metastases due to osteosarcoma. PATIENT CONCERNS: A 74-year-old male presented with 1-year history of heel pain. A conventional high-grade osteosarcoma in his calcaneus was diagnosed. Below-knee amputation was performed. However, lung metastases were found in both lungs 1 year after amputation. CT-guided lung RFA was chosen since surgical intervention for lung metastases was abandoned because of tumor multiplicity and medical comorbidities. A total of 18 lung metastases were treated by CT-guided RFA. The most frequent complication was pneumothoraxes in 4 of 8 (50%) procedures and chest tube drainage was required in 2 of these (2 of 8 (25%) procedures). DIAGNOSES: Six lung metastases of osteosaroma were found in both lungs at 1 year after surgery. INTERVENTIONS: CT-guided lung RFA was performed. A total of 18 lung metastases were treated in 8 lung RF procedures. OUTCOMES: The patient has been alive with disease for 5.5 years after the initial surgery. LESSONS: CT-guided lung RFA is effective for elderly patients with osteosarcoma lung metastases in spite of discouragement of lung metastasectomy due to multiplicity of metastases and medical-comorbidities.


Assuntos
Neoplasias Ósseas/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Osteossarcoma/patologia , Ablação por Radiofrequência/métodos , Idoso , Calcâneo/patologia , Humanos , Masculino , Radiografia Intervencionista , Tomografia Computadorizada por Raios X
2.
J Cell Physiol ; 236(5): 3946-3962, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33164232

RESUMO

The epigenome has an essential role in orchestrating transcriptional activation and modulating key developmental processes. Previously, we developed a library of pyrrole-imidazole polyamides (PIPs) conjugated with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor, for the purpose of sequence-specific modification of epigenetics. Based on the gene expression profile of SAHA-PIPs and screening studies using the α-myosin heavy chain promoter-driven reporter and SAHA-PIP library, we identified that SAHA-PIP G activates cardiac-related genes. Studies in mouse ES cells showed that SAHA-PIP G could enhance the generation of spontaneous beating cells, which is consistent with upregulation of several cardiac-related genes. Moreover, ChIP-seq results confirmed that the upregulation of cardiac-related genes is highly correlated with epigenetic activation, relevant to the sequence-specific binding of SAHA-PIP G. This proof-of-concept study demonstrating the applicability of SAHA-PIP not only improves our understanding of epigenetic alterations involved in cardiomyogenesis but also provides a novel chemical-based strategy for stem cell differentiation.

3.
Chem Commun (Camb) ; 56(15): 2296-2299, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31989125

RESUMO

We developed an epigenetically active, cooperative DNA binding transcription factor platform assisted by cucurbit[7]uril (CB7) host-guest modules. This new type of molecule termed ePIP-HoGu not only mimics the operation of transcription factors as a pair but also recruits the epigenetic modifier to a particular DNA locus.


Assuntos
DNA/química , Epigênese Genética/genética , Fatores de Transcrição/química , Hidrocarbonetos Aromáticos com Pontes/química , DNA/genética , Imidazóis/química , Estrutura Molecular , Fatores de Transcrição/síntese química , Fatores de Transcrição/genética
4.
Oncotarget ; 10(52): 5403-5411, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31534626

RESUMO

Objectives: To examine the prognostic value of interim 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) findings after 2-4 cycles of rituximab, plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with diffuse large B-cell lymphoma (DLBCL) receiving standardized treatment. Results: After a median 3.36 years (range 0.33 to 9.14 years), 24 of the 80 patients had documented relapse. In Interim-PET findings, 2-year PFS was significantly shorter for PET-positive as compared with PET-negative patients (50.0% vs. 86.4%; p = 0.0012). In End-PET findings, 2-year PFS was significantly shorter for PET-positive as compared with PET-negative patients (25.0% vs. 84.7%; p < 0.0001). The positive predictive value (PPV) and negative predictive value (NPV) of Interim-PET for predicting relapse or disease progression were 57.1% and 75.8%, respectively, while those for End-PET were 75.0% and 75.0%, respectively. Methods: Eighty DLBCL patients treated with first-line 6-8 R-CHOP courses regardless of interim imaging findings were enrolled. Each underwent FDG-PET/CT scanning at staging, and again during (Interim-PET) and at the end of (End-PET) therapy. PET positivity or negativity at Interim-PET and End-PET as related to progression-free survival (PFS) was examined using Kaplan-Meier analysis. Conclusion: Mid-treatment FDG-PET/CT findings may be useful for determining disease status in patients with DLBCL undergoing induction R-CHOP chemotherapy, though are not recommended for treatment decisions as part of routine clinical practice.

6.
Oxf Med Case Reports ; 2018(12): omy097, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30410777

RESUMO

Numb chin syndrome (NCS) is defined as reduced or absent sensation in an area of the chin and lower lip within the distribution of the mental or inferior alveolar nerves. The causes of NCS may be neoplastic, traumatic, dental, toxic, drug-induced, inflammatory, autoimmune or infectious. NCS may be the preliminary symptom of malignancy or recurrence/metastasis in patients with cancer. Therefore, the occurrence of NCS warrants careful examination and monitoring of such patients. This article presents two cases of NCS reported in a patient with prostate cancer and in a patient with Burkitt lymphoma/leukaemia.

7.
J Am Chem Soc ; 140(23): 7108-7115, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29792694

RESUMO

While the central role of locus-specific acetylation of histone proteins in eukaryotic gene expression is well established, the availability of designer tools to regulate acetylation at particular nucleosome sites remains limited. Here, we develop a unique strategy to introduce acetylation by constructing a bifunctional molecule designated Bi-PIP. Bi-PIP has a P300/CBP-selective bromodomain inhibitor (Bi) as a P300/CBP recruiter and a pyrrole-imidazole polyamide (PIP) as a sequence-selective DNA binder. Biochemical assays verified that Bi-PIPs recruit P300 to the nucleosomes having their target DNA sequences and extensively accelerate acetylation. Bi-PIPs also activated transcription of genes that have corresponding cognate DNA sequences inside living cells. Our results demonstrate that Bi-PIPs could act as a synthetic programmable histone code of acetylation, which emulates the bromodomain-mediated natural propagation system of histone acetylation to activate gene expression in a sequence-selective manner.

8.
Sci Rep ; 8(1): 6423, 2018 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-29686309

RESUMO

The dual function of runt-related transcriptional factor 1 (RUNX1) as an oncogene or oncosuppressor has been extensively studied in various malignancies, yet its role in gastric cancer remains elusive. Up-regulation of the ErbB2/HER2 signaling pathway is frequently-encountered in gastric cancer and contributes to the maintenance of these cancer cells. This signaling cascade is partly mediated by son of sevenless homolog (SOS) family, which function as adaptor proteins in the RTK cascades. Herein we report that RUNX1 regulates the ErbB2/HER2 signaling pathway in gastric cancer cells through transactivating SOS1 expression, rendering itself an ideal target in anti-tumor strategy toward this cancer. Mechanistically, RUNX1 interacts with the RUNX1 binding DNA sequence located in SOS1 promoter and positively regulates it. Knockdown of RUNX1 led to the decreased expression of SOS1 as well as dephosphorylation of ErbB2/HER2, subsequently suppressed the proliferation of gastric cancer cells. We also found that our novel RUNX inhibitor (Chb-M') consistently led to the deactivation of the ErbB2/HER2 signaling pathway and was effective against several gastric cancer cell lines. Taken together, our work identified a novel interaction of RUNX1 and the ErbB2/HER2 signaling pathway in gastric cancer, which can potentially be exploited in the management of this malignancy.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Receptor ErbB-2/metabolismo , Transdução de Sinais/fisiologia , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Subunidade alfa 2 de Fator de Ligação ao Core/antagonistas & inibidores , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Relação Dose-Resposta a Droga , Humanos , Proteína SOS1/metabolismo , Neoplasias Gástricas/patologia , Regulação para Cima
9.
Blood Adv ; 2(5): 509-515, 2018 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-29500219

RESUMO

Although the function of Runt-related (RUNX) transcription factors has been well characterized in leukemogenesis and regarded as an ideal target in antileukemia strategies, the effect of RUNX-inhibition therapy on bone marrow niche cells andr its impact on the engraftment of acute myeloid leukemia (AML) cells have largely been unknown. Here, we provide evidence suggesting the possible involvement of RUNX transcription factors in the transactivation of E-selectin, a member of selectin family of cell adhesion molecules, on the vascular endothelial cells of the mice bone marrow niche. In our experiments, gene switch-mediated silencing of RUNX downregulated E-selectin expression in the vascular niche and negatively controlled the engraftment of AML cells in the bone marrow, extending the overall survival of leukemic mice. Our work identified the novel role of RUNX family genes in the vascular niche and showed that the vascular niche, a home for AML cells, could be strategically targeted with RUNX-silencing antileukemia therapies. Considering the excellent efficacy of RUNX-inhibition therapy on AML cells themselves as we have previously reported, this strategy potentially targets AML cells both directly and indirectly, thus providing a better chance of cure for poor-prognostic AML patients.


Assuntos
Vasos Sanguíneos/metabolismo , Medula Óssea/irrigação sanguínea , Subunidades alfa de Fatores de Ligação ao Core/fisiologia , Selectina E/genética , Animais , Subunidades alfa de Fatores de Ligação ao Core/genética , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Inativação Gênica , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Fatores de Transcrição/fisiologia
10.
Sci Rep ; 7(1): 16604, 2017 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-29192243

RESUMO

Although runt-related transcription factor 1 (RUNX1) and its associating core binding factor-ß (CBFB) play pivotal roles in leukemogenesis, and inhibition of RUNX1 has now been widely recognized as a novel strategy for anti-leukemic therapies, it has been elusive how leukemic cells could acquire the serious resistance against RUNX1-inhibition therapies and also whether CBFB could participate in this process. Here, we show evidence that p53 (TP53) and CBFB are sequentially up-regulated in response to RUNX1 depletion, and their mutual interaction causes the physiological resistance against chemotherapy for acute myeloid leukemia (AML) cells. Mechanistically, p53 induced by RUNX1 gene silencing directly binds to CBFB promoter and stimulates its transcription as well as its translation, which in turn acts as a platform for the stabilization of RUNX1, thereby creating a compensative RUNX1-p53-CBFB feedback loop. Indeed, AML cells derived from relapsed cases exhibited higher CBFB expression levels compared to those from primary AML cells at diagnosis, and these CBFB expressions were positively correlated to those of p53. Our present results underscore the importance of RUNX1-p53-CBFB regulatory loop in the development and/or maintenance of AML cells, which could be targeted at any sides of this triangle in strategizing anti-leukemia therapies.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Subunidade beta de Fator de Ligação ao Core/metabolismo , Leucemia Mieloide Aguda/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Modelos Biológicos , RNA Interferente Pequeno/genética , Transcrição Genética , Proteína Supressora de Tumor p53/genética
11.
Nucleic Acids Res ; 45(16): 9219-9228, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-28934500

RESUMO

Targeted differentiation of human induced pluripotent stem cells (hiPSCs) using only chemicals would have value-added clinical potential in the regeneration of complex cell types including cardiomyocytes. Despite the availability of several chemical inhibitors targeting proteins involved in signaling pathways, no bioactive synthetic DNA-binding inhibitors, targeting key cell fate-controlling genes such as SOX2, are yet available. Here, we demonstrate a novel DNA-based chemical approach to guide the differentiation of hiPSCs using pyrrole-imidazole polyamides (PIPs), which are sequence-selective DNA-binding synthetic molecules. Harnessing knowledge about key transcriptional changes during the induction of cardiomyocyte, we developed a DNA-binding inhibitor termed PIP-S2, targeting the 5'-CTTTGTT-3' and demonstrated that inhibition of SOX2-DNA interaction by PIP-S2 triggers the mesoderm induction in hiPSCs. Genome-wide gene expression analyses revealed that PIP-S2 induced mesoderm by targeted alterations in SOX2-associated gene regulatory networks. Also, employment of PIP-S2 along with a Wnt/ß-catenin inhibitor successfully generated spontaneously contracting cardiomyocytes, validating our concept that DNA-binding inhibitors could drive the directed differentiation of hiPSCs. Because PIPs can be fine-tuned to target specific DNA sequences, our DNA-based approach could be expanded to target and regulate key transcription factors specifically associated with desired cell types.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Mesoderma/citologia , Miócitos Cardíacos/citologia , Nylons/farmacologia , Pirróis/farmacologia , Fatores de Transcrição SOXB1/antagonistas & inibidores , Sequência de Bases , Sítios de Ligação , Linhagem Celular , Sequência Consenso , Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Mesoderma/efeitos dos fármacos , Mesoderma/metabolismo , Miócitos Cardíacos/metabolismo , Nylons/química , Pirróis/química , Fatores de Transcrição SOXB1/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
12.
Eur J Med Chem ; 138: 320-327, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28686912

RESUMO

In parallel to monomeric epigenetic regulators, sequence-specific epigenetic regulators represent versatile synthetic dual-target ligands that achieve regulatory control over multi-gene networks. Development of DNA-binding domain (DBD)-HDAC inhibitors and DBD-HAT activators, which result in increased histone acetylation, has become one promising research field. However, there is no report regarding the gene regulatory pattern by sequence-specific epigenetic repressor. We report here for the first time, the synthesis of DBD-HAT inhibitors and demonstrate that these conjugates could retain their dual-target activity using predicted working model of thermal stability assay and in vitro HAT activity assay. Evaluation of antiproliferative activity in cancer cells showed that 2 (with a medium linker length of 13-atom) exhibited the highest antiproliferative activity in p53 wild-type cancer cell lines (IC50 of 1.8-2.6 µM in A549 and MV4-11 cells) and not in p53 mutant cancer cell lines. A mechanistic investigation using microarray analysis and an apoptotic assay showed that the antiproliferative effect of 2 occurred via the up-regulation of p53 target genes, and the subsequent initiation of p53-dependent apoptosis. Our research on sequence-specific dual-target epigenetic repressor offers us an alternative way to modulate HAT-governed therapeutically important genes and contributes to offer a fresh insight into antitumor therapeutics.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Histona Acetiltransferases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Oximas/farmacologia , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Estrutura Molecular , Oximas/química , Pirróis/química , Relação Estrutura-Atividade
13.
J Am Chem Soc ; 139(25): 8444-8447, 2017 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-28614654

RESUMO

Synthetic ligands capable of recognizing the specific DNA sequences inside human mitochondria and modulating gene transcription are in increasing demand because of the surge in evidence linking mitochondrial genome and diseases. In the work described herein, we created a new type of mitochondria-specific synthetic ligand, termed MITO-PIPs, by conjugating a mitochondria-penetrating peptide with pyrrole-imidazole polyamides (PIPs). The designed MITO-PIPs showed specific localization inside mitochondria in HeLa cells and recognized the target DNA in a sequence-specific manner. Furthermore, MITO-PIPs that inhibit the binding of mitochondrial transcription factor A to the light-strand promoter (LSP) also triggered targeted transcriptional suppression. The tunability of PIPs' properties suggests the potential of the MITO-PIPs as potent modulators of not only mitochondrial gene transcription but also its DNA mutations.


Assuntos
DNA Mitocondrial/efeitos dos fármacos , Regiões Promotoras Genéticas , Sítios de Ligação , Células HeLa , Humanos , Ligantes , Modelos Biológicos , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética
14.
J Clin Invest ; 127(7): 2815-2828, 2017 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-28530640

RESUMO

Runt-related transcription factor 1 (RUNX1) is generally considered to function as a tumor suppressor in the development of leukemia, but a growing body of evidence suggests that it has pro-oncogenic properties in acute myeloid leukemia (AML). Here we have demonstrated that the antileukemic effect mediated by RUNX1 depletion is highly dependent on a functional p53-mediated cell death pathway. Increased expression of other RUNX family members, including RUNX2 and RUNX3, compensated for the antitumor effect elicited by RUNX1 silencing, and simultaneous attenuation of all RUNX family members as a cluster led to a much stronger antitumor effect relative to suppression of individual RUNX members. Switching off the RUNX cluster using alkylating agent-conjugated pyrrole-imidazole (PI) polyamides, which were designed to specifically bind to consensus RUNX-binding sequences, was highly effective against AML cells and against several poor-prognosis solid tumors in a xenograft mouse model of AML without notable adverse events. Taken together, these results identify a crucial role for the RUNX cluster in the maintenance and progression of cancer cells and suggest that modulation of the RUNX cluster using the PI polyamide gene-switch technology is a potential strategy to control malignancies.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Subunidades alfa de Fatores de Ligação ao Core , Leucemia Mieloide Aguda , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos Alquilantes/química , Linhagem Celular Tumoral , Subunidades alfa de Fatores de Ligação ao Core/genética , Subunidades alfa de Fatores de Ligação ao Core/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Nylons/química , Nylons/farmacologia , Pirróis/química , Pirróis/farmacologia , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Blood Adv ; 1(18): 1440-1451, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-29296785

RESUMO

Besides being a classical tumor suppressor, runt-related transcription factor 1 (RUNX1) is now widely recognized for its oncogenic role in the development of acute myeloid leukemia (AML). Here we report that this bidirectional function of RUNX1 possibly arises from the total level of RUNX family expressions. Indeed, analysis of clinical data revealed that intermediate-level gene expression of RUNX1 marked the poorest-prognostic cohort in relation to AML patients with high- or low-level RUNX1 expressions. Through a series of RUNX1 knockdown experiments with various RUNX1 attenuation potentials, we found that moderate attenuation of RUNX1 contributed to the enhanced propagation of AML cells through accelerated cell-cycle progression, whereas profound RUNX1 depletion led to cell-cycle arrest and apoptosis. In these RUNX1-silenced tumors, amounts of compensative upregulation of RUNX2 and RUNX3 expressions were roughly equivalent and created an absolute elevation of total RUNX (RUNX1 + RUNX2 + RUNX3) expression levels in RUNX1 moderately attenuated AML cells. This elevation resulted in enhanced transactivation of glutathione S-transferase α 2 (GSTA2) expression, a vital enzyme handling the catabolization of intracellular reactive oxygen species (ROS) as well as advancing the cell-cycle progressions, and thus ultimately led to the acquisition of proliferative advantage in RUNX1 moderately attenuated AML cells. Besides, treatment with ethacrynic acid, which is known for its GSTA inhibiting property, actually prolonged the survival of AML mice in vivo. Collectively, our findings indicate that moderately attenuated RUNX1 expressions paradoxically enhance leukemogenesis in AML cells through intracellular environmental change via GSTA2, which could be a novel therapeutic target in antileukemia strategy.

16.
ChemistryOpen ; 5(6): 517-521, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-28032018

RESUMO

An integrated multi-target small molecule capable of altering dynamic epigenetic and transcription programs associated with the brain and nervous system has versatile applications in the regulation of therapeutic and cell-fate genes. Recently, we have been constructing targeted epigenetic ON switches by integrating sequence-specific DNA binding pyrrole-imidazole polyamides with a potent histone deacetylase inhibitor SAHA. Here, we identified a DNA-based epigenetic ON switch termed SAHA-L as the first-ever multi-target small molecule capable of inducing transcription programs associated with the human neural system and brain synapses networks in BJ human foreskin fibroblasts and 201B7-iPS cells. Ingenuity pathway analysis showed that SAHA-L activates the signaling of synaptic receptors like glutamate and γ-aminobutyric acid, which are key components of autism spectrum disorders. The long-term incubation of SAHA-L in 201B7-iPS cells induced morphology changes and promoted a neural progenitor state. Our finding suggests that the tunable SAHA-L could be advanced as a cell-type-independent multi-target small molecule for therapeutic and/or cell-fate gene modulation.

17.
Shinrigaku Kenkyu ; 87(1): 70-8, 2016 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-27180515

RESUMO

Self-compassion is defined as being compassionate towards the self in times of suffering, and is composed of the following three components: self-kindness, common humanity, and mindfulness. This article reports the development of the Japanese version of the Self-Compassionate Reactions Inventory (SCRI-J). The SCRI-J measures self-compassion based on the degree to which people choose self-compassionate reactions to 8 hypothetical hardships. Study 1: (N = 179) showed that the SCRI-J had sufficient internal consistency. In terms of its validity, results showed a positive correlation between the SCRI-J and the Japanese version of the Self-Compassion Scale, supporting its concurrent validity. In addition, the SCRI-J was positively correlated with self-esteem and negatively correlated with psychological stress responses. Moreover, the association between the SCRI-J and stress responses remained significant when the effect of self-esteem was removed. In Study 2 (N = 90), the SCRI-J demonstrated high test-retest reliability over 3 weeks. Overall, the present study indicates that the SCRI-J has sufficient reliability and validity as a new scale for self-compassion.


Assuntos
Ego , Empatia , Inventário de Personalidade , Psicometria , Adolescente , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Masculino , Atenção Plena , Reprodutibilidade dos Testes , Estresse Psicológico
18.
Sci Rep ; 6: 25327, 2016 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-27138239

RESUMO

Reducing Na(+) in the extracellular environment may lead to two beneficial effects for increasing agonist binding to cell surface G-protein coupled receptors (GPCRs): reduction of Na(+)-mediated binding block and reduce of receptor internalization. However, such combined effects have not been explored. We used Chinese Hamster Ovary cells expressing vasopressin V1b receptors as a model to explore Na(+) sensitivity in agonist binding and receptor internalization. Under basal conditions, a large fraction of V1b receptors is located intracellularly, and a small fraction is in the plasma membrane. Decreases in external Na(+) increased cell surface [(3)H]AVP binding and decreased receptor internalization. Substitution of Na(+) by Cs(+) or NH4(+) inhibited agonist binding. To suppress receptor internalization, the concentration of NaCl, but not of CsCl, had to be less than 50 mM, due to the high sensitivity of the internalization machinery to Na(+) over Cs(+). Iso-osmotic supplementation of glucose or NH4Cl maintained internalization of the V1b receptor, even in a low-NaCl environment. Moreover, iodide ions, which acted as a counter anion, inhibited V1b agonist binding. In summary, we found external ionic conditions that could increase the presence of high-affinity state receptors at the cell surface with minimum internalization during agonist stimulations.


Assuntos
Arginina Vasopressina/metabolismo , Cátions/metabolismo , Receptores de Vasopressinas/metabolismo , Sódio/metabolismo , Compostos de Amônio/metabolismo , Animais , Células CHO , Césio/metabolismo , Cricetulus
19.
Diabetes Res Clin Pract ; 110(1): e5-e8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26293448

RESUMO

An association between remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome and insulin or dipeptidyl peptidase-4 (DPP4) inhibitor therapy were previously reported. We encountered four cases of RS3PE syndrome with type 2 diabetes mellitus or impaired glucose tolerance (IGT) without insulin or DPP4 inhibitor medication.


Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Edema/diagnóstico , Intolerância à Glucose/diagnóstico , Sinovite/diagnóstico , Idoso , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Edema/complicações , Feminino , Intolerância à Glucose/complicações , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Síndrome , Sinovite/complicações
20.
Angew Chem Int Ed Engl ; 54(30): 8700-3, 2015 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-26094767

RESUMO

Synthetic dual-function ligands targeting specific DNA sequences and histone-modifying enzymes were applied to achieve regulatory control over multi-gene networks in living cells. Unlike the broad array of targeting small molecules for histone deacetylases (HDACs), few modulators are known for histone acetyltransferases (HATs), which play a central role in transcriptional control. As a novel chemical approach to induce selective HAT-regulated genes, we conjugated a DNA-binding domain (DBD) "I" to N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide (CTB), an artificial HAT activator. In vitro enzyme activity assays and microarray studies were used to demonstrate that distinct functional small molecules could be transformed to have identical bioactivity when conjugated with a targeting DBD. This proof-of-concept synthetic strategy validates the switchable functions of HDACs and HATs in gene regulation and provides a molecular basis for developing versatile bioactive ligands.


Assuntos
Benzamidas/química , Benzamidas/farmacologia , DNA/metabolismo , Redes Reguladoras de Genes/efeitos dos fármacos , Histona Acetiltransferases/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Linhagem Celular , DNA/genética , Epigênese Genética/efeitos dos fármacos , Histona Acetiltransferases/química , Histonas/genética , Histonas/metabolismo , Humanos , Estrutura Terciária de Proteína
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