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1.
Sensors (Basel) ; 22(12)2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35746105

RESUMO

We developed a path-planning system for radiation source identification devices using 4π gamma imaging. The estimated source location and activity were calculated by an integrated simulation model by using 4π gamma images at multiple measurement positions. Using these calculated values, a prediction model to estimate the probability of identification at the next measurement position was created by via random forest analysis. The path-planning system based on the prediction model was verified by integrated simulation and experiment for a 137Cs point source. The results showed that 137Cs point sources were identified using the few measurement positions suggested by the path-planning system.


Assuntos
Diagnóstico por Imagem , Planejamento da Radioterapia Assistida por Computador , Radioisótopos , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos
2.
Cancer Sci ; 113(3): 940-949, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34897916

RESUMO

The activation of RIG-I-like receptor (RLR) signaling in cancer cells is widely recognized as a critical cancer therapy method. The expected mechanism of RLR ligand-mediated cancer therapy involves the promotion of cancer cell death and strong induction of interferon (IFN)-ß that affects the tumor microenvironment. We have recently shown that activation of RLR signaling in triple-negative breast cancer cells (TNBC) attenuates transforming growth factor-ß (TGF-ß) signaling, which partly contributes to the promotion of cancer cell pyroptosis. However, the consequences of suppression of TGF-ß signaling by RLR ligands with respect to IFN-ß-mediated tumor suppression are not well characterized. This study showed that transfection of a typical RLR ligand polyI:C in cancer cells produces significant levels of IFN-ß, which inhibits the growth of the surrounding cancer cells. In addition, IFN-ß-induced cell cycle arrest in surrounding cancer cells was inhibited by the expression of constitutively active Smad3. Constitutively active Smad3 suppresses IFN-ß expression through the alleviation of IFN regulatory factor 3 binding to the canonical target genes, as suggested by ChIP sequencing analysis. Based on these findings, a new facet of the protumorigenic function of TGF-ß that suppresses IFN-ß expression is suggested when RLR-mediated cancer treatment is used in TNBC.


Assuntos
Interferon beta/metabolismo , Poli I-C/farmacologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Fator Regulador 3 de Interferon/metabolismo , Poli I-C/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteína Smad3/genética , Proteína Smad3/metabolismo , Transfecção , Fator de Crescimento Transformador beta/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/efeitos dos fármacos
3.
Mol Oncol ; 15(5): 1289-1307, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33342034

RESUMO

Development of innovative therapeutic modalities would address an unmet clinical need in the treatment of triple negative breast cancer (TNBC). Activation of retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) such as melanoma differentiation-associated gene 5 (MDA5) and RIG-I in cancer cells is suggested to suppress tumor progression by inducing cell death. Transfection of polyI:C, a conventionally used synthetic double-stranded RNA (dsRNA) analogue that activates RLRs, has been evaluated in clinical trials. However, detailed mechanisms of tumor suppression by RLRs, especially interactions with other signaling pathways, remain elusive. Here, we showed that transfection of polyI:C suppressed transforming growth factor-ß (TGF-ß) signaling in a MDA5- and RIG-I-dependent manner. We found that suppression of TGF-ß signaling by polyI:C promoted cancer cell death, which was attenuated by forced expression of constitutively active Smad3. More detailed analysis suggested that cell death by polyI:C transfection exhibited characteristics of pyroptosis, which is distinct from apoptosis. Therapeutic efficacy of polyI:C transfection was also demonstrated using a mouse model. These results indicated that intratumor administration of polyI:C and related dsRNA analogues may be promising treatments for TNBC through inhibition of the anti-pyroptotic function of TGF-ß.


Assuntos
Piroptose , RNA de Cadeia Dupla/farmacologia , Fator de Crescimento Transformador beta/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Animais , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Poli I-C/farmacologia , Poli I-C/uso terapêutico , Piroptose/efeitos dos fármacos , Piroptose/genética , RNA de Cadeia Dupla/síntese química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Células THP-1 , Fator de Crescimento Transformador beta/fisiologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/terapia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Nat Cell Biol ; 22(4): 465-475, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203421

RESUMO

Advanced clear cell renal cell carcinoma (ccRCC) frequently causes systemic inflammation. Recent studies have shown that cancer cells reshape the immune landscape by secreting cytokines or chemokines. This phenotype, called cancer-cell-intrinsic inflammation, triggers a metastatic cascade. Here, we identified the functional role and regulatory mechanism of inflammation driven by advanced ccRCC cells. The inflammatory nature of advanced ccRCC was recapitulated in a preclinical model of ccRCC. Amplification of cancer-cell-intrinsic inflammation during ccRCC progression triggered neutrophil-dependent lung metastasis. Massive expression of inflammation-related genes was transcriptionally activated by epigenetic remodelling through mechanisms such as DNA demethylation and super-enhancer formation. A bromodomain and extra-terminal motif inhibitor synchronously suppressed C-X-C-type chemokines in ccRCC cells and decreased neutrophil-dependent lung metastasis. Overall, our findings provide insight into the nature of inflammatory ccRCC, which triggers metastatic cascades, and suggest a potential therapeutic strategy.


Assuntos
Carcinoma de Células Renais/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Animais , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Linhagem Celular Tumoral , Quimiocinas CXC/genética , Quimiocinas CXC/metabolismo , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Inflamação , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Camundongos , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Neutrófilos/metabolismo , Neutrófilos/patologia , Prognóstico , Análise de Sobrevida , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Mol Oncol ; 14(2): 277-293, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31782890

RESUMO

Thyroid transcription factor-1 (TTF-1, encoded by the NKX2-1 gene) is highly expressed in small-cell lung carcinoma (SCLC) and lung adenocarcinoma (LADC), but how its functional roles differ between SCLC and LADC remains to be elucidated. Here, we compared the genome-wide distributions of TTF-1 binding regions and the transcriptional programs regulated by TTF-1 between NCI-H209 (H209), a human SCLC cell line, and NCI-H441 (H441), a human LADC cell line, using chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq). TTF-1 binding regions in H209 and H441 cells differed by 75.0% and E-box motifs were highly enriched exclusively in the TTF-1 binding regions of H209 cells. Transcriptome profiling revealed that TTF-1 is involved in neuroendocrine differentiation in H209 cells. We report that TTF-1 and achaete-scute homolog 1 (ASCL1, also known as ASH1, an E-box binding basic helix-loop-helix transcription factor, and a lineage-survival oncogene of SCLC) are coexpressed and bound to adjacent sites on target genes expressed in SCLC, and cooperatively regulate transcription. Furthermore, TTF-1 regulated expression of the Bcl-2 gene family and showed antiapoptotic function in SCLC. Our findings suggest that TTF-1 promotes SCLC growth and contributes to neuroendocrine and antiapoptotic gene expression by partly coordinating with ASCL1.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Proliferação de Células/genética , Neoplasias Pulmonares/genética , Carcinoma de Pequenas Células do Pulmão/genética , Fator Nuclear 1 de Tireoide/metabolismo , Apoptose/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Sequenciamento de Cromatina por Imunoprecipitação , Regulação Neoplásica da Expressão Gênica/genética , Ontologia Genética , Estudo de Associação Genômica Ampla , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Motivos de Nucleotídeos , Prognóstico , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , RNA-Seq , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/mortalidade , Análise Serial de Tecidos
6.
Cancer Sci ; 110(1): 209-220, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30343527

RESUMO

Cyclin-dependent kinase (CDK) 4 and CDK6 inhibitors are effective therapeutic options for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Although CDK4/6 inhibitors mainly target the cyclin D-CDK4/6-retinoblastoma tumor suppressor protein (RB) axis, little is known about the clinical impact of inhibiting phosphorylation of other CDK4/6 target proteins. Here, we focused on other CDK4/6 targets, SMAD proteins. We showed that a CDK4/6 inhibitor palbociclib and activin-SMAD2 signaling cooperatively inhibited cell cycle progression of a luminal-type breast cancer cell line T47D. Palbociclib enhanced SMAD2 binding to the genome by inhibiting CDK4/6-mediated linker phosphorylation of the SMAD2 protein. We also showed that cyclin G2 plays essential roles in SMAD2-dependent cytostatic response. Moreover, comparison of the SMAD2 ChIP-seq data of T47D cells with those of Hs578T (triple-negative breast cancer cells) indicated that palbociclib augmented different SMAD2-mediated functions based on cell type, and enhanced SMAD2 binding to the target regions on the genome without affecting its binding pattern. In summary, palbociclib enhances the cytostatic effects of the activin-SMAD2 signaling pathway, whereas it possibly strengthens the tumor-promoting aspect in aggressive breast cancer.


Assuntos
Ativinas/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Receptores de Estrogênio/metabolismo , Proteína Smad2/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Citostáticos/farmacologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteína Smad2/genética
7.
Int Immunol ; 30(4): 141-154, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29617862

RESUMO

Immunotherapies have led to the successful development of novel therapies for cancer. However, there is increasing concern regarding the adverse effects caused by non-tumor-specific immune responses. Here, we report an effective strategy to generate high-avidity tumor-antigen-specific CTLs, using Cas9/single-guide RNA (sgRNA) ribonucleoprotein (RNP) delivery. As a proof-of-principle demonstration, we selected the gp100 melanoma-associated tumor antigen, and cloned the gp100-specific high-avidity TCR from gp100-immunized mice. To enable rapid structural dissection of the TCR, we developed a 3D protein structure modeling system for the TCR/antigen-major histocompatibility complex (pMHC) interaction. Combining these technologies, we efficiently generated gp100-specific PD-1(-) CD8+ T cells, and demonstrated that the genetically engineered CD8+ T cells have high avidity against melanoma cells both in vitro and in vivo. Our methodology offers computational prediction of the TCR response, and enables efficient generation of tumor antigen-specific CD8+ T cells that can neutralize tumor-induced immune suppression leading to a potentially powerful cancer therapeutic.


Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Sistemas CRISPR-Cas , Edição de Genes , Neoplasias/genética , Neoplasias/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/química , Linhagem Celular Tumoral , Feminino , Técnicas de Inativação de Genes , Genes Reporter , Melanoma Experimental , Camundongos , Modelos Moleculares , Complexos Multiproteicos , Neoplasias/metabolismo , Peptídeos/química , Peptídeos/imunologia , Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Antígeno gp100 de Melanoma/química , Antígeno gp100 de Melanoma/imunologia , Antígeno gp100 de Melanoma/metabolismo
8.
Sci Transl Med ; 10(429)2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-29467297

RESUMO

Radiation-induced intestinal fibrosis (RIF) is a serious complication after abdominal radiotherapy for pelvic tumor or peritoneal metastasis. Herein, we show that RIF is mediated by eosinophil interactions with α-smooth muscle actin-positive (α-SMA+) stromal cells. Abdominal irradiation caused RIF especially in the submucosa (SM) of the small intestine, which was associated with the excessive accumulation of eosinophils in both human and mouse. Eosinophil-deficient mice showed markedly ameliorated RIF, suggesting the importance of eosinophils. After abdominal irradiation, chronic crypt cell death caused elevation of extracellular adenosine triphosphate, which in turn activated expression of C-C motif chemokine 11 (CCL11) by pericryptal α-SMA+ cells in the SM to attract eosinophils in mice. Inhibition of C-C chemokine receptor 3 (CCR3) by genetic deficiency or neutralizing antibody (Ab) treatment suppressed eosinophil accumulation in the SM after irradiation in mice, suggesting a critical role of the CCL11/CCR3 axis in the eosinophil recruitment. Activated α-SMA+ cells also expressed granulocyte-macrophage colony-stimulating factor (GM-CSF) to activate eosinophils. Transforming growth factor-ß1 from GM-CSF-stimulated eosinophils promoted collagen expression by α-SMA+ cells. In translational studies, treatment with a newly developed interleukin-5 receptor α-targeting Ab, analogous to the human agent benralizumab, depleted intestinal eosinophils and suppressed RIF in mice. Collectively, we identified eosinophils as a crucial factor in the pathogenesis of RIF and showed potential therapeutic strategies for RIF by targeting eosinophils.


Assuntos
Eosinófilos/metabolismo , Fibrose/etiologia , Fibrose/metabolismo , Intestino Delgado/efeitos da radiação , Lesões Experimentais por Radiação/metabolismo , Animais , Modelos Animais de Doenças , Fibrose/prevenção & controle , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Lesões Experimentais por Radiação/prevenção & controle
9.
Cancer Res ; 77(15): 4026-4038, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28611046

RESUMO

Poor prognoses for colorectal cancer patients with metastatic lesions have driven demand for the development of novel targeted therapies. Here, we demonstrate that expression of bone morphogenetic protein 4 (BMP-4) is universally upregulated in human colorectal cancer cells and tissues, resulting in activated BMP signaling. Inhibition of endogenous BMP signaling by the BMP type I receptor inhibitor LDN-193189 elevated expression of the phosphatase DUSP5 in colorectal cancer cells, inducing apoptosis via dephosphorylation of Erk MAPK. Administering LDN-193189 to mice diminished tumor formation of colorectal cancer cells. Our findings suggest inhibition of autocrine BMP-4 as a candidate treatment strategy for colorectal cancer. Cancer Res; 77(15); 4026-38. ©2017 AACR.


Assuntos
Comunicação Autócrina/fisiologia , Proteína Morfogenética Óssea 4/metabolismo , Neoplasias Colorretais/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Comunicação Autócrina/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Humanos , Immunoblotting , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pirazóis/farmacologia , Pirimidinas/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Mol Oncol ; 11(9): 1241-1262, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28618162

RESUMO

Zinc finger E-box binding protein 1 (ZEB1) and ZEB2 induce epithelial-mesenchymal transition (EMT) and enhance cancer progression. However, the global view of transcriptional regulation by ZEB1 and ZEB2 is yet to be elucidated. Here, we identified a ZEB1-regulated inflammatory phenotype in breast cancer cells using chromatin immunoprecipitation sequencing and RNA sequencing, followed by gene set enrichment analysis (GSEA) of ZEB1-bound genes. Knockdown of ZEB1 and/or ZEB2 resulted in the downregulation of genes encoding inflammatory cytokines related to poor prognosis in patients with cancer, including IL6 and IL8, therefore suggesting that ZEB1 and ZEB2 have similar functions in terms of the regulation of production of inflammatory cytokines. Antibody array and ELISA experiments confirmed that ZEB1 controlled the production of the IL-6 and IL-8 proteins. The secretory proteins regulated by ZEB1 enhanced breast cancer cell proliferation and tumor growth. ZEB1 expression in breast cancer cells also affected the growth of fibroblasts in cell culture, and the accumulation of myeloid-derived suppressor cells in tumors in vivo. These findings provide insight into the role of ZEB1 in the progression of cancer, mediated by inflammatory cytokines, along with the initiation of EMT.


Assuntos
Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Animais , Sequência de Bases , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimiocinas/metabolismo , Meios de Cultivo Condicionados/farmacologia , DNA de Neoplasias/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Inflamatórias Mamárias/genética , Neoplasias Inflamatórias Mamárias/metabolismo , Neoplasias Inflamatórias Mamárias/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Comunicação Parácrina/efeitos dos fármacos , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
11.
Sci Rep ; 7(1): 1166, 2017 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-28446749

RESUMO

Epithelial-mesenchymal transition (EMT) is induced by transforming growth factor (TGF)-ß and facilitates tumor progression. We here performed global mapping of accessible chromatin in the mouse mammary gland epithelial EpH4 cell line and its Ras-transformed derivative (EpRas) using formaldehyde-assisted isolation of regulatory element (FAIRE)-sequencing. TGF-ß and Ras altered chromatin accessibility either cooperatively or independently, and AP1, ETS, and RUNX binding motifs were enriched in the accessible chromatin regions of EpH4 and EpRas cells. Etv4, an ETS family oncogenic transcription factor, was strongly expressed and bound to more than one-third of the accessible chromatin regions in EpRas cells treated with TGF-ß. While knockdown of Etv4 and another ETS family member Etv5 showed limited effects on the decrease in the E-cadherin abundance and stress fiber formation by TGF-ß, gene ontology analysis showed that genes encoding extracellular proteins were most strongly down-regulated by Etv4 and Etv5 siRNAs. Accordingly, TGF-ß-induced expression of Mmp13 and cell invasiveness were suppressed by Etv4 and Etv5 siRNAs, which were accompanied by the reduced chromatin accessibility at an enhancer region of Mmp13 gene. These findings suggest a mechanism of transcriptional regulation during Ras- and TGF-ß-induced EMT that involves alterations of accessible chromatin, which are partly regulated by Etv4 and Etv5.


Assuntos
Transformação Celular Neoplásica , Cromatina/metabolismo , Células Epiteliais/fisiologia , Transição Epitelial-Mesenquimal , Glândulas Mamárias Animais/citologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Sítios de Ligação , Linhagem Celular , DNA/metabolismo , Regulação da Expressão Gênica , Camundongos , Ligação Proteica
12.
Mass Spectrom (Tokyo) ; 3(1): A0026, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24860715

RESUMO

Iron oxide nanoparticle (NP)-coated target plates were employed for the direct detection and analysis of low molecular weight lipids by laser desorption/ionization (LDI) mass spectrometry (MS). We have demonstrated that the use of the iron oxide NP-coated target provides a simple, direct, and rapid detection method for lipid standards and epidermal surface lipids without any cumbersome sample pretreatment as well as mass spectra that are free of background matrix peaks. Lipid standards (1-stearoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycerol, 1-palmitoyl-2-oleoyl-3-linoleoyl-rac-glycerol, 1,2-distearoyl-sn-glycero-3-phosphocholine) were detected as either protonated or cationated species. Clean MS/MS spectra for each lipid were also successfully obtained. Pre-MS surface cleaning of the target plates with UV-ozone treatment successfully removed organic contaminants that would interfere with the mass spectra especially in the low molecular weight region. Preliminary application of the presented target plate to the detection of endogenous lipids in latent fingerprints showed promising results and for potential use in the visualization and chemical composition determination of latent fingerprints by nanoparticle assistance.

13.
Mol Med ; 19: 183-94, 2013 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-23821362

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory synovitis that leads to the destruction of bone and cartilage. The receptor for advanced glycation end products (RAGE) is a multiligand membrane-bound receptor for high-mobility group box-1 (HMGB1) associated with development of RA by inducing production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6. We developed a bone-targeting therapeutic agent by tagging acidic oligopeptide to a nonmembrane-bound form of RAGE (endogenous secretory RAGE [esRAGE]) functioning as a decoy receptor. We assessed its tissue distribution and therapeutic effectiveness in a murine model of collagen-induced arthritis (CIA). Acidic oligopeptide-tagged esRAGE (D6-esRAGE) was localized to mineralized region in bone, resulting in the prolonged retention of more than 1 wk. Weekly administration of D6-esRAGE with a dose of 1 mg/kg to RA model mice significantly ameliorated inflammatory arthritis, synovial hyperplasia, cartilage destruction and bone destruction, while untagged esRAGE showed little effectiveness. Moreover, D6-esRAGE reduced plasma levels of proinflammatory cytokines including TNF-α, IL-1 and IL-6, while esRAGE reduced the levels of IL-1 and IL-6 to a lesser extent, suggesting that production of IL-1 and IL-6 reduced along the blockade of HMGB1 receptor downstream signals by D6-esRAGE could be attributed to remission of CIA. These findings indicate that D6-esRAGE enhances drug delivery to bone, leading to rescue of clinical and pathological lesions in murine CIA.


Assuntos
Artrite Experimental/tratamento farmacológico , Osso e Ossos/metabolismo , Sistemas de Liberação de Medicamentos , Oligopeptídeos/administração & dosagem , Receptores Imunológicos/administração & dosagem , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide , Ácido Aspártico/química , Linhagem Celular , Colágeno Tipo II/imunologia , Citocinas/sangue , Proteína HMGB1/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Receptor para Produtos Finais de Glicação Avançada
14.
Nucleic Acids Symp Ser (Oxf) ; (49): 69-70, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-17150637

RESUMO

An RNA aptamer containing two binding sites of HIV Tat exhibits extremely high affinity to Tat. We have determined the structure of the aptamer complexed with an RNA-binding peptide of Tat. The analysis was made feasible by the use of several peptides in which a single arginine residue was specifically 13C, 15N-labeled. Residue specific labeling of the peptide enhanced the identification of intermolecular contacts, which are otherwise hard to identify due to spectral overlapping. The structure of the complex has revealed the origin of the high affinity of the aptamer to Tat.


Assuntos
Aptâmeros de Nucleotídeos/química , Produtos do Gene tat/química , Proteínas de Ligação a RNA/química , Arginina/química , Sítios de Ligação , Isótopos de Carbono , Produtos do Gene tat/metabolismo , HIV , Isótopos de Nitrogênio , Ressonância Magnética Nuclear Biomolecular , Conformação de Ácido Nucleico , Peptídeos/química , Proteínas de Ligação a RNA/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana
15.
Nucleic Acids Symp Ser (Oxf) ; (48): 111-2, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-17150503

RESUMO

An RNA aptamer containing two binding sites exhibits extremely high affinity to the HIV Tat protein. We previously reported the structure of the aptamer complexed with argininamide as the simplest analogue of Tat. Here, we have analyzed the structure of the aptamer complexed with the partial peptide of Tat, RKKRR. The profile of chemical sift perturbations for the aptamer upon complex formation with RKKRR revealed that RKKRR can be a realistic analogue of Tat to address the interactions between the arginine-rich motif of Tat and the aptamer. It was suggested that the aptamer interacts with different arginine residues of RKKRR simultaneously at the two binding sites, which can explain the extremely high affinity to Tat.


Assuntos
Aptâmeros de Nucleotídeos/química , Produtos do Gene tat/química , Produtos do Gene tat/metabolismo , Peptídeos/química , Sequência de Aminoácidos , Aptâmeros de Nucleotídeos/genética , Sequência de Bases , Marcação por Isótopo , Espectroscopia de Ressonância Magnética , Dados de Sequência Molecular , Conformação de Ácido Nucleico
16.
Mayo Clin Proc ; 78(7): 901-7, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12839087

RESUMO

We describe a patient with acute necrotizing eosinophilic myocarditis who recovered rapidly after pericardial drainage and without corticosteroid therapy. The 25-year- old man was referred to our hospital with suspected acute myocardial infarction on the basis of severe epigastralgia, abnormal Q waves and ST elevation on electrocardiography, and an increase in cardiac enzymes. Echocardiography disclosed pericardial effusion that compressed the right ventricle, left ventricular dysfunction in conjunction with posterolateral hypokinesis, and a thickened ventricular wall but no mural thrombus. The eosinophil count in the peripheral blood was slightly increased. Coronary angiography showed normal arteries and thus prompted an endomyocardial biopsy. The patient was transferred to the intensive care unit with a clinical diagnosis of myocarditis associated with cardiac tamponade. Emergency pericardiocentesis relieved symptoms immediately. The cells in the pericardial effusion were mainly eosinophils; interleukin 5 and interleukin 13 levels were predominantly elevated, and the effusion was drained for 5 days. The biopsy specimen revealed necrotizing eosinophilic myocarditis. Left ventricular function recovered within a week without corticosteroid therapy. No relapse was observed as of 8 months after diagnosis.


Assuntos
Tamponamento Cardíaco/etiologia , Eosinofilia/complicações , Miocardite/cirurgia , Pericardiocentese , Adulto , Tamponamento Cardíaco/complicações , Eosinofilia/patologia , Humanos , Masculino , Miocardite/complicações , Miocardite/fisiopatologia , Resultado do Tratamento
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