RESUMO
Pulmonary fibrosis (PF) is chronic and irreversible damage to the lung characterized by fibroblast activation and matrix deposition. Although recently approved novel anti-fibrotic agents can improve the lung function and survival of patients with PF, the overall outcomes remain poor. In this study, a novel imidazopurine compound, 3-(2-chloro-6-fluorobenzyl)-1,6,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (IM-1918), markedly inhibited transforming growth factor (TGF)-ß-stimulated reporter activity and reduced the expression of representative fibrotic markers, such as connective tissue growth factor, fibronectin, collagen and α-smooth muscle actin, on human lung fibroblasts. However, IM-1918 neither decreased Smad-2 and Smad-3 nor affected p38MAPK and JNK. Instead, IM-1918 reduced Akt and extracellular signal-regulated kinase 1/2 phosphorylation increased by TGF-ß. Additionally, IM-1918 inhibited the phosphorylation of fibroblast growth factor receptors 1 and 3. In a bleomycin-induced murine lung fibrosis model, IM-1918 profoundly reduced fibrotic areas and decreased collagen and α-smooth muscle actin accumulation. These results suggest that IM-1918 can be applied to treat lung fibrosis.
Assuntos
Inibidores Enzimáticos/farmacologia , Imidazóis/química , Fibrose Pulmonar/tratamento farmacológico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismo , Animais , Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Fibronectinas/genética , Fibronectinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fator de Crescimento Transformador beta/genéticaRESUMO
Radiotherapy is one of the most common treatments for cancer, but radioresistance and injury to normal tissue are considered major obstacles to successful radiotherapy. Thus, there is an urgent need to develop radiosensitizers to improve the therapeutic outcomes of radiotherapy in cancer patients. Our previous efforts to identify novel radiosensitizers, using high-throughput screening targeting p53 and Nrf2 revealed a promising N-phenylpyrimidin-2-amine (PPA) lead compound. In the present study, 17 derivatives of this lead compound were examined, and it was found that 4-(4-fluorophenyl)-N-(4-nitrophenyl)-6-phenylpyrimidin-2-amine (PPA5), 4-((4-(4-fluorophenyl)pyrimidin-2-yl)amino)-3-methoxy-N-methyl -benzamide (PPA13), 4-((4-(4-fluorophenyl)pyrimidin-2-yl)amino)benzenesulfonamide (PPA14), 4-((4-(2-chlorophenyl)pyrimidin-2-yl)amino)benzenesulfonamide (PPA15), and 4-((4-(2-chlorophenyl)pyrimidin-2-yl)amino)-N-methylbenzamide (PPA17) inhibited cell viability by more than 50%, with a marked increase in the proportion of cells arrested at the G2/M phase of cell cycle. Among these compounds, PPA15 markedly increased the sub-G1 cell population and increased the levels of cyclin B1 and the phosphorylation levels of cyclin-dependent kinase (CDK) 1. Combined treatment with radiation and PPA14 or PPA15 significantly decreased clonogenic survival. An in vitro kinase assay revealed that PPA15 inhibited multiple CDKs involved in cell cycle regulation. Compared with drug or radiation treatment alone, combined treatment with PPA15 and radiation resulted in the suppression of A549 tumor growth in mice by 59.5% and 52.7%, respectively. Treatment with PPA15 alone directly inhibited tumor growth by 25.7%. These findings suggest that the novel pan CDK inhibitor, PPA15, may be a promising treatment to improve the effectiveness of radiotherapy for the treatment of cancer. SIGNIFICANCE STATEMENT: Several inhibitors of CDK have been successfully evaluated in combination with other chemotherapeutics in clinical trials, but negative side effects have partially restricted their clinical use. In this study, we identified a novel pan-CDK inhibitor to increase radiosensitivity, and we hope this work will encourage the development of promising small-molecule radiosensitizers.
Assuntos
Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Pirimidinas/química , Pirimidinas/farmacologia , Radiossensibilizantes/química , Radiossensibilizantes/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Feminino , Humanos , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Ionizing radiation (IR) has been widely used in the treatment of cancer. Radiation-induced DNA damage triggers the DNA damage response (DDR), which can confer radioresistance and early local recurrence by activating DNA repair pathways. Since karyopherin-α2 (KPNA2), playing an important role in nucleocytoplasmic transport, was significantly increased by IR in our previous study, we aimed to determine the function of KPNA2 with regard to DDR. Exposure to radiation upregulated KPNA2 expression in human colorectal cancer HT29 and HCT116 cells and breast carcinoma MDA-MB-231 cells together with the increased expression of DNA repair protein BRCA1. The knockdown of KPNA2 effectively increased apoptotic cell death via inhibition of BRCA1 nuclear import following IR. Therefore, we propose that KPNA2 is a potential target for overcoming radioresistance via interruption to DDR.
Assuntos
Proteína BRCA1/metabolismo , Morte Celular/efeitos da radiação , Sobrevivência Celular/fisiologia , alfa Carioferinas/metabolismo , Apoptose/efeitos da radiação , Proteína BRCA1/genética , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/genética , Ensaio Cometa , Dano ao DNA/efeitos da radiação , Reparo do DNA/efeitos da radiação , Células HCT116 , Células HT29 , Humanos , Imunoprecipitação , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Radiação IonizanteRESUMO
Although favorable immune responses to low-dose irradiation (LDI) have been observed in normal mice, i.e., a hormesis effect, little is known about the effects of LDI in infectious diseases. In this study, we examined the effects of LDI on mice with sepsis, a severe and often lethal hyperinflammatory response to bacteria. Female C57BL/6 mice were whole-body irradiated with 10cGy 48h before Escherichia coli infection, and survival, bacterial clearance, cytokines, and antioxidants were quantified. LDI pretreatment significantly increased survival from 46.7% in control mice to 75% in mice with sepsis. The bacterial burden was significantly lower in the blood, spleen, and kidney of LDI-treated mice than in those of control septic mice. The levels of pro-inflammatory cytokines, e.g., IL-1ß and IL-6, as well as anti-inflammatory IL-10 were markedly reduced in pre-LDI septic mice. Nitric oxide production by peritoneal macrophages was also reduced in pre-LDI septic mice. Immune cells in the spleen increased and Nrf2 and HO-1 were induced in pre-LDI septic mice. LDI stimulates the immune response and minimizes lethality in septic mice via enhanced bacterial clearance and reduced initial proinflammatory responses.
Assuntos
Infecções por Escherichia coli/radioterapia , Sepse/radioterapia , Irradiação Corporal Total , Animais , Contagem de Colônia Microbiana , Citocinas/sangue , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/sangue , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Feminino , Rim/microbiologia , Rim/efeitos da radiação , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Células RAW 264.7 , Sepse/sangue , Sepse/imunologia , Sepse/microbiologia , Baço/microbiologia , Baço/efeitos da radiaçãoRESUMO
Rab GTPases regulate various types of intracellular membrane trafficking in all eukaryotes. Since Rab27a and its multiple effectors are involved in exocytosis of lysosome-related organelles and play a major role in malignancy, compounds targeting Rab27a could be likely used to inhibit invasive growth and tumor metastasis. Thus, we designed and synthesized several compounds based on the previously reported Rab27a-targeting synthetic compounds identified by virtual screening, and investigated their anti-metastatic effects in MDA-MB231 and A375 cells. Among the synthesized compounds, (E)-N-(3-chlorophenyl)-6-(2-(3,4-dihydroxy benzylidene)hydrazinyl)pyridine-3-sulfonamide (3d) and (E)-N-benzyl-6-(2-(3,4-dihydroxy benzylidene)hydrazinyl)-N-methylpyridine-3-sulfonamide (3f) significantly inhibited the invasiveness of both tumor cell lines. Compounds 3d and 3f also decreased the levels of signature extracellular matrix marker proteins (fibronectin, collagen, and α-smooth muscle actin) and representative mesenchymal cell markers (N-cadherin and vimentin). Taken together, our results suggest that novel sulfonamide analogs have anti-metastatic activity in breast and melanoma cancer cell lines and may be used as therapeutic agents to treat malignant cancer.
Assuntos
Antineoplásicos/química , Sulfonamidas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Sítios de Ligação , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proteínas da Matriz Extracelular/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Vimentina/metabolismo , Proteínas rab de Ligação ao GTP/antagonistas & inibidores , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab27 de Ligação ao GTPRESUMO
Numerous studies have attempted to develop biological markers for the response to radiation for broad and straightforward application in the field of radiation. Based on a public database, the present study selected several molecules involved in the DNA damage repair response, cell cycle regulation and cytokine signaling as promising candidates for lowdose radiationsensitive markers. The HuT 78 and IM9 cell lines were irradiated in a concentrationdependent manner, and the expression of these molecules was analyzed using western blot analysis. Notably, the activation of ataxia telangiectasia mutated (ATM), checkpoint kinase 2 (CHK2), p53 and H2A histone family member X (H2AX) significantly increased in a concentrationdependent manner, which was also observed in human peripheral blood mononuclear cells. To determine the radioprotective effects of cinobufagin, as an ATM and CHK2 activator, an in vivo model was employed using sublethal and lethal doses in irradiated mice. Treatment with cinobufagin increased the number of bone marrow cells in sublethal irradiated mice, and slightly elongated the survival of lethally irradiated mice, although the difference was not statistically significant. Therefore, KU60019, BML277, pifithrinα, and nutlin3a were evaluated for their ability to modulate radiationinduced cell death. The use of BML277 led to a decrease in radiationinduced pCHK2 and γH2AX levels and mitigated radiationinduced apoptosis. On the whole, the present study provides a novel approach for developing drug candidates based on the profiling of biological radiationsensitive markers. These markers hold promise for predicting radiation exposure and assessing the associated human risk.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia , Dano ao DNA , Radiação Ionizante , Transdução de Sinais , Dano ao DNA/efeitos da radiação , Dano ao DNA/efeitos dos fármacos , Humanos , Animais , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Camundongos , Quinase do Ponto de Checagem 2/metabolismo , Quinase do Ponto de Checagem 2/genética , Histonas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Masculino , Imidazóis/farmacologia , Protetores contra Radiação/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta à RadiaçãoRESUMO
Radiotherapy (RT) is a commonly used treatment option for patients with cancer because it can effectively control tumor growth and kill tumor cells. However, the impact of RT goes beyond direct tumor cell killing because it can change the tumor microenvironment by altering surrounding tissues and infiltrating cells and modulating the expression of immune checkpoints. Poliovirus receptor (PVR, cluster of differentiation (CD)155), a member of the nectin-like molecule family, is overexpressed in many human cancers. However, its role in the tumor growth and T-cell immune responses of triple-negative breast cancer (TNBC) remains unclear. In the present study, we observe that radiation exposure increases PVR expression in MDA-MB-231 and BT549 cells. Silencing PVR not only inhibited the proliferation of breast cancer cells but also significantly enhanced the cytotoxicity of cytotoxic T lymphocytes (CTLs) compared with the control or RT groups. Treatment of T cells with PVR decreased CD8+ T cells, increased CD4+ T cells, and induced PVR ligands such as T cell immunoreceptor with immunoglobulin and ITIM domain, CD226, and CD96. However, after treatment with PVR, CTL responses decreased and secretion of interferon-γ, tumor necrosis factor-α, interleukin (IL)-2, IL-6, and IL-10 was significantly inhibited. In contrast, PVR knockdown increased the production of these cytokines, illustrating the immunosuppressive function of PVR. Suppression of PVR using an anti-PVR antibody inhibited 4T1 tumor growth by increasing immune cell infiltration. These results provide new insights into the role of PVR in TNBC and highlight its potential as a target for T cell-mediated immunotherapy in breast cancer.
RESUMO
Glutaminyl cyclases (QC, isoQC) convert N-terminal glutamine or glutamate into pyroglutamate (pGlu) on substrates. IsoQC has recently been demonstrated to promote pGlu formation on the N-terminus of CD47, the SIRPα binding site, contributing to the "don't eat me" cancer immune signaling of CD47-SIRPα. We developed new QC inhibitors by applying a structure-based optimization approach starting from fragments identified through library screening. Screening of metal binding fragments identified 5-(1H-benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine (9) as a potent fragment, and further modification provided 5-(1-(3-methoxy-4-(3-(piperidin-1-yl)propoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-1,3,4-thiadiazol-2-amine (22b) as a potent QC inhibitor. Treatment with 22b in A549 and H1975 lung cancer cells decreased the CD47/αhCD47-CC2C6 interaction, indicative of the CD47/SIRPα interaction, and enhanced the increased phagocytic activity of both THP-1 and U937 macrophages.
RESUMO
The survival and death of eukaryotic cells are tightly controlled by a variety of proteins in response to the cellular environment. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a receptor-interacting Ser/Thr kinase that has recently been reported as an important regulator of cell survival, apoptosis, and necroptosis; however, its role in liver cancer remains unclear. In this study, we examined the effect of siRNA-mediated RIPK1 knockdown on the survival and death of liver cancer cells. Treatment with siRIPK1 decreased the growth rate of liver cancer cells and increased apoptotic, but not necrotic cell death, which was higher in wild-type p53 (wt-p53) cells than in mutant-type p53 (mt-p53) cells. In addition, RIPK1 knockdown increased p53 expression and G1 phase arrest in wt-p53 cells. Although suppressing p53 did not alter RIPK1 expression, it did attenuate siRIPK1-induced cell death. Interestingly, RIPK1 knockdown also increased the generation of reactive oxygen species and DNA damage by inhibiting signal transduced and activator of transcription 3 (STAT3) and ATM and RAD3-related (ATR) in wt-p53 cells but not in mt-p53 cells. Moreover, STAT3 or ATR inhibition in p53 mutant cells restored siRIPK1-mediated cell death. Together, the results of this study suggest that RIPK1 suppression induces apoptotic cell death by inhibiting the STAT3/ATR axis in a p53-dependent manner. Furthermore, these findings suggest that RIPK1, alone or in combination, may be a promising target for treating liver cancer.
RESUMO
Our previous work demonstrated that (E)-N-benzyl-6-(2-(3, 4-dihydroxybenzylidene) hydrazinyl)-N-methylpyridine-3-sulfonamide (BHMPS), a novel synthetic inhibitor of Rab27aSlp(s) interaction, suppresses tumor cell invasion and metastasis. Here, we aimed to further investigate the mechanisms of action and biological significance of BHMPS. BHMPS decreased the expression of epithelial-mesenchymal transition transcription factors through inhibition of focal adhesion kinase and c-Jun N-terminal kinase activation, thereby reducing the migration and invasion of breast cancer. Additionally, knockdown of Rab27a inhibited tumor migration, with changes in related signaling molecules, whereas overexpression of Rab27a reversed this phenomenon. BHMPS effectively prevented the interaction of Rab27a and its effector Slp4, which was verified by co-localization, immunoprecipitation, and in situ proximity ligation assays. BHMPS decreased the secretion of epidermal growth factor receptor and fibronectin by interfering with vesicle trafficking, as indicated by increased perinuclear accumulation of CD63-positive vesicles. Moreover, administration of BHMPS suppressed tumor growth in Rab27a-overexpressing MDA-MB-231 xenograft mice. These findings suggest that BHMPS may be a promising candidate for attenuating tumor migration and invasion by blocking Rab27a-mediated exocytosis.
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BACKGROUND/OBJECTIVES: This study was conducted to examine disparities in food and nutrient intakes based on family types identified among 1,856 participants who were the Korean elderly people in the 6th Korea National Health and Nutrition Examination Survey (KNHNES) excluding those who were currently practicing the diet therapy. SUBJECTS/METHODS: We separated the subjects into two groups: living alone (LA, n = 638) and living with a spouse (LS, n = 1,218). We also examined the disparities of dietary quantity and quality of those two groups using complex sampling design general linear regression analyses (CS GLM). RESULTS: In the LA group, there was a higher percentage of females and average age in LA group was higher than the participants in the LS group. Household income and education level were significantly lower in LA compared to those of LS. The frequencies of skipping meals were higher in LA. LA's food and nutrient intakes showed lower consumption of vegetables, fruits, seaweeds, and of most nutrients. Even after adjusting for the confounding factors, the consumption of vegetables, seaweeds, carbohydrates, potassium, riboflavin, and vitamin C showed lower in LA than LS. Moreover, LA's nutrient intake ratios compared to the KDRIs were lower which turned out to be similar to their nutrient intakes. CONCLUSIONS: These results show that dietary behavior and food intake of the elderly are associated with family types. Frequently skipping meals and less dietary variety are more common with elderly persons who were living alone. Therefore, it is necessary to integrate the supplementary food programs and nutrition education programs for the elderly living alone.
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Low-dose irradiation (LDI) has recently been shown to have various beneficial effects on human health, such as on cellular metabolic activities, DNA repair, antioxidant activity, homeostasis potency, and immune activation. Although studies on the immunogenic effects of LDI are rapidly accumulating, clinical trials for cancer treatment are considered premature owing to the lack of available preclinical results and protocols. Here, we aim to investigate anti-tumor and anti-metastatic effects of whole-body LDI in several tumor-bearing mouse models. Mice were exposed to single or fractionated whole-body LDI prior to tumor transplantation, and tumor growth and metastatic potential were determined, along with analysis of immune cell populations and expression of epithelial-mesenchymal transition (EMT) markers. Whole-body fractionated-LDI decreased tumor development and lung metastasis not only by infiltration of CD4+, CD8+ T-cells, and dendritic cells (DCs) but also by attenuating EMT. Moreover, a combination of whole-body LDI with localized high-dose radiation therapy reduced the non-irradiated abscopal tumor growth and increased infiltration of effector T cells and DCs. Therefore, whole-body LDI in combination with high-dose radiation therapy could be a potential therapeutic strategy for treating cancer.
RESUMO
OBJECTIVE: Tumor-treating fields are currently used to successfully treat various cancers; however, the specific pathways associated with its efficacy remain unknown in the immune responses. Here, we evaluated tumor-treating fields-mediated initiation of the macrophage-specific immune response. MATERIALS AND METHODS: We subjected RAW 264.7 mouse macrophages to clinically relevant levels of tumor-treating fields (0.9 V/cm, 150 kHz) and evaluated alterations in cytokine expression and release, as well as cell viability. Additionally, we investigated the status of immunomodulatory pathways to determine their roles in tumor-treating fields-mediated immune activation. RESULTS AND DISCUSSION: Our results indicated that tumor-treating fields treatment at 0.9 V/cm decreased cell viability and increased cytokine messenger RNA/protein levels, as well as levels of nitric oxide and reactive oxygen species, relative to controls. The levels of tumor necrosis factor α, interleukin 1ß, and interleukin 6 were markedly increased in tumor-treating fields-treated RAW 264.7 cells cocultured with 4T1 murine mammary carcinoma cells compared with those in 4T1 or RAW 264.7 cells with or without tumor-treating fields treatment. Moreover, the viability of 4T1 cells treated with the conditioned medium of tumor-treating fields-stimulated RAW 264.7 cells decreased, indicating that macrophage activation by tumor-treating fields effectively killed the tumor cells. Moreover, tumor-treating fields treatment activated the nuclear factor κB and mitogen-activated protein kinase pathways involved in immunomodulatory signaling. CONCLUSION: These results provide critical insights into the mechanisms through which tumor-treating fields affect macrophage-specific immune responses and the efficacy of this method for cancer treatment.
Assuntos
Antígenos de Histocompatibilidade Classe II/imunologia , Ativação de Macrófagos/imunologia , Magnetoterapia , Neoplasias/radioterapia , Animais , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/efeitos da radiação , Humanos , Sistema de Sinalização das MAP Quinases/efeitos da radiação , Ativação de Macrófagos/genética , Ativação de Macrófagos/efeitos da radiação , Macrófagos/imunologia , Macrófagos/efeitos da radiação , Camundongos , NF-kappa B/genética , Neoplasias/imunologia , Neoplasias/patologia , Células RAW 264.7 , Transdução de Sinais/imunologia , Transdução de Sinais/efeitos da radiaçãoRESUMO
Focal adhesion kinase 1 (FAK1) is known to promote tumor progression and metastasis by controlling cell movement, invasion, survival and the epithelial-to-mesenchymal transition in the tumor microenvironment. As recent reports imply that FAK1 is highly associated with tumor cell development and malignancy, the inhibition of FAK1 activity could be an effective therapeutic approach for inhibiting the growth and metastasis of tumor cells. In this study, we aimed to determine the effect of a novel synthetic FAK1 inhibitor 2-[2-(2-methoxy-4-morpholin-4-yl-phenylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-N-methyl-benzamide, (MPAP) on lung cancer cells. MPAP suppressed cancer cell proliferation and the phosphorylation of FAK1. Combined treatment with MPAP and irradiation (IR) showed enhanced suppression of cancer cell proliferation in wild-type p53 cells and more intense suppression in p53-null cells. In addition, the combination treatment effectively induced G1 cell cycle arrest in a p53-independent manner. In an in vivo tumor xenograft mouse model, treatment with both MPAP and IR reduced tumor growth more than the treatment with IR or MPAP alone. Overall, these data demonstrate that the radiosensitizing effect of MPAP is mediated by the regulation of retinoblastoma protein (RB) phosphorylation in a p53-independent manner.
Assuntos
Quinase 1 de Adesão Focal/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Tolerância a Radiação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Benzamidas/administração & dosagem , Benzamidas/síntese química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos da radiação , Quinase 1 de Adesão Focal/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Radiação , Tolerância a Radiação/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos da radiação , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Chronic tissue injury with fibrosis results in disruption of tissue architecture, organ dysfunction and eventually organ failure. Currently, therapeutic options for tissue fibrosis are severely limited and organ transplantation including high cost and co-morbidities is the only effective treatment for end-stage fibrotic disease. Therefore, it is imperative to develop effective anti-fibrotic agents. Integrins are transmembrane proteins and are major receptors for cell-extracellular matrix (ECM) and cell-cell adhesion. Modulation of these molecules, particularly αv integrin family, has exhibited profound effects on fibrosis in multiple organ and disease state. Based on the several studies, the integrins αvß3, αvß5, αvß6, and αvß8 have been known to modulate the fibrotic process via activation of latent transforming growth factor (TGF)-ß in pre-clinical models of fibrosis. In this perspective, we reviewed the functions of αvß1 integrin as a potentially useful target molecule for antifibrotic agent and introduced novel specific small-molecule inhibitors targeting this integrin.
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Accumulating evidence suggests the potential for radiation therapy to generate antitumor immune responses against tumor cells by inducing immunogenic cell death and phenotypic changes. We recently found that ionizing radiation upregulated karyopherin α2 (KPNA2) in HT-29 colorectal tumor cells using quantitative proteomic analysis. To determine whether this increased KPNA2 could function as a damage-associated molecular pattern to induce antitumor immune responses, mouse bone-marrow-derived dendritic cells (BMDCs) were treated with KPNA2. KPNA2 enhanced the surface expression of CD40, CD54, CD80, CD86, and MHC class I/II on BMDCs. DCs treated with KPNA2 exhibited increased secretion of pro-inflammatory cytokines such as IL-1ß, IL-6, IL-12, IL-23, and TNF-α. Co-culture of CD4(+) T cells and KPNA2-treated DCs resulted in induction of Th1/17 cytokines (IFN-γ and IL-17) and reduction of TGF-ß production. Moreover, KPNA2-treated DCs were capable of increasing granzyme B and perforin expression in cytotoxic T lymphocytes. These results demonstrated that radiation-induced dying colorectal cancer cells released considerable amounts of KPNA2 that induce the maturation and activation of DCs for synergistic antitumor effect of radiation.
Assuntos
Neoplasias Colorretais/imunologia , Neoplasias Colorretais/radioterapia , Células Dendríticas/imunologia , Proteínas Nucleares/imunologia , alfa Carioferinas/imunologia , Animais , Morte Celular/fisiologia , Morte Celular/efeitos da radiação , Diferenciação Celular/fisiologia , Diferenciação Celular/efeitos da radiação , Proliferação de Células/fisiologia , Proliferação de Células/efeitos da radiação , Neoplasias Colorretais/patologia , Células Dendríticas/efeitos da radiação , Feminino , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Nucleares/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/efeitos da radiação , Regulação para Cima/efeitos da radiação , alfa Carioferinas/metabolismoRESUMO
Mongolian immigration into South Korea has increased rapidly over the last decade. It is important to better understand dietary patterns of immigrants because these patterns are associated with health risk. This study aimed to characterize dietary patterns of Mongolian immigrants in South Korea. Dietary intakes of 500 Mongolian adults living in South Korea were assessed using the interviewer-administered 24-h dietary recall method. By cluster analysis, three dietary patterns were identified: "Mongolian" (26%), "Transitional" (43%) and "Korean" (31%). The "Korean" pattern had a favorable food intake profile, with higher intakes of healthy foods, while the other patterns had features of an unhealthy diet. There were significant differences between the dietary patterns that were related to risk for chronic diseases. Overall, subjects following the "Korean" dietary pattern showed high adherence to World Health Organization recommendations for preventing diet-related chronic diseases, whereas the "Mongolian" and "Transitional" patterns showed low compliance. The results suggest the need for education programs targeting Mongolian immigrants who retain traditional dietary habits, to enhance their healthy food choices.
Assuntos
Dieta/etnologia , Emigrantes e Imigrantes/estatística & dados numéricos , Comportamento Alimentar/etnologia , Aculturação , Adulto , Antropometria , Estudos Transversais , Ingestão de Energia , Feminino , Humanos , Masculino , Mongólia/etnologia , República da Coreia/epidemiologia , Fatores SocioeconômicosRESUMO
Triple-negative breast cancer (TNBC) is an aggressive cancer with a poor prognosis due to its epithelialto-mesenchymal transition (EMT) phenotype. Cancer patients often experience several detrimental effects of cancer treatment, such as chemoresistance, radioresistance and the maintenance of cancer stem cells due to EMT. Thus, EMT signaling is considered to be a valuable therapeutic target for cancer treatment, and its inhibition is being attempted as a new treatment option for TNBC patients. Previously, we showed that 3-(2-chlorobenzyl)-1,7-dimethyl-1H-imidazo[2,1-f]purine2,4(3H,8H)-dione (IM-412) inhibits transforming growth factor-ß (TGF-ß)-induced differentiation of human lung fibroblasts through both Smad-dependent and -independent pathways. In the present study, we examined the inhibitory effect of IM-412 on EMT pathways and invasiveness in TNBC cells since the TGF-ß signaling pathway is a typical signaling pathway that functions in EMT. IM-412 not only potently suppressed the migration and invasion of MDA-MB-231 cells, but also lowered the expression of mesenchymal markers and EMT-activating transcription factors in these cells. IM-412 inhibited the activation of several signaling proteins, including Smad2/Smad3, p38MAPK, Akt and JNK, and it also attenuated the phosphorylation of FGFR1 and FGFR3. Collectively, our findings suggest that the synthetic compound IM-412 suppressed the EMT process in MDA-MB-231 cells and thereby effectively inhibited the migration and invasion of these cancer cells. Thus, IM-412 could serve as a novel therapeutic agent for malignant cancers.
Assuntos
Biomarcadores Tumorais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Imidazóis/farmacologia , Purinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Fosforilação/efeitos dos fármacos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
BACKGROUND/OBJECTIVES: To encourage healthier food choices for children in fast-food restaurants, many initiatives have been proposed. This study aimed to examine the effect of disclosing nutritional information on parents' meal choices for their children at fast-food restaurants in South Korea. SUBJECTS/METHODS: An online experimental survey using a menu board was conducted with 242 parents of children aged 2-12 years who dined with them at fast-food restaurants at least once a month. Participants were classified into two groups: the low-calorie group (n = 41) who chose at least one of the lowest calorie meals in each menu category, and the high-calorie group (n = 201) who did not. The attributes including perceived empowerment, use of provided nutritional information, and perceived difficulties were compared between the two groups. RESULTS: The low-calorie group perceived significantly higher empowerment with the nutritional information provided than did the high-calorie group (P = 0.020). Additionally, the low-calorie group was more interested in nutrition labeling (P < 0.001) and considered the nutritional value of menus when selecting restaurants for their children more than did the high-calorie group (P = 0.017). The low-calorie group used the nutritional information provided when choosing meals for their children significantly more than did the high-calorie group (P < 0.001), but the high-calorie group had greater difficulty using the nutritional information provided (P = 0.012). CONCLUSIONS: The results suggest that improving the empowerment of parents using nutritional information could be a strategy for promoting healthier parental food choices for their children at fast-food restaurants.
RESUMO
PURPOSE: In contrast to high-dose therapeutic irradiation, definitive research detailing the physiological effects of low-dose irradiation is limited. Notably, the immunological response elicited after low-dose irradiation remains controversial. MATERIALS AND METHODS: Female C57BL/6 mice were whole- body-irradiated with a single or three daily fractions up to a total dose of 0.1, 1, or 10 cGy. Blood and spleen were harvested 2, 7 and 14 days after irradiation. RESULTS: The splenic CD4(+) T cell subpopulations were temporarily increased at 2 days after single or fractionated irradiation, whereas the percentage of dendritic cells (DC) and macrophages was decreased. Whereas CD8(+) T cell populations were decreased in single-dose irradiated mice at day 7, early and sustained reduction of CD8(+) T cell numbers was observed in fractionated- dose-irradiated mice from day 2 until day 14. In addition, single-dose irradiation resulted in a Th1 cytokine expression profile, whereas fractionated-dose irradiation drove a Th2 shift. Additionally, increased expression of immune-related factors was observed at early time-points with single-dose irradiation, in contrast to the dose-independent induction following fractionated-dose irradiation. CONCLUSIONS: Our results demonstrate that low-dose irradiation modulates the immune response in mice, where the sensitivity and kinetics of the induced response vary according to the dosing method.