RESUMO
Most studies investigating the association between physical activity and osteoporosis prevention only focused on specific types of physical activity. This study's evidence regarding the combined effects or interaction of sleep duration and physical activity. The findings emphasize the role of sleep duration and physical activity in association with osteoporosis. PURPOSE: The associations between physical activity, sleep duration, and prevalent osteoporosis in Taiwanese adults were studied in this cross-sectional study. METHODS: The Taiwan Biobank enrolled a community-based cohort of ~ 120,000 volunteers (as of April 30, 2020) between 30 and 76 years of age with no history of cancer. Amongst, bone mineral density (BMD) measures by dual-energy X-ray absorptiometry (DXA) were available in 22,402 participants. After excluding individuals who had no complete data of BMI (n = 23), MET score (n = 207), T-score (n = 8,826), and sleep duration (n = 16), 13,330 subjects were included as the primary cohort. Univariate and multivariable regression analyses were performed to determine the associations between the presence of osteoporosis, physical activity level, sleep duration, and other variables. RESULTS: The results showed that after adjustment, subjects with physical activity < 20 METs/week and ≥ 20 METs/week (aOR = 1.017 and 0.767, respectively) were associated with risk of osteoporosis than those with zero MET. The odds of osteoporosis were not significantly lower in subjects who slept for ≥ 8 h/day (aOR = 0.934,p=0.266). In addition, compared to short sleepers with no physical activity, adults with increased physical activity ≥ 20 METs/week and sleep ≥ 8 h/day had a significantly lowest likelihood of osteoporosis (aOR = 0.702). Those with medium physical activity (< 20 METs/week) plus average sleep duration (6.5-8 h/day) did not have significant higher odds of osteoporosis (aOR = 1.129,p=0.151). CONCLUSION: The findings emphasize the joint role of sleep duration and physical activity in association with osteoporosis. Adults with high physical activity plus high sleep hours have the highest BMD and lowest risk of osteoporosis.
Assuntos
Osteoporose , Duração do Sono , Adulto , Humanos , Taiwan/epidemiologia , Estudos Transversais , Bancos de Espécimes Biológicos , Osteoporose/etiologia , Osteoporose/complicações , Densidade Óssea , Absorciometria de Fóton , Exercício FísicoRESUMO
Rheumatoid arthritis (RA) is a well-known autoimmune disorder related with joint pain, joint swelling, cartilage and bone degradation as well as deformity. Fibroblast growth factor 23 (FGF23) is an endocrine factor of the FGF family primarily produced by osteocytes and osteoblasts, involves an essential effect in pathogenesis of RA. IL-1ß is a vital proinflammatory factor in the development of RA. However, the role of FGF23 on IL-1ß synthesis in RA has not been fully explored. Our analysis of database revealed higher levels of FGF23 and IL-1ß in RA samples compared with healthy controls. High-throughput screening demonstrated that IL-1ß is a potential candidate factor after FGF23 treatment in RA synovial fibroblasts (RASFs). FGF23 concentration dependently promotes IL-1ß synthesis in RASFs. FGF23 enhances IL-1ß expression by activating the PI3K, Akt, and NF-κB pathways. Our findings support the notion that FGF23 is a promising target in the remedy of RA.
Assuntos
Artrite Reumatoide , Fator de Crescimento de Fibroblastos 23 , Fibroblastos , Interleucina-1beta , Transdução de Sinais , Feminino , Humanos , Masculino , Artrite Reumatoide/metabolismo , Células Cultivadas , Fatores de Crescimento de Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Interleucina-1beta/metabolismo , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismoRESUMO
Osteoarthritis (OA) is characterized by the infiltration and adhesion of monocytes into the inflamed joint synovium. Interleukin (IL)-17 is a critical inflammatory mediator that participates in the progression of OA, although the mechanisms linking IL-17 and monocyte infiltration are not well understood. Our analysis of synovial tissue samples retrieved from the Gene Expression Omnibus (GEO) dataset exhibited higher monocyte marker (CD11b) and vascular cell adhesion molecule 1 (VCAM-1) levels in OA samples than in normal, healthy samples. The stimulation of human OA synovial fibroblasts (OASFs) with IL-17 increased VCAM-1 production and subsequently enhanced monocyte adhesion. IL-17 affected VCAM-1-dependent monocyte adhesion by reducing miR-5701 expression through the protein kinase C (PKC)-α and c-Jun N-terminal kinase (JNK) signaling cascades. Our findings improve our understanding about the effect of IL-17 on OA progression and, in particular, VCAM-1 production and monocyte adhesion, which may help with the design of more effective OA treatments.
Assuntos
MicroRNAs , Osteoartrite , Fibroblastos/metabolismo , Humanos , Interleucina-17/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Monócitos/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismo , Membrana Sinovial/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Colorectal cancer (CRC) is one of the most common cancers in Han Chinese and is characterized by low rates of early diagnosis and poor survival rates. Angiopoietin-2 (Ang2), an endothelial tyrosine kinase, is involved in CRC progression, but little is known about the association between single nucleotide polymorphisms (SNPs) and diagnosis or prognosis of CRC. This study reports on the association between 5 SNPs of the Angpt2 gene (rs2442598, rs734701, rs1823375, 11137037, and rs12674822) and CRC susceptibility as well as clinical outcomes in 379 patients with CRC and in 1,043 cancer-free healthy controls. Carriers of the CG allele at rs1823375 and those with the GT+TT allele of the variant rs12674822 were at greater risk of CRC than their respective wild-type counterparts. Moreover, carriers of the GT or GT+TT allele in rs12674822 were significantly more likely to have tumor involvement in both the colon and rectum compared with wild-type (GG) carriers, while 5-year progression-free survival was also significantly worse in those carrying the GT+TT allele in rs12674822 compared with wild-type carriers. Our study is the first to describe correlations between Angpt2 polymorphisms and CRC development and progression in people of Chinese Han ethnicity.
Assuntos
Angiopoietina-2/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Adulto , Alelos , Neoplasias Colorretais/patologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Estudos de Associação Genética , Genótipo , Heterozigoto , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , PrognósticoRESUMO
In rheumatoid arthritis (RA), a chronic inflammatory disease, loss of muscle mass is an important contributor to the loss of muscle strength in RA patients. Myostatin, a myokine involved in the process of muscle hypertrophy and myogenesis, enhances osteoclast differentiation and inflammation. Here, we investigated the mechanisms of myostatin in RA synovial inflammation. We found a positive correlation between myostatin and tumor necrosis factor-α (TNF-α), a well-known proinflammatory cytokine, in RA synovial tissue. Our in vitro results also showed that myostatin dose-dependently induced TNF-α expression through the phosphatidylinositol 3-kinase (PI3K)-Akt-AP-1 signaling pathway. Myostatin treatment of human MH7A cells stimulated AP-1-induced luciferase activity and activation of the c-Jun binding site on the TNF-α promoter. Our results indicated that myostatin increases TNF-α expression via the PI3K-Akt-AP-1 signaling pathway in human RA synovial fibroblasts. Myostatin appears to be a promising target in RA therapy.
Assuntos
Artrite Reumatoide/metabolismo , Fibroblastos/metabolismo , Miostatina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/genéticaRESUMO
The hormone melatonin has many properties, including antioxidant, anti-inflammatory, and immunomodulatory effects. Melatonin has been demonstrated to be beneficial in several inflammatory autoimmune diseases, but its effects in rheumatoid arthritis (RA) remain controversial. We sought to determine how melatonin regulates inflammation in RA. We found that melatonin dose-dependently inhibits tumor necrosis factor-α (TNF-α) and interleukin (IL)-1ß expression through the PI3K/AKT, ERK, and NF-κB signaling pathways. We also identified that melatonin inhibits TNF-α and IL-1ß production by upregulating miR-3150a-3p expression. Synovial tissue specimens from RA patients and culture of human rheumatoid fibroblast-like synoviocytes confirmed that the MT1 receptor is needed for the anti-inflammatory activities of melatonin. Importantly, melatonin also significantly reduced paw swelling, cartilage degradation, and bone erosion in the collagen-induced arthritis mouse model. Our results indicate that melatonin ameliorates RA by inhibiting TNF-α and IL-1ß production through downregulation of the PI3K/AKT, ERK, NF-κB signaling pathways, as well as miR-3150a-3p overexpression. The role of melatonin as an adjuvant treatment in patients with RA deserves further clinical studies.
Assuntos
Artrite Reumatoide/metabolismo , Fibroblastos/efeitos dos fármacos , Interleucina-1beta/biossíntese , Melatonina/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , MicroRNAs/metabolismo , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismoRESUMO
The Angiopoietin-2 (Ang2) gene encodes angiogenic factor, and the polymorphisms of Ang2 gene predict risk of various human diseases. We want to investigate whether the single nucleotide polymorphisms (SNPs) of the Ang2 gene can predict the risk of rheumatoid arthritis (RA). Between 2016 and 2018, we recruited 335 RA patients and 700 control participants. Comparative genotyping for SNPs rs2442598, rs734701, rs1823375 and rs12674822 was performed. We found that when compared with the subjects with the A/A genotype of SNP rs2442598, the subjects with the T/T genotype were 1.78 times likely to develop RA. The subjects with C/C genotype of SNP rs734701 were 0.53 times likely to develop RA than the subjects with TT genotype, suggesting the protective effect. The subjects with G/G genotype of SNP rs1823375 were 1.77 times likely to develop RA than the subjects with C/C genotype. The subjects with A/C and C/C genotype of SNP rs11137037 were 1.65 and 2.04 times likely to develop RA than the subjects with A/A genotype. The subjects with G/T and T/T genotype of SNP rs12674822 were 2.42 and 2.25 times likely to develop RA than the subjects with G/G genotype. The T allele over rs734701 can lead to higher serum erythrocyte sedimentation rate level (p = 0.006). The A allele over rs11137037 was associated with longer duration between disease onset and blood sampling (p = 0.003). Our study suggested that Ang2 might be a diagnostic marker and therapeutic target for RA therapy. Therapeutic agents that directly or indirectly modulate the activity of Ang2 may be the promising modalities for RA treatment.
Assuntos
Angiopoietina-2/genética , Artrite Reumatoide/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Vascular endothelial growth factor C (VEGF-C) promotes angiogenesis, a prominent feature in rheumatoid synovitis, contributing to the perpetuation of the global burden of rheumatoid arthritis (RA). VEGF-C gene polymorphisms predict the risk of developing various human diseases, such as urothelial cell carcinoma, oral cancer and coronary artery disease. We sought to determine whether single nucleotide polymorphisms (SNPs) of the VEGF-C gene can predict the risk of RA. Our study recruited 210 patients with RA and 373 healthy controls between 2007 and 2015, and performed comparative genotyping for SNPs rs7664413, rs11947611, rs1485766, rs2046463 and rs3775194. In analyses adjusted for potential covariates, we found that compared with subjects with the A/A genotype of SNP rs11947611, those with the A/G genotype were 40% more likely to develop RA (adjusted odds ratio [AOR] 0.61; 95% confidence interval [CI] 0.40 to 0.92; p = 0.02). In addition, subjects lacking the A/A genotype (A/G, G/G) of SNP rs2046463 were more than twice as likely as those with the A/A genotype to require methotrexate (AOR 2.23, 95% CI 1.25 to 3.98; p = 0.01), while those who lacked the G/G genotype (G/C, C/C) in the SNP rs3775194 had a significantly lower risk of requiring prednisolone as compared with those with the G/G genotype (AOR 0.39, 95% CI 0.19 to 0.79; p = 0.01). Our findings suggest that VEGF-C gene polymorphisms might serve as a diagnostic marker and therapeutic target for RA therapy. Pharmacotherapies that modulate the activity of the VEGF-C gene may be promising for RA treatment.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/genética , Predisposição Genética para Doença , Fator C de Crescimento do Endotélio Vascular/genética , Adulto , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Biomarcadores , Estudos de Casos e Controles , Monitoramento de Medicamentos/métodos , Feminino , Técnicas de Genotipagem , Voluntários Saudáveis , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prednisolona/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Medição de Risco/métodos , Resultado do Tratamento , Adulto JovemRESUMO
Hepatocellular carcinoma (HCC) is a liver malignancy and a major cause of cancer mortality worldwide. Matrix metalloproteinase-11 (MMP-11), also known as stromelysin-3, plays a critical role during tumor migration, invasion and metastasis. Here, we report on the association between five single nucleotide polymorphisms (SNPs) - rs738791, rs2267029, rs738792, rs28382575, and rs131451 - of the MMP-11 gene and HCC susceptibility, as well as clinical outcomes, in 293 patients with HCC and in 586 cancer-free controls. We found that carriers of the CT+TT allele of the rs738791 variant were at greater risk of HCC compared with wild-type (CC) carriers. Moreover, carriers of at least one C allele (C/T+C/C genotype) at the MMP-11 SNP rs738792 were likely to progress to Child-Pugh B or C grade, while individuals with at least one C allele (C/T+C/C genotype) at the MMP-11 SNP rs28382575 were at higher risk of developing stage III/IV disease, large tumors or lymph node metastasis. We believe that genetic variations in the MMP-11 gene may help to predict early-stage HCC and act as reliable biomarkers for HCC progression.
Assuntos
Carcinoma Hepatocelular/genética , Predisposição Genética para Doença , Neoplasias Hepáticas/genética , Metaloproteinase 11 da Matriz/genética , Adulto , Idoso , Alelos , Progressão da Doença , Feminino , Estudos de Associação Genética , Genótipo , Heterozigoto , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Hepatocellular carcinoma (HCC) is a liver malignancy and a major cause of cancer mortality worldwide. AURKA (aurora kinase A) is a mitotic serine/threonine kinase that functions as an oncogene and plays a critical role in hepatocarcinogenesis. We report on the association between 4 single nucleotide polymorphisms (SNPs) of the AURKA gene (rs1047972, rs2273535, rs2064836, and rs6024836) and HCC susceptibility as well as clinical outcomes in 312 patients with HCC and in 624 cancer-free controls. We found that carriers of the TT allele of the variant rs1047972 were at greater risk of HCC compared with wild-type (CC) carriers. Moreover, carriers of at least one A allele in rs2273535 were less likely to progress to stage III/IV disease, develop large tumors or be classified into Child-Pugh class B or C. Individuals with at least one G allele at AURKA SNP rs2064863 were at lower risk of developing large tumors or progressing to Child-Pugh grade B or C. Our results indicate that genetic variations in the AURKA gene may serve as an important predictor of early-stage HCC and be a reliable biomarker for the development of HCC.
Assuntos
Aurora Quinase A/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Polimorfismo de Nucleotídeo Único , Povo Asiático/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Breast cancer is a major cause of cancer mortality worldwide. High-mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein found in all mammal eukaryotic cells that participates in tumor progression, migration and metastasis. HMGB1 overexpression has been indicated in breast cancer patients. However, scant information is available regarding the association between HMGB1 single nucleotide polymorphisms (SNPs) and the risk or prognosis of breast cancer. We report on the association between 4 SNPs of the HMGB1 gene (rs1360485, rs1045411, rs2249825 and rs1412125) and breast cancer susceptibility as well as clinical outcomes in 313 patients with breast cancer and in 217 healthy controls. Patients with one G allele in the rs1360485 or rs2249825 domains are likely to progress to T2 tumor and lymph node metastasis. In addition, the presence of one G allele in SNPs rs1360485 or rs2249825 was associated with a higher risk of progressing to T2 tumor and distant metastasis amongst HER2-enriched and triple-negative breast cancer (TNBC) tumors compared with luminal A and luminal B tumors. Furthermore, having one C allele in the rs1412125 domain increased the risk of pathologic grade 3 disease in HER2-enriched and TNBC tumors. Our results indicate that genetic variations in the HMGB1 gene may serve as an important predictor of breast cancer progression and metastasis.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Proteína HMGB1/genética , Adulto , Alelos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Genótipo , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptor ErbB-2/genética , Fatores de RiscoRESUMO
Breast cancer is a major cause of cancer mortality amongst women. Chemokine (C-C motif) ligand 4 is encoded by the CCL4 gene; specific CCL4 gene polymorphisms are related to the risks and prognoses of various diseases. In this study, we examined whether CCL4 gene single nucleotide polymorphisms (SNPs) predict the risk and progression of breast cancer. Between 2014 and 2016, we recruited 314 patients diagnosed with breast cancer and a cohort of 209 healthy participants (controls) without a history of cancer. Genotyping of the CCL4 rs1634507, rs10491121 and rs1719153 SNPs revealed no significant between-group differences for these polymorphisms. However, amongst luminal A and luminal B subtypes, compared with patients with the AA genotype, those carrying the AG genotype at SNP rs10491121 were less likely to develop lymph node metastasis. In addition, compared with AA carriers, those carrying the AG + GG genotype at SNP rs10491121 were at lower risk of developing distant metastasis, while the presence of the AT genotype at SNP rs1719153 increased the likelihood of pathologic grade (G3 or G4) disease. Variations in the CCL4 gene may help to predict breast cancer progression and metastasis.
Assuntos
Neoplasias da Mama/genética , Quimiocina CCL4/genética , Metástase Linfática , Polimorfismo de Nucleotídeo Único , Adulto , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Angiogenesis, the growth of new blood vessels, is essential in the pathogenesis of joint inflammatory disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA), facilitating the invasion of inflammatory cells and increase in local pain receptors that contribute to structural damage and pain. The angiogenic process is perpetuated by various mediators such as growth factors, primarily vascular endothelial growth factor (VEGF) and hypoxia-inducible factors (HIFs), as well as proinflammatory cytokines, various chemokines, matrix components, cell adhesion molecules, proteases, and others. Despite the development of potent, well-tolerated nonbiologic (conventional) and biologic disease-modifying agents that have greatly improved outcomes for patients with RA, many remain resistant to these therapies, are only partial responders, or cannot tolerate biologics. The only approved therapies for OA include symptom-modifying agents, such as analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, and hyaluronic acid. None of the available treatments slow the disease progression, restore the original structure or enable a return to function of the damaged joint. Moreover, a number of safety concerns surround current therapies for RA and OA. New treatments are needed that not only target inflamed joints and control articular inflammation in RA and OA, but also selectively inhibit synovial angiogenesis, while preventing healthy tissue damage. This narrative review of the literature in PubMed focuses on the evidence illustrating the therapeutic benefits of modulating angiogenic activity in experimental RA and OA. This evidence points to new treatment targets in these diseases.
Assuntos
Artrite Reumatoide/metabolismo , Neovascularização Patológica/metabolismo , Osteoartrite/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Osteoartrite/tratamento farmacológico , Osteoartrite/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Osteopontin (OPN) is an important proinflammatory cytokine in rheumatoid arthritis (RA). Levels of OPN have been shown to be significantly correlated with interleukin-17 (IL-17) production and expression of Th17 cells in the synovial fluid of RA patients. Here, we investigated the role of OPN in monocyte migration, IL-17 production and osteoblasts. METHODS: OPN and IL-17 expression profiles in osteoarthritis (OA) and RA synovial fluid were determined by enzyme-linked immunosorbent assay (ELISA). The expression of the microRNA, miR-129-3p, in osteoblasts was analyzed by real-time quantitative polymerase chain reaction (qPCR). Immunoreactive proteins were spotted by Western blotting. We used the collagen-induced arthritis (CIA) mouse model to investigate the role of OPN in monocyte migration during RA. RESULTS: OPN and IL-17 expression were higher in RA synovial fluid as compared to OA samples. We also found that OPN promotes IL-17 expression in osteoblasts and thereby enhances monocyte migration via the Syk/PI3K/Akt signaling pathway. miR-129-3p expression was found to be negatively regulated by OPN via the Syk/PI3K/Akt signal cascade. In contrast, lentiviral vectors expressing short hairpin RNA inhibited OPN expression and ameliorated articular swelling, cartilage erosion and monocyte infiltration in the ankle joints of CIA mice. CONCLUSION: To our knowledge, our study is the first to describe how OPN promotes monocyte migration by upregulating IL-17 expression in osteoblasts in RA disease. SIGNIFICANCE: These findings indicate that OPN could serve as a potential therapeutic target for the treatment of RA.
Assuntos
Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Movimento Celular/fisiologia , Interleucina-17/metabolismo , MicroRNAs/metabolismo , Monócitos/patologia , Osteopontina/metabolismo , Adulto , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Linhagem Celular , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/fisiologia , Quinase Syk/metabolismo , Líquido Sinovial/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patologiaRESUMO
Accumulating evidence indicates that subchondral bone might play an essential role in rheumatoid arthritis (RA). Osteopontin (OPN) induces the production of an important proinflammatory cytokine involved in the pathogenesis of RA. This study evaluated the activation of oncostatin M (OSM) by OPN in human primary osteoblasts to understand RA pathogenesis and characterized the intracellular signaling pathways involved in this activation. Quantitative PCR, ELISA, and Western blot results indicated that stimulation of human primary osteoblasts with OPN induces OSM expression through αvß3 integrin/c-Src/platelet-derived growth factor receptor transactivation/MEK/ERK. Treatment of osteoblasts with OPN also increased c-Jun phosphorylation, AP-1 luciferase activity, and c-Jun binding to the AP-1 element on the OSM promoter, as demonstrated using chromatin immunoprecipitation assay. Moreover, inhibition of OPN expression using lentiviral-OPN short hairpin RNA resulted in the amelioration of articular swelling, cartilage erosion, and OSM expression in the ankle joint of mice with collagen-induced arthritis as shown using microcomputed tomography and immunohistochemistry staining. Our results imply that OSM expression in osteoblasts increases in response to OPN-induced inflammation in vitro. Finally, lentiviral-OPN short hairpin RNA ameliorates the inflammatory response and bone destruction in mice with collagen-induced arthritis. Therefore, OPN may be a potential therapeutic target for RA.
Assuntos
Artrite Experimental/patologia , Artrite Reumatoide/patologia , Oncostatina M/biossíntese , Osteoblastos/metabolismo , Osteopontina/metabolismo , Adulto , Animais , Artrite Reumatoide/terapia , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células HEK293 , Humanos , Integrina alfaVbeta3/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Oncostatina M/genética , Osteopontina/genética , Fosforilação , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/fisiologia , Fator de Transcrição AP-1/metabolismoRESUMO
Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and the third most common cause of cancer mortality. In Taiwan, HCC is the second leading cause of cancer death. CCL4 (C-C chemokine ligand 4), is a macrophage inflammatory protein with a chief effect in inflammation and immune-regulation, and was documented in cancer progression by promoting instability in the tumor environment. Polymorphisms in chemokine genes help to determine host-pathogen interactions that influence chemokine levels. We investigated the effects of CCL4 gene polymorphisms on the risk of hepatocellular carcinoma (HCC) disease progression in a cohort of Taiwanese patients. We recruited total of 1,546 participants in current study, including 1,200 healthy control and 346 patients with HCC. Three single-nucleotide polymorphisms (SNPs) of the CCL4 gene were examined by a real-time PCR. We found that the A/G homozygotes of CCL4 rs10491121 polymorphism reduced the risks for HCC. On the other hand, AG and GA haplotypes of 2 CCL4 SNPs (rs1049112 and rs171915) also reduced the risks for HCC by 0.025 and 0.515 fold, respectively. The present report is the first time to examine the risk factors associated with CCL4 SNPs in HCC progression in Taiwan.
Assuntos
Carcinoma Hepatocelular/genética , Quimiocina CCL4/genética , Predisposição Genética para Doença , Neoplasias Hepáticas/genética , Adulto , Idoso , Povo Asiático/genética , Carcinoma Hepatocelular/patologia , Feminino , Estudos de Associação Genética , Genótipo , Haplótipos/genética , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , TaiwanRESUMO
Lung cancer is one of the most frequently diagnosed malignancies and is associated with a poor survival rate in the Chinese Han population. Analysis of genetic variants could lead to improvements in prognosis following lung cancer therapy. High-mobility group box 1 protein (HMGB1) is a ubiquitous nuclear protein found in eukaryotic cells that participates in several biological functions including immune response, cell survival, apoptosis and cancer development. We investigated the effects of HMGB1 gene polymorphisms on the risk of lung cancer progression in a Chinese Han population. Our sample of 751 participants included 372 patients with lung cancer and 379 healthy controls. Four single-nucleotide polymorphisms (SNPs) of the HMGB1 gene were examined by real-time polymerase chain reaction (RT-PCR). We found that the CT or CC+CT heterozygotes of the HMGB1 rs1045411 polymorphism reduced the risks for lung cancer, while the G/T/C haplotypes of three HMGB1 SNPs (rs1360485, rs1045411 and rs2249825) also reduced the risk for lung cancer by almost half (0.486-fold). The current study is the first to examine the risk factors associated with HMGB1 SNPs in lung cancer development in the Chinese Han population.
Assuntos
Povo Asiático/genética , Predisposição Genética para Doença , Proteína HMGB1/genética , Neoplasias Pulmonares/genética , Adulto , Idoso , Estudos de Casos e Controles , Progressão da Doença , Feminino , Genótipo , Haplótipos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de RiscoRESUMO
Rheumatoid arthritis (RA) is a systemic inflammatory disease that causes chronic inflammation of the joints. Analysis of genetic variants offers promise for guiding treatment and improving outcomes in RA. High-mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein found in all mammal eukaryotic cells that participates in several biological functions including immune response, cell survival and apoptosis. We investigated the effects of HMGB1 gene polymorphisms on the risk of RA disease progression in a cohort of Chinese Han individuals. Four single nucleotide polymorphisms (SNPs) from the HMGB1 gene were selected and genotyped in 232 patients with RA and 353 healthy controls. We found that having one C allele in rs1360485 and one G allele in rs2249825 polymorphisms lowered the risk of RA in females. Moreover, among healthy controls, those who bore the C/G/T haplotype at SNPs rs1360485, rs2249825 and rs1412125 were at reduced risk of developing RA by 0.13-fold (p <0.05). This is the first report to examine the risk factors associated with HMGB1 SNPs in the development of RA disease in the Chinese Han population.
Assuntos
Artrite Reumatoide/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Proteína HMGB1/genética , Adulto , Idoso , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/fisiopatologia , China/epidemiologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Endothelial progenitor cells (EPCs) promote angiogenesis and are therefore key contributors to a wide variety of angiogenesis-related autoimmune diseases such as rheumatoid arthritis (RA). However, the signaling mechanisms through which these progenitor cells influence RA pathogenesis remain unknown. The aim of this study was to examine whether resistin plays a role in the pathogenesis of and angiogenesis associated with RA by circulating EPCs. We found that levels of resistin in synovial fluid and tissue from patients with RA and from mice with collagen-induced arthritis were overexpressed and promoted the homing of EPCs into the synovium, thereby inducing angiogenesis. EPCs isolated from healthy donors were used to investigate the signal transduction pathway underlying EPC migration and tube formation after treatment with resistin. We found that resistin directly induced a significant increase in expression of vascular endothelial growth factor (VEGF) in EPCs. We also found that the expression of microRNA-206 (miR-206) was negatively correlated with the expression of resistin during EPC-mediated angiogenesis. Notably, the increased expression of VEGF was associated with decreased binding of miR-206 to the VEGF-A 3' untranslated region through protein kinase C delta-dependent AMP-activated protein kinase signaling pathway. Moreover, blockade of resistin reduced EPC homing into synovial fluid and angiogenesis in vivo. Taken together, our study is the first to demonstrate that resistin promotes EPCs homing into the synovium during RA angiogenesis via a signal transduction pathway that involves VEGF expression in primary EPCs. These findings provide support for resistin as a therapeutic target for the patients with RA. Stem Cells 2015;33:2243-2255.
Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Células Progenitoras Endoteliais/metabolismo , MicroRNAs/metabolismo , Neovascularização Patológica/patologia , Adulto , Animais , Embrião de Galinha , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Resistina , TransfecçãoRESUMO
Hepatocellular carcinoma (HCC) is a malignancy of liver and a leading cause of cancer mortality worldwide. Its management is compounded by biological and clinical heterogeneity. These interindividual genetic variations can modulate the effects of HCC treatment. High-mobility group box protein 1 (HMGB1) is a well investigated, ubiquitous nuclear protein found in eukaryotic cells that plays a multiple biological roles such as DNA stability, program cell death, immune response, and furthermore in cancer progression. In this report, we examined HMGB1 single nucleotide polymorphisms (SNPs) with multiple risk factors related to HCC susceptibility and clinicopathological characteristics. Four HMGB1 SNPs (rs1412125, rs2249825, rs1045411, and rs1360485) were assessed by using a TaqMan SNPs Genotyping in 324 patients with HCC and in 695 cancer-free controls. The results showed that HMGB1 SNP rs1045411 with CT or at least one T alleles has lower risk of HCC than wild-type (CC) carriers. Moreover, HMGB1 SNP rs1412125 with TT allele has a higher risk of distant metastasis compared with patients carrying at least one C allele. The present study is the first report to discuss the risk factors associated with HMGB1 SNPs in HCC progression in Taiwan.