Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 11.345
Filtrar
1.
J Transl Med ; 19(1): 386, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503521

RESUMO

OBJECTIVE: Little is known regarding the functional role of microRNA-193-3p (miR-193-3p) in sepsis. Hence, the aim of the present study was to investigate the effect of miR-193-3p on myocardial injury in mice with sepsis and its mechanism through the regulation of signal transducers and activators of transcription 3 (STAT3). METHODS: The mice model of sepsis was established by cecal ligation and puncture (CLP), septic mice were injected with miR-193-3p agomir, miR-193-3p antagomir or siRNA-STAT3. The expression of miR-193-3p, STAT3 and HMGB1 in the myocardial tissue of septic mice were detected. Cardiac ultrasound, hemodynamics, myocardial injury markers, inflammatory factors and cardiomyocyte apoptosis in septic mice were measured. RESULTS: MiR-193-3p expression was reduced while STAT3 expression was increased in septic mice. Down-regulated STAT3 or up-regulated miR-193-3p improved cardiac function, attenuated myocardial injury, inflammation and cardiomyocyte apoptosis in septic mice. Knockdown STAT3 reversed the role of inhibited miR-193-3p for mice with sepsis. miR-193-3p targeted STAT3, thereby inhibiting HMGB1 expression. CONCLUSION: This study provides evidence that miR-193-3p targets STAT3 expression to reduce HMGB1 expression, thereby reducing septic myocardial damage. MiR-193-3p might be a potential candidate marker and therapeutic target for sepsis.


Assuntos
Proteína HMGB1/metabolismo , MicroRNAs , Fator de Transcrição STAT3/metabolismo , Sepse , Animais , Apoptose , Ceco , Proteína HMGB1/genética , Camundongos , MicroRNAs/genética , Fator de Transcrição STAT3/genética , Sepse/complicações
2.
J Transl Med ; 19(1): 383, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496870

RESUMO

BACKGROUND: Antiangiogenic therapy has increasingly become an important strategy for the treatment of colorectal cancer. Recent studies have shown that the tumour microenvironment (TME) promotes tumour angiogenesis. Bufalin is an active antitumour compound whose efficacy has been indicated by previous studies. However, there are very few studies on the antiangiogenic effects of bufalin. METHODS: Herein, human umbilical vein endothelial cell (HUVEC) tube formation, migration and adhesion tests were used to assess angiogenesis in vitro. Western blotting and quantitative PCR were used to detect relevant protein levels and mRNA expression levels. A subcutaneous xenograft tumour model and a hepatic metastasis model were established in mice to investigate the influence of bufalin on angiogenesis mediated by the TME in vivo. RESULTS: We found that angiogenesis mediated by cells in the TME was significantly inhibited in the presence of bufalin. The results demonstrated that the proangiogenic genes in HUVECs, such as VEGF, PDGFA, E-selectin and P-selectin, were downregulated by bufalin and that this downregulation was mediated by inhibition of the STAT3 pathway. Overexpression of STAT3 reversed the inhibitory effects of bufalin on angiogenesis. Furthermore, there was little reduction in angiogenesis when bufalin directly acted on the cells in the tumour microenvironment. CONCLUSION: Our findings demonstrate that bufalin suppresses tumour microenvironment-mediated angiogenesis by inhibiting the STAT3 signalling pathway in vascular endothelial cells, revealing that bufalin may be used as a new antiangiogenic adjuvant therapy medicine to treat colorectal cancer.


Assuntos
Neoplasias Hepáticas , Microambiente Tumoral , Inibidores da Angiogênese/farmacologia , Animais , Bufanolídeos , Movimento Celular , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Camundongos Nus , Neovascularização Patológica/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo
3.
J Immunol ; 207(5): 1265-1274, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34348976

RESUMO

IL-9-producing Th cells, termed Th9 cells, contribute to immunity against parasites and cancers but have detrimental roles in allergic disease and colitis. Th9 cells differentiate in response to IL-4 and TGF-ß, but these signals are insufficient to drive Th9 differentiation in the absence of IL-2. IL-2-induced STAT5 activation is required for chromatin accessibility within Il9 enhancer and promoter regions and directly transactivates the Il9 locus. STAT5 also suppresses gene expression during Th9 cell development, but these roles are less well defined. In this study, we demonstrate that human allergy-associated Th9 cells exhibited a signature of STAT5-mediated gene repression that is associated with the silencing of a Th17-like transcriptional signature. In murine Th9 cell differentiation, blockade of IL-2/STAT5 signaling induced the expression of IL-17 and the Th17-associated transcription factor Rorγt. However, IL-2-deprived Th9 cells did not exhibit a significant Th17- or STAT3-associated transcriptional signature. Consistent with these observations, differentiation of IL-17-producing cells under these conditions was STAT3-independent but did require Rorγt and BATF. Furthermore, ectopic expression of Rorγt and BATF partially rescued IL-17 production in STAT3-deficient Th17 cells, highlighting the importance of these factors in this process. Although STAT3 was not required for the differentiation of IL-17-producing cells under IL-2-deprived Th9 conditions, their prolonged survival was STAT3-dependent, potentially explaining why STAT3-independent IL-17 production is not commonly observed in vivo. Together, our data suggest that IL-2/STAT5 signaling plays an important role in controlling the balance of a Th9 versus a Th17-like differentiation program in vitro and in allergic disease.


Assuntos
Fator de Transcrição STAT5 , Células Th17 , Animais , Diferenciação Celular , Regulação da Expressão Gênica , Humanos , Interleucina-9/genética , Interleucina-9/metabolismo , Camundongos , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Células Th17/metabolismo
4.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34445170

RESUMO

Triple-negative breast cancer (TNBC) is a highly aggressive disease with invasive and metastasizing properties associated with a poor prognosis. The STAT3 signaling pathway has shown a pivotal role in cancer cell migration, invasion, metastasis and drug resistance of TNBC cells. IL-6 is a main upstream activator of the JAK2/STAT3 pathway. In the present study we examined the impact of the NO-donor glyceryl trinitrate (GTN) on the activation of the JAK2/STAT3 signaling pathway and subsequent migration, invasion and metastasis ability of TNBC cells through in vitro and in vivo experiments. We used a subtoxic dose of carboplatin and/or recombinant IL-6 to activate the JAK2/STAT3 signaling pathway and its functional outcomes. We found an inhibitory effect of GTN on the activation of the JAK2/STAT3 signaling, migration and invasion of TNBC cells. We discovered that GTN inhibits the activation of JAK2, the upstream activator of STAT3, and mediates the S-nitrosylation of JAK2. Finally, the effect of GTN (Nitronal) on lung metastasis was investigated to assess its antitumor activity in vivo.


Assuntos
Janus Quinase 2/metabolismo , Doadores de Óxido Nítrico/farmacologia , Nitroglicerina/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica/prevenção & controle , Doadores de Óxido Nítrico/uso terapêutico , Nitroglicerina/uso terapêutico , Neoplasias de Mama Triplo Negativas/metabolismo
5.
Sci Rep ; 11(1): 16174, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376712

RESUMO

Oncostatin M (OSM) is a pleiotropic, interleukin-6 family inflammatory cytokine that plays an important role in inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis, and cancer progression and metastasis. Recently, elevated OSM levels have been found in the serum of COVID-19 patients in intensive care units. Multiple anti-OSM therapeutics have been investigated, but to date no OSM small molecule inhibitors are clinically available. To pursue a high-throughput screening and structure-based drug discovery strategy to design a small molecule inhibitor of OSM, milligram quantities of highly pure, bioactive OSM are required. Here, we developed a reliable protocol to produce highly pure unlabeled and isotope enriched OSM from E. coli for biochemical and NMR studies. High yields (ca. 10 mg/L culture) were obtained in rich and minimal defined media cultures. Purified OSM was characterized by mass spectrometry and circular dichroism. The bioactivity was confirmed by induction of OSM/OSM receptor signaling through STAT3 phosphorylation in human breast cancer cells. Optimized buffer conditions yielded 1H, 15N HSQC NMR spectra with intense, well-dispersed peaks. Titration of 15N OSM with a small molecule inhibitor showed chemical shift perturbations for several key residues with a binding affinity of 12.2 ± 3.9 µM. These results demonstrate the value of bioactive recombinant human OSM for NMR-based small molecule screening.


Assuntos
Descoberta de Drogas/métodos , Oncostatina M/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Humanos , Espectroscopia de Ressonância Magnética/métodos , Simulação de Acoplamento Molecular , Oncostatina M/química , Oncostatina M/metabolismo , Fosforilação , Ligação Proteica , Fator de Transcrição STAT3/metabolismo , Bibliotecas de Moléculas Pequenas/química
6.
J Leukoc Biol ; 110(3): 511-524, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34342041

RESUMO

Periodontitis is one of the most common oral diseases worldwide, and it is associated with various systemic diseases, including cognitive diseases. STAT3 regulates the inflammatory cascade and influences adaptive immunity by modulating Th17/Treg cell differentiation. In this study, we aimed to explore the effect of adaptive immunity inside and outside the brain on the association between periodontitis and cognitive impairment and understand the role of the STAT3 signaling pathway. We established Porphyromonas gingivalis LPS-induced periodontitis mice models by injecting P. gingivalis LPS into the gingival sulcus of mice. Behavioral tests showed that learning and memory abilities were impaired. The flow cytometry data showed an imbalance in the Th17/Treg ratio in the blood and brain samples of the mice. The expression of Th17-related cytokines (IL-1ß, IL-17A, IL-21, and IL-22) increased, whereas that of Treg-related cytokines (IL-2 and IL-10) decreased in both the blood and the brain. The level of LPS increased and the STAT3 signaling pathway was activated during this process. These effects were reversed by C188-9, a STAT3 inhibitor. In conclusion, P. gingivalis LPS-induced periodontitis may promote the occurrence and progression of cognitive impairment by modulating the Th17/Treg balance inside and outside the brain. The STAT3 signaling pathway may have immunoregulatory effects on the mouth-to-brain axis.


Assuntos
Disfunção Cognitiva/imunologia , Disfunção Cognitiva/microbiologia , Periodontite/imunologia , Periodontite/microbiologia , Porphyromonas gingivalis/fisiologia , Fator de Transcrição STAT3/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Processo Alveolar/patologia , Animais , Astrócitos/patologia , Reabsorção Óssea/complicações , Reabsorção Óssea/imunologia , Reabsorção Óssea/microbiologia , Reabsorção Óssea/patologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico por imagem , Citocinas/metabolismo , Gengiva/patologia , Lipopolissacarídeos , Memória , Camundongos , Microglia/patologia , Periodontite/complicações , Periodontite/diagnóstico por imagem , Transdução de Sinais , Aprendizagem Espacial
7.
J Enzyme Inhib Med Chem ; 36(1): 1905-1915, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34369236

RESUMO

Epidermal growth factor receptor (EGFR) signalling and the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) are aberrantly activated in ovarian cancer. However, inhibition of EGFR signalling in ovarian cancer patients resulted in a disappointing clinical benefit. In this study, we found that EGFR could activate IL-6-STAT3 pathway in ovarian cancer cells. However, we also demonstrated that EGFR knockdown could increase STAT3 phosphorylation in HO8910 and OVCAR-3 ovarian cancer cells. Interestingly, we further demonstrated that the non-coding RNA miR-146b could simultaneously block both the EGFR and IL-6-STAT3 pathways. Finally, our data demonstrated that miR-146b overexpression resulted in a greater suppression of cell migration than STAT3 pathway inhibition alone.These results suggest a complex and heterogeneous role of EGFR in ovarian cancer. Combined blockade of EGFR and IL-6-STAT3 pathways by miR-146b might be a strategy for improving the clinical benefit of targeting the EGFR pathway in ovarian cancer patients in the future.


Assuntos
Carcinoma Epitelial do Ovário/metabolismo , Receptores ErbB/metabolismo , Interleucina-6/metabolismo , MicroRNAs/metabolismo , Neoplasias Ovarianas/metabolismo , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Receptores ErbB/genética , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Fosforilação , Transdução de Sinais
8.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360971

RESUMO

Interleukin-22 (IL-22) plays a role in epithelial barrier function and repair, and may provide benefits in conditions like inflammatory bowel disease. However, limited human data are available to assess the clinical effect of IL-22 administration. This study used a human intestinal cell line to identify an IL-22-dependent gene signature that could serve as a pharmacodynamic biomarker for IL-22 therapy. The response to IL-22Fc (UTTR1147A, an Fc-stabilized version of IL-22) was assessed in HT-29 cells by microarray, and the selected responsive genes were confirmed by qPCR. HT-29 cells demonstrated dose-dependent increases in STAT3 phosphorylation and multiple gene expression changes in response to UTTR1147A. Genes were selected that were upregulated by UTTR1147A, but to a lesser extent by IL-6, which also signals via STAT3. IL-1R1 was highly upregulated by UTTR1147A, and differential gene expression patterns were observed in response to IL-22Fc in the presence of IL-1ß. An IL-22-dependent gene signature was identified that could serve as a pharmacodynamic biomarker in intestinal biopsies to support the clinical development of an IL-22 therapeutic. The differential gene expression pattern in the presence of IL-1ß suggests that an inflammatory cytokine milieu in the disease setting could influence the clinical responses to IL-22.


Assuntos
Anti-Inflamatórios/farmacologia , Imunoglobulina G/genética , Doenças Inflamatórias Intestinais/metabolismo , Interleucinas/genética , Transcriptoma/efeitos dos fármacos , Biomarcadores/metabolismo , Células HT29 , Humanos , Imunoglobulina G/metabolismo , Interleucinas/metabolismo , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Fator de Transcrição STAT3/metabolismo
9.
Molecules ; 26(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34443472

RESUMO

Feruloylacetone (FER) is a natural degradant of curcumin after heating, which structurally reserves some functional groups of curcumin. It is not as widely discussed as its original counterpart has been previously; and in this study, its anticancer efficacy is investigated. This study focuses on the suppressive effect of FER on colon cancer, as the efficacious effect of curcumin on this typical cancer type has been well evidenced. In addition, demethoxy-feruloylacetone (DFER) was applied to compare the effect that might be brought on by the structural differences of the methoxy group. It was revealed that both FER and DFER inhibited the proliferation of HCT116 cells, possibly via suppression of the phosphorylated mTOR/STAT3 pathway. Notably, FER could significantly repress both the STAT3 phosphorylation and protein levels. Furthermore, both samples showed capability of arresting HCT116 cells at the G2/M phase via the activation of p53/p21 and the upregulation of cyclin-B. In addition, ROS elevation and changes in mitochondrial membrane potential were revealed, as indicated by p-atm elevation. The apoptotic rate rose to 36.9 and 32.2% after being treated by FER and DFER, respectively. In summary, both compounds exhibited an anticancer effect, and FER showed a greater proapoptotic effect, possibly due to the presence of the methoxy group on the aromatic ring.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Curcumina/farmacologia , Mitocôndrias/efeitos dos fármacos , Estirenos/farmacologia , Antineoplásicos/química , Antioxidantes/química , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Curcumina/química , Curcumina/metabolismo , Ciclina B1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/agonistas , Fase G2/efeitos dos fármacos , Células HCT116 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Fenol/química , Fenol/farmacologia , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Estirenos/química , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/agonistas
10.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445309

RESUMO

In our previous work, we built the model of PPARγ dependent pathways involved in the development of the psoriatic lesions. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor and transcription factor which regulates the expression of many proinflammatory genes. We tested the hypothesis that low levels of PPARγ expression promote the development of psoriatic lesions triggering the IL17-related signaling cascade. Skin samples of normally looking and lesional skin donated by psoriasis patients and psoriatic CD3+ Tcells samples (n = 23) and samples of healthy CD3+ T cells donated by volunteers (n = 10) were analyzed by real-time PCR, ELISA and immunohistochemistry analysis. We found that the expression of PPARγ is downregulated in human psoriatic skin and laser treatment restores the expression. The expression of IL17, STAT3, FOXP3, and RORC in psoriatic skin before and after laser treatment were correlated with PPARγ expression according to the reconstructed model of PPARγ pathway in psoriasis.In conclusion, we report that PPARγ weakens the expression of genes that contribute in the development of psoriatic lesion. Our data show that transcriptional regulation of PPARγ expression by FOSL1 and by STAT3/FOSL1 feedback loop may be central in the psoriatic skin and T-cells.


Assuntos
PPAR gama/metabolismo , Psoríase/metabolismo , Transdução de Sinais , Adulto , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , PPAR gama/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos T/metabolismo
11.
J Immunol ; 207(5): 1322-1332, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34341171

RESUMO

MicroRNA-21 (miR-21) inhibits IL-12 expression and impairs the Th1 response necessary for control of Leishmania infection. Recent studies have shown that Leishmania infection induces miR-21 expression in dendritic cells and macrophages, and inhibition of miR-21 restores IL-12 expression. Because miR-21 is known to be expressed due to inflammatory stimuli in a wide range of hematopoietic cells, we investigated the role of miR-21 in regulating immune responses during visceral leishmaniasis (VL) caused by Leishmania donovani infection. We found that miR-21 expression was significantly elevated in dendritic cells, macrophages, inflammatory monocytes, polymorphonuclear neutrophils, and in the spleen and liver tissues after L. donovani infection, concomitant with an increased expression of disease exacerbating IL-6 and STAT3. Bone marrow dendritic cells from miR-21 knockout (miR-21KO) mice showed increased IL-12 production and decreased production of IL-10. On L. donovani infection, miR-21KO mice exhibited significantly greater numbers of IFN-γ- and TNF-α-producing CD4+ and CD8+ T cells in their organs that was associated with increased production of Th1-associated IFN-γ, TNF-α, and NO from the splenocytes. Finally, miR-21KO mice displayed significantly more developing and mature hepatic granulomas leading to reduction in organ parasitic loads compared with wild type counterparts. Similar results were noted in L. donovani-infected wild type mice after transient miR-21 depletion. These observations indicate that miR-21 plays a critical role in pathogenesis of VL by suppressing IL-12- and Th1-associated IFN-γ and also inducing disease-promoting induction of the IL-6 and STAT-3 signaling pathway. miR-21 could therefore be used as a potential target for developing host-directed treatment for VL.


Assuntos
Células Dendríticas/imunologia , Leishmania donovani/fisiologia , Leishmaniose Visceral/imunologia , MicroRNAs/genética , Monócitos/imunologia , Neutrófilos/imunologia , Células Th1/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Resistência à Doença , Imunidade Celular , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT3/metabolismo , Regulação para Cima
12.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445513

RESUMO

The activation of signal transducer and activator of transcription 3 (STAT3), as well as up-regulation of cytokines and growth factors to promote STAT3 activation, have been found in the epidermis of psoriatic lesions. Recently, a series of synthetic compounds possessing the Michael acceptor have been reported as STAT3 inhibitors by covalently binding to cysteine of STAT3. We synthesized a Michael acceptor analog, SKSI-0412, and confirmed the binding affinity between STAT3 and SKSI-0412. We hypothesized that the SKSI-0412 can inhibit interleukin (IL)-17A-induced inflammation in keratinocytes. The introduction of IL-17A increased the phosphorylation of STAT3 in keratinocytes, whereas the inactivation of STAT3 by SKSI-0412 reduced IL-17A-induced STAT3 phosphorylation and IκBζ expression. In addition, human ß defensin-2 and S100A7, which are regulated by IκBζ, were significantly decreased with SKSI-0412 administration. We also confirmed that SKSI-0412 regulates cell proliferation, which is the major phenotype of psoriasis. Based on these results, we suggest targeting STAT3 with SKSI-0412 as a novel therapeutic strategy to regulate IL-17A-induced psoriatic inflammation in keratinocytes.


Assuntos
Anti-Inflamatórios/farmacologia , Interleucina-17/efeitos adversos , Queratinócitos/citologia , Fator de Transcrição STAT3/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Fator de Transcrição STAT3/química , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química
13.
Oxid Med Cell Longev ; 2021: 7385160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457118

RESUMO

Obesity is considered as a risk factor of osteoarthritis (OA), but the precise relationship is still poorly understood. Leptin, one of the most relevant factors secreted by adipose tissues, plays an important role in the pathogenesis of OA. Our aim was to investigate the regulation and molecular mechanism of the leptin signaling pathway in obesity-related OA. SD rats were fed with a high-fat diet (HFD) for 5, 15, and 27 weeks. The levels of leptin in serum increased from W5, while in the synovial fluid increased from W15. The histological evaluation showed that the pathological changes of OA occurred at 27 weeks rather than 5 or 15 weeks. We also found that leptin induced CD14/TLR4 activation by the JAK2-STAT3 signaling pathway to promote OA. Moreover, silencing SOCS3 enhanced leptin-induced JAK2-STAT3-CD14/TLR4 activation in rat primary chondrocytes. Our findings indicated that leptin may be one of the initiating factors of obesity-related OA. TLR4 is at least partially regulated by leptin through the JAK2-STAT3-CD14 pathway. Meanwhile, SOCS3 acting as a negative feedback inhibitor of leptin signaling presented a potential therapeutic prospect for obesity-related OA. Our study provided new evidence suggesting the key role of leptin in mediating obesity-related OA process and its underlying mechanisms.


Assuntos
Regulação da Expressão Gênica , Janus Quinase 2/metabolismo , Leptina/metabolismo , Obesidade/complicações , Osteoartrite/patologia , Fator de Transcrição STAT3/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Janus Quinase 2/genética , Masculino , Osteoartrite/etiologia , Osteoartrite/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/genética , Receptor 4 Toll-Like/genética
14.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445110

RESUMO

Epidermal growth factor receptor (EGFR) is overexpressed in lung cancer patients. Despite treatment with various EGFR tyrosine kinase inhibitors, recurrence and metastasis of lung cancer are inevitable. Docetaxel (DTX) is an effective conventional drug that is used to treat various cancers. Several researchers have studied the use of traditional herbal medicine in combination with docetaxel, to improve lung cancer treatment. SH003, a novel herbal mixture, exerts anticancer effects in different cancer cell types. Here, we aimed to investigate the apoptotic and anticancer effects of SH003 in combination with DTX, in human non-small-cell lung cancer (NSCLC). SH003, with DTX, induced apoptotic cell death, with increased expression of cleaved caspases and cleaved poly (ADP-ribose) polymerase in NSCLC cells. Moreover, SH003 and DTX induced the apoptosis of H460 cells via the suppression of the EGFR and signal transducer and activator of transcription 3 (STAT3) signaling pathways. In H460 tumor xenograft models, the administration of SH003 or docetaxel alone diminished tumor growth, and their combination effectively killed cancer cells, with increased expression of apoptotic markers and decreased expression of p-EGFR and p-STAT3. Collectively, the combination of SH003 and DTX may be a novel anticancer strategy to overcome the challenges that are associated with conventional lung cancer therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células A549 , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição STAT3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
15.
Molecules ; 26(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34443375

RESUMO

The study aimed to evaluate the possible modulation of Nrf2, NF-ĸB and STAT3 signaling pathways in the colorectal cancer (CRC) cells line DLD-1 and HCT116 by secondary metabolites of lichens. An attempt was made to indicate the most promising targets in these signaling pathways. Attention was also paid to the effects of the compounds tested on CRC cells using anakoinosis-that is, simultaneous analysis of several signaling pathways. The effects of the tested natural compounds on the activity of selected transcriptional factors related to CRC were analyzed by Western blot and RT-PCR assays. The highest activity against CRC cells was shown by physodic and salazinic acids from the studied secondary metabolites of lichens. As a result, an increase in the activation of transcription factor Nrf2 and the expression of its selected target genes was observed. Physodic and salazinic acids induced the opposite effect in relation to the NF-κB and STAT3 pathways. These results confirmed our earlier observations that lichen-derived compounds have the ability to modulate signaling pathway networks. While caperatic acid affected Wnt/ß-catenin to the most extent, salazinic acid was the most potent modulator of Nrf2, NF-κB and STAT3 pathways. Physodic acid seemed to affect all the investigated pathways.


Assuntos
Neoplasias Colorretais/metabolismo , Depsídeos/farmacologia , Lactonas/farmacologia , Líquens/química , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Depsídeos/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lactonas/química , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Metabolismo Secundário/efeitos dos fármacos
16.
FASEB J ; 35(9): e21795, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403508

RESUMO

Intervertebral disc degeneration is an irreversible process associated with accumulation of senescent nucleus pulposus (NP) cells. This study investigates the hypothesis that Tumor necrosis factor-α (TNF-α)-treated senescent NP cells propagate senescence of neighboring healthy cells via a paracrine effect that involves p-Stat3 signaling and the cytokine interleukin-6 (IL-6). NP cells isolated from bovine caudal intervertebral disc (IVD) were treated with TNF-α to induce senescence which was confirmed by demonstrating upregulation of senescence-associated ß-galactosidase and p16. This was correlated with downregulation of NP-associated markers, Aggrecan, Col2A1, and Sox9. Direct contact and non-contact co-culture of healthy and senescent cells showed that TNF-α-treated cells increased the senescence in healthy cells via a paracrine effect. The senescent cells have a secretory phenotype as indicated by increased gene and protein levels of IL-6. Phosphorylated Signal Transducer and Activator of Transcription 3 (pStat3) levels were also high in treated cells and appeared to upregulate IL-6 as inhibition of Stat3 phosphorylation by StatticV downregulated IL-6 mRNA expression in cells and protein levels in the culture media. All trans retinoic acid, an IL-6 inhibitor, also decreased the secretion of IL-6 and reduced the paracrine effect of senescent cells on healthy cells. Decreased pStat3 levels and inhibition of IL-6 secretion did not fully restore NP gene expression of Col2A1 but importantly, appeared to cause senescent cells to undergo apoptosis and cell death. This study demonstrated the paracrine effect of senescent NP cells which involves Stat3 and IL-6 and may explain why senescent NP cells accumulate in IVD with age. The role of pSTAT3 and IL-6 in mediating NP senescence requires further study as it may be a novel strategy for modulating the senescent-inducing effects of TNF-α.


Assuntos
Senescência Celular/efeitos dos fármacos , Núcleo Pulposo/citologia , Núcleo Pulposo/efeitos dos fármacos , Comunicação Parácrina/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Animais , Apoptose/efeitos dos fármacos , Bovinos , Morte Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Núcleo Pulposo/metabolismo , Fosforilação , Fator de Transcrição STAT3/metabolismo
17.
J Transl Med ; 19(1): 338, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34372858

RESUMO

BACKGROUND: Fine tuned balance of reactive oxygen species (ROS) is essential for tumor cells and tumor cells use immune checkpoints to evade attack form immunity system. However, it's unclear whether there is any crosstalk between these two pathways. CYB561D2, an antioxidant protein, is part of 5-gene prognosis signature in gliomas and its involvement in gliomas is unknown. Here, we aim to provide a detailed characterization of CYB561D2 in gliomas. METHODS: CYB561D2 expression was measured in clinical samples of gilomas and normal tissues. The effects of CYB561D2 on immunity related genes and tumor behaviors were investigated in glioma cell lines with various in vitro and in vivo assays. RESULTS: CYB561D2 expression was enhanced in gliomas compared to control tissues. CYB561D2 up-regulation was associated with high grading of gliomas and short survival in patients. CYB561D2 expression was induced by H2O2 in glioma cell lines. CYB561D2 and its functional product ascorbate activated STAT3 dose-dependently. CYB561D2 over-expression increased PD-L1, CCL2 and TDO2 expression, and induced immunosuppression in co-cultured T cells. In in vitro assays, CYB561D2 knock-down suppressed cell growth, colony formation, migration and promoted apoptosis. In contrast, CYB561D2 over-expression reduced survival rate in intracranial glioma model and this effect could be blocked by dominant negative-STAT3. The CYB561D2 up-regulation and the positive association of CYB561D2 with PD-L1, CCL2 and TDO2 expression were cross-validated in open-access datasets. CONCLUSIONS: CYB561D2 up-regulation induces immunosuppression and aggression via activating STAT3 in gliomas and CYB561D2 mediates ROS-tumor immunity crosstalk.


Assuntos
Neoplasias Encefálicas , Glioma , Agressão , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Humanos , Peróxido de Hidrogênio , Imunossupressão , Fator de Transcrição STAT3/metabolismo , Regulação para Cima/genética
18.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 50(3): 396-402, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34402263

RESUMO

Proteasome is the eukaryotic organelle responsible for degradation of short-lived proteins and involved in maintaining cellular protein homeostasis. It has been reported that during the occurrence and development of hepatocellular carcinoma (HCC), the regulatory particle subunits of proteasome regulate a series of tumor-related proteins, and proliferation, survival-associated signaling molecules, including PTEN gene, P53, Bcl-2, Bcl-2 interacting mediator of cell death (Bim), cyclin-dependent kinase 4(CDK4), transforming growth factor ß receptor (TGFBR), E2F1, growth factor receptor-bound protein 2 (GRB2) . Meanwhile, these subunits regulate some tumor-associated pathway protein, such as signal transducer and activator of transcription 3 (STAT3) and protein kinase B (AKT), inducing their malfunction to promote the occurrence, proliferation, invasion and metastasis of HCC. The core particle subunits are more to perform the degradation of HCC-related proteins, so inhibitors targeting the core particle show a good anti-tumor effect. This review summarizes the current research progress on the regulation and mechanism of proteasome subunits in promoting the occurrence and development .


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
19.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361081

RESUMO

Cancer cachexia is a common deleterious paraneoplastic syndrome that represents an area of unmet clinical need, partly due to its poorly understood aetiology and complex multifactorial nature. We have interrogated multiple genetically defined larval Drosophila models of tumourigenesis against key features of human cancer cachexia. Our results indicate that cachectic tissue wasting is dependent on the genetic characteristics of the tumour and demonstrate that host malnutrition or tumour burden are not sufficient to drive wasting. We show that JAK/STAT and TNF-α/Egr signalling are elevated in cachectic muscle and promote tissue wasting. Furthermore, we introduce a dual driver system that allows independent genetic manipulation of tumour and host skeletal muscle. Overall, we present a novel Drosophila larval paradigm to study tumour/host tissue crosstalk in vivo, which may contribute to future research in cancer cachexia and impact the design of therapeutic approaches for this pathology.


Assuntos
Caquexia/patologia , Carcinogênese/patologia , Modelos Animais de Doenças , Larva/crescimento & desenvolvimento , Neoplasias/complicações , Animais , Caquexia/etiologia , Caquexia/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Drosophila , Perfilação da Expressão Gênica , Humanos , Janus Quinases/genética , Janus Quinases/metabolismo , Larva/genética , Larva/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
20.
Theranostics ; 11(16): 7797-7812, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335965

RESUMO

Rationale: Corticosteroid resistance (CR) is a serious drawback to steroid therapy in patients with ulcerative colitis (UC); the underlying mechanism is incompletely understood. Twist1 protein (TW1) is an apoptosis inhibitor and has immune regulatory functions. This study aims to elucidate the roles of TW1 in inducing and sustaining the CR status in UC. Methods: Surgically removed colon tissues of patients with ulcerative colitis (UC) were collected, from which neutrophils were isolated by flow cytometry. The inflammation-related gene activities in neutrophils were analyzed by RNA sequencing. A CR colitis mouse model was developed with the dextran sulfate sodium approach in a hypoxia environment. Results: Higher TW1 gene expression was detected in neutrophils isolated from the colon tissues of UC patients with CR and the CR mouse colon tissues. TW1 physically interacted with glucocorticoid receptor (GR)α in CR neutrophils that prevented GRα from interacting with steroids; which consequently abrogated the effects of steroids on regulating the cellular activities of neutrophils. STAT3 (Signal Transducer and Activator of Transcription-3) interacted with Ras protein activator like 1 to sustain the high TW1 expression in colon mucosal neutrophils of CR patients and CR mice. Inhibition of TW1 restored the sensitivity to corticosteroid of neutrophils in the colon tissues of a CR murine model. Conclusions: UC patients at CR status showed high TW1 expression in neutrophils. TW1 prevented steroids from regulating neutrophil activities. Inhibition of TW1 restored the sensitivity to corticosteroids in the colon tissues at the CR status.


Assuntos
Colite Ulcerativa/metabolismo , Resistência a Medicamentos/genética , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Corticosteroides/farmacologia , Adulto , Animais , China , Colite , Colite Ulcerativa/genética , Colo/metabolismo , Dexametasona/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Proteínas Nucleares/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína 1 Relacionada a Twist/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...