RESUMO
As the pace of society increases and lifestyles change， the incidence and mortality rates of breast cancer continue to rise. Targeted therapies are now promising in the treatment of breast cancer， and a variety of protein targets have been identified to play an important role in the development of breast cancer. Among them， signal transducer and activator of transcription （STAT） proteins constitute a crucial group that serves as important targets for transducing cellular transcriptional information， which can regulate downstream cell proliferation， apoptosis， cell migration， invasion， angiogenic factors， etc. and then affect the progression of breast cancer. The STAT family is closely associated with the inflammatory response to tumors and plays a landmark role in tumor development as well as in diagnosis and prognosis. The "inflammation-cancer" transformation refers to the process in which the inflammatory microenvironment caused by uncontrolled inflammation promotes normal cells to become cancerous. According to the theory of Chinese medicine， "heat toxicity" in "cancer toxicity" corresponds to inflammation， which is closely related to tumor development. As a major link associated with the inflammatory response， the STAT family has a promising role in the development and treatment of a variety of tumors， but its relevance to breast cancer remains inadequately explored. Chinese medicine has been shown to have good efficacy in the prevention and treatment of breast cancer， and some current studies have shown that the active ingredients and compounds of Chinese medicine have certain intervention effects on breast cancer-related STAT proteins， but there has not been a systematic review. In order to better sort out and summarize the studies on the effects of Chinese herbal medicines based on the STAT family interventions in breast cancer， this paper reviewed the studies on Chinese herbal medicines acting on the STAT family in recent years， aiming to provide new ideas for clinical applications in breast cancer and to provide thoughts for the development of STAT protein-based drugs.
RESUMO
ObjectiveThis study was designed to observe the effect of Didang Xianxiong decoction on the cardiac myocardial microvascular endothelial cells （CMECs） injury， and to explore its related mechanism based on the CMECs model induced by high glucose. MethodRat primary myocardial cells were cultured in vitro and 33 mmol·L-1 glucose was added for modeling. After modeling， the rats were randomly divided into model group （final glucose concentration： 33 mmol·L-1）， normal group， Didang Xianxiong decoction low dose group （glucose + 5% Didang Xianxiong decoction containing serum）， Didang Xianxiong decoction medium dose group （glucose+10% Didang Xianxiong decoction containing serum）， Didang Xianxiong decoction high dose group （glucose+20% Didang Xianxiong decoction containing serum） and alagebrium chloride （ALT-711） group （glucose+10% ALT-711 containing serum）. The influence of drug-containing serum on the proliferation of CMECs was detected by MTT tetrazolium salt colorimetric assay. The relative mRNA expression of c-Jun was detected by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. The protein expression of phosphorylated Janus kinase 1 （p-JAK1）， phosphorylated signal transducer and activator of transcription 1 （p-STAT1） and transforming growth factor-β1 （TGF-β1） was determined by Western blot. ResultCompared with the conditions in normal group， the mRNA expression of c-Jun and protein expression of p-JAK1， p-STAT1 and TGF-β1 were up-regulated in model group （P<0.01）. Compared with model group， all treatment groups had decreased mRNA expression of c-Jun （P<0.01）. Didang Xianxiong decoction medium and high dose groups and ALT-711 group showed reduced protein expression of p-JAK1 and p-STAT1 （P<0.05， P<0.01）， while there was no significant change in Didang Xianxiong decoction low dose group. TGF-β1 protein expression was lowered in all treatment groups （P<0.05， P<0.01）， and the decrease was more significant in Didang Xianxiong decoction medium and high dose groups than Didang Xianxiong decoction low dose group. ConclusionDidang Xianxiong decoction can protect CMECs with high glucose-induced injury， and the mechanism may be related to reducing the activity of JAK/STAT signaling pathway in cells.
RESUMO
ObjectiveTo investigate the effect of calycosin-mediated glucoprotein130/Janus kinase/signal transducer and activator of transcription factor （GP130/JAK/STAT） signaling pathway on oxidative injury of astrocytes in spinal cord. MethodAstrocytes in rat spinal cord were isolated and identified by immunofluorescence detection of glial fibrillary acidic protein （GFAP）. The cells were respectively pre-treated with 5， 10， 20 μmol·L-1 calycosin for 12 h， and then 100 μmol·L-1 H2O2 （24 h） was added to induce oxidative injury. Cell counting kit-8 （CCK-8） assay was employed to detect cell proliferation and select the optimal concentration of calycosin. The following experimental groups were designed： control group， model group （100 μmol·L-1 H2O2）， calycosin group （20 μmol·L-1 calycosin）， calycosin + LY294002 group （20 μmol·L-1 calycosin + 10 μmol·L-1 LY294002）， and calycosin + Stattic group （20 μmol·L-1 calycosin + 3 μmol·L-1 Stattic）. CCK-8 assay and immunofluorescence method were used to detect the proliferation of cells and flow cytometry was applied to detect cell apoptosis and cycle. The protein expression of phosphorylated （p）-JAK2， p-STAT3， p-protein kinase B （Akt）， GP130， and interleukin-6 （IL-6） was detected by Western blotting. ResultCompared with the control group， the model group showed low proliferation activity and high apoptosis rate of cells （P<0.05）. Compared with the model group， calycosin （20 μmol·L-1） group displayed high proliferation activity and low apoptosis rate of cells （P<0.05）. Compared with calycosin （20 μmol·L-1） group， both phosphatidylinosirtol-3-kinases （PI3K） inhibitor LY294002 and STAT3 inhibitor Stattic significantly reduced the proliferation activity and increased the apoptosis rate of cells （P<0.05）. The protein expression of p-JAK2， p-STAT3， p-Akt， GP130， and IL-6 in the model group was higher than that in the control group （P<0.05）， and the expression of the above indicators was lower in each treatment group than in the model group （P<0.05）. ConclusionCalycosin can promote the proliferation and inhibit the apoptosis of astrocytes with oxidative injury by inhibiting the phosphorylation of PI3K/Akt pathway and JAK2/STAT3 pathway.
RESUMO
ObjectiveTo investigate the effect of calycosin-mediated glucoprotein130/Janus kinase/signal transducer and activator of transcription factor （GP130/JAK/STAT） signaling pathway on oxidative injury of astrocytes in spinal cord. MethodAstrocytes in rat spinal cord were isolated and identified by immunofluorescence detection of glial fibrillary acidic protein （GFAP）. The cells were respectively pre-treated with 5， 10， 20 μmol·L-1 calycosin for 12 h， and then 100 μmol·L-1 H2O2 （24 h） was added to induce oxidative injury. Cell counting kit-8 （CCK-8） assay was employed to detect cell proliferation and select the optimal concentration of calycosin. The following experimental groups were designed： control group， model group （100 μmol·L-1 H2O2）， calycosin group （20 μmol·L-1 calycosin）， calycosin + LY294002 group （20 μmol·L-1 calycosin + 10 μmol·L-1 LY294002）， and calycosin + Stattic group （20 μmol·L-1 calycosin + 3 μmol·L-1 Stattic）. CCK-8 assay and immunofluorescence method were used to detect the proliferation of cells and flow cytometry was applied to detect cell apoptosis and cycle. The protein expression of phosphorylated （p）-JAK2， p-STAT3， p-protein kinase B （Akt）， GP130， and interleukin-6 （IL-6） was detected by Western blotting. ResultCompared with the control group， the model group showed low proliferation activity and high apoptosis rate of cells （P<0.05）. Compared with the model group， calycosin （20 μmol·L-1） group displayed high proliferation activity and low apoptosis rate of cells （P<0.05）. Compared with calycosin （20 μmol·L-1） group， both phosphatidylinosirtol-3-kinases （PI3K） inhibitor LY294002 and STAT3 inhibitor Stattic significantly reduced the proliferation activity and increased the apoptosis rate of cells （P<0.05）. The protein expression of p-JAK2， p-STAT3， p-Akt， GP130， and IL-6 in the model group was higher than that in the control group （P<0.05）， and the expression of the above indicators was lower in each treatment group than in the model group （P<0.05）. ConclusionCalycosin can promote the proliferation and inhibit the apoptosis of astrocytes with oxidative injury by inhibiting the phosphorylation of PI3K/Akt pathway and JAK2/STAT3 pathway.
RESUMO
Tofacitinib is a Janus kinase inhibitor and can block the Janus kinase-signal transducer and activator of transcription signal transduction pathway and reduce the production and release of a variety of cytokines. It has great potential in the treatment of various rheumatic diseases with a rapid onset of action and can reduce corticosteroid dependence and related adverse events. The therapeutic effect of tofacitinib in adult patients has been confirmed, and it has been increasingly used in pediatric patients in recent years. This article reviews the clinical application of tofacitinib in the treatment of pediatric autoimmune diseases.
Assuntos
Adulto , Criança , Humanos , Janus Quinases/metabolismo , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Doenças Reumáticas/tratamento farmacológicoRESUMO
Background: Alopecia areata is an autoimmune disease that occurs as a result of the loss of the inherent immune privilege of the hair follicle. It has been recently demonstrated that the interferon-γ/interleukin-15 feedback loop that signals via the Janus kinase–signal transducer and activator of transcription pathway is critical to the breakdown of this immune privilege. Aims: To evaluate the immunological distribution of CD4+ T-cells, CD8+ T-cells, phosphorylated signal transducer and activator of transcription 1 and study its relation with the clinical and histopathological findings of the disease. Materials and Methods: A total of 30 patients of alopecia areata were included in the study. Following a detailed history and clinical examination, a scalp biopsy was performed. Histopathology was studied and immunohistochemistry was done to demonstrate the positivity and distribution of CD4+ T-cells, CD8+ T-cells and phosphorylated signal transducer and activator of transcription 1. Results: The follicular count, number of anagen and terminal hair were found to be decreased, whereas the catagen, telogen and vellus hair were found to be increased in number. A peribulbar CD4+ T-cell infiltrate was seen in 70% cases, whereas a CD8+ T-cell infiltrate was seen in 83.3% cases. An intrabulbar CD4+ T-cell infiltrate was seen in 26.7% cases, whereas a CD8+ T-cell infiltrate was seen in 70% cases. Among the 25 hair follicles dermal papilla identified, 36.8% cases were found to be positive for phospho-signal transducer and activation of transcription-1. Limitations: The drawbacks of our study included a small sample size and the use of only vertical sectioning for the scalp biopsy samples. Conclusion: Phosphorylated signal transducer and activator of transcription 1 positivity as an indicator of signalling via the Janus kinase-1/2 pathway was seen in 36.8% of our cases highlighting the integral role of this pathway in the pathogenesis of alopecia areata.
RESUMO
Objective The mechanisms of epimedium and Ligustrum Lucidum with glucocorticoid (GC) acting on asthma are closely related to the regulation of the JAKs / STATs pathway associated with the Th1/Th2 balance in the lung tissue of the asthmatic rats. This study aimed to investigate the synergistic effect of icariin and oleanolic acid with dexamethasone on the protein expressions of JAKs/STATs in GC-sensitive CEM-C7 and GC-resistant CEM-C1 cells.Methods We divided CEM-C7 and CEM-C1 cells into groups A (complete culture medium control), B (dexamethasone at 10-6mol/L), C (icarrin at 100 mg/mL), D (oleanolic acid at 100 mg/mL), E (icarrin+oleanolic acid both at 50 mg/mL), and F (icariin+oleanolic acid+dexamethasone at 50 mg/mL, 50 mg/mL and 10-6 mol/L, respectively), and treated them with corresponding agents for 24 hours. Then, we determined the protein expressions of JAKs (JAK1 and JAK2) and STATs (STAT1, STAT3, STAT5, and STAT6) in the CEM-C7 and CEM-C1 cells of different groups by Western blot.Results The protein expressions of JAK1 and JAK2 in the CEM-C1 cells were 0.22±0.01 and 0.23±0.01 in group A, 0.24±0.01 and 0.24±0.01 in group B, 0.23±0.01 and 0.22±0.01 in group C, 0.24±0.01 and 0.23±0.01 in group D, 0.22±0.01 and 0.21±0.01 in group E, and 0.18±0.01 and 0.19±0.01 in group F, both significantly lower in groups E and F than in B (P<0.01), and in groups C, D and F than in E (P<0.01). The expressions of STAT1 and STAT3 proteins were 0.23±0.01 and 0.23±0.01 in group A, 0.23±0.01 and 0.22±0.01 in group B, 0.23±0.01 and 0.22±0.01 in group C, 0.23±0.01 and 0.23±0.01 in group D, 0.18±0.01 and 0.20±0.02 in group E, and 0.17±0.01 and 0.16±0.01 in group F, both remarkably lower in groups E and F than in B (P<0.01), and that of STAT3 even lower in F than in E (P<0.01). The expressions of STAT5 and STAT6 were 0.24±0.01 and 0.24±0.01 in group A, 0.23±0.01 and 0.23±0.02 in group B, 0.23±0.01 and 0.24±0.01 in group C, 0.23±0.01 and 0.24±0.01 in group D, 0.19±0.01 and 0.19±0.01 in group E, and 0.16±0.01 and 0.20±0.02 in group F, both markedly lower in groups E and F than in B (P<0.01), and even lower in F than in E (P<0.01). The protein expressions of JAK1 and JAK2 in the CEM-C7 cells were 0.24±0.01 and 0.22±0.02 in group A, 0.12±0.01 and 0.49±0.01 in group B, 0.23±0.01 and 0.27±0.01 in group C, 0.25±0.01 and 0.25±0.02 in group D, 0.27±0.01 and 0.23±0.01 in group E, and 0.20±0.01 and 0.32±0.01 in group F, the former increased while the latter decreased significantly in groups B, C, D, E and F as compared with group A (P<0.01), the former even lower and the latter even higher in groups C and F than in E (P<0.01). The expressions of STAT1 and STAT3 were 0.23±0.01 and 0.23±0.01 in group A, 0.10±0.01 and 0.11±0.02 in group B, 0.27±0.01 and 0.26±0.01 in group C, 0.27±0.01 and 0.27±0.01 in group D, 0.28±0.01 and 0.27±0.01 in group E, and 0.21±0.01 and 0.23±0.02 in group F, both remarkably higher in groups C, D, E and F than in B (P<0.01), though lower in F than in E (P<0.01). The expressions of STAT5 and STAT6 were 0.24±0.01 and 0.24±0.01 in group A, 0.10±0.01 and 0.11±0.02 in group B, 0.23±0.01 and 0.23±0.02 in group C, 0.23±0.01 and 0.23±0.01 in group D, 0.24±0.01 and 0.24±0.01 in group E, and 0.20±0.01 and 0.21±0.05 in group F, both significantly upregulated in groups C, D, E and F as compared with B (P<0.01), though lower in F than in E (P<0.05).Conclusion In case of hormone resistance, icariin and oleanolic acid combined with dexamethasone may regulate the JAKs/STATs signaling pathway and improve the sensitivity to hormone action.
RESUMO
<p><b>OBJECTIVES</b>To investigate the mechanism of Liuwei Dihuang Pill (, LDP) in treating postmenopausal osteoporosis (PMOP) with Shen (Kidney) yin deficiency.</p><p><b>METHODS</b>In this study, 205 cases of PMOP were divided into the PMOP Shen-yin deficiency group (Group A), PMOP Shen-yang deficiency group (Group B), PMOP without Shen deficiency group (Group C), and control group (Group N). Real-time polymerase chain reaction (RT-PCR) and Western blot techniques were used to observe the effects of LDP treatment on the cardiotrophin-like cytokine factor 1 (CLCF1), ankyrin repeat and SOCS box containing 1 (ASB1), and prokineticin 2 (PROK2) genes and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway.</p><p><b>RESULTS</b>The mRNA (P<0.05) and protein (P<0.01) expression levels of the CLCF1 gene in Group A were significantly lower than the corresponding levels in Group N. After LDP treatment for 3 months, the mRNA expression levels of the CLCF1 gene were obviously up-regulated (P<0.01). After 6-month treatment, the expression levels of CLCF1 mRNA and protein were significantly up-regulated (both P<0.01), and the average bone density of the top femur had significantly increased (P<0.05). In vitro, CLCF1 overexpression resulted in a significant increase in the total protein and phosphorylated protein levels of JAK2 and STAT3.</p><p><b>CONCLUSIONS</b>The CLCF1 gene is an important gene associated with PMOP Shen-yin deficiency and the therapeutic effects of LDP may be mediated by up-regulation of CLCF1 gene expression and activation of the JAK/STAT signaling pathway.</p>
Assuntos
Feminino , Humanos , Pessoa de Meia-Idade , Citocinas , Genética , Metabolismo , Medicamentos de Ervas Chinesas , Farmacologia , Usos Terapêuticos , Regulação da Expressão Gênica , Janus Quinases , Metabolismo , Osteoporose Pós-Menopausa , Tratamento Farmacológico , Genética , RNA Mensageiro , Genética , Metabolismo , Fatores de Transcrição STAT , Metabolismo , Transdução de Sinais , Regulação para Cima , Deficiência da Energia Yin , Tratamento Farmacológico , GenéticaRESUMO
Background Retinal ischemia reperfusion injury (RIRI) is a common pathological process of many retinal vascular diseases with comprehensive pathogenesis mechanism.Researches showed that apoptosis of retinal cells and nerve fiber loss is the finally common pathway of RIRI,and Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway is a newly discovered signal transcript channel in recent years,which is involved in varieties of pathological processes.However,whether JAK-STAT pathway is associated with RIRI is still unelucidated.Objective This study was to investigate the time course of activation of JAK-STAT signal pathway and its significance during RIRI.Methods Forty clear adult male Sprague-Dawley rats were randomized into RIRI 6-hour,12-hour,24-hour and 48-hour groups.RIRI models were induced in lateral eyes of the rats by perfusing normal saline solution into the anterior chamber to elevate intraocular pressure (IOP) to 110 mmHg for 60 minutes and then allowing reperfusion,and the fellow eyes of the rats served as normal control group.The rats were sacrificed and the eyeballs were enucleated at 6,12,24 and 48 hours after reperfusion.The expressions of JAK2 and STAT3 protein (absorbance) in the retinas were located and detected by immunohistochemistry,and the relative expression levels of JAK2 and STAT3 mRNA in the retinas were detected by real-time fluorescence quantitative PCR.The use and care of the rats followed the ARVO Statement.Results Immunohistochemistry showed that JAK2 and STAT3 were faintly expressed in inner nuclear layer and retinal ganglion cells (RGCs) in the normal control group and strongly expressed in various RIRI groups.Significant differences were found in the expression intensities of JAK2 and STAT3 protein among the five groups (F =88.735,96.625,both at P ＜ 0.01).Compared with the normal control group,the expression intensities of JAK2 and STAT3 were enhanced in RIRI groups,with the peak values in RIRI 12-hour group (JAK2:t=4.308,5.559,5.315,4.726;all at P＜0.01.STAT3:t=5.047,7.843,6.281,4.887;all at P＜0.01).The thickening of inner retinal layer,loosening of retinal tissue,vacuolus degeneration of cells and decrease of RGCs were seen in the RIRI eyes.The relative expressing levels of the JAK2 mRNA and STAT3 mRNA in the retinas were significantly different among the groups (F =111.239,129.539;both at P＜0.01),and the relative expressing levels of JAK2 mRNA and STAT3 mRNA in the retinas were significantly increased in RIRI 6-hour,12-hour,24-hour and 48-hour groups in comparison with the normal control group (JAK2 mRNA:t=3.504,5.102,4.679,4.213;all at P＜0.01.STAT3 mRNA:t =6.541,8.787,5.693,5.898;all at P＜0.01).Conclusions The retinal morphology appears to be abnormal and RGCs are evidently decreased in rat eyes with RIRI,and the expressions of JAK2 and STAT3 in the retinas are simultaneously up-regulated,indicating that JAK-STAT signal pathway is involved during the RIRI process.
RESUMO
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) are a major signal transduction pathway in controlling and regulating a number of cytokine-mediated responses, including interferon-?, interleukin-1 (IL-1), IL-6, IL-10 and IL-4. The JAK/STAT pathway is particularly elegant because of its very rapid and simple cytoplasm-to-nucleus signaling. Recently, it has been found that JAK/STAT pathway might also be involved in the regulation of high mobility group box-1 protein (HMGB1), which plays an important role as a potential late mediator of sepsis. Inhibition of the activation of JAK/STAT pathway can down-regulate the gene expression of HMGB1 in vital organs, especially in the liver and lungs. In addition, treatment with JAK/STAT pathway inhibitors can effectively prevent the occurrence and development of multiple organ dysfunction syndrome following sepsis, and the probable underlying mechanism of which involves a reduction of direct or indirect harmful effect of HMGB1. Over the past few years, numerous investigations have contributed to our knowledge of the JAK/STAT pathway and its role in cytokine-mediated abnormality of immune function as well as inflammatory response during sepsis, and it might be helpful in further identifying a potential strategy of intervention for posttraumatic or postburn sepsis. This review summarizes the salient features of JAK/STAT pathway and focuses on the pathophysiological role of JAK/STAT in regulating proinflammatory cytokine activity and HMGB1 expression in vivo.
RESUMO
Objective To investigate the effect of lipopolysaccharide (LPS) on stimulating high mobility group box-1 protein (HMGB1) mRNA expression in peritoneal macrophages in rats and its potential signaling mechanism. Methods Abdominal macrophages obtained from male Wistar rats were seeded on 24-well (1?10 6 cells/well) tissue culture plates. The cells were incubated for 3 days before they were stimulated with LPS, fludarabine (specific inhibitor of signal transducer and activator of transcription 1, STAT1), or rapamycin (specific inhibitor of signal transducer and activator of transcription 3, STAT3). After being stimulated, macrophages were denatured directly in tissue culture plates to determine HMGB1 mRNA expression. The time-dependent and dose-dependent responses between LPS stimulation and HMGB1 mRNA expression were analyzed, and the effect of treatment with fludarabine and rapamycin on HMGB1 mRNA expression was also observed. Results After being stimulated with 75-100ng/ml LPS, the HMGB1 mRNA expressions in macrophages were up-regulated markedly, peaking at 24-36 hours, and remained elevated up to 48 hours. It was found that the HMGB1 mRNA expression was significantly inhibited by treatment with either fludarabine (100?mol/L) or rapamycin (25ng/ml). Conclusions These data suggest that LPS stimulation can result in up-regulation of HMGB1 mRNA expression in peritoneal macrophages in rats. Janus kinase/STAT pathway may be involved in modulating HMGB1 mRNA expression in LPS-activated macrophages.
RESUMO
Objective To investigate the relationship between activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and multiple organ dysfunction in rats with sepsis. Methods Using a sepsis model produced by cecal ligation and puncture (CLP), 98 male Wistar rats were randomly divided into normal control group (n=10), CLP group (n=40), AG490 (JAK2 inhibitor) treatment group (n=24) and rapamycin (RPM, STAT3 inhibitor) treatment group (n=24). At serial time points, the animals in each group were sacrificed, then tissue samples from the liver, lungs, kidneys and small intestine were harvested to detect STAT1/3 activity, pulmonary myeloperoxidase (MPO) and small intestinal diamine oxidase (DAO) activities. Meanwhile, organ function parameters including serum aspartate transaminase (AST) and blood urea nitrogen (BUN) contents were also measured. Results At 2 hours after CLP, STAT1 activities were found to be enhanced rapidly in the liver, lungs and small intestine, peaking at 6-24 hours, but their increase was delayed in the kidneys. Compared with STAT1, STAT3 activities were weaker and detected only in the liver and lungs, with no detectable STAT3 in the small intestine and kidneys. Pretreatment with either AG490 or RPM significantly lowered STAT1 activities in the liver, lungs and small intestine as well as STAT3 activities in the liver and lungs (P0.05). Conclusions These data suggest that abdominal infection can result in intensive activation of STAT1 and STAT3 in vital organs, and they play important roles in the pathogenesis of sepsis. Inhibition of JAK/STAT pathway can attenuate multiple organ dysfunction secondary to CLP-induced sepsis in rats.