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Signal transducer and activator of transcription（STAT）is a unique protein family that binds to DNA,coupled with tyrosine phosphorylation signaling pathways,acting as a transcriptional regulator to mediate a variety of biological effects.Cerebral ischemia and reperfusion can activate STATs signaling pathway,but no studies have confirmed whether STAT activation can be verified by diffusion-weighted magnetic resonance imaging（DWI）in rats after cerebral ischemia/reperfusion.Here,we established a rat model of focal cerebral ischemia injury using the modified Longa method.DWI revealed hyperintensity in parts of the left hemisphere before reperfusion and a low apparent diffusion coefficient.STAT3 protein expression showed no significant change after reperfusion,but phosphorylated STAT3 expression began to increase after 30 minutes of reperfusion and peaked at 24 hours.Pearson correlation analysis showed that STAT3 activation was correlated positively with the relative apparent diffusion coefficient and negatively with the DWI abnormal signal area.These results indicate that DWI is a reliable representation of the infarct area and reflects STAT phosphorylation in rat brain following focal cerebral ischemia/reperfusion.

Interferons (IFNs), which were discovered a half century ago, are a group of secreted proteins that play key roles in innate immunity against viral infection. The major signaling pathway activated by IFNs is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which leads to the expression of IFN-stimulated genes (ISGs), including many antiviral effectors. Viruses have evolved various strategies with which to antagonize the JAK/STAT pathway to influence viral virulence and pathogenesis. In recent years, notable progress has been made to better understand the JAK/STAT pathway activated by IFNs and antagonized by viruses. In this review, recent progress in research of the JAK/STAT pathway activated by type I IFNs, non-canonical STAT activation, viral antagonism of the JAK/STAT pathway, removing of the JAK/STAT antagonist from viral genome for attenuation, and the potential pathogenesis roles of tyrosine phosphorylation-independent non-canonical STATs activation during virus infection are discussed in detail. We expect that this review will provide new insight into the understanding the complexity of the interplay between JAK/STAT signaling and viral antagonism.

Background Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in several malignancies. Here, we define the correlation between STAT3 expression and lymph node micrometastasis of early‐stage non‐small cell lung cancer. Then we highlight some possibilities associated with developing a way to detect tumor micrometastasis and an anticancer drug that might therapeutically inhibit the STAT3 signaling pathway. Methods The samples were collected from 50 patients with early‐stage non‐small cell lung cancer and 50 patients with benign lung tumors. Mucin 1 mRNA expression was evaluated to determine lymph node micrometastasis status. STAT3 mRNA, STAT3 protein, and phosphorylated STAT3 protein expression were evaluated through reverse transcription polymerase chain reaction, western blot, and immunohistochemistry, respectively. Measurement data was represented as mean ± standard deviation, and the t‐rest or F‐test were used. The χ2‐test was used in enumeration data. Logistic regression analysis was carried out to determine the independent risk factors influencing lymph node micrometastasis. Results STAT3 mRNA and proteins expression were correlated with lymph node micrometastasis (P < 0.05). Logistic regression analysis revealed STAT3 protein overexpression and the differentiation degree of tumors were independent risk factors for lymph node micrometastasis. Conclusion Overexpression of STAT3 might promote lymphatic micrometastasis of early‐stage non‐small cell lung cancer and might be a clinical predictor of lymph node micrometastasis.

Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5‐fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X‐linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor β receptor 2‐mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling. Metformin and phenformin decreased the expression of pro‐apoptotic proteins by inhibiting STAT3 phosphorylation at Ser‐727 and suppressed invasion and migration by inhibiting TGFBR2‐mediated signaling

Type 2 cytokine-associated immunity may be involved in the pathogenesis of allergic asthma. Although interleukin 27 (IL-27) has been reported as an initiator and suppressor of T-helper 1 (Th1) and T-helper 2 (Th2) responses, respectively, its effects on the development of asthma remain unclear. In the present study, mice were induced and challenged with ovalbumin and received subsequent intranasal administration of IL-27. Total and differential cell counts were determined from Wright-Giemsa-stained cytospins, whereas the cytokine levels were detected using ELISA. In addition, the expression levels of signal transducer and activator of transcription (STAT) 1, STAT3, GATA-binding protein-3 (GATA3) and T-bet (T-box transcription factor) were analyzed in T cells by western blot analysis. Their corresponding mRNA expression levels were determined by quantitative PCR. Airway remodeling was assessed by conventional pathological techniques. The results indicated that intranasal administration of IL-27 ameliorated airway inflammation and hyperresponsiveness in an acute model of asthma. Furthermore, IL-27 prevented airway remodeling in a chronic model of asthma. Following administration of IL-27, the mRNA expression levels of STAT1 and T-bet were upregulated, while those of GATA3 were downregulated. Moreover, the phosphorylation levels of STAT1 and STAT3 were increased. Taken together, these findings demonstrated that intranasal administration of IL-27 ameliorated Th2-related allergic lung inflammation and remodeling in mouse models of asthma by repairing both the STAT1 and STAT3 pathways.

Tanshinone IIA (Tan-IIA) is an extract from the widely used traditional Chinese medicine (TCM) Danshen (Salvia miltiorrhiza), and has been found to attenuate the proliferation of bladder cancer (BCa) cells (The IC50 were: 5637, 2.6 μg/mL; BFTC, 2 μg/mL; T24, 2.7 μg/mL, respectively.). However, the mechanism of the effect of Tan-IIA on migration inhibition of BCa cells remains unclear. This study investigates the anti-metastatic effect of Tan-IIA in human BCa cells and clarifies its molecular mechanism. Three human BCa cell lines, 5637, BFTC and T24, were used for subsequent experiments. Cell migration and invasion were evaluated by transwell assays. Real-time RT-PCR and western blotting were performed to detect epithelial-mesenchymal transition (EMT)-related gene expression. The enzymatic activity of matrix metalloproteinases (MMP) was evaluated by zymography assay. Tan-IIA inhibited the migration and invasion of human BCa cells. Tan-IIA suppressed both the protein expression and enzymatic activity of MMP-9/-2 in human BCa cells. Tan-IIA up-regulated the epithelial marker E-cadherin and down-regulated mesenchymal markers such as N-cadherin and Vimentin, along with transcription regulators such as Snail and Slug in BCa cells in a time- and dose-dependent manner. Mechanism dissection revealed that Tan-IIA-inhibited BCa cell invasion could function via suppressed chemokine (C-C motif) ligand 2 (CCL2) expression, which could be reversed by the addition of CCL2 recombinant protein. Furthermore, Tan-IIA could inhibit the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) (Tyr705), which cannot be restored by the CCL2 recombinant protein addition. These data implicated that Tan-IIA might suppress EMT on BCa cells through STAT3-CCL2 signaling inhibition. Tan-IIA inhibits EMT of BCa cells via modulation of STAT3-CCL2 signaling. Our findings suggest that Tan-IIA can serve as a potential anti-metastatic agent in BCa therapy.

Aims Remote ischemic pre‐conditioning (RIPC) protects against ischemia/reperfusion (I/R) injury. However, the mechanisms underlying this protection remain unclear. In the present study, we investigated the role of Janus‐activated kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway and cell cycle arrest, and their relationship with neuronal apoptosis following RIPC. Methods A rat cerebral I/R injury model was induced by middle cerebral artery occlusion (MCAO), and AG490 was used to investigate the mechanisms of RIPC. p‐JAK2‐, p‐STAT3‐, cyclin D1‐, and cyclin‐dependent kinase 6 (CDK6) expression was assessed by Western blotting and immunofluorescence staining. Results RIPC reduced the infarct volume, improved neurological function, and increased neuronal survival. Furthermore, p‐JAK2 and p‐STAT3 were detected during the initial phase of reperfusion; the expression levels were significantly increased at 3 and 24 h after reperfusion and were suppressed by RIPC. Additionally, the MCAO‐induced upregulation of the cell cycle regulators cyclin D1 and CDK6 was ameliorated by RIPC. Meanwhile, cyclin D1 and CDK6 were colocalized with p‐STAT3 in the ischemic brain. Conclusion RIPC ameliorates the induction of the JAK2/STAT3 pathway and cell cycle regulators cyclin D1 and CDK6 by MCAO, and this net inhibition of cell cycle re‐entry by RIPC is associated with downregulation of STAT3 phosphorylation. Three days’ RIPC mitigates I/R injury by decreasing the induction of JAK2/STAT3 pathway and cell cycle regulators cyclin D1 and CDK6 by MCAO, and this net inhibition of cell cycle re‐entry by RIPC is associated with downregulation of STAT3 phosphorylation.

Chlorogenic acid (CGA) is the primary constituent of Caulis Lonicerae, a Chinese herb used for the treatment of rheumatoid arthritis (RA). The present study aimed to investigate whether CGA was able to inhibit the proliferation of the fibroblast-like synoviocyte cell line (RSC-364), stimulated by interleukin (IL)-6, through inducing apoptosis. Following incubation with IL-6 or IL-6 and CGA, the cellular proliferation of RSC-364 cells was detected by MTT assay. The ratio of apoptosed cells were detected by flow cytometry. Western blot analysis was performed to observe protein expression levels of key molecules involved in the Janus-activated kinase/signal transducer and activator of transcription 3 (JAK/STAT) signaling pathway [phosphorylated (p)-STAT3, JAK1 and gp130] and the nuclear factor κB (NF-κB) signaling pathway [phosphorylated (p)-inhibitor of κB kinase subunit α/β and NF-κB p50). It was revealed that CGA was able to inhibit the inflammatory proliferation of RSC-364 cells mediated by IL-6 through inducing apoptosis. CGA was also able to suppress the expression levels of key molecules in the JAK/STAT and NF-κB signaling pathways, and inhibit the activation of these signaling pathways in the inflammatory response through IL-6-mediated signaling, thereby resulting in the inhibition of the inflammatory proliferation of synoviocytes. The present results indicated that CGA may have potential as a novel therapeutic agent for inhibiting inflammatory hyperplasia of the synovium through inducing synoviocyte apoptosis in patients with RA.

Macrophage polarization has been well documented. Macrophages can aquire two phenotypes, the pro-inflammatory M1 phenotype, and the anti-inflammatory and wound healing M2 phenotype. The M1 macrophage phenotype has been linked to metabolic disease and is also associated with cancer-related inflammation. Of note, macrophage polarization can be influenced by the extracellular environment. In the current study, we examined the effects of Pyropia yezoensis glycoprotein (PYGP) on M1 to M2 macrophage polarization in lipopolysaccharide (LPS)-stimulated macrophages. RAW 264.7 macrophages stimulated with LPS exhibited an upregulated expression of pro-inflammatory mediators, namely of the M1 markers, nitric oxide (NO), reactive oxygen species (ROS), interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and nitric oxide synthase-2 (NOS-2). Treatment with PYGP inhibited the production of M1 markers and increased arginase 1 (ARG1), chitinase-like 3 (Chil3; also known as Ym1), resistin like beta (RETNLB; also known as FIZZ1), IL-10, CD163, CD206, peroxisome proliferator-activated receptor γ (PPARγ) and Krüppel-like factor 4 (KLF4) M2 marker gene expression. The signal transducer and activator of transcription (STAT)3 and STAT6 transcription factors were phosphorylated following treatment with PYGP. However, the silencing of STAT3 and STAT6 using siRNA in the macrophages decreased ARG1, Ym1 and FIZZ1 M2 marker gene expression in spite of treatment of PYGP. These findings suggest that PYGP exerts anti-inflammatory effects by regulating the M1 to M2 phenotypic switch through STAT3 and STAT6. Thus, PYGP may have potential for use as a natural remedy for inflammatory diseases.

Interleukin (IL)-27 can inhibit the differentiation of Th2 cells and plays a role in the development of asthma. However, whether the therapeutic administration of IL-27 in a mouse model of asthma can inhibit allergic responses remains a matter of debate. Additionally, the mechanisms through which IL-27 ameliorates inflammatory responses in asthma are not yet fully understood. Thus, the aim of the present study was to examine the effects of IL-27 on asthma using a mouse model and to elucidate the underlying mechanisms. For this purpose, mice received an intranasal administration of IL-27 and the total and differential cell counts, levels of cytokines and type 1 regulatory T (Tr1) cells in the lungs were detected. The protein and mRNA levels of signal transducer and activator of transcription (STAT)1 and STAT3 were analyzed and airway remodeling was assessed. The results indicated that IL-27 did not ameliorate airway inflammation, airway hyperresponsiveness, and airway remolding when administrated therapeutically. Preventatively, the administration of IL-27 decreased the concentrations of Th2 cytokines and increased the number of Tr1 cells. The protein and mRNA levels of STAT1 and STAT3 were increased. Taken together, these findings demonstrate that the prophylactic administration of IL-27 ameliorates asthma by alleviating the lung Th2 inflammatory environment through the restoration of both the STAT1 and STAT3 pathways. IL-27 may thus prove to be useful as a novel agent for the prevention of asthma.