Targeting the JAK-STAT signaling pathway in the treatment of psoriasis / 中华皮肤科杂志

The Janus kinase (JAK) -signal transducer and activator of transcription (STAT) signaling pathway is closely related to the occurrence of psoriasis. Various cytokines, including interleukin (IL) -23, IL-22, interferon (IFN) -γ, etc., can promote some key pathologic processes (such as the proliferation and abnormal differentiation of keratinocytes, and infiltration of inflammatory cells) via the JAK-STAT pathway in psoriasis, which suggests that targeting JAK-STAT pathway is a new strategy for the treatment of psoriasis. In recent years, small-molecule JAK inhibitors have shown good efficacy and safety in the treatment of psoriasis, and drugs targeting STAT pathway have been under development, which provide more treatment options for psoriasis. This review summarizes progress in drugs targeting the JAK-STAT signaling pathway in the treatment of psoriasis.

Change in expression of tumor necrosis factor receptor-associated factor 6 in lung tissues of rats with pulmonary hypertension / 中华麻醉学杂志

Objective:To determine the change in the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) in lung tissues of rats with pulmonary hypertension (PH).Methods:Sixteen SPF-grade healthy male Sprague-Dawley rats, aged 8 weeks, weighing 200-220 g, were divided into 2 groups ( n=8 each) by the random number table method: control group (group C1) and PH group (group PH1). The model of PH was prepared by subcutaneous injection of monocrotaline. On day 28 after developing the model, the mean pulmonary arterial pressure (mPAP) was measured, and the Fulton index was calculated, and the percentage of media wall thickness of the small and medium pulmonary arteries and percentage of muscularized vessels were also calculated. The expression of TRAF6, transcription-3 (STAT3), phosphorylated STAT3 (p-STAT3) and Cyclin D1 in lung tissues was detected by Western blot, and p-STAT3/STAT3 ratio was calculated. The interaction between TRAF6 and STAT3 was determined by immunoprecipitation assay. Primarily cultured pulmonary artery smooth muscle cells of normal rats (group C2) and pulmonary artery smooth muscle cells of rats with PH (group PH2) were inoculated in 6-well plates ( n=3 each). The expression of TRAF6 mRNA was detected by quantitative polymerase chain reaction. The expression of TRAF6, STAT3, p-STAT3 and Cyclin D1 was detected by Western blot. Results:Compared with group C1, the mPAP, Fulton index, percentage of media wall thickness of the small and medium pulmonary arteries and percentage of muscularized vessels were significantly increased, the expression of TRAF6 and Cyclin D1 in lung tissues was up-regulated, the p-STAT3/STAT3 ratio was increased ( P<0.05 or 0.01), and the results of immunoprecipitation showed that TRAF6 interacted with STAT3 in group PH1. Compared with group C2, the expression of TRAF6 protein and mRNA and Cyclin D1 was significantly up-regulated, and the p-STAT3/STAT3 ratio was increased in group PH2 ( P<0.05 or 0.01). Conclusions:The expression of TRAF6 in the lung tissue is up-regulated in rats with PH, which may be related to pulmonary vascular remodeling by promoting the activation of STAT3.

Effect of pyruvate peritoneal resuscitation on JAK/STAT signaling pathway in intestinal tissues of rats with hemorrhagic shock / 中华麻醉学杂志

Objective To evaluate the effect of pyruvate peritoneal resuscitation on Janus kinase (JAK) /signal transducer and activator of transcription (STAT) signaling pathway in intestinal tissues of rats with hemorrhagic shock.Methods Twenty-four healthy male Sprague-Dawley rats,weighing 200-300 g,were divided into 3 groups (n=8 each) using a random number table method:sham operation group (S group),intravenous resuscitation group (VR group),and peritoneal resuscitation with pyruvate group (PY group).Hemorrhagic shock was induced by blood-letting and infusing blood withdrawn with mean arterial pressure reduced to 30-40 mmHg for 60 min in pentobarbital-anesthetized rats.Hemorrhagic shock was resuscitated with autologous blood and normal saline 2 times the volume of blood withdrawn at the end of hemorrhagic shock in group VR.Pyruvate was intraperitoneally infused for 30 min using a micro-perfusion pump simultaneously with the intravenous resuscitation in group PY.The animals were sacrificed at 2 h after resuscitation,and intestinal tissues were obtained for determination of malondialdehyde (MDA) content (by thiobarbituric acid method),superoxide dismutase (SOD) activity (using xanthine oxidase method),myeloperoxidase (MPO) activity (using chemical colorimetry),and expression of phosphorylated STAT3 (pSTAT3),phosphorylated JAK2 (p-JAK2) and caspase-3 expression (by Western blot).Results Compared with group S,the MDA content and MPO activity were significantly increased,the SOD activity was decreased,and the expression of p-STAT3,p-JAK2 and caspase-3 was up-regulated in the other two groups (P＜0.05).Compared with group VR,the MDA content and MPO activity were significantly decreased,the SOD activity was increased,and the expression of p-STAT3,p-JAK2 and caspase-3 was down-regulated in group PY (P＜0.05).Conclusion The mechanism by which peritoneal resuscitation with pyruvate mitigates intestinal damage may be related to inhibiting activation of JAK/STAT signaling pathway in the rats with hemorrhagic shock.

Activación de STAT3 por hipoxia en modelos in vitro de cáncer de cuello uterino y en células endoteliales / STAT3 activation by hypoxia in in vitro models of cervix cancer and endothelial cells

resumen Introducción: El microambiente tumoral influye en el comportamiento de las células cancerosas. Especialmente, el estímulo de agentes estresantes, como la hipoxia, se convierte en un factor crítico para la evolución y el tratamiento del cáncer. La reacción celular frente a diversos estímulos se manifiesta en la activación de vías de señalización como la JAK/STAT, una de las más importantes por sus efectos en la diferenciación y proliferación celular. Objetivo: Evaluar el estado de la vía JAK/STAT mediante la expresión o activación de la proteína STAT3 en células de cáncer de cuello uterino (HeLa) y en células endoteliales (EA.hy926) sometidas a hipoxia. Materiales y métodos: Las líneas celulares se sometieron a condiciones de hipoxia física (1 % de O2) o química (100 μM de deferoxamina, DFO) durante dos, seis y 24 horas. Mediante Western blot se determinó el cambio en la expresión y activación de STAT3, y mediante inmunofluorescencia indirecta su localización subcelular. Resultados:. La hipoxia se evidenció por la activación y translocación al núcleo del HIF-1. Ni la hipoxia física ni la química alteraron la expresión de STAT3, pero sí la activación, según se comprobó por su fosforilación y su translocación al núcleo en los dos modelos bajo estudio. Conclusiones: Se evidenció la importancia de la hipoxia como un estímulo que modifica la activación de la proteína STAT3 en las células HeLa y EA.hy926, lo cual la convierte en un elemento importante en el diseño de estrategias terapéuticas contra el cáncer.

Abstract Introduction: The biological behavior of cancer cells is influenced by the tumor microenvironment in which they develop. In this context, stressor stimuli such as hypoxia are considered critical for tumor development and therapeutic management. Cellular response to various stimuli is evidenced in the activation of intracellular signaling pathways such as JAK/STAT, which is one of the most important for its effects in differentiation and cell proliferation. Objective: To evaluate the condition of the JAK/STAT pathway through the expression/activation of the STAT3 protein in cervix cancer cells (HeLa) and endothelial cells (EA.hy926) subjected to ypoxia. Material and methods: Cell lines were subjected to physical (1% O2) or chemical (deferoxamine, DFO, 100 μM) hypoxia for 2, 6 and 24 hours. Changes in the expression and activation of STAT3, and its subcellular localization by indirect immunofluorescence, were determined by western blot. Results: Hypoxia was evidenced by the activation and translocation to the nucleus of HIF-1. Neither physical nor chemical hypoxia altered STAT3 expression, but it did affect its activation, as seen in its phosphorylation and translocation to the nucleus in the two models under study. Conclusions: The present study highlights the importance of hypoxia as a stimulus that modifies the activation of the STAT3 protein in HeLa and EA.hy926 cells, which makes it an important factor in the design of therapeutic strategies against cancer.

Effect of dexmedetomidine pretreatment on activation of JAK/STAT signaling pathway during intestinal injury in rats undergoing liver transplantation / 中华麻醉学杂志

Objective To evaluate the effect of dexmedetomidine pretreatment on activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway during intestinal injury in rats undergoing liver transplantation.Methods Thirty-two pathogen-free healthy adult male Sprague-Dawley rats,weighing 220-250 g,aged 8-10 weeks,were divided into 4 groups (n =8 each) using a random number table:sham operation group (S group),liver transplantation group (LT group),dexmedetomidine pretreatment group (D group) and dexmedetomidine plus atipamezole (specific α2-adrenergic receptor antagonist) group (D+A group).The model of liver transplantation was established in LT,D and D+A groups except group S.In group D,dexmedetomidine 50 μg/kg was injected intraperitoneally at 30 min before skin incision.In group D+A,atipamzole 250 μg/kg was injected intraperitoneally at 5 min before administration of dexmedetomidine.At 6 h of reperfusion,blood samples were collected from the inferior vena cava for determination of serum concentrations of intestinal fatty acid binding protein (iFABP),lipopolysaccharide (LPS),tumor necrosis factor-alpha (TNF-ct) and high-mobility group box 1 protein (HMGB1).Intestinal specimens were then obtained for examination of the pathological changes of intestinal tissues (under light microscope) and for determination of the expression of activated caspase-3,phosphorylated JAK2 (p-JAK2),phosphorylated STAT1 (p-STAT1) and phosphorylated STAT3 (p-STAT3).Intestinal damage was assessed and scored.Wet/dry weight ratio (W/D ratio) was calculated.Results Compared with group S,the concentrations of iFABP,LPS,TNF-α and HMGB1 in serum,intestinal damage scores and W/D ratio were significantly increased,and the expression of activated caspase-3,p-JAK2,pSTATI and p-STAT3 in intestinal tissues was up-regulated in LT and D groups (P＜0.05).Compared with group LT,the concentrations of iFABP,LPS,TNF-cα and HMGB1 in serum,intestinal damage scores and W/D ratio were significantly decreased,and the expression of activated caspase-3,p-JAK2,p-STAT1 and p-STAT3 in intestinal tissues was down-regulated in group D (P＜0.05).Compared with group D,the concentrations of iFABP,LPS,TNF-cα and HMGB1 in serum,intestinal damage scores and W/D ratio were significantly increased,and the expression of activated caspase-3,p-JAK2,p-STAT1 and p-STAT3 in intestinal tissues was up-regulated in group D+A (P＜0.05).The pathological changes of intestinal tissues were significantly attenuated in group D as compared with group LT.Conclusion The mechanism by which dexmedetomidine pretreatment reduces intestinal injury may be related to inhibition of JAK/STAT signaling pathway activation in rats undergoing liver transplantation.

Myeloproliferative neoplasms and the JAK/STAT signaling pathway: an overview

ABSTRACTMyeloproliferative neoplasms are caused by a clonal proliferation of a hematopoietic progenitor. First described in 1951 as 'Myeloproliferative Diseases' and reevaluated by the World Health Organization classification system in 2011, myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia and primary myelofibrosis in a subgroup called breakpoint cluster region-Abelson fusion oncogene-negative neoplasms. According to World Health Organization regarding diagnosis criteria for myeloproliferative neoplasms, the presence of the JAK2 V617F mutation is considered the most important criterion in the diagnosis of breakpoint cluster region-Abelson fusion oncogene-negative neoplasms and is thus used as a clonal marker. The V617F mutation in the Janus kinase 2(JAK2) gene produces an altered protein that constitutively activates the Janus kinase/signal transducers and activators of transcription pathway and other pathways downstream as a result of signal transducers and activators of transcription which are subsequently phosphorylated. This affects the expression of genes involved in the regulation of apoptosis and regulatory proteins and modifies the proliferation rate of hematopoietic stem cells.

Estudo imunoistoquímico de componentes da Via Sonic Hedgehog, Stat3 e Mcm3 em tumores de glândula salivar / Immunohistochemical study components of Via Sonic Hedgehog, Stat3 and MCM3 in salivary gland tumors

O adenoma pleomórfico (AP), o carcinoma mucoepidermóide (CME) e o carcinoma adenóide cístico (CAC) representam tumores frequentes em glândula salivar. A via de sinalização Sonic Hedgehog (Hh) e o Transdutor de sinal e ativador da transcrição 3 (STAT3) desempenham funções importantes na proliferação celular, favorecendo o desenvolvimento tumoral e a proteína MCM3 tem sido considerada uma nova classe de marcadores de proliferação celular. Portanto, o presente trabalho propõe-se a estudar componentes da via Hh, bem como o STAT3 e o MCM3 em neoplasias de glândula salivar, na tentativa de adicionar informações sobre as características biológicas dessas neoplasias. Foram utilizados 9 casos de AP, 17 casos de CAC e 20 casos de CME e, por meio da técnica imunoistoquímica, realizou-se a detecção das seguintes proteínas: SHH, GLI1, SUFU, HHIP, STAT3 e MCM3. No AP, observou-se alta expressão citoplasmática de SHH e SUFU, e baixa expressão de STAT3 e MCM3. No CAC, observou-se alta expressão de GLI1, HHIP e STAT3 e baixa expressão de SHH, SUFU e MCM3. No CME, observou-se alta expressão de SHH, GLI1, SUFU e HHIP e baixa expressão de STAT3 e MCM3. Quando comparado entre os tipos tumorais, observou-se diferença estatisticamente significante para expressão de SHH (p=0.0064), STAT3 (p=0.0003) e MCM3 (p=0.0257)...

The pleomorphic adenoma (PA), mucoepidermoid carcinoma (MEC) and the adenoid cystic carcinoma (ACC) are common tumors arising from salivary glands. The Sonic Hedgehog signaling pathway (Hh) and signal transducer and activator of transcription 3 (STAT3) play important roles in cell proliferation, favoring tumor growth. The MCM3 protein has been considered as a novel class of cell proliferation markers. The aim of this investigation was to study components of the Hh pathway, as well as STAT3 and MCM3 in salivary gland neoplasms in an attempt to add information about the biological characteristics of these neoplasms. We used 9 cases of PA, 17 cases of ACC and 20 cases of MEC. Using immunohistochemistry, were investigated: SHH, GLI1, Sufu, HHIP, STAT3 and MCM3. In PA, there was high expression of cytoplasmic SHH and Sufu, and low expression of STAT3 and MCM3. In the ACC, there was high expression of GLI1, HHIP and STAT3 and low expression of SHH, SUFU and MCM3. In the MEC, we observed high expression of SHH, GLI1, SUFU and HHIP and low expression of STAT3 and MCM3. There was a statistically significant difference between SHH (p=0.0064), STAT3 (p=0.0003) and MCM3 (p=0.0257) when all tumors were compared...

The effects of erythropoietin on STAT1 and STAT3 levels following cerebral ischemia-reperfusion in rats / 中华核医学与分子影像杂志

Objective To explore the effects of erythropoietin (EPO) on the expression of signal transducer and activator of transcription (STAT) 1,phosphorylated STAT1 (P-STAT1),STAT3,P-STAT3 and cell apoptosis in rat models of focal cerebral ischemia-reperfusion.Methods Eighty male SpragueDawley rats were randomly and evenly divided into four groups by completely random design method: shamoperation (group A),cerebral ischemia-reperfusion (group B),cerebral ischemia-reperfusion ± saline (group C) and cerebral ischemia-reperfusion ± EPO (group D).The model of focal cerebral ischemiareperfusion injury was established by blocking the left middle cerebral artery.All rats underwent MRI for the detection of the changes of infarct area between 2 h post ischemia and 24 h of reperfusion.Western blot was used to observe the expression of STAT1,P-STAT1,STAT3,P-STAT3.Terminal oxynucleotidyl transferase mediated dUTP biotin nick end labeling (TUNEL) was used to evaluate the cell apoptosis including the relative area (ROI area/whole brain area of the same layer × 100％) of abnormal signal region,relative optical density (rOD) and apoptotic index.One-way analysis of variance and q test were used to analyze the data.Results On T2WI imaging,rats in group B and group C presented large hyperintense areas in the cortex and subcortex of left hemispheric ((28.00±4.60)％ and (29.70±4.80)％ respectively).Group D presented less hyperintense areas in the cortex and subcortex of left hemispheric compared with group B and group C ((21.10±2.40) ％; F=11.285,P＜0.01).The expression of STAT1 and STAT3 proteins was not significantly affected by ischemia-reperfusion and EPO intervention compared with normal brain tissue (F=0.806,1.558,both P＞0.05).However,the level of P-STAT1 was low in group A (rOD =0.75±0.13) but increased after cerebral ischemia-reperfusion.Compared with group B and group C,P-STAT1 expression was lower in group D (B-D: 2.08±0.15,2.05±0.16,1.92±0.05; F=3.274,P＞0.05).The level of P-STAT3was also low in group A (rOD=1.02±0.09).Compared with group B and group C,P-STAT3 expression in group D was significandy higher (B-D: 2.22±0.13,2.04±0.14,4.21±0.21 ; F=40.719,P＜0.01).The apoptotic index of group B and group C was (42.00±1.30)％ and (41.20±2.50)％,respectively,which was significantly higher than that of group D ((20.90± 1.46) ％ ; F=378.704,P＜0.01).Conclusion Intraperitoneal injection of EPO can reduce the cerebral ischemic area and the number of apoptotic cells in the ischemic penumbra in rat ischemia-reperfusion models through increasing P-STAT3 and decreasing P-STAT1 levels.

Dynamic signal pathway changes of signal transducer and activator of transcription factor-3 in hippocampal neurons induced by oxygen and glucose deprivation in vitro / 中华创伤杂志

Objective To observe the phosphorylation level and nuclear translocation of signal transducer and activator of transcription factor-3 (STAT3) in hippocampal neurons induced by oxygen and glucose deprivation in vitro and discuss the dynamic changes of STAT3 signal pathway in an in vitro cell model of brain hypoxia and ischemia.Methods Hippocampal neurons from newly born SD rats (within 24 hours from birth) were cultured with DMEM/F12 for nine days,and then were transferred to oxygen and glucose deprivation environment for four hours to establish experimental cell models.The distribution of phosphorylated STAT3 (p-STAT3) in the hippocampal neurons in different groups was observed under laser scanning confocal microscope after immunofluorescence staining.Expression intensity of p-STAT3 at different time points after oxygen and glucose deprivation in the hippocampal neurons was detected by Western blotting.Results Expression of p-STAT3 was unobvious in the nucleus of the control group,but it was observed in the nucleus of the model group one hour after modeling,and peaked at three hour.Expression levels of p-STAT3 in the hippocampal neurons at each time point between the two groups showed significant difference (P ＜ 0.05).Conclusion Oxygen and glucose deprivation induces noticeable up-regulation of p-STAT3 in the hippocampal neuronal nucleus,which indicates the overactivation of signal transduction pathway of STAT3.

MicroRNAs and signal transducers and activators of transcription / 第二军医大学学报

MicroRNAs (miRNAs) are important gene expression regulators and are involved in a variety of pathogeneses such as cancers and autoimmune diseases. Signal transducers and activators of transcription (STAT), the principle signaling proteins of many cytokines and growth factors, play significant roles in regulating immune cell homeostasis, cell differentiation and cell functions. In this review we discussed the recent advances in interactions between STATs and miRs, with focus on their interaction during the promotion and inhibition of immue cells and tumor cells. MiR-STAT interaction is still a new area of study, and more effort is needed to elucidate miR-STAT mechanisms.

Modulation of host cell signaling pathways as a therapeutic approach in periodontal disease

Recently, new treatment approaches have been developed to target the host component of periodontal disease. This review aims at providing updated information on host-modulating therapies, focusing on treatment strategies for inhibiting signal transduction pathways involved in inflammation. Pharmacological inhibitors of MAPK, NFκB and JAK/STAT pathways are being developed to manage rheumatoid arthritis, periodontal disease and other inflammatory diseases. Through these agents, inflammatory mediators can be inhibited at cell signaling level, interfering on transcription factors activation and inflammatory gene expression. Although these drugs offer great potential to modulate host response, their main limitations are lack of specificity and developments of side effects. After overcoming these limitations, adjunctive host modulating drugs will provide new therapeutic strategies for periodontal treatment.