Myeloproliferative neoplasms ( MPN ) is a class of clonal hematopoietic stem cell disease. Studies found that the JAK-STAT signaling pathway is closely related to the pathogenesis of MPN. The lymphocyte-specific adaptor protein (LNK) gene negatively regulates Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling and may play an important role in the pathogenesis of MPN. Especially in JAK2 mutation-negative MPN, LNK gene specific mutations may be the key to cause MPN subtypes. Certain single nucleotide polymorphism of LNK gene regulation of hematopoietic cells in different directions may also be important influence factors of MPN performance for different subtypes. LNK gene functional changes lead to abnormal activation of the JAK-STAT signaling pathway, and may be a new mechanism of MPN. In this review, the role of LNK gene in MPN pathogenesis is briefly summarized.
Humans ; Janus Kinases ; metabolism ; Mutation ; Myeloproliferative Disorders ; genetics ; Proteins ; genetics ; STAT Transcription Factors ; metabolism ; Signal Transduction

Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative disorder of clonal expansion of cytotoxic T- or NK-cells in blood and bone marrow, and often associated with autoimmune disorders. According to the current WHO classification of the hematopoietic and lymphoid tissue tumors, the clonal LGL expansions are further classified as T-cell large granular lymphocytic leukemia (T-LGLL), chronic lymphoproliferative disorders of NK cells (CLPD-NK) and aggressive NK cell leukemia. Since there is a general lack of awareness of this disease, some patients may be misdiagnosed or some cases may be missed when diagnosis was done. At present, the pathogenesis of LGLL remains incomplete and unclear, and the therapeutic effects are unsatisfactory. For this reason, it is necessary to find prognostic marks and therapeutic targets of this disease. The constitutive activation of JAK/STAT pathway has been claimed to be involved in the development of LGLL. Recently, the somatic mutations in the SH2 domain of STAT3 in LGLL are frequently observed, which lead to the activation of JAK/STAT pathway. STAT3 is the first molecular markers that are highly specific for LGLL, and STAT3 mutations have been rarely detected in other tumor types studied, thus the STAT3 mutations can be used as molecular markers for LGLL diagnosis and can provide a novel therapeutic target for patients with LGLL.
Humans ; Janus Kinases ; genetics ; metabolism ; Leukemia, Large Granular Lymphocytic ; genetics ; metabolism ; Mutation ; STAT3 Transcription Factor ; genetics ; metabolism ; Signal Transduction

Animals ; Carcinoma, Non-Small-Cell Lung ; metabolism ; Humans ; Janus Kinases ; metabolism ; Lung Neoplasms ; metabolism ; STAT3 Transcription Factor ; metabolism ; Signal Transduction ; genetics ; physiology

OBJECTIVETo elucidate the roles of JAK/STATs signal pathway on anti-proliferative effects induced by IFN-alpha in MHCC97.

METHODSAn IRF9 expression vector was transfected into MHCC97 with Dosper. The expression of IRF9, cycle regulating proteins and the forming of ISGF3 complex were detected using Western blot and EMSA, respectively. Cell proliferation and distribution were monitored using MTT and flow cytometry.

RESULTSHigh expression of IRF9 restored the anti-proliferative response of MHCC97 on IFN-alpha treatment and delayed the cell transition from S phase to G2 phase induced by IFN-alpha.

CONCLUSIONThe integrity and functions of JAK/STATs signal pathway played an important role in mediating the anti-proliferative effects of IFN-alpha in MHCC97.

Carcinoma, Hepatocellular ; genetics ; metabolism ; pathology ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Interferon-Stimulated Gene Factor 3, gamma Subunit ; genetics ; Interferon-alpha ; metabolism ; pharmacology ; Janus Kinases ; genetics ; physiology ; Liver Neoplasms ; genetics ; metabolism ; pathology ; STAT Transcription Factors ; genetics ; physiology ; Signal Transduction ; Transfection

OBJECTIVETo explore the changes in the gene expression profiles in HepG2 cells transfected by human hepatocyte growth factor (hHGF) and analyze the signal transduction pathway in liver fibrosis regulated by hHGF.

METHODA 20,000 gene cDNA microarray (Affymetrix) was used to examine the gene expressions in the HepG2 cells transfected by hHGF. The differentially expressed genes were identified and some genes with possible contribution to hepatic fibrosis were subjected to real-time PCR analysis.

RESULTThe differentially expressed genes were mostly transcription regulatory molecules, cytokines, signal transduction, glucose metabolism, lipid metabolism. The results of real-time PCR showed up-regulated STAT1 and MAPK1 expression in the cells as were consistent with genechip analysis results.

CONCLUSIONhHGF gene transfection results in the gene expression profile changes in HepG2 cells. HGF may regulate liver fibrosis via the JAK/STAT and MAPK pathways.

Gene Expression Profiling ; Gene Expression Regulation ; Hep G2 Cells ; Hepatocyte Growth Factor ; genetics ; metabolism ; Humans ; Janus Kinases ; metabolism ; Liver Cirrhosis ; genetics ; metabolism ; Mitogen-Activated Protein Kinase 1 ; metabolism ; STAT1 Transcription Factor ; metabolism ; Signal Transduction ; physiology ; Transfection

OBJECTIVETo explore the mechanism of warming-needle therapy in treatment of knee osteoarthritis of deficiency-cold syndrome.

METHODSEight cases of knee osteoarthritis of deficiency-cold syndrome were selected and treated with warming-needle therapy at Guanyuan (CV 4), Qihai (CV 6) , Zosanli (ST 36), etc.. The gene expression profiles before and after treatment in 4 cases who showed better therapeutic effect were compared. Taking ratio < 0.5 or ratio > 2.0 as differentially expression gene and obtaining differentially expression pathway (P < 0.5, n>3) by http://www. DAVID 2006.

RESULTSTwo cases were clinically cured, 4 cases were markedly effective, 1 case was effective and 1 case was ineffective. With help of the microarray, 449 differentially expression genes, and 10 differentially expression pathways were obtained including 2 energy metabolism pathways (oxidative phosphorylation, ATP synthetase), 4 cell signal transduction pathways (insulin signal pathway, Toll-like receptor signal pathway, JAK-STAT signal pathway, and MAPK signal pathway) and cell apoptosis pathway.

CONCLUSIONWarming-needle therapy is an effective therapy for knee osteoarthritis with deficiency-cold syndrome , which is possibly involved in the control and regulation of many gene expression by various signal transduction pathways.

Acupuncture Therapy ; methods ; Aged ; Female ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Janus Kinases ; genetics ; MAP Kinase Signaling System ; Male ; Middle Aged ; Myeloid Differentiation Factor 88 ; genetics ; Needles ; Osteoarthritis, Knee ; metabolism ; therapy ; STAT Transcription Factors ; genetics ; Yang Deficiency ; metabolism ; therapy

OBJECTIVETo investigate the potential role of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in regulation of gene expression of high mobility group box-1 protein (HMGB1) in various tissues in rats with sepsis.

METHODSA sepsis model reproduced by cecal ligation and puncture (CLP), and 128 male Wistar rats were randomly divided into normal control group (n = 10), sham operation group (n = 10), CLP group (n = 60), AG490 treatment group (n = 24), and rapamycin (RPM) treatment group (n = 24). At serial time points animals in each group were sacrificed after CLP, then tissue samples were harvested to determine HMGB1 mRNA expression and STAT1/3 DNA binding activity.

RESULTSSTAT1 activities increased rapidly in the liver, lungs and small intestine after CLP, peaking at 6 - 12 h, while it increased slowly, and still kept at mild level from 2 to 48 h in the kidneys. Compared with STAT1, lower STAT3 activities were detected only in the liver and lungs, with negative detection in the small intestine and kidneys. HMGB1 mRNA levels significantly increased in liver, lungs and small intestine at various time points after CLP respectively (P < 0.05 or P < 0.01), while they didn't change in the kidneys. Treatment with AG490 could markedly inhibit HMGB1 mRNA expression in the liver and small intestine at 24 and 48 h (P < 0.05 or P < 0.01), and in lungs at 2 h following CLP (P < 0.01). Similarly, treatment with RPM significantly decreased HMGB1 mRNA expression in the lungs at 2, 6, 24 and 48 h, in the liver at 6 and 24 h, and in the small intestine at 24 and 48 h (P < 0.05 or P < 0.01). In addition, STAT1 and STAT3 activities in the liver and lungs were significantly correlated with corresponding tissue HMGB1 mRNA expression.

CONCLUSIONSPeritoneal infection could extensively activate STAT1 and limitedly activate STAT3 in vital organs. Activation of JAK/STAT pathway might be involved in up-regulating the gene expression of HMGB1 and systemic inflammation secondary to severe septic challenge.

Animals ; Disease Models, Animal ; Gene Expression ; physiology ; HMGB1 Protein ; genetics ; Janus Kinases ; metabolism ; Male ; RNA, Messenger ; genetics ; Random Allocation ; Rats ; Rats, Wistar ; STAT Transcription Factors ; metabolism ; Sepsis ; genetics ; physiopathology ; Signal Transduction

Apoptosis ; Fas Ligand Protein ; metabolism ; Germinal Center ; pathology ; Humans ; Janus Kinases ; metabolism ; Lymphoma, Large B-Cell, Diffuse ; etiology ; genetics ; metabolism ; pathology ; NF-kappa B ; metabolism ; Positive Regulatory Domain I-Binding Factor 1 ; Proto-Oncogene Proteins c-bcl-6 ; genetics ; metabolism ; Repressor Proteins ; metabolism ; STAT3 Transcription Factor ; metabolism ; Signal Transduction ; Translocation, Genetic ; fas Receptor ; metabolism

OBJECTIVESTo investigate the mechanism of Liuwei Dihuang Pill (, LDP) in treating postmenopausal osteoporosis (PMOP) with Shen (Kidney) yin deficiency.

METHODSIn 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.

RESULTSThe 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.

CONCLUSIONSThe 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.

Cytokines ; genetics ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Female ; Gene Expression Regulation ; Humans ; Janus Kinases ; metabolism ; Middle Aged ; Osteoporosis, Postmenopausal ; drug therapy ; genetics ; RNA, Messenger ; genetics ; metabolism ; STAT Transcription Factors ; metabolism ; Signal Transduction ; Up-Regulation ; Yin Deficiency ; drug therapy ; genetics

OBJECTIVETo evaluate the impact and long-term effect of three prescriptions regulating and tonifying lung and kidney (prescription tonifying lung and spleen, prescription tonifying lung and kidney, and prescription tonifying Qi and kidney) on JAK/STAT signaling of COPD rats.

METHODRats were randomly divided into the control group, the model group, the Bufeijianpi group, the Bufeiyishen group, the Yiqizishen group and the aminophyline group. The COPD rat model was established by smoke inhalations and bacterial infections. In the 9th week, the control group and the model group were administered with normal saline, while the remaining groups are orally given corresponding medicines. In the 20th and 32nd week, the rats were sacrificed in batches to observe the pathology in their lung tissues, protein expressions of JAK2, STAT1, STAT3, STAT5, and expressions of JAK2 and SOCS3 mRNA.

RESULTIn the 20th and 32nd week, protein expressions of JAK2 mRNA and phosphorylation-JAK2, STAT1, STAT3 and STAT5 in the model group were higher than the control group (P < 0.01), whereas the three traditional Chinese medicine (TCM) (Bufeijianpi, Bufeiyishen and Yiqizishen) groups and the aminophyline group were significantly lower (P < 0.05, P < 0.01). The expression of SOCS3 mRNA in the model group was higher than the control group (P < 0.01), whereas the level was notably higher in the three TCM groups and the aminophylline group (P < 0.01). The three TCM groups were remarkably higher than the aminophylline group (P < 0.05, P < 0.01). Compared with the figures in the 20th week, JAK2 mRNA and phosphorylation-JAK2, STAT3 and STAT5 were significantly lower in the Bufeijianpi group in the 32nd week (P < 0.05, P < 0.01), and so did phosphorylation-STAT3 in Bufeiyishen group (P < 0.01) and phosphorylation-STAT3 and STAT5 in the Yiqizishen group (P < 0.05, P < 0.01). However, the aminophylline group showed no significant difference in above indicators.

CONCLUSIONThe three medicines regulating and tonifying lung and kidney can effectively relieve injury of lung tissues, and have long-term effect, which may be related to the regulation of JAK/ STAT signaling. Specifically, prescription tonifying lung and spleen shows good effect in reducing JAK2, STAT3 and STAT5, prescription tonifying lung and kidney shows good effect in reducing p-STAT3, and prescription tonifying Qi and kidney shows good effect in reducing p-STAT3 and p-STAT5.

Animals ; Disease Models, Animal ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Humans ; Janus Kinases ; genetics ; metabolism ; Kidney ; drug effects ; enzymology ; metabolism ; Lung ; drug effects ; enzymology ; metabolism ; Male ; Pulmonary Disease, Chronic Obstructive ; drug therapy ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; STAT Transcription Factors ; genetics ; metabolism ; Signal Transduction ; drug effects ; Time