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

OBJECTIVETo investigate the expression of JAK, ERK and Cyclin D proteins in squamous-cell carcinoma of tongue.

METHODSThe expression of JAK, ERK and Cyclin D1 proteins was determined with SP immunohistochemical method in 30 cases of lingual Squamous cell carcinoma, 20 of normal lingual mucosa, 10 of mild epithelial dysplasia and 20 of severe epithelial dysplasia.

RESULTSThe expression of pJAK in lingual squamous-cell carcinoma and epithelial dysplasia was stronger than that of normal lingual mucosa (chi2=37.54, P<0.01), and the expression of pJAK in lingual squamous-cell carcinoma was significantly higher than that of the epithelial dysplasia (chi2=6.83, P<0.05). pJAK expression in squamous-cell carcinoma of low-middle differentiation was stronger than that of high differentiation. There was no significant difference in pERK expression among lingual squamous-cell carcinoma, normal lingual mucosa and epithelial dysplasia. There was a significantly positive correlation between pJAK and Cyclin D1 expression in SCC (r=0.619, P<0.05). There was no significant correlation between the expression of pERK and Cyclin D1 (r=0.231, P>0.05).

CONCLUSIONOver-expression of pJAK and Cyclin D1 may be associated with the occurrence and development of squamous-cell carcinoma of the tongue.

Carcinoma, Squamous Cell ; metabolism ; pathology ; Cyclin D1 ; metabolism ; Extracellular Signal-Regulated MAP Kinases ; metabolism ; Humans ; Immunohistochemistry ; Janus Kinases ; metabolism ; Phosphorylation ; Tongue Neoplasms ; metabolism ; pathology

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

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.
Adult ; Child ; Humans ; Janus Kinases/metabolism* ; Piperidines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use* ; Pyrimidines/therapeutic use* ; Rheumatic Diseases/drug therapy*

OBJECTIVETo investigate the effects of simvastatin (SIM) on in vivo and in vitro cardiac hypertrophy models and changes on JAK/STAT signal pathways.

METHODSMyocardial hypertrophy was induced by Cardiotrophin-1 (CT-1) in neonatal cardiomyocytes and by abdominal aortic constriction (AC) for 4 weeks in adult SD rats. In vitro study groups were as follows (n = 3 each): (1) control, (2) CT-1 (10(-10) mol/L), (3) CT-1 + SIM (10(-6) mol/L), (4) CT-1 + AG490(JAK inhibitor, 10(-4) mol/L), (5)SIM (10(-6) mol/L), (6) AG490 (10(-4) mol/L). In vivo study groups were as follows (n = 8 each): (1) sham group, (2) AC group, (3) AC + SIM group, (4) AC + captopril group. Total protein content was measured by Lowry's method and the cell surface area was measured by phase contrast microscope. The expression of AGT mRNA and c-fos mRNA were detected by RT-PCR. Systolic blood pressure (SBP), heart weight/body weight (HW/BW) and left ventricle weight/body weight (LVW/BW) were measured. The expressions of p-JAK2 and p-STAT3 were detected by Western blot.

RESULTSThe total protein content and cardiomyocytes size were significantly increased in CT-1 treated cells and which could be blocked by SIM. The expressions of p-JAK2 and p-STAT3 as well as the expression of AGT mRNA and c-fos mRNA significantly activated by CT-1, which could be inhibited by SIM or Janus Kinase-selective inhibitor AG490. Similar as captopril, SIM also attenuated cardiac hypertrophy in AC rats as shown on reduced systolic blood pressure, heart weight to body weight, left ventricular weight to body weight ratios as well as cross sectional area of cardiomyocytes.

CONCLUSIONSIM prevented CT-1 and AC induced cardiomyocyte hypertrophy via inhibiting JAK/STAT pathways.

Animals ; Cardiomegaly ; metabolism ; prevention & control ; Cytokines ; metabolism ; Disease Models, Animal ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; metabolism ; Janus Kinases ; metabolism ; Male ; Myocardium ; metabolism ; Rats ; Rats, Sprague-Dawley ; STAT Transcription Factors ; metabolism ; Signal Transduction ; drug effects ; Simvastatin ; pharmacology

OBJECTIVETo explore the effects of oxymatrine (OMT) on JAK/STAT iteral in rat lung tissue with sepsis.

METHODFifty-six male SD rats were randomly divided into 6 groups: sham operation group, model (CLP) group, CLP + OMT high, middle, low-dose groups (52, 26, 13 mg x kg(-1), vena caudalis bolus), and positive control group (dexamethasone, 10 mg x kg(-1), vena caudalis bolus) to observe the effects of oxymatrine on the ratio between wet weight of the lung and dry weight of the lung (W/D) and pulmonary coefficient, gross changes and pathological changes examined with lightmicroscope in the pulmonary tissue. Changes in JAK2 and STAT3 activity in the pulmonary tissue were determined by immunohistochemical method. Tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels in pulmonary tissue were determined by radioimmunoassay.

RESULTOMT could decrease significantly the JAK2 and STAT3 positive reaction and activity in the pulmonary tissue (P < 0.05). TNF-alpha and IL-6 levels in pulmonary tissue homogenate decreased markedly (TNF-alpha decreased 36%, 26%, 16% and IL-6 decreased 46%, 39%, 24% on CLP + OMT 52, 26 mg x kg(-1) and 13 mg x kg(-1) groups. P < 0.05 or P < 0.01). OMT could decrease the ratio between wet weight of the lung and dry weight of the lung and the pulmonary coefficient, improve the condition of pulmonary hyperemia, edema, infiltrate of heterophil granulocyte and emerge of asphyxial membrane, and alleviate the inflammatory reaction. And the results were equal to those of the positive control (CLP + dexamethasone) group.

CONCLUSIONOMT can inhibit JAK/STAT iteral activity and reduce the expression of proinflammatory factor (TNF-alpha, IL-6) and antagonize the lung injury in a rat model of sepsis.

Acute Lung Injury ; drug therapy ; metabolism ; Alkaloids ; therapeutic use ; Animals ; Immunohistochemistry ; Janus Kinases ; metabolism ; Lung ; drug effects ; metabolism ; pathology ; Male ; Quinolizines ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; STAT3 Transcription Factor ; metabolism ; Sepsis ; drug therapy ; metabolism

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

This study was aimed to determine the in vivo signal transduction pathway responsible for isoproterenol (ISO)-induced cardiac hypertrophy or remodeling. Mice were treated with ISO (15 mg/kg body weight) or vehicle by intraperitoneal injection (i.p.). Activation of mitogen-activted protein kinase (MAPK), NF-kappaB and JAK/STAT pathway in the left ventricular myocardium was measured by Western blot analysis. ISO significantly activated MAPK (ERK1/2 and p38) at early phase (5 min); biphasic activation of NF-kappaB was observed in our in vivo study; and ISO caused a delayed STAT3 activation (at 60 to 240 min) in mouse myocardium. Taken together, these results indicate that ISO activates these signal transduction pathways in different time course.
Animals ; Heart ; drug effects ; Isoproterenol ; pharmacology ; Janus Kinase 1 ; metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mitogen-Activated Protein Kinases ; metabolism ; Myocardium ; metabolism ; NF-kappa B ; metabolism ; STAT3 Transcription Factor ; metabolism ; Signal Transduction ; Time Factors

Objective To explore the therapeutic effect of ethambutol tablets (EMB) on pulmonary tuberculosis (PTB) in rats and whether the action mechanism of EMB is related to Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Methods Sixty SD rats were assigned into a control group,a PTB group,a PTB+EMB group (30 mg/kg),and a PTB+EMB+Colivelin (JAK/STAT pathway activator) group (30 mg/kg+1 mg/kg) via the random number table method,with 15 rats in each group.The rats in other groups except the control group were injected with 0.2 ml of 5 mg/ml Mycobacterium tuberculosis suspension to establish the PTB model.After the modeling,the rats were administrated with corresponding drugs for 4 consecutive weeks (once a day).On days 1,14,and 28 of administration,the body weights of rats were measured and the Mycobacterium tuberculosis colonies were counted.Hematoxylin-eosin staining was carried out to detect the pathological changes in the lung tissue.Enzyme-linked immunosorbent assay was employed to measure the levels of interleukin(IL)-6,tumor necrosis factor-α (TNF-α),IL-1β,and interferon-γ (IFN-γ) in the serum.Flow cytometry was used to determine the levels of T lymphocyte subsets CD3+,CD4+,CD8+,and CD4+/CD8+.The 16S rRNA sequencing was performed to detect the relative abundance of the intestinal microorganisms.Western blotting was employed to determine the expression of the proteins in the JAK/STAT pathway. Results Compared with the control group,the modeling of PTB reduced the rat body weight (on days 14 and 28),increased Mycobacterium tuberculosis colonies,caused severe pathological changes in the lung tissue,and elevated the levels of IL-6,TNF-α,and IL-1β in serum and CD8+.Moreover,the modeling increased the relative abundance of Bacteroides,Peptococcus,Clostridium,Actinomyces,Lactobacillus,Verrucomicrobium,and Veillonella in the intestine,up-regulated the protein levels of phosphorylated JAK2 and phosphorylated STAT3 in the lung tissue,and lowered the levels of CD3+,CD4+,CD4+/CD8+,and IFN-γ levels (all P<0.001).Compared with the PTB group,PTB+EMB increased the rat body weight (on days 14 and 28),reduced Mycobacterium tuberculosis colonies,alleviated the pathological damage in lung tissue,lowered the levels of IL-6,TNF-α,and IL-1β in serum and CD8+.Moreover,the treatment decreased the relative abundance of Bacteroides,Peptococcus,Clostridium,Actinomyces,Lactobacillus,Verrucomicrobium,Veillonella in the intestine,down-regulated the protein levels of phosphorylated JAK2 and phosphorylated STAT3 in the lung tissue,and elevated the levels of CD3+,CD4+,CD4+/CD8+,and IFN-γ (all P<0.001).Colivelin weakened the alleviation effect of EMB on PTB (all P<0.001). Conclusion EMB can inhibit the JAK/STAT signaling pathway to alleviate the PTB in rat.
Animals ; Body Weight ; Ethambutol/pharmacology* ; Interferon-gamma/pharmacology* ; Interleukin-6/metabolism* ; Janus Kinases/pharmacology* ; Mycobacterium tuberculosis/metabolism* ; RNA, Ribosomal, 16S ; Rats ; Rats, Sprague-Dawley ; STAT Transcription Factors/pharmacology* ; Signal Transduction ; Tablets/pharmacology* ; Tuberculosis, Pulmonary/metabolism* ; Tumor Necrosis Factor-alpha/metabolism*