Sesquiterpenoid is a kind of compound widely distributed in nature, which has a wide range of biological activities, such as anti-inflammatory, anti-tumor and immunomodulatory activities. This paper would review the anti-inflammatory mechanism of sesquiterpenoid. The mechanism is mainly by inhibiting the activation of nuclear factor (NF-κB), mitogen-activated protein kinase (MAPKs) and signal transducers and activators of transcription (STAT) signaling pathways and down-regulating the inflammatory gene expression including tumor necrosis factor- (TNF-), prostaglandin E₂ (PGE₂), nitric oxide (NO), interleukin-1(IL-1), IL-6, IL-8 and other inflammatory factors. Thereby, the production and release of inflammatory cytokines are reduced to exert anti-inflammatory effect. This review is intended to provide reference for related research.
Anti-Inflammatory Agents ; pharmacology ; Dinoprostone ; Humans ; Interleukins ; MAP Kinase Signaling System ; NF-kappa B ; Nitric Oxide ; STAT Transcription Factors ; Sesquiterpenes ; pharmacology ; Signal Transduction ; Tumor Necrosis Factor-alpha

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*

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 investigate the effects of granulocyte colony stimulating factor (G-CSF) on myocardial apoptosis following coronary microembolization (CME) and possible role of Janus kinase/singnal transducer and activator of transcription (JAK/STAT) pathway in this process.

METHODSA total of 92 male Sprague Dawley rats were randomized into CME (n = 24), G-CSF (100 microg x kg(-1) x d(-1) i.p. 2 hours post CME for 5 days, n = 24), JAK2 inhibitor AG490 (G-CSF plus AG490, 5 mg x kg(-1) x d(-1) i.p. 2 hours post CME for 5 days, n = 24), all rats received left ventricular injection of homologous microthrombotic particle suspension post clamping the ascending aorta. Sham-operated group (n = 20) served as control. The rats were sacrificed at day 3, 7, 14 and 28 after operation. The myocardial mRNA expressions of Bcl-2, Bax, Fas, FasL and GAPDH which was used as the intercomparison, were evaluated by real time PCR. The ratio of Bcl-2/Bax was compared. The protein expression of Caspase-3, cleaved PARP, t-JAK2, p-JAK2, t-STAT3 and p-STAT3 were detected by western blot. Myocardial apoptosis were examined by TUNEL staining.

RESULTSCompared with Sham rats, the mRNA of Bcl-2, Bax, Fas and FasL significantly increased whereas the ratio of Bcl-2/Bax (0.28 +/- 0.04 vs. 2.98 +/- 0.49) significantly decreased and the protein expression of Caspase-3 (0.762 +/- 0.129 vs. 0.133 +/- 0.027), PARP (0.992 +/- 0.146 vs. 0.386 +/- 0.074) and the myocardial apoptosis index (17.2 +/- 1.9 vs. 1.2 +/- 0.6) significantly increased in CME hearts (all P < 0.05). rhG-CSF significantly attenuated CME induced changes and cotreatment with JAK2 inhibitor AG490 abolished the effects of rhG-CSF. The protein expressions of t-JAK2 and t-STAT3 among the groups were similar. P-JAK2 and p-STAT3 protein expressions were significantly increased in G-CSF group compared to other groups (P < 0.05).

CONCLUSIONG-CSF attenuated myocardial apoptosis induced by CME via JAK2/STAT3 pathway.

Animals ; Apoptosis ; Coronary Artery Disease ; metabolism ; pathology ; Disease Models, Animal ; Embolism, Cholesterol ; metabolism ; pathology ; Granulocyte Colony-Stimulating Factor ; pharmacology ; Janus Kinase 2 ; metabolism ; Male ; Myocardium ; metabolism ; pathology ; Rats ; Rats, Sprague-Dawley ; STAT Transcription Factors ; metabolism ; Signal Transduction

OBJECTIVETo evaluate the effect of JAK/STAT signaling pathway activation on the transdifferentiation and secretion of transforming growth factor-beta1 (TGF-beta1) induced by high glucose in renal proximal tubular epithelial cells.

METHODSHuman kidney cells (HKC) were cultured and then divided into four groups: low glucose (LG) group, high glucose (HG) group, high mannitol (LG + M) group, and HG + AG490 group. Immunoprecipitation and Western blot analysis were used to determine the expression of tryosine phosphorylated Janus kinase 2 ( p-JAK2). The protein expressions of STAT1, STAT3, p-STAT1, and p-STAT3 and the expressions of alpha-SMA and E-Cadherin were observed by Western blot. The contents of TGF-B1, fibronectin and type I collagen in the supernatants of the cultured HKC were detected by enzyme-linked immunosorbent assay (ELISA). The expression of TGF-beta1 mRNA was measured by reverse transcription and polymerase chain reaction (RT-PCR).

RESULTSCompared with LG group, the expressions of JAK2, p-STAT1, p-STAT3, and TGF-beta1, mRNA were significantly increased in HG group from 6 to 72 hours. Meanwhile, the contents of TGF-beta1 and collagen I in the supernatants and the expression of alpha-SMA increased and the expression of E-Cadherin decreased. The expressions of JAK2, p-STAT1, p-STAT3, and TGF-beta mRNA as well as the levels of TGF-beta1 and collagen I in the supernatant s in HG + AG490 group were significantly lower than in the HG group. The expressions of alpha-SMA and E-Cadherin were also decreased in HG + AG490 group.

CONCLUSIONActivation of JAK/STAT signaling pathway may be involved in the high glucose-induced transdifferentiation and overproduction of TGF-beta1, and ECM proteins in HKCs.

Cell Line ; Cell Transdifferentiation ; Epithelial Cells ; cytology ; metabolism ; Glucose ; metabolism ; pharmacology ; Humans ; Janus Kinases ; physiology ; Kidney Tubules, Proximal ; cytology ; metabolism ; STAT Transcription Factors ; physiology ; Signal Transduction ; Transforming Growth Factor beta1 ; biosynthesis ; secretion ; Urothelium ; cytology ; metabolism

Intracellular signal transduction plays an important role in the process of cellular metabolism, segmentation, differentiation, biological behaviour and cell death. Overactive signal transduction relates to tumor development and progression. Signaling pathways operated by protein tyrosine kinases (PTKs) will be illuminated here briefly. The Ras/Raf/MAPK and PI-3K/Akt pathways through receptor protein tyrosine kinases (RTKs), the Src, Bcr-Abl and JAK/STAT pathways by non-receptor protein tyrosine kinases (nrPTKs) are shown separately. Antitumor agents targeting the key proteins involved in the above five signalling routes are also summarized in this review.
Animals ; Antineoplastic Agents ; pharmacology ; Humans ; Phosphatidylinositol 3-Kinases ; metabolism ; Protein-Tyrosine Kinases ; metabolism ; Receptor Protein-Tyrosine Kinases ; metabolism ; STAT Transcription Factors ; metabolism ; Signal Transduction ; drug effects ; ras Proteins ; metabolism ; src-Family Kinases ; metabolism

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

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

Persistently activated JAK/STAT3 signaling pathway plays a pivotal role in various human cancers including major carcinomas and hematologic tumors, and is implicated in cancer cell survival and proliferation. Therefore, inhibition of JAK/STAT3 signaling may be a clinical application in cancer therapy. Here, we report that 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo [1,3]oxathiol-4-one (BOT-4-one), a small molecule inhibitor of JAK/STAT3 signaling, induces apoptosis through inhibition of STAT3 activation. BOT-4-one suppressed cytokine (upd)-induced tyrosine phosphorylation and transcriptional activity of STAT92E, the sole Drosophila STAT homolog. Consequently, BOT-4-one significantly inhibited STAT3 tyrosine phosphorylation and expression of STAT3 downstream target gene SOCS3 in various human cancer cell lines, and its effect was more potent in JAK3-activated Hodgkin's lymphoma cell line than in JAK2-activated breast cancer and prostate cancer cell lines. In addition, BOT-4-one-treated Hodgkin's lymphoma cells showed decreased cell survival and proliferation by inducing apoptosis through down-regulation of STAT3 downstream target anti-apoptotic gene expression. These results suggest that BOT-4-one is a novel small molecule inhibitor of JAK3/STAT3 signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK3/STAT3 signaling, specifically Hodgkin's lymphoma.
Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/drug effects ; Bicyclo Compounds, Heterocyclic/chemistry/*pharmacology ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drosophila/enzymology/metabolism ; Drosophila Proteins/antagonists & inhibitors/metabolism ; Enzyme Activation/*drug effects ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Janus Kinase 3/*antagonists & inhibitors/metabolism ; Lymphoma/enzymology/*metabolism ; Phosphorylation/drug effects ; STAT Transcription Factors/antagonists & inhibitors/metabolism ; STAT3 Transcription Factor/*antagonists & inhibitors/metabolism ; Signal Transduction/*drug effects

Inflammation is a part of the complex biological responses of a tissue to injury that protect the organ by removing injurious stimuli and initiating the healing process, and is considered as a mechanism of innate immunity. To identify biologically active compounds against pathogenic inflammatory and immune responses, we fractionated water, aqueous methanol and n-hexane layers from nine kinds of leguminosae and examined anti-inflammatory activity of the fractions in human keratinocytes and mouse skin. Among the fractions, rf3 and rf4, isolated from the aqueous methanol layer of Astragalus sinicus L., exhibited the strongest reactive oxygen species (ROS)-scavenging and anti-inflammatory activities as measured by inhibition of the intracellular ROS production, nuclear factor-kappaB (NF-kappaB), janus kinase (JAK)/signal transducer and activator of transcription (STAT), and phosphatidylinositol 3-kinase/Akt signaling in cytokine-stimulated human keratinocytes, as well as by effects on T-cell differentiation in mouse CD4+ T cells. In addition, topical application of rf3 and rf4 suppressed the progression of psoriasis-like dermatitis and expression of pro-inflammatory mediators in interleukin (IL)-23-injected mouse ears. Our results suggest that Astragalus sinicus L. may ameliorate chronic inflammatory skin diseases due to its antioxidant and anti-inflammatory activities via regulation of the intracellular ROS production, NF-kappaB, JAK/STAT and PI3/Akt signaling cascades as well as immune responses, and these results are the first report that Astragalus sinicus L. exhibits pharmacological activity.
Animals ; Anti-Inflammatory Agents/isolation & purification/*pharmacology/therapeutic use ; Astragalus Plant/*chemistry ; Cell Line ; Dermatitis/drug therapy ; Humans ; Interleukin-23/pharmacology ; Janus Kinases/metabolism ; Keratinocytes/*drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Plant Extracts/isolation & purification/*pharmacology/therapeutic use ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; STAT Transcription Factors/metabolism ; Skin/*drug effects/metabolism