tyrphostin (AG 490)

Ion substitution of Cl- or CFTR inhibitors NPPB and glibenclamide or a Na+/K+/2Cl- cotransporter inhibitor bumetanide attenuated kaempferol-induced I sc response...The kaempferol-induced I Cl was mostly abolished by protein kinase A inhibitor H89, but not by tyrosine kinase inhibitors, AG490 and tyrphostin A23, or tyrosine phosphatase inhibitor vanadate...The mechanisms may involve the cAMP/PKA pathway and CFTR expression. Taken together, these findings reveal the beneficial effects of kaempferol to increase fluid secretion which can be used to treat constipation.

Rats were randomly divided into 5 groups, i.e. Sham group, MCAO+saline group, MCAO+Bre group, MCAO+DMSO (Dimethyl sulfoxide) group, and MCAO+Bre+AG490 (Tyrphostin AG490, the inhibitor of STAT5) group...The JAK2 inhibitor AG490 reversed these effects. These findings indicate that breviscapine can improve neural recovery following ischemia through alleviating excessive autophagy and activation of the JAK2/STAT5/BCL2 axis.

The inhibitor AG490 of JAK-STAT signaling pathway was used to identify the functional mechanism of CXCL1/JAK-STAT underlying progression of CRC, and tumor xenograft experiments were performed for further validation...CXCL1 could be regulated by miR-302e to inactivate JAK-STAT signaling pathway, in turn affecting cell proliferation, migration, invasion, and apoptosis of CRC. Our result provides a potential therapeutic target for CRC treatment.

The link between the decrease in phosphorylated STAT3 by MBS and IBS and BCL1 cell death was confirmed by detection of enhanced cell death after addition of AG490, an inhibitor of Jak2 kinase. It seems that IBS and MBS, by decreasing STAT3 phosphorylation, trigger apoptosis, inhibit cell proliferation, and attenuate leukemia cell stemness.

This invasive phenotype was prevented by EGCG, the JAK/STAT inhibitors Tofacitinib and AG490, as well as upon STAT3 gene silencing. In conclusion, dietary catechin-mediated interventions could, in part through the inhibition of adipogenesis and modulation of adipocytes secretome profile, prevent the onset of an obesogenic environment that favors TNBC development.

Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC values below that of the clinically relevant multikinase inhibitor sorafenib, which served as a reference...Additional bioinformatic analysis of the VEGFR-2 binding modes by docking and molecular dynamics calculations supported the experimental findings and indicated that the hydroxy group of 1c might be crucial for its distinct inhibitory potency against VEGFR-2. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in HCC treatment.

By retrospective analysis of NSCLC patient tissues obtained from the tumor biobank; pre-clinical studies with Hiltonol alone or Hiltonol cocktail [Hiltonol+anti-IL6+AG490 (JAK2 inhibitor)+Stattic (STAT3 inhibitor)]; cytokine analysis; gene knockdown and gain/loss-of-function studies, we uncovered the mechanisms of action of Hiltonol. Ex vivo analysis of NSCLC patient tissues corroborated that loss of PKR and OAS is associated with cancer advancement. Altogether, our findings unraveled the significance of studying tumor biobank tissues, which suggests PKR and OAS as precision oncological suppressor candidates to be targeted by this novel Hiltonol cocktail which represents a prospective drug for development into a potent and tailored therapy for NSCLC subtypes.

Losartan promotes myocardial apoptosis after AMI in the rats through inhibiting the Ang II-induced JAK/STAT pathway.

Significant reductions in cell survival, mutagenic activity, Cyclin D1, CDK4, Snail, and JAK2/STAT3 expression were found after inhibitor AG490, ANF and CHJ223191 treatment. These findings reveal that BaP enhances the proliferative and mutagenic activity via JAK2-STAT3 pathway in PC-3 cells, and provide the additional evidence to understand the crucial role of BaP in prostate cancer carcinogenesis.

AG490, an IL-6 inhibitor, inhibited the occurrence of EMT. Insufficient ablation performed at low temperature successfully induces EMT and promotes tumor aggressiveness, which is mediated by the IL-6/STAT3/Snail pathway in both cell and mouse models.

Studies using AGS, RIE1, and Caco-2 cells, C57BL/6 mice, and Sprague Dawley rats showed protective effects of egg against gut injury. Enhanced results were seen if colostrum and egg were coadministered. Egg powder with or without colostrum may have therapeutic value for prevention and treatment of gut injuries.

In addition, blocking the JAK2 pathway by its antagonist AG490 reversed CM-induced osteosarcoma cell proliferation, migration and doxorubicin resistance. Collectively, NGR1 may directly restrain osteosarcoma cell growth and migration, or indirectly antagonize MSC-evoked malignancy and drug resistance by interdicting IL-6 secretion-evoked activation of the JAK2/STAT3 pathway. Consequently, the current study may highlight a promising therapeutic strategy against osteosarcoma by regulating tumor cells and the tumor microenvironment.

AN components contribute to oral carcinogenesis by stimulating MMP-9 secretion, thus enhancing tumor invasion/metastasis. These events are related to reactive oxygen species, TGF-β1, Smad2-dependent and -independent signaling, but not COX. These signaling molecules can be biomarkers of BQ carcinogenesis. PBL, HC and melatonin and other targeting therapy can be used for oral cancer treatment.

AG-490 can inhibit the growth of prostate cancer cells in a miR-503-5p-dependent manner by targeting STAT3. AG-490 is expected to become a new candidate drug for the treatment of prostate cancer.

IL-17a was blocked with a polyclonal antibody, and JAK2/STAT3 signaling pathway was blocked by a specific inhibitor AG490...CAFs secreted IL-17a, which promoted the migration and invasion of GC cells through activating JAK2/STAT3 signaling. These results may identify IL-17a as a promising prognostic marker and therapeutic target of GC.

RET gene is highly expressed in PTC acting as an oncogene. Silencing RET gene expression may inhibit the invasion and promote the apoptosis of PTC cells by inhibiting the activation of EGFR signaling pathway and mediating the process of EMT. It suggests that RET may offer the possibility of a promising therapeutic target for the treatment of PTC on the basis of the explored mechanism.

As STAT3 expression was the most increased, the effect of STAT3 inhibition in a DIPG cell line was assessed via STAT3 short hairpin (sh)RNA transfection and treatment with AG490, a STAT3 inhibitor...Finally, when radiation was administered in combination with STAT3 inhibition, the therapeutic efficiency, assessed by cell viability and DNA damage repair, was increased. The present results suggest that STAT3 is a potential therapeutic target in DIPG, especially when combined with radiation therapy.

Compared with CXCL8 siRNA group, the expression of JAK2, STAT3, vimentin and N-cadherin in CXCL8 siRNA + AG490 group were significantly decreased, the expression of E-cadherin was significantly increased, cell proliferation ability was decreased and apoptosis was increased (P<0.05). In conclusion, CXCL8 gene expression silencing may inhibit EMT and cell proliferation while promoting cell apoptosis of human cutaneous melanoma cells by inhibiting the activation of JAK-STAT signaling pathway.

ZHONGL-CS may induce FLS apoptosis in CIA rats. Activation of the JAK/STAT signaling pathway was inhibited in FLS in vitro.

RPS6 overexpression enhanced the tumorsphere potential of GSCs and these effects were attenuated by STAT3 inhibitor (AG490)...Furthermore, RPS6 and other ribosomal proteins were upregulated in GSC-predominant areas in this database. The present results indicate that, in GSC niches, ribosomal proteins play crucial roles in the development and maintenance of GSCs and are clinically associated with chemoradioresistance and GBM recurrence.

Interestingly, the depletion of IL-6 or the blockade of the JAK/STAT3 signaling with AG490 were able to prevent the EC hyperpermeability. Overall, we demonstrated that IL-6 released during MG-GBM crosstalk leads to barrier dysfunction through the activation of the JAK/STAT3 pathway in ECs and downregulation of intercellular junction proteins. These results provide new insights into the mechanisms underlying the disruption of BBB permeability in GBM.

Additionally, we demonstrate that small interfering RNAs targeting the production of STAT3, AG490, and CL-821983 in cancer cells depleted of SIRT1 reduce metastasis...We postulate that the upregulation of SIRT1 in gastric cancer patients may be the result of a feedback mechanism that aims to oppose the damaging effects of STAT3 signaling. As such, SIRT1 activators could potentially serve as preventive and therapeutic treatments for metastatic gastric cancer.

Finally, the specific JAK2/STAT3 signaling pathway inhibitor AG490 and autophagy inhibitor 3-MA were used to investigate the involvement of this pathway and autophagy in IL-17-induced regulation of RANKL expression. Initially, we found that IL-17 treatment promoted growth of osteoblasts in a time- and dose-dependent manner...Furthermore, our findings indicated that high concentrations of IL-17 promoted the differentiation, calcification, and RANKL expression of murine osteoblasts via activation of the JAK2/STAT3 pathway. Importantly, downregulation of autophagy at high IL-17 concentrations further enhanced RANKL expression via suppressing the JAK2/STAT3 cascade. Overall, our findings demonstrate, for the first time, that IL-17 modulates RANKL expression of osteoblasts through an autophagy-JAK2-STAT3 signaling pathway, thus affecting bone metabolism.

The data indicate that astrocytic endothelin-1 overexpression promotes progenitor stem cell proliferation and astr ocytic differentiation via the Jak2/Stat3 pathway.

NEAT1 promoted M2 macrophage polarization by sponging miR-214 and then regulating B7-H3, thus accelerating MM progression via the JAK2/STAT3 signaling pathway. Our study revealed novel mechanisms of M2 macrophage polarization and provided new potential clinical therapeutic targets for MM.

Treatments of AG490 and luteolin blocked the JAK/STAT3 signaling pathways which attenuated IL-6 activation on the HO-1 expression. Our results indicated that HO-1 is the antitumor gene induced by IL-6 through the IL-6/JAK/STAT3 pathways; moreover, a feedback circuit may exist between IL-6 and HO-1 in hepatoma cells.

We also confirmed this with the use of a JAK2 chemical inhibitor, AG490, as a positive control. In a 4T1 orthotopic allograft model, morphological and TdT-mediated dUTP nick-end labeling analyses showed that MSA treatment (1.5 mg/kg/weight) for 28 days inhibits tumor growth consistent with the clinical anticancer drug cyclophosphamide. Our observations demonstrate that MSA is a potent anticancer drug in breast cancer and uncovered a key role of the JAK2/STAT3 pathway in modulating tumor growth.

Intrathecal injection of Janus Kinase 2 Inhibitor AG490 significantly alleviated scratching behaviors in ACD mice...Our results indicate that the spinal IL-33/ST2 signaling pathway contributes to chronic itch via astrocytic JAK2-STAT3 cascade activation, promoting TNF-α release to regulate the GRP/GRPR signaling-related itch response. Thus, these findings provide a potential therapeutic option for treating chronic pruritus.

Moreover, the addition of AG490, the protein inhibitor of JAK2, significantly alleviated cerebral ischemic damage in vivo and HO-induced injury in vitro, and JAK2 siRNA also alleviated HO-induced injury in N2a cell. These findings suggest that JAK2/STAT3 pathway may play a crucial role in mediating reactive oxidative species (ROS)-induced cell injury in rat middle cerebral artery occlusion (MCAO) model and N2a cells. ROS scavenging and down-regulation of STAT3 activation might be a candidate design of therapeutic strategies against oxidative stress-related neurological diseases.

AG490 alleviated DDP-induced AKI in lung cancer mice with improved oxidative stress and inflammation, and the suppression of JAK2/STAT3 pathway.

The effects of AG490 on the expression of STAT3, p-STAT3, MMP2 and Cyclin D1 in Pumc-91 were evaluated using qRT-PCR and Western blot...The proliferation and migration of Pumc-91/ADM were suppressed by inhibiting of STAT3. STAT3 pathway regulated the proliferation and migration of bladder cancer drug-resistant cells by modulating the expression of Cyclin D1 and MMP2.

Leptin increased PGC-1α, BCL-2, and BCL-XL protein levels, cell viability, and MMP and decreased apoptosis both in vitro and in vivo; these effects were reversed by AG490 treatment. Our findings suggest that leptin-mediated neuroprotective effects in tMCAO may peak at 1 h to induce the transcription of its target gene PGC-1α, stabilization of MMP, inhibition of mitochondrial permeability transition pore opening, release of cytochrome c, and apoptosis.