tyrphostin (AG 490) / Hebrew University of Jerusalem, Yissum Research Development Company, Pfizer, EMD Serono - LARVOL DELTA

Kaempferol activates chloride secretion via the cAMP/PKA signaling pathway and expression of CFTR in T84 cells. (PubMed, Front Pharmacol) - "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."

Journal • Colon Cancer • Colorectal Cancer • Constipation • Gastroenterology • Gastrointestinal Disorder • Oncology • Solid Tumor • CFTR

Breviscapine ameliorates autophagy by activating the JAK2/STAT5/BCL2 pathway in a transient cerebral ischemia rat model. (PubMed, J Neuropathol Exp Neurol) - "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."

IO biomarker • Journal • Preclinical • Cardiovascular • Lymphoma • Oncology • BECN1 • STAT5

Blockade of JAK2 retards cartilage degeneration and IL-6-induced pain amplification in osteoarthritis. (PubMed, Int Immunopharmacol) - "Together, we suggest that tyrphostin AG490 protected against progression of OA and improved OA prognosis by reducing cartilage degeneration and arthritis pain. Our findings provide further evidence for targeting IL-6 signaling in the treatment of OA."

Journal • Immunology • Inflammation • Musculoskeletal Pain • Osteoarthritis • Pain • Rheumatology • IL6 • JAK2 • STAT3

JAK2/STAT3 Signaling Pathway and Klotho Gene in Cadmium-induced Neurotoxicity In Vitro and In Vivo. (PubMed, Biol Trace Elem Res) - "In comparison with the high-dose Cd exposure group, after adding tyrphostin AG490 (AG490), the apoptosis rate of PC12 cells increased, whereas the phosphorylation levels of JAK2 and STAT3 in the cells decreased significantly (p < 0.05). Cd exposure may cause neurotoxicity by regulating the JAK2/STAT3 signaling pathway and down-regulating klotho protein expression, leading to cognitive dysfunction."

Journal • Preclinical • Alzheimer's Disease • Cognitive Disorders • KL

CXCL1 Regulated by miR-302e Is Involved in Cell Viability and Motility of Colorectal Cancer via Inhibiting JAK-STAT Signaling Pathway. (PubMed, Front Oncol) - "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."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CXCL1 • MIR30E

[VIRTUAL] DEDIFFERENTIATION AND REPROGRAMMING OF EPITHELIAL CELLS DURING GASTRIC ULCER HEALING IS TRIGGERED BY HYPOXIA AND A WELL-COORDINATED, SEQUENTIAL ACTIVATION OF EGFR SIGNALING: CROSS TALK WITH IGF1 AND COX2 (DDW 2021) - "Studies: 1) Ulcer size; 2) histological quantification of epithelial structures and cell type; 3) expression of hypoxia-inducible factor-1α (HIF-1α) by RT-PCR, Western blotting and immunostaining; 4) expression of EGFR, EGF, IGF1 & COX2 and signal quantification by artificial intelligence (AI); 5) EGFR protein levels, tyrosine kinase activity and phosphorylation; ERK1/2 levels and activity; 6) effect of Tyrphostin A46 (potent EGFR inhibitor) on all (1-5) parameters...1) Dedifferentiation/reprogramming of EpCs occurs in response to injury (in GU margins) and is triggered by hypoxia, EGFR and its signaling; 2) the hypoxia-EGFR axis is a major regulator of dedifferentiation/reprogramming in GU healing; 3) hypoxia-EGFR-mediated dedifferentiation of GU margin EpCs is a key step in regeneration of epithelial structures during GU healing. These studies provide new insight into dedifferentiation and reprogramming of EpCs in response to injury."

Peptic Ulcer • HIF1A • IGF1

[VIRTUAL] EGCG targeting of adipogenesis reveals a STAT3-mediated paracrine oncogenic control of triple-negative breast cancer cell invasive phenotype (AACR 2021) - "Adipocytes secretome plays a key role in the paracrine regulation of TNBC cells invasive phenotype. Dietary catechin-mediated interventions may, in part through the inhibition of adipogenesis and modulation of adipocytes secretome, prevent the onset of an obesogenic environment that favors TNBC development."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • FABP4 • FASN • LEP • LPL • STAT3

Brain-derived neurotrophic factor increases cell number of neural progenitor cells derived from human induced pluripotent stem cells. (PubMed, PeerJ) - "Moreover, a specific signal transduction pathway important in cell proliferation was investigated using a JAK2 inhibitor (AG490) to clarify the role of that pathway...However, this inhibitor partially decreased BDNF-induced hNPCs proliferation. These results demonstrated the potential role of BDNF for the amelioration of AD through the increase of AD-derived hNPCs number."

Journal • Alzheimer's Disease • CNS Disorders • BDNF • STAT3

Effect of Inhibition of the JAK2/STAT3 Signaling Pathway on the Th17/IL-17 Axis in Acute Cellular Rejection After Heart Transplantation in Mice. (PubMed, J Cardiovasc Pharmacol) - "In this study, we used Bagg's Albino c mice and C57BL/6 mice to construct heterotopic heart transplantation models, which were divided into the acute rejection group and AG490-treated group (n = 5), and donor tissue and serum were collected in 3 experimental days from the recipient mice for H&E staining analysis of paraffin sections and ELISA, Western blot, flow cytometry, and real time-polymerase chain reaction. The results showed that the acute rejection rating of the heart decreased, and the expression of related factors decreased significantly after using the inhibitor AG490, suggesting that the JAK2/STAT3 signaling pathway regulates expression of the Th17/IL-17 axis in cardiac allograft rejection."

Journal • Preclinical • Cardiovascular • Transplantation • CD4 • IL17A • PCR

iPSC-endothelial cell phenotypic drug screening and in silico analyses identify tyrphostin-AG1296 for pulmonary arterial hypertension. (PubMed, Sci Transl Med) - "Specifically, AG1296 up-regulated small mothers against decapentaplegic (SMAD) 1/5 coactivators, cAMP response element-binding protein 3 (CREB3), and CREB5: CREB3 induced inhibitor of DNA binding 1 and downstream genes that improved vascular function. Thus, drug discovery for PAH can be accelerated by combining phenotypic screening with in silico analyses of publicly available datasets."

Journal • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • CREB5 • SMAD4

The interplay between HIF-1α and long noncoding GAS5 regulates the JAK1/STAT3 signalling pathway in hypoxia-induced injury in myocardial cells. (PubMed, Cardiovasc Diagn Ther) - "GAS5 and HIF-1α could regulate hypoxic injury in H9C2 cells through JAK1/STAT3 signaling pathway. This scenario suggests that the inhibitors of GAS5 and HIF-1α may synergize with AG-490 to protect myocardial cells from hypoxic injury."

Journal • Immunology • Inflammation • GAS5 • HIF1A • JAK1

SOCS1/JAK2/STAT3 axis regulates early brain injury induced by subarachnoid hemorrhage via inflammatory responses. (PubMed, Neural Regen Res) - "Furthermore, primary neurons stimulated with oxyhemoglobin were used to simulate subarachnoid hemorrhage in vitro, and the JAK2 inhibitor AG490 was used as an intervention...This study was approved by the Animal Ethics Committee of Anhui Medical University and the First Affiliated Hospital of University of Science and Technology of China (approval No. LLSC-20180202) on March 1, 2018."

Journal • CNS Disorders • Hematological Disorders • Immunology • Inflammation • Subarachnoid Hemorrhage • Vascular Neurology • IL10 • IL1B • IL4 • JAK2 • SOCS1 • TNFA

Central Nervous System Inflammation Induced by Lipopolysaccharide Up-Regulates Hepatic Hepcidin Expression by Activating the IL-6/JAK2/STAT3 Pathway in Mice. (PubMed, Front Nutr) - "AG490 was used to verify the effect of the IL-6/JAK2/STAT3 pathway on hepatic hepcidin expression. Our present study demonstrated that LPS ICV injection up-regulated hepatic hepcidin expression. This finding provides further evidence for highlighting the importance of the central inflammation on hepatic hepcidin expression and peripheral iron metabolism."

Journal • Preclinical • Immunology • Inflammation • IL6

[VIRTUAL] JAK INHIBITORS AND THE EPIGENETIC CONTROL OF THE INTERFERON PATHWAY IN SJÖGREN’S SYNDROME (AUTO 2021) - "Mediated by IFNs, and reactive oxygen species (ROS), the expression of TET3 and in turn global DNA hydroxymethylation were controlled through the induction of STAT3. This process can be reversed by using JAK inhibitors (AG490 and ruxolitinib), leading to the control of DNA methylation/demethylation as well as the control of two plasma-membrane molecules: ICAM-1 and PD-L1 present in IFN activated SGEC.ConclusionsTreatment with JAK1/2 inhibitors reverses the epigenetic activation profile mediated by interferon pathway, suggesting new ways for establishing innovative treatment regimens in patients with primary SjS."

Epigenetic controller • IO biomarker • Immunology • Sjogren's Syndrome • ICAM1 • PD-L1 • STAT3

Inhibition of JAK-STAT Signaling Pathway Alleviates Age-Related Phenotypes in Tendon Stem/Progenitor Cells. (PubMed, Front Cell Dev Biol) - "Pharmacological inhibition of JAK-STAT signaling pathway with AG490 similarly attenuated cellular senescence and senescence-associated secretory phenotype (SASP) of aged TSPCs. In addition, inhibition of JAK-STAT signaling pathway also restored the age-related dysfunctions of TSPCs, including self-renewal, migration, actin dynamics, and stemness. Together, our findings reveal the critical role of JAK-STAT signaling pathway in the regulation of TSPC aging and suggest an ideal therapeutic target for the age-related tendon disorders."

Journal • JAK2 • STAT3

EGCG Inhibits Adipose-Derived Mesenchymal Stem Cells Differentiation into Adipocytes and Prevents a STAT3-Mediated Paracrine Oncogenic Control of Triple-Negative Breast Cancer Cell Invasive Phenotype. (PubMed, Molecules) - "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."

Journal • Breast Cancer • Immunology • Inflammation • Obesity • Oncology • Solid Tumor • Triple Negative Breast Cancer • FABP4 • FASN • LEP • LPL • STAT3

Shikonin Derivatives from Onsoma visianii Decrease Expression of Phosphorylated STAT3 in Leukemia Cells and Exert Antitumor Activity. (PubMed, Nutrients) - "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."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Prolymphocytic Leukemia • CCND1 • PCR

Knockout of NOS2 Promotes Adipogenic Differentiation of Rat MSCs by Enhancing Activation of JAK/STAT3 Signaling. (PubMed, Front Cell Dev Biol) - "Both AG490 and S3I-201, small molecule inhibitors that selectively inhibit STAT3 activation, reversed this adipogenic effect. Furthermore, after high-fat diet (HFD) feeding, knockout of NOS2 in rat MSCs resulted in significant obesity. In summary, NOS2 is involved in the regulation of rat MSC adipogenic differentiation via the STAT3 signaling pathway."

Journal • Preclinical • Genetic Disorders • Immune Modulation • Inflammation • Obesity • FABP4 • NOS2

Functional metabolomics reveal the role of AHR/GPR35 mediated kynurenic acid gradient sensing in chemotherapy-induced intestinal damage. (PubMed, Acta Pharm Sin B) - "Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity in vivo suggests that chemotherapeutics combined with the two could be a promising therapeutic strategy for cancer patients in clinic. This work highlights GPR35 and AHR as the guardian of kynurenine pathway metabolism and core component of defense responses against intestinal damage."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • IDO1 • IL6

Bone marrow stem cells secretome accelerates simulated birth trauma-induced stress urinary incontinence recovery in rats. (PubMed, Aging (Albany NY)) - "Treatment with the JAK2 inhibitor AG490 reversed BMSC-CM-induced activation of the JAK2/STAT4 pathway...Histological analysis revealed increased numbers of fibroblasts, improved collagen fibers arrangement and elevated collagens content in the AVW of rats receiving BMSC-CCM. These findings suggest the BMSC secretome activates AVW fibroblasts and contributes to the functional and anatomic recovery of simulated birth trauma-induced SUI in rats."

Journal • Preclinical • Mood Disorders • Urinary Incontinence • Urology

Electroacupuncture ameliorates intestinal inflammation by activating α7nAChR-mediated JAK2/STAT3 signaling pathway in postoperative ileus. (PubMed, Theranostics) - "The effects of α7nAChR antagonists (methyllycaconitine and α-bungarotoxin) and JAK2/STAT3 inhibitors (AG490 and WP1066) were also administered in a subset of mice prior to EA. Furthermore, we also demonstrated that hindlimb region stimulation drove vagal efferent output by inhibiting the expression of GABA receptor in DMV to ameliorate inflammation. The present study revealed that EA of hindlimb regions inhibited the expression of GABA receptor in DMV neurons, whose excited vagal nerve, in turn suppressed IM-induced inflammation via activation of α7nAChR-mediated JAK2/STAT3 signaling pathway."

Journal • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease

KCa3.1 Inhibition of Macrophages Suppresses Inflammatory Response Leading to Endothelial Damage in a Cell Model of Kawasaki Disease. (PubMed, J Inflamm Res) - "RAW264.7 cells were stimulated with Lactobacillus casei cell wall extract (LCWE) with or without TRAM-34 or PDTC or AG490...This study demonstrates that KCa3.1 blockade of macrophages suppresses inflammatory reaction leading to mouse coronary artery endothelial cell injury in a cell model of KD by hampering the activation of NF-κB and STAT3 signaling pathway. These findings imply that KCa3.1 may be a potential therapeutic target for KD."

Journal • Immunology • Inflammation

Exercise-induced peptide EIP-22 protect myocardial from ischaemia/reperfusion injury via activating JAK2/STAT3 signalling pathway. (PubMed, J Cell Mol Med) - "Moreover, AG490, a selective inhibitor of JAK2/STAT3, eliminated the protective roles of EIP-22. The results uncovered that exercise-induced peptide EIP-22 protected cardiomyocytes from myocardial I/R injury via activating JAK2/STAT3 signalling pathway and might be a new candidate molecule for the treatment of myocardial I/R injury."

Journal • Cardiovascular • Fibrosis • Immunology • Myocardial Infarction • Reperfusion Injury

New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells. (PubMed, Int J Mol Sci) - "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."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • KDR

STAT3 Suppresses Cardiomyocytes Apoptosis in CVB3-Induced Myocarditis Via Survivin. (PubMed, Front Pharmacol) - "To further clarify what role did STAT3 play in VMC, AG490, an inhibitor of STAT3, was used to suppress p-STAT3...Following that, we explored what elements are involved in the anti-apoptotic mechanism of activated STAT3 by using survivin inhibitor YM155. The result showed the anti-apoptotic effect of activated STAT3 does not work in the case of survivin inhibition. Our findings demonstrated STAT3 by targeting survivin alleviated cardiomyocyte apoptosis in CVB3-induced myocarditis."

Journal • Cardiovascular • Immunology • Inflammation • BIRC5 • STAT3