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1
Hofmann, Hans-Dieter, and Matthias Kirsch. "JAK2-STAT3 signaling." JAK-STAT 1, no. 3 (July 2012): 191–93. http://dx.doi.org/10.4161/jkst.20446.
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Zhou, Zehua, Ying Chen, Wenmin Dong, Rui An, Kun Liang, and Xinhong Wang. "Da Cheng Qi Decoction Alleviates Cerulein-Stimulated AR42J Pancreatic Acinar Cell Injury via the JAK2/STAT3 Signaling Pathway." Evidence-Based Complementary and Alternative Medicine 2021 (April 9, 2021): 1–13. http://dx.doi.org/10.1155/2021/6657036.
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Background. Acute pancreatitis (AP) is a common acute abdomen inflammation, characterized by the dysregulation of digestive enzyme production and secretion. Many studies have shown that Da Cheng Qi Decoction (DCQD) is a secure, effective prescription on AP. In this study, cerulein-stimulated AR42J cells damage model was established to further explore the feasibility and underlying mechanism of DCQD as a potential inhibitor of JAK2/STAT3 pathway for the treatment of AP. Methods. Cell viability of DCQD was measured using a cell counting Kit-8 assay. Pancreatic biochemical markers such as amylase, lipase, and C-reactive protein production were measured by assay kits, respectively. Cytokines (TNF-α, IL-6, IL-10, and IL-1β) were assayed by ELISA. Protein location and protein expression were detected by immunofluorescence staining and Western blotting, respectively. Gene expression was assessed by real-time PCR. For mechanistic analysis of the effect of DCQD on JAK2/STAT3 signaling pathway, selective JAK2 inhibitor (Fedratinib) and STAT3 inhibitor (Stattic) as well as STAT3 activator (Garcinone D) were used. Results. DCQD protected cells by regulating cerulein-induced inflammation and reducing the secretion of pancreatic biochemical markers. Moreover, DCQD could not only inhibit the nuclear translocation of p-STAT3, but also decrease the mRNA expression of JAK2 and STAT3 as well as the ratio of p-JAK2/JAK2 and p-STAT3/STAT3 in protein level. Additionally, DCQD could regulate the mRNA and protein expression of JAK2/STAT3 downstream effectors, Bax and Bcl-XL. The activated effect of cerulein on JAK2/STAT3 pathway was also reversed by JAK2 inhibitor Fedratinib or STAT3 inhibitor Stattic. And the overexpression of JAK2/STAT3 pathway, via STAT3 activator Garcinone D, did exert damage on cells, which bore a resemblance to cerulein. Conclusion. The activation of JAK2/STAT3 pathway may play a key role in the pathogenesis of cerulein-stimulated AR42J pancreatic acinar cell injury. DCQD could improve inflammatory cytokines and cell injury, which might be mediated by suppressing the activation of JAK2/STAT3 signaling pathway.
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Jin, Wenyin, and Yinfeng Shen. "Da-Cheng-Qi Decoction Alleviates Intestinal Injury in Rats with Severe Acute Pancreatitis by Inhibiting the JAK2-STAT3 Signaling Pathway." Evidence-Based Complementary and Alternative Medicine 2019 (August 14, 2019): 1–12. http://dx.doi.org/10.1155/2019/3909468.
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Objective. To investigate the effect of Da-Cheng-Qi decoction (DCQD) on treating intestinal injury in rats with severe acute pancreatitis (SAP), based on the Janus kinase 2 (JAK2)/signal transducers and transcription 3 (STAT3) signaling pathway. Methods. Rats were randomly divided into the SAP group, SAP + ruxolitinib (JAK2 inhibitor) group, SAP + Stattic (STAT3 inhibitor) group, SAP + DCQD group, and sham operation group. They were further divided into 3-hour, 6-hour, 12-hour, and 18-hour subgroups. Levels of amylase and the inflammatory cytokines tumor necrosis factor-α, interleukin 6, interleukin 10, and interleukin 4 in plasma were tested. The messenger ribonucleic acid (mRNA) expression of JAK2 and STAT3 and the protein expression of phosphorylated JAK2 (p-JAK2) and phosphorylated STAT3 (p-STAT3) in the pancreas and terminal ileum tissues were examined. Results. Rats with SAP had severe changes in plasma levels of amylase and inflammatory cytokines and showed an overexpression of JAK2 mRNA, STAT3 mRNA, p-JAK2 protein, and p-STAT3 protein in the pancreas and terminal ileum. The events could be downregulated by treatment with DCQD, JAK2 inhibitor, and STAT3 inhibitor. Conclusions. In rats with SAP, DCQD ameliorated inflammatory cytokines and intestinal injury, which may be closely associated with the inhibition of the JAK2/STAT3 signaling pathway.
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Kim, Hyunkyung, Dongha Kim, Seon Ah Choi, Chang Rok Kim, Se Kyu Oh, Ki Eun Pyo, Joomyung Kim, et al. "KDM3A histone demethylase functions as an essential factor for activation of JAK2−STAT3 signaling pathway." Proceedings of the National Academy of Sciences 115, no. 46 (October 30, 2018): 11766–71. http://dx.doi.org/10.1073/pnas.1805662115.
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Janus tyrosine kinase 2 (JAK2)−signal transducer and activator of transcription 3 (STAT3) signaling pathway is essential for modulating cellular development, differentiation, and homeostasis. Thus, dysregulation of JAK2−STAT3 signaling pathway is frequently associated with human malignancies. Here, we provide evidence that lysine-specific demethylase 3A (KDM3A) functions as an essential epigenetic enzyme for the activation of JAK2−STAT3 signaling pathway. KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2−KDM3A signaling cascade induced by IL-6 leads to alteration of histone H3K9 methylation as a predominant epigenetic event, thereby providing the functional and mechanistic link between activation of JAK2−STAT3 signaling pathway and its epigenetic control. Together, our findings demonstrate that inhibition of KDM3A phosphorylation could be a potent therapeutic strategy to control oncogenic effect of JAK2−STAT3 signaling pathway.
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Bouaouiche, Sarra, Silvia Ghione, Randa Sghaier, Olivier Burgy, Cindy Racoeur, Valentin Derangère, Ali Bettaieb, and Stéphanie Plenchette. "Nitric Oxide-Releasing Drug Glyceryl Trinitrate Targets JAK2/STAT3 Signaling, Migration and Invasion of Triple-Negative Breast Cancer Cells." International Journal of Molecular Sciences 22, no. 16 (August 6, 2021): 8449. http://dx.doi.org/10.3390/ijms22168449.
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Triple-negative breast cancer (TNBC) is a highly aggressive disease with invasive and metastasizing properties associated with a poor prognosis. The STAT3 signaling pathway has shown a pivotal role in cancer cell migration, invasion, metastasis and drug resistance of TNBC cells. IL-6 is a main upstream activator of the JAK2/STAT3 pathway. In the present study we examined the impact of the NO-donor glyceryl trinitrate (GTN) on the activation of the JAK2/STAT3 signaling pathway and subsequent migration, invasion and metastasis ability of TNBC cells through in vitro and in vivo experiments. We used a subtoxic dose of carboplatin and/or recombinant IL-6 to activate the JAK2/STAT3 signaling pathway and its functional outcomes. We found an inhibitory effect of GTN on the activation of the JAK2/STAT3 signaling, migration and invasion of TNBC cells. We discovered that GTN inhibits the activation of JAK2, the upstream activator of STAT3, and mediates the S-nitrosylation of JAK2. Finally, the effect of GTN (Nitronal) on lung metastasis was investigated to assess its antitumor activity in vivo.
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Barber, Ruth, Jenny Zobel, Daniel Beck, Sian Evans, Richard Elliott, Christopher J. Lord, Alan Ashworth, Andrew G. C. Porter, and Simon D. Wagner. "JAK2 Is a Direct BCL6 Target Gene: Implications for Therapy in Diffuse Large B-Cell Lymphoma." Blood 124, no. 21 (December 6, 2014): 3112. http://dx.doi.org/10.1182/blood.v124.21.3112.3112.
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Abstract Increased STAT3 signalling is a factor in driving ~50% of diffuse large B-cell lymphoma. In some cases increased cytokine production by the lymphoma is responsible for activation of JAK2 and STAT3 but the regulation of signalling through this pathway is not clear. We constructed a conditional BCL6 deficient cell line through disruption of the endogenous BCL6 loci of a genetically tractable human B-cell lymphoma by homologous recombination, and insertion of a tetracycline regulatable BCL6 transgene. On induction of BCL6 deficiency growth of the cell line slowed by 3 to 4-fold. A synthetic lethal screen employing a library of small molecule inhibitors in genetically BCL6 deficient lymphoma cells showed that lestaurtinib, a JAK2 inhibitor, enhanced loss of viability. We investigated the hypothesis that JAK2 is a direct BCL6 target gene. JAK2 mRNA and protein expression were induced by BCL6 deficiency. Inspection of the JAK2 proximal promoter region demonstrated a potential BCL6 binding site. BCL6 bound to this sequence in vitro and mutagenesis of the binding site relieved BCL6 mediated transcriptional repression in luciferase reporter assays. Analysis of ChIP-seq data showed a binding peak in the JAK2 proximal promoter region confirming in vivo BCL6 binding. Data from a large and publicly available gene expression dataset confirmed an inverse correlation between BCL6 and JAK2 mRNA whilst there was a positive correlation between JAK2 and STAT3 mRNA. STAT3 is a known target of BCL6 transcriptional repression. We suggest that BCL6 represses both JAK2 and STAT3 and that relatively high BCL6 levels will tend to reduce JAK2-STAT3 signalling whereas lower BCL6 levels will amplify this pathway. Mouse xenografts utilising our conditional BCL6 deficient cell line showed that lestaurtinib alone caused minimum reduction to tumour size but the combination of BCL6 deficiency and JAK2 inhibitor caused growth reduction with central necrosis. In summary we identify JAK2 as a BCL6 target gene and propose that BCL6 has an important role in regulation of JAK2-STAT3 signalling in DLBCL. BCL6 mRNA expression may be a biomarker to enable the rational use of JAK2 inhibitors in DLBCL. Disclosures No relevant conflicts of interest to declare.
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Li, Yun-Qing. "Down-Regulation of Insulin Signaling Is Involved in Painful Diabetic Neuropathy in Type 2 Diabetes." Pain Physician 2;16, no. 2;3 (March 14, 2013): E71—E83. http://dx.doi.org/10.36076/ppj.2013/16/e71.
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Background: Previous theories considered that the main cause of painful diabetic neuropathy (PDN) was due to hyperglycemia. However, recent evidence indicated that hyperinsulinemia plays a greater role in type 2 diabetic metabolisms (T2DM). Objectives: Our aim was to explore insulin signaling to determine the molecular mechanism involved in the pathogenesis of PDN in T2DM. Study Design: A randomized, double blind, controlled animal trial. Methods: We observed the localization of insulin receptor (IR) and phosphorylated insulin receptor substrate 1 (IRS-1) in the spinal cord using in situ hybridization and immunohistochemistry. Then we investigated the alternations of IR and pIRS-1 and the activity of the JAK2/STAT3 pathway by immunohistochemistry, Western Blotting, and cell culture. Finally, we detected the influence of intrathecal JAK2/STAT3 inhibitor (AG490) on nociceptive behavior and insulin signaling in ob/ob mice using Western Blotting. Results: We found that IR and pIRS-1 are mainly located in neurons in the superficial layer of the spinal dorsal horn. The expressions of IR and pIRS-1 decreased and the JAK2/STAT3 pathway activated in the spinal dorsal horn in ob/ob mice with mechanical hyperalgesia. Next, our in vitro results indicated that hyperinsulinemia and hyperglycemia impaired insulin signaling along with the activated JAK2/STAT3 pathway in differentiated human neuronal cells (SH-SY5Y). Treatment through intrathecal injection of AG490, an inhibitor of the JAK2/STAT3 pathway, alleviated mechanical hyperalgesia in ob/ob mice and prevented impaired insulin signaling in the spinal cord. Limitations: The activation of the JAK2/STAT3 pathway could not explain the mechanism of PDN in T1DM. Conclusions: We demonstrate that insulin signaling impairment in the spinal dorsal horn is associated with the activated JAK2/STAT3 pathway, which contributes to the progressive PDN in T2DM. Key words: Painful diabetic neuropathy, mouse, insulin receptor, insulin receptor substance 1, JAK2, STAT3
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Lei, Bo, Ju Bai, Wanggang Zhang, Aili He, Yinxia Chen, Pengyu Zhang, Lu Qian, and Fuling Zhou. "Acute Monocytic Leukemia Associated Antigen MLAA-34 up-Regulates JAK2/STAT3 Expression and JAK2/STAT3 Enhances MLAA-34 Activation in a Positive Feedback Loop." Blood 126, no. 23 (December 3, 2015): 1393. http://dx.doi.org/10.1182/blood.v126.23.1393.1393.
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Abstract Backgroud: The MLAA-34 gene (GenBank no. AY288977.2) was first discovered in acute monocytic leukemia (M5) in an effort to identify monocytic leukemia-associated antigens by serologic analysis of a recombinant cDNA expression library (SEREX). Previous study showed that high MLAA-34 levels were independently associated with a poorer relapse-free survival and overall survival in AML patients. The MLAA-34 is located on 13q14.2 and has been confirmed to be a novel splice variant of CAB39L (calcium binding protein 39-like). Both mRNA and protein levels of MLAA-34 were found to be higher in U937 cells and M5 patients. The study confirmed that MLAA-34 plays a role in the antiapoptosis of U937 cells, and has the function of oncogenes. Objective: This study is to explore the relationship of MLAA-34 and JAK2/STAT3 signaling pathway so as to further clarify antiapoptotic mechanisms of MLAA-34. Method: Potential binding sites for STAT3 was identified by computer-assisted analysis of the core promoter of MLAA-34 gene. We analyzed the role of STAT3 in the regulation of MLAA-34 gene expression in U937 cells by site-specific mutation, chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA). The expression of MLAA-34 was detected by RT-PCR and western blot after over-expressing and interfering STAT3. Through the different concentrations of AG490 (JAK2 inhibitors) and different concentrations of IL- 6 (JAK2 activator) study JAK2/STAT3 signaling pathway upregulated MLAA-34 expression. The gene chip and co-IP were applied to study the MLAA-34-induced JAK2/STAT3 activation. Peripheral blood mononuclear cells and bone marrow (BM) cells of M5 patients were obtained. In M5 patients, mRNA and protein expression of JAK-2, STAT3, p-STAT3 and MLAA-34 were determined by quantitative RT-PCR and western blot respectively to verify the forward feedback regulation pathway. Result: The reporter assay showed that the activity of reporter gene was downregulated after the mutation of STAT3 binding sites. ChIP assay and EMSA showed that STAT3 can directly bind to MLAA-34 gene promoter. The expression vectors of MLAA-34 as well as siRNA eukaryotic expression vectors respectively targeting STAT3 were successfully constructed. RT-PCR and western blot results showed that STAT3 can increase the level of MLAA-34. Research of administration of different concentrations of AG490 and different concentrations of IL-6 showed that JAK2/STAT3 signaling pathway could upregulate MLAA-34 expression. AML-M5 NOD / SCID mice leukemia model was successfully constructed,.Konckdown of MLAA-34 gene can promote apoptosis of leukemia cells, inhibit tumor growth and prolong survival time. Total RNA from shRNA-MLAA-34/U937 and Vec/U937 cells were analyzed by Human Genome U133 chip. Heat-map showed reduced expression of JAK2/STAT3 pathway genes. The result was verified by qPCR and western blot. CO-IP showed that MLAA-34 could form a complex with endogenous JAK2 under the enhanced role of IL-6. Thereby activating JAK2 may directly or indirectly dependent on the presence of MLAA-34. Furthermore, we detected JAK-2, STAT3, P-STAT3 and MLAA-34 gene and protein level in M5 patients, the results showed that they have a positive correlation. Conclusion: JAK2/STAT3 pathway up-regulates MLAA-34 transcription, and MLAA-34 enhances JAK2/STAT3 pathway activation. The forward feedback regulation may have profound therapeutic implications for M5 and could help invent novel approaches in treatment for acute monocytic leukemia. Disclosures No relevant conflicts of interest to declare.
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Zhang, Xuekang, Jun Zhou, Qian Hu, Zhengren Liu, Qiuhong Chen, Wenxiang Wang, Huaigen Zhang, Qin Zhang, and Yuanlu Huang. "The Role of Janus Kinase/Signal Transducer and Activator of Transcription Signalling on Preventing Intestinal Ischemia/Reperfusion Injury with Dexmedetomidine." Journal of Nanoscience and Nanotechnology 20, no. 5 (May 1, 2020): 3295–302. http://dx.doi.org/10.1166/jnn.2020.16416.
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Dexmedetomidine (Dex) works as a crucial agent for the treatment of intestinal ischemia/reperfusion (I/R), but its mechanism remains unclear. Recent articles demonstrated the pivotal role of Janus kinase/signal transducer and activator of transcription (JAK2/STAT3) signalling in I/R. Therefore, it is reasonable to explore the associated mechanism of JAK2/STAT3 signalling in Dex treatment. The study purpose was to evaluate the JAK2/STAT3 signalling regulatory mechanisms of Dex in preventing I/R. Anaesthetized rats were subjected to superior mesenteric artery occlusion consisting of 1 h of ischemia and 2 h of reperfusion while served as controls. Animals received subcutaneous administration of 50 μg/kg Dex, JAK1 and JAK2 inhibitor, Ruxolitinib, selective JAK2 inhibitor, 10 mg/kg AG490 or STAT inhibitor and 0.4 mg/kg rapamycin; or Dex-treatment in the presence of α2-adrenoceptor antagonists Atip or Dex-treatment alone after I/R. Injury was scored histologically, apoptosis was detected via the apoptotic mediators caspase-3 and Bcl-2/Bax and the degree of activation of the JAK/STAT pathway was evaluated. Dex inhibited I/R injury by decreasing apoptosis significantly with rescue of cleaved caspase-3 and the Bcl-2/Bax ratio. Furthermore, phosphorylation of JAK2, STAT1 and STAT3 was affected, suggesting the involvement of activated JAK/STAT in response to Dex. Meanwhile, the JAK2 or STAT inhibitors AG490 and rapamycin, but not Ruxolitinib, exhibited a similar but even greater JAK2 and STAT3 regulatory effect, thus leading to a greater benefit. JAK2/STAT3 activation is crucial to the diminishing effect of Dex on mesenteric I/R injury; however, the efficacy and timing of Dex administration should be considered in clinical practice.
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Liu, Fa-Yu, Jawad Safdar, Zhen-Ning Li, Qi-Gen Fang, Xu Zhang, Zhong-Fei Xu, and Chang-Fu Sun. "CCR7 Regulates Cell Migration and Invasion through JAK2/STAT3 in Metastatic Squamous Cell Carcinoma of the Head and Neck." BioMed Research International 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/415375.
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Squamous cell carcinoma of the head and neck (SCCHN) frequently involves metastasis at diagnosis. Our previous research has demonstrated that CCR7 plays a key role in regulating SCCHN metastasis, and this process involves several molecules, such as PI3K/cdc42, pyk2, and Src. In this study, the goals are to identify whether JAK2/STAT3 also participates in CCR7’s signal network, its relationship with other signal pathways, and its role in SCCHN cell invasion and migration. The results showed that stimulation of CCL19 could induce JAK2/STAT3 phosphorylation, which can be blocked by Src and pyk2 inhibitors. After activation, STAT3 was able to promote low expression of E-cadherin and had no effect on vimentin. This JAk2/STAT3 pathway not only mediated CCR7-induced cell migration but also mediated invasion speed. The immunohistochemistry results also showed that the phosphorylation of STAT3 was correlated with CCR7 expression in SCCHN, and CCR7 and STAT3 phosphorylation were all associated with lymph node metastasis. In conclusion, JAk2/STAT3 plays a key role in CCR7 regulating SCCHN metastasis.
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Rong, Jing, Lizhong Li, Li Jing, Haiqin Fang, and Shuangqing Peng. "JAK2/STAT3 Pathway Mediates Protection of Metallothionein Against Doxorubicin-Induced Cytotoxicity in Mouse Cardiomyocytes." International Journal of Toxicology 35, no. 3 (November 2, 2015): 317–26. http://dx.doi.org/10.1177/1091581815614261.
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Doxorubicin (Dox) is one of the most important anticancer agents; however, its clinical application is limited by its severe cardiotoxicity. In our previous study, we found that the gene expression levels of the Janus-activated kinase/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway were different between MT−/− cardiomyocytes and MT+/+ cardiomyocytes when they were treated with Dox. Thus, this study was intended to investigate the role of JAK2/STAT3 pathway in metallothionein (MT) protection of Dox-induced cardiotoxicity. Tyrphostin AG490 (α-cyano-(3,4-dihydroxy)-N-benzylcinnamide) is a synthetic protein tyrosine kinase inhibitor which at first has been considered as a specific JAK2 inhibitor and can inhibit the JAK2/STAT3 signaling pathway. In the present study, AG490 was used to assess the role of JAK2/STAT3 in MT protection against Dox-induced cardiotoxicity. The AG490 can attenuate the MT protection by increasing lactate dehydrogenase and the number of apoptotic cells. Interestingly, pretreated with AG490, MT−/− cardiomyocytes were more sensitive than MT+/+ to Dox-induced cytotoxicity as measured by reactive oxygen species generation, lipid peroxidation, and protein carbonylation. Metallothionein 1 and MT-2 messenger RNA were upregulated by Dox, and AG490 decreased the protein expression of MT-1 and MT-2. After Dox treatment, the protein expression of p-Jak2 and p-Stat3 levels was significantly increased in MT+/+ cardiomyocytes, suggesting that the JAK2/STAT3 pathway was partially involved in MT protection against Dox-induced cardiotoxicity.
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Koh, Jin Sung, Jong-Jae Park, Moon Kyung Joo, Hyo Soon Yoo, Jiwon Kim, Yong Jeoung, Ho Kim, et al. "Antitumorigenic effect of plumbagin by induction of SHP1 in human gastric carcinoma cell lines." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 74. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.74.
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74 Background: Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a plant-drived natural agent extracted from the root of Plumbago zeylanic. A recent study reported that plumbagin down-regulated the activity of Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway to show various anti-tumor effects. We aimed in this in vitrostudy to demonstrate the inhibition of JAK2-STAT3 pathway by plumbagin through inducing SH2-containing protein tyrosine phosphatase 1 (SHP1) expression in gastric cancer cell line. Methods: We performed Wetern blot to measure SHP1, phospho-JAK2/STAT3 level, and reverse transcriptase-polymerase chain reaction (RT-PCR) to evaluate target gene expression of STAT3. Several functional studies such as water soluble tetrazolium-1 (WST-1) assay, wound closure assay and matrigel invasion assay were also performed. Results: Plumbagin induced SHP1 expression and simultaneously down-regulated phospho-JAK2/STAT3 level via dose-and time-dependant manner in MKN28 cell, a gastric carcinoma cell line which has negative SHP1 expression. This effect was consistent when JAK2-STAT3 signaling was activated by interleukin-6, and ameliorated when cells were treated with prevanadate, a protein tyrosin phosphatase inhibitor. Furthermore, plumbagin significantly reduced gene expression of cyclin D1, VEGF1, survivin, MMP9, known target products of STAT3 activation in gastric cancinogenesis. The functional effect of plumbagin could be validated as inhibition of cell proliferation, migration and invasion, which are the results of activation of JAK2-STAT3 pathway in gastric cancer cells. Conclusions: Plumbagin is a potential negative regulator of cellular growth, migration and invasion by inhibiting both constitutive and inducible STAT3 activity through induction of SHP1 in gastric cancer cells.
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Mao, Ying, Yang Yao, and Li Liu. "Small molecule inhibitor azd1480 reverses radiotherapy resistance in NSCLC by targeting JAK2/STAT3 pathway." Tropical Journal of Pharmaceutical Research 23, no. 1 (February 5, 2024): 45–50. http://dx.doi.org/10.4314/tjpr.v23i1.6.
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Purpose: To investigate the effect of small molecule inhibitor AZD1480 on radiotherapy resistance in non-small cell lung cancer (NSCLC), and the involvement of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in the process.
Methods: Radiation-resistant cell lines A549-20F, A549-30F, A549-40F and H460, H46040F, H460- 40F, and H460-40F were established, and expressions of proteins related to JAK/STAT pathway, mitogen-activated protein (MAPK) pathway and transforming growth factor-β (TGF- β) were assayed. The JAK2V617FH460 overexpression cell line and JAK2H460 cell line were established, and expressions of ATGL and CPT1A were compared. The H460 cells and H460-40F cells were treated with JAK2 small molecule inhibitor AZD1480, and the expressions of ATGL, CPT1A and JAK2/STAT3 pathway-related proteins were compared. The survival and proliferation of cell lines were also compared.
Results: The JAK/STAT pathway was significantly enriched, and MAPK and TGF-β were up-regulated. In H460 cells, JAK2/STAT3 route was obvious, suggesting that radiotherapy activated JAK2/STAT3 pathway in NSCLC cells. Significant down-regulations of p- JAK2Y1007, JAK2, p-STAT3s727, STAT3, ATGL and CPT1A proteins expressions were seen in H460 + AZD1480 group, relative to H460 group, but protein levels of p-JAK2Y1007, JAK2, p-STAT3s727, STAT3, ATGL and CPT1A were significantly lower in H460-40F + AZD1480 group than in H460-40F group (p < 0.05). The survival and proliferation rates were significantly lower in A549 + AZD1480 group than in A549 and A549-40F groups (p < 0.05).
Conclusion: Radiotherapy up-regulates the expressions of ATGL and CPT1A in NSCLC cells by activating the JAK2/STAT3 pathway, while AZD1480, a small molecule inhibitor, reverses the radiation resistance of NSCLC by targeting JAK2/STAT3 pathway and key enzymes of lipid metabolism. Therefore, azd1480 may enhance clinical treatment efficacy in NSCLC patients by reducing radiation resistance.
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Zhu, Mingming, Min Yang, Quanyu Yang, Wenling Liu, Hui Geng, Li Pan, Lu Wang, et al. "Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway." BioMed Research International 2020 (January 25, 2020): 1–10. http://dx.doi.org/10.1155/2020/9204708.
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Chronic hypoxia (CH) is characterized by long-term hypoxia that is associated with microvessel proliferation and basal membrane (BM) degradation in tissues. The IL-6/JAK2/STAT3/MMP-9 pathway has been described in a variety of human cancers and plays an essential role in microvessel proliferation and BM degradation. Therefore, this study investigated the role of the IL-6/JAK2/STAT3/MMP-9 pathway in hypoxia-mediated microvessel proliferation and BM degradation in the rat bone marrow. Eighty pathogen-free Sprague Dawley male rats were randomly divided into four groups (20 per group)—control group, CH group (exposed to hypoxia in a hypobaric chamber at a simulated altitude of 5000 m for 28 d), CH + STAT3 inhibitor group (7.5 mg/kg/d), and CH + DMSO group. Microvessel density (MVD) and BM degradation in the bone marrow were determined by immunofluorescence staining and transmission electron microscopy. Serum IL-6 levels were assessed by enzyme-linked immunosorbent assay (ELISA), and the levels of P-JAK2, P-STAT3, and MMP-9 were assessed by western blot analysis and real-time reverse transcription PCR (RT-PCR). Hypoxia increased serum IL-6 levels, which in turn increased JAK2 and STAT3 phosphorylation, which subsequently upregulated MMP-9. Overexpression of MMP-9 significantly promoted the elevation of MVD and BM degradation. Inhibition of STAT3 using an inhibitor, SH-4-54, significantly downregulated MMP-9 expression and decreased MVD and BM degradation. Surprisingly, STAT3 inhibition also decreased serum IL-6 levels and JAK2 phosphorylation. Our results suggest that the IL-6/JAK2/STAT3/MMP-9 pathway might be related to CH-induced microvessel proliferation and BM degradation in the bone marrow.
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Morgan, Ethan L., and Andrew Macdonald. "JAK2 Inhibition Impairs Proliferation and Sensitises Cervical Cancer Cells to Cisplatin-Induced Cell Death." Cancers 11, no. 12 (December 4, 2019): 1934. http://dx.doi.org/10.3390/cancers11121934.
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Persistent infection with high-risk human papillomavirus (HPV) is the underlying cause of ~5% of all human cancers, including the majority of cervical carcinomas and many other ano-genital and oral cancers. A major challenge remains to identify key host targets of HPV and to reveal how they contribute to virus-mediated malignancy. The HPV E6 oncoprotein aberrantly activates the signal transducer and activator of transcription 3 (STAT3) transcription factor and this is achieved by a virus-driven increase in the levels of the pro-inflammatory cytokine interleukin-6 (IL-6) in HPV positive cervical cancers cells. Crucially, STAT3 activity is essential for the proliferation and survival of cervical cancer cells, suggesting that targeting STAT3 may have therapeutic potential. Unfortunately, the development of direct STAT3 inhibitors has been problematic in the clinic due to toxicity issues identified in early stage trials. To overcome this issue, we focused on the protein Janus kinase 2 (JAK2), which phosphorylates STAT3 and is essential for STAT3 activation. Here, we demonstrate that inhibiting JAK2 reduces cell proliferation and induces apoptosis in HPV transformed cervical cancer cells. We further establish that this is due to inhibition of phosphorylation of the JAK2 substrates STAT3 and STAT5. Finally, we demonstrate that the clinically available JAK2 inhibitor Ruxolitinib synergises with cisplatin in inducing apoptosis, highlighting JAK2 as a promising therapeutic target in HPV-driven cancers.
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Yu, Xin, Zhi Li, Qilong Wan, Xin Cheng, Jing Zhang, Janak L. Pathak, and Zubing Li. "Inhibition of JAK2/STAT3 signaling suppresses bone marrow stromal cells proliferation and osteogenic differentiation, and impairs bone defect healing." Biological Chemistry 399, no. 11 (October 25, 2018): 1313–23. http://dx.doi.org/10.1515/hsz-2018-0253.
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Abstract Mesenchymal stem cells (MSCs) undergo osteogenic differentiation during bone defect healing. However, the role of JAK2/STAT3 in the osteogenic differentiation of MSCs and bone defect healing is still not fully understood. In this study, we aimed to analyze the effect of AG490, a JAK2-specific inhibitor, on MSCs proliferation and osteogenic differentiation as well as in bone defect healing. We used AG490 to inhibit the JAK2/STAT3 signaling in a mice bone marrow stromal cells (BMSCs) culture. AG490 inhibited BMSCs proliferation and osteogenic differentiation markers, i.e. Col1α, Alp and Ocn expression in mRNA and protein levels. Inhibition of JAK2 reduced ALP activity and matrix mineralization in BMSCs culture. Inhibition of JAK2 reduced phosphorylation of STAT3, AKT, P38, and JNK phosphorylation. Immunohistochemistry showed high numbers of pJAK2, pSTAT3 and ALP positive cells and AG490 reduced this effect in vivo. Histology and μ-computed tomography (CT) data showed that AG490 treatment inhibits bone regeneration and bone defect healing. Our results clearly showed the inhibitory effect of AG490 on proliferation and osteogenic differentiation of BMSCs, bone regeneration and bone defect healing. Moreover, AG490 inhibited phosphorylation of STAT3, P38, JNK and AKT. This suggests the possible role of JAK2/STAT3 signaling in hypoxia-induced osteogenic differentiation of MSCs and bone defect healing.
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Kapuria, Vaibhav, Geoffrey Bartholomeusz, William Bornmann, Ling Y. Kong, Moshe Talpaz, and Nicholas J. Donato. "Inhibition of JAK2/STAT Signaling by Degrasyn through a Novel Mechanism." Blood 108, no. 11 (November 16, 2006): 3423. http://dx.doi.org/10.1182/blood.v108.11.3423.3423.
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Abstract Janus Kinase 2 (JAK2) is a cytokine receptor associated tyrosine kinase. Cytokine stimulation results in JAK2 activation and tyrosine phosphorylation of the cytokine receptor. Cytosolic SH2 domain containing proteins, such as the signal transducer and activator of transcription 3 (STAT3) are recruited to phospho-tyrosine residues on the activated cytokine receptor, and phosphorylated by JAK2 to form stable dimers, followed by their translocation to the nucleus where they function as transcription factors. Deregulation of the JAK-STAT pathway is seen in several epithelial tumors and many hematological malignancies. Recent studies demonstrate that an activating mutation in the pseudokinase domain of JAK2 (V617F) underlies hematological disorders like polycythemia vera. Therefore, inhibition of JAK2 may have therapeutic significance in many cancers. The tryphostin AG490 is the most widely studied inhibitor of JAK2, which inhibits tumor cell growth and increases sensitivity to apoptotic stimuli in vitro. However, in vivo studies with AG490 have been less promising due to its poor pharmacology and requirement for high concentrations to achieve significant anti-tumor activity. To identify a more effective inhibitor of the JAK2-STAT pathway, we screened over 300 analogues of AG490 for their ability to inhibit IL-6 dependent activation of STAT3. A lead compound, Degrasyn (WP1130), was identified from this screen that inhibited IL-6 mediated STAT3 activation at low microM concentrations. Preliminary studies using in vitro kinase assays revealed that Degrasyn is a weak JAK2 kinase inhibitor despite being a strong suppressor of STAT3 activation, suggesting a different mechanism of inhibition of the JAK2-STAT pathway. We show that Degrasyn inhibits STAT3 phosphorylation by inducing the down-regulation of JAK2 protein without affecting STAT3. The loss of JAK2 protein via Degrasyn is a rapid and irreversible process. A decrease in JAK2 protein levels is observed as early as 30 minutes after treatment with near complete loss of JAK2 after 2 hours of Degrasyn incubation. While other tyrosine kinases are not affected, both wild type and mutant (V617F) forms of JAK2 are equally down-regulated by Degrasyn. Loss of JAK2 protein by Degrasyn is not blocked by inhibition of calpain or serine/threonine proteases or by inhibition of the proteosomal or lysosomal pathway. Real-Time PCR analysis of JAK2 transcript levels after Degrasyn treatment showed no significant change, suggesting a direct effect of Degrasyn on the JAK2 protein itself. Recent studies suggest that Degrasyn alters the cytoplasmic compartmentalization of JAK2, sequestering the kinase in an insoluble fraction. In vivo studies show that Degrasyn has significant anti-tumor effects against models of leukemia and lymphoma. These results suggest that Degrasyn induces JAK2 degradation by a unique mechanism and may be useful in treating tumors and diseases where the JAK2 kinase plays a pivotal role.
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Perrone, Giulia, Elisabetta Calabrese, Teru Hideshima, Gullu Gorgun, Ikeda Hiroshi, Diana Cristea, Loredana Santo, Hu Yiguo, and Kenneth C. Anderson. "Panobinostat Inhibits JAK2/STAT3 Pathway in Multiple Myeloma." Blood 114, no. 22 (November 20, 2009): 2849. http://dx.doi.org/10.1182/blood.v114.22.2849.2849.
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Abstract Abstract 2849 Poster Board II-825 Histone deacetylase inhibitors (HDACi) are emerging as a potential therapy for Multiple Myeloma (MM). Their antineoplastic activity depends not only on nucleosomal histone acetylation, but also on direct modulation of non-histone proteins, including p53 or HSP90. Previous studies suggest that histone deacetylases inhibitors modulate Jak2/Stat3 signaling pathway, a cascade mediating tumor cell survival. Here we examine how Panobinostat, a class I-HDAC inhibitor currently in phase I/II clinical trial, can modulate the function of the Jak2/ Stat3 pathway in MM. We first observed that Panobinostat inhibited IL6-induced Stat3 phosphorylation (Tyr705) and Jak2 phosphorylation (Tyr 1007/1008) in MM cell lines ( MM1S and INA6) in a dose- and time- depend fashion, associated with induction of Stat3 acetylation (Lys 685). Since acetylation of Stat3 alters the distribution rather than the functional status of Stat3, we next examined whether Panobinostat altered the nuclear versus cytoplasmic localization of Stat3 in MM cell lines. Although total STAT3 protein level did not change, Panobinostat treatment did trigger decreased nuclear Stat3 phosphorylation, suggesting that Panobinostat blocks Stat3 transcriptional activity. We showed by western blot analysis that the down stream pathway induced by Stat3 (Survivin, Bcl XL, c-Myc) was also down regulated after Panobinostat treatment, further confirming inhibition of STAT3 activity. Take together, our results suggest that Panobinostat inhibits the Jak2/Stat3 pathway by inhibiting STAT3 binding to DNA consensus region, rather than modulating nuclear translocation. To establish the molecular mechanism whereby Panobinostat regulates this pathway, we examined IL6/gp130 receptor, which is upstream in the Jak2 /Stat3 pathway. Panobinostat decreased both cell surface and intracellular gp130 protein expression. Interestingly, Panobinostat also inhibited IL6-induced phosphorylation of gp130, suggesting that it can directly inhibit gp130 activation. Our study therefore suggests a dual mechanism of inhibition of the JAK2/Stat3 pathway induced by Panobinostat via modulation of STAT 3 transcriptional function and gp130 -induced STAT3 activation. Finally, we observed upregulation of the MEK/ERK signaling pathway associated with HDAC inhibition, suggesting that combined blockade of these cascades may be useful. Indeed our preliminary data demonstrate enhanced cytotoxicity in MM cell lines (MM1S and INA6) induced by treatment with combined Panobinostat and MEK inhibitors, even in the presence of bone marrow stromal cells or survival cytokines ( IL6 or IGF). Our study therefore suggests a novel mechanism of action of HDAC inhibitors that provides the rationale for clinical evaluation of novel combinations based upon targeting STAT3 signaling pathway. Disclosures: Anderson: Celgene : Research Funding; Novartis: Research Funding; Millennium: Research Funding.
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Severin, Filippo, Federica Frezzato, Veronica Martini, Flavia Raggi, Valentina Trimarco, Andrea Visentin, Monica Facco, Gianpietro Semenzato, and Livio Trentin. "Three Different Jak2/Stat3-Related Pathways Favor the Survival of Chronic Lymphocytic Leukemia Neoplastic Clone." Blood 132, Supplement 1 (November 29, 2018): 4405. http://dx.doi.org/10.1182/blood-2018-99-114591.
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Abstract INTRODUCTION Chronic lymphoproliferative disorders are characterized by the expansion of malignant lymphocytes, the most common form being Chronic Lymphocytic Leukemia (CLL). Besides intrinsic abnormalities, the acquisition of the transformed phenotype and the diffusion of disease are related to the favorable cross-talking tumor cell-microenvironment. Furthermore, it has been demonstrated that CLL cells own an amplified mitochondrial respiration leading to an increased Reactive Oxygen Species (ROS) production and intrinsic oxidative stress. Several molecules released by microenvironmental partners signal through JAK-STAT pathway. The deregulation of JAK2/STAT3 axis may lead to aberrant activation of STAT3 and, as a result, to tumor development in hematopoietic cells. We previously analyzed STAT3 and JAK2 expression, phosphorylation and localization in normal and leukemic B cells, demonstrating an abnormal activation of this pathway in the neoplastic clone with respect to normal B lymphocytes. We focused on STAT3 constitutive phosphorylation at serine (Ser) 727 residue since it has been recently observed that the presence of mt-STAT3 Ser727 promotes mitochondrial respiration and, generally, cell viability. We hypothesized the involvement of JAK2/STAT3 axis in 3 different pathways: (i) canonical "IL-6 related pathway"; (ii) JAK2/STAT3 - BCR/Lyn crosstalk; (iii) STAT3 effects on mitochondrial regulation. METHODS STAT3 expression and phosphorylation were evaluated by Western Blotting (WB) and Flow Cytometry (FC). Purified cells (2x106 cells/ml) were cultured, and treated with the JAK2 inhibitor AG490 (10, 50 and 100μM) and the STAT3 inhibitor Stattic (5, 7.5, and 10μM) for 24, 48 and 72h. Experiments with AG490 and Stattic were performed with/without MSCs and with/without Ibrutinib (2.5μM) and Venetoclax (1nM). CLL and normal B cell viability was tested with Annexin V/PI test by FC. P-STAT3 Ser727 expression has been correlated with p44/42, SAPK-JNK, NF-kB p65 and p38 MAPK activation by Reverse Phase Protein Microarrays (RPPA) in 57 therapy-free patients presenting good (mutated IGHV, absence of CD38 or normal karyotype) and poor (unmutated IGHV, CD38 expression or 17p deletion) prognostic factors. RESULTS We found that STAT3 was highly expressed in malignant B cells with respect to normal B lymphocytes. We demonstrated that STAT3 and JAK2 were similarly overexpressed in both good and poor prognosis CLL patients. However, a significant correlation between STAT3 expression levels and their overall survival was observed. Considering STAT3 over-expression and its correlation with the clinical outcome in CLL and, according to our hypothesis, we moved forward with the analysis of the three different JAK2/STAT3 pathways. We demonstrated that AG490 and Stattic were able to induce a dose-dependent apoptosis in CLL cells, also bypassing environmental protection. AG490, targeting JAK2, inhibited the phosphorylation of SHP-1 at Ser591, activating the phosphatase. In turn, SHP-1 activation led to Lyn Tyr396 dephosphorylation/inactivation. Treatment with Stattic did not affect Lyn and SHP-1 phosphorylation since this inhibitor acts downstream to AG490. In fact, simultaneous administration of Ibrutinib led to an increase of apoptosis only in Stattic, but not in AG490 treated cells. This confirms a possible dual role of JAK2 inhibition. Venetoclax/AG490 and Venetoclax/Stattic co-treatment did not show an increased cell death rate, consistent with a downstream effect of Venetoclax to both AG490 and Stattic. RPPA analysis demonstrated a correlation between STAT3, Ser727 constitutively phosphorylated in CLL, and P-p44/42 Thr202/Tyr204, P-SAPK-JNK Thr-183/Tyr185, NF-kB p65 Ser-536 and p38 MAPK Thr-180/Tyr-182 expression. All these proteins are described as involved in an alternative pathway that allows STAT3 Ser727 to exert a pro-survival effect thorough the regulation of mitochondrial activity. CONCLUSIONS The analysis of JAK2 and STAT3 expression, activation and inhibition lets us to highlight the importance of JAK2/STAT3 axis in the maintenance of 3 different survival pathways in CLL B cells. Furthermore, the correlation we demonstrated with clinical outcome of patients and the strengthening of Ibrutinib effect when we targeted this axis could represent a starting point for the development of new therapeutic strategies in CLL. Disclosures Trentin: Abbvie: Honoraria; Gilead: Research Funding; Janssen: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees.
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Nicholson, SE, U. Novak, SF Ziegler, and JE Layton. "Distinct regions of the granulocyte colony-stimulating factor receptor are required for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44MAPK." Blood 86, no. 10 (November 15, 1995): 3698–704. http://dx.doi.org/10.1182/blood.v86.10.3698.bloodjournal86103698.
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The protein tyrosine kinases JAK1 and JAK2 are phosphorylated tyrosine after the interaction of granulocyte colony-stimulating factor (G-CSF) with its transmembrane receptor. So too is Stat3, a member of the STAT family of transcriptional activators thought to be activated by the JAK kinases. Truncated G-CSF receptor (G-CSF-R) mutants were used to determine the different regions of the cytoplasmic domain necessary for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44MAPK. We have shown that G-CSF-induced tyrosine phosphorylation and kinase activation of JAK2 requires the membrane proximal 57 amino acids of the cytoplasmic domain. In contrast, maximal Stat3 tyrosine phosphorylation required amino acids 96 to 183 of the G-CSF-R cytoplasmic domain, Stat3 DNA binding could occur with a receptor truncated 96 amino acids from the transmembrane domain and containing a single tyrosine residue, but was reduced in comparison with the full- length receptor. Together with the tyrosine phosphorylation of Stat3, this finding suggests that additional Stat3 does not appear to be required for proliferation. MAP kinase tyrosine phosphorylation correlated with both the proliferative response and JAK2 activation.
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Grisouard, Jean, Takafumi Shimizu, Adrian Duek, Lucia Kubovcakova, Hui Hao-Shen, Stephan Dirnhofer, and Radek C. Skoda. "Deletion of Stat3 in hematopoietic cells enhances thrombocytosis and shortens survival in a JAK2-V617F mouse model of MPN." Blood 125, no. 13 (March 26, 2015): 2131–40. http://dx.doi.org/10.1182/blood-2014-08-594572.
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Key Points Loss of Stat3 in hematopoietic cells enhances JAK2-V617F–driven thrombopoiesis and negatively impacts survival in mouse models. The phenotypic changes of Stat3-deficient JAK2-V617F mice could in part be mediated by increased Stat1 expression and activation.
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Wu, Yang, Tan Yuan, Wei-Wei Wang, Peng-Lei Ge, Zhi-Qiang Gao, Gong Zhang, Zhe Tang, et al. "Long Noncoding RNA HOST2 Promotes Epithelial-Mesenchymal Transition, Proliferation, Invasion and Migration of Hepatocellular Carcinoma Cells by Activating the JAK2-STAT3 Signaling Pathway." Cellular Physiology and Biochemistry 51, no. 1 (2018): 301–14. http://dx.doi.org/10.1159/000495231.
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Background/Aims: This study aims to examine the effect of long noncoding RNA HOST2 (LncRNA HOST2) on epithelial-mesenchymal transition (EMT), proliferation, invasion and migration of hepatocellular carcinoma (HCC) cells via activation of the JAK2-STAT3 signaling pathway. Methods: HCC and para-cancerous tissues were collected from 136 HCC patients. Immunohistochemistry was used to detect the expression of JAK2 and STAT3. HCC SMMC7721 cells were grouped into blank, negative control (NC), HOST2 mimic and HOST2 inhibitor groups. The mRNA and protein expression levels of HOST2, JAK2, STAT3, E-cadherin, vimentin, Snail, Slug, Twist and Zeb1 in tissues and cells were determined by reverse transcription -quantitative polymerase chain reaction (RT-qPCR) and Western blotting, respectively. An MTT assay, scratch test and Transwell assay were applied to measure cell proliferation, migration and invasion, respectively. Results: The levels of JAK2, STAT3 and vimentin were higher in HCC tissues, while the expression of E-cadherin was lower in HCC tissues compared with para-cancerous tissues. The silencing of HOST2 significantly decreased cell proliferation, migration and invasion, reduced the levels of HOST2, JAK2, STAT3 and vimentin, and elevated the expression of E-cadherin. HOST2 silencing also decreased the levels of Snail, Slug and Twist but increased the level of Zeb1 protein, while the opposite findings were observed in the HOST2 mimic group. Conclusion: These results reveal a possible mechanism in HCC in which LncRNA HOST2 may increase EMT and enhance proliferation, invasion and metastasis of HCC cells via activation of the JAK2-STAT3 signaling pathway.
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Wu, Yi-Hong, Hsing-Yu Chen, Wei-Chin Hong, Chen-Ying Wei, and Jong-Hwei Su Pang. "Carboplatin-Induced Thrombocytopenia through JAK2 Downregulation, S-Phase Cell Cycle Arrest, and Apoptosis in Megakaryocytes." International Journal of Molecular Sciences 23, no. 11 (June 3, 2022): 6290. http://dx.doi.org/10.3390/ijms23116290.
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Chemotherapy-induced thrombocytopenia (CIT) is a common complication when treating malignancies with cytotoxic agents wherein carboplatin is one of the most typical agents causing CIT. Janus kinase 2 (JAK2) is one of the critical enzymes to megakaryocyte proliferation and differentiation. However, the role of the JAK2 in CIT remains unclear. In this study, we used both carboplatin-induced CIT mice and MEG-01 cell line to examine the expression of JAK2 and signal transducer and activator of transcription 3 (STAT3) pathway. Under CIT, the expression of JAK2 was significantly reduced in vivo and in vitro. More surprisingly, the JAK2/STAT3 pathway remained inactivated even when thrombopoietin (TPO) was administered. On the other hand, carboplatin could cause prominent S phase cell cycle arrest and markedly increased apoptosis in MEG-01 cells. These results showed that the thrombopoiesis might be interfered through the downregulation of JAK2/STAT3 pathway by carboplatin in CIT, and the fact that exogenous TPO supplement cannot reactivate this pathway.
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Xu, Hong, Ya-min Zhang, Hua Sun, Su-hui Chen, and Ying-kui Si. "Electroacupuncture at GV20 and ST36 Exerts Neuroprotective Effects via the EPO-Mediated JAK2/STAT3 Pathway in Cerebral Ischemic Rats." Evidence-Based Complementary and Alternative Medicine 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/6027421.
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Background. While electroacupuncture (EA) in cerebral ischemia has been used to promote functional recovery, the underlying mechanism of its protective effect remains poorly understood.Objective. We investigated the effects of EA stimulation at GV20 and ST36 to observe the changes in erythropoietin- (EPO-) mediated Janus family tyrosine kinases 2 (JAK2) signal transducers and activators of the transcription 3 (STAT3) cell pathway.Methods. Thirty-six specific pathogen-free Sprague-Dawley (SD) male rats were randomly assigned to three groups: the sham-operated group (S group), the middle cerebral artery occlusion (MCAO) group (M group), and the EA group. Neurological deficits were assessed through the Ludmila Belayev 12-score test and 2,3,5-triphenyltetrazolium chloride (TTC) staining was shown. The protein and mRNA expression levels of EPO, the EPO receptor (EpoR), p-JAK2, JAK2, p-STAT3, and STAT3 were examined to explore the EA effect on rats with cerebral ischemic reperfusion injury (CIRI).Results. EA significantly decreased infarct size and improved neurological function. Furthermore, target EPO, EpoR, JAK2, and STAT3 mRNA and protein levels significantly increased in the EA group.Conclusions. EA exerts a neuroprotective effect, possibly via the regulation of the EPO-mediated JAK2/STAT3 cell pathway and downstream apoptotic pathways in a rat CIRI model.
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Alanazi, Ahmed Z., and Michelle A. Clark. "Angiotensin III Induces JAK2/STAT3 Leading to IL-6 Production in Rat Vascular Smooth Muscle Cells." International Journal of Molecular Sciences 20, no. 22 (November 7, 2019): 5551. http://dx.doi.org/10.3390/ijms20225551.
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The Janus kinase-2/ signal transducer and activators of transcription-3 (JAK2/STAT3) pathway and interleukin-6 (IL-6) are pleiotropic signal transduction systems that are responsible for induction of many cytokines and growth factors. It is unknown whether the renin angiotensin aldosterone system (RAAS) peptide, angiotensin (Ang) III induces JAK2/STAT3 and IL-6 in vascular smooth muscle cells (VSMCs). Thus, the purpose of this study was to investigate whether Ang III induces the JAK2/STAT3 pathway leading to IL-6 production in cultured VSMCs isolated from Wistar rats and determine whether differences exist in spontaneously hypertensive rat (SHR) VSMCs. We gauged Ang III’s effects on this pathway by measuring its action on STAT3 as well as IL-6 production. Ang III behaved similarly as Ang II in stimulation of STAT3 phosphorylation in Wistar and SHR VSMCs. Moreover, there were no differences in this Ang III effect in SHR versus Wistar VSMCs. In Wistar VSMCs, Ang II and Ang III significantly induced IL-6 protein secretion and mRNA expression. However, IL-6 protein secretions mediated by these peptides were significantly greater in SHR VSMCs. Ang III induced the JAK2/STAT3 pathway, leading to IL-6 protein secretion and IL-6 mRNA expression via actions on AT1Rs. Moreover, the actions of Ang III to induce IL-6 production was dysregulated in SHR VSMCs. These findings suggest that Ang III acts on AT1Rs to induce JAK2/STAT3, leading to an increase in IL-6 in cultured VSMCs. These findings are important in establishing Ang III as an important physiologically relevant peptide in VSMCs.
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Zhang, Zuo, Hongli Zhou, and Jiyin Zhou. "Neuritin inhibits astrogliosis to ameliorate diabetic cognitive dysfunction." Journal of Molecular Endocrinology 66, no. 4 (May 1, 2021): 259–72. http://dx.doi.org/10.1530/jme-20-0321.
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Earlier, it was shown that reversing the downregulation of neuritin expression in the brain improves central neuropathy in diabetic rats. We investigated the protective mechanism of neuritin in diabetic cognitive dysfunction via astrocytes. Further, the impact of the overexpression of neuritin in the cortex and the hippocampus on diabetic cognitive dysfunction and astrogliosis in type 2 diabetic (db/db) mice was assessed. Antagonists were used to inhibit the JAK2/STAT3 signaling pathway in U-118MG, an astrocyte cell line. Immunofluorescence, Western blotting, and real-time PCR were performed. Neuritin overexpression in the hippocampus of db/db mice significantly ameliorated cognitive dysfunction, hippocampal neuronal impairment, and synaptic plasticity deterioration, and inhibited astrogliosis and the JAK2/STAT3 signaling pathway in the hippocampus. Neuritin suppressed the JAK2/STAT3 signaling pathway to inhibit lipopolysaccharide-induced gliosis in U-118MG cells. It was observed that neuritin regulates the JAK2/STAT3 signaling pathway in astrocytes to inhibit astrogliosis and improve diabetic cognitive dysfunction.
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Ji, Hongyun, Hui Lu, Feng Li, Ying Qu, Qing Hu, and Xiaoran Li. "MiR-189 Exerts Anticancer Activity Through Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) Pathway in Non-Small Cell Lung Cancer." Journal of Biomaterials and Tissue Engineering 11, no. 12 (December 1, 2021): 2421–26. http://dx.doi.org/10.1166/jbt.2021.2846.
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Non-small cell lung cancer (NSCLC) remains a threat to human health but its etiology remains unclear. MicroRNAs (miRNAs) are involved in NSCLC progression. This study aims to elucidate the mechanism by how exosomal miR-189 functions in NSCLC. After identification, BMSCs were co-cultured with NSCLC cells which were then transfected with miR-189 mimics followed by analysis of the expression of JAK2/Stat3 proteins and miR-189, cell migration and invasion by Transwell assay, cell viability by MTT assay, apoptosis by flow cytometry. miR-189 is downregulated in NSCLC cells and tissues. miR-189 overexpression inhibited the phosphorylation of JAK2/Stat3 and suppressed malignant characteristics of cancer cells and induced apoptosis. Co-culture with BMSCs and NSCLC cells elevated miR-189 level and inactivated JAK2/STAT3 signaling, thereby suppressing malignant characteristics of cancer cells. In conclusion, BMSCs carrying miR-189 restrain NSCLC progression by blocking JAK2/STAT3 signaling, which may help development of gene therapy for NSCLC.
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Auer, Franziska, Minhui Lin, Karin Nebral, Christoph G. W. Gertzen, Oskar A. Haas, Michaela Kuhlen, Holger Gohlke, et al. "Novel Recurrent Germline JAK2 G571S Variant in Childhood Acute B-Lymphoblastic Leukemia: A Double Hit One Pathway Scenario." Blood 132, Supplement 1 (November 29, 2018): 387. http://dx.doi.org/10.1182/blood-2018-99-115293.
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Abstract Introduction: Current studies demonstrate an involvement of germline predispositions in the development of approximately 5% of childhood leukemias (Zhang J et al.,N Engl J Med, 2015), although their actual contribution is believed to be much higher. Being able to understand tumor evolution starting from a predisposed cell, opens up a new avenue in the form of disease prevention rather than treatment. Here, we present a novel finding of a double hit - one pathway scenario, in which a rare (MAF<0.01) germline JAK2 variant (G571S), inherited paternally, and a newly described germline STAT3 variant (K370R), transmitted from the mother's side, act synergistically to induce Ph-like B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods: WES was carried out to identify predisposing germline variants. The cooperative functionality of the di-genic candidate mutations was experimentally tested using BaF3 oncogenic transformation assays, western blot and cell cycle analyses. In addition, we used structural homology calculations to visualize the cooperative impact of both mutations. Results: Utilizing Trio-calling based on WES we identified two concomitant germline SNVs in the JAK2/STAT3 pathway in a boy affected with BCP-ALL. The JAK2 variant, rs139504737, leads to an amino acid substitution from Glycine to Serine (p.G571S) (MAF<0.01). The second variant constitutes an extremely rare and so far for leukemia undescribed missense mutation in the STAT3 gene (c.1109A>G), causing an exchange of Lysine to Arginine (p.K370R). Structural modeling of STAT3 K370R showed that K370, which is an important site for acetylation, is located in a loop adjacent to the DNA binding site of STAT3. The substitution of Lys to Arg at position 370 leads to a strengthening of the beta-sheet due to simultaneous interaction of Arg with both E455 and E442. Moreover, in contrast to Lys, Arg cannot be acetylated, leading to a constitutively non-acetylated form of STAT3. JAK2 G571S on the other hand has a unique position affecting amino acid 571, which lies adjacent to the Y570 residue that downregulates kinase activity via autophosphorylation, indicating a potential functional mechanism of the G571S mutation by inhibiting Y570-directed negative feedback. To assess the cooperative oncogenic transforming potential of both variants, BaF3 depletion assays were carried out. In BaF3/CRLF2-IL-7Rwt cells, JAK2 G571S conferred IL-3 independent growth at similar rates as the well-known oncogenic JAK2 V617F mutation. Moreover, the combination of both JAK2 G571S and STAT3 K370R further increased the growth advantage significantly starting 2 days after IL-3 withdrawal (p=0.0226). Western Blot analyses revealed increased pSTAT5 levels, as well as high pSTAT-3 levels in the double mutant cells. We further observed that STAT3 K370R alone changed the phenotype of the in-vitro culture, with an accumulation of enlarged BaF3 cells. Surprisingly, this phenotype was reversed in cells expressing both STAT3 K370R and JAK2 G571S. Cell cycle analysis showed a significant increase of aneuploid cells (G2/M) (p=0.0009), while the G-1 phase was significantly decreased (p=0.0031) in STAT3 K370R expressing BaF3 cells compared to STAT3 WT cells. Again, this phenotype was drastically reduced in cells transfected with both mutations simultaneously (G1 phase p=0.0026; G2/M p=0.0032). Western Blot analyses confirmed increased p-CDC-2, p-Cyclin/Cyclin-B1, and Cyclin-A2 levels in BaF3 cells harboring both variants, suggesting that the cell cycle arrest observed in cells expressing STAT3 K370R is rescued by JAK2 G571S expression by enabling re-entering of the M-Phase. The link between the oncogenic capacity of JAK2 G571S and leukemia could further be strengthened by the identification of an additional B-precursor ALL patient from an independent family harboring the same JAK2 G571S germline mutation. The patient belongs to a previously described DS-ALL cohort (Bercovich D. et al., Lancet, 2008). In this patient with Down syndrome, we did neither identify the STAT3 K370R mutation nor CRLF2 activation. Thus, we hypothesize that the germline JAK2 G571S in combination with the constitutional trisomy 21 act in synergy. Conclusion: Taken together, we present evidence of an oncogenic potential of germline JAK2 G571S, which is significantly increased through additional expression of STAT3 K370R in a double-hit one-pathway scenario. Disclosures No relevant conflicts of interest to declare.
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Wu, Jianjiang, Jin Yu, Peng Xie, Yiliyaer Maimaitili, Jiang Wang, Long Yang, Haiping Ma, Xing Zhang, Yining Yang, and Hong Zheng. "Sevoflurane postconditioning protects the myocardium against ischemia/reperfusion injury via activation of the JAK2–STAT3 pathway." PeerJ 5 (April 4, 2017): e3196. http://dx.doi.org/10.7717/peerj.3196.
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BackgroundSevoflurane postconditioning (S-post) has similar cardioprotective effects as ischemic preconditioning. However, the underlying mechanism of S-post has not been fully elucidated. Janus kinase signaling transduction/transcription activator (JAK2–STAT3) plays an important role in cardioprotection. The purpose of this study was to determine whether the cardioprotective effects of S-post are associated with activation of the JAK2–STAT3 signal pathway.MethodsAn adult male Sprague–Dawley (SD) rat model of myocardial ischemia/reperfusion (I/R) injury was established using the Langendorff isolated heart perfusion apparatus. At the beginning of reperfusion, 2.4% sevoflurane alone or in combination with AG490 (a JAK2 selective inhibitor) was used as a postconditioning treatment. The cardiac function indicators, myocardial infarct size, lactic dehydrogenase (LDH) release, mitochondrial ultrastructure, mitochondrial reactive oxygen species (ROS) generation rates, ATP content, protein expression of p-JAK, p-STAT3, Bcl-2 and Bax were measured.ResultsCompared with the I/R group, S-post significantly increased the expression of p-JAK, p-STAT3 and Bcl-2 and reduced the protein expression of Bax, which markedly decreased the myocardial infarction areas, improved the cardiac function indicators and the mitochondrial ultrastructure, decreased the mitochondrial ROS and increased the ATP content. However, the cardioprotective effects of S-post were abolished by treatment with a JAK2 selective inhibitor (p< 0.05).ConclusionThis study demonstrates that the cardioprotective effects of S-post are associated with the activation of JAK2–STAT3. The mechanism may be related to an increased expression of p-JAK2 and p-STAT3 after S-post, which reduced mitochondrial ROS generation and increased mitochondrial ATP content, thereby reducing apoptosis and myocardial infarct size.
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Kim, Ji-Hyang, Hack Sun Choi, Su-Lim Kim, and Dong-Sun Lee. "The PAK1-Stat3 Signaling Pathway Activates IL-6 Gene Transcription and Human Breast Cancer Stem Cell Formation." Cancers 11, no. 10 (October 10, 2019): 1527. http://dx.doi.org/10.3390/cancers11101527.
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Cancer stem cells (CSCs) have unique properties, including self-renewal, differentiation, and chemoresistance. In this study, we found that p21-activated kinase (PAK1) inhibitor (Group I, PAK inhibitor, IPA-3) and inactivator (ivermectin) treatments inhibit cell proliferation and that tumor growth of PAK1-knockout cells in a mouse model is significantly reduced. IPA-3 and ivermectin inhibit CSC formation. PAK1 physically interacts with Janus Kinase 2 (JAK2), and JAK2 inhibitor (TG101209) treatment inhibits mammosphere formation and reduces the nuclear PAK1 protein level. PAK1 interacts with signal transducer and activator of transcription 3 (Stat3), and PAK1 and Stat3 colocalize in the nucleus. We show through electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and reporter assays that the PAK1/Stat3 complex binds to the IL-6 promoter and regulates the transcription of the IL-6 gene. Inhibition of PAK1 and JAK2 in mammospheres reduces the nuclear pStat3 and extracellular IL-6 levels. PAK1 inactivation inhibits CSC formation by decreasing pStat3 and extracellular IL-6 levels. Our results reveal that JAK2/PAK1 dysregulation inhibits the Stat3 signaling pathway and CSC formation, the PAK1/Stat3 complex regulates IL-6 gene expression, PAK1/Stat3 signaling regulates CSC formation, and PAK1 may be an important target for treating breast cancer.
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Lee, Jennifer K., Jung-Heun Ha, Do-Kyun Kim, JaeHee Kwon, Young-Eun Cho, and In-Sook Kwun. "Depletion of Zinc Causes Osteoblast Apoptosis with Elevation of Leptin Secretion and Phosphorylation of JAK2/STAT3." Nutrients 15, no. 1 (December 23, 2022): 77. http://dx.doi.org/10.3390/nu15010077.
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Zinc (Zn) has been reported to mediate leptin secretion, and thus leptin can be an important candidate molecule linking Zn with bone formation. The present study investigated whether zinc deficiency induces leptin secretion by activating a JAK2/STAT3 signaling pathway and leads to osteoblastic apoptosis. MC3T3-E1 cells were incubated for 24 h in normal osteogenic differentiation medium (OSM) or OSM treated with either 1 μM (Low Zn) or 15 μM (High Zn) of ZnCl2 containing 5 μM TPEN (Zn chelator). Our results demonstrated that low Zn stimulated extracellular leptin secretion and increased mRNA and protein expression of leptin in osteoblastic MC3T3-E1 cells. The OB-Rb (long isoform of leptin receptor) expressions were also elevated in osteoblasts under depletion of Zn. Leptin-signaling proteins, JAK2 and p-JAK2 in the cytosol of low Zn osteoblast conveyed leptin signaling, which ultimately induced higher p-STAT3 expression in the nucleus. Apoptotic effects of JAK2/STAT3 pathway were shown by increased caspase-3 in low Zn osteoblasts as well as apoptotic morphological features observed by TEM. Together, these data suggest that low Zn modulates leptin secretion by activating JAK2/STAT3 signaling pathway and induces apoptosis of osteoblastic MC3T3-E1 cells.
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Li, Xiangzi, Liangtong Li, Xuanchen Liu, Jiawen Wu, Xiaoyu Sun, Zhilin Li, Yong-Jian Geng, Fulin Liu, and Yujuan Zhou. "Attenuation of Cardiac Ischaemia-reperfusion Injury by Treatment with Hydrogen-rich Water." Current Molecular Medicine 19, no. 4 (June 10, 2019): 294–302. http://dx.doi.org/10.2174/1566524019666190321113544.
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Background: Hydrogen has been shown to exert a bioactive effect on the myocardium. This study examined the signalling pathways for hydrogen attenuating ischaemia-reperfusion injury. Methods: In total, 20 male Wistar rats were evaluated for the effects of hydrogen-rich water on ischaemia-reperfusion in hearts. Left ventricular tissue was taken for screening and analysis of active protein factors by protein chip technology. The enrichment of the KEGG pathway was obtained by using the Gene Ontology (GO) enrichment principle. The expression of JAK2, STAT1, STAT3, p-STAT1, p-JAK2, p-STAT3 in rat myocardium was detected by Western blot analysis and immunohistochemistry. The apoptosis rates of the control and hydrogen-rich water groups were detected by TUNEL staining. Results: The expression levels of 25 proteins, including five transduction pathways, were downregulated in the hydrogen-rich water group. The expression levels of p- JAK2/JAK2, p-STAT3/STAT3 were upregulated in the hydrogen-rich water group compared with the control group, and p-STAT1/STAT1 was downregulated in the hydrogen-rich water group compared with the control group. Furthermore, the apoptosis rate was significantly decreased in the hydrogen-rich water group, as well. Conclusion: Hydrogen-rich water may inhibit the apoptosis of cardiomyocytes after ischaemia-reperfusion by upregulating the expression of the JAK2-STAT3 signalling pathway, which reduces ischaemia-reperfusion injury.
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Sun, Yueyue, Huan Tong, Lingyu Zeng, Kailin Xu, and Jianlin Qiao. "Notch1 Regulates Hepatic Thrombopoietin Production." Blood 142, Supplement 1 (November 28, 2023): 281. http://dx.doi.org/10.1182/blood-2023-177812.
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Notch signaling is highly conserved and regulates cell-fate decisions in several developmental processes and cell functions. However, a role for Notch in hepatic thrombopoietin (TPO) production has not been described. We noted that mice with a deficiency in hepatic Notch1 had thrombocytopenia, and so investigated TPO production and other features of platelets in these mice. We found that the liver ultrastructure and hepatocyte function were comparable between control mice and Notch1-deficient mice. However, the Notch1-deficient mice had significantly lower plasma TPO and hepatic TPO mRNA levels, concomitant with lower numbers of circulating platelets and impaired megakaryocyte differentiation and maturation. Addition of exogenous TPO rescued megakaryocyte maturation and circulating platelet numbers. Additionally, JAK2/STAT3 phosphorylation was significantly inhibited in Notch1-deficient hepatocytes. RNA-seq analysis showed significantly reduced JAK-STAT signaling. JAK2/STAT3 phosphorylation and TPO production was also impaired in purified cultured Notch1-deficient hepatocytes after treatment with desialylated platelets. Interestingly, Notch1 deficiency downregulated the expression of HES5 but not HES1. Moreover, desialylated platelets promoted the binding of HES5 to JAK2/STAT3, leading to JAK2/STAT3 phosphorylation and pathway activation. Furthermore, blockage of Dll4 on desialylated platelets inhibited hepatocyte Notch1 activation and HES5 expression, JAK2/STAT3 phosphorylation and subsequent TPO production. In conclusion, our study identifies a novel regulatory role of Notch1 in hepatic TPO production, indicating that it might be a target for modulating TPO level.
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Wulansari, Noviana, Yanuar Alan Sulistio, Wahyu Handoko Wibowo Darsono, Chang-Hoon Kim, and Sang-Hun Lee. "LIF maintains mouse embryonic stem cells pluripotency by modulating TET1 and JMJD2 activity in a JAK2-dependent manner." Stem Cells 39, no. 6 (February 11, 2021): 750–60. http://dx.doi.org/10.1002/stem.3345.
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Abstract The LIF-JAK2-STAT3 pathway is the central signal transducer that maintains undifferentiated mouse embryonic stem cells (mESCs), which is achieved by the recruitment of activated STAT3 to the master pluripotency genes and activation of the gene transcriptions. It remains unclear, however, how the epigenetic status required for the master gene transcriptions is built into LIF-treated mESC cultures. In this study, Jak2, but not Stat3, in the LIF canonical pathway, establishes an open epigenetic status in the pluripotency gene promoter regions. Upon LIF activation, cytosolic JAK2 was translocalized into the nucleus of mESCs, and reduced DNA methylation (5mC levels) along with increasing DNA hydroxymethylation (5hmC) in the pluripotent gene (Nanog/Pou5f1) promoter regions. In addition, the repressive histone codes H3K9m3/H3K27m3 were reduced by JAK2. Activated JAK2 directly interacted with the core epigenetic enzymes TET1 and JMJD2, modulating its activity and promotes the DNA and histone demethylation, respectively. The JAK2 effects were attained by tyrosine phosphorylation on the epigenetic enzymes. The effects of JAK2 phosphorylation on the enzymes were diverse, but all were merged to the epigenetic signatures associated with open DNA/chromatin structures. Taken together, these results reveal a previously unrecognized epigenetic regulatory role of JAK2 as an important mediator of mESC maintenance.
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Chatterjee, Prodyot K., Yousef Al-Abed, Barbara Sherry, and Christine N. Metz. "Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation." American Journal of Physiology-Cell Physiology 297, no. 5 (November 2009): C1294—C1306. http://dx.doi.org/10.1152/ajpcell.00160.2009.
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The cholinergic anti-inflammatory pathway is a physiological mechanism that inhibits cytokine production and minimizes tissue injury during inflammation. Previous investigations revealed that cholinergic stimulation (via cholinergic agonists and vagus nerve stimulation) suppresses endothelial cell activation and leukocyte recruitment. The purpose of this study was to investigate the mechanisms by which cholinergic agonists (e.g., nicotine and GTS-21) regulate endothelial cell activation. Specifically, we examined the effects of cholinergic agonists on IL-6-mediated endothelial cell activation through the JAK2/STAT3 signaling pathway. Treatment of macrovascular human umbilical vein endothelial cells (HUVECs) and microvascular endothelial cells (MVECs) with the cholinergic agonists nicotine and GTS-21 significantly reduced IL-6-mediated monocyte chemoattractant protein-1 (MCP-1) production and ICAM-1 expression which are regulated through the JAK2/STAT3 pathway. We found that treatment of endothelial cells with cholinergic agonists significantly reduced STAT3 activation by phosphorylation and DNA binding. The inhibition of STAT3 phosphorylation was reversed by sodium orthovanadate, an inhibitor of tyrosine phosphatases, as well as by NSC-87877 suggesting a SHP1/2-dependent mechanism. Further investigations showed that cholinergic agonists reduced the phosphorylation of JAK2, an upstream component of the JAK2/STAT3 pathway. Finally, we observed that nicotine and GTS-21 treatment decreased levels of SOCS3 (suppressor of cytokine signaling; a regulator of the inflammatory activity of IL-6) in activated endothelial cells. These data demonstrate that cholinergic agonists suppress IL-6-mediated endothelial cell activation through the JAK2/STAT3 pathway. Our results have significant implications for better understanding the therapeutic potential of cholinergic agonists for treating IL-6 mediated inflammatory conditions.
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Severin, Frezzato, Visentin, Martini, Trimarco, Carraro, Tibaldi, et al. "In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment." Cancers 11, no. 12 (December 4, 2019): 1939. http://dx.doi.org/10.3390/cancers11121939.
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The bone marrow microenvironment promotes proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Although ibrutinib is active in CLL, it is rarely able to clear leukemic cells protected by bone marrow mesenchymal stromal cells (BMSCs) within the marrow niche. We investigated the modulation of JAK2/STAT3 pathway in CLL by BMSCs and its targeting with AG490 (JAK2 inhibitor) or Stattic (STAT3 inhibitor). B cells collected from controls and CLL patients, were treated with medium alone, ibrutinib, JAK/Signal Transducer and Activator of Transcription (STAT) inhibitors, or both drugs, in the presence of absence of BMSCs. JAK2/STAT3 axis was evaluated by western blotting, flow cytometry, and confocal microscopy. We demonstrated that STAT3 was phosphorylated in Tyr705 in the majority of CLL patients at basal condition, and increased following co-cultures with BMSCs or IL-6. Treatment with AG490, but not Stattic, caused STAT3 and Lyn dephosphorylation, through re-activation of SHP-1, and triggered CLL apoptosis even when leukemic cells were cultured on BMSC layers. Moreover, while BMSCs hamper ibrutinib activity, the combination of ibrutinib+JAK/STAT inhibitors increase ibrutinib-mediated leukemic cell death, bypassing the pro-survival stimuli derived from BMSCs. We herein provide evidence that JAK2/STAT3 signaling might play a key role in the regulation of CLL-BMSC interactions and its inhibition enhances ibrutinib, counteracting the bone marrow niche.
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Ni, Chih-Wen, Hsyue-Jen Hsieh, Yuen-Jen Chao, and Danny Ling Wang. "Interleukin-6-induced JAK2/STAT3 signaling pathway in endothelial cells is suppressed by hemodynamic flow." American Journal of Physiology-Cell Physiology 287, no. 3 (September 2004): C771—C780. http://dx.doi.org/10.1152/ajpcell.00532.2003.
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Endothelial cells (ECs) are constantly exposed to shear stress, the action of which triggers signaling pathways and cellular responses. During inflammation, cytokines such as IL-6 increase in plasma. In this study, we examined the effects of steady flow on IL-6-induced endothelial responses. ECs exposed to IL-6 exhibited STAT3 activation via phosphorylation of Tyr705. However, when ECs were subjected to shear stress, shear force-dependent suppression of IL-6-induced STAT3 phosphorylation was observed. IL-6 treatment increased the phosphorylation of JAK2, an upstream activator of STAT3. Consistently, shear stress significantly reduced IL-6-induced JAK2 activation. Pretreatment of ECs with an inhibitor of MEK1 did not alter this suppression by shear stress, indicating that extracellular signal-regulated kinase (ERK1/2) was not involved. However, pretreatment of ECs with an endothelial nitric oxide synthase inhibitor (nitro-l-arginine methyl ester) attenuated this inhibitory effect of shear stress on STAT3 phosphorylation. Shear stress-treated ECs displayed decreased nuclear transmigration of STAT3 and reduced STAT3 binding to DNA. Intriguingly, ECs exposed to IL-6 entered the cell cycle, as evidenced by increasing G2/M phase, and shear stress to these ECs significantly reduced IL-6-induced cell cycle progression. STAT3-mediated IL-6-induced cell cycle was confirmed by the inhibition of the cell cycle in ECs infected with adenovirus carrying the inactive mutant of STAT3. Our study clearly shows that shear stress exerts its inhibitory regulation by suppressing the IL-6-induced JAK2/STAT3 signaling pathway and thus inhibits IL-6-induced EC proliferation. This shear force-dependent inhibition of IL-6-induced JAK2/STAT3 activation provides new insights into the vasoprotective effects of steady flow on ECs against cytokine-induced responses.
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Zhang, Le, Bing-Hui Wu, Ting-Ting Liang, Zhe Liu, Wei Ju, Yi Wang, Yu-Ting Wen, Ming-Cui Liu, and Jun-Hui Du. "Leptin activates the JAK/STAT pathway to promote angiogenesis in RF/6A cells in vitro." International Journal of Ophthalmology 15, no. 4 (April 18, 2022): 554–59. http://dx.doi.org/10.18240/ijo.2022.04.05.
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AIM: To investigate the effect of leptin on the angiogenesis of RF/6A cells (monkey retinal choroidal endothelial cells) in vitro and test the cellular signaling in the mechanism. METHODS: RF/6A cells were cultured in vitro and randomly divided into four groups: normal control, with leptin at 50, 100, 200 ng/mL for cell counting kit-8 (CCK8). RF/6A cell proliferation and migration were examined by Transwell assays, while RF/6A cell tube formation by Matrigel assay. JAK2, p-JAK2, STAT3, and p-STAT3 protein expression was measured by Western blotting. Cells were then divided into the following treatment groups: control, 100 ng/mL leptin and AG-490 (100 ng/mL leptin+10 μmol/L AG-490) for examinations of RF/6A cellular behaviour again. Analysis of differences was carried out using one-way ANOVA and least significant difference (LSD). RESULTS: RF/6A cell proliferation, migration and cell tube formation were promoted significantly by leptin in a dose-dependent manner (P<0.05). Western blotting showed that leptin up-regulated p-JAK2 and p-STAT3 expression levels. Treatment with the JAK/STAT pathway inhibitor, AG-490, decreased leptin-induced p-JAK2 and p-STAT3 expression, and inhibited cell proliferation, migration and cell tube formation induced by leptin (P<0.05). CONCLUSION: Leptin can promote RF/6A cell angiogenesis in vitro via activation of the JAK2/STAT3 signaling pathway.
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Yu, Yechen, Xu Wang, Fan Yang, Ke Xing, Lihong Ren, and Guangfei Xu. "Effect of Jiawei Tangzhiqing granules on JAK2/STAT3 signal pathway and Th17/Treg ratio in diabetic nephropathy mice." Tropical Journal of Pharmaceutical Research 23, no. 2 (March 12, 2024): 279–89. http://dx.doi.org/10.4314/tjpr.v23i2.7.
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Purpose: To investigate the effect of Jiawei Tangzhiqing granules on JAK2/STAT3 signaling pathway and Th17/Treg ratio in diabetic nephropathy (DN) mice.
Methods: Selected 60 male SPF C57BL/6N mice, divided into control group and DN model group; the latter was further further split into model control, Western medicine group, and three Jiawei Tangzhiqing granule groups (high, medium, and low doses). Treatments were administered orally for 12 weeks. Key health indicators and renal tissue pathology were analyzed. Th17 and Treg levels in CD4+ T cells were quantified, and JAK2 and STAT3 protein expression in renal tissues was determined via Western blot.
Results: Model group showed a significant decrease in body weight and increases in 24-h urine volume, food, and water consumption compared to the control group. Th17 cell count increased, and Treg cell count decreased, leading to a higher Th17: Treg ratio. Conversely, Jiawei Tangzhiqing granules reduced this effect dose-dependently, with the highest dose being more effective than irbesartan. JAK2 and STAT3 protein expressions, elevated in model group, were significantly reduced in the granule-treated groups.
Conclusion: Jiawei Tangzhiqing granules alleviate renal damage in DN by suppressing JAK2/STAT3 signaling pathway and correcting the Th17: Treg ratio imbalance. These findings suggest a potential therapeutic role for these granules in managing DN. There is a need to find out if there is a correlation between Th17/Treg balance and JAK2/STAT3 signaling pathway.
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Xu, Yefang, Jingjing Zhang, Jing Wu, Sheng Zhong, and Hongxia Li. "Inhibition of JAK2 Reverses Paclitaxel Resistance in Human Ovarian Cancer Cells." International Journal of Gynecologic Cancer 25, no. 9 (November 2015): 1557–64. http://dx.doi.org/10.1097/igc.0000000000000550.
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ObjectiveResistance to chemotherapy is a major factor that limits the postsurgical survival of ovarian cancer patients. Janus-activated kinase 2 (JAK2) has been implicated in cancer cell survival and the development of drug resistance in ovarian cancers. In the present study, we sought to determine whether inhibition of JAK2 reverses drug resistance in OC3/TAX300 cells, a paclitaxel-resistant human ovarian cancer cell line previously established in our laboratory.MethodsOC3/TAX300 cells were transduced with lentivirus expressing small interference RNA (siRNA) against JAK2 and treated with JAK2 kinase inhibitor AG490.ResultsTreatment with JAK2-siRNA markedly decreased the messenger RNA and protein of JAK2 as determined by real-time polymerase chain reaction and Western blot analysis. OC3/TAX300 cells treated with JAK2-siRNA exhibited stalled growth, increased cell cycle arrest in G2/M phase, and enhanced apoptosis in response to paclitaxel. In keeping with this, JAK2-siRNA also inhibited the expression of multidrug resistance protein 1. To determine whether JAK2 promotes paclitaxel resistance via phosphorylation of signal transducer and activator of transcription 3 (STAT3), a transcription factor known to be involved in resistance to chemotherapy, we treated OC3/TAX300 cells with JAK2 kinase inhibitor AG490. Of note, AG490 reduced the level of p-STAT3 and inhibited the expression of multidrug resistance protein 1 in a dose-dependent manner.ConclusionsCollectively, we conclude that the JAK2-STAT3 pathway promotes the development of paclitaxel resistance via upregulating the expression of prosurvival and antiapoptotic genes. Targeting this pathway may be effective in reversing resistance to chemotherapy in ovarian cancers.
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Mellado, M., J. M. Rodríguez-Frade, A. Aragay, G. del Real, A. M. Martín, A. J. Vila-Coro, A. Serrano, F. Mayor, and C. Martínez-A. "The Chemokine Monocyte Chemotactic Protein 1 Triggers Janus Kinase 2 Activation and Tyrosine Phosphorylation of the CCR2B Receptor." Journal of Immunology 161, no. 2 (July 15, 1998): 805–13. http://dx.doi.org/10.4049/jimmunol.161.2.805.
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Abstract The chemokines are a growing family of low m.w., 70- to 80-residue proinflammatory cytokines that operate by interacting with G protein-coupled receptors. Chemokines are involved in cell migration and in the activation of specific leukocyte subsets. Using the Mono Mac 1 monocytic cell line, we show that monocyte chemotactic protein 1 (MCP-1) triggers activation of the Janus kinase 2 (JAK2)/STAT3 pathway and CCR2 receptor tyrosine phosphorylation. Both Ca2+ mobilization and cell migration are blocked in Mono Mac 1 cells by tyrphostin B42, a specific JAK2 kinase inhibitor. Within seconds of MCP-1 activation, JAK2 phosphorylates CCR2 at the Tyr139 position and promotes JAK2/STAT3 complex association to the receptor. This MCP-1-initiated phosphorylation and association to JAK2 is also observed in CCR2B-transfected HEK293 cells. In contrast, when a CCR2B Tyr139Phe mutant is expressed in HEK293 cells, it is not phosphorylated in tyrosine and triggers neither JAK2/STAT3 activation nor Ca2+ mobilization in response to MCP-1. These results implicate the tyrosine kinase pathway in early chemokine signaling, suggesting a key role for this kinase in later events.
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Regua, Angelina T., Dongqin Zhu, Daniel L. Doheny, Grace L. Wong, Sara G. Manore, Calvin J. Wagner, Austin Arrigo, Mariana Najjar, and Hui-Wen Lo. "Abstract 1039: TrkA and JAK2-STAT3 pathway crosstalk promotes breast cancer stem cells in HER2-enriched and triple-negative breast cancers." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1039. http://dx.doi.org/10.1158/1538-7445.am2022-1039.
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Abstract Breast cancer is the most commonly diagnosed cancer in American women and accounts for ~15% of cancer-related deaths. Despite the current standard of care, metastatic HER2-enriched breast cancer and triple-negative breast cancer remain difficult to treat due to poor response to treatment, lack of actionable targets, or eventual acquired resistance. The high mortality rate of metastatic HER2-enriched breast cancers and triple-negative breast cancers highlights the need for novel actionable targets for improved response to therapeutic intervention. Through datamining of publicly available breast cancer patient datasets, we recently found that Tropomyosin receptor kinase A (TrkA) and Janus kinase 2 (JAK2)-STAT3 pathways are co-activated and co-enriched in HER2-enriched breast cancers and triple-negative breast cancers (Cancers 10:2340-2360, 2021). We also found that TrkA, a receptor tyrosine kinase, directly interacts with and phosphorylates STAT3 on Y705 residue, resulting in STAT3 activation, nuclear translocation, and increased transcription of STAT3 target genes SOX2 and c-MYC, which are associated with breast cancer stem cell formation as well as tumor recurrence and metastasis. In this study, we aimed to further characterize the effects of the TrkA-JAK2/STAT3 pathway crosstalk on breast cancer stem cells. Our data showed that overexpression of TrkA enhances mammosphere formation and ALDH activity of breast cancer cells, which are further enhanced upon co-overexpression of STAT3. Our study further revealed that TrkA and JAK2 inhibitors synergize to reduce breast cancer stemness since co-inhibition of TrkA and JAK2 significantly reduces the CD44high/CD24low cell subpopulation, mammosphere formation, and ALDH activity to a greater extent compared to vehicle or monotherapies. Western blot analysis of breast cancer cells treated with TrkA and/or JAK2 inhibitors showed that co-inhibition of these two kinases significantly reduces levels of p-STAT3 (Y705), as well as stemness markers SOX2, MYC, and CD44. Taken together, these findings suggest that TrkA cooperates with the JAK2-STAT3 signaling pathway to promote breast cancer stem cells through increasing expression of SOX2, c-MYC, and CD44, and that co-inhibition of TrkA and JAK2 significantly suppressed breast cancer stemness, suggesting its future utility as a promising new treatment modality for patients with HER2-enriched breast cancers and triple-negative breast cancers. Citation Format: Angelina T. Regua, Dongqin Zhu, Daniel L. Doheny, Grace L. Wong, Sara G. Manore, Calvin J. Wagner, Austin Arrigo, Mariana Najjar, Hui-Wen Lo. TrkA and JAK2-STAT3 pathway crosstalk promotes breast cancer stem cells in HER2-enriched and triple-negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1039.
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Bao, Yan, Wei Liang, Yingchun Ye, and Bo Yi. "PERK-Dependent Activation of the JAK2/STAT3 Pathway Contributes to High Glucose-Induced Extracellular Matrix Deposition in Renal Tubular Epithelial Cells." International Journal of Endocrinology 2021 (July 19, 2021): 1–9. http://dx.doi.org/10.1155/2021/8475868.
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Background. Although the deposition of extracellular matrix (ECM) is critical leading to tubular damage in diabetic kidney disease (DKD), the mechanism still remains unclear. The purpose of this study was to demonstrate a role for protein kinase R-like endoplasmic reticulum kinase (PERK) (a protein located in the endoplasmic reticulum membrane) in this pathologic process. Methods. NRK-52E cells were grown in the media containing different concentrations of glucose or thapsigargin for different durations. Cells were subsequently incubated with or without AG490, a selective inhibitor of Janus kinase 2 (JAK2) or GSK2606414 (a selective PERK inhibitor). We evaluated the production of TGF-β1, fibronectin, and collagen I proteins by ELISA. The levels of 78 kD-glucose-regulated protein (GRP78) and PERK, as well as the phosphorylation statues of PERK and JAK2/signal transducer and activator of transcription (STAT3), were determined by western blotting analysis. Results. We showed that the increased phosphorylation of JAK2 and STAT3 was accompanied by overexpression of TGF-β1 and ECM deposition in high glucose medium. Disruption of the JAK2/STAT3 pathway with AG490 significantly prevents the high glucose-induced increase in TGF-β1, fibronectin, and collagen I. High glucose induced the overproduction of GRP78 and phosphorylation of PERK, which indicated that endoplasmic reticulum stress (ERS) was triggered in NRK-52E cells cultured under high glucose condition. Inhibition of PERK phosphorylation with GSK2606414, however, blocked the effect of JAK2/STAT3 on the production of TGF-β1 and ECM components in NRK-52E cells. Conclusion. Our data indicated that the ECM accumulation induced by high glucose arouse via the PERK-dependent JAK2/STAT3-signaling pathway in renal tubular epithelial cells.
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Wang, Kun, Yong-Gui Wu, Jing Su, Jing-Jing Zhang, Pei Zhang, and Xiang-Ming Qi. "Total Glucosides of Paeony Regulates JAK2/STAT3 Activation and Macrophage Proliferation in Diabetic Rat Kidneys." American Journal of Chinese Medicine 40, no. 03 (January 2012): 521–36. http://dx.doi.org/10.1142/s0192415x12500401.
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Total glucosides of paeony (TGP) is the major active constituent of Paeonia lactiflora Pall., which has shown renoprotection in experimental diabetic nephropathy. Activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) is an important mechanism by which hyperglycemia contributes to renal damage. Macrophages also play an essential role in the pathogenesis of diabetic nephropathy. Herein, we investigated the ability of TGP to modulate JAK2/STAT3 activation and macrophage proliferation in rats with streptozotocin (STZ)-induced diabetes. TGP (50, 100, and 200 mg/kg) was administered orally once a day for eight weeks. Levels of p-JAK2 and p-STAT3 were determined by Western blot analysis. Immunohistochemistry and double immunohistochemistry were used to identify p-STAT3, ED-1, PCNA/ED-1, and p-STAT3/ED-1-positive (+) cells. The elevated 24-h urinary albumin excretion rate was markedly attenuated by treatment with 50, 100, and 200 mg/kg TGP. Western blot analysis showed that the significantly increased levels of p-JAK2, p-STAT3 proteins in the kidneys of diabetic rats were significantly inhibited by 50, 100, and 200 mg/kg TGP treatment. The marked accumulation and proliferation of macrophages in diabetic kidneys were significantly inhibited by TGP treatment. ED-1+/p-STAT3+ cells were significantly increased in the kidneys from the model group but were significantly inhibited by TGP treatment. These results show that TGP significantly inhibited diabetic nephropathy progression and suggest that these protective effects are associated with the ability of TGP to inhibit the JAK2/STAT3 pathway and macrophage proliferation and action.
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Proietti, Cecilia, Mariana Salatino, Cinthia Rosemblit, Romina Carnevale, Adalí Pecci, Alberto R. Kornblihtt, Alfredo A. Molinolo, et al. "Progestins Induce Transcriptional Activation of Signal Transducer and Activator of Transcription 3 (Stat3) via a Jak- and Src-Dependent Mechanism in Breast Cancer Cells." Molecular and Cellular Biology 25, no. 12 (June 15, 2005): 4826–40. http://dx.doi.org/10.1128/mcb.25.12.4826-4840.2005.
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ABSTRACT Interactions between steroid hormone receptors and signal transducer and activator of transcription (Stat)-mediated signaling pathways have already been described. In the present study, we explored the capacity of progestins to modulate Stat3 transcriptional activation in an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in BALB/c mice and in the human breast cancer cell line T47D. We found that C4HD epithelial cells, from the MPA-induced mammary tumor model, expressed Stat3 and that MPA treatment of C4HD cells up-regulated Stat3 protein expression. In addition, MPA induced rapid, nongenomic Stat3, Jak1, and Jak2 tyrosine phosphorylation in C4HD and T47D cells. MPA treatment of C4HD cells also resulted in rapid c-Src tyrosine phosphorylation. These effects were completely abolished by the progestin antagonist RU486. Abrogation of Jak1 and Jak2 activity by transient transfection of C4HD cells with dominant negative (DN) Jak1 or DN Jak2 vectors, or inhibition of Src activity by preincubation of cells with the Src family kinase inhibitor PP2, blocked the capacity of MPA to induce Stat3 phosphorylation. Treatment of C4HD cells with MPA induced Stat3 binding to DNA. In addition, MPA promoted strong Stat3 transcriptional activation in C4HD and T47D cells that was inhibited by RU486 and by blockage of Jak1, Jak2, and Src activities. To investigate the correlation between MPA-induced Stat3 activation and cell growth, C4HD cells were transiently transfected with a DN Stat3 expression vector, Stat3Y705-F, or with a constitutively activated Stat3 mutant, Stat3-C. While expression of Stat3Y705-F mutant had an inhibitory effect on MPA-induced growth of C4HD cells, transfection with the constitutively activated Stat3-C vector resulted in MPA-independent proliferation. Finally, we addressed the effect of targeting Stat3 in in vivo growth of C4HD breast tumors. Blockage of Stat3 activation by transfection of C4HD cells with the DN Stat3Y705-F expression vector significantly inhibited these cells' ability to form tumors in syngeneic mice. Our results have for the first time demonstrated that progestins are able to induce Stat3 transcriptional activation, which is in turn an obligatory requirement for progestin stimulation of both in vitro and in vivo breast cancer growth.
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Chao, Angel, Min-Jie Liao, Shun-Hua Chen, Yun-Shien Lee, Chi-Neu Tsai, Chiao-Yun Lin, and Chia-Lung Tsai. "JAK2-Mediated Phosphorylation of Stress-Induced Phosphoprotein-1 (STIP1) in Human Cells." International Journal of Molecular Sciences 23, no. 5 (February 22, 2022): 2420. http://dx.doi.org/10.3390/ijms23052420.
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Stress-induced phosphoprotein-1 (STIP1)—a heat shock protein (HSP)70/HSP90 adaptor protein—is commonly overexpressed in malignant cells, where it controls proliferation via multiple signaling pathways, including JAK2/STAT3. We have previously shown that STIP1 stabilizes the protein tyrosine kinase JAK2 in cancer cells via HSP90 binding. In this study, we demonstrate that STIP1 may act as a substrate for JAK2 and that phosphorylation of tyrosine residues 134 and 152 promoted STIP1 protein stability, induced its nuclear-cytoplasmic shuttling, and promoted its secretion into the extracellular space. We also found that JAK2-mediated STIP1 phosphorylation enhanced cell viability and increased resistance to cisplatin-induced cell death. Conversely, interference STIP1 with JAK2 interaction—attained either through site-directed mutagenesis or the use of cell-penetrating peptides—decreased JAK2 protein levels, ultimately leading to cell death. On analyzing human ovarian cancer specimens, JAK2 and STIP1 expression levels were found to be positively correlated with each other. Collectively, these results indicate that JAK2-mediated phosphorylation of STIP-1 is critical for sustaining the JAK2/STAT3 signaling pathway in cancer cells.
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Wang, MingJun, Jian Wu, Jing Cao, Erye Zhou, Yufeng Yin, Xin Chang, and Tao Cheng. "Action of Tofacitinib in a Rat Model of Synovitis." Journal of Biomaterials and Tissue Engineering 12, no. 10 (October 1, 2022): 1981–87. http://dx.doi.org/10.1166/jbt.2022.3130.
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Purpose: To evaluate effects and mechanism of tofacitinib in treatment of rheumatoid arthritis (RA) model rats. Materials and Methods: Dividing 27 rats into 3 groups: NC (normal control), Model (RA model) and Tofacitinib (RA model rats treated with tofacitinib) groups. Observation joint swelling and articular synovium pathology by HE staining, IL-1β, IL-6, IL-10 and TNF-α levels by ELISA assay, JAK2, STAT3 and NF-κB(p65) proteins by IHC and WB assay. Results: Compared with NC group, joint swelling, histopathological score IL-1β, IL-6, IL-10 and TNF-α significantly deteriorated (P < 0.001, respectively); by IHC and WB assay, JAK2, STAT3 and NF-κB(p65) proteins expression were significantly up-regulation in joint synovial tissue in model group (P < 0.001, respectively). With tofacitinib supplement, joint swelling, histopathological score IL-1β, IL-6, IL-10 and TNF-α significantly improved (P < 0.001, respectively); by IHC and WB assay, JAK2, STAT3 and NF-κB(p65) proteins expression significantly down-regulation in joint synovial tissue in Tofacitinib group (P < 0.001, respectively). Conclusion: Tofacitinib could improve RA via regulation JAK2/STAT3/NF-κB(p65) pathway in vivo study.
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Li, Rong, Juan Yue, Qi Song, and Haiyan He. "miR-375 antagonist modified ferroferric oxide nanoparticles inhibited invasion and migration of ovarian cancer cells." Materials Express 13, no. 7 (July 1, 2023): 1154–62. http://dx.doi.org/10.1166/mex.2023.2459.
Full textAbstract:
This experiment assessed the effect of miR-375 antagonist (mA) modified ferroferric oxide nanoparticles (FONPs) on ovarian cancer cells. SKOV 3 cells were assigned into blank group (normal culture SKOV 3 cells), control group (intervention with FONPs), and intervention group (mA-FONPs), followed by analysis of cell biological behaviors and expressions of Bax, Bcl-2, Caspase-3, E-cadherin, N-cadherin, Vimentin, TL-6, JAK2, and STAT3. The nanoparticles were spherical with excellent dispersion and about 77 nm. Compared with the other two groups, the intervention group showed decreased cell vitality, increased apoptosis (P <0.05). Cell number (44.63+2.37)% and migration quantity (89.75+4.01)% decreased significantly after intervention (P <0.05) along with higher levels of E cadherin, Bax, Caspase 3 activity and lower levels of Bcl-2, N-cadherin, Vimentin, IL-6, JAK2 and STAT3 (P <0.05). miR-375 targeted and inhibited the activity of JAK2/STAT3 pathway, reducing levels of IL-6, p-JAK2, and p-STAT3, up-regulating the expression of Bax and Caspase-3, reducing levels of N-cadherin and Vimentin, and finally regulating cell apoptosis and inhibiting cell migration and invasion.
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Li, Wen-Jie, and Hong Lu. "Morroniside ameliorates lipopolysaccharide-induced inflammatory damage in iris pigment epithelial cells through inhibition of TLR4/JAK2/STAT3 pathway." International Journal of Ophthalmology 16, no. 12 (December 18, 2023): 1928–34. http://dx.doi.org/10.18240/ijo.2023.12.03.
Full textAbstract:
AIM: To investigate the effect of morroniside (Mor) on lipopolysaccharide (LPS)-treated iris pigment epithelial cells (IPE). METHODS: IPE cells were induced by LPS and treated with Mor. Cell proliferation was detected by cell counting kit (CCK) -8, apoptosis was detected by flow cytometry, the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-8 were measured by enzyme-linked immunosorbent assay (ELISA) kits, and the protein expression of TLR4, JAK2, p-JAK2, STAT3, and p-STAT3 was analyzed by Western blotting. In addition, overexpression of TLR4 and Mor treatment of LPS-stimulated IPE cells were also tested for the above indices. RESULTS: Mor effectively promoted the proliferation and inhibited the apoptosis of LPS-treated IPE cells. In addition, Mor significantly reduced the levels of TNF-α, IL-6, and IL-8 and significantly inhibited the expression of TLR4, p-JAK2, and p-STAT3 in LPS-treated IPE cells. The effect of Mor on LPS-treated IPE cells was markedly attenuated after overexpression of TLR4. CONCLUSION: These findings suggest that Mor may ameliorate LPS-induced inflammatory damage and apoptosis in IPE through inhibition of TLR4/JAK2/STAT3 pathway.
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Li, Minjing, Ju Gao, Defang Li, and Yancun Yin. "CEP55 Promotes Cell Motility via JAK2–STAT3–MMPs Cascade in Hepatocellular Carcinoma." Cells 7, no. 8 (August 8, 2018): 99. http://dx.doi.org/10.3390/cells7080099.
Full textAbstract:
Hepatocellular carcinoma (HCC) is one of the most common malignancies and has a poor prognosis. Novel diagnostic or prognostic biomarkers and potential therapeutic targets for HCC are thus urgently needed. CEP55 plays a crucial role in regulating physical cytokinesis. Whether, and how, CEP55 contributes to HCC development remains unclear. Herein, we demonstrate that CEP55 is abnormally upregulated in HCC tissue, and these high levels of CEP55 are closely related to the poor prognosis of HCC patients. Knockdown of CEP55 expression significantly inhibits HCC cell migration and invasion. We also demonstrate that CEP55 physiologically interacts with JAK2 and promotes its phosphorylation; thus, it is a novel regulator of JAK2–STAT3 signaling and its target genes MMP2/9. Finally, blocking JAK2 or STAT3 blunts the stimulation of migration and invasion due to CEP55 overexpression. In summary, our results suggest that CEP55, as an oncogene, promotes HCC cell migration and invasion through regulating JAK2–STAT3–MMPs signaling.