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Jak2 inhibitor

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https://www.readbyqxmd.com/read/29043002/humanin-analogue-s14g-humanin-has-neuroprotective-effects-against-oxygen-glucose-deprivation-reoxygenation-by-reactivating-jak2-stat3-signaling-through-the-pi3k-akt-pathway
#1
Guang-Sheng Gao, Yun Li, Heng Zhai, Jing-Wen Bi, Fu-Sen Zhang, Xiao-Ying Zhang, Shao-Hua Fan
Stroke, characterized by a disruption of blood supply to the brain, is a major cause of morbidity and mortality worldwide. Although humanin, a 24-amino acid polypeptide, has been identified to have multiple neuroprotective functions, the level of humanin in plasma has been demonstrated to decrease with age, which likely limits the effects against stroke injury. A potent humanin analogue, S14G-humanin (HNG), generated by replacement of Ser14 with glycine, has been demonstrated to have 1,000-fold stronger biological activity than humanin...
October 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29042365/ruxolitinib-induced-defects-in-dna-repair-cause-sensitivity-to-parp-inhibitors-in-myeloproliferative-neoplasms
#2
Margaret Nieborowska-Skorska, Silvia Maifrede, Yashodhara Dasgupta, Katherine Sullivan, Sylwia Flis, Bac Viet Le, Martyna Solecka, Elizaveta A Belyaeva, Lucia Kubovcakova, Morgan Nawrocki, Martin Kirschner, Huaqing Zhao, Josef T Prchal, Katarzyna Piwocka, Alison R Moliterno, Mariusz Wasik, Steffen Koschmieder, Tony R Green, Radek C Skoda, Tomasz Skorski
Myeloproliferative neoplasms (MPNs) often carry JAK2(V617F), MPL(W515L), or CALR(del52) mutations. Current treatment options for MPNs include cytoreduction by hydroxyurea and JAK1/2 inhibition by ruxolitinib, both of which are not curative. We show here that cell lines expressing JAK2(V617F), MPL(W515L) or CALR(del52) accumulated reactive oxygen species-induced DNA double-strand breaks (DSBs) and were modestly sensitive to poly-ADP-ribose polymerase (PARP) inhibitors olaparib and BMN673. At the same time primary MPN cell samples from individual patients displayed a high degree of variability in the sensitivity to these drugs...
October 17, 2017: Blood
https://www.readbyqxmd.com/read/29039526/promoting-effects-of-il%C3%A2-23-on-myocardial-ischemia-and-reperfusion-are-associated-with-increased-expression-of-il%C3%A2-17a-and-upregulation-of-the-jak2%C3%A2-stat3-signaling-pathway
#3
Yanxi Liao, Xiaorong Hu, Xin Guo, Bofang Zhang, Weipan Xu, Hong Jiang
Interleukin (IL)‑23, as a novel pro‑inflammatory cytokine, is important in several inflammatory diseases, including myocardial ischemia and reperfusion (I/R) injury, however, the underlying mechanism remains to be elucidated. The present study was designed to investigate the specific role of IL‑23 in myocardial I/R injury, and whether the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2‑STAT3) signaling pathway, one of the important downstream signaling pathways of IL‑23, and the IL‑17A downstream pro‑inflammatory cytokine, were involved...
October 12, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29032602/muscle-specific-differences-in-expression-and-phosphorylation-of-the-janus-kinase-2-signal-transducer-and-activator-of-transcription-3-following-long-term-mechanical-ventilation-and-immobilization-in-rats
#4
Heba Salah, Wen Fury, Jesper Gromada, Yu Bai, Tamar Tchkonia, James L Kirkland, Lars Larsson
AIM: Muscle wasting is one of the factors most strongly predicting mortality and morbidity in critically ill intensive care unit (ICU). This muscle wasting affects both limb and respiratory muscles but the understanding of underlying mechanisms and muscle-specific differences remains incomplete. This study aims at investigating the temporal expression and phosphorylation of the Janus kinase / signal transducer and activator of transcription (JAK/STAT) pathway in muscle wasting associated with the ICU condition in order to characterize the JAK/STAT proteins and the related changes leading or responding to their activation during exposure to the ICU condition...
October 15, 2017: Acta Physiologica
https://www.readbyqxmd.com/read/29026328/phosphorylation-of-stat-proteins-by-recombinant-human-il-6-in-immortalized-human-chondrocyte-cell-lines-t-c28a2-and-c28-i2
#5
Evan C Meszaros, Charles J Malemud
Two immortalized human juvenile chondrocyte cell lines, T/C28a2 and C28/I2, were employed to determine the extent to which recombinant human (rh) IL-6, a known cytokine activator of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway in many cell types, caused STAT proteins to be phosphorylated. The results showed that STAT3 was constitutively phosphorylated in the absence of rhIL-6 in T/C28a2 chondrocytes. However, C28/I2 chondrocytes treated with rhIL-6 caused STAT1, STAT3, and STAT5 to be phosphorylated without altering total unphosphorylated STAT proteins...
2017: Journal of Inflammation Research
https://www.readbyqxmd.com/read/29025601/a-neoplasm-with-fip1l1-pdgfra-fusion-presenting-as-pediatric-t-cell-lymphoblastic-leukemia-lymphoma-without-eosinophilia
#6
Matthew J Oberley, Christopher Denton, Jianling Ji, Matthew Hiemenz, Deepa Bhojwani, Dejerianne Ostrow, Samuel Wu, Paul Gaynon, Gordana Raca
The 2016 World Health Organization (2016 WHO) classification of hematopoietic malignancies classifies neoplasms with a fusion between the FIP1L1 and PDGFRA genes in 4q12 into a group called "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2". Neoplasms characterized by this fusion are pluripotent stem cell disorders that can show both myeloid and lymphoid differentiation. They typically occur in adult patients and most are characterized by eosinophilia...
October 2017: Cancer Genetics
https://www.readbyqxmd.com/read/29025600/a-novel-somatic-jak2-kinase-domain-mutation-in-pediatric-acute-lymphoblastic-leukemia-with-rapid-on-treatment-development-of-loh
#7
Teresa Sadras, Susan L Heatley, Chung H Kok, Barbara J McClure, David Yeung, Timothy P Hughes, Rosemary Sutton, David S Ziegler, Deborah L White
We report a novel somatic mutation in the kinase domain of JAK2 (R938Q) in a high-risk pediatric case of B-cell acute lymphoblastic leukemia (ALL). The patient developed on-therapy relapse at 12 months, and interestingly, the JAK2 locus acquired loss of heterozygosity during treatment resulting in 100% mutation load. Furthermore, we show that primary ALL mononuclear cells harboring the JAK2 R938Q mutation display reduced sensitivity to the JAK1/2 ATP-competitive inhibitor ruxolitinib in vitro, compared to ALL cells that carry a more common JAK2 pseudokinase domain mutation...
October 2017: Cancer Genetics
https://www.readbyqxmd.com/read/29022919/dcz3301-a-novel-cytotoxic-agent-inhibits-proliferation-in-diffuse-large-b-cell-lymphoma-via-the-stat3-pathway
#8
Xi Sun, Bo Li, Bingqian Xie, Zhijian Xu, Gaomei Chang, Yi Tao, Yong Zhang, Shuaikang Chang, Yingcong Wang, Dandan Yu, Yongsheng Xie, Tingye Li, Houcai Wang, Gege Chen, Liangning Hu, Jun Hou, Yiwen Zhang, Wenqin Xiao, Lu Gao, Jumei Shi, Weiliang Zhu
Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in adults, characterized by a rapidly increasing painless mass. A novel compound, DCZ3301, was synthesized that exerted direct cytotoxicity against DLBCL cell lines. The effects of DCZ3301 on DLBCL cells in vitro and in vivo and the associated mechanisms were investigated. DCZ3301 inhibited the viability of DLBCL cell lines, even in the presence of protumorigenesis cytokines. Additionally, the compound induced apoptosis and cell cycle arrest at the G2/M phase by reducing mitochondrial membrane potential...
October 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/29018784/peroxisome-proliferator-activated-receptor-gamma-inhibits-the-activation-of-stat3-in-cerulein-stimulated-pancreatic-acinar-cells
#9
Kyung Don Ju, Joo Weon Lim, Hyeyoung Kim
Cerulein-induced pancreatitis is similar to human edematous pancreatitis, characterized by the dysregulation of digestive enzyme production, edema formation, and an infiltration of inflammatory cells into the pancreas. We previously showed that the Janus kinase 2 (JAK2)/STAT3 pathway mediates inflammatory signaling in cerulein-stimulated pancreatic acinar cells. PPAR-γ has been implicated in the regulation of inflammatory responses in several cells. In the present study, we investigated the role of PPAR-γ in cerulein-induced activation of JAK2/STAT3 in pancreatic acinar cells...
September 2017: Journal of Cancer Prevention
https://www.readbyqxmd.com/read/28994166/newer-treatments-of-psoriasis-regarding-il-23-inhibitors-phosphodiesterase-4-inhibitors-and-janus-kinase-inhibitors
#10
REVIEW
Dominika Wcisło-Dziadecka, Martyna Zbiciak-Nylec, Ligia Brzezińska-Wcisło, Katarzyna Bebenek, Agata Kaźmierczak
The rapid progress of genetic engineering furthermore opens up new prospects in the therapy of this difficult-to-treat disease. IL-23 inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and Janus kinase (JAK) inhibitors are currently encouraging further research. Two drugs which are IL-23 inhibitors are now in phase III of clinical trials. The aim of the action of both drugs is selective IL-23 inhibition by targeting the p19 subunit. Guselkumab is a fully human monoclonal antibody. Tildrakizumab is a humanized monoclonal antibody, which also belongs to IgG class and is targeted to subunit p19 of interleukin 23 (IL-23)...
October 10, 2017: Dermatologic Therapy
https://www.readbyqxmd.com/read/28990048/chlorogenic-acid-suppresses-lipopolysaccharide%C3%A2-induced-nitric-oxide-and-interleukin%C3%A2-1%C3%AE-expression-by-inhibiting-jak2-stat3-activation-in-raw264-7-cells
#11
Sang-Hun Kim, Sun-Young Park, Young-Lan Park, Dae-Seong Myung, Jong-Sun Rew, Young-Eun Joo
Chlorogenic acid (CA) is a phenolic compound purified from coffee, fruits and their associated beverages, which possess various biological properties, such as antioxidant and anticarcinogenic activities. The present study evaluated the effects of CA on lipopolysaccharide (LPS)‑induced inflammation in RAW264.7 cells and the associated intracellular signaling pathways using reverse transcription‑quantitative polymerase chain reaction, western blotting and enzyme‑linked immunosorbent assays. CA pretreatment inhibited LPS‑induced expression of inducible nitric oxide synthase (iNOS), nitric oxide (NO) and pro‑inflammatory mediators including interleukin (IL)‑6, tumor necrosis factor‑α (TNF‑α), macrophage inflammatory protein‑2 (MIP‑2) and IL‑1β in RAW264...
October 2, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28986762/evaluation-of-the-dose-and-efficacy-of-ruxolitinib-in-japanese-patients-with-myelofibrosis
#12
Keita Kirito, Shinichiro Okamoto, Kohshi Ohishi, Tetsuzo Tauchi, Hiroshi Handa, Shigeki Saito, Katsuto Takenaka, Kazuya Shimoda, Kenji Oritani, Koichi Akashi, Hikaru Okada, Taro Amagasaki, Kazuyuki Suzuki, Toshio Yonezu, Norio Komatsu
Ruxolitinib, a potent JAK1/JAK2 inhibitor, improved splenomegaly and myelofibrosis-associated symptoms and prolonged survival compared with placebo and best available therapy in the phase 3 COMFORT studies. Although cytopenias were the most common adverse events associated with ruxolitinib treatment, a COMFORT-I analysis showed that they were managed effectively with dose modifications, without a negative impact on the efficacy of ruxolitinib. Subsequently, studies A2202 and AJP01 showed that ruxolitinib is an effective treatment for Japanese patients with myelofibrosis...
October 6, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28975683/involvement-of-the-jak-stat-pathway-in-collagen-regulation-of-decidual-nk-cells
#13
Qiang Fu, Yufei Sun, Yu Tao, Hailan Piao, Xiaoqiu Wang, Xiying Luan, Meirong Du, Dajin Li
PROBLEM: The mechanisms underlying the regulation of decidual natural killer cells (dNKs) at the maternal-fetal interface are unclear. METHOD OF STUDY: Primary trophoblasts (TROs), decidual stromal cells (DSCs), and dNKs were cocultured, and responses to LAIR-2 (LAIR-1 inhibitor) and P4H shRNA (collagen inhibitor) were studied. RESULTS: Coculture of dNKs with primary TROs/DSCs resulted in downregulation of Th1 cytokine production by dNKs. These effects were abrogated by LAIR-2 and P4H shRNA...
October 4, 2017: American Journal of Reproductive Immunology: AJRI
https://www.readbyqxmd.com/read/28972016/philadelphia-chromosome-like-acute-lymphoblastic-leukemia
#14
Sarah K Tasian, Mignon L Loh, Stephen P Hunger
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; also referred to as BCR-ABL1-like ALL) is a high risk subset with a gene expression profile that shares significant overlap with that of Philadelphia chromosome positive (Ph(+)) ALL and is suggestive of activated kinase signaling. While Ph(+) ALL is defined by BCR-ABL1 fusion, Ph-like ALL cases contain a variety of genomic alterations that activate kinase and cytokine receptor signaling. These alterations can be grouped into major subclasses that include ABL-class fusions involving ABL1, ABL2, CSF1R, and PDGFRB that phenocopy BCR-ABL1, and alterations of CRLF2, JAK2, and EPOR that activate JAK/STAT signaling...
October 2, 2017: Blood
https://www.readbyqxmd.com/read/28968979/mir-122-socs1-jak2-axis-regulates-allergic-inflammation-and-allergic-inflammation-promoted-cellular-interactions
#15
Kyeonga Noh, Misun Kim, Youngmi Kim, Hanearl Kim, Hyuna Kim, Jaehwan Byun, Yeongseo Park, Hansoo Lee, Yun Sil Lee, Jongseon Choe, Young Myeong Kim, Dooil Jeoung
The regulatory role of suppressor of cytokine signaling 1 (SOCS1) in inflammation has been reported. However, its role in allergic inflammation has not been previously reported. SOCS1 mediated in vitro and in vivo allergic inflammation. Histone deacetylase-3 (HDAC3), a mediator of allergic inflammation, interacted with SOCS1, and miR-384 inhibitor, a positive regulator of HDAC3, induced features of allergic inflammation in an SOCS1-dependent manner. miRNA array analysis showed that the expression of miR-122 was decreased by antigen-stimulation...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28962635/long-term-survival-in-patients-treated-with-ruxolitinib-for-myelofibrosis-comfort-i-and-ii-pooled-analyses
#16
Srdan Verstovsek, Jason Gotlib, Ruben A Mesa, Alessandro M Vannucchi, Jean-Jacques Kiladjian, Francisco Cervantes, Claire N Harrison, Ronald Paquette, William Sun, Ahmad Naim, Peter Langmuir, Tuochuan Dong, Prashanth Gopalakrishna, Vikas Gupta
BACKGROUND: Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF. METHODS: This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy)...
September 29, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28962085/effects-of-apigenin-pretreatment-against-renal-ischemia-reperfusion-injury-via-activation-of-the-jak2-stat3-pathway
#17
Yang Liu, Lei Wang, Yang Du, Zhiyuan Chen, Jia Guo, Xiaodong Weng, Xiao Wang, Min Wang, Danyang Chen, Xiuheng Liu
The aim of our study is to investigate the protective effect of apigenin and the role of the JAK2/STAT3 signaling pathway in renal ischemia/reperfusion injury (IRI) in rats. For in vivo experiments, rat kidneys were subjected to 45min of ischemia, followed by 24h of reperfusion. The kidneys were pretreated for 24h with apigenin (4mg/kg) intraperitoneally in the absence or presence of the JAK2 kinase-specific inhibitor AZD1480 (30mg/kg). The serum creatinine and urea nitrogen levels were analyzed. Histologic examinations were evaluated...
September 25, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28956263/ruxolitinib-is-effective-and-safe-in-japanese-patients-with-hydroxyurea-resistant-or-hydroxyurea-intolerant-polycythemia-vera-with-splenomegaly
#18
Keita Kirito, Kenshi Suzuki, Koichi Miyamura, Masahiro Takeuchi, Hiroshi Handa, Shinichiro Okamoto, Brian Gadbaw, Kyosuke Yamauchi, Taro Amagasaki, Kazuo Ito, Masayuki Hino
Ruxolitinib, a potent JAK1/JAK2 inhibitor, was found to be superior to the best available therapy (BAT) in controlling hematocrit, reducing splenomegaly, and improving symptoms in the phase 3 RESPONSE study of patients with polycythemia vera with splenomegaly who experienced an inadequate response to or adverse effects from hydroxyurea. We report findings from a subgroup analysis of Japanese patients in RESPONSE (n = 18). The composite response rate (hematocrit control and spleen response) was higher in patients receiving ruxolitinib (50...
September 27, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28953386/design-and-synthesis-of-ligand-efficient-dual-inhibitors-of-janus-kinase-jak-and-histone-deacetylase-hdac-based-on-ruxolitinib-and-vorinostat
#19
Lianbin Yao, Nurulhuda Mustafa, Eng Chong Tan, Anders Poulsen, Prachi Singh, Minh-Dao Duong-Thi, Jeannie X T Lee, Pondy Murugappan Ramanujulu, Wee Joo Chng, Jeffrey J Y Yen, Sten Ohlson, Brian W Dymock
Concomitant inhibition of multiple oncogenic pathways is a desirable goal in cancer therapy. To achieve such an outcome with a single molecule would simplify treatment regimes. Herein the core features of ruxolitinib (1), a marketed JAK1/2 inhibitor, have been merged with the HDAC inhibitor vorinostat (2), leading to new molecules which are bispecific targeted JAK/HDAC inhibitors. A preferred pyrazole substituted pyrrolopyrimidine, 24, inhibits JAK1 and HDACs 1,2,3,6 and 10 with IC50s of less than 20 nM, is <100 nM potent against JAK2 and HDAC11 and is selective for the JAK family against a panel of 97 kinases...
September 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28946703/acyclic-triterpenoids-from-alpinia-katsumadai-inhibit-il-6-induced-stat3-activation
#20
Hyun-Jae Jang, Seung-Jae Lee, Soyoung Lee, Kyungsook Jung, Seung Woong Lee, Mun-Chual Rho
The seeds of Alpinia katsumadai yielded two new acyclic triterpenoids, 2,3,6,22,23-pentahydroxy-2,6,11,15,19,23-hexamethyl-tetracosa-7,10,14,18-tetraene (3) and 2,3,6,22,23-pentahydroxy-2,10,15,19,23-hexamethyl-7-methylenetetracosa-10,14,18-triene (4), as well as two known compounds, 2,3,22,23-tertrahydroxy-2,6,10,15,19,23-hexamethyl-tetracosa-6,10,14,18-tetraene (1) and 2,3,5,22,23-pentahydroxy-2,6,10,15,19,23-hexamethyl-tetracosa-6,10,14,18-tetraene (2). The absolute configurations of 2 and 3, which were determined by means of a modified Mosher's method, are suggested as (3R; 5S; 22R) and (3R; 22R), respectively...
September 25, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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