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Yi-Kun Chen, Ying-Kun Xu, Hao Zhang, Jiang-Tao Yin, Xin Fan, Da-Dong Liu, Hai-Yan Fu, Bing Wan
Emodin is an anthraquinone derived from Chinese herb that exerts anti-inflammation effects. This study aimed to investigate whether emodin provides the protection for jejunum injury by inhibiting inflammation. We established a model of sepsis caused by cecal ligation and puncture. Forty-eight male Wistar rats were divided into four groups (n=12). Jejunum injury was assessed by pathological examination. The activity of pJAK1/pSTAT3 and protein levels of Bcl-2 and Bax were detected by Western blot analysis. Inflammatory factors IL-6, TNF-α and procalcitonin were detected by ELISA...
October 18, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
M Marchetti, G Barosi, F Cervantes, G Birgegård, M Griesshammer, C Harrison, R Hehlmann, J-J Kiladjian, N Kröger, M F McMullin, F Passamonti, A Vannucchi, T Barbui
Ruxolitinib is an oral JAK1/JAK2 inhibitor approved for the treatment of patients with myelofibrosis (MF) based on the results of two randomized clinical trials. However, discordant indications were provided by regulatory agencies and scientific societies for selecting the most appropriate candidates to this drug. The European LeukemiaNet and the Italian Society of Hematology shared the aim of building evidence-based recommendations for the use of ruxolitinib according to the GRADE methodology. Eighteen patient-intervention-comparator-outcome profiles were listed, each of them comparing ruxolitinib to other therapies with the aim of improving one of three clinical outcomes: a) splenomegaly, b) disease-related symptoms, and c) survival...
October 14, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Wen-Juan Lu, Scheffer C G Tseng, Shuangling Chen, Sean Tighe, Yuan Zhang, Xin Liu, Szu-Yu Chen, Chen-Wei Su, Ying-Ting Zhu
Human corneal endothelial cells (HCECs) have limited proliferative capacity due to "contact-inhibition" at G1 phase. Such contact-inhibition can be delayed from Day 21 to Day 42 by switching EGF-containing SHEM to LIF/bFGF-containing MESCM through transient activation of LIF-JAK1-STAT3 signaling that delays eventual nuclear translocation of p16(INK4a). Using the latter system, we have reported a novel tissue engineering technique by implementing 5 weekly knockdowns with p120 catenin (p120) and Kaiso siRNAs since Day 7 to achieve effective expansion of HCEC monolayers to a transplantable size with a normal HCEC density, through reprogramming of HCECs into neural crest progenitors by activating p120-Kaiso-RhoA-ROCK-canonical BMP signaling...
October 14, 2016: Scientific Reports
Catherine Dold, Carles Rodriguez Urbiola, Guido Wollmann, Lisa Egerer, Alexander Muik, Lydia Bellmann, Heidelinde Fiegl, Christian Marth, Janine Kimpel, Dorothee von Laer
Previously, we described an oncolytic vesicular stomatitis virus variant pseudotyped with the nonneurotropic glycoprotein of the lymphocytic choriomeningitis virus, VSV-GP, which was highly effective in glioblastoma. Here, we tested its potency for the treatment of ovarian cancer, a leading cause of death from gynecological malignancies. Effective oncolytic activity of VSV-GP could be demonstrated in ovarian cancer cell lines and xenografts in mice; however, remission was temporary in most mice. Analysis of the innate immune response revealed that ovarian cancer cell lines were able to respond to and produce type I interferon, inducing an antiviral state upon virus infection...
2016: Molecular Therapy Oncolytics
Di Zhang, Alexander Wlodawer, Jacek Lubkowski
The crystal structure of a construct consisting of the FERM and SH2-like domains of the human Janus kinase 1 (JAK1) bound to a fragment of the intracellular domain of the interferon-λ receptor 1 (IFNLR1) has been determined at the nominal resolution of 2.1Å. In this structure, the receptor peptide forms an 85-Å-long extended chain, in which both the previously identified box1 and box2 regions bind simultaneously to the FERM and SH2-like domains of JAK1. Both domains of JAK1 are generally well ordered, with regions not seen in the crystal structure limited to loops located away from the receptor-binding regions...
October 7, 2016: Journal of Molecular Biology
Suchismita Daw, Ritam Chatterjee, Aditya Law, Sujata Law
Hematological disorders like myelodysplastic syndrome (MDS) may arise due to cumulative dysregulation of various signalling pathways controlling proliferation, differentiation, maturation and apoptosis of bone marrow cells. This devastating bone marrow condition can be due to consequential abnormalities in haematopoiesis as well as its supportive microenvironment. Although mutations related to JAK/STAT pathway are common in myeloproliferative neoplasms, further studies are required to fully explore the myelodysplastic scenario regarding the concerned pathway...
October 7, 2016: Chemico-biological Interactions
Y Mori, K Ikeda, T Inomata, G Yoshimoto, N Fujii, H Ago, T Teshima
Jak1/2 inhibitor ruxolitinib is a promising agent for treating steroid-refractory GvHD after allogeneic hematopoietic stem cell transplantation (SCT) to produce quick and durable responses. However, optimal dose and tapering schedule of ruxolitinib remain to be determined. Discontinuation of ruxolitinib in myelofibrosis often induces 'withdrawal syndrome' characterized by acute relapse of the disease, but this issue is not well addressed in the treatment of GvHD. Four patients with GvHD (one acute and three chronic) after SCT for myelofibrosis were treated with ruxolitinib...
October 10, 2016: Bone Marrow Transplantation
Sheikh Fayaz Ahmad, Mushtaq Ahmad Ansari, Ahmed Nadeem, Khairy M A Zoheir, Saleh A Bakheet, Abdulaziz M S Alsaad, Othman A Al-Shabanah, Sabry M Attia
We set out to investigate the influence of STA-21, a dynamic STAT-3 inhibitor, on the expansion and progression of rheumatoid arthritis (RA), and to determine its potential mechanisms of action in a mouse model of collagen antibody-induced arthritis (CAIA). To this end, arthritis was induced via intravenous (IV) injection of Balb/c mice with a cocktail of antibodies directed against type II collagen (1.5μg/mouse, IV), followed by lipopolysaccharide (LPS) at a dose of (25μg/mouse, i.p.) on day 3. Mice were then left untreated or were simultaneously treated with STA-21 (0...
October 3, 2016: Immunobiology
Ana Karina Alves de Medeiros, Reinhart Speeckaert, Eline Desmet, Mireille Van Gele, Sofie De Schepper, Jo Lambert
The recent interest and elucidation of the JAK/STAT signaling pathway created new targets for the treatment of inflammatory skin diseases (ISDs). JAK inhibitors in oral and topical formulations have shown beneficial results in psoriasis and alopecia areata. Patients suffering from other ISDs might also benefit from JAK inhibition. Given the development of specific JAK inhibitors, the expression patterns of JAKs in different ISDs needs to be clarified. We aimed to analyze the expression of JAK/STAT family members in a set of prevalent ISDs: psoriasis, lichen planus (LP), cutaneous lupus erythematosus (CLE), atopic dermatitis (AD), pyoderma gangrenosum (PG) and alopecia areata (AA) versus healthy controls for (p)JAK1, (p)JAK2, (p)JAK3, (p)TYK2, pSTAT1, pSTAT2 and pSTAT3...
2016: PloS One
Robert E Chapin, Douglas J Ball, Zaher A Radi, Steven W Kumpf, Petra H Koza-Taylor, David M Potter, W Mark Vogel
Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis. Tofacitinib preferentially inhibits receptor signaling through JAK3 and JAK1, relative to JAK2. In the 2-year rat carcinogenicity study, there were tofacitinib, dose-related increases in the incidences of testicular Leydig cell hyperplasia and benign adenomas in male rats, and decreased incidences of mammary tumors and duct dilatation/galactocele in female rats. Such findings in rats are typical of agents, such as dopamine agonists, which decrease prolactin (PRL) activity...
October 5, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Julian Mackay-Wiggan, Ali Jabbari, Nhan Nguyen, Jane E Cerise, Charlotte Clark, Grace Ulerio, Megan Furniss, Roger Vaughan, Angela M Christiano, Raphael Clynes
BACKGROUND. Alopecia areata (AA) is a common autoimmune disease with a lifetime risk of 1.7%; there are no FDA-approved treatments for AA. We previously identified a dominant IFN-γ transcriptional signature in cytotoxic T lymphocytes (CTLs) in human and mouse AA skin and showed that treatment with JAK inhibitors induced durable hair regrowth in mice by targeting this pathway. Here, we investigated the use of the oral JAK1/2 inhibitor ruxolitinib in the treatment of patients with moderate-to-severe AA. METHODS...
September 22, 2016: JCI Insight
Shingo Nakayamada, Satoshi Kubo, Shigeru Iwata, Yoshiya Tanaka
Considerable advances in the treatment of rheumatoid arthritis (RA) have been made following the advent of biological disease-modifying anti-rheumatic drugs (DMARDs). However, biological DMARDs require intravenous or subcutaneous injection and some patients fail to respond to these drugs or lose their primary response. Currently, Janus kinase (JAK) inhibitors have been developed as a new class of DMARD that inhibits the non-receptor tyrosine kinase family JAK involved in intracellular signaling of various cytokines and growth factors...
October 3, 2016: Expert Opinion on Pharmacotherapy
Brandon J Dixon, Di Chen, Yang Zhang, Jerry Flores, Jay Malaguit, Derek Nowrangi, John H Zhang, Jiping Tang
Neonatal hypoxic-ischemic encephalopathy (HIE) is an injury that often leads to detrimental neurological deficits. Currently, there are no established therapies for HIE and it is critical to develop treatments that provide protection after HIE. The objective of this study was to investigate the ability of interferon beta (IFNβ) to provide neuroprotection and reduce apoptosis after HIE. Postnatal Day 10 rat pups were subjected to unilateral carotid artery ligation followed by 2.5 hr of exposure to hypoxia (8% O2)...
October 2016: ASN Neuro
D T Saenz, W Fiskus, T Manshouri, K Rajapakshe, S Krieger, B Sun, C P Mill, C DiNardo, N Pemmaraju, T Kadia, S Parmar, S Sharma, C Coarfa, P Qiu, S Verstovsek, K N Bhalla
Myeloproliferative Neoplasms with myelofibrosis (MPN-MF) demonstrate constitutive activation of JAK-STAT signaling, which responds to treatment with the JAK1 & 2 kinase inhibitor (JAKi) ruxolitinib. However, MPN-MF often progresses (~20%) to secondary AML (sAML), where standard induction chemotherapy or ruxolitinib is relatively ineffective, necessitating the development of novel therapeutic approaches. In the present studies, we demonstrate that treatment with BET (bromodomain and extra terminal) protein inhibitor (BETi), e...
September 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Kazuhito Sakamoto, Barbara L Wehde, Patrick D Rädler, Aleata A Triplett, Kay-Uwe Wagner
The biological functions of the Janus kinase 1 (JAK1) are suggested to be pleiotropic since this signal transducer is ubiquitously expressed and coupled to a variety of cytokine receptors. Consequently, mice that are deficient in this tyrosine kinase were reported to die shortly after birth. To facilitate studies that address the biological and molecular functions of JAK1 during postnatal development, we performed gene targeting in embryonic stem cells and generated a Cre/lox-based conditional knockout mouse model...
September 27, 2016: Genesis: the Journal of Genetics and Development
Eleni Vrontaki, Georgia Melagraki, Antreas Afantitis, Thomas Mavromoustakos, George Kollias
The Janus kinases (JAKs) play a pivotal role in cytokine receptor signaling pathways via activation of downstream signal transducers and activators of transcription (STAT) pathway. Intracellular pathways that include JAKs are critical to immune cell activation and pro-inflammatory cytokine production. Selective inhibitors of JAKs are potentially disease-modifying anti-inflammatory drugs for the treatment of rheumatoid arthritis (RA). Each of the four members of the JAK family plays an individual role in the oncogenesis of the immune system, and therefore, the development of potent and specific inhibitors for each member is needed...
September 19, 2016: Mini Reviews in Medicinal Chemistry
Hanlin Zeng, Jia Qu, Nan Jin, Jun Xu, Chenchu Lin, Yi Chen, Xinying Yang, Xiang He, Shuai Tang, Xiaojing Lan, Xiaotong Yang, Ziqi Chen, Min Huang, Jian Ding, Meiyu Geng
Histone deacetylase (HDAC) inhibitors have demonstrated clinical benefits in subtypes of hematological malignancies. However, the efficacy of HDAC inhibitors in solid tumors remains uncertain. This study takes breast cancer as a model to understand mechanisms accounting for limited response of HDAC inhibitors in solid tumors and to seek combination solutions. We discover that feedback activation of leukemia inhibitory factor receptor (LIFR) signaling in breast cancer limits the response to HDAC inhibition. Mechanistically, HDAC inhibition increases histone acetylation at the LIFR gene promoter, which recruits bromodomain protein BRD4, upregulates LIFR expression, and activates JAK1-STAT3 signaling...
September 12, 2016: Cancer Cell
Jean-François Spinella, Pauline Cassart, Chantal Richer, Virginie Saillour, Manon Ouimet, Sylvie Langlois, Pascal St-Onge, Thomas Sontag, Jasmine Healy, Mark D Minden, Daniel Sinnett
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with variable prognosis. It represents 15% of diagnosed pediatric ALL cases and has a threefold higher incidence among males. Many recurrent alterations have been identified and help define molecular subgroups of T-ALL, however the full range of events involved in driving transformation remain to be defined. Using an integrative approach combining genomic and transcriptomic data, we molecularly characterized 30 pediatric T-ALLs and identified common recurrent T-ALL targets such as FBXW7, JAK1, JAK3, PHF6, KDM6A and NOTCH1 as well as novel candidate T-ALL driver mutations including the p...
September 1, 2016: Oncotarget
Sina Oppermann, Avery J Lam, Stephanie Tung, Yonghong Shi, Lindsay McCaw, Guizhei Wang, Jarkko Ylanko, Brian Leber, David Andrews, David E Spaner
Glucorticoids (GCs) such as dexamethasone (DEX) remain important treatments for Chronic Lymphocytic Leukemia (CLL) but the mechanisms are poorly understood and resistance is inevitable. Proliferation centers (PC) in lymph nodes and bone marrow offer protection against many cytotoxic drugs and circulating CLL cells were found to acquire resistance to DEX-mediated killing in conditions encountered in PCs including stimulation by toll-like receptor agonists and interactions with stromal cells. The resistant state was associated with impaired glucocorticoid receptor-mediated gene expression, autocrine activation of STAT3 through Janus Kinases (JAKs), and increased glycolysis...
August 25, 2016: Oncotarget
Shingo Nakayamada, Satoshi Kubo, Shigeru Iwata, Yoshiya Tanaka
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation and joint destruction. Considerable advance in the treatment of RA has been made following the advent of biological disease-modifying anti-rheumatic drugs (DMARDs). However, these biologics require intravenous or subcutaneous injection and some patients fail to respond to biological DMARDs or lose their primary response. Various cytokines and cell surface molecules bind to receptors on the cell surface, resulting in the activation of various cell signaling pathways, including phosphorylation of kinase proteins...
October 2016: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
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