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Mohamed Salla, Rodrigo Aguayo-Ortiz, Danmaliki Gaddafi Ibrahim, Alaa Zare, Ahmed Said, Jack Moore, Vrajeshkumar Pandya, Robin Manaloor, Sunny Fong, Anna R Blankstein, Spencer Gibson, Laura Ramos Garcia, Pascal Meier, Khushwant S Bhullar, Basil P Hubbard, Yahya Fiteh, Harissios Vliagoftis, Ing Swie Goping, Dion Brocks, Peter Hwang, Jose Carlos A Martinez Velazquez, Shairaz Baksh
Receptor interacting protein kinase 2 (RIP2 or RICK herein referred to as RIPK2) is linked to the pathogen pathway that activates NFkB and autophagic activation. Using molecular modeling (docking) and chemoinformatics analyses we utilized the RIPK2/ponatinib crystal structure and searched in chemical databases for small molecules exerting binding interactions similar to those exerted by ponatinib. The identified RIPK2 inhibitors potently inhibited the proliferation of cancer cells by > 70% as well as inhibition of NFkB activity...
March 19, 2018: Journal of Pharmacology and Experimental Therapeutics
Huiling Zhu, Haibo Wang, Shuhui Wang, Zhixiao Tu, Lin Zhang, Xiuying Wang, Yongqing Hou, Chunwei Wang, Jie Chen, Yulan Liu
SCOPE: Flaxseed oil is a rich source of α-linolenic acid (ALA), which is the precursor of the long-chain n-3 polyunsaturated fatty acids (PUFAs) including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). This study investigated the protective effect of flaxseed oil against intestinal injury induced by lipopolysaccharide (LPS). MATERIALS AND RESULTS: Twenty-four weaned pigs were used in a 2 × 2 factorial experiment with dietary treatment (5% corn oil vs...
March 6, 2018: Molecular Nutrition & Food Research
Masafumi Ota, Tomomitsu Tahara, Toshimi Otsuka, Wu Jing, Tomoe Nomura, Ranji Hayashi, Takeo Shimasaki, Masakatsu Nakamura, Tomoyuki Shibata, Tomiyasu Arisawa
The present study aimed to investigate whether single nucleotide polymorphisms in receptor interacting serine/threonine kinase 2 ( RIPK2 ), which encodes a component of the nucleotide binding oligomerization domain containing 2-RIP2 pathway, may compromise the innate immune response to Helicobacter pylori infection, leading to increased susceptibility to gastric cancer in the Japanese population. The present case control study investigated the associations between RIPK2 single nucleotide polymorphisms and gastric mucosal inflammation, atrophy and cancer susceptibility in 528 patients with gastric cancer and 697 patients without gastric malignancies on upper gastro-duodenal endoscopy...
March 2018: Oncology Letters
Josiane V Cruz, Moysés F A Neto, Luciane B Silva, Ryan da S Ramos, Josivan da S Costa, Davi S B Brasil, Cleison C Lobato, Glauber V da Costa, José Adolfo H M Bittencourt, Carlos H T P da Silva, Franco H A Leite, Cleydson B R Santos
The Protein Kinase Receptor type 2 (RIPK2) plays an important role in the pathogenesis of inflammatory diseases; it signals downstream of the NOD1 and NOD2 intracellular sensors and promotes a productive inflammatory response. However, excessive NOD2 signaling has been associated with various diseases, including sarcoidosis and inflammatory arthritis; the pharmacological inhibition of RIPK2 is an affinity strategy that demonstrates an increased expression of pro-inflammatory secretion activity. In this study, a pharmacophoric model based on the crystallographic pose of ponatinib, a potent RIPK2 inhibitor, and 30 other ones selected from the BindingDB repository database, was built...
February 18, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Chalada Suebsuwong, Daniel M Pinkas, Soumya S Ray, Joshua C Bufton, Bing Dai, Alex N Bullock, Alexei Degterev, Gregory D Cuny
Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting the activation loop might offer improved inhibitor selectivity since this region of kinases is less conserved. However, the strategy presents difficulties due to activation loop flexibility. Herein, we report the design of receptor-interacting protein kinase 2 (RIPK2) inhibitors based on pan-kinase inhibitor regorafenib that aim to engage basic activation loop residues Lys169 or Arg171...
January 31, 2018: Bioorganic & Medicinal Chemistry Letters
Le Son Tran, Darren Tran, Amanda De Paoli, Kimberley D'Costa, Sarah J Creed, Garrett Z Ng, Lena Le, Philip Sutton, J Silke, U Nachbur, Richard L Ferrero
Helicobacter pylori causes chronic inflammation which is a key precursor to gastric carcinogenesis. It has been suggested that H. pylori may limit this immunopathology by inducing the production of IL-33 in gastric epithelial cells, thus promoting T helper 2 immune responses. The molecular mechanism underlying IL-33 production in response to H. pylori infection, however, remains unknown. In the current study, we demonstrate that H. pylori activates signalling via the pathogen recognition molecule NOD1 and its adaptor protein RIPK2, to promote production of both full-length and processed IL-33 in gastric epithelial cells...
February 2, 2018: Cellular Microbiology
Andrew Y Sun, Bryan Hinck, Benjamin R Cohen, Karen Keslar, Robert L Fairchild, Manoj Monga
INTRODUCTION: Intrarenal inflammation has been implicated in the pathogenesis of nephrolithiasis, with prior work showing increased urine levels of IL-6, IL-8, and CCL-2 in stone patients. However, no studies have assessed for inflammation in the renal papillae. We sought to characterize novel papillary tip and urinary biomarkers in stone patients. MATERIALS AND METHODS: Ninety-two patients with nephrolithiasis undergoing percutaneous nephrolithotomy were enrolled...
February 28, 2018: Journal of Endourology
Jessica M Perez, Yinghua Chen, Tsan S Xiao, Derek W Abbott
Heightened and extended inflammation underlies the pathogenesis of many disorders, including inflammatory bowel disease, sepsis, and inflammatory arthritis. Ubiquitin networks help dictate the strength and duration of inflammatory signaling. In innate immunity, the itchy E3 ubiquitin protein ligase (ITCH)-A20 ubiquitin-editing complex inhibits receptor-interacting Ser/Thr kinase (RIPK) activation by removing Lys-63-linked polyubiquitinated chains from key proteins in the nuclear factor kappa B (NF-κB) signaling pathway...
January 19, 2018: Journal of Biological Chemistry
Xiaohui He, Sara Da Ros, John Nelson, Xuefeng Zhu, Tao Jiang, Barun Okram, Songchun Jiang, Pierre-Yves Michellys, Maya Iskandar, Sheryll Espinola, Yong Jia, Badry Bursulaya, Andreas Kreusch, Mu-Yun Gao, Glen Spraggon, Janine Baaten, Leah Clemmer, Shelly Meeusen, David Huang, Robert Hill, Vân Nguyen-Tran, John Fathman, Bo Liu, Tove Tuntland, Perry Gordon, Thomas Hollenbeck, Kenneth Ng, Jian Shi, Laura Bordone, Hong Liu
NOD2 (nucleotide-binding oligomerization domain-containing protein 2) is an internal pattern recognition receptor that recognizes bacterial peptidoglycan and stimulates host immune responses. Dysfunction of NOD2 pathway has been associated with a number of autoinflammatory disorders. To date, direct inhibitors of NOD2 have not been described due to technical challenges of targeting the oligomeric protein complex. Receptor interacting protein kinase 2 (RIPK2) is an intracellular serine/threonine/tyrosine kinase, a key signaling partner, and an obligate kinase for NOD2...
October 12, 2017: ACS Medicinal Chemistry Letters
Armin Soave, Felix K-H Chun, Timo Hillebrand, Michael Rink, Lars Weisbach, Bettina Steinbach, Margit Fisch, Klaus Pantel, Heidi Schwarzenbach
The aim of the present study was to establish a rapid profiling method using multiplex ligation-dependent probe amplification (MLPA) and characterize copy number variations (CNV) in circulating, cell-free DNA (cfDNA) in 85 urothelial carcinoma of the bladder (UCB) patients treated with radical cystectomy (RC). MLPA was tested for the use of cfDNA extracted from serum and plasma by various commercial extraction kits. Eighteen probes served as reference to control denaturation, ligation and amplification efficiency...
August 22, 2017: Oncotarget
L M Shaddox, A F Mullersman, H Huang, S M Wallet, T Langaee, I Aukhil
BACKGROUND: We have previously demonstrated a Toll-like receptor (TLR)-mediated hyper-responsive phenotype in our cohort of localized aggressive periodontitis (LAP) individuals. However, mechanisms related to this phenotype are still not clear in the literature. The objective of this cross-sectional study is to examine the role of epigenetic regulation, specifically DNA methylation status of genes in the TLR pathway in this cohort. Peripheral blood was collected from 20 LAP patients and 20 healthy unrelated controls...
2017: Clinical Epigenetics
Cristina Cirauqui, Cristina Benito-Villalvilla, Silvia Sánchez-Ramón, Sofía Sirvent, Carmen M Diez-Rivero, Laura Conejero, Paola Brandi, Lourdes Hernández-Cillero, Juliana Lucía Ochoa, Beatriz Pérez-Villamil, David Sancho, José Luis Subiza, Oscar Palomares
Recurrent respiratory tract infections (RRTIs) are the first leading cause of community- and nosocomial-acquired infections. Antibiotics remain the mainstay of treatment, enhancing the potential to develop antibiotic resistances. Therefore, the development of new alternative approaches to prevent and treat RRTIs is highly demanded. Daily sublingual administration of the whole heat-inactivated polybacterial preparation (PBP) MV130 significantly reduced the rate of respiratory infections in RRTIs patients, however, the immunological mechanisms of action remain unknown...
August 11, 2017: European Journal of Immunology
Junqin Liang, Yilinuer Halipu, Fengxia Hu, Buwajieer Yakeya, Wenjing Chen, Huan Zhang, Xiaojing Kang
Naringenin is known to have anti-oxidative activity; however, the effect of naringenin on the progression of pemphigus vulgaris (PV) still remains unclear. This study aims to analyze the effect of naringenin on HaCaT cell apoptosis and oxidative damage under the treatment of PV serum. The results showed that PV serum significantly induced cell apoptosis compared with the control group; whereas, comparing with PV group, naringenin inhibited cell apoptosis. Moreover, PV serum increased the expression of bax and caspase-3, and decreased the expression of bcl-2; but naringenin significantly suppressed the expression of bax and caspase-3, induced the expression of bcl-2...
August 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Armin Soave, Felix K-H Chun, Timo Hillebrand, Michael Rink, Lars Weisbach, Bettina Steinbach, Margit Fisch, Klaus Pantel, Heidi Schwarzenbach
The aim of the present study was to establish a rapid profiling method using multiplex ligation-dependent probe amplification (MLPA) and characterize copy number variations (CNV) in circulating, cell-free DNA (cfDNA) in 85 urothelial carcinoma of the bladder (UCB) patients treated with radical cystectomy (RC). MLPA was tested for the use of cfDNA extracted from serum and plasma by various commercial extraction kits. Eighteen probes served as reference to control denaturation, ligation and amplification efficiency...
May 7, 2017: Oncotarget
Brittany M Duggan, Kevin P Foley, Brandyn D Henriksbo, Joseph F Cavallari, Akhilesh K Tamrakar, Jonathan D Schertzer
Inflammation underpins aspects of insulin resistance and dysglycemia. Microbiota-derived cell wall components such as muropeptides or endotoxin can trigger changes in host immunity and metabolism. Specific peptidoglycan motifs promote metabolic tissue inflammation, lipolysis and insulin resistance via Nucleotide-binding oligomerization domain-containing protein 1 (Nod1). Receptor-interacting serine/threonine-protein kinase 2 (Ripk2) mediates Nod1-induced immunity, but the role of Ripk2 in metabolism is ill-defined...
May 8, 2017: Scientific Reports
Jeremy W Prokop, Jozef Lazar, Gabrielle Crapitto, D Casey Smith, Elizabeth A Worthey, Howard J Jacob
Protein modeling and molecular dynamics hold a unique toolset to aide in the characterization of clinical variants that may result in disease. Not only do these techniques offer the ability to study under characterized proteins, but they do this with the speed that is needed for time-sensitive clinical cases. In this paper we retrospectively study a clinical variant in the XIAP protein, C203Y, while addressing additional variants seen in patients with similar gastrointestinal phenotypes as the C203Y mutation...
March 2017: Journal of Molecular Modeling
Masaki Takeuchi, Nobuhisa Mizuki, Akira Meguro, Michael J Ombrello, Yohei Kirino, Colleen Satorius, Julie Le, Mary Blake, Burak Erer, Tatsukata Kawagoe, Duran Ustek, Ilknur Tugal-Tutkun, Emire Seyahi, Yilmaz Ozyazgan, Inês Sousa, Fereydoun Davatchi, Vânia Francisco, Farhad Shahram, Bahar Sadeghi Abdollahi, Abdolhadi Nadji, Niloofar Mojarad Shafiee, Fahmida Ghaderibarmi, Shigeaki Ohno, Atsuhisa Ueda, Yoshiaki Ishigatsubo, Massimo Gadina, Sofia A Oliveira, Ahmet Gül, Daniel L Kastner, Elaine F Remmers
We analyzed 1,900 Turkish Behçet's disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated SNP was rs1050502, a tag SNP for HLA-B*51. In the Turkish discovery set, we identified three new risk loci, IL1A-IL1B, IRF8, and CEBPB-PTPN1, with genome-wide significance (P < 5 × 10(-8)) by direct genotyping and ADO-EGR2 by imputation. We replicated the ADO-EGR2, IRF8, and CEBPB-PTPN1 loci by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls further replicated ADO-EGR2 and IRF8, and meta-analysis additionally identified RIPK2 and LACC1...
March 2017: Nature Genetics
T Jessica Gambino, Steven P Williams, Carol Caesar, Daniel Resnick, Cameron J Nowell, Rae H Farnsworth, Marc G Achen, Steven A Stacker, Tara Karnezis
The lymphatic system is a series of vessels that transport cells and excess fluid from tissues to the blood vascular system. Normally quiescent, the lymphatics can grow or remodel in response to developmental, immunological, or cells pathological stimuli. Lymphatic vessels comprise lymphatic endothelial cells (LECs) that can respond to external growth factors by undergoing proliferation, migration, adhesion, and tube and lumen formation into new vessel structures, a process known as lymphangiogenesis. To understand the key gene and signaling pathways necessary for lymphangiogenesis and lymphatic vessel remodeling, we have developed a three-dimensional LEC tube formation assay to explore the role of kinase signaling in these processes...
January 2017: Assay and Drug Development Technologies
Yi-Hsin Fan, Sujayita Roy, Rupkatha Mukhopadhyay, Arun Kapoor, Priya Duggal, Genevieve L Wojcik, Robert F Pass, Ravit Arav-Boger
Induction of nucleotide-binding oligomerization domain 2 (NOD2) and downstream receptor-interacting serine/threonine-protein kinase 2 (RIPK2) by human cytomegalovirus (HCMV) is known to up-regulate antiviral responses and suppress virus replication. We investigated the role of nucleotide-binding oligomerization domain 1 (NOD1), which also signals through RIPK2, in HCMV control. NOD1 activation by Tri-DAP (NOD1 agonist) suppressed HCMV and induced IFN-β. Mouse CMV was also inhibited through NOD1 activation...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
John J Wilson, Janelle Grendler, Azaline Dunlap-Smith, Brian F Beal, Shallee T Page
Mya arenaria is a bivalve mollusk of commercial and economic importance, currently impacted by ocean warming, acidification, and invasive species. In order to inform studies on the growth of M. arenaria, we selected and inbred a population of soft-shell clams for a fast-growth phenotype. This population displayed significantly faster growth (p < 0.0001), as measured by 35.4% greater shell size. To assess the biological basis of this growth heterosis, we characterized the complete transcriptomes of six individuals and identified differentially expressed genes by RNAseq...
2016: International Journal of Genomics
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