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complement inhibitor

Darshan Khangura, L Romayne Kurukulasuriya, Adam Whaley-Connell, James R Sowers
The presence of hypertension in individuals with type 2 diabetes augments the risk for cardiovascular morbidity and mortality. In this regard, data support that management of hypertension in this high-risk population is a critical risk reduction strategy. In recent years, a number of work groups have redefined hypertension, management strategies, and targets. In this context, there is still considerable discussion on an appropriate target for blood pressure in the diabetic population. However, despite this discussion on target blood pressure, it is widely recognized that there is considerable residual risk for heightened cardiovascular events in the hypertensive, diabetic population despite widespread awareness and treatment...
March 14, 2018: American Journal of Hypertension
Abdullateef Abdulkareem, Ryan S D'Souza, Joshua Mundorff, Pragya Shrestha, Oluwaseun Shogbesan, Anthony Donato
Acquired angioedema due to C1 inhibitor deficiency (C1INH-AAE) is a rare and potentially fatal syndrome of bradykinin-mediated angioedema characterized by episodes of angioedema without urticaria. It typically manifests with nonpitting edema of the skin and edema in the gastrointestinal (GI) tract mucosa or upper airway. Edema of the upper airway and tongue may lead to life-threatening asphyxiation. C1INH-AAE is typically under-diagnosed because of its rarity and its propensity to mimic more common abdominal conditions and allergic reactions...
2018: Case Reports in Hematology
Anas H Abu-Humaidan, Malin Elvén, Andreas Sonesson, Peter Garred, Ole E Sørensen
The complement system is an ancient part of the innate immune system important for both tissue homeostasis and host defense. However, bacteria like Staphylococcus aureus (SA) possess elaborative mechanisms for evading both the complement system and other parts of the immune system. One of these evasive mechanisms-important in causing chronic and therapy resistant infections-is the intracellular persistence in non-immune cells. The objective of our study was to investigate whether persistent intracellular SA infection of epidermal keratinocytes resulted in complement activation...
2018: Frontiers in Immunology
Shuang-An Li, Wei-Dan Jiang, Lin Feng, Yang Liu, Pei Wu, Jun Jiang, Sheng-Yao Kuang, Ling Tang, Wu-Neng Tang, Yong-An Zhang, Juan Yang, Xu Tang, He-Qun Shi, Xiao-Qiu Zhou
In this study, we investigated the effects of dietary myo-inositol on the intestinal immune barrier function and related signaling pathway in young grass carp (Ctenopharyngodon idella). A total of 540 young grass carp (221.33 ± 0.84 g) were fed six diets containing graded levels of myo-inositol (27.0, 137.9, 286.8, 438.6, 587.7 and 737.3 mg/kg) for 10 weeks. After the growth trial, fish were challenged with Aeromonas hydrophila. The results indicated that compared with the optimal dietary myo-inositol level, myo-inositol deficiency (27...
March 12, 2018: Fish & Shellfish Immunology
Mariola A Dietrich, Piotr Hliwa, Mikołaj Adamek, Dieter Steinhagen, Halina Karol, Andrzej Ciereszko
The environmental temperature affects plasma biochemical indicators, antioxidant status and hematological and immunological parameters in fish. So far, only single blood proteins have been identified in response to temperature changes. The aim of this study was to compare the proteome of carp blood plasma from males acclimated to warm (30 °C) and cold (10 °C) temperatures by two-dimensional differential gel electrophoresis followed by MALDI-TOF/TOF mass spectrometry. A total of 47 spots were found to be differentially regulated by temperature (>1...
March 12, 2018: Fish & Shellfish Immunology
Sheena L P Regan, Phil G Knight, John L Yovich, Yee Leung, Frank Arfuso, Arun Dharmarajan
Primordial germ cells migrate to the fetal gonads and proliferate during gestation to generate a fixed complement of primordial follicles, the so-called ovarian reserve. Primordial follicles comprise an oocyte arrested at the diplotene stage of meiosis, surrounded by a layer of pregranulosa cells. Activation of primordial follicles to grow beyond this arrested stage is of particular interest because, once activated, they are subjected to regulatory mechanisms involved in growth, selection, maturation, and ultimately, ovulation or atresia...
2018: Vitamins and Hormones
Shyam Nyati, Nauman Chaudhry, Areeb Chatur, Brandon S Gregg, Lauren Kimmel, Dheeraj Khare, Venkatesha Basrur, Dipankar Ray, Alnawaz Rehemtulla
Post-translational K63-linked poly-ubiquitination of AKT is required for its membrane recruitment and phosphorylation dependent activation in response to growth-factor stimulation. Current assays for target specific poly-ubiquitination involve cumbersome enzymatic preparations and semi-quantitative readouts. We have engineered a reporter that can quantitatively and in a target specific manner report on AKT-directed K63-polyubiquitination (K63UbR) in live cells. The reporter constitutes the AKT-derived poly-ubiquitination substrate peptide, a K63 poly-ubiquitin binding domain (UBD) as well as the split luciferase protein complementation domains...
February 16, 2018: Oncotarget
Chen Zou, Changjing Han, Minjie Zhao, Jingjing Yu, Lin Bai, Yuan Yao, Shuaixin Gao, Hui Cao, Zhi Zheng
Background: Preoperative treatment of anti-vascular endothelial growth factor (VEGF) agents is extensively used in proliferative diabetic retinopathy (PDR), but the molecular mechanism is not fully understood. The objective of this research is to observe change of protein profile induced by ranibizumab (an anti-VEGF agent) in vitreous humor from PDR patients and reveal the effects of anti-VEGF treatment on PDR. Methods: A proteomic method was used to identify differentially expressed proteins in vitreous humor...
2018: Clinical Proteomics
Itay Cohen, Si Naftaly, Efrat Ben-Zeev, Alexandra Hockla, Evette S Radisky, Niv Papo
High structural and sequence similarity within protein families can pose significant challenges to the development of selective inhibitors, especially towards proteolytic enzymes. Such enzymes usually belong to large families of closely similar proteases and may also hydrolyze, with different rates, protein or peptide-based inhibitors. To address this challenge, we employed a combinatorial yeast surface display library approach complemented with a novel pre-equilibrium, competitive screening strategy for facile assessment of the effects of multiple mutations on inhibitor association rates and binding specificity...
March 13, 2018: Biochemical Journal
Fei Xiao, Stanley Wang, Rina Barouch-Bentov, Gregory Neveu, Szuyuan Pu, Melanie Beer, Stanford Schor, Sathish Kumar, Vlad Nicolaescu, Brett D Lindenbach, Glenn Randall, Shirit Einav
Hepatitis C virus (HCV) spreads via secreted cell-free particles or direct cell-to-cell transmission. Yet, virus-host determinants governing differential intracellular trafficking of cell-free- and cell-to-cell-transmitted virus remain unknown. The host adaptor proteins (APs) AP-1A, AP-1B, and AP-4 traffic in post-Golgi compartments, and the latter two are implicated in basolateral sorting. We reported that AP-1A mediates HCV trafficking during release, whereas the endocytic adaptor AP-2 mediates entry and assembly...
March 13, 2018: MBio
Min Liu, Hui Wang, Jiaxiang Zhang, Xiaodong Yang, Bodong Li, Changhao Wu, Qixing Zhu
Both NF-κB pathway and complement activation appear to be involved in kidney damage induced by trichloroethylene (TCE). However, any relationship between these two systems has not yet been established. The present study aimed to clarify the role of NF-κB in complement activation and renal injury in TCE-sensitized BALB/c mice. Mice were sensitized by an initial subcutaneous injection and repeated focal applications of TCE to dorsal skin at specified timepoints. NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) was injected (intraperitoneal) before the final two focal TCE challenges...
December 2018: Journal of Immunotoxicology
Nilisha Fernando, Riccardo Natoli, Tanja Racic, Yvette Wooff, Jan Provis, Krisztina Valter
The complement system is highly implicated in both the prevalence and progression of Age-Related Macular Degeneration (AMD). Complement system inhibitors therefore have potential therapeutic value in managing excessive activation of the complement pathways in retinal degenerations. The vaccinia virus complement control protein (VCP) has been shown to be effective as a complement inhibitor in neuroinflammatory models including traumatic brain injury and spinal cord injury. We aimed to investigate the potential of VCP as a therapeutic molecule for retinal degenerations...
2018: PloS One
Kinga Nyíri, Haydyn D T Mertens, Borbála Tihanyi, Gergely N Nagy, Bianka Kőhegyi, Judit Matejka, Matthew J Harris, Judit E Szabó, Veronika Papp-Kádár, Veronika Németh-Pongrácz, Olivér Ozohanics, Károly Vékey, Dmitri I Svergun, Antoni J Borysik, Beáta G Vértessy
Human deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), essential for DNA integrity, acts as a survival factor for tumor cells and is a target for cancer chemotherapy. Here we report that the Staphylococcal repressor protein StlSaPIBov1 (Stl) forms strong complex with human dUTPase. Functional analysis reveals that this interaction results in significant reduction of both dUTPase enzymatic activity and DNA binding capability of Stl. We conducted structural studies to understand the mechanism of this mutual inhibition...
March 12, 2018: Scientific Reports
Martin Everett, Nicolas Sprynski, Alicia Coelho, Jérôme Castandet, Maëlle Bayet, Juliette Bougnon, Clarisse Lozano, David T Davies, Simon Leiris, Magdalena Zalacain, Ian Morrissey, Sophie Magnet, Kirsty Holden, Peter Warn, Filomena De Luca, Jean-Denis Docquier, Marc Lemonnier
Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) are increasingly prevalent and have become a major worldwide threat to human health. Carbapenem resistance is driven primarily by the acquisition of β-lactamase enzymes which are able to degrade carbapenem antibiotics (hence termed carbapenemases) and can result in high levels of resistance and treatment failure. Clinically relevant carbapenemases include both serine-β-lactamases (SBLs, e.g. KPC-2 and OXA-48) and metallo-β-lactamases (MBLs), such as NDM-1...
March 12, 2018: Antimicrobial Agents and Chemotherapy
Petra Bilić, Nicolas Guillemin, Alan Kovačević, Blanka Beer Ljubić, Ines Jović, Asier Galan, Peter David Eckersall, Richard Burchmore, Vladimir Mrljak
Idiopathic dilated cardiomyopathy (iDCM) is a primary myocardial disorder with an unknown aetiology, characterized by reduced contractility and ventricular dilation of the left or both ventricles. Naturally occurring canine iDCM was used herein to identify serum proteomic signature of the disease compared to the healthy state, providing an insight into underlying mechanisms and revealing proteins with biomarker potential. To achieve this, we used high-throughput label-based quantitative LC-MS/MS proteomics approach and bioinformatics analysis of the in silico inferred interactome protein network created from the initial list of differential proteins...
March 9, 2018: Journal of Proteomics
Sabine Buhner, Hannes Hahne, Kerstin Hartwig, Qin Li, Sheila Vignali, Daniela Ostertag, Chen Meng, Gabriele Hörmannsperger, Breg Braak, Christian Pehl, Thomas Frieling, Giovanni Barbara, Roberto De Giorgio, Ihsan Ekin Demir, Güralp Onur Ceyhan, Florian Zeller, Guy Boeckxstaens, Dirk Haller, Bernhard Kuster, Michael Schemann
BACKGROUND & AIMS: The causes of gastrointestinal complaints in irritable bowel syndrome (IBS) remain poorly understood. Altered nerve function has emerged as an important pathogenic factor as IBS mucosal biopsy supernatants consistently activate enteric and sensory neurons. We investigated the neurally active molecular components of such supernatants from patients with IBS and quiescent ulcerative colitis (UC). METHOD: Effects of supernatants from 7 healthy controls (HC), 20 IBS and 12 UC patients on human and guinea pig submucous neurons were studied with neuroimaging techniques...
2018: PloS One
Manish Kesherwani, Devadasan Velmurugan
Undecaprenyl phosphate (C55-P) acts as carrier lipid in the synthesis of peptidoglycan, which is de novo synthesized from dephosphorylation of undecaprenyl pyrophosphate (C55-PP). The phosphatidylglycerol phosphate phosphatase B (PgpB) catalyzes the dephosphorylation of C55-PP and forms C55-P. As no structural study has been made regarding the binding of C55-PP to PgpB, in the current study, in silico molecular docking, followed by 150 ns molecular dynamics simulation of the putative binding complex in membrane/solvent environment has been performed to understand conformational dynamics...
March 12, 2018: Journal of Biomolecular Structure & Dynamics
Michal Lusthaus, Niv Mazkereth, Natalie Donin, Zvi Fishelson
The complement system participates in the pathogenesis of many diseases. Complement activation produces several active protein complexes and peptides, including the terminal C5b-9 complexes. It was reported that C5b-9 complexes insert into the plasma membrane and cause membrane perturbation, intracellular calcium surge, metabolic depletion, and osmotic lysis. Previously, we showed that complement-dependent cytotoxicity (CDC) is regulated by JNK and Bid. Here, we demonstrate that three mediators in TNFα-induced necroptosis (regulated necrosis), the receptor-interacting protein kinases, receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3), and mixed-lineage kinase domain-like protein (MLKL), are activated by complement and contribute to CDC...
2018: Frontiers in Immunology
Dorien Reijnders, Chin-Chi Liu, Xinjing Xu, Anna Zhao, Kelsey Olson, Scott D Butler, Nataki C Douglas, Jenny L Sones
Preeclampsia (PE), a hypertensive disease of pregnancy, is a leading cause of fetal and maternal morbidity/mortality. Early angiogenic and inflammatory disturbances within the placenta are thought to underlie the development of the maternal PE syndrome and poor pregnancy outcomes. However, the exact etiology remains largely unknown. Here, we use the BPH/5 mouse model of PE to elucidate the way in which inflammation early in pregnancy contributes to abnormal expression of angiogenic factors at the maternal-fetal interface...
March 9, 2018: Physiological Genomics
Ronghua Zhang, Qiaofei Liu, Quan Liao, Yupei Zhao
CD59 has been identified as a glycosylphosphatidylinositol-anchored membrane protein that acts as an inhibitor of the formation of the membrane attack complex to regulate complement activation. Recent studies have shown that CD59 is highly expressed in several cancer cell lines and tumor tissues. CD59 also regulates the function, infiltration and phenotypes of a variety of immune cells in the tumor microenvironment. Herein, we summarized recent advances related to the functions and mechanisms of CD59 in the tumor microenvironment...
March 9, 2018: Future Oncology
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