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Miaojuan Qiu, Suchun Li, Lizi Jin, Pinning Feng, Yonglun Kong, Xiaoduo Zhao, Yu Lin, Yunyun Xu, Chunling Li, Weidong Wang
BACKGROUND: Lipotoxicity plays an important role in the pathogenesis of kidney injury. Our previous study demonstrated that activation of local renin-angiotensin system (RAS) was involved in saturated free fatty acids palmitic acid (PA)-induced tubular cell injuries. The current study aims to investigate whether suppression of RAS by combination of direct renin inhibitor aliskiren and noncanonical RAS pathway chymase inhibitor chymostatin attenuates PA or cholesterol induced-endoplasmic reticulum stress (ER stress) and apopotosis in cultured human proximal tubular HK2 cells...
July 31, 2018: Lipids in Health and Disease
Lei Zhao, Yasuto Yamaguchi, Xiaomei Ge, William H Robinson, John Morser, Lawrence L K Leung
BACKGROUND: Chemerin is a chemoattractant involved in immunity that also functions as an adipokine. Chemerin is secreted as an inactive precursor (chem163S), and its activation requires proteolytic cleavages at its C-terminus, involving proteases in coagulation, fibrinolysis, and inflammation. Previously, we found chem158K was the dominant chemerin form in synovial fluids from patients with arthritis. In this study, we aimed to characterize a distinct cleaved chemerin form, chem156F, in osteoarthritis (OA) and rheumatoid arthritis (RA)...
July 4, 2018: Arthritis Research & Therapy
T Z Salem, F Zhang, N Sahly, S Thiem
Integral membrane proteins (IMPs) are popular target for drugs, but their resolved structures have been overlooked when compared with cytosolic proteins. The main reason is that IMPs usually need intensive post-translational modifications and they are bound to membranes, which increase the complexity of purifying or crystalizing them. Although different expression systems are used to express IMPs, baculovirus is considered one of the most successful expression systems for those proteins. Despite that, there are always unknown discrepancies in the level of IMPs expression in the baculovirus expression system...
August 2018: Molecular Biotechnology
Friederike Kanefendt, Uwe Thuß, Michael Becka, Stefanie Boxnick, Matthias Berse, Armin Schultz, Christiane Otto
The orally available chymase inhibitor BAY 1142524 is currently being developed as a first-in-class treatment for left-ventricular dysfunction after myocardial infarction. Results from 3 randomized, single-center, phase 1 studies in healthy male volunteers examining the safety, tolerability, and pharmacokinetics of BAY 1142524 are summarized. In this first-in-human study, single oral doses of 1-200 mg were administered in fasted state as liquid service formulation or immediate release (IR) tablets. The relative bioavailability and the effect of a high-fat/high-calorie meal were investigated at the 5-mg dose...
June 7, 2018: Clinical Pharmacology in Drug Development
Nurul A S Binti Mohd Amir, Amanda E Mackenzie, Laura Jenkins, Karim Boustani, Marston C Hillier, Tomoko Tsuchiya, Graeme Milligan, James E Pease
The chemokine CXCL17 is associated with the innate response in mucosal tissues but is poorly characterized. Similarly, the G protein-coupled receptor GPR35, expressed by monocytes and mast cells, has been implicated in the immune response, although its precise role is ill-defined. A recent manuscript reported that GPR35 was able to signal in response to CXCL17, which we set out to confirm in this study. GPR35 was readily expressed using transfection systems but failed to signal in response to CXCL17 in assays of β-arrestin recruitment, inositol phosphate production, calcium flux, and receptor endocytosis...
July 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Takayuki Matsuno, Shota Toyoshima, Tomomi Sakamoto-Sasaki, Jun-Ichi Kashiwakura, Akira Matsuda, Yasuo Watanabe, Hiromitsu Azuma, Kei Kawana, Tatsuo Yamamoto, Yoshimichi Okayama
BACKGROUND: Although rodent decidual mast cells (MCs) reportedly play an important role in implantation and placenta formation, the characterization of human decidual MCs has been not well clarified. The aims of this study were to investigate the distribution and characteristics of MCs in human decidua and to establish a culture system for decidua-derived MCs. METHODS: Decidual tissues were obtained from patients who underwent a legal elective abortion (6th week to 9th week of pregnancy), and decidual MCs were enzymatically dispersed...
May 18, 2018: Allergology International: Official Journal of the Japanese Society of Allergology
Shabana T Malik, Brian R Birch, David Voegeli, Mandy Fader, Vipul Foria, Alan J Cooper, Andrew F Walls, Bashir A Lwaleed
AIMS: To identify the presence and geographical distribution of mast cell (MC) subtypes: MCT (tryptase positive-chymase negative) and MCTC (tryptase positive-chymase positive) in bladder tissue. METHODS: Bladder tissue was obtained from patients with painful bladder syndrome/interstitial cystitis (n=14) and normal histology from University Hospital Southampton tissue bank. Sequential tissue slices were immunohistochemically stained for MC subtypes using anti-MC tryptase (for MCT and MCTC ) and anti-MC chymase (for MCTC )...
May 15, 2018: Journal of Clinical Pathology
Miho Inokuchi, Shyam Prakash Dumre, Shusaku Mizukami, Mya Myat Ngwe Tun, Mohamed Gomaa Kamel, Dao Huy Manh, Le Hong Phuc, Nguyen Van Thuong, Tran Van An, Lan Nguyen Weiss, Tarek Turk, Tran Ngoc Dang, Vu Thi Que Huong, Kouichi Morita, Nguyen Tien Huy, Kenji Hirayama
There is no definitive predictor of dengue severity, and this has led to a very large number of unnecessary hospitalizations worldwide. Although mast cell mediators are believed to a play role in dengue severity, the lack of precise kinetic data demands further research on early predictors. We enrolled 111 patients with confirmed dengue and 85 with "other febrile illness" (OFI) in a hospital-based prospective study in Vietnam. Dengue patients were classified as level 1, 2, or 3 based on the clinical intervention received...
May 4, 2018: Archives of Virology
Sankar Devarajan, Eiji Yahiro, Yoshinari Uehara, Rieko Kuroda, Yoshio Hirano, Kaori Nagata, Shinichiro Miura, Keijiro Saku, Hidenori Urata
A novel chymase inhibitor has been reported to have depressor effect in salt-induced hypertension. Therefore, we examined the hypothesis that chymase inhibitory dried young leaves of Polygonum hydropiper (PPH) or young leaves extract of Polygonum hydropiper (PHE) could reduce salt-induced hypertension. In this study, 8-wk old wild-type mice were allocated into three experiments and experiment I included groups, I- normal water drinking, II- high salt (2% NaCl) water (HSW) drinking, and III- HSW plus PPH (500 mg kg-1 , orally) for 12-wk...
June 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Katariina Maaninka, Su Duy Nguyen, Mikko I Mäyränpää, Riia Plihtari, Kristiina Rajamäki, Perttu J Lindsberg, Petri T Kovanen, Katariina Öörni
BACKGROUND AND AIMS: Subendothelial interaction of LDL with extracellular matrix drives atherogenesis. This interaction can be strengthened by proteolytic modification of LDL. Mast cells (MCs) are present in atherosclerotic lesions, and upon activation, they degranulate and release a variety of neutral proteases. Here we studied the ability of MC proteases to cleave apoB-100 of LDL and affect the binding of LDL to proteoglycans. METHODS: Mature human MCs were differentiated from human peripheral blood-derived CD34+ progenitors in vitro and activated with calcium ionophore to generate MC-conditioned medium...
April 13, 2018: Atherosclerosis
Tiankai Li, Xiaowei Zhang, Heng-Jie Cheng, Zhi Zhang, Sarfaraz Ahmad, Jasmina Varagic, Weimin Li, Che Ping Cheng, Carlos M Ferrario
BACKGROUND: Angiotensin-(1-12) [Ang-(1-12)] is a chymase-dependent source for angiotensin II (Ang II) cardiac activity. The direct contractile effects of Ang-(1-12) in normal and heart failure (HF) remain to be demonstrated. We assessed the hypothesis that Ang-(1-12) may modulate [Ca2+ ]i regulation and alter cardiomyocyte contractility in normal and HF rats. METHODS AND RESULTS: We compared left ventricle (LV) myocyte contractile and calcium transient ([Ca2+ ]iT ) responses to angiotensin peptides in 16 SD rats with isoproterenol-induced HF and 16 age-matched controls...
August 1, 2018: International Journal of Cardiology
Michael Thorpe, Zhirong Fu, Gurdeep Chahal, Srinivas Akula, Jukka Kervinen, Lawrence de Garavilla, Lars Hellman
Human neutrophils express at least four active serine proteases, cathepsin G, N-elastase, proteinase 3 and neutrophil serine protease 4 (NSP4). They have all been extensively studied due to their importance in neutrophil biology and immunity. However, their extended cleavage specificities have never been determined in detail. Here we present a detailed cleavage specificity analysis of human cathepsin G (hCG). The specificity was determined by phage display analysis and the importance of individual amino acids in and around the cleavage site was then validated using novel recombinant substrates...
2018: PloS One
Maurício B Costa, Kallyne K O Mimura, Aline A Freitas, Emerith M Hungria, Ana Lúcia O M Sousa, Sonia M Oliani, Mariane M A Stefani
Mast cells (MCs) have important immunoregulatory roles in skin inflammation. Annexin A1 (ANXA1) is an endogenous anti-inflammatory protein that can be expressed by mast cells, neutrophils, eosinophils, monocytes, epithelial and T cells. This study investigated MCs heterogeneity and ANXA1 expression in human dermatoses with special emphasis in leprosy. Sixty one skin biopsies from 2 groups were investigated: 40 newly diagnosed untreated leprosy patients (18 reaction-free, 11 type 1 reaction/T1R, 11 type 2 reaction/T2R); 21 patients with other dermatoses...
May 2018: Microbial Pathogenesis
Ilona Kareinen, Marc Baumann, Su Duy Nguyen, Katariina Maaninka, Andrey Anisimov, Minoru Tozuka, Matti Jauhiainen, Miriam Lee-Rueckert, Petri T Kovanen
ApoA-I, the main structural and functional protein of HDL particles, is cardioprotective, but also highly sensitive to proteolytic cleavage. Here, we investigated the effect of cardiac mast cell activation and ensuing chymase secretion on apoA-I degradation using isolated rat hearts in the Langendorff perfusion system. Cardiac mast cells were activated by injection of compound 48/80 into the coronary circulation or by low-flow myocardial ischemia, after which lipid-free apoA-I was injected and collected in the coronary effluent for cleavage analysis...
June 2018: Journal of Lipid Research
Shinji Takai, Denan Jin
Non-alcoholic steatohepatitis (NASH) is characterized by inflammation and fibrosis, in addition to steatosis, of the liver, but no therapeutic agents have yet been established. The mast cell protease chymase can generate angiotensin II, matrix metalloproteinase-9 and transforming growth factor-β, all of which are associated with liver inflammation or fibrosis. In animal models of NASH, augmented chymase has been observed in the liver. In histological analysis, chymase inhibitor prevented hepatic steatosis, inflammation, and fibrosis...
2018: Frontiers in Pharmacology
Łukasz Lewicki, Janusz Siebert, Tomasz Koliński, Karolina Piekarska, Magdalena Reiwer-Gostomska, Radosław Targoński, Piotr Trzonkowski, Natalia Marek-Trzonkowska
BACKGROUND: Coronary artery disease (CAD) affects milions of people and can result in myocardial infarction (MI). Previously, mast cells (MC) have been extensively investigated in the context of hypersensitivity, however as regulators of the local inflammatory response they can potentially contribute to CAD and/or its progression. The aim of the study was to assess if serum concentration of MC proteases: carboxypeptidase A3, cathepsin G and chymase 1 is associated with the extension of CAD and MI...
March 7, 2018: Cardiology Journal
Patrícia Rocha Martins, Rodolfo Duarte Nascimento, Aline Tomaz Dos Santos, Enio Chaves de Oliveira, Patricia Massara Martinelli, Débora d'Avila Reis
Chagas disease is an infection caused by the parasite Trypanosoma cruzi that affects millions of people worldwide and is endemic in Latin America. Megacolon is the most frequent complication of the digestive chronic form and happens due to lesions of the enteric nervous system. The neuronal lesions seem to initiate in the acute phase and persist during the chronic phase, albeit the mechanisms involved in this process are still debated. Among the cells of the immune system possibly involved in this pathological process is the mast cell (MC) due to its well-known role in the bi-directional communication between the immune and nervous systems...
April 2018: Parasitology Research
Louis J Dell'Italia, James F Collawn, Carlos M Ferrario
Chymase is the most efficient Ang II (angiotensin II)-forming enzyme in the human body and has been implicated in a wide variety of human diseases that also implicate its many other protease actions. Largely thought to be the product of mast cells, the identification of other cellular sources including cardiac fibroblasts and vascular endothelial cells demonstrates a more widely dispersed production and distribution system in various tissues. Furthermore, newly emerging evidence for its intracellular presence in cardiomyocytes and smooth muscle cells opens an entirely new compartment of chymase-mediated actions that were previously thought to be limited to the extracellular space...
January 19, 2018: Circulation Research
Scott P Levick, Alexander Widiapradja
Historically, increased numbers of mast cells have been associated with fibrosis in numerous cardiac pathologies, implicating mast cells in the development of cardiac fibrosis. Subsequently, several approaches have been utilised to demonstrate a causal role for mast cells in animal models of cardiac fibrosis including mast cell stabilising compounds, rodents deficient in mast cells, and inhibition of the actions of mast cell-specific proteases such as chymase and tryptase. Whilst most evidence supports a pro-fibrotic role for mast cells, there is evidence that in some settings these cells can oppose fibrosis...
January 12, 2018: International Journal of Molecular Sciences
Yuta Miyaoka, Denan Jin, Keitaro Tashiro, Shinsuke Masubuchi, Maiko Ozeki, Fumitoshi Hirokawa, Michihiro Hayashi, Shinji Takai, Kazuhisa Uchiyama
Nonalcoholic steatohepatitis (NASH), in which there is steatosis and fibrosis in the liver, is linked to metabolic syndrome and progresses to hepatic cirrhosis. In this study, a novel hamster NASH model derived from metabolic syndrome was made using hamsters. Hamsters were fed a normal or a high-fat and high-cholesterol (HFC) diet for 12 weeks. Body weight and the ratio of liver weight to body weight were significantly greater in HFC diet-fed hamsters than in normal diet-fed hamsters. Triglyceride, low-density lipoprotein cholesterol, and glucose levels in blood were significantly increased in HFC diet-fed hamsters, and blood pressure also tended to be high, suggesting that the HFC diet-fed hamsters developed metabolic syndrome...
May 10, 2018: Experimental Animals
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