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Justin T Hsieh, Abhay P S Rathore, Gayathri Soundarajan, Ashley L St John
Japanese encephalitis virus (JEV) is a leading cause of viral encephalitis. However, the mechanisms of JEV penetration of the blood-brain-barrier (BBB) remain poorly understood. Mast cells (MCs) are granulated innate immune sentinels located perivascularly, including at the BBB. Here we show that JEV activates MCs, leading to the release of granule-associated proteases in vivo. MC-deficient mice display reduced BBB permeability during JEV infection compared to congenic wild-type (WT) mice, indicating that enhanced vascular leakage in the brain during JEV infection is MC-dependent...
February 11, 2019: Nature Communications
Hao Wang, Xuming Sun, Sarfaraz Ahmad, Jing Su, Carlos Maria Ferrario, Leanne Groban
Chymases, a family of serine proteases with chymotryptic activity, play a significant role in cardiac angiotensin II (Ang II) formation from its substrate Ang-(1-12) in both human and rodent models. No studies, to date, have assessed the differences in enzymatic activity among these isoforms in Ang II formation, particularly in the cardiomyocyte (CM). Using PCR and DNA sequencing, we demonstrated that MCP-1, MCP-2, MCP-4, and MCP-5 mRNAs are expressed in the CM of both spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY)...
February 2, 2019: Molecular and Cellular Biochemistry
Maiko Ozeki, Denan Jin, Yuta Miyaoka, Shinsuke Masubuchi, Fumitoshi Hirokawa, Michihiro Hayashi, Shinji Takai, Kazuhisa Uchiyama
Adhesion formation that occurred after alkali-induced injury of the cecum was used as a novel adhesion model in rats, and it was compared with that of a common adhesion model after abrading the cecum. Using the novel adhesion model, inhibition of adhesion formation by a chymase inhibitor, Suc-Val-Pro-PheP(OPh)2, and by sodium hyaluronate/carboxymethylcellulose (Seprafilm) was evaluated, and their mechanisms were assessed. The degree of adhesion formation was more severe and more stable in the alkali-induced injury model than in the abrasion-induced injury model...
2019: PloS One
Keisuke Okamura, Tetsu Okuda, Kazuyuki Shirai, Hidenori Urata
A previous clinical study revealed elevation of chymase- and cathepsin G-dependent angiotensin II-forming activity (AIIFA) in the myocardium after acute myocardial infarction (AMI). This study examined the time course of chymase- and cathepsin G-dependent AIIFA in circulating mononuclear leukocytes (CML) after AMI. Consecutive patients with AMI were recruited. Chymase- and cathepsin G-dependent AIIFA in CML were assayed using a modified angiotensin I substrate with Nma/Dnp fluorescence quenching. The changes of CML AIIFA were monitored over time in the patients...
January 24, 2019: Heart and Vessels
Ramona D'amico, Roberta Fusco, Enrico Gugliandolo, Marika Cordaro, Rosalba Siracusa, Daniela Impellizzeri, Alessio F Peritore, Rosalia Crupi, Salvatore Cuzzocrea, Rosanna Di Paola
BACKGROUND: Myocardial ischemia/reperfusion (I/R) injury is the principal cause of death, happens after prolonged obstruction of the coronary arteries.  The first intervention to limit myocardial damage is directed to restoration of perfusion, to avoid inflammatory response and a significant oxidative stress triggered by infarction. Palmitoylethanolamide (PEA), is a well-known fatty acid amide-signaling molecule that possess an important anti-inflammatory and analgesic effects. PEA does not hold the ability to inhibit free radicals formation...
September 19, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Yunzhe Wang, Cong-Lin Liu, Wenqian Fang, Xian Zhang, Chongzhe Yang, Jie Li, Jing Liu, Galina K Sukhova, Michael F Gurish, Peter Libby, Guo-Ping Shi, Jinying Zhang
Mouse mast cell protease-4 (mMCP4) is a chymase that has been implicated in cardiovascular diseases, including myocardial infarction (MI). This study tested a direct role of mMCP4 in mouse post-MI cardiac dysfunction and myocardial remodeling. Immunoblot and immunofluorescent double staining demonstrated mMCP4 expression in cardiomyocytes from the infarct zone from mouse heart at 28 day post-MI. At this time point, mMCP4-deficient Mcpt4-/- mice showed no difference in survival from wild-type (WT) control mice, yet demonstrated smaller infarct size, improved cardiac functions, reduced macrophage content but increased T-cell accumulation in the infarct region compared with those of WT littermates...
January 10, 2019: Biochimica et biophysica acta. Molecular basis of disease
Wen-Yeh Hsieh, Teng-Hsiang Chang, Hui-Fang Chang, Wan-Hsuan Chuang, Li-Che Lu, Chung-Wei Yang, Chih-Sheng Lin, Chia-Chu Chang
Angiotensin-converting enzyme (ACE) is the primary enzyme that converts angiotensin I (Ang I) to angiotensin II (Ang II) in the renin-angiotensin system (RAS). However, chymase hydrates Ang I to Ang II independently of ACE in some kidney diseases, and it may play an important role. The present study investigated whether chymase played a crucial role in aristolochic acid I (AAI)-induced nephropathy. C57BL/6 mice were treated with AAI via intraperitoneal injection for an accumulated AAI dosage of 45 mg/kg body weight (BW) (15 mg/kg BW per day for 3 days)...
2019: PloS One
Amit Dubey, Serena Dotolo, Pramod W Ramteke, Angelo Facchiano, Anna Marabotti
Inhibitors of chymase have good potential to provide a novel therapeutic approach for the treatment of cardiovascular diseases. We used a computational approach based on pharmacophore modeling, docking, and molecular dynamics simulations to evaluate the potential ability of 13 natural compounds from chamomile extracts to bind chymase enzyme. The results indicated that some chamomile compounds can bind to the active site of human chymase. In particular, chlorogenic acid had a predicted binding energy comparable or even better than that of some known chymase inhibitors, interacted stably with key amino acids in the chymase active site, and appeared to be more selective for chymase than other serine proteases...
December 21, 2018: Biomolecules
Keisuke Okamura, Rieko Kuroda, Kaori Nagata, Hidenori Urata
BACKGROUND AND PURPOSE: Human chymase (h-chymase) is a serine protease that forms local angiotensin II and has been proven to be related to onset of hypertension, arteriosclerosis, and post myocardial infarction cardiac remodeling. Since no chymase inhibitor was clinically available, an extensive screening for inhibition of h-chymase in three different extracts (water, hot water,  and ethanol) of approximately 800 food ingredients had been performed and we identified Polygonum hydropiper L (Polygonum)...
December 23, 2018: Clinical and Experimental Hypertension: CHE
Denan Jin, Shinji Takai, Yosuke Nonaka, Satoko Yamazaki, Masatoshi Fujiwara, Yoshikazu Nakamura
We have reported that mast cell chymase, an angiotensin II-generating enzyme, is important in cardiovascular tissues. Recently, we developed a new chymase-specific inhibitory RNA aptamer, HA28, and we evaluated the effects of HA28 on cardiac function and the mortality rate after myocardial infarction. Echocardiographic parameters, such as the left ventricular ejection fraction, fractional shortening, and the ratio of early to late ventricular filling velocities, were significantly improved by treatment with HA28 after myocardial infarction...
November 13, 2018: Molecular Therapy. Nucleic Acids
Artur Mayerhofer, Lena Walenta, Christine Mayer, Katja Eubler, Harald Welter
In man, the wall of seminiferous tubules forms a testicular compartment, which contains several layers of smooth muscle-like, "myoid", peritubular cells and extracellular matrix. Its architecture and its cellular composition change in male infertility associated with impaired spermatogenesis. Increased deposits of extracellular matrix, changes in the smooth muscle-like phenotype of peritubular cells and accumulation of immune cells, especially mast cells, are among the striking alterations. Taken together, the changes indicate that inflammatory events take place in particular within this compartment...
December 2018: Andrologia
T Lipitsä, H Siiskonen, A Naukkarinen, I T Harvima
BACKGROUND: The accumulation of immunoreactants and fibrinoid necrosis of postcapillary vessel walls are common pathological features of cutaneous immune complex vasculitis. In more advanced lesions, these immunoreactants are subject to proteolysis. Mast cell chymase is a powerful enzyme that can degrade several substrates including the extracellular matrix. Heparin can influence the catalytic properties of chymase. OBJECTIVES: We aimed to study the effects of recombinant human (rh) chymase on fibrinogen, coagulation and fibrinolysis, and to relate these effects to the vasculitis pathogenesis...
December 18, 2018: British Journal of Dermatology
Michael Thorpe, Zhirong Fu, Emanuelle Albat, Srinivas Akula, Lawrence de Garavilla, Jukka Kervinen, Lars Hellman
Serine proteases constitute the major protein content of mast cell secretory granules. Here we present the extended cleavage specificity of two such proteases from the golden hamster, Mesocricetus auratus. Analysis by phage display technique showed that one of them (HAM1) is a classical chymase with a specificity similar to the human mast cell chymase. However, in contrast to the human chymase, it does not seem to have a particular preference for any of the three aromatic amino acids, Phe, Tyr and Trp, in the P1 position of substrates...
2018: PloS One
Flavie Ngo Nyekel, Emeline Pacreau, Samira Benadda, Rasha Msallam, Magnus Åbrink, Gunnar Pejler, Jean Davoust, Marc Benhamou, Nicolas Charles, Pierre Launay, Ulrich Blank, Gregory Gautier
Recent evidences indicate an important role of tissue inflammatory responses by innate immune cells in allograft acceptance and survival. Here we investigated the role of mast cells (MC) in an acute male to female skin allograft rejection model using red MC and basophil (RMB) mice enabling conditional MC depletion. Kinetic analysis showed that MCs markedly accelerate skin rejection. They induced an early inflammatory response through degranulation and boosted local synthesis of KC, MIP-2, and TNF. This enhanced early neutrophil infiltration compared to a female-female graft-associated repair response...
2018: Frontiers in Immunology
Daniel Elieh Ali Komi, Leif Bjermer
Improving the lung function after experimental allergen challenge by blocking of mast cell (MC) mediators and the capability of MC mediators (including histamine, prostaglandin (PG) D2, and leukotriene (LT) C4) in induction of mucosal edema, bronchoconstriction, and mucus secretion provide evidence that MCs play a key role in pathophysiology of asthma. In asthma, the number of MCs increases in the airways and infiltration of MCs in a variety of anatomical sites including the epithelium, the submucosal glands, and the smooth muscle bundles occurs...
November 30, 2018: Clinical Reviews in Allergy & Immunology
Zhirong Fu, Srinivas Akula, Michael Thorpe, Gurdeep Chahal, Lawrence de Garavilla, Jukka Kervinen, Lars Hellman
Serine proteases constitute the major protein content of mammalian mast cell granules and the selectivity for substrates by these proteases is of major importance for the role of mast cells in immunity. In order to address this subject, we present here the extended cleavage specificity of sheep mast cell protease-2 (MCP2), a chymotrypsin-type serine protease. Comparison of the extended specificity results to a panel of mammalian mast cell chymases show, in almost all aspects, the same cleavage characteristics...
November 24, 2018: Developmental and Comparative Immunology
Arnar Bragi Ingason, Fatich Mechmet, Diahann Alexandra Maria Atacho, Eiríkur Steingrímsson, Pétur Henry Petersen
Although mast cell distribution has been described in both human and canine hearts, cardiac mast cells in mice have yet to be categorically localized. We therefore sought to describe mast cell distribution within the mouse heart and characterize their dependence on the Microphthalmia-associated transcription factor (Mitf). Cardiac mast cells were visualized using Toluidine Blue and avidin staining, and their distribution within the heart described. Cardiac mast cells were most prevalent in the epicardium (50%) or myocardium (45%)...
November 21, 2018: Molecular Immunology
Anne Dudeck, Martin Köberle, Oliver Goldmann, Nicole Meyer, Jan Dudeck, Stefanie Lemmens, Manfred Rohde, Nestor González Roldán, Kirsten Dietze-Schwonberg, Zane Orinska, Eva Medina, Sven Hendrix, Martin Metz, Ana Claudia Zenclussen, Esther von Stebut, Tilo Biedermann
Mast cells (MC), well known for their effector functions in Th2 skewed allergic and also autoimmune inflammation, become increasingly acknowledged for their role in protection of health. It is now clear that they are also key modulators of immune responses at interface organs like skin or gut. MC can prime tissues for adequate inflammatory responses and cooperate with dendritic cells in T cell activation. They also regulate harmful immune responses in trauma and help to successfully orchestrate pregnancy. This review focusses on the beneficial effects of mast cells on tissue homeostasis and elimination of toxins or venoms...
November 20, 2018: Journal of Allergy and Clinical Immunology
Jingyi Liu, Zhirong Fu, Lars Hellman, Staffan G Svärd
Giardia intestinalis is a protozoan parasite and the causative agent of giardiasis, a common diarrheal disease. Cysteine protease (CP) activities have been suggested to be involved in Giardia's pathogenesis and we have recently identified and characterized three secreted Giardia CPs; CP14019, CP16160 and CP16779. Here we have studied the cleavage specificity of these CPs using substrate phage display and recombinant protein substrates. The phage display analyses showed that CP16160 has both chymase and tryptase activity and a broad substrate specificity...
November 17, 2018: Molecular and Biochemical Parasitology
Hans-Dirk Düngen, Lars Kober, Savina Nodari, Morten Schou, Christiane Otto, Michael Becka, Friederike Kanefendt, Bernhard R Winkelmann, Gunnar Gislason, Frank Richard, Olav Wendelboe Nielsen, Mihai Gheorghiade, Michele Senni
The chymase inhibitor fulacimstat is developed as a first-in-class treatment option for the inhibition of adverse cardiac remodeling in patients with left ventricular dysfunction (LVD) after acute myocardial infarction (MI). The aim of the study was to examine the safety and tolerability of fulacimstat in patients with LVD after remote MI. A multicenter, multinational randomized, placebo-controlled study was performed in clinically stable patients (40-79 years of age, left ventricular ejection fraction ≤ 45% because of MI in medical history) who were on stable evidence-based standard-of-care therapies for LVD post-MI including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker at doses of at least half the recommended target dose...
November 19, 2018: Clinical Pharmacology in Drug Development
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