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https://www.readbyqxmd.com/read/28808141/a-critical-role-for-plasma-kallikrein-in-the-pathogenesis-of-autoantibody-induced-arthritis
#1
Aizhen Yang, Junsong Zhou, Bo Wang, Jihong Dai, Robert W Colman, Wenchao Song, Yi Wu
The plasma kallikrein-kinin system (KKS) consists of serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-MW kininogen (HK). Upon activation, activated pKal and FXII cleave HK to release bradykinin. Activation of this system has been noted in patients with rheumatoid arthritis, and its pathogenic role has been characterized in animal arthritic models. In this study, we generated 2 knockout mouse strains that lacked pKal and HK and determined the role of KKS in autoantibody-induced arthritis...
August 14, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28805938/what-is-new-in-the-pathophysiology-of-acne-an-overview
#2
REVIEW
B Dréno
Acne is a chronic inflammatory disease of the pilosebaceous unit. Its pathophysiology includes hyperseborrhoea, abnormal follicular keratinization and Propionibacterium acnes proliferation in the pilosebaceous unit. Recent research has shed some new light on the involvement of the sebaceous gland, as well as on the pro-inflammatory activity of the cutaneous microbiome. During puberty, alteration of the sebaceous lipid profile, called dysseborrhoea, stress, irritation, cosmetics and potential dietary factors lead to inflammation and formation of different types of acne lesions...
September 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28802158/lipidation-increases-antiviral-activities-of-coronavirus-fusion-inhibiting-peptides
#3
Jung-Eun Park, Tom Gallagher
Coronaviruses (CoVs) can cause life-threatening respiratory diseases. Their infectious entry requires viral spike (S) proteins, which attach to cell receptors, undergo proteolytic cleavage, and then refold in a process that catalyzes virus-cell membrane fusion. Fusion-inhibiting peptides bind to S proteins, interfere with refolding, and prevent infection. Here we conjugated fusion-inhibiting peptides to various lipids, expecting this to secure peptides onto cell membranes and thereby increase antiviral potencies...
August 9, 2017: Virology
https://www.readbyqxmd.com/read/28801903/synthetic-tumor-specific-promoters-for-transcriptional-regulation-of-viral-replication
#4
Maria Veronica Lopez, Eduardo G Cafferata, Diego L Viale, Osvaldo L Podhajcer
Here we describe a collection of methods that have been adapted to isolate and modify tumor-specific promoters (TSPs ) to drive viral replication for cancer therapy and other uses. We will describe as examples the secreted protein acidic and rich in cysteine (SPARC ) and the protease-activated receptor-1 (PAR-1) promoter. We outline strategies to select appropriate TSPs using bioinformatics resources and the methods utilized in their subsequent cloning, assessment of transcriptional activity, and their use in conditionally replicative oncolytic adenoviruses ...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28797985/the-role-and-mechanism-of-cathepsin-g-in-dermatomyositis
#5
Siming Gao, Honglin Zhu, Huan Yang, Huali Zhang, Qiuxiang Li, Hui Luo
Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by CD4+ T cells and B cells infiltration in perivascular and muscle tissue. Although the infiltration of inflammatory cells plays a key role in muscle damage, the exact mechanism is not clear. Cathepsin G (CTSG) is a member of the serine proteases family and can increase the permeability of vascular endothelial cells and the chemotaxis of inflammatory cells. In this study, we found that the expression of CTSG was increased in peripheral blood mononuclear cells and muscle tissues of DM patients...
August 7, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28795730/role-of-garp-in-the-activation-of-latent-tgf-%C3%AE-1
#6
REVIEW
Julie Stockis, Olivier Dedobbeleer, Sophie Lucas
TGF-β1, 2 and 3 cytokines are involved in many cellular processes including cell proliferation, differentiation, migration and survival. Whereas TGF-β2 and 3 play important roles in embryonic development, TGF-β1 is mostly implicated in controlling immune responses after birth. The production of TGF-β1 is a tightly regulated process, occurring mostly at a post-translational level. Virtually all cells produce the latent, inactive form of TGF-β1. In latent TGF-β1, the mature TGF-β1 dimer is non-covalently associated to the Latency Associated Peptide, or LAP, which prevents binding to the TGF-β1 receptor...
August 10, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28777256/the-p-407-induced-mouse-model-of-dose-controlled-hyperlipidemia-and-atherosclerosis-twenty-five-years-later
#7
Thomas P Johnston, Tatyana A Korolenko, Amirhossein Sahebkar
The poloxamer 407 (P-407) non-genetic, non-diet-induced mouse model of dose-controlled hyperlipidemia and atherosclerosis was first introduced in 1992. Dyslipidemia is produced in C57BL/6 mice of either sex following the intraperitoneal administration of P-407, which is a polyether-based nonionic surface-active-agent. Aortic atherosclerotic lesions begin to form after 1 month of repeated P-407 administration and obtain maximum size, numerical density, and human-like pathological features by 4 months. Our laboratory published a review of this model in 2004, although an update would seem both appropriate and timely based on new findings since 2004...
August 4, 2017: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/28769809/apixaban-enhances-vasodilatation-mediated-by-protease-activated-receptor-2-in-isolated-rat-arteries
#8
Ambra Villari, Giovanni Giurdanella, Claudio Bucolo, Filippo Drago, Salvatore Salomone
Apixaban (APX) is a direct inhibitor of factor X (FXa) approved for prophylaxis and treatment of deep venous thrombosis and atrial fibrillation. Because FXa activates protease-activated receptor 2 (PAR-2) in endothelium and vascular smooth muscle, inhibition of FXa by APX may affect vasomotor function. The effect of APX was assessed in vitro, by wire myography, in rat mesenteric resistance arteries (MRAs) and basilar arteries challenged with vasoconstrictors [phenylephrine (PE); 5-hydroxytryptamine (5-HT)], vasodilators [acetylcholine (ACh); sodium nitroprusside (SNP)] or with the PAR-2 peptide agonist SLIGRL...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28769800/cathepsin-s-is-involved-in-th17-differentiation-through-the-upregulation-of-il-6-by-activating-par-2-after-systemic-exposure-to-lipopolysaccharide-from-porphyromonas-gingivalis
#9
Masato Dekita, Zhou Wu, Junjun Ni, Xinwen Zhang, Yicong Liu, Xu Yan, Hiroshi Nakanishi, Ichiro Takahashi
Positive links have been found between periodontitis and numerous diseases in humans via persistent inflammation throughout the body. However, the main factors responsible for maintaining this pro-inflammatory condition are poorly understood. The spleen, the largest secondary immune organ, is a central hub regulating the immune response/inflammation due to the dendritic cell (DC) response to CD4(+) T cell subtype differentiation, and lysosomal proteinase cathepsin S (CatS) is known to be involved in DC functions...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28768771/activation-of-mas-related-g-protein-coupled-receptors-by-the-house-dust-mite-cysteine-protease-der-p1-provides-a-new-mechanism-linking-allergy-and-inflammation
#10
Vemuri B Reddy, Ethan A Lerner
Cysteine and serine proteases function via protease-activated (PARs) and mas-related G-protein coupled receptors (Mrgprs) to contribute to allergy and inflammation. Der p1 is a cysteine protease and major allergen from the house dust mite and is associated with allergic rhinitis and allergic asthma. Der p1 activates PAR2 and induces the release of the pro-inflammatory cytokine IL-6 from cells. However, the possibility that Der p1 acts on Mrgprs has not been considered. We report here that ratiometric calcium imaging reveals that Der p1 activates the human receptor MRGPRX1 and the mouse homolog MrgprC11, implicated previously in itch...
August 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28765050/role-of-ubiquitination-and-proteolysis-in-the-regulation-of-pro-and-anti-apoptotic-tnf-r1-signaling
#11
Jürgen Fritsch, Philipp Zingler, Vinzenz Särchen, Anna Laura Heck, Stefan Schütze
Tumor Necrosis Factor Receptor 1 (TNF-R1) transmits various intracellular signaling cascades leading to diverse biological outcomes, ranging from proliferation, differentiation, survival to the induction of various forms of cell death (i.e. apoptosis, necrosis, necroptosis). These signaling pathways have to be tightly regulated. Proteolysis is an important regulatory mechanism in TNF-R1 pro-apoptotic as well as anti-apoptotic/pro-inflammatory signaling. Some key players in these signaling cascades are known (mainly the caspase-family of proteases and a previously unrecognized "lysosomal death pathway" involving cathepsins), however the interaction of proteases in the regulation of TNF signaling is still enigmatic...
July 29, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28760777/sumoylation-negatively-regulates-angiogenesis-by-targeting-endothelial-notch-signaling
#12
Xiaolong Zhu, Sha Ding, Cong Qiu, Yanna Shi, Lin Song, Yueyue Wang, Yuewen Wang, Jinying Li, Yiran Wang, Yi Sun, Lingfeng Qin, Jun Chen, Michael Simons, Wang Min, Luyang Yu
Rationale: The highly conserved NOTCH signaling pathway functions as a key cell-cell interaction mechanism controlling cell-fate and tissue patterning, while its dysregulation is implicated in a variety of developmental disorders and cancers. The pivotal role of endothelial NOTCH in regulation of angiogenesis is widely appreciated; however, little is known about what controls it signal transduction. Our previous study indicated the potential role of post-translational small ubiquitin-like modifier (SUMO) modification (SUMOylation) in vascular disorders...
July 31, 2017: Circulation Research
https://www.readbyqxmd.com/read/28759649/the-tetraspanin-cd9-facilitates-mers-coronavirus-entry-by-scaffolding-host-cell-receptors-and-proteases
#13
James T Earnest, Michael P Hantak, Kun Li, Paul B McCray, Stanley Perlman, Tom Gallagher
Infection by enveloped coronaviruses (CoVs) initiates with viral spike (S) proteins binding to cellular receptors, and is followed by proteolytic cleavage of receptor-bound S proteins, which prompts S protein-mediated virus-cell membrane fusion. Infection therefore requires close proximity of receptors and proteases. We considered whether tetraspanins, scaffolding proteins known to facilitate CoV infections, hold receptors and proteases together on cell membranes. Using knockout cell lines, we found that the tetraspanin CD9, but not the tetraspanin CD81, formed cell-surface complexes of dipeptidyl peptidase 4 (DPP4), the MERS-CoV receptor, and the type II transmembrane serine protease (TTSP) member TMPRSS2, a CoV-activating protease...
July 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28759300/par-1-and-par-2-expression-is-enhanced-in-inflamed-odontoblast-cells
#14
M M P Alvarez, G E Moura, M F M Machado, G M Viana, C A de Souza Costa, L Tjäderhane, H B Nader, I L S Tersariol, F D Nascimento
Protease-activated receptors (PARs) are G protein-coupled receptors, which are activated by proteolytical cleavage of the amino-terminus and act as sensors for extracellular proteases. We hypothesized that PAR-1 and PAR-2 can be modulated by inflammatory stimulus in human dental pulp cells. PAR-1 and PAR-2 gene expression in human pulp tissue and MDPC-23 cells were analyzed by quantitative polymerase chain reaction. Monoclonal PAR-1 and PAR-2 antibodies were used to investigate the cellular expression of these receptors using Western blot, flow cytometry, and confocal microscopy in MDPC-23 cells...
July 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/28755170/identification-and-validation-of-uterine-stimulant-methylergometrine-as-a-potential-inhibitor-of-caspase-1-activation
#15
Guillermo García-Laínez, Mónica Sancho, Vanessa García-Bayarri, Mar Orzáez
Inflammasomes are intracellular multiprotein complexes of the innate immune system. Upon an inflammatory insult, such as infection or intracellular damage, a nucleotide-binding oligomerization domain-like receptor (NLR) sensor protein and the adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) are assembled to activate protease procaspase-1. This protease processes pro-IL-1β and pro-IL-18 cytokines, which are released to induce the inflammatory response...
July 28, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/28754863/pathological-expression-of-tissue-factor-confers-promising-antitumor-response-to-a-novel-therapeutic-antibody-sc1-in-triple-negative-breast-cancer-and-pancreatic-adenocarcinoma
#16
Xuesai Zhang, Qingrou Li, Hui Zhao, Lanping Ma, Tao Meng, Jianchang Qian, Rui Jin, Jingkang Shen, Ker Yu
The pathological presence of tissue factor (TF) in cancer cells promotes tumor-initiated thrombosis and cancer metastasis. We found that TF is aberrantly present in large percentage of aggressive triple negative breast cancer (TNBC) and pancreatic adenocarcinoma (PaC), two most lethal forms of malignancy that urgently need effective treatment. TF expression in TNBC clustered with higher levels of vimentin, basal-type keratins KRT5/14 and caveolin-1 but lower levels of luminal-type biomarkers. We developed a novel and specific anti-TF therapeutic antibody SC1, which displayed an exceedingly high potency against TF extracellular domain (EC50: 0...
July 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28751819/effects-of-secreted-mast-cell-mediators-on-retinal-pigment-epithelial-cells-focus-on-mast-cell-tryptase
#17
Rei Arai, Ayumi Usui-Ouchi, Yosuke Ito, Keitaro Mashimo, Akira Murakami, Nobuyuki Ebihara
Numerous mast cells are present in the choroid, but the effects of mast cell mediators on retinal pigment epithelial (RPE) cells are not well understood. We investigated the influence of mast cell mediators on RPE cells in vitro, focusing on tryptase. Expression of receptors was examined by the reverse transcription polymerase chain reaction. We also assessed production of interleukin 8 and vascular endothelial growth factor (VEGF) after RPE cells were stimulated with mast cell mediators by using an antibody array and enzyme-linked immunosorbent assay...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28751379/the-interleukin-like-epithelial-mesenchymal-transition-inducer-ilei-exhibits-a-non-interleukin-like-fold-and-is-active-as-a-domain-swapped-dimer
#18
Anna M Jansson, Agnes Csiszar, Joachim Maier, Ann-Christin Nyström, Elisabeth Ax, Patrik Johansson, Lovisa Holmberg Schiavone
Production and secretion of pro-metastatic proteins is a feature of many tumor cells. The FAM3C Interleukin-like epithelial-to-mesenchymal-transition (EMT) inducer, ILEI has been shown to be strongly up-regulated in several cancers and to be essential for tumor formation and metastasis in epithelial cells, correlating with a significant decrease in overall survival in colon and breast cancer patients. ILEI has been seen to interact with the γ-secretase presenilin 1 subunit (PS1). However, not much is known about the mechanism-of-action or the detailed ILEI structure...
July 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28751263/improving-insect-control-protein-activity-for-gm-crops-a-case-study-demonstrating-that-increased-target-insect-potency-can-be-achieved-without-impacting-mammalian-safety
#19
Donna R Farmer, Thomas C Edrington, Colton R Kessenich, Cunxi Wang, Jay S Petrick
Many insect-protected crops express insecticidal crystal (Cry) proteins derived from the soil bacterium Bacillus thuringiensis (Bt), including both naturally-occurring Cry proteins and chimeric Cry proteins created through biotechnology. The Cry51Aa2 protein is a naturally-occurring Cry protein that was modified to increase its potency and expand its insect activity spectrum through amino acid sequence changes. The improved Cry51Aa2 variant, Cry51Aa2.834_16, and other developmental variants belong to the ETX_MTX2 family of proteins but share a low level of sequence similarity to other members of this family...
July 24, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28745507/discovery-of-potent-orally-active-protease-activated-receptor-1-par1-antagonists-based-on-andrographolide
#20
Jun Liu, Bin Sun, Xiaoyu Zhao, Jie Xing, Yanhui Gao, Wenqiang Chang, Jianbo Ji, Hongbo Zheng, Changyi Cui, Aiguo Ji, Hong-Xiang Lou
Protease-activated receptor-1 (PAR1), a G protein-coupled receptor, plays a critical role in thrombin-mediated platelet aggregation. It is regarded as a promising antithrombosis target that is unlikely to result in bleeding. Here, we describe the synthesis of a series of novel PAR1 antagonists by borrowing the chiral fragment of andrographolide, an easily accessible natural molecule from Andrographis paniculata, to produce natural product/synthesis hybrids. An in vitro PAR1 inhibition assay and an in vivo pharmacokinetic profile led to the identification of compound 39 as the best PAR1 inhibitor...
July 26, 2017: Journal of Medicinal Chemistry
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