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signal peptidase

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https://www.readbyqxmd.com/read/29137240/mutational-re-modeling-of-di-aspartyl-intramembrane-proteases-uncoupling-physiologically-relevant-activities-from-those-associated-with-alzheimer-s-disease
#1
Anastasia P Grigorenko, Youri K Moliaka, Olga V Plotnikova, Alexander Smirnov, Vera A Nikishina, Andrey Y Goltsov, Fedor Gusev, Tatiana V Andreeva, Omar Nelson, Ilya Bezprozvanny, Evgeny I Rogaev
The intramembrane proteolytic activities of presenilins (PSEN1/PS1 and PSEN2/PS2) underlie production of β-amyloid, the key process in Alzheimer's disease (AD). Dysregulation of presenilin-mediated signaling is linked to cancers. Inhibition of the γ-cleavage activities of PSENs that produce Aβ, but not the ε-like cleavage activity that release physiologically essential transcription activators, is a potential approach for the development of rational therapies for AD. In order to identify whether different activities of PSEN1 can be dissociated, we designed multiple mutations in the evolutionary conserved sites of PSEN1...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29130686/thioamide-substitution-selectively-modulates-proteolysis-and-receptor-activity-of-therapeutic-peptide-hormones
#2
Xing Chen, Elizabeth G Mietlicki-Baase, Taylor M Barrett, Lauren E McGrath, Kieran Koch-Laskowski, John J Ferrie, Matthew R Hayes, E James Petersson
Peptide hormones are attractive as injectable therapeutics and imaging agents, but they often require extensive modification by mutagenesis and/or chemical synthesis to prevent rapid in vivo degradation. Alternatively, the single-atom, O-to-S modification of peptide backbone thioamidation has the potential to selectively perturb interactions with proteases while preserving interactions with other proteins, such as target receptors. Here, we use the validated diabetes therapeutic, glucagon-like peptide-1 (GLP-1), and the target of clinical investigation, gastric inhibitory polypeptide (GIP), as proof-of-principle peptides to demonstrate the value of thioamide substitution...
November 13, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29122893/prospective-postmarketing-surveillance-of-acute-myocardial-infarction-in-new-users-of-saxagliptin-a-population-based-study
#3
Sengwee Toh, Marsha E Reichman, David J Graham, Christian Hampp, Rongmei Zhang, Melissa G Butler, Aarthi Iyer, Malcolm Rucker, Madelyn Pimentel, Jack Hamilton, Samuel Lendle, Bruce H Fireman
OBJECTIVE: The cardiovascular safety of saxagliptin, a dipeptidyl-peptidase 4 inhibitor, compared with other antihyperglycemic treatments is not well understood. We prospectively examined the association between saxagliptin use and acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS: We identified patients aged ≥18 years, starting from the approval date of saxagliptin in 2009 and continuing through August 2014, using data from 18 Mini-Sentinel data partners...
November 9, 2017: Diabetes Care
https://www.readbyqxmd.com/read/29115211/measurement-of-gastrointestinal-hormones
#4
Nicolai J Wewer Albrechtsen
Towards the end of the 20th century, the number of subjects with diabetes and obesity rose exponentially. The discoveries of insulin- and appetite-modulating chemical signals, including glucagon-like peptide-1 (GLP-1), secreted from the gastrointestinal system, led to development of a new group of drugs which now are being used for glucose-lowering therapy and weight loss. Understanding of the physiology of gut derived signals and their pathophysiologi-cal importance requires accurate measurements of their circulat-ing levels...
November 2017: Danish Medical Journal
https://www.readbyqxmd.com/read/29114002/sdf-1%C3%AE-stromal-cell-derived-factor-1%C3%AE-induces-cardiac-fibroblasts-renal-microvascular-smooth-muscle-cells-and-glomerular-mesangial-cells-to-proliferate-cause-hypertrophy-and-produce-collagen
#5
Edwin K Jackson, Yumeng Zhang, Delbert D Gillespie, Xiao Zhu, Dongmei Cheng, Travis C Jackson
BACKGROUND: Activated cardiac fibroblasts (CFs), preglomerular vascular smooth muscle cells (PGVSMCs), and glomerular mesangial cells (GMCs) proliferate, cause hypertrophy, and produce collagen; in this way, activated CFs contribute to cardiac fibrosis, and activated PGVSMCs and GMCs promote renal fibrosis. In heart and kidney diseases, SDF-1α (stromal cell-derived factor 1α; endogenous CXCR4 [C-X-C motif chemokine receptor 4] receptor agonist) levels are often elevated; therefore, it is important to know whether and how the SDF-1α/CXCR4 axis activates CFs, PGVSMCs, or GMCs...
November 7, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29082232/ydj1-governs-fungal-morphogenesis-and-stress-response-and-facilitates-mitochondrial-protein-import-via-mas1-and-mas2
#6
Jinglin L Xie, Iryna Bohovych, Erin O Y Wong, Jean-Philippe Lambert, Anne-Claude Gingras, Oleh Khalimonchuk, Leah E Cowen, Michelle D Leach
Mitochondria underpin metabolism, bioenergetics, signalling, development and cell death in eukaryotes. Most of the ~1,000 yeast mitochondrial proteins are encoded in the nucleus and synthesised as precursors in the cytosol, with mitochondrial import facilitated by molecular chaperones. Here, we focus on the Hsp40 chaperone Ydj1 in the fungal pathogen Candida albicans, finding that it is localised to both the cytosol and outer mitochondrial membrane, and is required for cellular stress responses and for filamentation, a key virulence trait...
October 2, 2017: Microbial Cell
https://www.readbyqxmd.com/read/29079626/compartmentalization-of-carbaryl-degradation-pathway-molecular-characterization-of-inducible-periplasmic-carbaryl-hydrolase-from-pseudomonas-spp
#7
Kamini Gautam, Dasvit Shetty, Vikas D Trivedi, Madhushri Varunjikar, Prashant S Phale
Pseudomonas sp. strains C5pp and C7 degrade carbaryl as the sole carbon source. Carbaryl hydrolase (CH) catalyzes the hydrolysis of carbaryl to 1-naphthol and methylamine. Bioinformatic analysis of mcbA encoding CH in C5pp predicted it to have a transmembrane domain (Tmd) and a signal peptide (Sp). In these isolates, the activity of CH was found to be 4 to 6-fold higher in the periplasm as compared to the cytoplasm. The recombinant CH (rCH) showed 4-fold higher activity in the periplasm of Escherichia coli The deletion of Tmd showed activity in the cytoplasmic fraction, while deletion of Tmd+Sp resulted in expression of the inactive protein...
October 27, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/29054111/dipeptidyl-peptidase-4-inhibitors-attenuates-the-decline-of-skeletal-muscle-mass-in-patients-with-type-2-diabetes
#8
Ryotaro Bouchi, Tatsuya Fukuda, Takato Takeuchi, Yujiro Nakano, Masanori Murakami, Isao Minami, Hajime Izumiyama, Koshi Hashimoto, Takanobu Yoshimoto, Yoshihiro Ogawa
BACKGROUND: Activation of dipeptidyl peptidase 4 (DPP4) has been reported to be associated with impairment of insulin signaling in skeletal muscle mass, presumably leading to loss of muscle function. This study was aimed to investigate whether the use of DPP4 inhibitors (DPP4i) could attenuate the progressive loss of muscle mass in patients with type 2 diabetes. METHODS: A total 105 patients with type 2 diabetes (mean age 62 ± 12 years; 39% female) were studied in this retrospective observational study...
October 20, 2017: Diabetes/metabolism Research and Reviews
https://www.readbyqxmd.com/read/29040650/interferon-alpha-reduces-human-hippocampal-neurogenesis-and-increases-apoptosis-via-activation-of-distinct-stat1-dependent-mechanisms
#9
Alessandra Borsini, Annamaria Cattaneo, Chiara Malpighi, Sandrine Thuret, Neil A Harrison, Patricia A Zunszain, Carmine M Pariante
Background: In humans, interferon-α treatment for chronic viral hepatitis is a well-recognized clinical model for inflammation-induced depression, but the molecular mechanisms underlying these effects are not clear. Following peripheral administration in rodents, interferon-α induces signal transducer and activator of transcription-1 (STAT1) within the hippocampus and disrupts hippocampal neurogenesis. Methods: We used the human hippocampal progenitor cell line HPC0A07/03C to evaluate the effects of 2 concentrations of interferon-α, similar to those observed in human serum during its therapeutic use (500 pg/mL and 5000 pg/mL), on neurogenesis and apoptosis...
October 10, 2017: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29040423/title-therapeutic-strategies-utilising-sdf-1%C3%AE-in-ischaemic-cardiomyopathy
#10
Oliver J Ziff, Daniel I Bromage, Derek M Yellon, Sean M Davidson
Heart failure is rapidly increasing in prevalence and will redraw the global landscape for cardiovascular health. Alleviating and repairing cardiac injury associated with myocardial infarction (MI) is key to improving this burden. Homing signals mobilise and recruit stem cells to the ischaemic myocardium where they exert beneficial paracrine effects. The chemoattractant cytokine SDF-1α and its associated receptor CXCR4 are upregulated after MI and appear to be important in this context. Activation of CXCR4 promotes both cardiomyocyte survival and stem cell migration towards the infarcted myocardium...
October 13, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/29037205/vildagliptin-ameliorates-pulmonary-fibrosis-in-lipopolysaccharide-induced-lung-injury-by-inhibiting-endothelial-to-mesenchymal-transition
#11
Toshio Suzuki, Yuji Tada, Santhi Gladson, Rintaro Nishimura, Iwao Shimomura, Satoshi Karasawa, Koichiro Tatsumi, James West
BACKGROUND: Pulmonary fibrosis is a late manifestation of acute respiratory distress syndrome (ARDS). Sepsis is a major cause of ARDS, and its pathogenesis includes endotoxin-induced vascular injury. Recently, endothelial-to-mesenchymal transition (EndMT) was shown to play an important role in pulmonary fibrosis. On the other hand, dipeptidyl peptidase (DPP)-4 was reported to improve vascular dysfunction in an experimental sepsis model, although whether DPP-4 affects EndMT and fibrosis initiation during lipopolysaccharide (LPS)-induced lung injury is unclear...
October 16, 2017: Respiratory Research
https://www.readbyqxmd.com/read/29035292/secreted-expression-of-the-cap-gene-of-porcine-circovirus-type-2-in-classical-swine-fever-virus-c-strain-potential-of-c-strain-used-as-a-vaccine-vector
#12
Lingkai Zhang, Yongfeng Li, Libao Xie, Xiao Wang, Xulei Gao, Yuan Sun, Hua-Ji Qiu
Bivalent vaccines based on live attenuated viruses expressing a heterologous protein are an attractive strategy to address co-infections with various pathogens in the field. Considering the excellent efficacy and safety of the lapinized live attenuated vaccine C-strain (HCLV strain) of classical swine fever virus (CSFV), we proposed that C-strain has the potential as a viral vector for developing bivalent vaccines. To this end, we generated three recombinant viruses based on C-strain, one expressing the capsid (Cap) gene of porcine circovirus type 2 (PCV2) with the nuclear localization signal (NLS) (rHCLV-2ACap), and the other two expressing the PCV2 Cap gene without the NLS yet containing the signal peptide of the prolactin gene (rHCLV-pspCap) or that of the ubiquitin-specific peptidase gene (rHCLV-uspCap)...
October 16, 2017: Viruses
https://www.readbyqxmd.com/read/29031724/elevated-hepatic-dpp4-activity-promotes-insulin-resistance-and-non-alcoholic-fatty-liver-disease
#13
Christian Baumeier, Luisa Schlüter, Sophie Saussenthaler, Thomas Laeger, Maria Rödiger, Stella Amelie Alaze, Louise Fritsche, Hans-Ulrich Häring, Norbert Stefan, Andreas Fritsche, Robert Wolfgang Schwenk, Annette Schürmann
OBJECTIVE: Increased hepatic expression of dipeptidyl peptidase 4 (DPP4) is associated with non-alcoholic fatty liver disease (NAFLD). Whether this is causative for the development of NAFLD is not yet clarified. Here we investigate the effect of hepatic DPP4 overexpression on the development of liver steatosis in a mouse model of diet-induced obesity. METHODS: Plasma DPP4 activity of subjects with or without NAFLD was analyzed. Wild-type (WT) and liver-specific Dpp4 transgenic mice (Dpp4-Liv-Tg) were fed a high-fat diet and characterized for body weight, body composition, hepatic fat content and insulin sensitivity...
October 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28986832/assays-to-assess-arenaviral-glycoprotein-function
#14
Junjie Shao, Xiaoying Liu, Yuying Liang, Hinh Ly
Arenaviruses, such as Lassa virus (LASV) and Pichindé virus (PICV), are enveloped viruses with a bi-segmented ambisense RNA genome. The large (L) genomic segment encodes the Z matrix protein and the L RNA-dependent RNA polymerase, whereas the small (S) genomic segment encodes the nucleoprotein (NP) and the glycoprotein precursor complex (GPC). GPC is processed by signal peptidase in the endoplasmic reticulum into the stable signal peptide (SSP) and GP1/GP2, which is further cleaved by the Golgi-resident subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P) into the cellular receptor-recognition subunit GP1 and the transmembrane subunit GP2, which helps promote the membrane fusion reaction to allow virus entry into the cell...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28985353/loss-of-adamts3-activity-causes-hennekam-lymphangiectasia-lymphedema-syndrome-3
#15
Pascal Brouillard, Laura Dupont, Raphael Helaers, Richard Coulie, George E Tiller, Joseph Peeden, Alain Colige, Miikka Vikkula
Primary lymphedema is due to developmental and/or functional defects in the lymphatic system. It may affect any part of the body, with predominance for the lower extremities. Twenty-seven genes have already been linked to primary lymphedema, either isolated, or as part of a syndrome. The proteins that they encode are involved in VEGFR3 receptor signaling. They account for about one third of all primary lymphedema cases, underscoring the existence of additional genetic factors. We used whole-exome sequencing to investigate the underlying cause in a non-consanguineous family with two children affected by lymphedema, lymphangiectasia and distinct facial features...
November 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28982310/the-dipeptidyl-peptidase-iv-inhibitor-gemigliptin-alone-or-in-combination-with-nvp-auy922-has-a-cytotoxic-activity-in-thyroid-carcinoma-cells
#16
Si Hyoung Kim, Jun Goo Kang, Chul Sik Kim, Sung-Hee Ihm, Moon Gi Choi, Hyung Joon Yoo, Seong Jin Lee
The effect of the dipeptidyl peptidase-IV inhibitor gemigliptin alone or in combination with the heat shock protein 90 inhibitor NVP-AUY922 (AUY922) on survival of thyroid carcinoma cells was elucidated. The SW1736 and TPC-1 human thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, cytotoxic activity, the percentage of apoptotic cells, and mitochondrial membrane potential were measured. To evaluate the combined effect of gemigliptin with AUY922, the interactions were estimated by calculating combination index...
October 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28977602/dipeptidyl-peptidase-4-inhibition-with-saxagliptin-ameliorates-angiotensin-ii-induced-cardiac-diastolic-dysfunction-in-male-mice
#17
Scott M Brown, Cassandra E Smith, Alex I Meuth, Maloree Khan, Annayya R Aroor, Hannah M Cleeton, Gerald A Meininger, James R Sowers, Vincent G DeMarco, Bysani Chandrasekar, Ravi Nistala, Shawn B Bender
Activation of the renin-angiotensin-aldosterone system is common in hypertension and obesity and contributes to cardiac diastolic dysfunction, a condition for which no treatment currently exists. In light of recent reports that antihyperglycemia incretin enhancing dipeptidyl peptidase (DPP)-4 inhibitors exert cardioprotective effects, we examined the hypothesis that DPP-4 inhibition with saxagliptin (Saxa) attenuates angiotensin II (Ang II)-induced cardiac diastolic dysfunction. Male C57BL/6J mice were infused with either Ang II (500 ng/kg/min) or vehicle for 3 weeks receiving either Saxa (10 mg/kg/d) or placebo during the final 2 weeks...
October 1, 2017: Endocrinology
https://www.readbyqxmd.com/read/28963101/chronic-psychological-stress-accelerates-vascular-senescence-and-impairs-ischemia-induced-neovascularization-the-role-of-dipeptidyl-peptidase-4-glucagon-like-peptide-1-adiponectin-axis
#18
Limei Piao, Guangxian Zhao, Enbo Zhu, Aiko Inoue, Rei Shibata, Yanna Lei, Lina Hu, Chenglin Yu, Guang Yang, Hongxian Wu, Wenhu Xu, Kenji Okumura, Noriyuki Ouchi, Toyoaki Murohara, Masafumi Kuzuya, Xian Wu Cheng
BACKGROUND: Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular aging and regeneration. Given that dipeptidyl peptidase-4 (DPP4) regulates several intracellular signaling pathways associated with the glucagon-like peptide-1 (GLP-1) metabolism, we investigated the role of DPP4/GLP-1 axis in vascular senescence and ischemia-induced neovascularization in mice under chronic stress, with a special focus on adiponectin -mediated peroxisome proliferator activated receptor-γ/its co-activator 1α (PGC-1α) activation...
September 28, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28947828/fenugreek-compound-n55-lowers-plasma-glucose-through-the-enhancement-of-response-of-physiological-glucagon-like-peptide-1
#19
I-Wen Chou, Yu-Hong Cheng, Yet-Ran Chen, Patrick Ching-Ho Hsieh, Klim King
Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) analogues are approved for treating type 2 diabetes, but are known to activate GLP-1R signaling globally and constitutively. Active compound N55, previously isolated from fenugreek, enhances the potency of GLP-1 without activating GLP-1R. Here we investigated if N55 lowers plasma glucose base on physiological levels of GLP-1. N55 was found to dose-dependently lower plasma glucose in non-fasted mice but not in the fasted mice, with the effect attenuated by GLP-1R antagonist exendin-(9-39) (Ex-9)...
September 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28944167/regulation-of-cytotoxic-t-cell-responses-by-p53-in-cancer
#20
Mitchell W Braun, Tomoo Iwakuma
An intriguing aspect of the tumor suppressor p53 is its ability to communicate to the adaptive immune system and control the cytotoxic T-lymphocyte (CTL) response to cancer cells. Wild-type p53 (wtp53) communicates with CTLs through proteins involved in the major histocompatibility complex (MHC) class I antigen presentation pathway [e.g., transporter associated with antigen processing 1 (TAP1) and endoplasmic reticulum amino peptidase 1 (ERAP1)], the apoptosis signal receptor Fas/APO-1, and the inhibitory immune-checkpoint programmed death-ligand 1 (PD-L1)...
December 2016: Translational Cancer Research
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