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Pancreatic enzyme inhibitor

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https://www.readbyqxmd.com/read/28062577/overlapping-specificity-of-duplicated-human-pancreatic-elastase-3-isoforms-and-archetypal-porcine-elastase-1-provides-clues-to-evolution-of-digestive-enzymes
#1
Eszter Boros, Katalin Zboray, Dávid Héja, Gábor Pál, Miklós Sahin-Tóth
Chymotrypsin-like elastases (CELAs) are pancreatic serine proteinases which digest dietary proteins. CELAs are typically expressed in multiple isoforms which can vary among different species. The human pancreas does not express CELA1 but secretes two CELA3 isoforms, CELA3A and CELA3B. The reason for the CELA3 duplication and the substrate preferences of the duplicated isoforms are unclear. Here, we tested whether CELA3A and CELA3B evolved unique substrate specificities to compensate for the loss of CELA1. We constructed a phage library displaying variants of the substrate-like Schistocerca gregaria proteinase inhibitor 2 (SGPI-2) to select reversible, high-affinity inhibitors of human CELA3A, CELA3B, and porcine CELA1...
January 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28040595/euphorbia-denticulata-lam-a-promising-source-of-phyto-pharmaceuticals-for-the-development-of-novel-functional-formulations
#2
Gokhan Zengin, Ahmet Uysal, Abdurrahman Aktumsek, Andrei Mocan, Adriano Mollica, Marcello Locatelli, Luisa Custodio, Nuno R Neng, José M F Nogueira, Zaahira Aumeeruddy-Elalfi, M Fawzi Mahomoodally
In this study, Methanolic extracts of Euphorbia denticulata parts (flowers, leaf, stem, and mix of aerial parts) were assessed for a panoply of bioactivities. Inhibitory potential against key enzymes involved in diabetes (α-glucosidase and α-amylase), obesity (pancreatic lipase), neurodegenerative diseases (cholinesterases), and hyperpigmentation (tyrosinase) was evaluated. The antioxidant and antibacterial properties were also assessed. The total phenolic, flavonoid, and phytochemical profile were established using HPLC/DAD and molecular modelling studies on specific target compounds were performed in silico...
December 29, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27998910/pancreatic-effects-of-liraglutide-or-sitagliptin-in-overweight-patients-with-type-2-diabetes-a-12-week-randomized-placebo-controlled-trial
#3
Mark M Smits, Lennart Tonneijck, Marcel H A Muskiet, Mark H H Kramer, Indra C Pieters-van den Bos, Karuna E W Vendrik, Trynke Hoekstra, Marco J Bruno, Michaela Diamant, Daniël H van Raalte, Djuna L Cahen
OBJECTIVE: To assess the mechanistic effects of the glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide and the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin on (exocrine) pancreatic physiology and morphology. RESEARCH DESIGN AND METHODS: For this randomized, double-blind, parallel-group trial, 55 patients with type 2 diabetes treated with metformin and/or sulfonylurea agents were included. Participants received liraglutide 1.8 mg (n = 19), sitagliptin 100 mg (n = 19), or matching placebos (n = 17) once daily for 12 weeks...
December 20, 2016: Diabetes Care
https://www.readbyqxmd.com/read/27992105/cyclobutanone-analogues-of-%C3%AE-lactam-antibiotics-%C3%AE-lactamase-inhibitors-with-untapped-potential
#4
Prarthana Devi, Peter J Rutledge
β-Lactam antibiotics have been used for many years to treat bacterial infections. However the effective treatment of an increasing range of microbial infections is threatened by bacterial resistance to β-lactams: the prolonged, widespread and at times reckless use of these drugs has spawned widespread resistance, which renders them ineffective against many bacterial strains. The cyclobutanone ring system is isosteric with β-lactam: in cyclobutanone analogues, the eponymous cyclic amide is replaced with an all-carbon ring, the amide N substituted by a tertiary C-H α to a ketone...
December 19, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/27923620/fluorescent-diphenylphosphonate-based-probes-for-detection-of-serine-protease-activity-during-inflammation
#5
Laura E Edgington-Mitchell, Nicholas Barlow, Luigi Aurelio, Aminath Samha, Monika Szabo, Bim Graham, Nigel Bunnett
Activity-based probes are small molecules that covalently bind to the active site of a protease in an activity-dependent manner. We synthesized and characterized two fluorescent activity-based probes that target serine proteases with trypsin-like or elastase-like activity. We assessed the selectivity and potency of these probes against recombinant enzymes and demonstrated that while they are efficacious at labeling active proteases in complex protein mixtures in vitro, they are less valuable for in vivo studies...
January 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27904116/symptomatic-acute-pancreatitis-induced-by-nilotinib-a-report-of-two-cases
#6
Toshiki Yamada, Yasuhito Nannya, Masahito Shimizu, Mitsuru Seishima, Hisashi Tsurumi
Nilotinib is a selective tyrosine kinase inhibitor for the treatment of Philadelphia chromosome-positive leukemias. An elevation of the pancreatic enzyme level is one of the major adverse events associated with nilotinib, but whether or not nilotinib induces symptomatic pancreatitis remains to be elucidated. The cases of two chronic myeloid leukemia patients treated with nilotinib who developed symptomatic acute pancreatitis on the third and fifth day of nilotinib administration are herein presented. Since both patients had no other etiologies for pancreatitis, nilotinib was considered to be the causal agent...
2016: Internal Medicine
https://www.readbyqxmd.com/read/27846200/the-use-of-drugs-acting-on-the-renin-angiotensin-system-and-the-incidence-of-pancreatic-cancer
#7
Victoria Mandilaras, Nathaniel Bouganim, Hui Yin, Jamil Asselah, Laurent Azoulay
BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensives. Recently, these drugs have been associated with a protective effect against pancreatic cancer, but data on this putative association remain limited. Thus, the objective of this study was to determine whether the use of ACEIs and/or ARBs is associated with a decreased risk of pancreatic cancer. METHODS: We conducted a population-based cohort study, using a nested case-control analysis within the UK Clinical Practice Research Datalink population...
January 3, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/27836541/substituted-e-2-2-benzylidenehydrazinyl-4-methylthiazole-5-carboxylates-as-dual-inhibitors-of-15-lipoxygenase-carbonic-anhydrase-ii-synthesis-biochemical-evaluation-and-docking-studies
#8
Aamer Saeed, Shafi Ullah Khan, Parvez Ali Mahesar, Pervaiz Ali Channar, Ghulam Shabir, Jamshed Iqbal
15-Lipoxygenase (15-LOX) plays a major role in many inflammatory lung diseases including chronic obstructive pulmonary disease (COPD), asthma and chronic bronchitis. Over-expression of 15-LOX is related with some specific carcinomas including pancreatic, gastric and brain tumor. Similarly among different isozymes of carbonic anhydrase (CA), CA II is expressed in pancreatic, gastric carcinomas as well as in brain tumors. Therefore, novel potent inhibitors of both 15-LOX and CA II are required to explore the role of these enzymes further and to enable the drug discovery efforts...
January 1, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27825371/effective-and-safe-proton-pump-inhibitor-therapy-in-acid-related-diseases-a-position-paper-addressing-benefits-and-potential-harms-of-acid-suppression
#9
EDITORIAL
Carmelo Scarpignato, Luigi Gatta, Angelo Zullo, Corrado Blandizzi
BACKGROUND: The introduction of proton pump inhibitors (PPIs) into clinical practice has revolutionized the management of acid-related diseases. Studies in primary care and emergency settings suggest that PPIs are frequently prescribed for inappropriate indications or for indications where their use offers little benefit. Inappropriate PPI use is a matter of great concern, especially in the elderly, who are often affected by multiple comorbidities and are taking multiple medications, and are thus at an increased risk of long-term PPI-related adverse outcomes as well as drug-to-drug interactions...
November 9, 2016: BMC Medicine
https://www.readbyqxmd.com/read/27793122/acute-pancreatitis-associated-with-everolimus-after-kidney-transplantation-a-case-report
#10
Francesco Fontana, Gianni Cappelli
BACKGROUND: Acute pancreatitis (AP) following KT is a rare and often fatal complication of the early post-transplant period. Common causative factors for AP are rare after KT; anti-rejection drugs as CyA, prednisone and MMF have been implicated, although evidence is not strong and we found no reports on possible causative role for mTOR inhibitors. CASE PRESENTATION: A 55-year-old Caucasian man with end-stage renal disease due to idiopathic membrano-prolipherative glomerulonephritis underwent single kidney transplantation (KT) from cadaveric donor...
October 28, 2016: BMC Nephrology
https://www.readbyqxmd.com/read/27779720/pace4-regulates-apoptosis-in-human-pancreatic-cancer-panc%C3%A2-1-cells-via-the-mitochondrial-signaling-pathway
#11
Xiao-Feng Tian, Guo-Min Huang, Hong-Liang Zang, Hong Cao
Previous studies have demonstrated the overexpression of paired basic amino acid cleaving enzyme 4 (PACE4) mRNA in prostate cancer tissues. This overexpression is correlated with higher circulating protein levels in certain patients, however, the role of PACE4 in apoptosis and the potential molecular mechanisms of pancreatic cancer remain to be elucidated. The aim of the present study was to investigate the effect and potential molecular mechanisms of PACE4 on apoptosis in the Panc‑1 pancreatic cancer cell line...
December 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27778022/upregulation-of-cystathionine-%C3%AE-synthetase-in-the-arcuate-nucleus-produces-pain-hypersensitivity-via-pkc-upregulation-and-glun2b-phosphorylation-in-rats-with-chronic-pancreatitis
#12
Hang Zheng, Hong-Yan Zhu, Xiao-Yu Zhang, Meng Wang, Ying Xiao, Guang-Yin Xu, Xing-Hong Jiang
Hydrogen sulfide (H2S) contributes to visceral hyperalgesia in primary sensory neurons, but its role in central nervous system remains largely unknown. This study was to investigate the roles and underlying mechanisms of H2S and its endogenous synthesis enzymes in the arcuate nucleus (ARC) in rat pancreatic hyperalgesia. Chronic pancreatitis (CP) was induced in male adult Sprague-Dawley rats by intra-pancreatic ductal injection of trinitrobenzene sulfonic acid (TNBS). Abdominal hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen...
October 25, 2016: Sheng Li Xue Bao: [Acta Physiologica Sinica]
https://www.readbyqxmd.com/read/27750213/acetyl-coa-carboxylase-inhibitors-attenuate-wnt-and-hedgehog-signaling-and-suppress-pancreatic-tumor-growth
#13
Elissaveta Petrova, Arne Scholz, Juliane Paul, Andrea Sturz, Katja Haike, Franziska Siegel, Dominik Mumberg, Ningshu Liu
Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in de novo fatty acid synthesis, and its ACC1 isoform is overexpressed in pancreatic and various other cancers. The activity of many oncogenic signaling molecules, including WNT and Hedgehog (HH), is post-translationally modified by lipidation. Here, we report that inhibition of ACC by a small molecule inhibitor, BAY ACC002, blocked WNT3A lipidation, secretion, and signaling. In pancreatic cancer cells, where WNT and HH are key oncogenic drivers, ACC inhibition simultaneously suppressed WNT and HH signaling, and led to anti-proliferative effects...
October 13, 2016: Oncotarget
https://www.readbyqxmd.com/read/27745548/enzyme-driven-chemo-and-radiation-therapy-with-12-pyrimidine-nucleoside-analogs-not-yet-in-the-clinic
#14
Sheldon Greer, Tieran Han, Cristina Dieguez, Nicola McLean, Rafael Saer, Isildinha Reis, Joe Levi, Victor E Marquez
Enzymatic activity from tumor and adjacent normal tissue of 200 patients involving deoxycytidine kinase (dCK), uridine/cytidine kinase (U/CK), cytidine deaminase (CD) and deoxycytidylate deaminase (dCMPD) was quantified. . Patients with brain (17), colon (24), and breast (30) tumors, 53, 67, and 73%, respectively, had an elevated T/N value (Specific Activity of tumor/ Specific Activity of normal tissue) involving dCK and dCMPD suggesting chemo therapy with 5-fluorodeoxycytidine (5-FdC) alone or in combination with thymidine plus deoxytetrahydrouridine, or with the radiosensitizer, 5-chlorodeoxycytidine (5-CldC) plus tetrahydrouridine (H4U)...
October 13, 2016: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/27739027/an-indispensable-role-of-cpt-1a-to-survive-cancer-cells-during-energy-stress-through-rewiring-cancer-metabolism
#15
Jingtao Luo, Yun Hong, Xiaoan Tao, Xi Wei, Lun Zhang, Qiang Li
Unlike normal cells, cancer cells are recently identified to rely on aerobic glycolysis for energy production called the Warburg effect. Several attempts are being made to target this metabolic reprogramming pathway in treating cancers; however, the successful rate is very limited. In this study, we investigated the functional roles of fatty acid oxidation key enzyme carnitine palmitoyl transferase 1a (CPT-1a), during the metabolic programming of pancreatic ductal adenocarcinoma (PDAC) cells induced by glucose deprivation...
October 13, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/27708394/fragment-based-de-novo-design-of-a-cystathionine-%C3%AE-lyase-selective-inhibitor-blocking-hydrogen-sulfide-production
#16
Angela Corvino, Beatrice Severino, Ferdinando Fiorino, Francesco Frecentese, Elisa Magli, Elisa Perissutti, Vincenzo Santagada, Mariarosaria Bucci, Giuseppe Cirino, Geoff Kelly, Luigi Servillo, Grzegorz Popowicz, Annalisa Pastore, Giuseppe Caliendo
Hydrogen sulfide is an essential catabolite that intervenes in the pathophysiology of several diseases from hypertension to stroke, diabetes and pancreatitis. It is endogenously synthesized mainly by two pyridoxal-5'-phosphate-dependent enzymes involved in L-cysteine metabolism: cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE). Research in this field is currently impaired by the lack of pharmacological tools such as selective enzymatic inhibitors that could target specifically only one of these pathways...
October 6, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27663206/antiobesity-and-antihyperglycaemic-effects-of-adiantum-capillus-veneris-extracts-in-vitro-and-in-vivo-evaluations
#17
Violet Kasabri, Entisar K Al-Hallaq, Yasser K Bustanji, Khalid K Abdul-Razzak, Ismail F Abaza, Fatma U Afifi
CONTEXT: Adiantum capillus-veneris L. (Adiantaceae) hypocholesterolemic activity is therapeutically praised. OBJECTIVES: Pharmacological modulation of pancreatic triacylglycerol lipase (PL) and α-amylase/α-glucosidase by A. capillus-veneris are evaluated. MATERIALS AND METHODS: Using positive controls (acarbose, orlistat, guar gum, atorvastatin, glipizide and metformin) as appropriate, crude aqueous extracts (AEs) of A. capillus-veneris aerial parts were tested via a combination of in vitro enzymatic (0...
December 2017: Pharmaceutical Biology
https://www.readbyqxmd.com/read/27637085/dual-oxidase2-and-pancreatic-adenocarcinoma-ifn-%C3%AE-mediated-dual-oxidase2-overexpression-results-in-h2o2-induced-erkassociated-up-regulation-of-hif-1%C3%AE-and-vegf-a
#18
Yongzhong Wu, Jennifer L Meitzler, Smitha Antony, Agnes Juhasz, Jiamo Lu, Guojian Jiang, Han Liu, Melinda Hollingshead, Diana C Haines, Donna Butcher, Michaela S Panter, Krishnendu Roy, James H Doroshow
Several NADPH oxidase family members, including dual oxidase 2 [DUOX2], are expressed in human tumors, particularly gastrointestinal cancers associated with long-standing chronic inflammation. We found previously that exposure of pancreatic ductal adenocarcinoma cells to the pro-inflammatory cytokine IFN-γ increased DUOX2 expression (but not other NADPH oxidases) leading to long-lived H2O2 production. To elucidate the pathophysiology of DUOX2-mediated H2O2 formation in the pancreas further, we demonstrate here that IFN-γ-treated BxPC-3 and CFPAC-1 pancreatic cancer cells (known to increase DUOX2 expression) produce significant levels of intracellular oxidants and extracellular H2O2 which correlate with concomitant up-regulation of VEGF-A and HIF-1α transcription...
October 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27617390/an-in-vivo-multiplexed-small-molecule-screening-platform
#19
Barbara M Grüner, Christopher J Schulze, Dian Yang, Daisuke Ogasawara, Melissa M Dix, Zoë N Rogers, Chen-Hua Chuang, Christopher D McFarland, Shin-Heng Chiou, J Mark Brown, Benjamin F Cravatt, Matthew Bogyo, Monte M Winslow
Phenotype-based small-molecule screening is a powerful method to identify molecules that regulate cellular functions. However, such screens are generally performed in vitro under conditions that do not necessarily model complex physiological conditions or disease states. Here, we use molecular cell barcoding to enable direct in vivo phenotypic screening of small-molecule libraries. The multiplexed nature of this approach allows rapid in vivo analysis of hundreds to thousands of compounds. Using this platform, we screened >700 covalent inhibitors directed toward hydrolases for their effect on pancreatic cancer metastatic seeding...
October 2016: Nature Methods
https://www.readbyqxmd.com/read/27614430/bis-acetylacetonato-oxidovanadium-iv-and-sodium-metavanadate-inhibit-cell-proliferation-via-ros-induced-sustained-mapk-erk-activation-but-with-elevated-akt-activity-in-human-pancreatic-cancer-aspc-1-cells
#20
Jing-Xuan Wu, Yi-Hua Hong, Xiao-Gai Yang
In this study, the antiproliferative effect of bis(acetylacetonato)-oxidovanadium(IV) and sodium metavanadate and the underlying mechanisms were investigated in human pancreatic cancer cell line AsPC-1. The results showed that both exhibited an antiproliferative effect through inducing G2/M cell cycle arrest and can also cause elevation of reactive oxygen species (ROS) levels in cells. Moreover, the two vanadium compounds induced the activation of both PI3K/AKT and MAPK/ERK signaling pathways dose- and time-dependently, which could be counteracted with the antioxidant N-acetylcysteine...
September 10, 2016: Journal of Biological Inorganic Chemistry: JBIC
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