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Pancreatic enzyme inhibitor

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https://www.readbyqxmd.com/read/28213892/opportunities-for-repurposing-of-poly-adp-ribose-polymerase-parp-inhibitors-for-the-therapy-of-non-oncological-diseases
#1
REVIEW
Nathan A Berger, Valerie C Besson, A Hamid Boulares, Alexander Bürkle, Alberto Chiarugi, Robert S Clark, Nicola J Curtin, Salvatore Cuzzocrea, Ted M Dawson, Valina L Dawson, György Haskó, Lucas Liaudet, Flavio Moroni, Pál Pacher, Peter Radermacher, Andrew L Salzman, Solomon H Snyder, Francisco Garcia Soriano, Robert P Strosznajder, Balázs Sümegi, Raymond A Swanson, Csaba Szabo
The recent clinical availability of the PARP inhibitor Lynparza (olaparib) opens the door for potential therapeutic repurposing for non-oncological indications. Considering (a) the preclinical efficacy data with PARP inhibitors in non-oncological diseases and (b) the risk-benefit ratio of treating patients with a compound that inhibits an enzyme that has physiological roles in the regulation of DNA repair, indications where (a) the severity of the disease is high, (b) the available therapeutic options are limited, and (c) the duration of PARP inhibitor administration could be short, provide first-line options for therapeutic repurposing...
February 18, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28186401/chemoproteomic-screening-of-covalent-ligands-reveals-uba5-as-a-novel-pancreatic-cancer-target
#2
Allison M Roberts, David K Miyamoto, Tucker R Huffman, Leslie A Bateman, Ashley N Ives, David Akopian, Martin J Heslin, Carlo M Contreras, Michael Rape, Christine F Skibola, Daniel K Nomura
Chemical genetic screening of small-molecule libraries has been a promising strategy for discovering unique and novel therapeutic compounds. However, identifying the targets of lead molecules that arise from these screens has remained a major bottleneck in understanding the mechanism of action of these compounds. Here, we have coupled the screening of a cysteine-reactive fragment-based covalent ligand library with an isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) chemoproteomic platform to rapidly couple the discovery of lead small molecules that impair pancreatic cancer pathogenicity with the identification of druggable hotspots for potential cancer therapy...
February 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28170007/lactucaxanthin-a-potential-anti-diabetic-carotenoid-from-lettuce-lactuca-sativa-inhibits-%C3%AE-amylase-and-%C3%AE-glucosidase-activity-in-vitro-and-in-diabetic-rats
#3
Sowmya Shree Gopal, Magisetty Jhansi Lakshmi, Gurunathan Sharavana, Gunaseelan Sathaiah, Yadahally N Sreerama, Vallikannan Baskaran
Intestinal and pancreatic α-amylase and α-glucosidase inhibitors offer an approach to lower the levels of post-prandial hyperglycemia through the control of dietary starch breakdown in digestion. This study hypothesized that lactucaxanthin (Lxn) in lettuce (Lactuca sativa) inhibits the activity of α-amylase and α-glucosidase. In this study, the interaction of Lxn with α-amylase and α-glucosidase in silico and its inhibitory effect on these enzymes were studied using in vitro and STZ-induced diabetic rat models...
February 7, 2017: Food & Function
https://www.readbyqxmd.com/read/28167504/inhibition-of-isoprenylcysteine-carboxylmethyltransferase-induces-cell-cycle-arrest-and-apoptosis-through-p21-and-p21-regulated-bnip3-induction-in-pancreatic-cancer
#4
Kanjoormana Aryan Manu, Tin Fan Chai, Jing Tsong Teh, Wan Long Zhu, Patrick J Casey, Mei Wang
Pancreatic cancer remains one of the most difficult to treat human cancers despite recent advances in targeted therapy. Inhibition of Isoprenylcysteine carboxylmethyltransferase (ICMT), an enzyme that post-translationally modifies a group of proteins including several small GTPases, suppresses proliferation of some human cancer cells. However, the efficacy of ICMT inhibition on human pancreatic cancer has not been evaluated. In this study we have evaluated a panel of human pancreatic cancer cell lines and identified those that are sensitive to ICMT inhibition...
February 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28157665/inhibition-of-cancer-migration-and-invasion-by-knocking-down-delta-5-desaturase-in-cox-2-overexpressed-cancer-cells
#5
Xiaoyu Yang, Yi Xu, Tao Wang, Dan Shu, Peixuan Guo, Keith Miskimins, Steven Y Qian
We recently reported that knockdown of delta-5-desaturase (a key enzyme that converts dihomo-γ-linolenic acid, DGLA, to the downstream ω-6 arachidonic acid) promotes formation of an anti-cancer byproduct 8-hydroxyoctanoic acid from cyclooxygenase (COX)-catalyzed DGLA peroxidation. 8-hydroxyoctanoic acid can exert its growth inhibitory effect on cancer cells (e.g. colon and pancreatic cancer) by serving as a histone deacetylase inhibitor. Since histone deacetylase inhibitors have been well-known to suppress cancer cell migration and invasion, we thus tested whether knockdown of delta-5-desaturase and DGLA treatment could also be used to inhibit cancer migration and invasion of colon cancer and pancreatic cancer cells...
January 26, 2017: Redox Biology
https://www.readbyqxmd.com/read/28124052/the-chemical-profiling-of-loquat-leaf-extract-by-hplc-dad-esi-ms-and-its-effects-on-hyperlipidemia-and-hyperglycemia-in-rats-induced-by-a-high-fat-and-fructose-diet
#6
Bo Chen, Piaopiao Long, Yue Sun, Qilu Meng, Xingxun Liu, Huanhuan Cui, Qingya Lv, Liang Zhang
In this study, the inhibitory effects of loquat leaf extract (LLE) on pancreatic α-amylase and α-glucosidase, and the preventative effects of LLE on hyperlipidemia and hyperglycemia in rats induced by a high fat and fructose diet have been evaluated. The LLE was chemically described using a high performance liquid chromatography-diode array detector coupled with a mass spectrometer (HPLC-DAD-MS/MS). 20 compounds including phenolic acids, flavonoids and triterpene acids were tentatively identified with authentic compounds or by referring to published articles and accessible databases (e...
January 26, 2017: Food & Function
https://www.readbyqxmd.com/read/28099250/interleukin-36%C3%AE-induces-inflammatory-mediators-from-human-pancreatic-myofibroblasts-via-a-myd88-dependent-pathway
#7
Atsushi Nishida, Osamu Inatomi, Takehide Fujimoto, Hirotsugu Imaeda, Masaji Tani, Akira Andoh
OBJECTIVES: Interleukin 36 (IL-36) is a recently described proinflammatory cytokine, characterized by the induction of inflammatory mediators. In the present study, we investigated the biological activity and the signal transduction of IL-36α in human pancreatic myofibroblasts. METHODS: The mRNA and protein expression of inflammatory mediators was evaluated using real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The expression of IL-36α and its receptor in the pancreatic tissue was evaluated using immunohistochemical technique...
January 18, 2017: Pancreas
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
#8
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
#9
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
#10
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
#11
REVIEW
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 is 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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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