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autophagy AND pancreatitis

Irmina A Elliott, Amanda M Dann, Shili Xu, Stephanie S Kim, Evan R Abt, Woosuk Kim, Soumya Poddar, Alexandra Moore, Lei Zhou, Jennifer L Williams, Joseph R Capri, Razmik Ghukasyan, Cynthia Matsumura, D Andrew Tucker, Wesley R Armstrong, Anthony E Cabebe, Nanping Wu, Luyi Li, Thuc M Le, Caius G Radu, Timothy R Donahue
Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells...
March 20, 2019: Proceedings of the National Academy of Sciences of the United States of America
Shaogui Wang, Hong-Min Ni, Xiaojuan Chao, Hua Wang, Brian Bridges, Sean Kumer, Timothy Schmitt, Olga Mareninova, Anna Gukovskaya, Robert C De Lisle, Andrea Ballabio, Pal Pacher, Wen-Xing Ding
Impaired macroautophagy/autophagy has been implicated in experimental and human pancreatitis. However, the transcriptional control governing the autophagy-lysosomal process in pancreatitis is largely unknown. We investigated the role and mechanisms of TFEB (transcription factor EB), a master regulator of lysosomal biogenesis, in the pathogenesis of experimental pancreatitis. We analyzed autophagic flux, TFEB nuclear translocation, lysosomal biogenesis, inflammation and fibrosis in GFP-LC3 transgenic mice, acinar cell-specific tfeb knockout (KO) and tfeb and tfe3 double-knockout (DKO) mice as well as human pancreatitis samples...
March 20, 2019: Autophagy
Iain Dickson
No abstract text is available yet for this article.
March 19, 2019: Nature Reviews. Gastroenterology & Hepatology
(no author information available yet)
Dual inhibition of autophagy and KRAS signaling shows promise in mouse models of pancreatic cancer, prompting trials in human patients.
March 19, 2019: Cancer Discovery
Qi Shen, Jie Wang, Chen-Xi Liu, Wei Cui, Lei Zhang, Yu-Chao Zhang, Yue Wang, Jing Wu, Jian-Xin Li
Pancreatic cancer is one of the most deadly neoplasm with a 5-year survival rate of less than 6% owing to its remarkable tolerance to nutrient starvation, and new drugs and treatment strategies are urgently needed. During a project aiming at discovery of anticancer agents, we performed a structure modification on polycyclic polyprenylated acylphloroglucinols (PPAPs) skeleton, and discovered that PPAP rearranged to a tetrahydroquinolin-2(1H)-one feature. Here, series of tetrahydroquinolin-2(1H)-one derivatives were designed, synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (PANC-1), and the structure-activity relationship was also discussed...
March 9, 2019: European Journal of Medicinal Chemistry
Chuan-Ming Xie, Mingjia Tan, Xiao-Tong Lin, Di Wu, Yihan Jiang, Ye Tan, Haomin Li, Yuanyuan Ma, Xiufang Xiong, Yi Sun
FBXW7 is a tumor suppressive E3 ligase, whereas RAS-ERK and mechanistic target of rapamycin kinase (mTORC1) are two major oncogenic pathways. Whether and how FBXW7 regulates these two oncogenic pathways are unknown. Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation. FBXW7-mediated SHOC2 degradation terminates the RAS-MAPK signals and inhibits proliferation...
March 12, 2019: Cell Reports
M Bugliani, S Mossuto, F Grano, M Suleiman, L Marselli, U Boggi, P De Simone, D L Eizirik, M Cnop, P Marchetti, V De Tata
Autophagy is the major mechanism involved in degradation and recycling of intracellular components, and its alterations have been proposed to cause beta cell dysfunction. In this study, we explored the effects of autophagy modulation in human islets under conditions associated to endoplasmic reticulum (ER) stress. Human pancreatic islets were isolated by enzymatic digestion and density gradient purification from pancreatic samples of non-diabetic (ND; n = 17; age 65 ± 21 years; gender: 5 M/12 F; BMI 23.4 ± 3...
2019: Frontiers in Endocrinology
Jianbiao Xu, Jianlin Song, Xiaochun Yang, Jianhui Guo, Tongmin Wang, Weidong Zhuo
BACKGROUND: Precursor of nerve growth factor (proNGF) was previously considered biologically inactive; however, it has recently been identified as having important roles in the pathology of cancer development. AIM: This study aimed to explore the therapeutic effects of proNGF siRNA on the proliferation, invasion, and anoikis of pancreatic cancer cells and determine the functions of proNGF. METHODS: Pancreatic ductal adenocarcinoma (PDAC) and paired paracancerous tissue samples were collected from 60 patients for evaluation of proNGF expression by immunohistochemistry staining, qPCR, and western blotting...
March 2019: Biomedicine & Pharmacotherapy
Yihua Wang, Hua Xiong, Dian Liu, Charlotte Hill, Ayse Ertay, Juanjuan Li, Yanmei Zou, Paul Miller, Eileen White, Julian Downward, Robert D Goldin, Xianglin Yuan, Xin Lu
Macroautophagy/autophagy inhibition is a novel anticancer therapeutic strategy, especially for tumors driven by mutant RAS. Here, we demonstrate that autophagy inhibition in RAS-mutated cells induces epithelial-mesenchymal transition (EMT), which is associated with enhanced tumor invasion. This is at least partially achieved by triggering the NFKB/NF-κB pathway via SQSTM1/p62. Knockdown of ATG3 or ATG5 increases oncogenic RAS-induced expression of ZEB1 and SNAI2/Snail2, and activates NFKB activity. Depletion of SQSTM1 abolishes the activation of the NFKB pathway induced by autophagy inhibition in RAS-mutated cells...
February 20, 2019: Autophagy
Ashok Saluja, Vikas Dudeja, Rajinder Dawra, Raghuwansh P Sah
Premature activation of digestive enzymes in the pancreas has been linked to development of pancreatitis for more than a century. Recent development of novel models to study the role of pathologic enzyme activation has led to advances in our understanding of the mechanisms of pancreatic injury. Co-localization of zymogen and lysosomal fraction occurs early after pancreatitis causing stimulus. Cathepsin B activates trypsinogen in these co-localized organelles. Active trypsin increases permeability of these organelles resulting in leakage of cathepsin B into the cytosol leading to acinar cell death...
February 15, 2019: Gastroenterology
Sharon A Tooze, Maria New, Tim Van Acker, Jun-Ichi Sakamaki, Ming Jiang, Rebecca E Saunders, Jaclyn Long, Victoria M-Y Wang, Axel Behrens, Padhmanand Sudhakar, Tamas Korcsmaros, Kevin M Ryan, Michael Howell, Joana Cerveira, Harold B J Jefferies
Pancreatic ductal adenocarcinoma (PDAC) is driven by metabolic changes in pancreatic cells caused by oncogenic mutations and dysregulation of p53. PDAC cell lines and PDAC-derived xenografts grow as a result of altered metabolic pathways, changes in stroma, and autophagy. Selective targeting and inhibition of one of these may open avenues for the development of new therapeutic strategies. In this study, we performed a genome-wide siRNA screen in a PDAC cell line using endogenous autophagy as a readout and identified several regulators of autophagy that were required for autophagy-dependent PDAC cell survival...
February 14, 2019: Cancer Research
Shengnan Jia, Xiaodong Xu, Senhao Zhou, Yan Chen, Guoping Ding, Liping Cao
Pancreatic cancer is one of the most aggressive tumors and patients have poor survival rates. Fisetin, a natural flavonoid, was recently reported to have antitumor effects in various cancer models. Autophagy is a conserved catabolic process that maintains cellular homoeostasis in response to stress, and together with apoptosis, determines cell fate. Herein, we examined the effect of fisetin on pancreatic cancer. We reveal that fisetin inhibits PANC-1 cell proliferation using a real-time cell analysis system...
February 13, 2019: Cell Death & Disease
Huan Yang, ShuCan Ma, Yu Guo, DongLai Cui, JinFeng Yao
Introduction: The mechanism by which intestinal mucosal barrier is damaged in severe acute pancreatitis (SAP)-associated impairment is not fully understood. Methods: We established an l-arginine-induced SAP rat model, pretreated with or without pyrrolidine dithiocarbamate (PDTC). Hematoxylin and eosin staining was performed to evaluate the pathological alterations. Western blotting was conducted to detect the expression of autophagy-related proteins. Oxidative stress was assessed by the levels of malondialdehyde and superoxide dismutase...
January 2019: Dose-response: a Publication of International Hormesis Society
Ben C King, Erik Renström, Anna M Blom
Complement component C3 is central to the complement system, a humoral effector mechanism of innate immune defense. When activated, C3 covalently binds to target particles, marking them for uptake and clearance by phagocytosis. We now show that C3 also exists within the cytosol where it interacts with ATG16L1, and is therefore involved in the intracellular clearance and recycling of material by macroautophagy/autophagy in pancreatic beta cells. C3 is highly expressed in isolated human islets, and its expression is upregulated in islets isolated from diabetic patients and rodents, and correlates with patient HBA1c and body mass index (BMI)...
February 11, 2019: Autophagy
Jiazhe Liu, Hongcheng Wang, Jianfa Wang, Qimeng Chang, Zhiqiu Hu, Xiaodong Shen, Jinfeng Feng, Ziping Zhang, Xubo Wu
ETHNOPHARMACOLOGICAL RELEVANCE: Radix Scutellariae (RS), the dried root of Scutellariae baicalensisGeorgi, known as a herbal medicine in several Asian countries including China, has been widely used to treat inflammation, hypertension, cardiovascular disease as well as cancer. The total flavonoid aglycone extracted (TFAE) was extracted by ethyl acetate and this extraction methodology was optimized and obtained the protection of Chinese patents. AIM OF THE STUDY: To investigate the underlying mechanism of the chemotherapeutic effects of TFAE in inducing autophagy and apoptosis in pancreatic cancer cells in vitro and in vivo...
February 6, 2019: Journal of Ethnopharmacology
Xiufeng Zhang, Ping Zhao, Caihong Wang, Benru Xin
BACKGROUND: Due to the poor prognosis and high mortality (over 90%), Pancreas ductal adenocarcinoma (PDAC) is listed as the 7th leading cause of cancer-related death in the world, while gemcitabine sensitivity is key important in PDAC therapy. SNHG14 is thought to be an oncogene in cancer progression. However, the possible role of SNHG14 underlying the progress of the PDAC cell, specifically in gemcitabine resistance remains to be determined. METHODS: We analyzed the PDAC-related data collected from TCGA...
February 5, 2019: Biochemical and Biophysical Research Communications
Pranav Murthy, Aatur D Singhi, Mark A Ross, Patricia Loughran, Pedram Paragomi, Georgios I Papachristou, David C Whitcomb, Amer H Zureikat, Michael T Lotze, Herbert J Zeh Iii, Brian A Boone
Background: Neutrophil extracellular traps (NETs) are generated when activated neutrophils, driven by PAD4, release their DNA, histones, HMGB1, and other intracellular granule components. NETs play a role in acute pancreatitis, worsening pancreatic inflammation, and promoting pancreatic duct obstruction. The autophagy inhibitor chloroquine (CQ) inhibits NET formation; therefore, we investigated the impact of CQ mediated NET inhibition in murine models of pancreatitis and human correlative studies. Methods: L-arginine and choline deficient ethionine supplemented (CDE) diet models of acute pancreatitis were studied in wild type and PAD4-/- mice, incapable of forming NETs...
2019: Frontiers in Immunology
Lei Yu, Min Chen, Rui Zhang, Ting Xu
BACKGROUND Pancreatic cancer has high incidence and low survival rates around the globe, mainly due to late diagnosis and unavailability of efficient chemotherapeutic agents. In the present study, the anticancer potential of glychionide-A was examined against PANC-1 pancreatic cancer cells. MATERIAL AND METHODS CellTiter-Glo Luminescent Cell Viability Assay Kits were used for assessment of cell viability. Electron microscopy and DAPI staining were used for the detection of apoptosis and autophagy, respectively...
February 3, 2019: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Zhi-Chao Wang, Fei-Zhou Huang, Hong-Bo Xu, Ji-Chun Sun, Chang-Fa Wang
PURPOSE: Autophagy play an important role in tumor chemotherapy resistance. It has been reported that miR-137 expression was reducedand involved in the regulation of sensitivity of PC cells to chemotherapy. However, little is known about the underlying molecular mechanisms. In this study, we hypothesized that miR-137 might sensitize PC cells to chemotherapy thought regulating cell autophagy. METHODS: Cell survival was determined with MTT assay. Apoptotic cells were assessed with flow cytometric analysis...
January 30, 2019: International Journal of Biochemistry & Cell Biology
Chih-Shia Lee, Liam C Lee, Tina L Yuan, Sirisha Chakka, Christof Fellmann, Scott W Lowe, Natasha J Caplen, Frank McCormick, Ji Luo
Oncogenic mutations in the small GTPase KRAS are frequently found in human cancers, and, currently, there are no effective targeted therapies for these tumors. Using a combinatorial siRNA approach, we analyzed a panel of KRAS mutant colorectal and pancreatic cancer cell lines for their dependency on 28 gene nodes that represent canonical RAS effector pathways and selected stress response pathways. We found that RAF node knockdown best differentiated KRAS mutant and KRAS WT cancer cells, suggesting RAF kinases are key oncoeffectors for KRAS addiction...
February 1, 2019: Proceedings of the National Academy of Sciences of the United States of America
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