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https://www.readbyqxmd.com/read/29770852/notch-inhibition-counteracts-paneth-cell-death-in-absence-of-caspase-8
#1
M K Jeon, E Kaemmerer, U Schneider, M Schiffer, C Klaus, J Hennings, T Clahsen, T Ackerstaff, M Niggemann, A Schippers, T Longerich, G Sellge, C Trautwein, N Wagner, C Liedtke, N Gassler
Opposing activities of Notch and Wnt signaling regulate mucosal barrier homeostasis and differentiation of intestinal epithelial cells. Specifically, Wnt activity is essential for differentiation of secretory cells including Wnt3-producing Paneth cells, whereas Notch signaling strongly promotes generation of absorptive cells. Loss of caspase-8 in intestinal epithelium (casp8∆int ) is associated with fulminant epithelial necroptosis, severe Paneth cell death, secondary intestinal inflammation, and an increase in Notch activity...
May 16, 2018: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/29735425/discovery-of-tetrahydroindazoles-as-a-novel-class-of-potent-and-in-vivo-efficacious-gamma-secretase-modulators
#2
Kai Gerlach, Scott Hobson, Christian Eickmeier, Ulrike Groß, Clemens Braun, Peter Sieger, Michel Garneau, Stefan Hoerer, Niklas Heine
The identification and optimization of a novel series of centrally efficacious gamma secretase modulators (GSMs) offering an alternative to the privileged aryl imidazole motif is described. Chiral bicyclic tetrahydroindazolyl amine substituted triazolopyridines were identified as structurally distinct novel series of GSMs. Representative compound BI-1408 ((R)-42) was demonstrated to be centrally efficacious in rats at a 30 mg/kg oral dose.
April 30, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29729742/inkjet-printing-based-%C3%AE-secretase-fluorescence-resonance-energy-transfer-fret-assay-for-screening-of-potential-%C3%AE-secretase-inhibitors-of-alzheimer-s-disease
#3
Jungmi Lee, Annie Agnes Suganya Samson, Joon Myong Song
Amyloid-β (Aβ) is generated by proteolytic processing of amyloid precursor protein (APP) by beta-secretase (BACE-1) and gamma-secretase. Amyloid-β is responsible for the formation of senile plaques in Alzheimer's disease (AD). Consequently, inhibition of β-secretase (BACE-1), a rate-limiting enzyme in the production of Aβ, constitutes an attractive therapeutic approach to the treatment of AD. This paper reports an inkjet printing-based fluorescence assay for high throughput screening of β-secretase inhibitors achieved by employing a BACE-1 FRET substrate (Rh-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-Lys-Quencher)...
August 31, 2018: Analytica Chimica Acta
https://www.readbyqxmd.com/read/29700109/a-high-content-screen-for-small-molecule-regulators-of-epithelial-cell-adhesion-molecule-epcam-cleavage-yields-a-robust-inhibitor
#4
Jana Ylva Tretter, Kenji Schorpp, Elke Luxenburger, Johannes Trambauer, Harald Steiner, Kamyar Hadian, Olivier Gires, Dierk Niessing
Epithelial cell-adhesion molecule (EpCAM) is a transmembrane protein that regulates cell cycle progression and differentiation and is overexpressed in many carcinomas. The EpCAM-induced mitogenic cascade is activated via regulated intramembrane proteolysis (RIP) of EpCAM by ADAM and gamma secretases, generating the signaling-active intracellular domain EpICD. Because of its expression pattern and molecular function, EpCAM is a valuable target in prognostic and therapeutic approaches for various carcinomas. So far, several immunotherapeutic strategies have targeted the extracellular domain of EpCAM...
April 26, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29569780/a-new-nonsense-mutation-in-the-poglut1-gene-in-two-sisters-with-dowling-degos-disease
#5
S Duchatelet, H Clerc, L Machet, P Gaboriaud, S Miskinyte, T Kervarrec, A Hovnanian
Dowling-Degos disease (DD) (OMIM: 179850, 615327, 615674, 615696) is a rare autosomal-dominant genetic disorder belonging to the spectrum of reticulated pigmented dermatitis(1). Galli-Galli disease is considered as being a variant of DD, harboring all clinical, histological and genetics features of DD in association with acantholysis (2). In 2006, exome sequencing revealed loss-of-function mutations in KRT5 (cytokeratin 5) (p.Ile140fsAsnfs*39, p.Ser5*) in 8 of 10 DD cases (3). Since then, mutations in POGLUT1, encoding O-glucosylosyltransferase 1 enzyme, were reported in Galli-Galli cases (4)...
March 23, 2018: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/29529279/nonclinical-safety-assessment-of-the-%C3%AE-secretase-inhibitor-avagacestat
#6
Frank J Simutis, Thomas P Sanderson, Gary D Pilcher, Michael J Graziano
The toxicity of avagacestat, a sulfonamide-based gamma (γ)-secretase inhibitor that was in development as a treatment for Alzheimer's disease, was evaluated in a comprehensive nonclinical toxicology program that included 6-month and 1-year repeat-dose toxicity studies in rats and dogs, respectively. There was a spectrum of mechanism-based changes attributed to inhibition of Notch signaling that regulates the differentiation and proliferation of cells throughout development and in adult tissues. In both rats and dogs, ovarian follicular degeneration and atrophy and a low incidence of granulosa cell hyperplasia and benign granulosa-thecal cell tumors were observed...
February 24, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29433569/mh84-improves-mitochondrial-dysfunction-in-a-mouse-model-of-early-alzheimer-s-disease
#7
Maximilian Pohland, Maren Pellowska, Heike Asseburg, Stephanie Hagl, Martina Reutzel, Aljoscha Joppe, Dirk Berressem, Schamim H Eckert, Mario Wurglics, Manfred Schubert-Zsilavecz, Gunter P Eckert
BACKGROUND: Current approved drugs for Alzheimer's disease (AD) only attenuate symptoms, but do not cure the disease. The pirinixic acid derivate MH84 has been characterized as a dual gamma-secretase/proliferator activated receptor gamma (PPARγ) modulator in vitro. Pharmacokinetic studies in mice showed that MH84 is bioavailable after oral administration and reaches the brain. We recently demonstrated that MH84 improved mitochondrial dysfunction in a cellular model of AD. In the present study, we extended the pharmacological characterization of MH84 to 3-month-old Thy-1 AβPPSL mice (harboring the Swedish and London mutation in human amyloid precursor protein (APP)) which are characterized by enhanced AβPP processing and cerebral mitochondrial dysfunction, representing a mouse model of early AD...
February 13, 2018: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/29394903/impact-of-amyloid-beta-changes-on-cognitive-outcomes-in-alzheimer-s-disease-analysis-of-clinical-trials-using-a-quantitative-systems-pharmacology-model
#8
Hugo Geerts, Athan Spiros, Patrick Roberts
BACKGROUND: Despite a tremendous amount of information on the role of amyloid in Alzheimer's disease (AD), almost all clinical trials testing this hypothesis have failed to generate clinically relevant cognitive effects. METHODS: We present an advanced mechanism-based and biophysically realistic quantitative systems pharmacology computer model of an Alzheimer-type neuronal cortical network that has been calibrated with Alzheimer Disease Assessment Scale, cognitive subscale (ADAS-Cog) readouts from historical clinical trials and simulated the differential impact of amyloid-beta (Aβ40 and Aβ42) oligomers on glutamate and nicotinic neurotransmission...
February 2, 2018: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/29290798/ultrasound-molecular-imaging-of-vegfr-2-in-clear-cell-renal-cell-carcinoma-tracks-disease-response-to-antiangiogenic-and-notch-inhibition-therapy
#9
Juan D Rojas, Fanglue Lin, Yun-Chen Chiang, Anna Chytil, Diana C Chong, Victoria L Bautch, W Kimryn Rathmell, Paul A Dayton
Metastatic clear-cell renal cell carcinoma (ccRCC) affects thousands of patients worldwide each year. Antiangiogenic therapy has been shown to have beneficial effects initially, but resistance is eventually developed. Therefore, it is important to accurately track the response of cancer to different therapeutics in order to appropriately adjust the therapy to maximize efficacy. Change in tumor volume is the current gold standard for determining efficacy of treatment. However, functional variations can occur much earlier than measurable volume changes...
2018: Theranostics
https://www.readbyqxmd.com/read/29249626/discovery-of-novel-scaffolds-for-%C3%AE-secretase-modulators-without-an-arylimidazole-moiety
#10
Ryuichi Sekioka, Eriko Honjo, Shugo Honda, Hideyoshi Fuji, Hiroki Akashiba, Yasuyuki Mitani, Shingo Yamasaki
Gamma-secretase modulators (GSMs) selectively inhibit the production of amyloid-β 42 (Aβ42) and may therefore be useful in the management of Alzheimer's disease. Most heterocyclic GSMs that are not derived from nonsteroidal anti-inflammatory drugs contain an arylimidazole moiety that potentially inhibits cytochrome P450 (CYP) activity. Here, we discovered imidazopyridine derivatives that represent a new class of scaffold for GSMs, which do not have a strongly basic end group such as arylimidazole. High-throughput screening identified 2-methyl-8-[(2-methylbenzyl)oxy]-3-(pyridin-4-yl)imidazo[1,2-a]pyridine (3a), which inhibited the cellular production of Aβ42 (IC50  = 7...
January 15, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29242286/hop-1-presenilin-deficiency-causes-a-late-onset-notch-signaling-phenotype-that-affects-adult-germline-function-in-caenorhabditis-elegans
#11
Ipsita Agarwal, Cassandra Farnow, Joshua Jiang, Kyung-Sik Kim, Donna E Leet, Ruth Z Solomon, Valerie A Hale, Caroline Goutte
Functionally redundant genes present a puzzle as to their evolutionary preservation, and offer an interesting opportunity for molecular specialization. In Caenorhabditis elegans , either one of two presenilin genes ( sel-12 or hop-1 ) facilitate Notch activation, providing the catalytic subunit for the γ secretase proteolytic enzyme complex. For all known Notch signaling events, sel-12 can mediate Notch activation, so the conservation of hop-1 remains a mystery. Here, we uncover a novel "late-onset" germline Notch phenotype in which HOP-1-deficient worms fail to maintain proliferating germline stem cells during adulthood...
February 2018: Genetics
https://www.readbyqxmd.com/read/29238071/app-upregulation-contributes-to-retinal-ganglion-cell-degeneration-via-jnk3
#12
Chao Liu, Cheng-Wu Zhang, Yi Zhou, Wan Qing Wong, Liying Corinne Lee, Wei Yi Ong, Sung Ok Yoon, Wanjin Hong, Xin-Yuan Fu, Tuck Wah Soong, Edward H Koo, Lawrence W Stanton, Kah-Leong Lim, Zhi-Cheng Xiao, Gavin S Dawe
Axonal injury is a common feature of central nervous system insults. Upregulation of amyloid precursor protein (APP) is observed following central nervous system neurotrauma and is regarded as a marker of central nervous system axonal injury. However, the underlying mechanism by which APP mediates neuronal death remains to be elucidated. Here, we used mouse optic nerve axotomy (ONA) to model central nervous system axonal injury replicating aspects of retinal ganglion cell (RGC) death in optic neuropathies. APP and APP intracellular domain (AICD) were upregulated in retina after ONA and APP knockout reduced Tuj1+ RGC loss...
March 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29229705/proteolytic-processing-of-neurexins-by-presenilins-sustains-synaptic-vesicle-release
#13
Emilia Servián-Morilla, Estefanía Robles-Lanuza, Ana C Sánchez-Hidalgo, Rafael J Camacho-Garcia, Juan A Paez-Gomez, Fabiola Mavillard, Carlos A Saura, Amalia Martinez-Mir, Francisco G Scholl
Proteolytic processing of synaptic adhesion components can accommodate the function of synapses to activity-dependent changes. The adhesion system formed by neurexins (Nrxns) and neuroligins (Nlgns) bidirectionally orchestrate the function of presynaptic and postsynaptic terminals. Previous studies have shown that presenilins (PS), components of the gamma-secretase complex frequently mutated in familial Alzheimer's disease, clear from glutamatergic terminals the accumulation of Nrxn C-terminal fragments (Nrxn-CTF) generated by ectodomain shedding...
January 24, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29227981/gamma-secretase-inhibitors-attenuate-neurotrauma-and-neurogenic-acute-lung-injury-in-rats-by-rescuing-the-accumulation-of-hypertrophic-microglia
#14
Hung-Jung Lin, Chien-Chin Hsu, Chung-Ching Chio, Yu-Feng Tian, Mao-Tsun Lin, Ting-Wei Lin, Chih-Hsien Chang, Ching-Ping Chang
BACKGROUND/AIMS: In response to traumatic brain injury (TBI), activated microglia exhibit changes in their morphology from the resting ramified phenotype toward the activated hypertrophic or amoeboid phenotype. Here, we provide the first description of the mechanism underlying the neuroprotective effects of γ-secretase inhibitors on TBI outcomes in rats. METHODS: The neuroprotective effects of γ-secretase inhibitors such as LY411575 or CHF5074 on TBI-induced neurotoxicity were analysed using a neurological motor function evaluation, cerebral contusion assay, immunohistochemical staining for microglia phenotypes, lung injury score and Evans Blue dye extravasation assay of brain and lung oedema...
2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29175872/notch-pathway-inhibition-targets-chemoresistant-insulinoma-cancer-stem-cells
#15
Y Capodanno, F O Buishand, L Y Pang, J Kirpensteijn, J A Mol, D J Argyle
Insulinomas (INS) are the most common neuroendocrine pancreatic tumours in humans and dogs. The long-term prognosis for malignant INS is still poor due to a low success rate of the current treatment modalities, particularly chemotherapy. A better understanding of the molecular processes underlying the development and progression of INS is required to develop novel targeted therapies. Cancer stem cells (CSCs) are thought to be critical for the engraftment and chemoresistance of many tumours, including INS. This study was aimed to characterise and target INS CSCs in order to develop novel targeted therapies...
February 2018: Endocrine-related Cancer
https://www.readbyqxmd.com/read/29138057/hidradenitis-suppurativa-like-lesions-associated-with-pharmacologic-inhibition-of-gamma-secretase
#16
Geraldine O'Sullivan Coyne, Therese S Woodring, Chyi-Chia R Lee, Alice P Chen, Heidi H Kong
No abstract text is available yet for this article.
April 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29104587/notch-and-its-oncogenic-activity-in-human-malignancies
#17
REVIEW
Marlena Brzozowa-Zasada, Adam Piecuch, Marek Michalski, Oliwia Segiet, Józef Kurek, Marzena Harabin-Słowińska, Romuald Wojnicz
Background: Increasing evidence has demonstrated that Notch signaling is deregulated in human hematological malignancies and solid tumors. This signaling has a protumorigenic effect but may also act as a tumor suppressor. How induction of a single pathway gives rise to the opposite effects in different cell types is still unknown. Methods: This review article includes available data from peer-reviewed publications associated with the role of Notch signaling during cancer pathogenesis...
2017: European Surgery: ACA: Acta Chirurgica Austriaca
https://www.readbyqxmd.com/read/29045054/variants-regulating-zbtb4-are-associated-with-age-at-onset-of-alzheimer-s-disease
#18
E E Blue, C-E Yu, T A Thornton, N H Chapman, E Kernfeld, N Jiang, K M Shively, K J Buckingham, C T Marvin, M J Bamshad, T D Bird, E M Wijsman
The identification of novel genetic modifiers of age-at-onset (AAO) of Alzheimer's disease (AD) could advance our understanding of AD and provide novel therapeutic targets. A previous genome scan for modifiers of AAO among families affected by early-onset AD caused by the PSEN2 N141I variant identified 2 loci with significant evidence for linkage: 1q23.3 and 17p13.2. Here, we describe the fine-mapping of these 2 linkage regions, and test for replication in 6 independent datasets. By fine-mapping these linkage signals in a single large family, we reduced the linkage regions to 11% their original size and nominated 54 candidate variants...
October 16, 2017: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/29027990/il6-blockade-potentiates-the-anti-tumor-effects-of-%C3%AE-secretase-inhibitors-in-notch3-expressing-breast-cancer
#19
Dong Wang, Jiahui Xu, Bingjie Liu, Xueyan He, Lei Zhou, Xin Hu, Feng Qiao, Anli Zhang, Xiaojun Xu, Huafeng Zhang, Max S Wicha, Lixing Zhang, Zhi-Ming Shao, Suling Liu
Notch pathways have important roles in carcinogenesis including pathways involving the Notch1 and Notch2 oncogenes. Pan-Notch inhibitors, such as gamma secretase inhibitors (GSIs), have been used in the clinical trials, but the outcomes of these trials have been insufficient and have yielded unclear. In the present study, we demonstrated that GSIs, such as MK-0752 and RO4929097, inhibit breast tumor growth, but increase the breast cancer stem cell (BCSC) population in Notch3-expressing breast cancer cells, in a process that is coupled with IL6 induction and is blocked by the IL6R antagonist Tocilizumab (TCZ)...
February 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28978720/gamma-secretase-inhibition-by-bms-906024-enhances-efficacy-of-paclitaxel-in-lung-adenocarcinoma
#20
Katherine M Morgan, Bruce S Fischer, Francis Y Lee, Jamie J Shah, Joseph R Bertino, Jeffrey Rosenfeld, Amartya Singh, Hossein Khiabanian, Sharon R Pine
Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancers (NSCLC). We characterized the interaction between BMS-906024, a clinically relevant Notch gamma secretase inhibitor, and front-line chemotherapy in preclinical models of NSCLC. Chemosensitivity assays were performed on 14 human NSCLC cell lines. There was significantly greater synergy between BMS-906024 and paclitaxel than BMS-906024 and cisplatin [mean combination index (CI) value, 0.54 and 0.85, respectively, P = 0...
December 2017: Molecular Cancer Therapeutics
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