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gamma secretase

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
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
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
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
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...
December 14, 2017: Bioorganic & Medicinal Chemistry
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 gamma 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...
December 14, 2017: Genetics
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...
December 13, 2017: Cell Death and Differentiation
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
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
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
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.
November 11, 2017: Journal of Investigative Dermatology
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
Elizabeth E Blue, Chang-En Yu, Timothy A Thornton, Nicola H Chapman, Eric Kernfeld, Nan Jiang, Kathryn M Shively, Kati J Buckingham, Colby T Marvin, Michael J Bamshad, Thomas D Bird, Ellen M Wijsman
The identification of novel genetic modifiers of age-at-onset of Alzheimer's disease could advance our understanding of AD and provide novel therapeutic targets. A previous genome scan for modifiers of age-at-onset among families affected by early-onset Alzheimer's disease caused by the PSEN2 N141I variant identified two loci with significant evidence for linkage: 1q23.3 and 17p13.2. Here, we describe the fine-mapping of these two linkage regions, and test for replication in six independent data sets. 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
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)...
October 13, 2017: Cell Death and Differentiation
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
Jean-Christophe Wyss, Rajesh Kumar, Josip Mikulic, Manfred Schneider, Johannes D Aebi, Lucienne Juillerat-Jeanneret, Dela Golshayan
The Notch pathway has been reported to control tissue damage in acute kidney diseases. To investigate potential beneficial nephroprotective effects of targeting Notch, we developed chemically functionalized γ-secretase inhibitors (GSIs) targeting γ-glutamyltranspeptidase (γ-GT) and/or γ-glutamylcyclotransfase (γ-GCT), two enzymes overexpressed in the injured kidney, and evaluated them in in vivo murine models of acute tubular and glomerular damage. Exposure of the animals to disease-inducing drugs together with the functionalized GSIs improved proteinuria and, to some extent, kidney dysfunction...
September 27, 2017: American Journal of Physiology. Renal Physiology
Tao Wang
Cholinesterase inhibitors and N-methyl-D-aspartic receptor antagonists are currently the main treatments for Alzheimer's disease (AD), targeting the clinical symptoms of AD. β-amyloid (Aβ) deposition and the highly-phosphorylated Tau protein-induced neurofibrillary tangles are some of the common pathological features of AD. In the past 20 years, many new drugs that focus on the pathogenesis of Alzheimer's disease have been assessed in clinical trials. Drugs such as β-amyloid monoclonal antibody and gamma-secretase inhibitor target the Aβ pathological pathway...
August 25, 2017: Shanghai Archives of Psychiatry
Hideyuki Ishiguro, Tomotaka Okubo, Yoshiyuki Kuwabara, Masahiro Kimura, Akira Mitsui, Nobuyoshi Sugito, Ryo Ogawa, Takeyasu Katada, Tatsuya Tanaka, Midori Shiozaki, Koji Mizoguchi, Yosuke Samoto, Yoichi Matsuo, Hiroki Takahashi, Shuji Takiguchi
PURPOSE AND METHODS: The translocation of β-catenin/CTNNB1 to the nucleus activates Wnt signaling and cell proliferation; however, the precise mechanism underlying this phenomenon remains unknown. Previous reports have provided evidence that NOTCH1 is involved in the Wnt signaling pathway. Therefore, we sought to determine the mechanism by which NOTCH1 influences the Wnt/β-catenin pathway. We constructed a vector expressing the NOTCH1 intracellular domain (NICD1) and transfected the vector into HCT116 which has low expression of NICD1...
September 1, 2017: Oncotarget
Mashoque Ahmad Rather, Arokiasamy Justin Thenmozhi, Thamilarasan Manivasagam, Mathiyazahan Dhivya Bharathi, Musthafa Essa, Gilles J Guillemin
Alzheimer's disease (AD) is the most common form of dementia, characterized by memory loss, cognitive impairment and personality disorders accompanied by diffuse structural abnormalities in the brain of elderly people. The current investigation explored the neuroprotective potential of asiatic acid (AA), a natural triterpene of Centella asiatica on aluminium chloride (AlCl3 ) induced rat model of AD. Oral administration of AlCl3 (100 mg/kg b.w.) for 42 days significantly elevated the levels of Al, activity of acetyl cholinesterase and expressions of amyloid precursor protein, amyloid beta1-42 , beta and gamma secretases, glial fibrillary acidic protein, ionized calcium binding adaptor molecule 1, interleukins -1β, 6, 4, 2, tumor necrosis factor alpha, inducible nitric oxide synthase, nuclear factor- k beta and cyclooxygenase-2 in the hippocampus and cortex  compared to the control group...
January 1, 2018: Frontiers in Bioscience (Scholar Edition)
M Pavlovsky, O Sarig, M Eskin-Schwartz, N Malchin, R Bochner, J Mohamad, A Gat, A Peled, A Hafner, E Sprecher
Dowling-Degos disease, featuring reticulate pigmentation, and familial hidradenitis suppurativa share many clinical features including autosomal dominant inheritance, flexural location and follicular defects. The co-existence of the two disorders was recently found to result from mutations in PSENEN, encoding protein presenilin enhancer gamma-secretase subunit. Here we report 4 additional families of Jewish Ashkenazi origin who presented with clinical features characteristic of both disorders. All patients were found to carry the same, heterozygous mutation in PSENEN (c...
September 18, 2017: British Journal of Dermatology
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