{"title":"Role of endolysosomes and cholesterol in the pathogenesis of Alzheimer's disease: Insights into why statins might not provide clinical benefit.","authors":"Xuesong Chen, Liang Hui, Jonathan D Geiger","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Altered cholesterol homeostasis in general and increased levels of low-density lipoprotein (LDL) cholesterol specifically is a robust risk factor for the pathogenesis of sporadic Alzheimer's disease (AD). Because of this, the family of drugs known as statins have been tried extensively to lower cholesterol levels in attempting to prevent and/or lessen the neuropathogenesis of AD. Unfortunately, evidence accumulated to date is insufficient to support the continued use of statins as a viable pharmacotherapeutic approach against AD. To understand these complex and inter-related issues it is important to review how altered cholesterol homeostasis contributes to AD pathogenesis and why statins have not provided clinical benefit against AD. Apolipoproteins with their different affinities for various lipids and the receptors that control cholesterol uptake can result in drastic differences in cholesterol trafficking into and its distribution within neurons. The presence of the apoE4 or elevated plasma levels of LDL cholesterol can lead to a set of conditions that resembles lysosomal lipid storage disorders observed in Niemann-Pick type C disease such as impaired recycling of cholesterol back to the endoplasmic reticulum (ER), Golgi and plasma membranes, cholesterol deficiencies in plasma membranes, and increased cholesterol accumulation in endolysosomes resulting in endolysosome dysfunction. Consequently, the use of statins to block cholesterol synthesis in ER might not only decrease further plasma membrane cholesterol levels thus disturbing synaptic integrity, but also could also increase cholesterol burden in endolysosomes thus worsening endolysosome dysfunction. Therefore, it is not surprising that the use of cholesterol-lowering strategies with statins has not resulted in clinical benefit for patients living with AD.</p>","PeriodicalId":90448,"journal":{"name":"Austin journal of pharmacology and therapeutics","volume":"2 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387891/pdf/nihms673111.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33203396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Allosteric Modulation of G Protein-Coupled Receptors: An Emerging Approach of Drug Discovery.","authors":"Christopher Wild, Kathryn A Cunningham, Jia Zhou","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Allosteric modulation of G protein-coupled receptors (GPCRs) confers several significant advantages over the traditional targeting of orthosteric sites. While the field of allosteric modulation of GPCRs as we now know it will benefit from continued investigation, the explosion of interest has led to a more in-depth understanding as to precisely how allosteric modulators may usher in a new paradigm for drug discovery.</p>","PeriodicalId":90448,"journal":{"name":"Austin journal of pharmacology and therapeutics","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852709/pdf/nihms780714.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34521555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shuang Zhou, Fengfei Wang, Ying Zhang, Max R Johnson, Steven Qian, Min Wu, Erxi Wu
{"title":"Salinomycin Suppresses PDGFRβ, MYC, and Notch Signaling in Human Medulloblastoma.","authors":"Shuang Zhou, Fengfei Wang, Ying Zhang, Max R Johnson, Steven Qian, Min Wu, Erxi Wu","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Medulloblastoma (MB) is the most common childhood brain tumor. Despite improved therapy and management, approximately 30% of patients die of the disease. To search for a more effective therapeutic strategy, the effects of salinomycin were tested on cell proliferation, cell death, and cell cycle progression in human MB cell lines. The results demonstrated that salinomycin inhibits cell proliferation, induces cell death , and disrupts cell cycle progression in MB cells. Salinomycin was also tested on the expression levels of key genes involved in proliferation and survival signaling and revealed that salinomycin down-regulates the expression of PDGFRβ, MYC, p21 and Bcl-2 as well as up-regulates the expression of cyclin A. In addition, the results reveal that salinomycin suppresses the expression of <i>Hes1</i> and <i>Hes5</i> in MB cells. Our data shed light on the potential of using salinomycin as a novel therapeutic agent for patients with MB.</p>","PeriodicalId":90448,"journal":{"name":"Austin journal of pharmacology and therapeutics","volume":"2 3","pages":"1020"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251667/pdf/nihms-607413.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32884738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Protein-Protein Interactions as New Targets for Ion Channel Drug Discovery.","authors":"Svetla Stoilova-McPhie, Syed Ali, Fernanda Laezza","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Protein-protein interactions (PPI) are key molecular elements that provide the basis of signaling in virtually all cellular processes. The precision and specificity of these molecular interactions have ignited a strong interest in pursuing PPI surfaces as new targets for drug discovery, especially against ion channels in the central nervous system (CNS) where selectivity and specificity are vital for developing drugs with limited side effects. Ion channels are large transmembrane domain proteins assembled with multiple regulatory proteins binding to the intracellular portion of channels. These macromolecular complexes are difficult to isolate, purify and reconstitute, posing a significant barrier in targeting these PPI for drug discovery purposes. Here, we will provide a short overview of salient features of PPI and discuss successful studies focusing on protein-channel interactions that could inspire new drug discovery campaigns targeting ion channel complexes.</p>","PeriodicalId":90448,"journal":{"name":"Austin journal of pharmacology and therapeutics","volume":"1 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2013-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255474/pdf/nihms607805.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32889493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}