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https://www.readbyqxmd.com/read/28829237/comparative-ultrastructural-hepatic-alterations-induced-by-free-and-liposome-encapsulated-mefenamic-acid
#1
Qais Bashir Jarrar, Muhammad Nazrul Hakim, Manraj Singh Cheema, Zainul Amiruddin Zakaria
Mefenamic acid (MFA) is used as an anti-inflammatory, antinociceptive, and antipyretic agent for treatment of a wide range of pathological disorders. While the uncertainty of its safety and the poor oral bioavailability constitute the major limiting factors of its medical use, considerable efforts including liposomal encapsulation are needed to achieve maximum therapeutic advantages. The current work was conducted to investigate the ultrastructural alterations in the liver induced by free MFA and its liposomal preparation...
September 2017: Ultrastructural Pathology
https://www.readbyqxmd.com/read/28828863/rerouting-native-hdl-to-predetermined-receptors-for-improved-tumor-targeted-gene-silencing-therapy
#2
Yang Ding, Yue Han, Ruoning Wang, Yazhe Wang, Cheng Chi, Ziqiang Zhao, Huaqing Zhang, Wei Wang, Lifang Yin, Jianping Zhou
High density lipoprotein (HDL) is an outstanding biocompatible nanovector for tumor-targeted delivery of multi-model drugs in cancer therapy. However, this seemingly promising delivery platform demonstrates an adverse accumulation in liver and adrenal due to the primary expression of natural target scavenger receptor class B type I (SR-BI), which overexpressed in malignant cells as well. Therefore, we endowed native HDLs with rerouting capacity, i.e. enabling HDLs to get away from natural receptors (SR-BI) to selectively alternate tumor-rich receptors...
August 22, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28828399/intracellular-proteolysis-of-progranulin-generates-stable-lysosomal-granulins-that-are-haploinsufficient-in-patients-with-frontotemporal-dementia-caused-by-grn-mutations
#3
Christopher J Holler, Georgia Taylor, Qiudong Deng, Thomas Kukar
Homozygous or heterozygous mutations in the GRN gene, encoding progranulin (PGRN), cause neuronal ceroid lipofuscinosis (NCL) or frontotemporal dementia (FTD), respectively. NCL and FTD are characterized by lysosome dysfunction and neurodegeneration, indicating PGRN is important for lysosome homeostasis in the brain. PGRN is trafficked to the lysosome where its functional role is unknown. PGRN can be cleaved into seven 6-kDa proteins called granulins (GRNs); however, little is known about how GRNs are produced or if levels of GRNs are altered in FTD-GRN mutation carriers...
July 2017: ENeuro
https://www.readbyqxmd.com/read/28827805/ferroptosis-and-autophagy-induced-cell-death-occur-independently-after-siramesine-and-lapatinib-treatment-in-breast-cancer-cells
#4
Shumei Ma, Rebecca F Dielschneider, Elizabeth S Henson, Wenyan Xiao, Tricia R Choquette, Anna R Blankstein, Yongqiang Chen, Spencer B Gibson
Ferroptosis is a cell death pathway characterized by iron-dependent accumulation of reactive oxygen species (ROS) within the cell. The combination of siramesine, a lysosome disruptor, and lapatinib, a dual tyrosine kinase inhibitor, has been shown to synergistically induce cell death in breast cancer cells mediated by ferroptosis. These treatments also induce autophagy but its role in this synergistic cell death is unclear. In this study, we determined that siramesine and lapatinib initially induced ferroptosis but changes to an autophagy induced cell death after 24 hours...
2017: PloS One
https://www.readbyqxmd.com/read/28827786/excess-%C3%AE-synuclein-compromises-phagocytosis-in-ipsc-derived-macrophages
#5
Walther Haenseler, Federico Zambon, Heyne Lee, Jane Vowles, Federica Rinaldi, Galbha Duggal, Henry Houlden, Katrina Gwinn, Selina Wray, Kelvin C Luk, Richard Wade-Martins, William S James, Sally A Cowley
To examine the pathogenic role of α-synuclein (αS) in Parkinson's Disease, we have generated induced Pluripotent Stem Cell lines from early onset Parkinson's Disease patients with SNCA A53T and SNCA Triplication mutations, and in this study have differentiated them to PSC-macrophages (pMac), which recapitulate many features of their brain-resident cousins, microglia. We show that SNCA Triplication pMac, but not A53T pMac, have significantly increased intracellular αS versus controls and release significantly more αS to the medium...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28827764/traf4-promotes-lung-cancer-aggressiveness-by-modulating-tumor-microenvironment-in-normal-fibroblasts
#6
EunGi Kim, Wanyeon Kim, Sungmin Lee, Jahyun Chun, JiHoon Kang, Gaeul Park, IkJoon Han, Hee Jung Yang, HyeSook Youn, BuHyun Youn
Normal fibroblasts surrounding tumor cells play a crucial role in cancer progression through formation of the tumor microenvironment. Because factors secreted from normal fibroblasts can modulate the tumor microenvironment, it is necessary to identify key factors associated with regulation of secreted factors and to investigate the molecular mechanisms contributing to the tumor microenvironment formation process. In this study, we found that radiation induced the expression and K63-linkage poly-ubiquitination of TRAF4 in normal lung fibroblasts...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28827412/macrophage-liver-kinase-b1-inhibits-foam-cell-formation-and-atherosclerosis
#7
Zhaoyu Liu, Huaiping Zhu, Xaoyan Dai, Cheng Wang, Ye Ding, Ping Song, Ming-Hui Zou
Rationale: Liver kinase B1 (LKB1) is a serine/threonine kinase and tumor suppressor, which regulates the homeostasis of hematopoietic cells and immune responses. Macrophages transform into foam cells upon taking-in lipids. No role for LKB1 in foam cell formation has previously reported. Objective: We sought to establish the role of LKB1 in atherosclerotic foam cell formation. Methods and Results: LKB1 expression was examined in human carotid atherosclerotic plaques and in western diet fed atherosclerosis-prone Ldlr(-/-) and ApoE(-/-) mice...
August 21, 2017: Circulation Research
https://www.readbyqxmd.com/read/28827407/arl8b-is-required-for-lysosomal-degradation-of-maternal-proteins-in-the-visceral-yolk-sac-endoderm-of-mouse-embryos
#8
Miho Oka, Keisuke Hashimoto, Yoshifumi Yamaguchi, Shin-Ichiro Saitoh, Yuki Sugiura, Yuji Motoi, Kurara Honda, Yorifumi Kikko, Shinya Ohata, Makoto Suematsu, Masayuki Miura, Kensuke Miyake, Toshiaki Katada, Kenji Kontani
The small GTPase Arl8b localizes primarily to lysosomes and is involved in lysosomal motility and fusion. Here, we show that Arl8b is required for lysosomal degradation of maternal proteins in the visceral yolk sac endoderm (VYSE), an apical cell layer of the visceral yolk sac, of mouse embryos. The VYSE actively takes up maternal materials from uterine fluid and degrades them in lysosomes to provide breakdown products to the embryo as energy sources. Arl8b gene-trap mice (Arl8b(-/-) ) displayed decreased early embryo body size...
August 21, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28826913/vorinostat-and-simvastatin-have-synergistic-effects-on-triple-negative-breast-cancer-cells-via-abrogating-rab7-prenylation
#9
Xinhui Kou, Yonghua Yang, Xiaoxiao Jiang, Huijuan Liu, Fanghui Sun, Xuan Wang, Longkai Liu, Hongrui Liu, Zhaohu Lin, Lan Jiang
Since the lack of targeted treatment, triple-negative breast cancer (TNBC) has poor outcomes. Histone deacetylase inhibitors (HDACi) blocking the activity of specific HDACs have emerged as cancer therapeutic agents. However, the therapeutic efficiency is still not satisfactory for patients with solid tumor. We thus performed screening for the synergistic agents of Vorinostat (SAHA). The resulting candidate Simvastatin was obtained. The efficacy and mechanism of combination have been studied in TNBC cells. The synergism of SAHA and Simvastatin was evaluated by IC50 of proliferation and combination index (CI)...
August 18, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28826719/advanced-glycation-end-products-receptor-rage-controls-myocardial-dysfunction-and-oxidative-stress-in-high-fat-fed-mice-by-sustaining-mitochondrial-dynamics-and-autophagy-lysosome-pathway
#10
Yichi Yu, Lei Wang, Florian Delguste, Arthur Durand, Axel Guilbaud, Clementine Rousselin, Ann Marie Schmidt, Frédéric Tessier, Eric Boulanger, Remi Neviere
Oxidative stress and mitochondrial dysfunction are recognized as major contributors of cardiovascular damage in diabetes and high fat diet (HFD) fed mice. Blockade of receptor for advanced glycation end products (RAGE) attenuates vascular oxidative stress and development of atherosclerosis. We tested whether HFD-induced myocardial dysfunction would be reversed in RAGE deficiency mice, in association with changes in oxidative stress damage, mitochondrial respiration, mitochondrial fission and autophagy-lysosomal pathway...
August 18, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28826672/delta-secretase-phosphorylation-by-srpk2-enhances-its-enzymatic-activity-provoking-pathogenesis-in-alzheimer-s-disease
#11
Zhi-Hao Wang, Pai Liu, Xia Liu, Fredric P Manfredsson, Ivette M Sandoval, Shan Ping Yu, Jian-Zhi Wang, Keqiang Ye
Delta-secretase, a lysosomal asparagine endopeptidase (AEP), simultaneously cleaves both APP and tau, controlling the onset of pathogenesis of Alzheimer's disease (AD). However, how this protease is post-translationally regulated remains unclear. Here we report that serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities...
August 7, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28826623/functional-characterization-of-hemocytes-from-chinese-mitten-crab-eriocheir-sinensis-by-flow-cytometry
#12
Zhihao Jia, Lingling Wang, Shuai Jiang, Mingzhe Sun, Mengqiang Wang, Qilin Yi, Linsheng Song
Hemocytes comprise a diversity of cell types with functional and structural heterogeneity, and they play key roles in the host defense of invertebrates. In the present study, the hemocytes from Chinese mitten crab Eriocheir sinensis were directly separated into two groups by flow cytometry. The hemocytes in P1 group were full of round and abundant granules with deeply staining cytoplasm, while P2 hemocytes were more diverse with a wide range of sizes and less granularity. Both P1 and P2 hemocytes exhibited phagocytic ability, but the phagocytic rate of P1 hemocytes increased which was significantly higher than that of P2 hemocytes after LPS stimulations...
August 4, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28822844/a-ph-sensitive-methenamine-mandelate-loaded-nanoparticle-induces-dna-damage-and-apoptosis-of-cancer-cells
#13
Linhua Zhang, Wenbo Hao, Lv Xu, Yongfeng Gao, Xusheng Wang, Dunwan Zhu, Zhuo Chen, Xudong Zhang, Hongbo Chen, Lin Mei
Methenamine mandelate is a urinary antibacterial agent, which can be converted to formaldehyde in urine that has a relatively low pH of average 5.5-6.8. Here, we prepare a pH-sensitive PLGA-based nanoparticle containing both methenamine mandelate and NaHCO3. Methenamine mandelate/NaHCO3-coloaded nanoparticle could enter cells via endosome/lysosome pathway. The pH in lysosomes and endo-lysosomes is approximately 5.0. In the acidic environment, NaHCO3 reacts with proton and produce CO2 bubbles, which burst nanoparticles and lead to the rapidly release of methenamine mandelate...
August 16, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28822075/recycling-endosomes-in-human-cytotoxic-t-lymphocytes-constitute-an-auxiliary-intracellular-trafficking-pathway-for-newly-synthesized-perforin
#14
Kelsey Lesteberg, Jordan Orange, George Makedonas
Although cytotoxic T lymphocytes (CTLs) store perforin within cytoplasmic secretory granules for immediate use, perforin is synthesized anew within hours of TCR stimulation. Previously, we observed new perforin protein at an immunologic synapse independent of secretory lysosomes; herein, we aimed to determine how new perforin transits to the synapse if not via lytic granules. We analyzed antigen-specific human CTLs via imaging flow cytometry and high-resolution confocal microscopy, with attention to intracellular trafficking components and new perforin...
August 18, 2017: Immunologic Research
https://www.readbyqxmd.com/read/28821796/cathepsin-k-knockout-protects-against-cardiac-dysfunction-in-diabetic-mice
#15
Rui Guo, Yinan Hua, Olivia Rogers, Travis E Brown, Jun Ren, Sreejayan Nair
Diabetes is a major risk factor for cardiovascular disease and the lysosomal cysteine protease cathepsin K plays a critical role in cardiac pathophysiology. To expand upon our previous findings, we tested the hypothesis that, knockout of cathepsin K protects against diabetes-associated cardiac anomalies. Wild-type and cathepsin K knockout mice were rendered diabetic by streptozotocin (STZ) injections. Body weight, organ mass, fasting blood glucose, energy expenditure, cardiac geometry and function, cardiac histomorphology, glutathione levels and protein levels of cathepsin K and those associated with Ca(2+) handling, calcineurin/NFAT signaling, insulin signaling, cardiac apoptosis and fibrosis were determined...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28821645/mutant-huntingtin-is-secreted-via-a-late-endosomal-lysosomal-unconventional-secretory-pathway
#16
Katarina Trajkovic, Hyunkyong Jeong, Dimitri Krainc
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG triplet in the gene encoding for huntingtin. The resulting mutant protein huntingtin (mHtt) with extended polyglutamine (polyQ) sequence at the N-terminus leads to neuronal degeneration both in cell-autonomous and non-cell-autonomous manners. Recent studies identified mHtt in the extracellular environment and suggested that its spreading contributes to toxicity, but the mechanism of mHtt release from the cell of origin remains unknown...
August 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28821638/fluorescent-probes-for-selective-protein-labeling-in-lysosomes-a-case-of-%C3%AE-galactosidase-a
#17
Cornelius Bohl, Adam Pomorski, Susanne Seemann, Anne-Marie Knospe, Chaonan Zheng, Artur Krężel, Arndt Rolfs, Jan Lukas
Fluorescence-based live-cell imaging (LCI) of lysosomal glycosidases is often hampered by unfavorable pH and redox conditions that reduce fluorescence output. Moreover, most lysosomal glycosidases are low-mass soluble proteins that do not allow for bulky fluorescent protein fusions. We selected α-galactosidase A (GALA) as a model lysosomal glycosidase involved in Anderson-Fabry disease (AFD) for the current LCI approach. Examination of the subcellular localization of AFD-causing mutants can reveal the mechanism underlying cellular trafficking deficits...
August 15, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28821621/protein-kinase-g-confers-survival-advantage-to-mycobacterium-tuberculosis-during-latency-like-conditions
#18
Mehak Zahoor Khan, Ashima Bhaskar, Sandeep Upadhyay, Pooja Kumari, Raju S Rajmani, Preeti Jain, Amit Singh, Dhiraj Kumar, Neel Sarovar Bhavesh, Vinay Kumar Nandicoori
Protein Kinase G (PknG), a thioredoxin-fold containing eukaryotic like serine/threonine protein kinase (STPK), is a virulence factor in the Mycobacterium tuberculosis, required for inhibition of phago-lysosomal fusion. Here, we unravelled novel functional facets of PknG during latency like conditions. We find that PknG mediates persistence under stressful conditions like hypoxia and abets drug tolerance. PknG mutant displayed minimal growth in nutrient limiting conditions suggesting its role in modulating cellular metabolism...
August 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28821575/ldl-switches-the-lrp6-internalization-route-from-flotillin-dependent-to-clathrin-dependent-in-hepatic-cells
#19
Hideki Yamamoto, Daisuke Umeda, Shinji Matsumoto, Akira Kikuchi
Low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) was originally identified as a coreceptor of the Wnt signaling pathway and has been shown to be involved in LDL transport. In polarized hepatocytes, many apical proteins are sorted to the basolateral membrane and then internalized and transported to the apical bile canalicular membrane-a process known as transcytosis. Herein, we show that LRP6 is transcytosed to the apical membrane of polarized hepatic HepG2 cells via a flotillin-dependent manner in the absence of LDL...
August 18, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28821398/urate-promotes-snca-%C3%AE-synuclein-clearance-via-regulating-mtor-dependent-macroautophagy
#20
Yu-Lan Sheng, Xing Chen, Xiao-Ou Hou, Xin-Yuan, Bao-Shi Yuan, Yu-Qing Yuan, Qi-Lin Zhang, Xian Cao, Chun-Feng Liu, Wei-Feng Luo, Li-Fang Hu
Serum urate levels are reported to be significantly lowered in patients with Parkinson's disease (PD) and inversely correlated to the risk and progression of PD. However, the mechanism by which urate affects PD is poorly understood. Here we showed that treatment with uric acid (UA) resulted in an autophagy activity enhancement in PC12 cells in dose- and time-dependent manners, as indicated by LC3-II increase and P62 decrease. Moreover, UA was still able to increase the LC3-II level and the number of LC3 puncta in the presence of Bafilomycin A1, a lysosomal inhibitor...
August 15, 2017: Experimental Neurology
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