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https://www.readbyqxmd.com/read/29342415/lysosomes-targeting-imaging-and-anticancer-properties-of-novel-bis-naphthalimide-derivatives
#1
Rui-Xue Rong, Shan-Shan Wang, Xuan Liu, Ren-Feng Li, Ke-Rang Wang, Zhi-Ran Cao, Xiao-Liu Li
A series of novel N,N-bis(3-aminopropyl)methylamine bridged bis-naphthalimide derivatives NI1-NI8 containing saturated nitrogenous heterocycles were designed and synthesized, their cytotoxic activities against Hela, MCF-7, A549 and MGC-803 cells were investigated, Compounds NI1-NI4 modified with piperidine and piperazine exhibited good and selective cytotoxic activity, for instance, compounds NI1 and NI4 showed potent cytotoxic activity against Hela cells and MGC-803 cells with the IC50 values of 2.89, 060, 2...
January 9, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29341879/mechanisms-of-mitochondrial-toxicity-of-the-kinase-inhibitors-ponatinib-regorafenib-and-sorafenib-in-human-hepatic-hepg2-cells
#2
Franziska Paech, Cécile Mingard, David Grünig, Vanessa F Abegg, Jamal Bouitbir, Stephan Krähenbühl
Previous studies have shown that certain kinase inhibitors are mitochondrial toxicants. In the current investigation, we determined the mechanisms of mitochondrial impairment by the kinase inhibitors ponatinib, regorafenib, and sorafenib in more detail. In HepG2 cells cultured in galactose and exposed for 24 hours, all three kinase inhibitors investigated depleted the cellular ATP pools at lower concentrations than cytotoxicity occurred, compatible with mitochondrial toxicity. The kinase inhibitors impaired the activity of different complexes of the respiratory chain in HepG2 cells exposed to the toxicants for 24 hours and in isolated mouse liver mitochondria exposed acutely...
January 13, 2018: Toxicology
https://www.readbyqxmd.com/read/29341130/mitochondrial-function-and-autophagy-integrating-proteotoxic-redox-and-metabolic-stress-in-parkinson-s-disease
#3
REVIEW
Jianhua Zhang, M Lillian Culp, Jason G Craver, Victor Darley-Usmar
Parkinson's disease (PD) is a movement disorder with widespread neurodegeneration in the brain. Significant oxidative, reductive, metabolic, and proteotoxic alterations have been observed in PD postmortem brains. The alterations of mitochondrial function resulting in decreased bioenergetic health is important and needs to be further examined to help develop biomarkers for PD severity and prognosis. It is now becoming clear that multiple hits on metabolic and signaling pathways are likely to exacerbate PD pathogenesis...
January 17, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29340649/optic-nerve-regeneration-after-crush-remodels-the-injury-site-molecular-insights-from-imaging-mass-spectrometry
#4
David T Stark, David M G Anderson, Jacky M K Kwong, Nathan Heath Patterson, Kevin L Schey, Richard M Caprioli, Joseph Caprioli
Purpose: Mammalian central nervous system axons fail to regenerate after injury. Contributing factors include limited intrinsic growth capacity and an inhibitory glial environment. Inflammation-induced optic nerve regeneration (IIR) is thought to boost retinal ganglion cell (RGC) intrinsic growth capacity through progrowth gene expression, but effects on the inhibitory glial environment of the optic nerve are unexplored. To investigate progrowth molecular changes associated with reactive gliosis during IIR, we developed an imaging mass spectrometry (IMS)-based approach that identifies discriminant molecular signals in and around optic nerve crush (ONC) sites...
January 1, 2018: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29340437/a-novel-lysosome-targeted-fluorogenic-probe-based-on-5-triazole-quinoline-for-the-rapid-detection-of-hydrogen-sulfide-in-living-cells
#5
Yandong Dou, Xiaoxu Gu, Shasha Ying, Shen Zhu, Shian Yu, Wei Shen, Qing Zhu
A fluorogenic probe based on the novel fluorophore 5-triazole-quinoline was developed for the detection of hydrogen sulfide, an endogenous signaling molecule associated with the development of various diseases. The lysosome-targeted probe Lyso-HS was synthesized via C-H direct azidation from 8-aminoquinoline; it was able to detect H2S in 1 min and exhibited excellent turn-on ability with 95-fold fluorescence enhancement based on a new fluorochrome. The high quenching efficiency was further verified using time-dependent density functional theory (TDDFT)...
January 17, 2018: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29340093/leucine-mediates-autophagosome-lysosome-fusion-and-improves-sperm-motility-by-activating-the-pi3k-akt-pathway
#6
Jin Zhang, Xuemei Zhang, Yingjie Liu, Zihao Su, Farman Ullah Dawar, Hong Dan, Yan He, Jian-Fang Gui, Jie Mei
Amino acid supplementation is an efficient and effective strategy to increase sperm quality. In our research, a comparative study was conducted to screen free amino acids to improve sperm motility, and we found that leucine was the most efficient one. Leucine treatment increases sperm motility depending on the activation of PI3K/Akt signaling pathway, while the chemical inhibitor of PI3K/Akt signal could reduce the amount of pAkt activated by leucine treatment. Moreover, leucine treatment improved the expression of P62 and LC3-II, substantially suppressed the autophagy process in zebrafish testis...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29339460/dot-icm-translocated-proteins-important-for-biogenesis-of-the-coxiella-burnetii-containing-vacuole-identified-by-screening-of-an-effector-mutant-sub-library
#7
Emerson Crabill, Whitman B Schofield, Hayley J Newton, Andrew L Goodman, Craig R Roy
Coxiella burnetii is an intracellular pathogen that replicates in a lysosome-derived vacuole. A determinant necessary for C. burnetii virulence is the Dot/Icm type IVB secretion system (T4SS). The Dot/Icm system delivers more than 100 proteins, called type IV effectors (T4E), across the vacuolar membrane into the host cell cytosol. Several T4Es have been shown to be important for vacuolar biogenesis. Here, transposon insertion sequencing technology (INSeq) was used to identify C. burnetii Nine Mile phase II mutants in an arrayed library, which facilitated the identification and clonal isolation of mutants deficient in 70 different T4E proteins...
January 16, 2018: Infection and Immunity
https://www.readbyqxmd.com/read/29339442/specific-substrate-for-the-assay-of-lysosomal-acid-lipase
#8
Sophia Masi, Naveen Chennamaneni, Frantisek Turecek, C Ronald Scott, Michael H Gelb
BACKGROUND: Deficiency of lysosomal acid lipase (LAL) causes Wolman disease and cholesterol ester storage disease. With the recent introduction of enzyme replacement therapy to manage LAL deficiency comes the need for a reliable assay of LAL enzymatic activity that can be applied to dried blood spots (DBS). METHODS: We prepared and tested a library of analogs of palmitoyl 4-methylumbelifferyl esters to find a highly active and specific substrate for LAL in DBS. The LAL assay was optimized leading to both LC-MS/MS and fluorometric assay of LAL...
January 16, 2018: Clinical Chemistry
https://www.readbyqxmd.com/read/29339408/development-of-the-swimbladder-surfactant-system-and-biogenesis-of-lysosome-related-organelles-is-regulated-by-blos1-in-zebrafish
#9
Tianbing Chen, Guili Song, Huihui Yang, Lin Mao, Zongbin Cui, Kaiyao Huang
Hermansky-Pudlak syndrome (HPS) is a human autosomal recessive disorder that is characterized by oculocutaneous albinism and a deficiency of the platelet storage pool resulting from defective biogenesis of lysosome-related organelles (LROs). To date, ten HPS genes have been identified, three of which belong to the octamer complex BLOC-1 (biogenesis of lysosome-related organelles complex 1). One subunit of the BLOC-1 complex, BLOS1, also participates in the BLOC-1-related complex (BORC). Due to lethality at the early embryo stage in BLOS1 knockout mice, the function of BLOS1 in the above two complexes and whether it has a novel function are unclear...
January 16, 2018: Genetics
https://www.readbyqxmd.com/read/29339341/health-status-alterations-in-ruditapes-philippinarum-after-continuous-secondary-effluent-exposure-before-and-after-additional-tertiary-treatment-application
#10
B Díaz-Garduño, J A Perales, C Garrido-Pérez, M L Martín-Díaz
A mobile pilot plant was set up in a wastewater treatment plant (WWTP) in southwest Spain to address potential adverse effects of effluents as a whole contaminant, which are discharging into marine environments. Ruditapes philippinarum specimens were exposed to different effluent concentrations (50%, 25%, 12.5%, 6.25%, and 3.15%) during seven days. After effluent exposure, lysosomal membrane stability alterations (LMS), changes in the energy status storage (total lipids content (TLP) and in the mitochondrial electron transport (MET), inhibition of inflammatory mechanisms (cyclooxygenase activity (COX)), and neurotoxic effects (acetylcholinesterase (AChE) were determined in exposed organisms...
January 12, 2018: Environmental Pollution
https://www.readbyqxmd.com/read/29339212/autophagy-and-t-cell-metabolism
#11
Samuel D Dowling, Fernando Macian
Autophagy, a highly conserved catabolic process that involves the degradation and recycling of intracellular components in the lysosome, has emerged as a key process in the maintenance of T cell homeostasis and the regulation of T cell differentiation and function. In this review, we provide an overview of the mechanisms that mediates the regulation of autophagy in T cells and discuss different cellular processes that are under the control of autophagy in CD4+ and CD8+ T cells. A special emphasis is placed on the role that autophagy plays in the modulation of T cell metabolism and the consequences of this regulation on functional states and programs of differentiation in specific T cell populations...
January 12, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29339186/uptake-and-intracellular-fate-of-cholera-toxin-subunit-b-modified-mesoporous-silica-nanoparticle-supported-lipid-bilayers-aka-protocells-in-motoneurons
#12
Maria A Gonzalez Porras, Paul Durfee, Sebastian Giambini, Gary C Sieck, C Jeffrey Brinker, Carlos B Mantilla
Cholera toxin B (CTB) modified mesoporous silica nanoparticle supported lipid bilayers (CTB-protocells) are a promising, customizable approach for targeting therapeutic cargo to motoneurons. In the present study, the endocytic mechanism and intracellular fate of CTB-protocells in motoneurons was examined to provide information for the development of therapeutic application and cargo delivery. Pharmacological inhibitors elucidated CTB-protocells endocytosis to be dependent on the integrity of lipid rafts and macropinocytosis...
January 12, 2018: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/29338710/a-genetically-encoded-ca2-indicator-based-on-circularly-permutated-sea-anemone-red-fluorescent-protein-eqfp578
#13
Yi Shen, Hod Dana, Ahmed S Abdelfattah, Ronak Patel, Jamien Shea, Rosana S Molina, Bijal Rawal, Vladimir Rancic, Yu-Fen Chang, Lanshi Wu, Yingche Chen, Yong Qian, Matthew D Wiens, Nathan Hambleton, Klaus Ballanyi, Thomas E Hughes, Mikhail Drobizhev, Douglas S Kim, Minoru Koyama, Eric R Schreiter, Robert E Campbell
BACKGROUND: Genetically encoded calcium ion (Ca2+) indicators (GECIs) are indispensable tools for measuring Ca2+ dynamics and neuronal activities in vitro and in vivo. Red fluorescent protein (RFP)-based GECIs have inherent advantages relative to green fluorescent protein-based GECIs due to the longer wavelength light used for excitation. Longer wavelength light is associated with decreased phototoxicity and deeper penetration through tissue. Red GECI can also enable multicolor visualization with blue- or cyan-excitable fluorophores...
January 16, 2018: BMC Biology
https://www.readbyqxmd.com/read/29337428/ap4-positively-regulates-laptm4b-to-promote-hepatocellular-carcinoma-growth-and-metastasis-whilst-reducing-chemotherapy-sensitivity
#14
Yue Meng, Lu Wang, Jianjun Xu, Qingyun Zhang
Polymorphisms of the Lysosomal-Associated Protein Transmembrane-4 beta (LAPTM4B) gene are related to various forms of tumour susceptibility, which led us to hypothesize that some unique transcription factors targeting this polymorphism region may affect the biological function of LAPTM4B in tumour progression. In this study, we found that the transcription factor AP4 directly binds to the polymorphism region of the LAPTM4B gene promoter and induces its transcription. In addition, we demonstrated that AP4 promotes hepatocellular carcinoma cell proliferation and metastasis, and depresses chemotherapy sensitivity via LAPTM4B by activating the PI3K/AKT signalling pathway and caspase-dependent pathway...
January 16, 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29337250/the-stim1-inhibitor-ml9-disrupts-basal-autophagy-in-cardiomyocytes-by-decreasing-lysosome-content
#15
S Shaikh, R Troncoso, D Mondaca-Ruff, V Parra, L Garcia, M Chiong, S Lavandero
Stromal-interaction molecule 1 (STIM1)-mediated store-operated Ca2+ entry (SOCE) plays a key role in mediating cardiomyocyte hypertrophy, both in vitro and in vivo. Moreover, there is growing support for the contribution of SOCE to the Ca2+ overload associated with ischemia/reperfusion injury. Therefore, STIM1 inhibition is proposed as a novel target for controlling both hypertrophy and ischemia/reperfusion-induced Ca2+ overload. Our aim was to evaluate the effect of ML9, a STIM1 inhibitor, on cardiomyocyte viability...
January 11, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/29337241/differential-effects-of-alzheimer-s-disease-a%C3%AE-40-and-42-on-endocytosis-and-intraneuronal-trafficking
#16
Rajesh S Omtri, Kevin Thompson, Xiojia Tang, Chaitanya C Gali, Ute Panzenboeck, Michael W Davidson, Krishna R Kalari, Karunya K Kadimalla
Anomalous neuronal accumulation of Aβ peptides was shown to affect synaptic transmission and contribute to neurodegeneration in Alzheimer's disease (AD) brain. Neuronal cells internalize amyloid beta (Aβ) peptides from the brain extracellular space even under normal physiological conditions, and these endocytotic pathways go awry during AD progression. We hypothesized that exposure to toxic Aβ species accumulating in AD brain contribute to perturbations in neuronal endocytosis. We have shown substantial down-regulation of KEGG endocytotic pathway genes in AD patient brain regions that accumulate Aβ compared to those in non-demented individuals...
January 11, 2018: Neuroscience
https://www.readbyqxmd.com/read/29336144/nanostructured-peptidotoxins-as-natural-pro-oxidants-induced-cancer-cell-death-via-amplification-of-oxidative-stress
#17
Hongzhi Qiao, Dong Fang, Lei Zhang, Xiaochen Gu, Yin Lu, Minjie Sun, Chunmeng Sun, Qineng Ping, Junsong Li, Zhipeng Chen, Jun Chen, Lihong Hu, Liuqing Di
Melittin (Mel), one of the host defense peptides (HDPs) derived from venom of honeybees, demonstrates substantial anticancer properties, which is considered attributed to augmenting reactive oxygen species (ROS) generation. However, little has been reported on its pro-oxidation capacity in cancer oxidation therapy. In this study, a ROS amplifying nanodevice was fabricated through direct complexation of two natural pro-oxidants, Mel and condensed epigallocatechin gallate (pEGCG). The obtained nanocomplex (NC) was further covered with phenylboronic acid derivatized hyaluronic acid (pHA) through ROS-responsive boronate ester coordination bond to produce pHA-NC...
January 16, 2018: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/29336143/a-water-soluble-fluorescent-probe-with-dual-mitochondria-lysosome-targetability-for-selective-superoxide-detection-in-live-cells-and-in-zebrafish-embryos
#18
Xiuhong Lu, Zhongjian Chen, Xiaochun Dong, Weili Zhao
A novel water soluble fluorescein-based fluorescent probe for superoxide detection was developed. The probe is fairly stable under neutral and acidic conditions. It can be used to detect superoxide both in solution with the detection limit of 2.2 μM and in living cells. Cell imaging experiments indicated that such a probe displayed good cell penetration and O2•- could be detected with PMA-stimulated HepG2 cells in both mitochondria and lysosome. Such a probe is the first dual mitochondria- and lysosome- targetable fluorescent chemodosimeter...
January 16, 2018: ACS Sensors
https://www.readbyqxmd.com/read/29336118/resveratrol-potently-counteracts-quercetin-starvation-induced-autophagy-and-sensitizes-hepg2-cancer-cells-to-apoptosis
#19
Sarah Tomas-Hernández, Jordi Blanco, Cristina Rojas, Joel Roca-Martínez, María José Ojeda-Montes, Raúl Beltrán-Debón, Santiago Garcia-Vallve, Gerard Pujadas, Lluís Arola, Miquel Mulero
SCOPE: Resveratrol (RSV) has been described as a potent antioxidant, anti-steatotic, and antitumor compound, and it has also been identified as a potent autophagy inducer. On the other hand, quercetin (QCT) is a dietary flavonoid with known antitumor, anti-inflammatory and antidiabetic effects. Additionally, QCT increases autophagy. To study the hypothetical synergistic effect of both compounds, we tested the combined effect of QCT and RSV on the autophagy process in HepG2 cells METHODS AND RESULTS: Autophagy was studied by western blotting, real-time RT-PCR, and cellular staining...
January 16, 2018: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/29334672/oxidative-and-interactive-challenge-of-cadmium-and-ocean-acidification-on-the-smooth-scallop-flexopecten-glaber
#20
Alessandro Nardi, Maura Benedetti, Daniele Fattorini, Francesco Regoli
Ocean acidification (OA) may affect sensitivity of marine organisms to metal pollution modulating chemical bioavailability, bioaccumulation and biological responsiveness of several cellular pathways. In this study, the smooth scallop Flexopecten glaber was exposed to various combinations of reduced pH (pH/pCO2 7.4/∼3000 μatm) and Cd (20 μg/L). The analyses on cadmium uptake were integrated with those of a wide battery of biomarkers including metallothioneins, single antioxidant defenses and total oxyradical scavenging capacity in digestive gland and gills, lysosomal membrane stability and onset of genotoxic damage in haemocytes...
January 8, 2018: Aquatic Toxicology
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