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Articles de revues sur le sujet « Agent lysosomotrope »

Auteur : Grafiati
Publié le 4 juin 2021
Mis à jour le 12 février 2022

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1

Firestone, Raymond A., Judith M. Pisano, George M. Garrity, Robert A. Fromtling et Sheldon B. Zimmerman. « Lysosomotropic agents. 7. Broad-spectrum antifungal activity of lysosomotropic detergents ». Journal of Medicinal Chemistry 30, no 8 (août 1987) : 1519–21. http://dx.doi.org/10.1021/jm00391a043.

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MIR, MUDASIR. « LYSOSOMOTROPIC PROPERTIES OF SODIUM BICARBONATE AND COVID-19 ». FARMACIA 68, no 5 (27 octobre 2020) : 771–78. http://dx.doi.org/10.31925/farmacia.2020.5.1.

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SARS-CoV-2 causing COVID-19 has appeared as an ongoing global public crisis, growing with geometric progression and has caused huge devastation till date majorly because of lack of targeted therapeutic agents like vaccines. SARS-Cov-2 entrance into the host cells is reliant on acidic pH. Thus, in the current clinical emergency there is a pressing need to look forward for adjunct therapies which could counter the acidic pH, so as to restrain the viral entry and its subsequent reproduction in the host cells. Therefore, the current review attempted to explore the possibility to use sodium bicarbonate as an alternative lysosomotropic agent based on the reported literature owing to its anti-flu properties and widespread use during 1918 Spanish flu pandemic. The suggestions put forward in the current review article based on the careful use of sodium bicarbonate could probably help to restrain SARS-CoV-2 infection.
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Kalina, M., et R. Socher. « Endocytosis in cultured rat alveolar type II cells : effect of lysosomotropic weak bases on the processes. » Journal of Histochemistry & ; Cytochemistry 39, no 10 (octobre 1991) : 1337–48. http://dx.doi.org/10.1177/39.10.1658127.

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We investigated the uptake of Lucifer yellow and surfactant complexed with gold (S-G) by isolated alveolar Type II cells. The fluid phase marker Lucifer yellow did not reach lamellar bodies (LB) even after prolonged incubation time, whereas S-G was internalized and found in LB. Treatment of Type II cells with lysosomotropic weak bases (NH4Cl and chloroquine) resulted in dilation of endosomes, lysosomes, and LB. The effect of these agents on LB resulted in disappearance of their lamellar organization, as detected by polarized light and electron microscopy. After incubation in lysosomotropic agent-free medium, endocytosis of Lucifer yellow and S-G in treated cells was mainly directed towards large vacuoles resembling either multivesicular bodies (MVB) or lysosomes. The possible relationship between LB, MVB, and lysosomes in freshly isolated as well as cultured alveolar Type II cells is discussed.
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Villamil Giraldo, Ana M., Hanna Appelqvist, Thomas Ederth et Karin Öllinger. « Lysosomotropic agents : impact on lysosomal membrane permeabilization and cell death ». Biochemical Society Transactions 42, no 5 (18 septembre 2014) : 1460–64. http://dx.doi.org/10.1042/bst20140145.

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Lysosomes are acidic organelles essential for degradation, signalling and cell homoeostasis. In addition, they play a key role in cell death. Permeabilization of the lysosomal membrane and release of hydrolytic enzymes to the cytosol accompanies apoptosis signalling in several systems. The regulatory mechanism of lysosomal stability is, however, poorly understood. Lipophilic or amphiphilic compounds with a basic moiety will become protonated and trapped within lysosomes, and such lysosomotropic behaviour is also found in many pharmacological drugs. The natural sphingolipid sphingosine exhibits lysosomotropic detergent ability and is an endogenous candidate for controlling lysosomal membrane permeabilization. The lysosomotropic properties of certain detergents might be of use in lysosome-targeting anticancer drugs and drug delivery system in the future. The present review summarizes the current knowledge on the targeting and permeabilizing properties of lysosomotropic detergents from a cellular and physicochemical perspective.
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Chen, Grace L., Sarah L. Sutrina, Karen L. Frayer et Winston W. Chen. « Effects of lysosomotropic agents on lipogenesis ». Archives of Biochemistry and Biophysics 245, no 1 (février 1986) : 66–75. http://dx.doi.org/10.1016/0003-9861(86)90190-6.

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Xiong, Subin, Hong Li, Bo Yu, Jun Wu et Robert J. Lee. « Triggering Liposomal Drug Release With a Lysosomotropic Agent ». Journal of Pharmaceutical Sciences 99, no 12 (décembre 2010) : 5011–18. http://dx.doi.org/10.1002/jps.22210.

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Doi, Syuichi, Kazuyuku Tanabe, Masayasu Watanabe et Masao Yoshimura. « Chloroquine, a lysosomotropic agent, inhibits zygote formation in yeast ». Archives of Microbiology 151, no 1 (décembre 1988) : 20–25. http://dx.doi.org/10.1007/bf00444663.

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Liu, Zhenxing, Shuan Zhao, Shuaishuai Wu, Jingyou Zhang, Zunyang Nie et Shenming Zeng. « A novel role of transient receptor potential mucolipin1 (TRPML1) in protecting against imidazole-induced cytotoxicity ». Biochemistry and Cell Biology 92, no 4 (août 2014) : 279–86. http://dx.doi.org/10.1139/bcb-2014-0044.

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Lysosomotropic amines cause serious side effects such as cytoplasmic vacuolation and cell death. TRPML1 (also known as mucolipin1), a member of the transient receptor potential (TRP) protein family, may regulate fusion/fission of vesicles along the endocytic pathway and some aspects of lysosomal ion homeostasis. Nevertheless, it is still unknown whether TRPML1 is involved in death of mammalian cells induced by lysosomotropic agents. In this study, imidazole was used as a model to investigate the role of TRPML1 in the cytotoxicity of lysosomotropic agents. Overexpression of wild-type TRPML1 inhibited imidazole-induced vacuole formation and cell death in human endometrial adenocarcinoma (HEC-1B) cells. In contrast, siRNA-mediated TRPML1 knockdown increased the cell death induced by imidazole. Bafilomycin A1 raises the pH of acidic organelles and therefore suppresses accumulation of weak bases in them. Similarly, lysosomal pH was raised in TRPML1-overexpressing cells; therefore, we inferred that TRPML1 protected against imidazole toxicity by regulating the pH of acidic organelles. We concluded that TRPML1 had a novel role in protecting against lysosomotropic amine toxicity.
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SHAMSADEEN, NASRIN, et C. J. DUNCAN. « Action of lysosomotropic agents on mammalian skeletal muscle ». Biochemical Society Transactions 16, no 5 (1 octobre 1988) : 786. http://dx.doi.org/10.1042/bst0160786.

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Duncan, R. « Designing polymer conjugates as lysosomotropic nanomedicines ». Biochemical Society Transactions 35, no 1 (22 janvier 2007) : 56–60. http://dx.doi.org/10.1042/bst0350056.

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Marriage of cell biology (the concept of ‘lysosomotropic drug delivery’) and the realization that water-soluble synthetic polymers might provide an ideal platform for targeted drug delivery led to the first synthetic polymer–drug conjugates that entered clinical trials as anticancer agents. Conceptually, polymer conjugates share many features with other macromolecular drugs, but they have the added advantage of the versatility of synthetic chemistry that allows tailoring of molecular mass and addition of biomimetic features. Conjugate characteristics must be optimized carefully to ensure that the polymeric carrier is biocompatible and that the polymer molecular mass enables tumour-selective targeting followed by endocytic internalization. The polymer–drug linker must be stable in transit, but be degraded at an optimal rate intracellularly to liberate active drug. Our early studies designed two HPMA [N-(2-hydroxypropyl)methacrylamide] copolymer conjugates containing doxorubicin that became the first synthetic polymer–drug conjugates to be tested in phase I/II clinical trials. Since, a further four HPMA copolymer–anticancer drug conjugates (most recently polymer platinates) and the first polymer-based γ-camera imaging agents followed. Polymer–drug linkers cleaved by lysosomal thiol-dependent proteases and the reduced pH of endosomes and lysosomes have been used widely to facilitate drug liberation. It is becoming clear that inappropriate trafficking and/or malfunction of enzymatic activation can lead to new mechanisms of clinical resistance. Recent studies have described HPMA copolymer conjugates carrying a combination of both endocrine and chemotherapy that are markedly more active than individual conjugates carrying a single drug. Moreover, current research is investigating novel dendritic polymer architectures and novel biodegradable polymers as drug carriers that will provide improved drug delivery and imaging probes in the future. The present paper reviews the clinical status of polymeric anticancer agents, the rationale for the design of polymer therapeutics and discusses the benefits and challenges of lysosomotropic delivery.
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Korolenko, Tatiana A., Thomas P. Johnston et Vaclav Vetvicka. « Lysosomotropic Features and Autophagy Modulators among Medical Drugs : Evaluation of Their Role in Pathologies ». Molecules 25, no 21 (30 octobre 2020) : 5052. http://dx.doi.org/10.3390/molecules25215052.

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The concept of lysosomotropic agents significantly changed numerous aspects of cellular biochemistry, biochemical pharmacology, and clinical medicine. In the present review, we focused on numerous low-molecular and high-molecular lipophilic basic compounds and on the role of lipophagy and autophagy in experimental and clinical medicine. Attention was primarily focused on the most promising agents acting as autophagy inducers, which offer a new window for treatment and/or prophylaxis of various diseases, including type 2 diabetes mellitus, Parkinson’s disease, and atherosclerosis. The present review summarizes current knowledge on the lysosomotropic features of medical drugs, as well as autophagy inducers, and their role in pathological processes.
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12

Niemann, Axel, Akira Takatsuki et Hans-Peter Elsässer. « The Lysosomotropic Agent Monodansylcadaverine Also Acts as a Solvent Polarity Probe ». Journal of Histochemistry & ; Cytochemistry 48, no 2 (février 2000) : 251–58. http://dx.doi.org/10.1177/002215540004800210.

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The autofluorescent substance monodansylcadaverine has recently been reported as a specific in vivo marker for autophagic vacuoles. However, the mechanism for this specific labeling remained unclear. Our results reveal that the common model of ion trapping in acidic compartments cannot completely account for the observed autophagic vacuole staining. Because autophagic vacuoles are characterized by myelin-like membrane inclusions, we tested whether this lipid-rich environment is responsible for the staining properties of monodansylcadaverine. In in vitro experiments using either liposomes or solvents of different polarity, monodansylcadaverine showed an increased relative fluorescence intensity in a hydrophobic environment as well as a Stokes shift dependent on the solvent polarity. To test the effect of autophagic vacuoles or autophagic vacuole lipids on monodansylcadaverine fluorescence, we isolated autophagic vacuoles and purified autophagic vacuole lipids depleted of proteins. Entire autophagic vacuoles and autophagic vacuole lipids had the same effect on monodansylcadaverine fluorescence properties, suggesting lipids as the responsible component. Our results suggest that the in vivo fluorescence properties of monodansylcadaverine do not depend exclusively on accumulation in acidic compartments by ion trapping but also on an effective interaction of this molecule with autophagic vacuole membrane lipids.
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Zou, Xiaoqian, Fei Meng, Chengyu Fu, Jieying Zhou, Yi Zhang, Ruixuan Wang, Chengwan Zhang, Zhiyu Li, Qinglong Guo et Lin Yang. « LZ-106, a potent lysosomotropic agent, causing TFEB-dependent cytoplasmic vacuolization ». Gene 760 (novembre 2020) : 145017. http://dx.doi.org/10.1016/j.gene.2020.145017.

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Hagforsen, Eva, Aida Paivandy, Maria Lampinen, Simone Weström, Gabriela Calounova, Fabio R. Melo, Ola Rollman et Gunnar Pejler. « Ablation of human skin mast cellsin situby lysosomotropic agents ». Experimental Dermatology 24, no 7 (16 avril 2015) : 516–21. http://dx.doi.org/10.1111/exd.12699.

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15

Zeman, R. J., P. L. Bernstein, R. Ludemann et J. D. Etlinger. « Regulation of Ca2+-dependent protein turnover in skeletal muscle by thyroxine ». Biochemical Journal 240, no 1 (15 novembre 1986) : 269–72. http://dx.doi.org/10.1042/bj2400269.

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Dantrolene, an agent that inhibits Ca2+ mobilization, improved protein balance in skeletal muscle, as thyroid status was increased, by altering rates of protein synthesis and degradation. Thyroxine (T4) caused increases in protein degradation that were blocked by leupeptin, a proteinase inhibitor previously shown to inhibit Ca2+-dependent non-lysosomal proteolysis in these muscles. In addition, T4 abolished sensitivity to the lysosomotropic agent methylamine and the autophagy inhibitor 3-methyladenine, suggesting that T4 inhibits autophagic/lysosomal proteolysis.
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Shaikh, Soni, Suman K. Nandy, Carles Cantí et Sergio Lavandero. « Bafilomycin-A1 and ML9 Exert Different Lysosomal Actions to Induce Cell Death ». Current Molecular Pharmacology 12, no 4 (15 octobre 2019) : 261–71. http://dx.doi.org/10.2174/1874467212666190308131250.

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Objective: Bafilomycin-A1 and ML9 are lysosomotropic agents, irrespective of cell types. However, the mechanisms of lysosome targeting either bafilomycin-A1 or ML9 are unclear. Methods: The present research has been carried out by different molecular and biochemical analyses like western blot, confocal imaging and FACS studies, as well as molecular docking. Results: Our data shows that pre-incubation of neonatal cardiomyocytes with ML9 for 4h induced cell death, whereas a longer period of time (24h) with bafilomycin-A1 was required to induce an equivalent effect. Neither changes in ROS nor ATP production is associated with such death mechanisms. Flow cytometry, LC3-II expression levels, and LC3-GFP puncta formation revealed a similar lysosomotropic effect for both compounds. We used a molecular docking approach, that predicts a stronger inhibitory activity against V-ATPase-C1 and C2 domains for bafilomycin-A1 in comparison to ML9. Conclusion: Bafilomycin-A1 and ML9 are lysosomotropic agents, involved in cell death events. But such death events are not associated with ATP and ROS production. Furthermore, both the drugs target lysosomes through different mechanisms. For the latter, cell death is likely due to lysosomal membrane permeabilization and release of lysosomal proteases into the cytosol.
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Hirano, T., A. Saluja, P. Ramarao, M. M. Lerch et M. L. Steer. « Effects of chloroquine and methylamine on lysosomal enzyme secretion by rat pancreas ». American Journal of Physiology-Gastrointestinal and Liver Physiology 262, no 3 (1 mars 1992) : G439—G444. http://dx.doi.org/10.1152/ajpgi.1992.262.3.g439.

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In vivo pancreatic secretion of the lysosomal hydrolase cathepsin B was found to be increased by infusion of the secretagogue caerulein. The basal as well as caerulein-stimulated in vivo rate of cathepsin B was further increased by infusion of either chloroquine or methylamine while neither the basal nor the secretagogue-stimulated rates of amylase secretion were altered by the lysosomotropic agents. These observations indicate that neutralization of the acidic prelysosomal compartment by administration of lysosomotropic agents results in lysosomal enzyme entry, by default, into the regulated secretory pathway. In vitro stimulation of pancreatic acini with caerulein was also found to stimulate cathepsin B secretion. That in vitro rate of cathepsin B secretion stimulated by caerulein was not increased in acini prepared from animals infused with caerulein, chloroquine, or methylamine, but the in vitro rate of cathepsin B secretion stimulated by caerulein was increased in acini prepared from animals infused with caerulein plus either chloroquine or methylamine. Under these conditions, redistribution of cathepsin B from the lysosome-enriched to the zymogen granule-enriched subcellular fraction was noted, and lysosomal enzyme-containing organelles became increasingly fragile. These observations indicate that in vivo secretagogue stimulation increases the degree of diversion of lysosomal hydrolases into the regulated secretory compartment when the prelysosomal compartment has been neutralized with lysosomotropic agents.
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Diaz-Griffero, Felipe, Steven Ari Hoschander et Jürgen Brojatsch. « Endocytosis Is a Critical Step in Entry of Subgroup B Avian Leukosis Viruses ». Journal of Virology 76, no 24 (15 décembre 2002) : 12866–76. http://dx.doi.org/10.1128/jvi.76.24.12866-12876.2002.

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ABSTRACT The avian leukosis virus (ALV) entry mechanism is controversial, with evidence for and against a low-pH requirement for viral fusion. To further address this question, we tested the entry of human immunodeficiency virus type 1 (HIV-1) pseudotyped with the envelope protein of subgroup B ALV (ALV-B) in the presence of three different lysosomotropic agents. These lysosomotropic agents were able to block the entry of wild-type and pseudotyped ALV-B in two different cell lines, strongly suggesting that ALV-B requires a low-pH step for entry. ALV-B and pH-dependent Semliki Forest virus (SFV) entered cells with slower uptake kinetics than HIV-1, which is pH independent. These slow uptake rates support the theory that ALV-B utilizes endocytic pathways to enter cells. Using immunofluorescence and electron microscopy analysis, we visualized the colocalization of virus particles with the endosomal marker transferrin and demonstrated virus particles in clathrin-coated vesicles and endosome-like structures. Surprisingly, a low-pH treatment did not overcome the inhibition of ALV-B entry by lysosomotropic agents. This indicates that, in contrast to SFV, ALV-B is unable to fuse at the cellular surface, even at a low pH. Taken together, our findings suggest that endocytosis and a subsequent low-pH step are critical for successful ALV-B infection.
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Miura, Kazuki, Sayaka Kawano, Takahiro Suto, Takaaki Sato, Noritaka Chida et Siro Simizu. « Identification of madangamine A as a novel lysosomotropic agent to inhibit autophagy ». Bioorganic & ; Medicinal Chemistry 34 (mars 2021) : 116041. http://dx.doi.org/10.1016/j.bmc.2021.116041.

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Ciftci, Kadriye, et Robert J. Levy. « Enhanced plasmid DNA transfection with lysosomotropic agents in cultured fibroblasts ». International Journal of Pharmaceutics 218, no 1-2 (mai 2001) : 81–92. http://dx.doi.org/10.1016/s0378-5173(01)00623-8.

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Kuwahara, Tomoki, Kai Funakawa, Tadayuki Komori, Maria Sakurai, Gen Yoshii, Tomoya Eguchi, Mitsunori Fukuda et Takeshi Iwatsubo. « Roles of lysosomotropic agents on LRRK2 activation and Rab10 phosphorylation ». Neurobiology of Disease 145 (novembre 2020) : 105081. http://dx.doi.org/10.1016/j.nbd.2020.105081.

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BARON, P., E. SCARPINI, G. MEOLA, M. MOGGIO, G. PELLEGRINI et G. SCARLATO. « Morphological changes in cultured human muscle treated with lysosomotropic agents ». Cell Biology International Reports 10, no 3 (mars 1986) : 212. http://dx.doi.org/10.1016/s0309-1651(86)80066-2.

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Offensperger, Wolf-Bernhard, Silke Offensperger, Eike Walter, Hubert E. Blum et Wolfgang Gerok. « Inhibition of duck hepatitis B virus infection by lysosomotropic agents ». Virology 183, no 1 (juillet 1991) : 415–18. http://dx.doi.org/10.1016/0042-6822(91)90157-7.

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Shiraishi, Norio, Shin-Ichi Akiyama, Michio Kobayashi et Michihiko Kuwano. « Lysosomotropic agents reverse multiple drug resistance in human cancer cells ». Cancer Letters 30, no 3 (mars 1986) : 251–59. http://dx.doi.org/10.1016/0304-3835(86)90049-2.

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De Lisle, R. C., et J. A. Williams. « Zymogen granule acidity is not required for stimulated pancreatic protein secretion ». American Journal of Physiology-Gastrointestinal and Liver Physiology 253, no 6 (1 décembre 1987) : G711—G719. http://dx.doi.org/10.1152/ajpgi.1987.253.6.g711.

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It has been demonstrated recently by acridine orange fluorescence that pancreatic zymogen granules are acidic in situ, with respect to the cytoplasm. To evaluate the relationship between the acidic intragranular pH and hormone-stimulated secretion, mouse pancreatic acini were treated with lysosomotropic agents to collapse the zymogen granule pH gradient. Methylamine, monensin, and chloroquine collapsed the granule pH gradient as evidenced by a disappearance of acridine orange fluorescence. Cholecystokinin octapeptide (CCK-8)-stimulated acinar amylase secretion was unaffected in the presence of up to 30 mM methylamine and slightly enhanced in the presence of 0.3-10 microM monensin or 3-300 microM chloroquine. Acini were also preincubated for 15 min before addition of either CCK-8 or bombesin with concentrations of the lysosomotropic agents that dissipated the granule acridine orange fluorescence within this time. With preincubation, basal amylase release was unaffected, while stimulated secretion was slightly enhanced by all three lysosomotropic agents. Monensin and methylamine caused vacuolization of Golgi and lysosomal membranes and inhibition of intracellular transport of newly synthesized proteins. Chloroquine affected lysosomes similarly but had little effect on Golgi membranes or on intracellular protein transport. We also demonstrate that parotid secretory granules are acidic in situ by the acridine orange technique. Thus acidified secretory granules may be a general feature of exocrine secretory granules, but the acid pH is not requisite for the final steps in protein secretion from isolated pancreatic acini.
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Lammers, G., et J. C. Jamieson. « Studies on the effect of lysosomotropic agents on the release of Gal β 1-4GlcNAc α-2,6-sialytransferase from rat liver slices during the acute-phase response ». Biochemical Journal 261, no 2 (15 juillet 1989) : 389–93. http://dx.doi.org/10.1042/bj2610389.

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The mechanism of release of Gal beta 1-4GlcNAc alpha-2,6-sialyltransferase (CMP-N-acetylneuraminate: beta-galactoside alpha-2,6-sialytransferase, EC 2.4.99.1) from rat liver during the acute-phase response is due to the action of a cathepsin D-like proteinase that cleaves the trans-Golgi membrane-bound enzyme from a membrane anchor; this allows a major portion of the enzyme containing the catalytic site to escape into the extracellular space [Lammers & Jamieson (1988) Biochem. J. 256, 623-631]. The release of sialytransferase was most effective at pH 5.6, suggesting that release of sialyltransferase from the Golgi in whole cells is dependent on maintaining an acidic environment in the trans-Golgi compartment of the hepatocyte. Golgi membranes contain a proton pump that maintains the acidic pH in these compartments [Glickman, Croen, Kelly & Al-Awquati (1983) J. Cell Biol. 97, 1303-1308; Yamashiro, Tycko & Maxfield (1984) Cell (Cambridge, Mass.) 37, 789-800; Zhang & Schneider (1983) Biochem. Biophys. Res. Commun. 114, 620-625; Anderson & Pathak (1985) Cell (Cambridge, Mass.) 40, 635-643]. Lysosomotropic agents, such as NH4Cl, chloroquine and methylamine can penetrate acidic compartments of the cell, such as the Golgi complex, raise the pH, and thus affect proteolytic cleavage events. The present paper describes the effect of lysosomotropic agents on the release of sialyltransferase from the hepatocyte using liver slices as a whole-cell system. Slices were prepared from control rats and rats suffering from the acute-phase response, where release of sialyltransferase is increased substantially [Lammers & Jamieson (1988) Biochem. J. 256, 623-631; Kaplan, Woloski, Hellman & Jamieson (1983) J. Biol. Chem. 258, 11505-11509]. Release of sialyltransferase was almost abolished in presence of 50 mM-NH4Cl, 50 mM-methylamine or 1 mM-chloroquine. Inhibition of release of sialyltransferase was reversed when the lysosomotropic agents were removed from the medium, showing that these agents are not cytotoxic to the cells under the conditions used. The secretion of rat alpha 1-acid glycoprotein, which is not subject to proteolytic processing in the Golgi complex, was not found to be substantially affected by the presence of lysosomotropic agents. The results suggest that proteolytic cleavage of the catalytic site of sialyltransferase is a process that is significantly affected by the intra-Golgi pH.
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Kondratskyi, A., M. Yassine, C. Slomianny, K. Kondratska, D. Gordienko, E. Dewailly, V. Lehen'kyi, R. Skryma et N. Prevarskaya. « Identification of ML-9 as a lysosomotropic agent targeting autophagy and cell death ». Cell Death & ; Disease 5, no 4 (avril 2014) : e1193-e1193. http://dx.doi.org/10.1038/cddis.2014.156.

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Ostenfeld, Marie Stampe, Maria Høyer-Hansen, Lone Bastholm, Nicole Fehrenbacher, Ole Dines Olsen, Line Groth-Pedersen, Pietri Puustinen et al. « Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation ». Autophagy 4, no 4 (16 mai 2008) : 487–99. http://dx.doi.org/10.4161/auto.5774.

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Zeilhofer, H. U., J. Mollenhauer et K. Brune. « Selective growth inhibition of ductal pancreatic adenocarcinoma cells by the lysosomotropic agent chloroquine ». Cancer Letters 44, no 1 (janvier 1989) : 61–66. http://dx.doi.org/10.1016/0304-3835(89)90109-2.

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Hurwitz, Selwyn J., Masanori Terashima, Nobuyuki Mizunuma et Christopher A. Slapak. « Vesicular Anthracycline Accumulation in Doxorubicin-Selected U-937 Cells : Participation of Lysosomes ». Blood 89, no 10 (15 mai 1997) : 3745–54. http://dx.doi.org/10.1182/blood.v89.10.3745.

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Abstract The U-A10 cell line, a doxorubicin-selected variant of human U-937 myeloid leukemia cells, exhibits a redistribution of anthracyclines into a expanded vesicular compartment. The acidic nature of this compartment was confirmed by vital staining with a pH sensitive dye, LysoSensor yellow/blue DND-160. Identification of the vesicular compartment was performed by immunofluorescence analysis. Staining for the LAMP-1 and LAMP-2 antigens showed that the vesicles are enlarged lysosomes that are eccentrically placed near the nucleus of U-A10 cells. By contrast, the expression of the multidrug resistance-associated protein and the P-glycoprotein was observed predominately on the plasma membrane of the drug-resistant cells. The accumulation of daunorubicin into cellular compartments was quantified using radiolabeled drug. Exposing cells to 3[H]-daunorubicin and then isolating intact nuclei showed that nuclei from U-A10 cells accumulated twofold to threefold less anthracycline than nuclei from U-937 cells. However, when nuclei were isolated first and then exposed to 3[H]-daunorubicin, little difference in net nuclear drug accumulation was detected. Cytoplasts prepared from U-A10 and U-937 cells were exposed to 3[H]-daunorubicin to measure cytoplasmic drug accumulation. At external daunorubicin concentrations of 100 ng/mL or higher, cytoplasts from U-A10 cells accumulated significantly more daunorubicin than cytoplasts from U-937 cells. Moreover, studies with the lysosomotropic agent chloroquine showed that U-A10 cells accumulated twofold more chloroquine and showed twofold enhanced sensitivity to this agent as compared with parental U-937 cells. Fluorescence microscopy showed that chloroquine affects vesicular anthracycline sequestration in U-A10 cells with an associated increase in daunorubicin nuclear fluorescence. Although chloroquine did not alter anthracycline cytotoxicity in parental cells, it restored daunorubicin and doxorubicin sensitivity to U-A10 cells. Taken together, these studies demonstrate that U-A10 cells exhibit a redistribution of the lysosomal compartment. The trapping of drug into an expanded acidic vesicular compartment results in decreased nuclear drug accumulation and decreased cytotoxicity. Lysosomotropic agents, such as chloroquine, warrant further study as modulators of this acquired drug-resistance phenotype.
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Hurwitz, Selwyn J., Masanori Terashima, Nobuyuki Mizunuma et Christopher A. Slapak. « Vesicular Anthracycline Accumulation in Doxorubicin-Selected U-937 Cells : Participation of Lysosomes ». Blood 89, no 10 (15 mai 1997) : 3745–54. http://dx.doi.org/10.1182/blood.v89.10.3745.3745_3745_3754.

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The U-A10 cell line, a doxorubicin-selected variant of human U-937 myeloid leukemia cells, exhibits a redistribution of anthracyclines into a expanded vesicular compartment. The acidic nature of this compartment was confirmed by vital staining with a pH sensitive dye, LysoSensor yellow/blue DND-160. Identification of the vesicular compartment was performed by immunofluorescence analysis. Staining for the LAMP-1 and LAMP-2 antigens showed that the vesicles are enlarged lysosomes that are eccentrically placed near the nucleus of U-A10 cells. By contrast, the expression of the multidrug resistance-associated protein and the P-glycoprotein was observed predominately on the plasma membrane of the drug-resistant cells. The accumulation of daunorubicin into cellular compartments was quantified using radiolabeled drug. Exposing cells to 3[H]-daunorubicin and then isolating intact nuclei showed that nuclei from U-A10 cells accumulated twofold to threefold less anthracycline than nuclei from U-937 cells. However, when nuclei were isolated first and then exposed to 3[H]-daunorubicin, little difference in net nuclear drug accumulation was detected. Cytoplasts prepared from U-A10 and U-937 cells were exposed to 3[H]-daunorubicin to measure cytoplasmic drug accumulation. At external daunorubicin concentrations of 100 ng/mL or higher, cytoplasts from U-A10 cells accumulated significantly more daunorubicin than cytoplasts from U-937 cells. Moreover, studies with the lysosomotropic agent chloroquine showed that U-A10 cells accumulated twofold more chloroquine and showed twofold enhanced sensitivity to this agent as compared with parental U-937 cells. Fluorescence microscopy showed that chloroquine affects vesicular anthracycline sequestration in U-A10 cells with an associated increase in daunorubicin nuclear fluorescence. Although chloroquine did not alter anthracycline cytotoxicity in parental cells, it restored daunorubicin and doxorubicin sensitivity to U-A10 cells. Taken together, these studies demonstrate that U-A10 cells exhibit a redistribution of the lysosomal compartment. The trapping of drug into an expanded acidic vesicular compartment results in decreased nuclear drug accumulation and decreased cytotoxicity. Lysosomotropic agents, such as chloroquine, warrant further study as modulators of this acquired drug-resistance phenotype.
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Fantus, I. G., R. George, S. Tang, P. Chong et M. J. Poznansky. « The Insulin-Mimetic Agent Vanadate Promotes Receptor Endocytosis and Inhibits Intracellular Ligand-Receptor Degradation by a Mechanism Distinct From the Lysosomotropic Agents ». Diabetes 45, no 8 (1 août 1996) : 1084–93. http://dx.doi.org/10.2337/diab.45.8.1084.

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Fantus, I. G., R. George, S. Tang, P. Chong et M. J. Poznansky. « The insulin-mimetic agent vanadate promotes receptor endocytosis and inhibits intracellular ligand-receptor degradation by a mechanism distinct from the lysosomotropic agents ». Diabetes 45, no 8 (1 août 1996) : 1084–93. http://dx.doi.org/10.2337/diabetes.45.8.1084.

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Van Oost, B. A., J. B. Smith, H. Holmsen et G. D. Vladutiu. « Lysosomotropic agents selectively potentiate thrombin-induced acid hydrolase secretion from platelets. » Proceedings of the National Academy of Sciences 82, no 8 (1 avril 1985) : 2374–78. http://dx.doi.org/10.1073/pnas.82.8.2374.

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Domagala, Antoni, Malgorzata Bobrowicz, Joanna Stachura, Marta Siernicka, Piotr Mrowka, Michal Dwojak, Beata Pyrzynska, Malgorzata Firczuk et Magdalena Winiarska. « Lysosomal Disruption Augments Obinutuzumab-Induced Direct Cell Death ». Blood 128, no 22 (2 décembre 2016) : 2766. http://dx.doi.org/10.1182/blood.v128.22.2766.2766.

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Abstract Anti-CD20 mononclonal antibodies (mAbs) have a well-established role in the treatment of B-cell lymphoid malignancies. In addition to classic Fc-dependent mechanisms, including antibody-dependent and complement-mediated cytotoxicity, the so-called type II mAbs induce direct cell death. It has been shown that obinutuzumab, without Fc-crosslinking agents or effector cells, triggers non-apoptotic, lysosomal-dependent programmed cell death (PCD). The mechanism of PCD is characterized by actin reorganization, followed by permeabilization of the lysosomal membrane and subsequent generation of reactive oxygen species (ROS) through NADPH oxidase. Although, mechanisms of PCD are well-described, little is known about factors influencing sensitivity of malignant B-cells to obinutuzumab-mediated direct cell killing. Strategies to improve PCD could be potentially exploited to eliminate malignant cells, which are refractory to conventional immunotherapy. In this study, we aimed to investigate the influence of lysosomotropic agent, chloroquine, on the efficacy of obinutuzumab-mediated cytotoxicity. As PCD is dependent on lysosomal destabilization, we hypothesized that combination of obinutuzumab with lysosome-destabilizing agent would result in increased cell death. In our study, we used a Burkitt lymphoma Raji cell line that is widely employed as a model to assess the efficacy of obinutuzumab. Raji cells were incubated with obinutuzumab, alone or in combination with increasing concentrations of chloroquine, followed by annexin V/PI staining. Chloroquine, significantly increased direct cell death induced by obinutuzumab, without being toxic alone. Those observations were further corroborated by cell staining with other viability dies - TO-PRO-3 iodide and 7-AAD.The efficacy of the tested combination was completely abrogated by cytochalasin D - an inhibitor of actin polymerization and concanamycin A - inhibitor of vacuolar ATPases that activate acidic vacuoles including lysosomes, suggesting that chloroquine and obinutuzumab share a common mechanism of action. Since chloroquine has been reported to promote ROS generation, we analyzed the production of ROS with DCFDA staining. We observed that chloroquine potentiated the oxidative effect of obinutuzumab. Consistently, the effect of the combination was completely abrogated by a cell-permeable ROS scavenger - Tiron. As obinutuzumab has been shown to induce ROS production via activation of NADPH oxidase, we investigated the influence of NADPH oxidase inhibitor - diphenylene iodonium (DPI) on the combination's efficacy. DPI only partially reversed the effect of obinutuzumab, while strongly decreasing the effect of the combination. Altogether, we show for the first time that chloroquine sensitizes cell to lysosomal cell death induced by obinutuzumab. The results of our study provide a strong rationale for combining obinutuzumab with lysosomotropic agents. These findings may have particular importance given the fact that another lysomotropic agent - siramesine has recently been shown to induce selective cytotoxicity in chronic lymphocytic leukemia (CLL). Disclosures No relevant conflicts of interest to declare.
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Shamsadeen, N., et C. J. Duncan. « Cytotoxic action of the lysosomotropic agent L-leucine methyl ester on mammalian skeletal muscle ». Virchows Archiv B Cell Pathology Including Molecular Pathology 57, no 1 (janvier 1989) : 315–21. http://dx.doi.org/10.1007/bf02899096.

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Villalpando-Rodriguez, Gloria E., Anna R. Blankstein, Carmen Konzelman et Spencer B. Gibson. « Lysosomal Destabilizing Drug Siramesine and the Dual Tyrosine Kinase Inhibitor Lapatinib Induce a Synergistic Ferroptosis through Reduced Heme Oxygenase-1 (HO-1) Levels ». Oxidative Medicine and Cellular Longevity 2019 (17 septembre 2019) : 1–14. http://dx.doi.org/10.1155/2019/9561281.

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Ferroptosis is an iron-dependent type of cell death distinct from apoptosis or necrosis characterized by accumulation of reactive oxygen species. The combination of siramesine, a lysosomotropic agent, and lapatinib, a dual tyrosine kinase inhibitor (TKI), synergistically induced cell death in breast cancer cells mediated by ferroptosis. In this study, we showed that this combination of siramesine and lapatinib induces synergistic cell death in glioma cell line U87 and lung adenocarcinoma cell line A549. This cell death was characterized by the increase in iron content, reactive oxygen species (ROS) production, and lipid peroxidation accumulation after 24 hours of treatment. Moreover, iron chelator DFO and ferrostatin-1, a ferroptosis inhibitor, significantly reduced cell death. The mechanism underlying the activation of the ferroptotic pathway involves lysosomal permeabilization and increase in reactive iron levels in these cells. In addition, the downregulation of heme oxygenase-1 (HO-1) protein occurred. Overexpression of HO-1 resulted in reduction of ROS and lipid peroxidation production and cell death. Furthermore, knocking down of HO-1 combined with siramesine treatment resulted in increased cell death. Finally, we found that the inhibition of the proteasome system rescued HO-1 expression levels. Our results suggest that the induction of ferroptosis by combining a lysosomotropic agent and a tyrosine kinase inhibitor is mediated by iron release from lysosomes and HO-1 degradation by the proteasome system.
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38

Doh-ura, K., T. Iwaki et B. Caughey. « Lysosomotropic Agents and Cysteine Protease Inhibitors Inhibit Scrapie-Associated Prion Protein Accumulation ». Journal of Virology 74, no 10 (15 mai 2000) : 4894–97. http://dx.doi.org/10.1128/jvi.74.10.4894-4897.2000.

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Degtyarev, Michael, Ann De Mazière, Christine Orr, Jie Lin, Brian B. Lee, Janet Y. Tien, Wei W. Prior et al. « Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents ». Journal of Cell Biology 183, no 1 (6 octobre 2008) : 101–16. http://dx.doi.org/10.1083/jcb.200801099.

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Although Akt is known as a survival kinase, inhibitors of the phosphatidylinositol 3-kinase (PI3K)–Akt pathway do not always induce substantial apoptosis. We show that silencing Akt1 alone, or any combination of Akt isoforms, can suppress the growth of tumors established from phosphatase and tensin homologue–null human cancer cells. Although these findings indicate that Akt is essential for tumor maintenance, most tumors eventually rebound. Akt knockdown or inactivation with small molecule inhibitors did not induce significant apoptosis but rather markedly increased autophagy. Further treatment with the lysosomotropic agent chloroquine caused accumulation of abnormal autophagolysosomes and reactive oxygen species, leading to accelerated cell death in vitro and complete tumor remission in vivo. Cell death was also promoted when Akt inhibition was combined with the vacuolar H+–adenosine triphosphatase inhibitor bafilomycin A1 or with cathepsin inhibition. These results suggest that blocking lysosomal degradation can be detrimental to cancer cell survival when autophagy is activated, providing rationale for a new therapeutic approach to enhancing the anticancer efficacy of PI3K–Akt pathway inhibition.
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Chengula, Augustino Alfred, Stephen Mutoloki, Øystein Evensen et Hetron Mweemba Munang’andu. « Tilapia Lake Virus Does Not Hemagglutinate Avian and Piscine Erythrocytes and NH4Cl Does Not Inhibit Viral Replication In Vitro ». Viruses 11, no 12 (12 décembre 2019) : 1152. http://dx.doi.org/10.3390/v11121152.

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Tilapia lake virus (TiLV) is a negative-sense single-stranded RNA (-ssRNA) icosahedral virus classified to be the only member in the family Amnoonviridae. Although TiLV segment-1 shares homology with the influenza C virus PB1 and has four conserved motifs similar to influenza A, B, and C polymerases, it is unknown whether there are other properties shared between TiLV and orthomyxovirus. In the present study, we wanted to determine whether TiLV agglutinated avian and piscine erythrocytes, and whether its replication was inhibited by lysosomotropic agents, such as ammonium chloride (NH4Cl), as seen for orthomyxoviruses. Our findings showed that influenza virus strain A/Puerto Rico/8 (PR8) was able to hemagglutinate turkey (Meleagris gallopavo), Atlantic salmon (Salmo salar L), and Nile tilapia (Oreochromis niloticus) red blood cells (RBCs), while infectious salmon anemia virus (ISAV) only agglutinated Atlantic salmon, but not turkey or tilapia, RBCs. In contrast to PR8 and ISAV, TiLV did not agglutinate turkey, Atlantic salmon, or tilapia RBCs. qRT-PCR analysis showed that 30 mM NH4Cl, a basic lysosomotropic agent, neither inhibited nor enhanced TiLV replication in E-11 cells. There was no difference in viral quantities in the infected cells with or without NH4Cl treatment during virus adsorption or at 1, 2, and 3 h post-infection. Given that hemagglutinin proteins that bind RBCs also serve as ligands that bind host cells during virus entry leading to endocytosis in orthomyxoviruses, the data presented here suggest that TiLV may use mechanisms that are different from orthomyxoviruses for entry and replication in host cells. Therefore, future studies should seek to elucidate the mechanisms used by TiLV for entry into host cells and to determine its mode of replication in infected cells.
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Gores, G. J., L. J. Miller et N. F. LaRusso. « Hepatic processing of cholecystokinin peptides. II. Cellular metabolism, transport, and biliary excretion ». American Journal of Physiology-Gastrointestinal and Liver Physiology 250, no 3 (1 mars 1986) : G350—G356. http://dx.doi.org/10.1152/ajpgi.1986.250.3.g350.

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We have shown that radiolabeled cholecystokinin octapeptide (CCK-8), CCK-8-desulfate, and CCK-4 are extracted by the liver in a structurally specific manner. Thus, we studied the fate of the extracted radiolabeled peptides by quantitating biliary excretion and determining the nature of the metabolites in bile. There was rapid biliary excretion of labeled CCK-8, CCK-8-desulfate, and CCK-4 by the isolated, perfused rat liver; greater than 75% of the extracted dose and greater than 20% of the injected dose appeared in bile within 20 min after a single pass across the liver. By means of high-performance liquid chromatography and immunoprecipitation, we showed that CCK-8-desulfate and CCK-4 appeared in bile in completely metabolized forms. In contrast, for CCK-8, approximately 20% of the major forms of the label in bile was intact labeled octapeptide. To gain insight into the subcellular sites of metabolism and transhepatic transport of CCK-8, we also determined the effects of taurocholate, lysosomotropic agents, and microtubule binding agents on biliary excretion. Taurocholate had no effect on the percentage of the extracted label excreted into bile. Neither the percentage of the extracted label excreted into bile. Neither lysosmotropic agent, leupeptin, nor chloroquine affected the percentage of the extracted label or the nature of the metabolites appearing in bile. Two microtubule binding agents, vinblastine and colchicine, also did not affect the percentage of the extracted label appearing in bile.(ABSTRACT TRUNCATED AT 250 WORDS)
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Niemann, Axel, Jennifer Baltes et Hans-Peter Elsässer. « Fluorescence Properties and Staining Behavior of Monodansylpentane, a Structural Homologue of the Lysosomotropic Agent Monodansylcadaverine ». Journal of Histochemistry & ; Cytochemistry 49, no 2 (février 2001) : 177–85. http://dx.doi.org/10.1177/002215540104900205.

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OUAR, Zahia, Marcelle BENS, Caroline VIGNES, Marc PAULAIS, Claudine PRINGEL, Jocelyne FLEURY, Françoise CLUZEAUD, Roger LACAVE et Alain VANDEWALLE. « Inhibitors of vacuolar H+-ATPase impair the preferential accumulation of daunomycin in lysosomes and reverse the resistance to anthracyclines in drug-resistant renal epithelial cells ». Biochemical Journal 370, no 1 (15 février 2003) : 185–93. http://dx.doi.org/10.1042/bj20021411.

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It has been suggested that the inappropriate sequestration of weak-base chemotherapeutic drugs in acidic vesicles by multidrug-resistance (MDR) cells contributes to the mechanisms of drug resistance. The function of the acidic lysosomes can be altered in MDR cells, and so we investigated the effects of lysosomotropic agents on the secretion of lysosomal enzymes and on the intracellular distribution of the weak-base anthracycline daunomycin in drug-resistant renal proximal tubule PKSV-PRcol50 cells and their drug-sensitive PKSV-PR cell counterparts. Imaging studies using pH-dependent lysosomotropic dyes revealed that drug-sensitive and drug-resistant cells exhibited a similar acidic lysosomal pH (around 5.6—5.7), but that PKSV-PRcol50 cells contained more acidic lysosomes and secreted more of the lysosomal enzymes N-acetyl-β-hexosaminidase and β-glucuronidase than their parent PKSV-PR cells. Concanamycin A (CCM A), a potent inhibitor of the vacuolar H+-ATPase, but not the P-glycoprotein modulator verapamil, stimulated the secretion of N-acetyl-β-hexosaminidase in both drug-sensitive and drug-resistant cells. Fluorescent studies and Percoll density gradient fractionation studies revealed that daunomycin accumulated predominantly in the lysosomes of PKSV-PRcol50 cells, whereas in PKSV-PR cells the drug was distributed evenly throughout the nucleo-cytoplasmic compartments. CCM A did not impair the cellular efflux of daunomycin, but induced the rapid nucleo-cytoplasmic redistribution of the drug in PKSV-PRcol50 cells. In addition, CCM A and bafilomycin A1 almost completely restored the sensitivity of these drug-resistant cells to daunomycin, doxorubicin and epirubicin. These findings indicate that lysosomotropic agents that impair the acidic-pH-dependent accumulation of weak-base chemotherapeutic drugs may reverse anthracycline resistance in MDR cells with an expanded acidic lysosomal compartment.
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Bestion, Eloïne, Zuzana Macek Jilkova, Jean-Louis Mège, Marie Novello, Keerthi Kurma, Seyedeh Tayebeh Ahmad Pour, Gilles Lalmanach et al. « GNS561 acts as a potent anti-fibrotic and pro-fibrolytic agent in liver fibrosis through TGF-β1 inhibition ». Therapeutic Advances in Chronic Disease 11 (janvier 2020) : 204062232094204. http://dx.doi.org/10.1177/2040622320942042.

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Background: Hepatic fibrosis is the result of chronic liver injury that can progress to cirrhosis and lead to liver failure. Nevertheless, there are no anti-fibrotic drugs licensed for human use. Here, we investigated the anti-fibrotic activity of GNS561, a new lysosomotropic molecule with high liver tropism. Methods: The anti-fibrotic effect of GNS561 was determined in vitro using LX-2 hepatic stellate cells (HSCs) and primary human HSCs by studying cell viability, activity of caspases 3/7, autophagic flux, cathepsin maturation and activity, HSC activation and transforming growth factor-β1 (TGF-β1) maturation and signaling. The contribution of GNS561 lysosomotropism to its anti-fibrotic activity was assessed by increasing lysosomal pH. The potency of GNS561 on fibrosis was evaluated in vivo in a rat model of diethylnitrosamine-induced liver fibrosis. Results: GNS561 significantly decreased cell viability and promoted apoptosis. Disrupting the lysosomal pH gradient impaired its pharmacological effects, suggesting that GNS561 lysosomotropism mediated cell death. GNS561 impaired cathepsin activity, leading to defective TGF-β1 maturation and autophagic processes. Moreover, GNS561 decreased HSC activation and extracellular matrix deposition by downregulating TGF-β1/Smad and mitogen-activated proteine kinase signaling and inducing fibrolysis. Finally, oral administration of GNS561 (15 mg/kg per day) was well tolerated and attenuated diethylnitrosamine-induced liver fibrosis in this rat model (decrease of collagen deposition and of pro-fibrotic markers and increase of fibrolysis). Conclusion: GNS561 is a new potent lysosomotropic compound that could represent a valid medicinal option for hepatic fibrosis treatment through both its anti-fibrotic and its pro-fibrolytic effects. In addition, this study provides a rationale for targeting lysosomes as a promising therapeutic strategy in liver fibrosis.
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A. Marinelli, Raúl, et Guillermo L. Pen̄alva. « Effect of lysosomotropic agents on the taurocholate-stimulated biliary excretion of horseradish peroxidase ». Biochemical Pharmacology 44, no 8 (octobre 1992) : 1683–86. http://dx.doi.org/10.1016/0006-2952(92)90488-5.

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Ndolo, Rosemary A., Yepeng Luan, Shaofeng Duan, M. Laird Forrest et Jeffrey P. Krise. « Lysosomotropic Properties of Weakly Basic Anticancer Agents Promote Cancer Cell Selectivity In Vitro ». PLoS ONE 7, no 11 (7 novembre 2012) : e49366. http://dx.doi.org/10.1371/journal.pone.0049366.

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Wernersson, S., M. Riihimäki, G. Pejler et I. Waern. « Equine Airway Mast Cells are Sensitive to Cell Death Induced by Lysosomotropic Agents ». Scandinavian Journal of Immunology 85, no 1 (janvier 2017) : 30–34. http://dx.doi.org/10.1111/sji.12502.

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Dielschneider, R. F., H. Eisenstat, S. Mi, J. M. Curtis, W. Xiao, J. B. Johnston et S. B. Gibson. « Lysosomotropic agents selectively target chronic lymphocytic leukemia cells due to altered sphingolipid metabolism ». Leukemia 30, no 6 (3 février 2016) : 1290–300. http://dx.doi.org/10.1038/leu.2016.4.

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Eng, Christina H., Zuncai Wang, Diane Tkach, Lourdes Toral-Barza, Savuth Ugwonali, Shanming Liu, Stephanie L. Fitzgerald et al. « Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy ». Proceedings of the National Academy of Sciences 113, no 1 (17 décembre 2015) : 182–87. http://dx.doi.org/10.1073/pnas.1515617113.

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Macroautophagy is a key stress-response pathway that can suppress or promote tumorigenesis depending on the cellular context. Notably, Kirsten rat sarcoma (KRAS)-driven tumors have been reported to rely on macroautophagy for growth and survival, suggesting a potential therapeutic approach of using autophagy inhibitors based on genetic stratification. In this study, we evaluated whether KRAS mutation status can predict the efficacy to macroautophagy inhibition. By profiling 47 cell lines with pharmacological and genetic loss-of-function tools, we were unable to confirm that KRAS-driven tumor lines require macroautophagy for growth. Deletion of autophagy-related 7 (ATG7) by genome editing completely blocked macroautophagy in several tumor lines with oncogenic mutations in KRAS but did not inhibit cell proliferation in vitro or tumorigenesis in vivo. Furthermore, ATG7 knockout did not sensitize cells to irradiation or to several anticancer agents tested. Interestingly, ATG7-deficient and -proficient cells were equally sensitive to the antiproliferative effect of chloroquine, a lysosomotropic agent often used as a pharmacological tool to evaluate the response to macroautophagy inhibition. Moreover, both cell types manifested synergistic growth inhibition when treated with chloroquine plus the tyrosine kinase inhibitors erlotinib or sunitinib, suggesting that the antiproliferative effects of chloroquine are independent of its suppressive actions on autophagy.
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Chu, J. J. H., et M. L. Ng. « Infectious Entry of West Nile Virus Occurs through a Clathrin-Mediated Endocytic Pathway ». Journal of Virology 78, no 19 (1 octobre 2004) : 10543–55. http://dx.doi.org/10.1128/jvi.78.19.10543-10555.2004.

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ABSTRACT The pathway of West Nile flavivirus early internalization events was mapped in detail in this study. Overexpression of dominant-negative mutants of Eps15 strongly inhibits West Nile virus (WNV) internalization, and pharmacological drugs that blocks clathrin also caused a marked reduction in virus entry but not caveola-dependent endocytosis inhibitory agent, filipin. Using immunocryoelectron microscopy, WNV particles were seen within clathrin-coated pits after 2 min postinfection. Double-labeling immunofluorescence assays and immunoelectron microscopy performed with anti-WNV envelope or capsid proteins and cellular markers (EEA1 and LAMP1) revealed the trafficking pathway of internalized virus particles from early endosomes to lysosomes and finally the uncoating of the virus particles. Disruption of host cell cytoskeleton (actin filaments and microtubules) with cytochalasin D and nocodazole showed significant reduction in virus infectivity. Actin filaments are shown to be essential during the initial penetration of the virus across the plasma membrane, whereas microtubules are involved in the trafficking of internalized virus from early endosomes to lysosomes for uncoating. Cells treated with lysosomotropic agents were largely resistant to infection, indicating that a low-pH-dependent step is required for WNV infection. In situ hybridization of DNA probes specific for viral RNA demonstrated the trafficking of uncoated viral RNA genomes to the endoplasmic reticulum.
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