The Experts below are selected from a list of 7428 Experts worldwide ranked by ideXlab platform
Shoji Ohkuma - One of the best experts on this subject based on the ideXlab platform.
-
In Bafilomycin A1-resistant cells, Bafilomycin A1 raised lysosomal pH and both prodigiosins and concanamycin A inhibited growth through apoptosis.
FEBS Letters, 2003Co-Authors: Keiji Tanigaki, Satoshi Sasaki, Shoji OhkumaAbstract:In Bafilomycin A(1)-resistant cells (Vero-317 and MC-3T3-E1), Bafilomycin A(1) neither inhibited cell growth, induced cell death, nor activated caspase-3. However, 100 nM Bafilomycin A(1) did raise the lysosomal pH similar to 10 mM NH(4)Cl. Prodigiosins, H(+)/Cl(-) symporters that raise the lysosomal pH, inhibited cell growth through apoptosis and caused the activation of caspase-3. Concanamycin A also inhibited the growth of these cells through apoptosis. 10 mM NH(4)Cl inhibited the growth of these cells as well, but cytostatically. These results suggest that plecomacrolides inhibited cell growth apoptotically through specific site(s), in contrast to the cytostatic effect of 10 mM NH(4)Cl, besides raising the lysosomal pH.
-
Bafilomycin a1 induces apoptosis in pc12 cells independently of intracellular ph
FEBS Letters, 1996Co-Authors: Kuninori Kinoshita, Takaki Waritani, Masahiko Noto, Kaori Takizawa, Yuzuru Minemoto, Yasuko Nishikawa, Shoji OhkumaAbstract:PC12 cells growth-arrested with Bafilomycin A1 died showing apoptotic chromatin condensation in the nuclei. The Bafilomycin A1-induced chromatin condensation was preceded by neurite outgrowth (NOG), required higher concentrations of Bafilomycin A1 than NOG, and was suppressed by cycloheximide and aurintricarboxylic acid. NH4Cl (10 mM), another acidotropic pH perturbing agent, neither induced apoptotic chromatin condensation by itself nor suppressed that induced by Bafilomycin A1, suggesting that Bafilomycin A1-induced apoptosis occurs independently of intracellular pH in PC12 cells.
-
induction of phagocytic activity of m1 cells by an inhibitor of vacuolar ft atpase Bafilomycin a1
FEBS Letters, 1994Co-Authors: Kuninori Kinoshita, Hiroyoshi Hidaka, Shoji OhkumaAbstract:Bafilomycin a1, a selective inhibitor of vacuolar H+-ATPase, time-and dose-dependently induced the differentiation of M1 cells, a murine myeloid leukemic cell line, into macrophage-like cells as revealed by the phagocytosis of polystyrene latex particles. This differentiation was inhibited not only by actinomycin D and cycloheximide but also by ST-638 (an inhibitor of tyrosine kinase). However, it was affected neither by K-252a (an inhibitor of C-kinase) nor by H-89 (an inhibitor of A-kinase), in contrast to the M1 cell differentiation induced by leukemia inhibitory factor (LIF). Okadaic acid inhibited both the Bafilomycin A1-induced and LIF-induced differentiation of M1 cells.
-
inhibition of cell growth by Bafilomycin a1 a selective inhibitor of vacuolar h atpase
In Vitro Cellular & Developmental Biology – Animal, 1993Co-Authors: Shoji Ohkuma, Kuninori Kinoshita, Masahiko Noto, Sakae Shimizu, Yoshimichi Sai, Hiroomi TamuraAbstract:Bafilomycin A1, a potent selective inhibitor of vacuolar H+-ATPase, inhibited the growth of a variety of cultured cells dose-dependently, including golden hamster embryo and NIH-3T3 fibroblasts, whether or not they were transformed, and PC12 and HeLa cells. The concentration of Bafilomycin A1 for 50% inhibition of cell growth ranged from 10 to 50 nM. The dose response was nearly parallel with that of the Bafilomycin A1-induced lysosomal pH increase. The degree of pH increase for growth inhibition produced by Bafilomycin A1 was similar to that produced by NH4Cl in which little difference was recognized in effect among cell types.
John J Shacka - One of the best experts on this subject based on the ideXlab platform.
-
low dose Bafilomycin attenuates neuronal cell death associated with autophagy lysosome pathway dysfunction
Journal of Neurochemistry, 2010Co-Authors: Violetta N Pivtoraiko, Kevin A Roth, Adam J Harrington, Burton J Mader, Austin Luker, Guy A Caldwell, Kim A Caldwell, John J ShackaAbstract:We have shown previously that the plecomacrolide antibiotics Bafilomycin A1 and B1 significantly attenuate cerebellar granule neuron death resulting from agents that disrupt lysosome function. To further characterize Bafilomycin-mediated cytoprotection, we examined its ability to attenuate the death of naive and differentiated neuronal SH-SY5Y human neuroblastoma cells from agents that induce lysosome dysfunction in vitro, and from in vivo dopaminergic neuron death in C. elegans. Low-dose Bafilomycin significantly attenuated SH-SY5Y cell death resulting from treatment with chloroquine, hydroxychloroquine amodiaquine and staurosporine. Bafilomycin also attenuated the chloroquine-induced reduction in processing of cathepsin D, the principal lysosomal aspartic acid protease, to its mature 'active' form. Chloroquine induced autophagic vacuole accumulation and inhibited autophagic flux, effects that were attenuated upon treatment with Bafilomycin and were associated with a significant decrease in chloroquine-induced accumulation of detergent-insoluble alpha-synuclein oligomers. In addition, Bafilomycin significantly and dose-dependently attenuated dopaminergic neuron death in C. elegans resulting from in vivo over-expression of human wild-type alpha-synuclein. Together, our findings suggest that low-dose Bafilomycin is cytoprotective in part through its maintenance of the autophagy-lysosome pathway, and underscores its therapeutic potential for treating Parkinson's disease and other neurodegenerative diseases that exhibit disruption of protein degradation pathways and accumulation of toxic protein species.
-
Bafilomycin a1 inhibits chloroquine induced death of cerebellar granule neurons
Molecular Pharmacology, 2006Co-Authors: John J Shacka, Barbara J Klocke, Masahiro Shibata, Yasuo Uchiyama, Geeta Datta, Robert E Schmidt, Kevin A RothAbstract:Treatment of cells with the macrolide antibiotic Bafilomycin A1, an inhibitor of vacuolar (V)-ATPase, or with the lysosomotropic agent chloroquine, has been shown to pharmacologically inhibit autophagy as evidenced by an accumulation of autophagosomes, which in turn causes Bax-dependent apoptosis. However, Bafilomycin A1 has also been reported to inhibit chloroquine-induced apoptosis, suggesting a complex interrelationship between these two inhibitors of autophagy. To determine whether the cytoprotective effect of Bafilomycin A1 on chloroquine-treated cells was dependent on inhibition of V-ATPase, we examined the single and combined effects of Bafilomycin and chloroquine on cultured cerebellar granule neurons. When added separately, chloroquine or high concentrations of Bafilomycin A1 (≥10 nM) induced a dose-dependent inhibition of autophagy (as measured by an increase in LC3-II, a marker specific for autophagosomes), followed by caspase-3 activation and cell death. When added in combination, Bafilomycin A1 potently inhibited chloroquine-induced caspase-3 activity and cell death at concentrations (≤1 nM) that neither altered vacuolar acidification nor inhibited autophagy. The neuroprotective effects of Bafilomycin A1 against chloroquine were substantially greater than those produced by Bax deficiency. Bafilomycin A1-induced neuroprotection seemed to be stimulus-specific, in that staurosporine-induced death was not attenuated by coaddition of Bafilomycin A1. Together, these data suggest that in addition to promoting death via inhibition of V-ATPase and autophagy, Bafilomycin A1 possesses novel, neuroprotective properties that inhibit Bax-dependent activation of the intrinsic apoptotic pathway resulting from the pharmacological inhibition of autophagy.
-
Bafilomycin A1 inhibits chloroquine-induced death of cerebellar granule neurons
2006Co-Authors: John J Shacka, Barbara J Klocke, Masahiro Shibata, Yasuo Uchiyama, Geeta Datta, Robert E Schmidt, Kevin A RothAbstract:Treatment of cells with the macrolide antibiotic Bafilomycin A1, an inhibitor of vacuolar (V)-ATPase, or with the lysosomotropic agent chloroquine, has been shown to pharmacologically in-hibit autophagy as evidenced by an accumulation of autopha-gosomes, which in turn causes Bax-dependent apoptosis. However, Bafilomycin A1 has also been reported to inhibit chloroquine-induced apoptosis, suggesting a complex interre-lationship between these two inhibitors of autophagy. To de-termine whether the cytoprotective effect of Bafilomycin A1 on chloroquine-treated cells was dependent on inhibition of V-ATPase, we examined the single and combined effects of Bafilomycin and chloroquine on cultured cerebellar granule neurons. When added separately, chloroquine or high concen-trations of Bafilomycin A1 (10 nM) induced a dose-dependen
Kevin A Roth - One of the best experts on this subject based on the ideXlab platform.
-
low dose Bafilomycin attenuates neuronal cell death associated with autophagy lysosome pathway dysfunction
Journal of Neurochemistry, 2010Co-Authors: Violetta N Pivtoraiko, Kevin A Roth, Adam J Harrington, Burton J Mader, Austin Luker, Guy A Caldwell, Kim A Caldwell, John J ShackaAbstract:We have shown previously that the plecomacrolide antibiotics Bafilomycin A1 and B1 significantly attenuate cerebellar granule neuron death resulting from agents that disrupt lysosome function. To further characterize Bafilomycin-mediated cytoprotection, we examined its ability to attenuate the death of naive and differentiated neuronal SH-SY5Y human neuroblastoma cells from agents that induce lysosome dysfunction in vitro, and from in vivo dopaminergic neuron death in C. elegans. Low-dose Bafilomycin significantly attenuated SH-SY5Y cell death resulting from treatment with chloroquine, hydroxychloroquine amodiaquine and staurosporine. Bafilomycin also attenuated the chloroquine-induced reduction in processing of cathepsin D, the principal lysosomal aspartic acid protease, to its mature 'active' form. Chloroquine induced autophagic vacuole accumulation and inhibited autophagic flux, effects that were attenuated upon treatment with Bafilomycin and were associated with a significant decrease in chloroquine-induced accumulation of detergent-insoluble alpha-synuclein oligomers. In addition, Bafilomycin significantly and dose-dependently attenuated dopaminergic neuron death in C. elegans resulting from in vivo over-expression of human wild-type alpha-synuclein. Together, our findings suggest that low-dose Bafilomycin is cytoprotective in part through its maintenance of the autophagy-lysosome pathway, and underscores its therapeutic potential for treating Parkinson's disease and other neurodegenerative diseases that exhibit disruption of protein degradation pathways and accumulation of toxic protein species.
-
Bafilomycin a1 inhibits chloroquine induced death of cerebellar granule neurons
Molecular Pharmacology, 2006Co-Authors: John J Shacka, Barbara J Klocke, Masahiro Shibata, Yasuo Uchiyama, Geeta Datta, Robert E Schmidt, Kevin A RothAbstract:Treatment of cells with the macrolide antibiotic Bafilomycin A1, an inhibitor of vacuolar (V)-ATPase, or with the lysosomotropic agent chloroquine, has been shown to pharmacologically inhibit autophagy as evidenced by an accumulation of autophagosomes, which in turn causes Bax-dependent apoptosis. However, Bafilomycin A1 has also been reported to inhibit chloroquine-induced apoptosis, suggesting a complex interrelationship between these two inhibitors of autophagy. To determine whether the cytoprotective effect of Bafilomycin A1 on chloroquine-treated cells was dependent on inhibition of V-ATPase, we examined the single and combined effects of Bafilomycin and chloroquine on cultured cerebellar granule neurons. When added separately, chloroquine or high concentrations of Bafilomycin A1 (≥10 nM) induced a dose-dependent inhibition of autophagy (as measured by an increase in LC3-II, a marker specific for autophagosomes), followed by caspase-3 activation and cell death. When added in combination, Bafilomycin A1 potently inhibited chloroquine-induced caspase-3 activity and cell death at concentrations (≤1 nM) that neither altered vacuolar acidification nor inhibited autophagy. The neuroprotective effects of Bafilomycin A1 against chloroquine were substantially greater than those produced by Bax deficiency. Bafilomycin A1-induced neuroprotection seemed to be stimulus-specific, in that staurosporine-induced death was not attenuated by coaddition of Bafilomycin A1. Together, these data suggest that in addition to promoting death via inhibition of V-ATPase and autophagy, Bafilomycin A1 possesses novel, neuroprotective properties that inhibit Bax-dependent activation of the intrinsic apoptotic pathway resulting from the pharmacological inhibition of autophagy.
-
Bafilomycin A1 inhibits chloroquine-induced death of cerebellar granule neurons
2006Co-Authors: John J Shacka, Barbara J Klocke, Masahiro Shibata, Yasuo Uchiyama, Geeta Datta, Robert E Schmidt, Kevin A RothAbstract:Treatment of cells with the macrolide antibiotic Bafilomycin A1, an inhibitor of vacuolar (V)-ATPase, or with the lysosomotropic agent chloroquine, has been shown to pharmacologically in-hibit autophagy as evidenced by an accumulation of autopha-gosomes, which in turn causes Bax-dependent apoptosis. However, Bafilomycin A1 has also been reported to inhibit chloroquine-induced apoptosis, suggesting a complex interre-lationship between these two inhibitors of autophagy. To de-termine whether the cytoprotective effect of Bafilomycin A1 on chloroquine-treated cells was dependent on inhibition of V-ATPase, we examined the single and combined effects of Bafilomycin and chloroquine on cultured cerebellar granule neurons. When added separately, chloroquine or high concen-trations of Bafilomycin A1 (10 nM) induced a dose-dependen
Sergio Lavandero - One of the best experts on this subject based on the ideXlab platform.
-
Bafilomycin a1 and ml9 exert different lysosomal actions to induce cell death
Current Molecular Pharmacology, 2019Co-Authors: Soni Shaikh, Suman Kumar Nandy, Carles Canti, Sergio LavanderoAbstract: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.
-
lysosomotropic Bafilomycin a1 and ml9 causes cell death without affecting the ros and atp level
Free Radical Biology and Medicine, 2018Co-Authors: Soni Shaikh, Suman Kumar Nandy, Carles Canti, Sergio LavanderoAbstract:Bafilomycin-A1 is known for its lysosomal V-ATPase targeting, irrespective of cell types. Recently ML9, prevents store-operated Ca2+ entry, also reported for targeting the lysosomes and causing cell death. However, no study has been performed on the mechanism of lysosome targeting of Bafilomycin and ML9. Here and, using cardiomyocytes, we observed 8 h pre-incubation of ML9 leads a significant cell death, but longer treatment was needed for Bafilomycin. But surprisingly the death is not associated with ROS or ATP production. The FACS study with lysotracker green and LC3II expression levels, as well as the LC3-GFP puncta formation, are in support of lysosomotropic nature both of Bafilomycin and of ML9 but significant differences on lysosomotropicity were not observed upon both of the treatments. However, in a molecular docking study, we found Bafilomycin-A1 as a better inhibitor of V-ATPase towards C1 and C2 domains than ML9. In conclusion, at this stage, V-ATPase may not be associated with death program, but ML9 may induce lysosomal membrane permeabilization to release the lysosomal protease in the cytosol for causing cell death.
Kazuo Ohuchi - One of the best experts on this subject based on the ideXlab platform.
-
Nitric Oxide Production by the Vacuolar-Type (H ϩ )-ATPase Inhibitors Bafilomycin A1 and Concanamycin A and Its Possible Role in Apoptosis in RAW 264.7 Cells
2020Co-Authors: Jangja Hong, Yasuhiro Nakano, Aya Yokomakura, Kenji Ishihara, Soon-joo Kim, Young-sook Kang, Kazuo Ohuchi, J H, S KAbstract:ABSTRACT In the mouse leukemic monocyte cell line RAW 264.7, the vacuolar-type (H ϩ )-ATPase (V-ATPase) inhibitors Bafilomycin A1 and concanamycin A induced nitric oxide (NO) production through the expression of inducible nitric-oxide synthase mRNA and its protein and decreased cell growth and survival as determined by 3-(4,5-dimethyl(thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Bafilomycin A1 and concanamycin A activated nuclear factor (NF)-B and activator protein-1 and decreased the level of IB-␣ and increased that of phosphorylated c-Jun N-terminal kinase (JNK). NO production induced by these V-ATPase inhibitors was suppressed by the NF-B inhibitor Bay 11-7082 [(E)3-[(4-methylphenyl)sulfonyl])-2-propenenitrile] and the JNK inhibitor SP600125 [anthra[1,9-cd]pyrazol-6(2H)-one] in parallel with the partial alleviation of the V-ATPase inhibitor-induced decrease in MTT response. The Na ϩ ,K ϩ -ATPase inhibitor dibucaine and the F-ATPase inhibitor oligomycin did not induce NO production at which concentrations the MTT response was decreased. The NO donor Snitroso-N-acetyl-DL-penicillamine further lowered the V-ATPase inhibitor-induced decrease in the MTT response, and the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, sodium salt (carboxy-PTIO) alleviated it partially. Mitochondrial depolarization, an index of apoptosis, was induced by Bafilomycin A1 and concanamycin A. On treatment with the nitric-oxide synthase inhibitor N G -monomethyl-L-arginine acetate, the disruption of mitochondrial membrane potential induced by Bafilomycin A1 and concanamycin A was alleviated partially in parallel with the decrease in NO production. Carboxy-PTIO also alleviated it partially. Our findings suggest that the V-ATPase inhibitors Bafilomycin A1 and concanamycin A similarly induce NO production and the newly produced NO participates partially in the V-ATPase inhibitorinduced apoptosis in RAW 264.7 cells
-
Nitric oxide production by the vacuolar-type (H+)-ATPase inhibitors Bafilomycin A1 and concanamycin A and its possible role in apoptosis in RAW 264.7 cells.
The Journal of pharmacology and experimental therapeutics, 2006Co-Authors: Jangja Hong, Yasuhiro Nakano, Aya Yokomakura, Kenji Ishihara, Soon-joo Kim, Young-sook Kang, Kazuo OhuchiAbstract:In the mouse leukemic monocyte cell line RAW 264.7, the vacuolar-type (H+)-ATPase (V-ATPase) inhibitors Bafilomycin A1 and concanamycin A induced nitric oxide (NO) production through the expression of inducible nitric-oxide synthase mRNA and its protein and decreased cell growth and survival as determined by 3-(4,5-dimethyl(thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Bafilomycin A1 and concanamycin A activated nuclear factor (NF)-κB and activator protein-1 and decreased the level of IκB-α and increased that of phosphorylated c-Jun N-terminal kinase (JNK). NO production induced by these V-ATPase inhibitors was suppressed by the NF-κB inhibitor Bay 11-7082 [( E )3-[(4-methylphenyl)sulfonyl])-2-propenenitrile] and the JNK inhibitor SP600125 [anthra[1,9- cd ]pyrazol-6(2 H )-one] in parallel with the partial alleviation of the V-ATPase inhibitor-induced decrease in MTT response. The Na+,K+-ATPase inhibitor dibucaine and the F-ATPase inhibitor oligomycin did not induce NO production at which concentrations the MTT response was decreased. The NO donor S -nitroso- N -acetyl-dl-penicillamine further lowered the V-ATPase inhibitor-induced decrease in the MTT response, and the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, sodium salt (carboxy-PTIO) alleviated it partially. Mitochondrial depolarization, an index of apoptosis, was induced by Bafilomycin A1 and concanamycin A. On treatment with the nitric-oxide synthase inhibitor NG -monomethyl-l-arginine acetate, the disruption of mitochondrial membrane potential induced by Bafilomycin A1 and concanamycin A was alleviated partially in parallel with the decrease in NO production. Carboxy-PTIO also alleviated it partially. Our findings suggest that the V-ATPase inhibitors Bafilomycin A1 and concanamycin A similarly induce NO production and the newly produced NO participates partially in the V-ATPase inhibitor-induced apoptosis in RAW 264.7 cells.
