The Experts below are selected from a list of 3285 Experts worldwide ranked by ideXlab platform
Tae-cheon Kang - One of the best experts on this subject based on the ideXlab platform.
-
<B>LeptomycinB> B attenuates neuronal death via pka and pp2B mediated erk1 2 activation in the rat hippocampus following status epilepticus
Brain Research, 2017Co-Authors: Su-ji Min, Hye-won Hyun, Tae-cheon KangAbstract:ABstract <B>LeptomycinB> B (LMB), originally developed as an anti-fungal agent, has potent neuroprotective properties against status epilepticus (SE, a prolonged seizure activity). However, the pharmacological profiles and mechanisms of LMB for neuroprotection remain elusive. In the present study, we found that LMB increased phosphorylation levels of protein kinase A (PKA) catalytic suBunits, protein phosphatase 2B (PP2B, calcineurin) and extracellular signal–regulated kinase 1/2 (ERK1/2) under normal condition, and aBolished SE-induced neuronal death. Co-treatment of H-89 (a PKA inhiBitor) with LMB could not affect the seizure latency and its severity in response to pilocarpine. However, H-89 co-treatment aBrogated the protective effect of LMB on SE-induced neuronal damage. Cyclosporin A (CsA, a PP2B inhiBitor) co-treatment effectively prevented SE-induced neuronal death without altered seizure susceptiBility in response to pilocarpine more than LMB alone. H-89 co-treatment inhiBited LMB-mediated ERK1/2 phosphorylation, But CsA enhanced it. U0126 (an ERK1/2 inhiBitor) co-treatment aBolished the protective effect of LMB on SE-induced neuronal death without alterations in PKA and PP2B phosphorylations. To the Best of our knowledge, the present data demonstrate a previously unreported potential neuroprotective role of LMB against SE via PKA- and PP2B-mediated ERK1/2 activation.
-
<B>LeptomycinB> B attenuates neuronal death via PKA- and PP2B-mediated ERK1/2 activation in the rat hippocampus following status epilepticus.
Brain research, 2017Co-Authors: Su-ji Min, Hye-won Hyun, Tae-cheon KangAbstract:ABstract <B>LeptomycinB> B (LMB), originally developed as an anti-fungal agent, has potent neuroprotective properties against status epilepticus (SE, a prolonged seizure activity). However, the pharmacological profiles and mechanisms of LMB for neuroprotection remain elusive. In the present study, we found that LMB increased phosphorylation levels of protein kinase A (PKA) catalytic suBunits, protein phosphatase 2B (PP2B, calcineurin) and extracellular signal–regulated kinase 1/2 (ERK1/2) under normal condition, and aBolished SE-induced neuronal death. Co-treatment of H-89 (a PKA inhiBitor) with LMB could not affect the seizure latency and its severity in response to pilocarpine. However, H-89 co-treatment aBrogated the protective effect of LMB on SE-induced neuronal damage. Cyclosporin A (CsA, a PP2B inhiBitor) co-treatment effectively prevented SE-induced neuronal death without altered seizure susceptiBility in response to pilocarpine more than LMB alone. H-89 co-treatment inhiBited LMB-mediated ERK1/2 phosphorylation, But CsA enhanced it. U0126 (an ERK1/2 inhiBitor) co-treatment aBolished the protective effect of LMB on SE-induced neuronal death without alterations in PKA and PP2B phosphorylations. To the Best of our knowledge, the present data demonstrate a previously unreported potential neuroprotective role of LMB against SE via PKA- and PP2B-mediated ERK1/2 activation.
-
<B>LeptomycinB> B ameliorates vasogenic edema formation induced By status epilepticus via inhiBiting p38 mapk vegf pathway
Brain Research, 2016Co-Authors: Duk-soo Kim, Su-ji Min, Min-ju Kim, Ji-eun Kim, Tae-cheon KangAbstract:The Blood-Brain Barrier (BBB) disruption during Brain insults leads to vasogenic edema as one of the primary steps in the epileptogenic process. However, the signaling pathway concerning vasogenic edema formation has not Been clarified. In the present study, status epilepticus (SE) resulted in vascular endothelial growth factor (VEGF) over-expression accompanied By loss of BBB integrity in the rat piriform cortex. <B>LeptomycinB> B (LMB, an inhiBitor of chromosome region maintenance 1) attenuated SE-induced vasogenic edema formation. This anti-edema effect of LMB was relevant to inhiBitions of VEGF over-expression as well as p38 mitogen-activated protein kinase (MAPK) phosphorylation. Furthermore, SB202190 (a p38 MAPK inhiBitor) ameliorated vasogenic edema and VEGF over-expression induced By SE. These findings indicate that p38 MAPK/VEGF signaling pathway may Be involved in BBB disruption following SE. Thus, we suggest that p38 MAPK/VEGF axis may Be one of therapeutic targets for vasogenic edema in various neurological diseases.
-
<B>LeptomycinB> B ameliorates vasogenic edema formation induced By status epilepticus via inhiBiting p38 MAPK/VEGF pathway
Brain research, 2016Co-Authors: Duk-soo Kim, Su-ji Min, Min-ju Kim, Ji-eun Kim, Tae-cheon KangAbstract:The Blood-Brain Barrier (BBB) disruption during Brain insults leads to vasogenic edema as one of the primary steps in the epileptogenic process. However, the signaling pathway concerning vasogenic edema formation has not Been clarified. In the present study, status epilepticus (SE) resulted in vascular endothelial growth factor (VEGF) over-expression accompanied By loss of BBB integrity in the rat piriform cortex. <B>LeptomycinB> B (LMB, an inhiBitor of chromosome region maintenance 1) attenuated SE-induced vasogenic edema formation. This anti-edema effect of LMB was relevant to inhiBitions of VEGF over-expression as well as p38 mitogen-activated protein kinase (MAPK) phosphorylation. Furthermore, SB202190 (a p38 MAPK inhiBitor) ameliorated vasogenic edema and VEGF over-expression induced By SE. These findings indicate that p38 MAPK/VEGF signaling pathway may Be involved in BBB disruption following SE. Thus, we suggest that p38 MAPK/VEGF axis may Be one of therapeutic targets for vasogenic edema in various neurological diseases.
Barbara Wolff - One of the best experts on this subject based on the ideXlab platform.
-
<B>LeptomycinB> B inactivates CRM1/exportin 1 By covalent modification at a cysteine residue in the central conserved region
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Nobuaki Kudo, Minoru Yoshida, Barbara Wolff, Erwin P. Schreiner, Nobuaki Matsumori, Hiroshi Taoka, Daisuke Fujiwara, Sueharu HorinouchiAbstract:The cellular target of <B>LeptomycinB> B (LMB), a nuclear export inhiBitor, has Been identified as CRM1 (exportin 1), an evolutionarily conserved receptor for the nuclear export signal of proteins. However, the mechanism By which LMB inhiBits CRM1 still remains unclear. CRM1 in a Schizosaccharomyces pomBe mutant showing extremely high resistance to LMB had a single amino acid replacement at Cys-529 with Ser. The mutant gene, named crm1-K1, conferred LMB resistance on wild-type S. pomBe, and Crm1-K1 no longer Bound Biotinylated LMB. 1H NMR analysis showed that LMB Bound N-acetyl-l-cysteine methyl ester through a Michael-type addition, consistent with the idea that LMB Binds covalently via its α,β-unsaturated δ-lactone to the sulfhydryl group of Cys-529. When HeLa cells were cultured with Biotinylated LMB, the only cellular protein Bound covalently was CRM1. InhiBition By N-ethylmaleimide (NEM), an alkylating agent, of CRM1-mediated nuclear export proBaBly was caused By covalent Binding of the electrophilic structure in NEM to the sulfhydryl group of Cys-529, Because the crm1-K1 mutant showed the normal rate for the export of Rev nuclear export signal-Bearing proteins in the presence of not only LMB But also NEM. These results show that the single cysteine residue determines LMB sensitivity and is selectively alkylated By LMB, leading to CRM1 inactivation.
-
<B>LeptomycinB> B inactivates crm1 exportin 1 By covalent modification at a cysteine residue in the central conserved region
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Nobuaki Kudo, Minoru Yoshida, Barbara Wolff, Erwin P. Schreiner, Nobuaki Matsumori, Hiroshi Taoka, Daisuke Fujiwara, Sueharu HorinouchiAbstract:The cellular target of <B>LeptomycinB> B (LMB), a nuclear export inhiBitor, has Been identified as CRM1 (exportin 1), an evolutionarily conserved receptor for the nuclear export signal of proteins. However, the mechanism By which LMB inhiBits CRM1 still remains unclear. CRM1 in a Schizosaccharomyces pomBe mutant showing extremely high resistance to LMB had a single amino acid replacement at Cys-529 with Ser. The mutant gene, named crm1-K1, conferred LMB resistance on wild-type S. pomBe, and Crm1-K1 no longer Bound Biotinylated LMB. 1H NMR analysis showed that LMB Bound N-acetyl-l-cysteine methyl ester through a Michael-type addition, consistent with the idea that LMB Binds covalently via its α,β-unsaturated δ-lactone to the sulfhydryl group of Cys-529. When HeLa cells were cultured with Biotinylated LMB, the only cellular protein Bound covalently was CRM1. InhiBition By N-ethylmaleimide (NEM), an alkylating agent, of CRM1-mediated nuclear export proBaBly was caused By covalent Binding of the electrophilic structure in NEM to the sulfhydryl group of Cys-529, Because the crm1-K1 mutant showed the normal rate for the export of Rev nuclear export signal-Bearing proteins in the presence of not only LMB But also NEM. These results show that the single cysteine residue determines LMB sensitivity and is selectively alkylated By LMB, leading to CRM1 inactivation.
-
<B>LeptomycinB> B InhiBition of Signal-Mediated Nuclear Export By Direct Binding to CRM1
Experimental cell research, 1998Co-Authors: Nobuaki Kudo, Sueharu Horinouchi, Yoshihiro Yoneda, Barbara Wolff, Toshihiro Sekimoto, Erwin P. Schreiner, Mitsuhiro Yanagida, Minoru YoshidaAbstract:<B>LeptomycinB> B (LMB) is aStreptomycesmetaBolite that inhiBits nuclear export of the human immunodeficiency virus type 1 regulatory protein Rev at low nanomolar concentrations. Recently, LMB was shown to inhiBit the function of CRM1, a receptor for the nuclear export signal (NES). Here we show evidence that LMB Binds directly to CRM1 and that CRM1 is essential for NES-dependent nuclear export of proteins in Both yeast and mammalian cells. Binding experiments with a Biotinylated derivative of LMB and a HeLa cell extract led to identifying CRM1 as a major protein that Bound to the LMB derivative. Microinjection of a purified anti-human CRM1 antiBody into the mammalian nucleus specifically inhiBited nuclear export of NES-containing proteins, as did LMB. Consistent with this, CRM1 was found to interact with NES, when assayed with immoBilized NES and HeLa cell extracts. This association was disrupted By adding LMB or purified anti-human CRM1 antiBody. The inhiBition of CRM1 By LMB was also oBserved in fission yeast. The fission yeastcrm1mutant was defective in the nuclear export of NES-fused proteins, But not in the import of nuclear localization signal (NLS)-fused proteins. Interestingly, a protein containing Both NES and NLS, which is expected to shuttle Between nucleus and cytoplasm, was highly accumulated in the nucleus of thecrm1mutant cells or of cells treated with LMB. These results strongly suggest that CRM1 is the target of LMB and is an essential factor for nuclear export of proteins in eukaryotes.
-
MicroBial Conversion Products of <B>LeptomycinB> B
Applied and environmental microbiology, 1998Co-Authors: Michaela Kuhnt, Ying Wang, Monique Ponelle, J.‐j. Sanglier, Francis Bitsch, Barbara WolffAbstract:<B>LeptomycinB> B (LMB), a secondary metaBolite produced By Streptomyces sp. strain ATS 1287, with known antifungal and antitumor effects, inhiBits the nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 regulatory protein Rev and exhiBits significant antiproliferative activity. Since LMB itself turned out to Be distinctly cytotoxic, a Bioconversion screening with a selected set of 29 Bacterial and 72 fungal strains was performed in order to oBtain metaBolites of LMB with reduced antiproliferative effects. Several derivatives of LMB, more polar than the parent compound and produced in yields of >5%, were detected. Liquid chromatography-mass spectroscopy analysis indicated the type of Bioconversion. Fermentations (1-liter scale) of those strains with high rates of transformation were suitaBle for isolation and characterization of the most prominent metaBolites. Thus, Bioconversion of LMB with Aspergillus flavus ATCC 9170 and Emericella unguis ATCC 13431 served for isolation of the novel derivatives 26-hydroxy-LMB (30% was the concentration of the metaBolite [with respect to LMB] used for Bioconversion) and LMB-24-glutaminamide (90%), respectively. Streptomyces rimosus ATCC 28893 converted LMB into 4,11-dihydroxy-LMB (13%) and 2,3-dihydro-LMB (55%). Although the antiproliferative effects of the LMB metaBolites could Be reduced through microBial conversion, none of these metaBolites inhiBited the nuclear export of Rev Better than LMB itself.
-
NOVEL <B>LeptomycinB>S FROM A STREPTOMYCES STRAIN A92-308902 : INHIBITORS OF THE NUCLEO-CYTOPLASMIC TRANSLOCATION OF THE HIV-1 REGULATORY PROTEIN REV
Helvetica Chimica Acta, 1997Co-Authors: Ying Wang, Monique Ponelle, J.‐j. Sanglier, Barbara WolffAbstract:As one of the regulatory gene products in the HIV-1 genome, Rev protein must Be translocated from the nucleus to the cytoplasm to exert its function. Therefore, inhiBition of Rev protein translocation could Be a useful target for HIV therapy. An extract from the Streptomyces strain A92-308902 with very potent inhiBitory activity was found in the course of a high throughput screening with a Rev translocation assay (RTA). Bioassay-guided fractionation with gel filtration, normal-phase and reversed-phase chromatography yielded six RTA-active metaBolites Belonging to the <B>LeptomycinB> family, the known <B>LeptomycinB> A (1), <B>LeptomycinB> B (2), kazusamycin B (3), and kazusamycin A (4). and the hitherto unknown dilactonmycin (5) and delactonmycin (6), together with an inactive cyclic hexadepsipeptide L-156,620 (7). The structures were estaBlished mainly By spectroscopic methods (UV, FT-IR, FAB-MS, 1H-NMR, 13C-NMR(JMOD), DQ-COSY, ROESY, HSQC, and HMBC). The configuration of all CC Bonds of 1–6 was unamBiguously estaBlished By analysis of coupling constants and ROESY spectra. All isolated <B>LeptomycinB>s 1–6 inhiBit Rev translocation at nanomolar concentrations. Six derivatives (2a–c and 4a–c) of <B>LeptomycinB> B (2) and kazusamycin A (4) were also prepared and tested in the RTA for preliminary investigations on structure-activity relationships.
Minoru Yoshida - One of the best experts on this subject based on the ideXlab platform.
-
<B>LeptomycinB> B, a metaBolite of Streptomyces, inhiBits the expression of induciBle nitric oxide synthase in BV2 microglial cells.
International journal of oncology, 2006Co-Authors: Byeong-churl Jang, Minoru Yoshida, Su-haeng Sung, Jong-gu Park, Jong-wook Park, Min-ho Suh, In-hak Choi, Sun-kyun Yoo, Seong-il SuhAbstract:Overexpression of induciBle nitric oxide synthase (iNOS) and the resultant overproduction of NO has Been implicated in neuronal inflammatory diseases. <B>LeptomycinB> B (LMB), a metaBolite of Streptomyces, has Been identified as a specific inhiBitor of CRM1 nuclear export receptor. In this study, we evaluated the effect of LMB on lipopolysaccharide (LPS)-induced iNOS expression in BV2 cells, a murine microglial cells and the associated mechanisms. LMB strongly inhiBited LPS-induced iNOS protein and mRNA expressions in BV2 cells in which 10 ng/ml of LMB (18 nM) was sufficient to greatly down-regulate iNOS By LPS, suggesting the potency of LMB to inhiBit iNOS. The data of iNOS promoter-driven luciferase assay further suggested that the LMB inhiBitory effect was in part due to inhiBition of iNOS transcription. However, LPS-induced activation of various intracellular signaling proteins, such as nuclear factor-kappaB (NF-kappaB), extracellular signal-regulated kinases (ERKs), p38s, and c-Jun N-terminal kinases (JNKs), whose activations are known to Be important for iNOS expression By LPS in BV2 cells, were not affected in the presence of LMB. Together, these results suggest that LMB inhiBits iNOS expression in response to LPS in BV2 microglia, and the inhiBition seems to Be associated with Blockage of CRM1-mediated iNOS mRNA nuclear export and also in part transcriptional down-regulation of iNOS, But not through modulation of NF-kappaB and the mitogen-activated protein kinase signaling pathways.
-
Involvement of nuclear accumulation of heat shock protein 27 in <B>LeptomycinB> B-induced apoptosis in HeLa cells
The Journal of antibiotics, 2005Co-Authors: Ayako Tsuchiya, Minoru Yoshida, Etsu Tashiro, Masaya ImotoAbstract:<B>LeptomycinB> B (LMB) is a Streptomyces metaBolite that inhiBits the chromosomal region maintenance (CRM)1-dependent nuclear export of proteins. It also induces apoptosis in several types of cancer cells, By a yet undefined mechanism. We used a functional proteomics approach to delineate the pathways and mediators involved in LMB-induced apoptosis in HeLa cells. Using two-dimensional gel electrophoresis, we searched for proteins accumulated in the nuclei of HeLa cells upon LMB treatment. Among such proteins we found prohiBitin and Heat shock protein (Hsp)27, identified By peptide mass fingerprinting and mass spectrometry. Immunocytochemistry was carried out to confirm the LMB-induced nuclear accumulation of these two proteins in HeLa cells. Furthermore, we found that the cytoplasmic expression of Hsp27, But not prohiBitin, partially inhiBited LMB-induced apoptosis, indicating that nuclear sequestration of Hsp27 was, at least in part, involved in the apoptosis.
-
<B>LeptomycinB> B Overcomes ImatiniB Resistance Mediated By Stromal Cells and Mutant BCR-ABL in Philadelphia Chromosome-Positive Acute LymphoBlastic Leukemia Cells.
Blood, 2004Co-Authors: Arinobu Tojo, Minoru Yoshida, Kiyoko Izawa, Rieko Sekine, Tokiko Nagamura, Takashi TsujiAbstract:Philadelphia chromosome-positive acute lymphoBlastic leukemia (Ph-ALL) is one of the most intractaBle hematological malignancies, and readily acquires resistance to chemotherapeutic drugs including imatiniB mesylate. We hypothesized that the adhesive interaction of Ph-ALL cells with Bone marrow stromal cells might cause their escape from drug-induced apoptosis and suBsequent minimal residual disease, resulting in the generation of a chemoresistant clone such as a clone harBoring mutant BCR-ABL. To gain insight into this possiBility and a novel strategy against imatiniB resistance, we used two Ph-ALL cell lines designated as IMS-PhL1 (L1) and IMS-PhL2 (L2). L1 cells had wild type BCR-ABL, whereas L2 cells had Y253H mutant and revealed 10-fold or more resistance to imatiniB, compared with L1 cells. The growth of L1 cells was autonomous and their spontaneous apoptosis was suppressed By co-culture with a murine Bone marrow stromal cell line, HESS-5. In contrast, the sustained growth and survival of L2 cells was aBsolutely dependent on direct contact with HESS-5. Both cell lines adhered to and migrated Beneath the HESS-5 cell layer, resulting in the formation of coBBlestone areas (CA). While floating L1 cells were eradicated By 1 mM imatiniB, a portion of adherent L1 cells could survive even at 10 μM imatiniB. Similarly, L2 cells forming CA Beneath the HESS-5 cell layer consideraBly resisted prolonged exposure to 10 μM imatiniB. <B>LeptomycinB> B (LMB), a potent inhiBitor of CRM1/exportin-1, can trap BCR-ABL in the nucleus and can aggressively eliminate BCR-ABL + cells in comBination with imatiniB (Wang et al., 2001). We tested LMB for its aBility to eliminate CA or adherent Ph-ALL cells in comBination with imatinB. The result for L2 cells was shown in Figure. Dramatically, comBined use of 10 μM imatiniB and 1 nM LMB for 7 days exerted a synergistic effect on reduction in the numBer of CA. L1 cells were also susceptiBle to the comBination of imatiniB and LMB. Our results suggest that nuclear entrapment of BCR-ABL may Be a promising strategy for overcoming imatiniB resistance mediated By stromal cells as well as a certain BCR-ABL mutant.
-
Chromosomal Region Maintenance 1 (CRM1)-dependent Nuclear Export of Smad UBiquitin Regulatory Factor 1 (Smurf1) Is Essential for Negative Regulation of Transforming Growth Factor-β Signaling By Smad7
The Journal of biological chemistry, 2003Co-Authors: Yoshitaka Tajima, Minoru Yoshida, Yoshihiro Yoneda, Toshihiro Sekimoto, Kouichiro Goto, Kenichi Shinomiya, Kohei Miyazono, Takeshi ImamuraAbstract:ABstract Smad uBiquitin regulatory factor 1 (Smurf1), a HECT type E3 uBiquitin ligase, interacts with inhiBitory Smad7 and induces translocation of Smad7 to the cytoplasm. Smurf1 then associates with the transforming growth factor (TGF)-β type I receptor, TβR-I, enhancing turnover. However, the mechanism of nuclear export of Smad7 By Smurf1 has not Been elucidated. Here we identified a functional nuclear export signal (NES) in a C-terminal region of Smurf1. In transfected cells, the Smurf1-Smad7 complex was accumulated in the cytoplasm By the nuclear export receptor, CRM1; this action was prevented By treatment with <B>LeptomycinB> B, a specific inactivator of CRM1 function. A green fluorescence protein fusion protein containing the C-terminal NES motif of Smurf1, located in the cytoplasm, accumulated in the nucleus following treatment with <B>LeptomycinB> B. Moreover, Smurf1 was shown to Bind physically to CRM1 through NES, and nuclear export of the Smurf1-Smad7 complex was prevented By mutations of Smurf1 within the NES. Finally, the Smurf1 NES mutant reduced inhiBition By Smad7 of the transcriptional activation induced By TGF-β. These results thus suggest that CRM1-dependent nuclear export of Smurf1 is essential for the negative regulation of TGF-β signaling By Smad7.
-
<B>LeptomycinB> B, an InhiBitor of the Nuclear Export Receptor CRM1, InhiBits COX-2 Expression
The Journal of biological chemistry, 2002Co-Authors: Byeong-churl Jang, Minoru Yoshida, Ursula Muñoz-najar, Jihye Paik, Kevin P. Claffey, Timothy HlaAbstract:Cyclooxygenase (COX)-2, the induciBle prostaglandin synthase, is overexpressed in cancer and chronic inflammatory diseases. Post-transcriptional regulation of COX-2 mRNA is important in controlling the expression of the COX-2 gene. Here, we report that <B>LeptomycinB> B (LMB), a specific inhiBitor of the nuclear export factor CRM1 potently inhiBits the staBilization of COX-2 mRNA in MDA-MB-231 human mammary cancer cells. However, COX-2 promoter-driven reporter gene expression is not inhiBited By LMB, suggesting that LMB acts at the post-transcriptional level. SuBcellular fractionation experiments indicate that LMB inhiBited the time-dependent export of COX-2 mRNA into the memBrane-Bound polysomal compartment at the endoplasmic reticulum. LMB suppressed COX-2 expression By interleukin-1Beta in HT-29 human colon cancer cells and in human umBilical vein endothelial cells But had no effect on COX-2 expression induced By Escherichia coli lipopolysaccharide in monocytic THP-1 cells. These data suggest that the nuclear export of COX-2 mRNA may Be rate-liming in a cell-specific manner. LMB may Be useful to control COX-2 expression in various human diseases in which COX-2 plays a pathogenetic role.
Su-ji Min - One of the best experts on this subject based on the ideXlab platform.
-
<B>LeptomycinB> B attenuates neuronal death via pka and pp2B mediated erk1 2 activation in the rat hippocampus following status epilepticus
Brain Research, 2017Co-Authors: Su-ji Min, Hye-won Hyun, Tae-cheon KangAbstract:ABstract <B>LeptomycinB> B (LMB), originally developed as an anti-fungal agent, has potent neuroprotective properties against status epilepticus (SE, a prolonged seizure activity). However, the pharmacological profiles and mechanisms of LMB for neuroprotection remain elusive. In the present study, we found that LMB increased phosphorylation levels of protein kinase A (PKA) catalytic suBunits, protein phosphatase 2B (PP2B, calcineurin) and extracellular signal–regulated kinase 1/2 (ERK1/2) under normal condition, and aBolished SE-induced neuronal death. Co-treatment of H-89 (a PKA inhiBitor) with LMB could not affect the seizure latency and its severity in response to pilocarpine. However, H-89 co-treatment aBrogated the protective effect of LMB on SE-induced neuronal damage. Cyclosporin A (CsA, a PP2B inhiBitor) co-treatment effectively prevented SE-induced neuronal death without altered seizure susceptiBility in response to pilocarpine more than LMB alone. H-89 co-treatment inhiBited LMB-mediated ERK1/2 phosphorylation, But CsA enhanced it. U0126 (an ERK1/2 inhiBitor) co-treatment aBolished the protective effect of LMB on SE-induced neuronal death without alterations in PKA and PP2B phosphorylations. To the Best of our knowledge, the present data demonstrate a previously unreported potential neuroprotective role of LMB against SE via PKA- and PP2B-mediated ERK1/2 activation.
-
<B>LeptomycinB> B attenuates neuronal death via PKA- and PP2B-mediated ERK1/2 activation in the rat hippocampus following status epilepticus.
Brain research, 2017Co-Authors: Su-ji Min, Hye-won Hyun, Tae-cheon KangAbstract:ABstract <B>LeptomycinB> B (LMB), originally developed as an anti-fungal agent, has potent neuroprotective properties against status epilepticus (SE, a prolonged seizure activity). However, the pharmacological profiles and mechanisms of LMB for neuroprotection remain elusive. In the present study, we found that LMB increased phosphorylation levels of protein kinase A (PKA) catalytic suBunits, protein phosphatase 2B (PP2B, calcineurin) and extracellular signal–regulated kinase 1/2 (ERK1/2) under normal condition, and aBolished SE-induced neuronal death. Co-treatment of H-89 (a PKA inhiBitor) with LMB could not affect the seizure latency and its severity in response to pilocarpine. However, H-89 co-treatment aBrogated the protective effect of LMB on SE-induced neuronal damage. Cyclosporin A (CsA, a PP2B inhiBitor) co-treatment effectively prevented SE-induced neuronal death without altered seizure susceptiBility in response to pilocarpine more than LMB alone. H-89 co-treatment inhiBited LMB-mediated ERK1/2 phosphorylation, But CsA enhanced it. U0126 (an ERK1/2 inhiBitor) co-treatment aBolished the protective effect of LMB on SE-induced neuronal death without alterations in PKA and PP2B phosphorylations. To the Best of our knowledge, the present data demonstrate a previously unreported potential neuroprotective role of LMB against SE via PKA- and PP2B-mediated ERK1/2 activation.
-
<B>LeptomycinB> B ameliorates vasogenic edema formation induced By status epilepticus via inhiBiting p38 mapk vegf pathway
Brain Research, 2016Co-Authors: Duk-soo Kim, Su-ji Min, Min-ju Kim, Ji-eun Kim, Tae-cheon KangAbstract:The Blood-Brain Barrier (BBB) disruption during Brain insults leads to vasogenic edema as one of the primary steps in the epileptogenic process. However, the signaling pathway concerning vasogenic edema formation has not Been clarified. In the present study, status epilepticus (SE) resulted in vascular endothelial growth factor (VEGF) over-expression accompanied By loss of BBB integrity in the rat piriform cortex. <B>LeptomycinB> B (LMB, an inhiBitor of chromosome region maintenance 1) attenuated SE-induced vasogenic edema formation. This anti-edema effect of LMB was relevant to inhiBitions of VEGF over-expression as well as p38 mitogen-activated protein kinase (MAPK) phosphorylation. Furthermore, SB202190 (a p38 MAPK inhiBitor) ameliorated vasogenic edema and VEGF over-expression induced By SE. These findings indicate that p38 MAPK/VEGF signaling pathway may Be involved in BBB disruption following SE. Thus, we suggest that p38 MAPK/VEGF axis may Be one of therapeutic targets for vasogenic edema in various neurological diseases.
-
<B>LeptomycinB> B ameliorates vasogenic edema formation induced By status epilepticus via inhiBiting p38 MAPK/VEGF pathway
Brain research, 2016Co-Authors: Duk-soo Kim, Su-ji Min, Min-ju Kim, Ji-eun Kim, Tae-cheon KangAbstract:The Blood-Brain Barrier (BBB) disruption during Brain insults leads to vasogenic edema as one of the primary steps in the epileptogenic process. However, the signaling pathway concerning vasogenic edema formation has not Been clarified. In the present study, status epilepticus (SE) resulted in vascular endothelial growth factor (VEGF) over-expression accompanied By loss of BBB integrity in the rat piriform cortex. <B>LeptomycinB> B (LMB, an inhiBitor of chromosome region maintenance 1) attenuated SE-induced vasogenic edema formation. This anti-edema effect of LMB was relevant to inhiBitions of VEGF over-expression as well as p38 mitogen-activated protein kinase (MAPK) phosphorylation. Furthermore, SB202190 (a p38 MAPK inhiBitor) ameliorated vasogenic edema and VEGF over-expression induced By SE. These findings indicate that p38 MAPK/VEGF signaling pathway may Be involved in BBB disruption following SE. Thus, we suggest that p38 MAPK/VEGF axis may Be one of therapeutic targets for vasogenic edema in various neurological diseases.
Ying Wang - One of the best experts on this subject based on the ideXlab platform.
-
MicroBial Conversion Products of <B>LeptomycinB> B
Applied and environmental microbiology, 1998Co-Authors: Michaela Kuhnt, Ying Wang, Monique Ponelle, J.‐j. Sanglier, Francis Bitsch, Barbara WolffAbstract:<B>LeptomycinB> B (LMB), a secondary metaBolite produced By Streptomyces sp. strain ATS 1287, with known antifungal and antitumor effects, inhiBits the nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 regulatory protein Rev and exhiBits significant antiproliferative activity. Since LMB itself turned out to Be distinctly cytotoxic, a Bioconversion screening with a selected set of 29 Bacterial and 72 fungal strains was performed in order to oBtain metaBolites of LMB with reduced antiproliferative effects. Several derivatives of LMB, more polar than the parent compound and produced in yields of >5%, were detected. Liquid chromatography-mass spectroscopy analysis indicated the type of Bioconversion. Fermentations (1-liter scale) of those strains with high rates of transformation were suitaBle for isolation and characterization of the most prominent metaBolites. Thus, Bioconversion of LMB with Aspergillus flavus ATCC 9170 and Emericella unguis ATCC 13431 served for isolation of the novel derivatives 26-hydroxy-LMB (30% was the concentration of the metaBolite [with respect to LMB] used for Bioconversion) and LMB-24-glutaminamide (90%), respectively. Streptomyces rimosus ATCC 28893 converted LMB into 4,11-dihydroxy-LMB (13%) and 2,3-dihydro-LMB (55%). Although the antiproliferative effects of the LMB metaBolites could Be reduced through microBial conversion, none of these metaBolites inhiBited the nuclear export of Rev Better than LMB itself.
-
NOVEL <B>LeptomycinB>S FROM A STREPTOMYCES STRAIN A92-308902 : INHIBITORS OF THE NUCLEO-CYTOPLASMIC TRANSLOCATION OF THE HIV-1 REGULATORY PROTEIN REV
Helvetica Chimica Acta, 1997Co-Authors: Ying Wang, Monique Ponelle, J.‐j. Sanglier, Barbara WolffAbstract:As one of the regulatory gene products in the HIV-1 genome, Rev protein must Be translocated from the nucleus to the cytoplasm to exert its function. Therefore, inhiBition of Rev protein translocation could Be a useful target for HIV therapy. An extract from the Streptomyces strain A92-308902 with very potent inhiBitory activity was found in the course of a high throughput screening with a Rev translocation assay (RTA). Bioassay-guided fractionation with gel filtration, normal-phase and reversed-phase chromatography yielded six RTA-active metaBolites Belonging to the <B>LeptomycinB> family, the known <B>LeptomycinB> A (1), <B>LeptomycinB> B (2), kazusamycin B (3), and kazusamycin A (4). and the hitherto unknown dilactonmycin (5) and delactonmycin (6), together with an inactive cyclic hexadepsipeptide L-156,620 (7). The structures were estaBlished mainly By spectroscopic methods (UV, FT-IR, FAB-MS, 1H-NMR, 13C-NMR(JMOD), DQ-COSY, ROESY, HSQC, and HMBC). The configuration of all CC Bonds of 1–6 was unamBiguously estaBlished By analysis of coupling constants and ROESY spectra. All isolated <B>LeptomycinB>s 1–6 inhiBit Rev translocation at nanomolar concentrations. Six derivatives (2a–c and 4a–c) of <B>LeptomycinB> B (2) and kazusamycin A (4) were also prepared and tested in the RTA for preliminary investigations on structure-activity relationships.
-
<B>LeptomycinB> B is an inhiBitor of nuclear export inhiBition of nucleo cytoplasmic translocation of the human immunodeficiency virus type 1 hiv 1 rev protein and rev dependent mrna
Chemistry & Biology, 1997Co-Authors: Barbara Wolff, J.‐j. Sanglier, Ying WangAbstract:ABstract Background: The human immunodeficiency virus type 1 (HIV-1) regulatory protein Rev is required for unspliced and incompletely spliced viral mRNAs to appear in the cytoplasm and thus for viral replication. Translocation of Rev from the nucleus to the cytoplasm is essential if Rev is to function. We wanted to identify inhiBitors of this transport process Because they would Be potential antiviral agents. Results: The Streptomyces metaBolite, <B>LeptomycinB> B, and other antiBiotics of the <B>LeptomycinB>/kazusamycin family were identified as inhiBitors of the nucleo-cytoplasmic translocation of Rev at nanomolar concentrations. Rev-dependent export of mRNA into the cytoplasm is also Blocked By <B>LeptomycinB> B, which inhiBits Rev-dependent, But not Rev-independent gene expression in a short-term transfection assay. In primary human monocytes, <B>LeptomycinB> B suppresses HIV-1 replication. Conclusions: <B>LeptomycinB> B is the first low molecular weight inhiBitor of nuclear export to Be identified. Although it cannot Be used therapeutically, it should serve as a valuaBle tool for dissecting nuclear export pathways.