The Experts below are selected from a list of 2031 Experts worldwide ranked by ideXlab platform
Arthi Kanthasamy - One of the best experts on this subject based on the ideXlab platform.
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neuroprotective effect of protein kinase c delta inhibitor Rottlerin in cell culture and animal models of parkinson s disease
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Danhui Zhang, Vellareddy Anantharam, Arthi KanthasamyAbstract:Recent studies from our laboratory demonstrated that the protein kinase C (PKC) delta isoform is an oxidative stress-sensitive kinase and a key mediator of apoptotic cell death in Parkinson's Disease (PD) models (Eur J Neurosci 18:1387-1401, 2003; Mol Cell Neurosci 25:406-421, 2004). We showed that native PKC delta is proteolytically activated by caspase-3 and that suppression of PKC delta by dominant-negative mutant or small interfering RNA against the kinase can effectively block apoptotic cell death in cellular models of PD. In an attempt to translate the mechanistic studies to a neuroprotective strategy targeting PKC delta, we systematically characterized the neuroprotective effect of a PKC delta inhibitor, Rottlerin, in 1-methyl-4-phenylpyridinium (MPP(+))-treated primary mesencephalic neuronal cultures as well as in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD. Rottlerin treatment in primary mesencephalic cultures significantly attenuated MPP(+)-induced tyrosine hydroxylase (TH)-positive neuronal cell and neurite loss. Administration of Rottlerin, either intraperitoneally or orally, to C57 black mice showed significant protection against MPTP-induced locomotor deficits and striatal depletion of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid. Notably, Rottlerin post-treatment was effective even when MPTP-induced depletion of dopamine and its metabolites was greater than 60%, demonstrating its neurorescue potential. Furthermore, the dose of Rottlerin used in neuroprotective studies effectively attenuated the MPTP-induced PKC delta kinase activity. Importantly, stereological analysis of nigral neurons revealed Rottlerin treatment significantly protected against MPTP-induced TH-positive neuronal loss in the substantia nigra compacta. Collectively, our findings demonstrate the neuroprotective effect of Rottlerin in both cell culture and preclinical animal models of PD, and they suggest that pharmacological modulation of PKC delta may offer a novel therapeutic strategy for treatment of PD.
Friedrich Marks - One of the best experts on this subject based on the ideXlab platform.
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Rottlerin a novel protein kinase inhibitor
Biochemical and Biophysical Research Communications, 1994Co-Authors: Michael Gschwendt, Walter Kittstein, H J Muller, K Kielbassa, R Zang, Gabriele Rincke, Friedrich MarksAbstract:Rottlerin, a compound from Mallotus philippinensis, is shown to inhibit protein kinases with some specificity for PKC. To some extent, the novel inhibitor is able to differentiate between PKC isoenzymes, with IC50 values for PKC delta of 3-6 microM, PKC alpha,beta,gamma of 30-42 microM and PKC epsilon,eta,zeta of 80-100 microM. Inhibition of PKC appears, at least in part, to be due to a competition between Rottlerin and ATP. Among the protein kinases tested, only CaM-kinase III is suppressed by Rottlerin as effectively as PKC delta. The chemical structure of Rottlerin might serve as a basis for the development of novel inhibitors with improved selectivity for a distinct PKC isoenzyme, such as PKC delta, or for CaM-kinase III.
Xiao-yong Man - One of the best experts on this subject based on the ideXlab platform.
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Rottlerin administration attenuates IMQ-treated mice.
2017Co-Authors: Min Min, Bing-xi Yan, Ping Wang, Lilla Landeck, Jia-qi Chen, Sui-qing Cai, Min Zheng, Xiao-yong ManAbstract:(A)Protocol for IPI model and dosing of Rottlerin. (B) Representative clinical presentations of IMQ-treated mice from the vehicle group (left) and Rottlerin group (right). (C) Quantification of body weight changes between the vehicle group and Rottlerin group. (D) Scoring was performed daily using the erythema, scales, and thickness elements of the PASI to assign a score of 0–4 to each animal and thereby assess the effects of Rottlerin in the IPI mouse model. The data points are presented as the mean±SEM of five mice per group. *P< 0.05, **P< 0.01 vs. vehicle. Data are representative of three independent experiments. (E) The relative size of spleens in the Rottlerin group (right) compared with vehicle group (left). The quantification of spleen mass in the two groups is shown as the mean±SEM (n = 5 for each group). **P
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Rottlerin regulates expression of proliferation and differentiation-related molecules in NHEKs.
2017Co-Authors: Min Min, Bing-xi Yan, Ping Wang, Lilla Landeck, Jia-qi Chen, Sui-qing Cai, Min Zheng, Xiao-yong ManAbstract:NHEKs were treated with 0, 1, 5, and 10μM Rottlerin for 24 hours. The effect of Rottlerin on miRNA expression levels of keratinocytes proliferation associated markers were investigated using qRT-PCR. U6 was used as the internal control. (A) miR-21, (B) miR-31 (n = 3, ** P
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Rottlerin decreases the number of effector cells that mainly infiltrate the skin in IMQ-treated mice.
2017Co-Authors: Min Min, Bing-xi Yan, Ping Wang, Lilla Landeck, Jia-qi Chen, Sui-qing Cai, Min Zheng, Xiao-yong ManAbstract:Immunohistochemical detection of immune cell-related markers was performed on paraffin-embedded sections obtained from the back skin of IMQ-induced mice treated with vehicle or Rottlerin. (A–C) Representatives IHC images of CD3 (A), CD11b (B), and CD11c (C) on the skin of the vehicle or Rottlerin-treated mice. Scale bar = 100μm. (D–F) Quantification analysis of IHC staining for CD3(D), CD11b(E), and CD11c (F) on the skin of the vehicle and Rottlerin treated mice. Two independent researchers counted the number of positive staining cells were per high-power field (HPF). The data are representative of three experiments (n = 5 mice per group).*P
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Rottlerin alters immunocytes compositions in IMQ-treated mice.
2017Co-Authors: Min Min, Bing-xi Yan, Ping Wang, Lilla Landeck, Jia-qi Chen, Sui-qing Cai, Min Zheng, Xiao-yong ManAbstract:An FACS analysis was applied to determine Rottlerin activity following the oral administration of Rottlerin or vehicle treatment in vivo. (A) Representative results of CD3+CD4+ T cell percentage in the DLN, spleen, and skin. The quantification of CD3+CD4+ T cell percentage is shown in the lower pannel. The data are represented as mean±SEM (n = 5 in each group). Similar results were seen in two other independent experiments. NS, P>0.05,*P
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Rottlerin exhibits anti-inflammatory effect in TPA-triggered keratinocytes.
2017Co-Authors: Min Min, Bing-xi Yan, Ping Wang, Lilla Landeck, Jia-qi Chen, Sui-qing Cai, Min Zheng, Xiao-yong ManAbstract:Near-confluent cultures of primary keratinocytes were treated with 0, 1, 5, and 10μM Rottlerin for 22 hours. The cells were then co-treated with 100nM TPA for 2 hours (for a total of 24 hours of exposure to Rottlerin). The mRNA expression levels were measured at 24h by qRT-PCR: (A) TNF-α; (B) IL-6; (C) IL-23. Mediators in the supernatant fluids at 24 h were measured by ELISA: (D) TNF-α; (E) IL-17; (F) IL-22. (n = 3, ** P
Emanuela Maioli - One of the best experts on this subject based on the ideXlab platform.
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doi:10.1155/2012/980658 Research Article Alternative Pathways of Cancer Cell Death by Rottlerin:
2016Co-Authors: Apoptosis Versus Autophagy, Michela Muscettola, Nila Volpi, Emanuela MaioliAbstract:Copyright © 2012 Claudia Torricelli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Since the ability of cancer cells to evade apoptosis often limits the efficacy of radiotherapy and chemotherapy, autophagy is emerging as an alternative target to promote cell death. Therefore, we wondered whether Rottlerin, a natural polyphenolic compound with antiproliferative effects in several cell types, can induce cell death in MCF-7 breast cancer cells. The MCF-7 cell line is a good model of chemo/radio resistance, being both apoptosis and autophagy resistant, due to deletion of caspase 3 gene, high expression of the antiapoptotic protein Bcl-2, and low expression of the autophagic Beclin-1 protein. The contribution of autophagy and apoptosis to the cytotoxic effects of Rottlerin was examined by light, fluorescence, and electron microscopic examination and by western blotting analysis of apoptotic and autophagicmarkers. By comparing caspases-3-deficient (MCF-73def
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Antiproliferative Effect of Rottlerin on Sk-Mel-28 Melanoma Cells
Hindawi Limited, 2015Co-Authors: Elena Daveri, Giuseppe Valacchi, Roberta Romagnoli, Emilia Maellaro, Emanuela MaioliAbstract:Melanoma is the most aggressive and chemoresistant form of skin cancer. Mutated, constitutively active B-RAF is believed to play a crucial role, although the selective B-RAF inhibition has shown poor clinical success, since phenomena of resistance usually occur, likely arising from additional genetic aberrations, such as loss of function of p53 and PTEN, overexpression of cyclin D1, hyperactivation of NF-κB, and downregulation of p21/Cip1. Since all of them are present in the Sk-Mel-28 melanoma cells, this cell line could be an ideal, albeit hard to study, model to develop new therapeutic strategies. In the current study, we tested the cytostatic action of Rottlerin on Sk-Mel-28 melanoma cells, on the basis of the known Rottlerin effects on the main proliferative signaling pathways. We presented evidence that the drug inhibits cell growth by an Akt- and p21/Cip1-independent mechanism, involving the dual inhibition of ERK and NF-κB and downregulation of cyclin D1. In addition, we found that Rottlerin increases ERK phosphorylation, but, surprisingly, this resulted in decreased ERK activity. Pull-down experiments, using Rottlerin-CNBr-conjugated Sepharose beads, revealed that Rottlerin binds to ERK, independently from its phosphorylation status. This direct interaction could in part explain the paradoxical blockage of ERK downstream signaling and growth arrest
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Rottlerin a multifaced regulator of keratinocyte cell cycle
Experimental Dermatology, 2009Co-Authors: Giuseppe Valacchi, Alessandra Pecorelli, Marzia Mencarelli, Paola Carbotti, Vittoria Fortino, Michela Muscettola, Emanuela MaioliAbstract:In this study we showed that Rottlerin (also called Kamala or Mallotoxin), a natural product purified from Mallotus phillippinensis, is a potent suppressor of human keratinocytes (HaCaT cell line) proliferation. Following Rottlerin treatment, Thymidine incorporation into DNA and re-epithelialisation in a scratch wound model was decreased. At the molecular level, Rottlerin hampered the NFkB activation process, causing loss of cyclin D1 and promoting, in a PKCdelta-dependent pathway, ERK activation, which, in turn induced the cell cycle inhibitor p21 Cip1/Kip1. The NFkB-dependent drop in cyclin D1, along with the PKCdelta/ERK-dependent induction of p21 Cip1/Kip1, is responsible for growth arrest. These results open the way to further investigation on the Rottlerin therapeutic potential against keratinocyte hyper-proliferative disorders.
Isa M Hussaini - One of the best experts on this subject based on the ideXlab platform.
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phorbol 12 myristate 13 acetate induces epidermal growth factor receptor transactivation via protein kinase cδ c src pathways in glioblastoma cells
Journal of Biological Chemistry, 2005Co-Authors: Samson Amos, Patrick M Martin, Gregory A Polar, Sarah J Parsons, Isa M HussainiAbstract:Abstract Both the epidermal growth factor receptor (EGFR) and protein kinase C (PKC) play important roles in glioblastoma invasive growth; however, the interaction between the EGFR and PKC is not well characterized in glioblastomas. Treatment with EGF stimulated global phosphorylation of the EGFR at Tyr845, Tyr992, Tyr1068, and Tyr1045 in glioblastoma cell lines (U-1242 MG and U-87 MG). Interestingly, phorbol 12-myristate 13-acetate (PMA) stimulated phosphorylation of the EGFR only at Tyr1068 in the two glioblastoma cell lines. Phosphorylation of the EGFR at Tyr1068 was not detected in normal human astrocytes treated with the phorbol ester. PMA-induced phosphorylation of the EGFR at Tyr1068 was blocked by bisindolylmaleimide (BIM), a PKC inhibitor, and Rottlerin, a PKCδ-specific inhibitor. In contrast, Go 6976, an inhibitor of classical PKC isozymes, had no effect on PMA-induced EGFR phosphorylation. Furthermore, gene silencing with PKCδ small interfering RNA (siRNA), siRNA against c-Src, and mutant c-Src(S12C/S48A) and treatment with a c-Src inhibitor (4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine) abrogated PMA-induced EGFR phosphorylation at Tyr1068. PMA induced serine/threonine phosphorylation of Src, which was blocked by both BIM and Rottlerin. Inhibition of the EGFR with AG 1478 did not significantly alter PMA-induced EGFR Tyr1068 phosphorylation, but completely blocked EGF-induced phosphorylation of the EGFR. The effects of PMA on MAPK phosphorylation and glioblastoma cell proliferation were reduced by BIM, Rottlerin, the MEK inhibitor U0126, and PKCδ and c-Src siRNAs. Taken together, our data demonstrate that PMA transactivates the EGFR and increases cell proliferation by activating the PKCδ/c-Src pathway in glioblastomas.
