The Experts below are selected from a list of 777 Experts worldwide ranked by ideXlab platform
Cristina Albanesi - One of the best experts on this subject based on the ideXlab platform.
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correction Sirtinol treatment reduces inflammation in human dermal microvascular endothelial cells
PLOS ONE, 2011Co-Authors: Angela Orecchia, Antonello Mai, Claudia Scarponi, Francesca Di Felice, Elisa Cesarini, Simona Avitabile, Maria Luisa Mauro, Valentina Sirri, Giovanna Zambruno, Cristina AlbanesiAbstract:The authors wish to add the following funding source to the financial disclosure information: "E.C. is recipient of the "Teresa Ariaudo Fellowship" from Istituto Pasteur-Fondazione Cenci Bolognetti".
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Sirtinol treatment reduces inflammation in human dermal microvascular endothelial cells.
PLoS ONE, 2010Co-Authors: Angela Orecchia, Antonello Mai, Claudia Scarponi, Francesca Di Felice, Elisa Cesarini, Simona Avitabile, Maria Luisa Mauro, Valentina Sirri, Giovanna Zambruno, Cristina AlbanesiAbstract:Histone deacetylases (HDAC) are key enzymes in the epigenetic control of gene expression. Recently, inhibitors of class I and class II HDAC have been successfully employed for the treatment of different inflammatory diseases such as rheumatoid arthritis, colitis, airway inflammation and asthma. So far, little is known so far about a similar therapeutic effect of inhibitors specifically directed against sirtuins, the class III HDAC. In this study, we investigated the expression and localization of endogenous sirtuins in primary human dermal microvascular endothelial cells (HDMEC), a cell type playing a key role in the development and maintenance of skin inflammation. We then examined the biological activity of Sirtinol, a specific sirtuin inhibitor, in HDMEC response to pro-inflammatory cytokines. We found that, even though Sirtinol treatment alone affected only long-term cell proliferation, it diminishes HDMEC inflammatory responses to tumor necrosis factor (TNF)α and interleukin (IL)-1β. In fact, Sirtinol significantly reduced membrane expression of adhesion molecules in TNFã- or IL-1β-stimulated cells, as well as the amount of CXCL10 and CCL2 released by HDMEC following TNFα treatment. Notably, Sirtinol drastically decreased monocyte adhesion on activated HDMEC. Using selective inhibitors for Sirt1 and Sirt2, we showed a predominant involvement of Sirt1 inhibition in the modulation of adhesion molecule expression and monocyte adhesion on activated HDMEC. Finally, we demonstrated the in vivo expression of Sirt1 in the dermal vessels of normal and psoriatic skin. Altogether, these findings indicated that sirtuins may represent a promising therapeutic target for the treatment of inflammatory skin diseases characterized by a prominent microvessel involvement.
Antonello Mai - One of the best experts on this subject based on the ideXlab platform.
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correction Sirtinol treatment reduces inflammation in human dermal microvascular endothelial cells
PLOS ONE, 2011Co-Authors: Angela Orecchia, Antonello Mai, Claudia Scarponi, Francesca Di Felice, Elisa Cesarini, Simona Avitabile, Maria Luisa Mauro, Valentina Sirri, Giovanna Zambruno, Cristina AlbanesiAbstract:The authors wish to add the following funding source to the financial disclosure information: "E.C. is recipient of the "Teresa Ariaudo Fellowship" from Istituto Pasteur-Fondazione Cenci Bolognetti".
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Sirtinol treatment reduces inflammation in human dermal microvascular endothelial cells.
PLoS ONE, 2010Co-Authors: Angela Orecchia, Antonello Mai, Claudia Scarponi, Francesca Di Felice, Elisa Cesarini, Simona Avitabile, Maria Luisa Mauro, Valentina Sirri, Giovanna Zambruno, Cristina AlbanesiAbstract:Histone deacetylases (HDAC) are key enzymes in the epigenetic control of gene expression. Recently, inhibitors of class I and class II HDAC have been successfully employed for the treatment of different inflammatory diseases such as rheumatoid arthritis, colitis, airway inflammation and asthma. So far, little is known so far about a similar therapeutic effect of inhibitors specifically directed against sirtuins, the class III HDAC. In this study, we investigated the expression and localization of endogenous sirtuins in primary human dermal microvascular endothelial cells (HDMEC), a cell type playing a key role in the development and maintenance of skin inflammation. We then examined the biological activity of Sirtinol, a specific sirtuin inhibitor, in HDMEC response to pro-inflammatory cytokines. We found that, even though Sirtinol treatment alone affected only long-term cell proliferation, it diminishes HDMEC inflammatory responses to tumor necrosis factor (TNF)α and interleukin (IL)-1β. In fact, Sirtinol significantly reduced membrane expression of adhesion molecules in TNFã- or IL-1β-stimulated cells, as well as the amount of CXCL10 and CCL2 released by HDMEC following TNFα treatment. Notably, Sirtinol drastically decreased monocyte adhesion on activated HDMEC. Using selective inhibitors for Sirt1 and Sirt2, we showed a predominant involvement of Sirt1 inhibition in the modulation of adhesion molecule expression and monocyte adhesion on activated HDMEC. Finally, we demonstrated the in vivo expression of Sirt1 in the dermal vessels of normal and psoriatic skin. Altogether, these findings indicated that sirtuins may represent a promising therapeutic target for the treatment of inflammatory skin diseases characterized by a prominent microvessel involvement.
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epigenetic multiple ligands mixed histone protein methyltransferase acetyltransferase and class iii deacetylase sirtuin inhibitors
Journal of Medicinal Chemistry, 2008Co-Authors: Antonello Mai, Donghang Cheng, Mark T Bedford, Sergio Valente, Andrea Perrone, Gianluca Sbardella, Gerald Brosch, Angela Nebbioso, Floriana De Bellis, Marco MiceliAbstract:A number of new compounds bearing two ortho-bromo- and ortho, ortho-dibromophenol moieties linked through a saturated/unsaturated, linear/(poly)cyclic spacer (compounds 1- 9) were prepared as simplified analogues of AMI-5 (eosin), a recently reported inhibitor of both protein arginine and histone lysine methyltransferases (PRMTs and HKMTs). Such compounds were tested against a panel of PRMTs (RmtA, PRMT1, and CARM1) and against human SET7 (a HKMT), using histone and nonhistone proteins as a substrate. They were also screened against HAT and SIRTs, because they are structurally related to some HAT and/or SIRT modulators. From the inhibitory data, some of tested compounds ( 1b, 1c, 4b, 4f, 4j, 4l, 7b, and 7f) were able to inhibit PRMTs, HKMT, HAT, and SIRTs with similar potency, thus behaving as multiple ligands for these epigenetic targets (epi-MLs). When tested on the human leukemia U937 cell line, the epi-MLs induced high apoptosis levels [i.e., 40.7% ( 4l) and 42.6% ( 7b)] and/or massive, dose-dependent cytodifferentiation [i.e., 95.2% ( 1c) and 96.1% ( 4j)], whereas the single-target inhibitors eosin, curcumin, and Sirtinol were ineffective or showed a weak effect.
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design synthesis and biological evaluation of Sirtinol analogues as class iii histone protein deacetylase sirtuin inhibitors
Journal of Medicinal Chemistry, 2005Co-Authors: Antonello Mai, S Massa, Siva Lavu, Riccardo Pezzi, Silvia Simeoni, Rino Ragno, Francesca Romana Mariotti, Francesco Chiani, Giorgio Camilloni, David A SinclairAbstract:In a search for potent inhibitors of class III histone/protein deacetylases (sirtuins), a series of Sirtinol analogues have been synthesized and the degree of inhibition was assessed in vitro using recombinant yeast Sir2, human SIRT1, and human SIRT2 and in vivo with a yeast phenotypic assay. Two analogues, namely, 3- and 4-[(2-hydroxy-1-naphthalenylmethylene)amino]-N-(1-phenylethyl)benzamide (i.e., m- and p-Sirtinol), were 2- to 10-fold more potent than Sirtinol against human SIRT1 and SIRT2 enzymes. In yeast in vivo assay, these two small molecules were as potent as Sirtinol. Compounds lacking the 2-hydroxy group at the naphthalene moiety or bearing several modifications at the benzene 2‘-position of the aniline portion (carbethoxy, carboxy, and cyano) were 1.3−13 times less potent than Sirtinol, whereas the 2‘-carboxamido analogue was totally inactive. Both (R)- and (S)-Sirtinol had similar inhibitory effects on the yeast and human enzymes, demonstrating no enantioselective inhibitory effect.
Leo I Gordon - One of the best experts on this subject based on the ideXlab platform.
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functional characterization of nad dependent de acetylases sirt1 and sirt2 in b cell chronic lymphocytic leukemia cll
Cancer Biology & Therapy, 2016Co-Authors: Savita Bhalla, Leo I GordonAbstract:ABSTRACTSirtuins (SIRT) are nicotinamide adenine dinucleotide (NAD+) dependent deacetylases or ADP- ribosyl transferases (ARTs) that deacetylate lysine residues on various proteins regulating a variety of cellular and metabolic processes. These enzymes regulate metabolism, cell survival, differentiation and DNA repair. SIRT proteins play an important role in the survival and drug resistance of cancer cells. The purpose of the present study was to investigate the expression and role of SIRT in chronic lymphocytic leukemia (CLL). We analyzed the expression of SIRT1 and SIRT2 in CLL and normal B cells using the Oncomine database as well as by Western blotting of fresh CLL cells from patients and pro-lymphocytic leukemia (PLL) cell lines, JVM-3 and MEC-2. We showed that both primary CLL cells and JVM-3 and MEC-2 cell lines overexpress high levels of functional SIRT1 and SIRT2. SIRT inhibitors EX-527 and Sirtinol impair cell growth, induce ROS production, loss of mitochondrial membrane potential and apoptosis ...
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functional characterization of nad dependent de acetylases sirt1 and sirt2 in b cell chronic lymphocytic leukemia cll
Blood, 2015Co-Authors: Savita Bhalla, Leo I GordonAbstract:Introduction: CLL is characterized by abnormal proliferation and accumulation of mature CD5 positive B-lymphocytes in blood, bone marrow, spleen and lymph nodes. Outcome and survival is determined in part by the presence of 11q deletions and17p deletion/ TP53 mutation with complex karyotype. Sirtuins are NAD+ dependent ADP-ribosyl transferases with evolutionary conserved function in cellular metabolism and chromatin regulation. Seven sirtuins (SIRT1-SIRT7) have been identified in mammals at distinct subcellular locations and targeting different substrates. SIRT1, 2, 6, and 7 are primarily found in the nucleus, SIRT2 in the cytoplasm and SIRT3, 4, 5 in the mitochondria. Sirtuins are associated with cancer as they deacetylate cancer associated transcription factors, and SIRT1 is overexpressed in acute myeloid leukemia, colon and prostate cancers. Several studies reported SIRT2 as a tumor suppressor as it is down regulated in human gliomas. SIRT1 and SIRT6 are reported to be significantly increased in CLL. We hypothesized that sirtuins play an important role in the development and maintenance of CLL and might therefore be a target. Methods: We measured SIRT 1 and 2 expression in fresh primary CLL cells, in the B-cell pro-lymphocytic cell lines JVM-3 and MEC-2 and by data-mining of the Oncomine microarray gene expression datasets. Oncomine is a bioinformatics initiative that collects, standardizes, analyzes, and delivers cancer transcriptome data to the biomedical research community. We then inhibited SIRT activity in primary CLL cells and cell lines by pharmacologic inhibitors EX-529 and Sirtinol, and by knock down using shRNA in cell lines and then measured cell viability, apoptosis, reactive oxygen species formation and mitochondrial membrane potential. To determine the metabolic contribution to SIRT activity, we studied the effect of SIRT inhibition under conditions of nutrient deprivation. Results: We observed an increase in SIRT1mRNA expression in CLL by data mining of the independent microarray dataset in the Oncomine database, with a total of 2022 leukemia samples and 74 normal controls (Figure1). SIRT1was significantly up regulated in CLL compared with normal PBMC as well as other leukemia types. We found that SIRT inhibitors EX-527 and Sirtinol impair cell growth (IC50 50-100 microM for EX-527 and 10-20 microM for Sirtinol), cause apoptosis (>2-fold increase in apoptosis in cell lines JVM-3 and MEC-2), induce ROS production (up to 90% increase in mean fluorescence intensity (MFI) with EX-527 and Sirtinol), loss of mitochondrial membrane potential, (MFI from 4 to <1 after treatment with SIRT inhibitors) and increase alpha-tubulin acetylation in primary CLL cells and cell lines. Using shRNA knock down of SIRT1 and SIRT2 in JVM-3 and MEC-2 cell lines, we showed that expression of both proteins is crucial for the survival of these cells. Furthermore, studies in nutrient deprived conditions suggest a role of SIRT in metabolism in CLL. Conclusion: These findings suggest that CLL cells are characterized by increased expression and function of SIRT1 and SIRT2, both directly inhibited by SIRT inhibitors. SIRT1 and SIRT2 inhibition using specific inhibitors could be a novel therapeutic approach for the treatment of CLL and other SIRT expressing hematologic malignancies. ![Figure 1.][1] Figure 1. Disclosures Gordon: Northwestern University: Employment; Dr Leo I. Gordon: Patents & Royalties: Patent for gold nanoparticles pending. [1]: pending:yes
Yu Han Huang - One of the best experts on this subject based on the ideXlab platform.
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trichostatin a and Sirtinol suppressed survivin expression through ampk and p38mapk in ht29 colon cancer cells
Biochimica et Biophysica Acta, 2012Co-Authors: Joen Rong Sheu, De Shin Yang, George Hsiao, George Ou, Pei Ting Chiu, Yu Han HuangAbstract:Abstract Background Elevated levels of survivin and histone deacetylases (HDACs) are often found over-expressed in human cancers, including colorectal cancer, and have been implicated in tumorigenesis. HDAC inhibition induces growth arrest and cell death in various transformed cell; however, the mechanisms by which this reduces cell viability in colorectal cancer cells remain unexplained. Methods We explored the actions of two HDAC inhibitors, trichostatin A (TSA) and Sirtinol, in HT29 colon cancer cells. Results TSA and Sirtinol induced apoptosis and inhibited cell proliferation in HT29 cells. These results are associated with the modulation of survivin. Survivin promoter luciferase activity and Sp1, a transcription factor that contributes to survivin expression, were suppressed in cells exposed to TSA or Sirtinol. TSA and Sirtinol also activated p38 mitogen-activated protein kinase (p38MAPK) and AMP-activated protein kinase (AMPK). Inhibitors of p38MAPK or AMPK signaling abrogated TSA and Sirtinol's effects of decreasing cell viability. Survivin promoter luciferase activity in the presence of TSA or Sirtinol was restored by AMPK dominant negative mutant or p38MAPK inhibitor. Furthermore, Sp1 binding to the survivin promoter region decreased while p63 binding to the promoter region increased after TSA or Sirtinol exposure. Conclusions We report a p38MAPK- and AMPK-mediated downregulation of survivin, and its functional correlation with decreased colon cancer cell viability in the presence of HDAC inhibitor. p63 and Sp1 may also contribute to TSA and Sirtinol actions. General significance This study delineates, in part, the underlying mechanisms of TSA and Sirtinol in decreasing survivin expression and subsequent colon cancer cell viability.
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trichostatin a and Sirtinol suppressed survivin expression through ampk and p38mapk in ht29 colon cancer cells
Biochimica et Biophysica Acta, 2012Co-Authors: Ya Fen Hsu, Joen Rong Sheu, De Shin Yang, George Hsiao, Pei Ting Chiu, Yu Han Huang, Chienhuang Lin, Wen Hsin Kuo, Ming Jen HsuAbstract:Abstract Background Elevated levels of survivin and histone deacetylases (HDACs) are often found over-expressed in human cancers, including colorectal cancer, and have been implicated in tumorigenesis. HDAC inhibition induces growth arrest and cell death in various transformed cell; however, the mechanisms by which this reduces cell viability in colorectal cancer cells remain unexplained. Methods We explored the actions of two HDAC inhibitors, trichostatin A (TSA) and Sirtinol, in HT29 colon cancer cells. Results TSA and Sirtinol induced apoptosis and inhibited cell proliferation in HT29 cells. These results are associated with the modulation of survivin. Survivin promoter luciferase activity and Sp1, a transcription factor that contributes to survivin expression, were suppressed in cells exposed to TSA or Sirtinol. TSA and Sirtinol also activated p38 mitogen-activated protein kinase (p38MAPK) and AMP-activated protein kinase (AMPK). Inhibitors of p38MAPK or AMPK signaling abrogated TSA and Sirtinol's effects of decreasing cell viability. Survivin promoter luciferase activity in the presence of TSA or Sirtinol was restored by AMPK dominant negative mutant or p38MAPK inhibitor. Furthermore, Sp1 binding to the survivin promoter region decreased while p63 binding to the promoter region increased after TSA or Sirtinol exposure. Conclusions We report a p38MAPK- and AMPK-mediated downregulation of survivin, and its functional correlation with decreased colon cancer cell viability in the presence of HDAC inhibitor. p63 and Sp1 may also contribute to TSA and Sirtinol actions. General significance This study delineates, in part, the underlying mechanisms of TSA and Sirtinol in decreasing survivin expression and subsequent colon cancer cell viability.
Sean X Leng - One of the best experts on this subject based on the ideXlab platform.
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suppressive effects of Sirtinol on human cytomegalovirus hcmv infection and hcmv induced activation of molecular mechanisms of senescence and production of reactive oxygen species
Mechanisms of Ageing and Development, 2016Co-Authors: Genxiang Mao, Xiang Ding, Xin Meng, Guofu Wang, Sean X LengAbstract:Substantial evidence suggests that chronic human cytomegalovirus (hCMV) infection contributes significantly to T-cell immunosenescence and adverse health outcomes in older adults. As such, it is important to search for compounds with anti-hCMV properties. Studies have shown that resveratrol, a sirtuin activator, suppresses hCMV infection. Here we report suppressive effects of Sirtinol, a sirtuin antagonist, on hCMV infection and its cellular and molecular consequences. Human diploid fibroblast WI-38 cells were infected by hCMV Towne strain in the absence or presence of Sirtinol. hCMV replication was measured using qPCR. Senescent phenotype was determined by senescence-associated β galactosidase (SA-β-Gal) activity. Expression of hCMV immediate early (IE) and early (E) proteins and senescence-associated proteins (pRb and Rb, p16(INK4), and p53) and production of reactive oxygen species (ROS) were assessed using standard laboratory assays. The results demonstrated that Sirtinol suppressed hCMV infection as well as hCMV-induced activation of molecular mechanisms of senescence and ROS production. While underlying molecular mechanisms remain to be elucidated, these findings indicate Sirtinol as a novel and potent anti-hCMV agent with the potential to be developed as an effective treatment for chronic hCMV infection and its cellular and molecular consequences that are important to ageing and health of older adults.
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resveratrol res and its antagonist Sirtinol suppress human cytomegalovirus hcmv replication and hcmv induced transcription of proinflammatory cytokines and chemokines in thp 1 derived macrophages
Journal of Immunology, 2016Co-Authors: Xiaoxuan Ning, Jintang Wang, Min Ouyang, Genxiang Mao, Sean X LengAbstract:Background Mounting evidence suggests significant contribution of chronic hCMV infection to T-cell immunosenenscence and chronic inflammation in old adults. THP-1, a human monocytic cell line and its derived macrophages serve as a useful cell culture model to study hCMV infection and its biology. Novel anti-CMV agents are needed as current anti-CMV treatment is limited in efficacy with significant side effects. We and others observed that Resveratrol (RES) and Sirtinol, suppressed CMV replication in human fibroblasts. Here we report their inhibition on hCMV replication and hCMV induced expression of IL-6, IP-10, MCP-1 and TNF-a in THP-1 derived macrophages. Methods THP-1 cells were differentiated into macrophages after incubation with PMA (50 ng/ml) in RPMI 1640 with 10%FBS for 24 hrs. RES or Sirtinol was added 2 h followed by hCMV (Towne strain) inoculation at multiplicity of infection of MOI 2 for 24 hrs. Cells were then cultured in hCMV-free medium for indicated times. qPCR and RT-PCR were performed to evaluate hCMV replication and transcription of IL-6, IP-10, MCP-1 and TNF-a, respectively. Results Both RES and Sirtinol suppressed hCMV replication. They also suppressed hCMV induced transcription of proinflammatory mediators except for TNF-a. Conclusions and discussion These findings indicate potent inhibition of hCMV infection and hCMV induced transcription of proinflammatory mediators by RES and Sirtinol in THP-1 derived macrophages. While being non-permissive, monocytes are important reservoir for chronic or latent CMV infection. Further investigation into the role and mechanisms of RES, Sirtinol and other agents in control of chronic CMV infection and its adverse impact is indicated.