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Hwan-soo Yoo - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of Ceramide Decreased the Expression of ATP-Binding Cassette Transporter G5/8 mRNA in an Animal Model of Cholesterol Gallstone.
Digestive diseases (Basel Switzerland), 2017Co-Authors: Hyo Jung Kim, Jae Seon Kim, Hwan-soo YooAbstract:Background: The increased risk of gallstone has been reported in patients with ATP-binding cassette (ABC) transporter polymorphism. The half-transporters ABCG5 and ABCG8 mediate the efflux of cholesterol in hepatocytes and the intestine. We investigated whether ceramide plays a role in cholesterol efflux through the ABC transporters. Methods: Six-week-old C57BL/6J mice were assigned to 3 groups. The normal group (n = 5) was fed a normal chow diet, the cholesterol group (n = 10) was fed a lithogenic diet, and the Myriocin group (n = 15) was fed the lithogenic diet and Myriocin, a specific inhibitor of serine-palmitoyl transferase. After 6 weeks, the ABCG5 and ABCG8 transporters were analyzed. Results: The rate of cholesterol gallstone formation in cholesterol group was also higher than that in normal and Myriocin groups (0, 70, and 40%, respectively). ABCG5 and ABCG8 mRNA levels were significantly increased in cholesterol group and less increased in Myriocin group, relative to that in normal group (p Conclusions: The inhibition of ceramide biosynthesis by Myriocin suppressed gallstone formation and ABCG5/8 mRNA expression. We expect that ceramide's role as a regulator of the ABCG5/8 transporter might be linked to cholesterol gallstone formation.
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Myriocin induces apoptotic lung cancer cell death via activation of DR4 pathway
Archives of Pharmacal Research, 2014Co-Authors: Kyung Eun Choi, Young Suk Jung, Dea Hwan Kim, Ju Kyung Song, Ji Young Kim, Yu Yeon Jung, So Young Eum, Joo Hwan Kim, Na Young Yoon, Hwan-soo YooAbstract:It has been known that Myriocin inhibits melanoma growth. However, the effects and action mechanisms of Myriocin on lung cancer cell growth have not been reported. In this study, we examined whether Myriocin isolated from Mycelia sterilia inhibits cell growth of lung cancer cells (A549 and NCI-H460) as well as possible signaling pathways involved in cell growth inhibition. Different concentrations of Myriocin inhibited the growth of lung cancer cells through the induction of apoptotic cell death. Consistent with cancer cell growth inhibition, Myriocin induced the expression of death receptors (DRs) as well as p-JNK and p-p38 in both cell lines. Moreover, the combination of Myriocin with DR4 ligand TRAIL, and other well known anti-tumor drugs (docetaxel and cisplatin) synergistically inhibited cancer cell growth, and induced DR4 expression. These results showed that Myriocin inhibits lung cancer cells growth through apoptosis via the activation of DR4 pathways, and enhanced anti-cancer effects with well known drugs. Thus, our study indicates that Myriocin could be effective for lung cancer cells as an anti-cancer drug and/or a conjunction agent with well known anti-cancers.
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Myriocin, a serine palmitoyltransferase inhibitor, suppresses tumor growth in a murine melanoma model by inhibiting de novo sphingolipid synthesis.
Cancer Biology & Therapy, 2012Co-Authors: Youn-sun Lee, Yong-moon Lee, Kyeong-mi Choi, Seunghyun Lee, Dong-mi Sin, Kwang-sik Yoo, Yong Lim, Jin-tae Hong, Yeo-pyo Yun, Hwan-soo YooAbstract:Advanced melanoma is the most virulent form of cancer and has a poor prognosis. In a previous study, Myriocin, an inhibitor of serine palmitoyltransferase, was found to suppress melanoma cell proliferation by cell cycle arrest at the G2/M phase through decreased sphingolipid levels and increased p53 and p21waf1/cip1 expression.1 In the present study, Myriocin (1 mg/kg, every other day for 3 weeks) was administered intradermally or intraperitoneally to melanoma mice. Tumor formation was significantly inhibited by intradermal and intraperitoneal administrations of Myriocin. The expression of Cdc25C, Cdc2 and cyclin B1 was decreased in tumor tissues from Myriocin-treated mice, while the expression of p53 and p21waf1/cip1 was increased compared with that of the controls. The levels of sphingolipids in serum, liver and tumor tissue from Myriocin-treated mice were decreased compared with those of controls. The decreased levels of sphingolipids in serum and liver of melanoma mice treated with Myriocin suggest th...
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© 2012 Landes Bioscience. Do not distribute. Myriocin, a serine palmitoyltransferase inhibitor, suppresses tumor growth in a murine melanoma model by inhibiting de novo sphingolipid synthesis
2012Co-Authors: Youn-sun Lee, Yong-moon Lee, Kyeong-mi Choi, Seunghyun Lee, Dong-mi Sin, Kwang-sik Yoo, Yong Lim, Jin-tae Hong, Yeo-pyo Yun, Hwan-soo YooAbstract:Advanced melanoma is the most virulent form of cancer and has a poor prognosis. In a previous study, Myriocin, an inhibitor of serine palmitoyltransferase, was found to suppress melanoma cell proliferation by cell cycle arrest at the G2/M phase through decreased sphingolipid levels and increased p53 and p21 waf1/cip1 expression. 1 In the present study, Myriocin (1 mg/kg, every other day for 3 weeks) was administered intradermally or intraperitoneally to melanoma mice. Tumor formation was significantly inhibited by intradermal and intraperitoneal administrations of Myriocin. The expression of Cdc25C, Cdc2 and cyclin B1 was decreased in tumor tissues from Myriocin-treated mice, while the expression of p53 and p21 waf1/cip1 was increased compared with that of the controls. The levels of sphingolipids in serum, liver and tumor tissue from Myriocin-treated mice were decreased compared with those of controls. The decreased levels of sphingolipids in serum and liver of melanoma mice treated with Myriocin suggest that Myriocin may be accessible to tumor tissues of advanced melanoma. Taken together, the suppression of sphingolipid synthesis by Myriocin inhibits the expression of Cdc25C or activates the expression of p53 and p21 waf1/cip1 . This is followed by Cdc2 and cyclin B1 inhibition which results in the suppression of tumor growth.
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2012 landes bioscience do not distribute Myriocin a serine palmitoyltransferase inhibitor suppresses tumor growth in a murine melanoma model by inhibiting de novo sphingolipid synthesis
2012Co-Authors: Youn-sun Lee, Yong-moon Lee, Kyeong-mi Choi, Seunghyun Lee, Dong-mi Sin, Kwang-sik Yoo, Yong Lim, Jin-tae Hong, Yeo-pyo Yun, Hwan-soo YooAbstract:Advanced melanoma is the most virulent form of cancer and has a poor prognosis. In a previous study, Myriocin, an inhibitor of serine palmitoyltransferase, was found to suppress melanoma cell proliferation by cell cycle arrest at the G2/M phase through decreased sphingolipid levels and increased p53 and p21 waf1/cip1 expression. 1 In the present study, Myriocin (1 mg/kg, every other day for 3 weeks) was administered intradermally or intraperitoneally to melanoma mice. Tumor formation was significantly inhibited by intradermal and intraperitoneal administrations of Myriocin. The expression of Cdc25C, Cdc2 and cyclin B1 was decreased in tumor tissues from Myriocin-treated mice, while the expression of p53 and p21 waf1/cip1 was increased compared with that of the controls. The levels of sphingolipids in serum, liver and tumor tissue from Myriocin-treated mice were decreased compared with those of controls. The decreased levels of sphingolipids in serum and liver of melanoma mice treated with Myriocin suggest that Myriocin may be accessible to tumor tissues of advanced melanoma. Taken together, the suppression of sphingolipid synthesis by Myriocin inhibits the expression of Cdc25C or activates the expression of p53 and p21 waf1/cip1 . This is followed by Cdc2 and cyclin B1 inhibition which results in the suppression of tumor growth.
Riccardo Ghidoni - One of the best experts on this subject based on the ideXlab platform.
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Myriocin modulates the altered lipid metabolism and storage in cystic fibrosis.
Cellular signalling, 2021Co-Authors: Paola Signorelli, Michele Dei Cas, Anna Caretti, Riccardo Ghidoni, Aida Zulueta, Francesca Pivari, Matteo Barcella, Ivan Merelli, Lorenzo Rosso, Rita ParoniAbstract:Cystic fibrosis (CF) is a hereditary disease mostly related to ΔF508 CFTR mutation causing a proteinopathy that is characterized by multiple organ dysfunction, primarily lungs chronic inflammation, and infection. Defective autophagy and accumulation of the inflammatory lipid ceramide have been proposed as therapeutic targets. Accumulation of lipids and cholesterol was reported in the airways of CF patients, together with altered triglycerides and cholesterol levels in plasma, thus suggesting a disease-related dyslipidemia. Myriocin, an inhibitor of sphingolipids synthesis, significantly reduces inflammation and activates TFEB-induced response to stress, enhancing fatty acids oxidation and promoting autophagy. Myriocin ameliorates the response against microbial infection in CF models and patients' monocytes. Here we show that CF broncho-epithelial cells exhibit an altered distribution of intracellular lipids. We demonstrated that lipid accumulation is supported by an enhanced synthesis of fatty acids containing molecules and that Myriocin is able to reduce such accumulation. Moreover, Myriocin modulated the transcriptional profile of CF cells in order to restore autophagy, activate an anti-oxidative response, stimulate lipid metabolism and reduce lipid peroxidation. Moreover, lipid storage may be altered in CF cells, since we observed a reduced expression of lipid droplets related proteins named perilipin 3 and 5 and seipin. To note, Myriocin up-regulates the expression of genes that are involved in lipid droplets biosynthesis and maturation. We suggest that targeting sphingolipids de novo synthesis may counteract lipids accumulation by modulating CF altered transcriptional profile, thus restoring autophagy and lipid metabolism homeostasis.
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Inhibition of Sphingolipid Synthesis as a Phenotype-Modifying Therapy in Cystic Fibrosis
Cellular physiology and biochemistry : international journal of experimental cellular physiology biochemistry and pharmacology, 2020Co-Authors: Alessandra Mingione, Michele Dei Cas, Fabiola Tecla Bonezzi, Anna Caretti, Marco Piccoli, Luigi Anastasia, Riccardo Ghidoni, Rita Paroni, Paola SignorelliAbstract:Background/aims Cystic Fibrosis (CF) is an inherited disease associated with a variety of mutations affecting the CFTR gene. A deletion of phenylalanine 508 (F508) affects more than 70% of patients and results in unfolded proteins accumulation, originating a proteinopathy responsible for inflammation, impaired trafficking, altered metabolism, cholesterol and lipids accumulation, impaired autophagy at the cellular level. Lung inflammation has been extensively related to the accumulation of the lipotoxin ceramide. We recently proved that inhibition of ceramide synthesis by Myriocin reduces inflammation and ameliorates the defence response against pathogens infection, which is downregulated in CF. Here, we aim at demonstrating the mechanisms of Myriocin therapeutic effects in Cystic Fibrosis broncho-epithelial cells. Methods The effect of Myriocin treatment, on F508-CFTR bronchial epithelial cell line IB3-1 cells, was studied by evaluating the expression of key proteins and genes involved in autophagy and lipid metabolism, by western blotting and real time PCR. Moreover, the amount of glycerol-phospholipids, triglycerides, and cholesterols, sphingomyelins and ceramides were measured in treated and untreated cells by LC-MS. Finally, Sptlc1 was transiently silenced and the effect on ceramide content, autophagy and transcriptional activities was evaluated as above mentioned. Results We demonstrate that Myriocin tightly regulates metabolic function and cell resilience to stress. Myriocin moves a transcriptional program that activates TFEB, major lipid metabolism and autophagy regulator, and FOXOs, central lipid metabolism and anti-inflammatory/anti-oxidant regulators. The activity of these transcriptional factors is associated with the induction of PPARs nuclear receptors activity, whose targets are genes involved in lipid transport compartmentalization and oxidation. Transient silencing of SPTCL1 recapitulates the effects induced by Myriocin. Conclusion Cystic Fibrosis bronchial epithelia accumulate lipids, exacerbating inflammation. Myriocin administration: i) activates the transcriptions of genes involved in enhancing autophagy-mediated stress clearance; ii) reduces the content of several lipid species and, at the same time, iii) enhances mitochondrial lipid oxidation. Silencing the expression of Sptlc1 reproduces Myriocin induced autophagy and transcriptional activities, demonstrating that the inhibition of sphingolipid synthesis drives a transcriptional program aimed at addressing cell metabolism towards lipid oxidation and at exploiting autophagy mediated clearance of stress. We speculate that regulating sphingolipid de novo synthesis can relieve from chronic inflammation, improving energy supply and anti-oxidant responses, indicating an innovative therapeutic strategy for CF.
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Sphingolipid Synthesis Inhibition by Myriocin Administration Enhances Lipid Consumption and Ameliorates Lipid Response to Myocardial Ischemia Reperfusion Injury
Frontiers in physiology, 2019Co-Authors: Fabiola Tecla Bonezzi, Alessandra Mingione, Michele Dei Cas, Anna Caretti, Marco Piccoli, Riccardo Ghidoni, Rita Paroni, Michelle M. Monasky, Chiara Riganti, Carlo PapponeAbstract:Myocardial infarct requires prompt thrombolytic therapy or primary percutaneous coronary intervention to limit the extent of necrosis, but reperfusion creates additional damage. Along with reperfusion, a maladaptive remodeling phase might occur and it is often associated with inflammation, oxidative stress, as well as a reduced ability to recover metabolism homeostasis. Infarcted individuals can exhibit reduced lipid turnover and their accumulation in cardiomyocytes, which is linked to a deregulation of peroxisome proliferator activated receptors (PPARs), controlling fatty acids metabolism, energy production, and the anti-inflammatory response. We previously demonstrated that Myriocin can be effectively used as post-conditioning therapeutic to limit ischemia/reperfusion-induced inflammation, oxidative stress, and infarct size, in a murine model. In this follow-up study, we demonstrate that Myriocin has a critical regulatory role in cardiac remodeling and energy production, by up-regulating the transcriptional factor EB, PPARs nuclear receptors and genes involved in fatty acids metabolism, such as VLDL receptor, Fatp1, CD36, Fabp3, Cpts, and mitochondrial FA dehydrogenases. The overall effects are represented by an increased β-oxidation, together with an improved electron transport chain and energy production. The potent immunomodulatory and metabolism regulatory effects of Myriocin elicit the molecule as a promising pharmacological tool for post-conditioning therapy of myocardial ischemia/reperfusion injury.
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Novel ophthalmic formulation of Myriocin: implications in retinitis pigmentosa
'Informa UK Limited', 2019Co-Authors: C.b.m. Platania, Riccardo Ghidoni, Rita Paroni, Dei M. Cas, S. Cianciolo, A. Fidilio, F. Lazzara, R. Pignatello, E. Strettoi, F. DragoAbstract:Myriocin is an antibiotic derived from Mycelia sterilia, and is a potent inhibitor of serine palmitoyltransferase, the enzyme involved in the first step of sphingosine synthesis. Myriocin, inhibiting ceramide synthesis, has a great potential for treatment of diseases characterized by high ceramide levels in affected tissues, such as retinitis pigmentosa (RP). Drug delivery to the retina is a challenging task, which is generally by-passed through intravitreal injection, that represents a risky invasive procedure. We, therefore, developed and characterized an ophthalmic topical nanotechnological formulation based on a nanostructured lipid carrier (NLC) and containing Myriocin. The ocular distribution of Myriocin in the back of the eye was assessed both in rabbits and mice using LC-MS/MS. Moreover, rabbit retinal sphingolipid and ceramides levels, after Myriocin-NLC (Myr-NLC) eye drops treatment, were assessed. The results demonstrated that Myr-NLC formulation is well tolerated and provided effective levels of Myriocin in the back of the eye both in rabbits and mice. We found that Myr-NLC eye drops treatment was able to significantly decrease retinal sphingolipid levels. In conclusion, these data suggest that the Myr-NLC ophthalmic formulation is suitable for pharmaceutical development and warrants further clinical evaluation of this eye drops for the treatment of RP
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determination of the serine palmitoyl transferase inhibitor Myriocin by electrospray and q trap mass spectrometry
Biomedical Chromatography, 2017Co-Authors: Giuseppe Matteo Campisi, Anna Caretti, Paola Signorelli, J Rizzo, Claudio Ghilardi, Jacopo Antognetti, Jelena Lazarevic, Enrica Strettoi, Elena Novelli, Riccardo GhidoniAbstract:Myriocin, is a potent inhibitor of serine-palmitoyl-transferase, the first and rate-determining enzyme in the sphingolipids biosynthetic pathway. This study developed, validated and applied a LC-MS/MS method to measure Myriocin in minute specimens of animal tissue. The chemical analog 14-OH-Myriocin is used as the internal standard. The two molecules are extracted from the tissue homogenate by solid-phase extraction, separated by gradient reverse-phase liquid chromatography and measured by negative ion electrospray mass spectrometry in the triple quadrupole. Detection is accomplished by Multiple Reaction Monitoring, employing the most representative transitions: 400@104 and 402@104 for Myriocin and 14-OH-Myriocin, respectively. The typical LoD and LLoQ of the optimized method are 0.9 pmoles/mL (approx. 0.016 pmoles injected) and 2.3 pmoles/mL, respectively, and the method is linear up to 250 pmoles/mL range (r2= 0.9996). The intra-and between-day repeatability affords a CV% ≤ 7.0. Applications included quantification of Myriocin in mouse lungs after 24 hrs from administration of ~4 nmoles by intra-trachea delivery. Measured levels ranged from 4.11 (median; 2.3-7.4 IQR, n=4) to 11.7 (median; 7.6-22.7 IQR, n=6) pmoles/lung depending on the different formulations used. Myriocin was also measured in retinas of mice treated by intravitreal injection and ranged from 0.045 (
Anna Caretti - One of the best experts on this subject based on the ideXlab platform.
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Myriocin modulates the altered lipid metabolism and storage in cystic fibrosis.
Cellular signalling, 2021Co-Authors: Paola Signorelli, Michele Dei Cas, Anna Caretti, Riccardo Ghidoni, Aida Zulueta, Francesca Pivari, Matteo Barcella, Ivan Merelli, Lorenzo Rosso, Rita ParoniAbstract:Cystic fibrosis (CF) is a hereditary disease mostly related to ΔF508 CFTR mutation causing a proteinopathy that is characterized by multiple organ dysfunction, primarily lungs chronic inflammation, and infection. Defective autophagy and accumulation of the inflammatory lipid ceramide have been proposed as therapeutic targets. Accumulation of lipids and cholesterol was reported in the airways of CF patients, together with altered triglycerides and cholesterol levels in plasma, thus suggesting a disease-related dyslipidemia. Myriocin, an inhibitor of sphingolipids synthesis, significantly reduces inflammation and activates TFEB-induced response to stress, enhancing fatty acids oxidation and promoting autophagy. Myriocin ameliorates the response against microbial infection in CF models and patients' monocytes. Here we show that CF broncho-epithelial cells exhibit an altered distribution of intracellular lipids. We demonstrated that lipid accumulation is supported by an enhanced synthesis of fatty acids containing molecules and that Myriocin is able to reduce such accumulation. Moreover, Myriocin modulated the transcriptional profile of CF cells in order to restore autophagy, activate an anti-oxidative response, stimulate lipid metabolism and reduce lipid peroxidation. Moreover, lipid storage may be altered in CF cells, since we observed a reduced expression of lipid droplets related proteins named perilipin 3 and 5 and seipin. To note, Myriocin up-regulates the expression of genes that are involved in lipid droplets biosynthesis and maturation. We suggest that targeting sphingolipids de novo synthesis may counteract lipids accumulation by modulating CF altered transcriptional profile, thus restoring autophagy and lipid metabolism homeostasis.
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Inhibition of Sphingolipid Synthesis as a Phenotype-Modifying Therapy in Cystic Fibrosis
Cellular physiology and biochemistry : international journal of experimental cellular physiology biochemistry and pharmacology, 2020Co-Authors: Alessandra Mingione, Michele Dei Cas, Fabiola Tecla Bonezzi, Anna Caretti, Marco Piccoli, Luigi Anastasia, Riccardo Ghidoni, Rita Paroni, Paola SignorelliAbstract:Background/aims Cystic Fibrosis (CF) is an inherited disease associated with a variety of mutations affecting the CFTR gene. A deletion of phenylalanine 508 (F508) affects more than 70% of patients and results in unfolded proteins accumulation, originating a proteinopathy responsible for inflammation, impaired trafficking, altered metabolism, cholesterol and lipids accumulation, impaired autophagy at the cellular level. Lung inflammation has been extensively related to the accumulation of the lipotoxin ceramide. We recently proved that inhibition of ceramide synthesis by Myriocin reduces inflammation and ameliorates the defence response against pathogens infection, which is downregulated in CF. Here, we aim at demonstrating the mechanisms of Myriocin therapeutic effects in Cystic Fibrosis broncho-epithelial cells. Methods The effect of Myriocin treatment, on F508-CFTR bronchial epithelial cell line IB3-1 cells, was studied by evaluating the expression of key proteins and genes involved in autophagy and lipid metabolism, by western blotting and real time PCR. Moreover, the amount of glycerol-phospholipids, triglycerides, and cholesterols, sphingomyelins and ceramides were measured in treated and untreated cells by LC-MS. Finally, Sptlc1 was transiently silenced and the effect on ceramide content, autophagy and transcriptional activities was evaluated as above mentioned. Results We demonstrate that Myriocin tightly regulates metabolic function and cell resilience to stress. Myriocin moves a transcriptional program that activates TFEB, major lipid metabolism and autophagy regulator, and FOXOs, central lipid metabolism and anti-inflammatory/anti-oxidant regulators. The activity of these transcriptional factors is associated with the induction of PPARs nuclear receptors activity, whose targets are genes involved in lipid transport compartmentalization and oxidation. Transient silencing of SPTCL1 recapitulates the effects induced by Myriocin. Conclusion Cystic Fibrosis bronchial epithelia accumulate lipids, exacerbating inflammation. Myriocin administration: i) activates the transcriptions of genes involved in enhancing autophagy-mediated stress clearance; ii) reduces the content of several lipid species and, at the same time, iii) enhances mitochondrial lipid oxidation. Silencing the expression of Sptlc1 reproduces Myriocin induced autophagy and transcriptional activities, demonstrating that the inhibition of sphingolipid synthesis drives a transcriptional program aimed at addressing cell metabolism towards lipid oxidation and at exploiting autophagy mediated clearance of stress. We speculate that regulating sphingolipid de novo synthesis can relieve from chronic inflammation, improving energy supply and anti-oxidant responses, indicating an innovative therapeutic strategy for CF.
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Inhibition of Sphingolipid Synthesis as a Phenotype-Modifying Therapy in Cystic Fibrosis
'Cell Physiol Biochem Press GmbH and Co KG', 2020Co-Authors: Alessandra Mingione, Fabiola Tecla Bonezzi, Anna Caretti, Marco Piccoli, Luigi Anastasia, Rita Paroni, Dei M. Cas, R. Ghidoni, P. SignorelliAbstract:Cystic Fibrosis (CF) is an inherited disease associated with a variety of mutations affecting the CFTR gene. A deletion of phenylalanine 508 (F508) affects more than 70% of patients and results in unfolded proteins accumulation, originating a proteinopathy responsible for inflammation, impaired trafficking, altered metabolism, cholesterol and lipids accumulation, impaired autophagy at the cellular level. Lung inflammation has been extensively related to the accumulation of the lipotoxin ceramide. We recently proved that inhibition of ceramide synthesis by Myriocin reduces inflammation and ameliorates the defence response against pathogens infection, which is downregulated in CF. Here, we aim at demonstrating the mechanisms of Myriocin therapeutic effects in Cystic Fibrosis broncho-epithelial cells
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Sphingolipid Synthesis Inhibition by Myriocin Administration Enhances Lipid Consumption and Ameliorates Lipid Response to Myocardial Ischemia Reperfusion Injury
Frontiers in physiology, 2019Co-Authors: Fabiola Tecla Bonezzi, Alessandra Mingione, Michele Dei Cas, Anna Caretti, Marco Piccoli, Riccardo Ghidoni, Rita Paroni, Michelle M. Monasky, Chiara Riganti, Carlo PapponeAbstract:Myocardial infarct requires prompt thrombolytic therapy or primary percutaneous coronary intervention to limit the extent of necrosis, but reperfusion creates additional damage. Along with reperfusion, a maladaptive remodeling phase might occur and it is often associated with inflammation, oxidative stress, as well as a reduced ability to recover metabolism homeostasis. Infarcted individuals can exhibit reduced lipid turnover and their accumulation in cardiomyocytes, which is linked to a deregulation of peroxisome proliferator activated receptors (PPARs), controlling fatty acids metabolism, energy production, and the anti-inflammatory response. We previously demonstrated that Myriocin can be effectively used as post-conditioning therapeutic to limit ischemia/reperfusion-induced inflammation, oxidative stress, and infarct size, in a murine model. In this follow-up study, we demonstrate that Myriocin has a critical regulatory role in cardiac remodeling and energy production, by up-regulating the transcriptional factor EB, PPARs nuclear receptors and genes involved in fatty acids metabolism, such as VLDL receptor, Fatp1, CD36, Fabp3, Cpts, and mitochondrial FA dehydrogenases. The overall effects are represented by an increased β-oxidation, together with an improved electron transport chain and energy production. The potent immunomodulatory and metabolism regulatory effects of Myriocin elicit the molecule as a promising pharmacological tool for post-conditioning therapy of myocardial ischemia/reperfusion injury.
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determination of the serine palmitoyl transferase inhibitor Myriocin by electrospray and q trap mass spectrometry
Biomedical Chromatography, 2017Co-Authors: Giuseppe Matteo Campisi, Anna Caretti, Paola Signorelli, J Rizzo, Claudio Ghilardi, Jacopo Antognetti, Jelena Lazarevic, Enrica Strettoi, Elena Novelli, Riccardo GhidoniAbstract:Myriocin, is a potent inhibitor of serine-palmitoyl-transferase, the first and rate-determining enzyme in the sphingolipids biosynthetic pathway. This study developed, validated and applied a LC-MS/MS method to measure Myriocin in minute specimens of animal tissue. The chemical analog 14-OH-Myriocin is used as the internal standard. The two molecules are extracted from the tissue homogenate by solid-phase extraction, separated by gradient reverse-phase liquid chromatography and measured by negative ion electrospray mass spectrometry in the triple quadrupole. Detection is accomplished by Multiple Reaction Monitoring, employing the most representative transitions: 400@104 and 402@104 for Myriocin and 14-OH-Myriocin, respectively. The typical LoD and LLoQ of the optimized method are 0.9 pmoles/mL (approx. 0.016 pmoles injected) and 2.3 pmoles/mL, respectively, and the method is linear up to 250 pmoles/mL range (r2= 0.9996). The intra-and between-day repeatability affords a CV% ≤ 7.0. Applications included quantification of Myriocin in mouse lungs after 24 hrs from administration of ~4 nmoles by intra-trachea delivery. Measured levels ranged from 4.11 (median; 2.3-7.4 IQR, n=4) to 11.7 (median; 7.6-22.7 IQR, n=6) pmoles/lung depending on the different formulations used. Myriocin was also measured in retinas of mice treated by intravitreal injection and ranged from 0.045 (
Youn-sun Lee - One of the best experts on this subject based on the ideXlab platform.
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Myriocin, a serine palmitoyltransferase inhibitor, suppresses tumor growth in a murine melanoma model by inhibiting de novo sphingolipid synthesis.
Cancer Biology & Therapy, 2012Co-Authors: Youn-sun Lee, Yong-moon Lee, Kyeong-mi Choi, Seunghyun Lee, Dong-mi Sin, Kwang-sik Yoo, Yong Lim, Jin-tae Hong, Yeo-pyo Yun, Hwan-soo YooAbstract:Advanced melanoma is the most virulent form of cancer and has a poor prognosis. In a previous study, Myriocin, an inhibitor of serine palmitoyltransferase, was found to suppress melanoma cell proliferation by cell cycle arrest at the G2/M phase through decreased sphingolipid levels and increased p53 and p21waf1/cip1 expression.1 In the present study, Myriocin (1 mg/kg, every other day for 3 weeks) was administered intradermally or intraperitoneally to melanoma mice. Tumor formation was significantly inhibited by intradermal and intraperitoneal administrations of Myriocin. The expression of Cdc25C, Cdc2 and cyclin B1 was decreased in tumor tissues from Myriocin-treated mice, while the expression of p53 and p21waf1/cip1 was increased compared with that of the controls. The levels of sphingolipids in serum, liver and tumor tissue from Myriocin-treated mice were decreased compared with those of controls. The decreased levels of sphingolipids in serum and liver of melanoma mice treated with Myriocin suggest th...
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© 2012 Landes Bioscience. Do not distribute. Myriocin, a serine palmitoyltransferase inhibitor, suppresses tumor growth in a murine melanoma model by inhibiting de novo sphingolipid synthesis
2012Co-Authors: Youn-sun Lee, Yong-moon Lee, Kyeong-mi Choi, Seunghyun Lee, Dong-mi Sin, Kwang-sik Yoo, Yong Lim, Jin-tae Hong, Yeo-pyo Yun, Hwan-soo YooAbstract:Advanced melanoma is the most virulent form of cancer and has a poor prognosis. In a previous study, Myriocin, an inhibitor of serine palmitoyltransferase, was found to suppress melanoma cell proliferation by cell cycle arrest at the G2/M phase through decreased sphingolipid levels and increased p53 and p21 waf1/cip1 expression. 1 In the present study, Myriocin (1 mg/kg, every other day for 3 weeks) was administered intradermally or intraperitoneally to melanoma mice. Tumor formation was significantly inhibited by intradermal and intraperitoneal administrations of Myriocin. The expression of Cdc25C, Cdc2 and cyclin B1 was decreased in tumor tissues from Myriocin-treated mice, while the expression of p53 and p21 waf1/cip1 was increased compared with that of the controls. The levels of sphingolipids in serum, liver and tumor tissue from Myriocin-treated mice were decreased compared with those of controls. The decreased levels of sphingolipids in serum and liver of melanoma mice treated with Myriocin suggest that Myriocin may be accessible to tumor tissues of advanced melanoma. Taken together, the suppression of sphingolipid synthesis by Myriocin inhibits the expression of Cdc25C or activates the expression of p53 and p21 waf1/cip1 . This is followed by Cdc2 and cyclin B1 inhibition which results in the suppression of tumor growth.
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2012 landes bioscience do not distribute Myriocin a serine palmitoyltransferase inhibitor suppresses tumor growth in a murine melanoma model by inhibiting de novo sphingolipid synthesis
2012Co-Authors: Youn-sun Lee, Yong-moon Lee, Kyeong-mi Choi, Seunghyun Lee, Dong-mi Sin, Kwang-sik Yoo, Yong Lim, Jin-tae Hong, Yeo-pyo Yun, Hwan-soo YooAbstract:Advanced melanoma is the most virulent form of cancer and has a poor prognosis. In a previous study, Myriocin, an inhibitor of serine palmitoyltransferase, was found to suppress melanoma cell proliferation by cell cycle arrest at the G2/M phase through decreased sphingolipid levels and increased p53 and p21 waf1/cip1 expression. 1 In the present study, Myriocin (1 mg/kg, every other day for 3 weeks) was administered intradermally or intraperitoneally to melanoma mice. Tumor formation was significantly inhibited by intradermal and intraperitoneal administrations of Myriocin. The expression of Cdc25C, Cdc2 and cyclin B1 was decreased in tumor tissues from Myriocin-treated mice, while the expression of p53 and p21 waf1/cip1 was increased compared with that of the controls. The levels of sphingolipids in serum, liver and tumor tissue from Myriocin-treated mice were decreased compared with those of controls. The decreased levels of sphingolipids in serum and liver of melanoma mice treated with Myriocin suggest that Myriocin may be accessible to tumor tissues of advanced melanoma. Taken together, the suppression of sphingolipid synthesis by Myriocin inhibits the expression of Cdc25C or activates the expression of p53 and p21 waf1/cip1 . This is followed by Cdc2 and cyclin B1 inhibition which results in the suppression of tumor growth.
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serine palmitoyltransferase inhibitor Myriocin induces growth inhibition of b16f10 melanoma cells through g2 m phase arrest
Cell Proliferation, 2011Co-Authors: Youn-sun Lee, Kyeong-mi Choi, Dong-mi Sin, Jin-tae Hong, Mihwa Choi, So Yong Lee, Youngjung Lee, Youngwon Yun, Hwan-soo YooAbstract:Objectives: Melanoma is the most aggressive form of skin cancer, and it resists chemotherapy. Candidate drugs for effective anti-cancer treatment have been sought from natural resources. Here, we have investigated anti-proliferative activity of Myriocin, serine palmitoyltransferase inhibitor, in the de novo sphingolipid pathway, and its mechanism in B16F10 melanoma cells. Material and methods: We assessed cell population growth by measuring cell numbers, DNA synthesis, cell cycle progression, and expression of cell cycle regulatory proteins. Ceramide, sphingomyelin, sphingosine and sphingosine-1-phosphate levels were analysed by HPLC. Results: Myriocin inhibited proliferation of melanoma cells and induced cell cycle arrest in the G2/M phase. Expressions of cdc25C, cyclin B1 and cdc2 were decreased in the cells after exposure to Myriocin, while expression of p53 and p21waf1/cip1 was increased. Levels of ceramide, sphingomyelin, sphingosine and sphingosine-1-phosphate in Myriocin-treated cells after 24 h were reduced by approximately 86%, 57%, 75% and 38%, respectively, compared to levels in control cells. Conclusions: Our results suggest that inhibition of sphingolipid synthesis by Myriocin in melanoma cells may inhibit expression of cdc25C or activate expression of p53 and p21waf1/cip1, followed by inhibition of cyclin B1 and cdc2, resulting in G2/M arrest of the cell cycle and cell population growth inhibition. Thus, modulation of sphingolipid metabolism by Myriocin may be a potential target of mechanism-based therapy for this type of skin cancer.
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serine palmitoyltransferase inhibitor Myriocin induces growth inhibition of b16f10 melanoma cells through g 2 m phase arrest
Cell Proliferation, 2011Co-Authors: Youn-sun Lee, Kyeong-mi Choi, Dong-mi Sin, Jin-tae Hong, Mihwa Choi, So Yong Lee, Youngjung Lee, Youngwon Yun, Hwan-soo YooAbstract:Objectives: Melanoma is the most aggressive form of skin cancer, and it resists chemotherapy. Candidate drugs for effective anti-cancer treatment have been sought from natural resources. Here, we have investigated anti-proliferative activity of Myriocin, serine palmitoyltransferase inhibitor, in the de novo sphingolipid pathway, and its mechanism in B16F10 melanoma cells. Material and methods: We assessed cell population growth by measuring cell numbers, DNA synthesis, cell cycle progression, and expression of cell cycle regulatory proteins. Ceramide, sphingomyelin, sphingosine and sphingosine-1-phosphate levels were analysed by HPLC. Results: Myriocin inhibited proliferation of melanoma cells and induced cell cycle arrest in the G2/M phase. Expressions of cdc25C, cyclin B1 and cdc2 were decreased in the cells after exposure to Myriocin, while expression of p53 and p21waf1/cip1 was increased. Levels of ceramide, sphingomyelin, sphingosine and sphingosine-1-phosphate in Myriocin-treated cells after 24 h were reduced by approximately 86%, 57%, 75% and 38%, respectively, compared to levels in control cells. Conclusions: Our results suggest that inhibition of sphingolipid synthesis by Myriocin in melanoma cells may inhibit expression of cdc25C or activate expression of p53 and p21waf1/cip1, followed by inhibition of cyclin B1 and cdc2, resulting in G2/M arrest of the cell cycle and cell population growth inhibition. Thus, modulation of sphingolipid metabolism by Myriocin may be a potential target of mechanism-based therapy for this type of skin cancer.
Raghubir P. Sharma - One of the best experts on this subject based on the ideXlab platform.
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Myriocin prevents fumonisin B1-induced sphingoid base accumulation in mice liver without ameliorating hepatotoxicity.
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2005Co-Authors: Ronald T. Riley, Raghubir P. SharmaAbstract:Fumonisin B(1) (FB(1)), a mycotoxin produced by Fusarium verticillioides present on corn and corn-based products, causes species- and organ-specific diseases. The hepatotoxic effects of FB(1) in mice have been closely correlated with the accumulation of free sphinganine, a marker for ceramide synthase inhibition, and reduced biosynthesis of more complex sphingolipids. It has been shown that FB(1) modulates expression of many cell signaling factors. In the current study we used Myriocin, a specific inhibitor of serine palmitoyltransferase, to investigate the role of free sphinganine accumulation in FB(1)-induced hepatotoxicity and increased expression of selected signaling genes in BALB/c mice. The mice were pretreated daily with intraperitoneal injection of 1.0 mg/kg Myriocin 30 min before subcutaneous injections of 2.25 mg/kg of FB(1) for 3 days. Results showed that Myriocin alone was not hepatotoxic and the combination of Myriocin plus FB(1) completely prevented the FB(1)-induced elevation of hepatic free sphinganine and prevented the FB(1)-induced induction of selected cell signaling genes, suggesting that accumulation of free sphinganine and/or its metabolites contribute to the FB(1)-modulation of the cell signaling factors. However, the combination of Myriocin and FB(1) did not prevent FB(1)-increased concentration of plasma alanine aminotransferase and only slightly attenuated aspartate aminotransferase; it did not affect the FB(1)-induced hepatocyte apoptosis or increased cell proliferation. A longer combined treatment of Myriocin and FB(1) was highly toxic. The hepatotoxic effects in mice seen in this study are most likely due to a combination of factors including accumulation of free sphinganine, depletion of more complex sphingolipids and sphingomyelin, or other unknown mechanisms.
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Disruption of sphingolipid homeostasis by Myriocin, a mycotoxin, reduces thymic and splenic T-lymphocyte populations.
Toxicology, 2004Co-Authors: Victor J. Johnson, Marcin F. Osuchowski, Raghubir P. SharmaAbstract:Myriocin is a naturally occurring fungal metabolite possessing potent immunosuppressive properties. The biochemical mechanism of action of this compound is inhibition of serine palmitoyltransferase (SPT), the key rate limiting enzyme in sphingolipid biosynthesis, intermediates of which are important mediators of immune signaling. Previous studies have shown that Myriocin strongly suppressed immune function with T-lymphocyte functions being most sensitive. To further our understanding of the mechanisms of this effect, we investigated the impact of subacute treatment with Myriocin on lymphocyte populations in the thymus and spleen of male BALB/c mice following intraperitoneal injection of Myriocin at 0, 0.1, 0.3, and 1.0 mg/kg daily for 5 consecutive days. Cellular analysis of the thymus demonstrated that total cellularity was dose-dependently reduced and the reduction was significant in mice treated with 1.0 mg/kg Myriocin. Phenotyping showed that CD4+ and CD4+/CD8+ double positive lymphocyte populations were sensitive to Myriocin. No change in total cellularity of the spleen was noted but there was a significant reduction in the CD4+ lymphocyte population in mice treated with 1.0 mg/kg Myriocin. There was a strong positive correlation between total CD4+ lymphocytes in the thymus and those in the spleen. Analysis of sphingolipid levels showed a dose-dependent reduction of sphinganine in the thymus, which were positively correlated with all reductions in lymphocyte populations. These results suggest that the immunosuppressive properties of Myriocin may be due to diminished T-lymphocyte populations likely related to inhibition of SPT and disruption of sphingolipid homeostasis.
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inhibition of serine palmitoyltransferase by Myriocin a natural mycotoxin causes induction of c myc in mouse liver
Mycopathologia, 2004Co-Authors: Victor J. Johnson, Marcin F. Osuchowski, Raghubir P. SharmaAbstract:Myriocin, a fungal metabolite isolated fromMyriococcum albomyces, Isaria sinclairi, and Mycelia sterilia, is a potent inhibitor ofserine palmitoyltransferase (SPT), a key enzyme in de novo synthesis of sphingolipids. To evaluatethe biological effects of Myriocin in vivo, we investigated the levels of free sphingoid basesand expression of selected genes regulating cell growth in mouse liver. Male Balb/c mice,weighing 22 g were injected intraperitoneally with Myriocin at 0, 0.1, 0.3, and 1.0 mg kg-1 bodyweight daily for 5 days. Animals were euthanized 24 hours after the last treatment. Levelsof plasma alanine aminotransferase and aspartate aminotransferase were not significantlyaltered by the treatment. A dose-dependent decrease in free sphinganine but not sphingosine wasdetected by high performance liquid chromatography in both liver and kidney. The decreaseof free sphinganine paralleled the decrease in SPT activity. Reverse transcriptasepolymerase chain reaction analysis on liver mRNA revealed an increase in expression of c-myc,but no changes in tumor necrosis factor α, transforming growth factor β, andhepatocyte growth factor. Results showed that Myriocin blocked de novo synthesis of sphingolipids in vivoby SPT inhibition and induced c-myc expression in liver.
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Myriocin, a serine palmitoyltransferase inhibitor, alters regional brain neurotransmitter levels without concurrent inhibition of the brain sphingolipid biosynthesis in mice.
Toxicology letters, 2004Co-Authors: Marcin F. Osuchowski, Victor J. Johnson, Raghubir P. SharmaAbstract:Myriocin is a specific serine palmitoyltransferase (SPT) inhibitor whose effect on the brain is unknown. Brain amine metabolism and sphingolipid biosynthesis were studied in mice treated intraperitoneally with 0, 0.1, 0.3 or 1 mg/kg per day of Myriocin for 5 days. Regional concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT, serotonin), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE), were determined. Sphinganine (Sa) and sphingosine (So) concentrations and SPT activity in brain and liver were used to evaluate the impact of Myriocin on sphingolipid biosynthesis. Myriocin treatment increased DA in striatum and hippocampus and reduced it in cortex. NE concentration decreased in cerebellum and 5-HT levels were reduced in cortex and in medulla oblongata. Changes in ratios for DOPAC/DA and HVA/DA were observed in hippocampus, cortex and midbrain. Brain Sa, So and SPT activity remained unchanged, whereas Sa and SPT activity decreased in liver. Results showed that Myriocin may alter the levels and metabolism of brain amines and this effect is not related with inhibition of sphingolipid biosynthesis in the nervous system.
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Pharmacological antagonism of fumonisin B1 cytotoxicity in porcine renal epithelial cells (LLC-PK1): a model for reducing fumonisin-induced nephrotoxicity in vivo.
Pharmacology & toxicology, 2002Co-Authors: Ronald T. Riley, Raghubir P. SharmaAbstract:Fumonisin B1 is a mycotoxin commonly found on corn. It is hepatotoxic and nephrotoxic in domestic and experimental animals, and causes equine leukoencephalomalacia and porcine pulmonary oedema. It is a potent inhibitor of ceramide synthase. Inhibition leads to accumulation of free sphingoid bases in cells and tissues. In pig kidney epithelial cells (LLC-PK1), fumonisin B1 induces increased tumour necrosis factor alpha (TNFalpha) expression independent of the accumulation of sphingoid bases. The objective of this study was to investigate pharmacological approaches for intervening in fumonisin B1 toxicity using the LLC-PK1 cell model. The toxicity of fumonisin B1 was assayed using cell viability and lactate dehydrogenase (lactate dehydrogenase) release. Pretreatment of cells with Myriocin, preventing sphinganine accumulates, prevented the fumonisin B1-induced decrease in cell viability and increased lactate dehydrogenase release. Modulation of adenosine receptor activity did not reduce the fumonisin B1 cytotoxicity. As with Myriocin, silymarin pretreatment prevented the fumonisin B1-induced effects on cell viability and lactate dehydrogenase release. When added 6 or 24 hr after treatment of cells with fumonisin B1, both Myriocin and silymarin reversed the decreased cell viability and suppressed the increased lactate dehydrogenase release. Myriocin, but not silymarin, blocked the accumulation of sphinganine in fumonisin B1-treated cells. Silymarin, unlike Myriocin, induced expression of TNFalpha to an extent similar to fumonisin B1, but pretreatment with silymarin decreased the fumonisin B1-induced TNFalpha expression in LLC-PK1 cells. Results suggest that the mechanisms by which Myriocin and silymarin protect renal cells are different, and silymarin potentially prevents fumonisin B1-induced toxicity by modulating TNFalpha expression or signals downstream of the inhibition of ceramide synthase.
