The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform
Yeong Shik Kim - One of the best experts on this subject based on the ideXlab platform.
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Alantolactone improves prolonged exposure of interleukin 6 induced skeletal muscle inflammation associated glucose intolerance and insulin resistance
Frontiers in Pharmacology, 2017Co-Authors: Minjee Kim, Kwangho Song, Yeong Shik KimAbstract:The pro-inflammatory cytokine, IL-6, has been proposed to be one of the mediators that link chronic inflammation to glucose intolerance and insulin resistance. Many studies have demonstrated the effects of IL-6 on insulin action in the skeletal muscle. However, few studies have investigated the effect of long-term treatment of IL-6, leading to glucose intolerance and insulin resistance. In the present study, we observed protective effects of Alantolactone, a sesquiterpene lactone isolated from Inula helenium against glucose intolerance and insulin resistance induced by prolonged exposure of IL-6. Alantolactone has been reported to have anti-inflammatory and anti-cancer effects through IL-6-induced signal transducer and activator of transcription 3 (STAT3) signaling pathway. The relationship between IL-6 exposure and expression of toll-like receptor 4 (TLR4), involved in inflammation in the skeletal muscle, and the underlying mechanisms were investigated. We observed maximum dysregulation of glucose uptake after 40 ng/ml IL-6 induction for 24 h in L6 myotubes. Prolonged IL-6 exposure suppressed glucose uptake regulating alpha serine/threonine-protein kinase (AKT) phosphorylation; however, pretreatment with Alantolactone activated AKT phosphorylation and improved glucose uptake. Alantolactone also attenuated IL-6-stimulated STAT3 phosphorylation, followed by an increase in expression of negative regulator suppressor of cytokine signaling 3 (SOCS3). Furthermore, IL-6-induced expression of pathogen recognition receptor, TLR4, was also suppressed by Alantolactone pretreatment. Post silencing of STAT3 using siRNA approach, IL-6-stimulated siRNA-STAT3 improved glucose uptake and suppressed TLR4 gene expression. Taken together, we propose that, as a STAT3 inhibitor, Alantolactone, improves glucose regulation in the skeletal muscle by inhibiting IL-6-induced STAT3-SOCS3 signaling followed by inhibition of the TLR4 gene expression. Therefore, Alantolactone can be a promising candidate for the treatment of inflammation-associated glucose intolerance and insulin resistance.
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Alantolactone Improves Prolonged Exposure of Interleukin-6-Induced Skeletal Muscle Inflammation Associated Glucose Intolerance and Insulin Resistance
Frontiers Media S.A., 2017Co-Authors: Minjee Kim, Kwangho Song, Yeong Shik KimAbstract:The pro-inflammatory cytokine, Interleukin-6 (IL-6), has been proposed to be one of the mediators that link chronic inflammation to glucose intolerance and insulin resistance. Many studies have demonstrated the effects of IL-6 on insulin action in the skeletal muscle. However, few studies have investigated the effect of long-term treatment of IL-6, leading to glucose intolerance and insulin resistance. In the present study, we observed protective effects of Alantolactone, a sesquiterpene lactone isolated from Inula helenium against glucose intolerance and insulin resistance induced by prolonged exposure of IL-6. Alantolactone has been reported to have anti-inflammatory and anti-cancer effects through IL-6-induced signal transducer and activator of transcription 3 (STAT3) signaling pathway. The relationship between IL-6 exposure and expression of toll-like receptor 4 (TLR4), involved in inflammation in the skeletal muscle, and the underlying mechanisms were investigated. We observed maximum dysregulation of glucose uptake after 40 ng/ml IL-6 induction for 24 h in L6 myotubes. Prolonged IL-6 exposure suppressed glucose uptake regulating alpha serine/threonine-protein kinase (AKT) phosphorylation; however, pretreatment with Alantolactone activated AKT phosphorylation and improved glucose uptake. Alantolactone also attenuated IL-6-stimulated STAT3 phosphorylation, followed by an increase in expression of negative regulator suppressor of cytokine signaling 3 (SOCS3). Furthermore, IL-6-induced expression of pathogen recognition receptor, TLR4, was also suppressed by Alantolactone pretreatment. Post-silencing of STAT3 using siRNA approach, IL-6-stimulated siRNA-STAT3 improved glucose uptake and suppressed TLR4 gene expression. Taken together, we propose that, as a STAT3 inhibitor, Alantolactone, improves glucose regulation in the skeletal muscle by inhibiting IL-6-induced STAT3-SOCS3 signaling followed by inhibition of the TLR4 gene expression. Therefore, Alantolactone can be a promising candidate for the treatment of inflammation-associated glucose intolerance and insulin resistance
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Alantolactone selectively suppresses stat3 activation and exhibits potent anticancer activity in mda mb 231 cells
Cancer Letters, 2015Co-Authors: Jaemoo Chun, Maosheng Cheng, Yeong Shik KimAbstract:The important goal of cancer drug discovery is to develop therapeutic agents that are effective, safe, and affordable. In the present study, we demonstrated that Alantolactone, which is a sesquiterpene lactone, has potential activity against triple-negative breast cancer MDA-MB-231 cells by suppressing the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Alantolactone effectively suppressed both constitutive and inducible STAT3 activation at tyrosine 705. Alantolactone decreased STAT3 translocation to the nucleus, its DNA-binding, and STAT3 target gene expression. Alantolactone significantly inhibits STAT3 activation with a marginal effect on MAPKs and on NF-κB transcription; however, this effect is not mediated by inhibiting STAT3 upstream kinases. Although SHP-1, SHP-2, and PTEN, which are protein tyrosine phosphatases (PTPs), were not affected by Alantolactone, the treatment with a PTP inhibitor reversed the Alantolactone-induced suppression of STAT3 activation, indicating that PTP plays an important role in the action of Alantolactone. Finally, Alantolactone treatment resulted in the inhibition of migration, invasion, adhesion, and colony formation. The in vivo administration of Alantolactone inhibited the growth of human breast xenograft tumors. These results provide preclinical evidence to continue the development of Alantolactone as a STAT3 inhibitor and as a potential therapeutic agent against breast cancer.
Yu Zhang - One of the best experts on this subject based on the ideXlab platform.
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Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cells
BMC, 2016Co-Authors: Yahui Ding, Huier Gao, Yu Zhang, Neil Vasdev, Yingdai Gao, Yue Chen, Quan ZhangAbstract:Abstract Background The poor outcomes for patients diagnosed with acute myeloid leukemia (AML) are largely attributed to leukemia stem cells (LSCs) which are difficult to eliminate with conventional therapy and responsible for relapse. Thus, new therapeutic strategies which could selectively target LSCs in clinical leukemia treatment and avoid drug resistance are urgently needed. However, only a few small molecules have been reported to show anti-LSCs activity. Methods The aim of the present study was to identify Alantolactone as novel agent that can ablate acute myeloid leukemia stem and progenitor cells from AML patient specimens and evaluate the anticancer activity of Alantolactone in vitro and in vivo. Results The present study is the first to demonstrate that Alantolactone, a prominent eudesmane-type sesquiterpene lactone, could specifically ablate LSCs from AML patient specimens. Furthermore, in comparison to the conventional chemotherapy drug, cytosine arabinoside (Ara-C), Alantolactone showed superior effects of leukemia cytotoxicity while sparing normal hematopoietic cells. Alantolactone induced apoptosis with a dose-dependent manner by suppression of NF-kB and its downstream target proteins. DMA-Alantolactone, a water-soluble prodrug of Alantolactone, could suppress tumor growth in vivo. Conclusions Based on these results, we propose that Alantolactone may represent a novel LSCs-targeted therapy and eudesmane-type sesquiterpene lactones offer a new scaffold for drug discovery towards anti-LSCs agents
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Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cells
'Springer Science and Business Media LLC', 2016Co-Authors: Ding Yahui, Yu Zhang, Gao Huier, Vasdev Neil, Gao Yingdai, Chen Yue, Zhang QuanAbstract:Background: The poor outcomes for patients diagnosed with acute myeloid leukemia (AML) are largely attributed to leukemia stem cells (LSCs) which are difficult to eliminate with conventional therapy and responsible for relapse. Thus, new therapeutic strategies which could selectively target LSCs in clinical leukemia treatment and avoid drug resistance are urgently needed. However, only a few small molecules have been reported to show anti-LSCs activity. Methods: The aim of the present study was to identify Alantolactone as novel agent that can ablate acute myeloid leukemia stem and progenitor cells from AML patient specimens and evaluate the anticancer activity of Alantolactone in vitro and in vivo. Results: The present study is the first to demonstrate that Alantolactone, a prominent eudesmane-type sesquiterpene lactone, could specifically ablate LSCs from AML patient specimens. Furthermore, in comparison to the conventional chemotherapy drug, cytosine arabinoside (Ara-C), Alantolactone showed superior effects of leukemia cytotoxicity while sparing normal hematopoietic cells. Alantolactone induced apoptosis with a dose-dependent manner by suppression of NF-kB and its downstream target proteins. DMA-Alantolactone, a water-soluble prodrug of Alantolactone, could suppress tumor growth in vivo. Conclusions: Based on these results, we propose that Alantolactone may represent a novel LSCs-targeted therapy and eudesmane-type sesquiterpene lactones offer a new scaffold for drug discovery towards anti-LSCs agents. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0327-5) contains supplementary material, which is available to authorized users
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Additional file 1: of Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cells
2016Co-Authors: Yahui Ding, Huier Gao, Yu Zhang, Neil Vasdev, Yingdai Gao, Yue Chen, Quan ZhangAbstract:Copies of NMR, MS, HPLC spectra of Alantolactone and copies of NMR spectra of DMA-Alantolactone. (DOCX 533 kb
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Alantolactone induces cell apoptosis partially through down regulation of testes specific protease 50 expression
Toxicology Letters, 2014Co-Authors: Zhenbo Song, Yu Zhang, Yong Li Bao, Ying Sun, Li Hua Zheng, Yuwei Zhang, Luguo Sun, Guannan WangAbstract:Testes-specific protease 50 (TSP50) is aberrantly expressed in many cancer biopsies and plays a crucial role in tumorigenesis, which make it a potential cancer therapeutic target for drug discovery. Here, we constructed a firefly luciferase reporter driven by the TSP50 gene promoter to screen natural compounds capable of inhibiting the expression of TSP50. Then we identified Alantolactone, a sesquiterpene lactone, could efficiently inhibit the promoter activity of TSP50 gene, further results revealed that Alantolactone also efficiently inhibited the expression of TSP50 in both mRNA and protein levels. Moreover, we found Alantolactone could increase the ratio of Bax/Bcl-2, and activate caspase-9 and caspase-3 in the cancer cells with high expression of TSP50, surprisingly, the same effects can also be observed in the same cells just by knockdown of TSP50 gene expression. Furthermore, our results suggested that overexpression of TSP50 decreased the cell sensitivity to Alantolactone-induced apoptosis in those cancer cells. Taken together, these results suggest that Alantolactone induces mitochondrial-dependent apoptosis at least partially via down-regulation of TSP50 expression.
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Alantolactone induces apoptosis in rko cells through the generation of reactive oxygen species and the mitochondrial pathway
Molecular Medicine Reports, 2013Co-Authors: Yu Zhang, Yong Li Bao, Yan Xin Huang, Ying Sun, Li Hua ZhengAbstract:Alantolactone, a methanol extract of Inula helenium, possesses anticancer properties in a number of cancer cell lines. However, its anticancer effect on human colorectal cancer cells and the underlying mechanisms remain to be elucidated. In the present study, the effects of Alantolactone on cell viability and apoptosis in RKO human colon cancer cells were investigated. Alantolactone treatment of RKO cells was found to result in dose‑dependent inhibition of cell viability and induction of apoptosis, accompanied with the accumulation of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential. In addition, these effects were blocked with N‑acetylcysteine, a specific ROS inhibitor. Western blotting indicated that exposure of RKO cells to Alantolactone is associated with the downregulation of Bcl‑2, induction of Bax and activation of caspase‑3 and ‑9. These results indicated that a ROS‑mediated mitochondria‑dependent pathway is involved in Alantolactone‑induced apoptosis. From these observations, it was hypothesized that Alantolactone may be used for the treatment of human colon cancer.
Kwangho Song - One of the best experts on this subject based on the ideXlab platform.
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Alantolactone improves prolonged exposure of interleukin 6 induced skeletal muscle inflammation associated glucose intolerance and insulin resistance
Frontiers in Pharmacology, 2017Co-Authors: Minjee Kim, Kwangho Song, Yeong Shik KimAbstract:The pro-inflammatory cytokine, IL-6, has been proposed to be one of the mediators that link chronic inflammation to glucose intolerance and insulin resistance. Many studies have demonstrated the effects of IL-6 on insulin action in the skeletal muscle. However, few studies have investigated the effect of long-term treatment of IL-6, leading to glucose intolerance and insulin resistance. In the present study, we observed protective effects of Alantolactone, a sesquiterpene lactone isolated from Inula helenium against glucose intolerance and insulin resistance induced by prolonged exposure of IL-6. Alantolactone has been reported to have anti-inflammatory and anti-cancer effects through IL-6-induced signal transducer and activator of transcription 3 (STAT3) signaling pathway. The relationship between IL-6 exposure and expression of toll-like receptor 4 (TLR4), involved in inflammation in the skeletal muscle, and the underlying mechanisms were investigated. We observed maximum dysregulation of glucose uptake after 40 ng/ml IL-6 induction for 24 h in L6 myotubes. Prolonged IL-6 exposure suppressed glucose uptake regulating alpha serine/threonine-protein kinase (AKT) phosphorylation; however, pretreatment with Alantolactone activated AKT phosphorylation and improved glucose uptake. Alantolactone also attenuated IL-6-stimulated STAT3 phosphorylation, followed by an increase in expression of negative regulator suppressor of cytokine signaling 3 (SOCS3). Furthermore, IL-6-induced expression of pathogen recognition receptor, TLR4, was also suppressed by Alantolactone pretreatment. Post silencing of STAT3 using siRNA approach, IL-6-stimulated siRNA-STAT3 improved glucose uptake and suppressed TLR4 gene expression. Taken together, we propose that, as a STAT3 inhibitor, Alantolactone, improves glucose regulation in the skeletal muscle by inhibiting IL-6-induced STAT3-SOCS3 signaling followed by inhibition of the TLR4 gene expression. Therefore, Alantolactone can be a promising candidate for the treatment of inflammation-associated glucose intolerance and insulin resistance.
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Alantolactone Improves Prolonged Exposure of Interleukin-6-Induced Skeletal Muscle Inflammation Associated Glucose Intolerance and Insulin Resistance
Frontiers Media S.A., 2017Co-Authors: Minjee Kim, Kwangho Song, Yeong Shik KimAbstract:The pro-inflammatory cytokine, Interleukin-6 (IL-6), has been proposed to be one of the mediators that link chronic inflammation to glucose intolerance and insulin resistance. Many studies have demonstrated the effects of IL-6 on insulin action in the skeletal muscle. However, few studies have investigated the effect of long-term treatment of IL-6, leading to glucose intolerance and insulin resistance. In the present study, we observed protective effects of Alantolactone, a sesquiterpene lactone isolated from Inula helenium against glucose intolerance and insulin resistance induced by prolonged exposure of IL-6. Alantolactone has been reported to have anti-inflammatory and anti-cancer effects through IL-6-induced signal transducer and activator of transcription 3 (STAT3) signaling pathway. The relationship between IL-6 exposure and expression of toll-like receptor 4 (TLR4), involved in inflammation in the skeletal muscle, and the underlying mechanisms were investigated. We observed maximum dysregulation of glucose uptake after 40 ng/ml IL-6 induction for 24 h in L6 myotubes. Prolonged IL-6 exposure suppressed glucose uptake regulating alpha serine/threonine-protein kinase (AKT) phosphorylation; however, pretreatment with Alantolactone activated AKT phosphorylation and improved glucose uptake. Alantolactone also attenuated IL-6-stimulated STAT3 phosphorylation, followed by an increase in expression of negative regulator suppressor of cytokine signaling 3 (SOCS3). Furthermore, IL-6-induced expression of pathogen recognition receptor, TLR4, was also suppressed by Alantolactone pretreatment. Post-silencing of STAT3 using siRNA approach, IL-6-stimulated siRNA-STAT3 improved glucose uptake and suppressed TLR4 gene expression. Taken together, we propose that, as a STAT3 inhibitor, Alantolactone, improves glucose regulation in the skeletal muscle by inhibiting IL-6-induced STAT3-SOCS3 signaling followed by inhibition of the TLR4 gene expression. Therefore, Alantolactone can be a promising candidate for the treatment of inflammation-associated glucose intolerance and insulin resistance
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high body clearance and low oral bioavailability of Alantolactone isolated from inula helenium in rats extensive hepatic metabolism and low stability in gastrointestinal fluids
Biopharmaceutics & Drug Disposition, 2016Co-Authors: Jaemoo Chun, Kwangho Song, Sukjae Chung, Insoo YoonAbstract:: Alantolactone (ALA) is a major bioactive sesquiterpene lactone present in the roots of Inula helenium L. (Asteraceae) which has been used widely in traditional medicine against various diseases such as asthma, cancer and tuberculosis. The pharmacologic activities of Alantolactone have been well characterized, yet information on the physicochemical and pharmacokinetic properties of Alantolactone and their mechanistic elucidation are still limited. Thus, this study aims to investigate the oral absorption and disposition of Alantolactone and their relevant mechanisms. Log P values of Alantolactone ranged from 1.52 to 1.84, and Alantolactone was unstable in biological samples such as plasma, urine, bile, rat liver microsomes (RLM) and simulated gastrointestinal fluids. The metabolic rate of Alantolactone was markedly higher in rat liver homogenates than in the other tissue homogenates. A saturable and concentration-dependent metabolic rate profile of Alantolactone was observed in RLM, and rat cytochrome P450 (CYP) 1 A, 2C, 2D and 3 A subfamilies were significantly involved in its hepatic metabolism. Based on the well-stirred model, the hepatic extraction ratio (HER) was estimated to be 0.890-0.933, classifying Alantolactone as a drug with high HER. Moreover, high total body clearance (111 ± 41 ml/min/kg) and low oral bioavailability (0.323%) of Alantolactone were observed in rats. Taken together, the present study demonstrates that the extensive hepatic metabolism, at least partially mediated by CYP, is primarily responsible for the high total body clearance of Alantolactone, and that the low oral bioavailability of Alantolactone could be attributed to its low stability in gastrointestinal fluids and a hepatic first-pass effect in rats. Copyright © 2016 John Wiley & Sons, Ltd.
Muhammad Rashid Khan - One of the best experts on this subject based on the ideXlab platform.
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targeting apoptosis pathways in cancer with Alantolactone and isoAlantolactone
The Scientific World Journal, 2013Co-Authors: Muhammad Rashid Khan, Azhar Rasul, Muhammad AliAbstract:Alantolactone and isoAlantolactone, main bioactive compounds that are present in many medicinal plants such as Inula helenium, L. Inula japonica, Aucklandia lappa, Inula racemosa, and Radix inulae, have been found to have various pharmacological actions including anti-inflammatory, antimicrobial, and anticancer properties, with no significant toxicity. Recently, the anticancer activity of Alantolactone and isoAlantolactone has been extensively investigated. Here, our aim is to review their natural sources and their anticancer activity with specific emphasis on mechanism of actions, by which these compounds act on apoptosis pathways. Based on the literature and also on our previous results, Alantolactone and isoAlantolactone induce apoptosis by targeting multiple cellular signaling pathways that are frequently deregulated in cancers and suggest that their simultaneous targeting by these compounds could result in efficacious and selective killing of cancer cells. This review suggests that Alantolactone and isoAlantolactone are potential promising anticancer candidates, but additional studies and clinical trials are required to determine their specific intracellular sites of actions and derivative targets in order to fully understand the mechanisms of therapeutic effects to further validate in cancer chemotherapy.
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Alantolactone induces apoptosis in hepg2 cells through gsh depletion inhibition of stat3 activation and mitochondrial dysfunction
BioMed Research International, 2013Co-Authors: Muhammad Rashid Khan, Meiyan Sun, Azhar Rasul, Muhammad Khalil Khan, Faisal Nawaz, Yongchen ZhengAbstract:Signal transducer and activator of transcription 3 (STAT3) constitutively expresses in human liver cancer cells and has been implicated in apoptosis resistance and tumorigenesis. Alantolactone, a sesquiterpene lactone, has been shown to possess anticancer activities in various cancer cell lines. In our previous report, we showed that Alantolactone induced apoptosis in U87 glioblastoma cells via GSH depletion and ROS generation. However, the molecular mechanism of GSH depletion remained unexplored. The present study was conducted to envisage the molecular mechanism of Alantolactone-induced apoptosis in HepG2 cells by focusing on the molecular mechanism of GSH depletion and its effect on STAT3 activation. We found that Alantolactone induced apoptosis in HepG2 cells in a dose-dependent manner. This Alantolactone-induced apoptosis was found to be associated with GSH depletion, inhibition of STAT3 activation, ROS generation, mitochondrial transmembrane potential dissipation, and increased Bax/Bcl-2 ratio and caspase-3 activation. This Alantolactone-induced apoptosis and GSH depletion were effectively inhibited or abrogated by a thiol antioxidant, N-acetyl-L-cysteine (NAC). The data demonstrate clearly that intracellular GSH plays a central role in Alantolactone-induced apoptosis in HepG2 cells. Thus, Alantolactone may become a lead chemotherapeutic candidate for the treatment of liver cancer.
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Alantolactone induces apoptosis in glioblastoma cells via gsh depletion ros generation and mitochondrial dysfunction
Iubmb Life, 2012Co-Authors: Muhammad Rashid Khan, Azhar Rasul, Nan Wang, Hongwen Gao, Rong GaoAbstract:Glioblastoma multiforme (GBM) is the most malignant and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies, the prognosis of glioblastoma remains very poor. Alantolactone, a sesquiterpene lactone compound, has been reported to exhibit antifungal, antibacteria, antihelminthic, and anticancer properties. In this study, we found that Alantolactone effectively inhibits growth and triggers apoptosis in glioblastoma cells in a time- and dose-dependent manner. The Alantolactone-induced apoptosis was found to be associated with glutathione (GSH) depletion, reactive oxygen species (ROS) generation, mitochondrial transmembrane potential dissipation, cardiolipin oxidation, upregulation of p53 and Bax, downregulation of Bcl-2, cytochrome c release, activation of caspases (caspase 9 and 3), and cleavage of poly (ADP-ribose) polymerase. This Alantolactone-induced apoptosis and GSH depletion were effectively inhibited or abrogated by a thiol antioxidant, N-acetyl-L-cysteine, whereas other antioxidant (polyethylene glycol (PEG)-catalase and PEG-superoxide-dismutase) did not prevent apoptosis and GSH depletion. Alantolactone treatment inhibited the translocation of NF-κB into nucleus; however, NF-κB inhibitor, SN50 failed to potentiate Alantolactone-induced apoptosis indicating that Alantolactone induces NF-κB-independent apoptosis in glioma cells. These findings suggest that the sensitivity of tumor cells to Alantolactone appears to results from GSH depletion and ROS production. Furthermore, our in vivo toxicity study demonstrated that Alantolactone did not induce significant hepatotoxicity and nephrotoxicity in mice. Therefore, Alantolactone may become a potential lead compound for future development of antiglioma therapy.
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Alantolactone induces apoptosis in glioblastoma cells via gsh depletion ros generation and mitochondrial dysfunction
Iubmb Life, 2012Co-Authors: Muhammad Rashid Khan, Azhar Rasul, Fei Yi, Ting Li, Nan WangAbstract:Summary Glioblastoma multiforme (GBM) is the most malignant and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies, the prognosis of glioblastoma remains very poor. Alantolactone, a sesquiterpene lactone compound, has been reported to exhibit antifungal, antibacteria, antihelminthic, and anticancer properties. In this study, we found that Alantolactone effectively inhibits growth and triggers apoptosis in glioblastoma cells in a time- and dose-dependent manner. The Alantolactone-induced apoptosis was found to be associated with glutathione (GSH) depletion, reactive oxygen species (ROS) generation, mitochondrial transmembrane potential dissipation, cardiolipin oxidation, upregulation of p53 and Bax, downregulation of Bcl-2, cytochrome c release, activation of caspases (caspase 9 and 3), and cleavage of poly (ADP-ribose) polymerase. This Alantolactone-induced apoptosis and GSH depletion were effectively inhibited or abrogated by a thiol antioxidant, N-acetyl-L-cysteine, whereas other antioxidant (polyethylene glycol (PEG)-catalase and PEG-superoxide-dismutase) did not prevent apoptosis and GSH depletion. Alantolactone treatment inhibited the translocation of NF-jB into nucleus; however, NF-jB inhibitor, SN50 failed to potentiate Alantolactone-induced apoptosis indicating that Alantolactone induces NF-jB-independent apoptosis in glioma cells. These findings suggest that the sensitivity of tumor cells to Alantolactone appears to results from GSH depletion and ROS production. Furthermore, our in vivo toxicity study demonstrated that Alantolactone did not induce significant hepatotoxicity and nephrotoxicity in mice. Therefore, Alantolactone may become a potential lead compound for future development of antiglioma therapy. 2012 IUBMB IUBMB Life, 64(9): 783‐794, 2012
Minjee Kim - One of the best experts on this subject based on the ideXlab platform.
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Alantolactone improves prolonged exposure of interleukin 6 induced skeletal muscle inflammation associated glucose intolerance and insulin resistance
Frontiers in Pharmacology, 2017Co-Authors: Minjee Kim, Kwangho Song, Yeong Shik KimAbstract:The pro-inflammatory cytokine, IL-6, has been proposed to be one of the mediators that link chronic inflammation to glucose intolerance and insulin resistance. Many studies have demonstrated the effects of IL-6 on insulin action in the skeletal muscle. However, few studies have investigated the effect of long-term treatment of IL-6, leading to glucose intolerance and insulin resistance. In the present study, we observed protective effects of Alantolactone, a sesquiterpene lactone isolated from Inula helenium against glucose intolerance and insulin resistance induced by prolonged exposure of IL-6. Alantolactone has been reported to have anti-inflammatory and anti-cancer effects through IL-6-induced signal transducer and activator of transcription 3 (STAT3) signaling pathway. The relationship between IL-6 exposure and expression of toll-like receptor 4 (TLR4), involved in inflammation in the skeletal muscle, and the underlying mechanisms were investigated. We observed maximum dysregulation of glucose uptake after 40 ng/ml IL-6 induction for 24 h in L6 myotubes. Prolonged IL-6 exposure suppressed glucose uptake regulating alpha serine/threonine-protein kinase (AKT) phosphorylation; however, pretreatment with Alantolactone activated AKT phosphorylation and improved glucose uptake. Alantolactone also attenuated IL-6-stimulated STAT3 phosphorylation, followed by an increase in expression of negative regulator suppressor of cytokine signaling 3 (SOCS3). Furthermore, IL-6-induced expression of pathogen recognition receptor, TLR4, was also suppressed by Alantolactone pretreatment. Post silencing of STAT3 using siRNA approach, IL-6-stimulated siRNA-STAT3 improved glucose uptake and suppressed TLR4 gene expression. Taken together, we propose that, as a STAT3 inhibitor, Alantolactone, improves glucose regulation in the skeletal muscle by inhibiting IL-6-induced STAT3-SOCS3 signaling followed by inhibition of the TLR4 gene expression. Therefore, Alantolactone can be a promising candidate for the treatment of inflammation-associated glucose intolerance and insulin resistance.
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Alantolactone Improves Prolonged Exposure of Interleukin-6-Induced Skeletal Muscle Inflammation Associated Glucose Intolerance and Insulin Resistance
Frontiers Media S.A., 2017Co-Authors: Minjee Kim, Kwangho Song, Yeong Shik KimAbstract:The pro-inflammatory cytokine, Interleukin-6 (IL-6), has been proposed to be one of the mediators that link chronic inflammation to glucose intolerance and insulin resistance. Many studies have demonstrated the effects of IL-6 on insulin action in the skeletal muscle. However, few studies have investigated the effect of long-term treatment of IL-6, leading to glucose intolerance and insulin resistance. In the present study, we observed protective effects of Alantolactone, a sesquiterpene lactone isolated from Inula helenium against glucose intolerance and insulin resistance induced by prolonged exposure of IL-6. Alantolactone has been reported to have anti-inflammatory and anti-cancer effects through IL-6-induced signal transducer and activator of transcription 3 (STAT3) signaling pathway. The relationship between IL-6 exposure and expression of toll-like receptor 4 (TLR4), involved in inflammation in the skeletal muscle, and the underlying mechanisms were investigated. We observed maximum dysregulation of glucose uptake after 40 ng/ml IL-6 induction for 24 h in L6 myotubes. Prolonged IL-6 exposure suppressed glucose uptake regulating alpha serine/threonine-protein kinase (AKT) phosphorylation; however, pretreatment with Alantolactone activated AKT phosphorylation and improved glucose uptake. Alantolactone also attenuated IL-6-stimulated STAT3 phosphorylation, followed by an increase in expression of negative regulator suppressor of cytokine signaling 3 (SOCS3). Furthermore, IL-6-induced expression of pathogen recognition receptor, TLR4, was also suppressed by Alantolactone pretreatment. Post-silencing of STAT3 using siRNA approach, IL-6-stimulated siRNA-STAT3 improved glucose uptake and suppressed TLR4 gene expression. Taken together, we propose that, as a STAT3 inhibitor, Alantolactone, improves glucose regulation in the skeletal muscle by inhibiting IL-6-induced STAT3-SOCS3 signaling followed by inhibition of the TLR4 gene expression. Therefore, Alantolactone can be a promising candidate for the treatment of inflammation-associated glucose intolerance and insulin resistance
