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Yeong Shik Kim – One of the best experts on this subject based on the ideXlab platform.

Yu Zhang – One of the best experts on this subject based on the ideXlab platform.

  • Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cells
    BMC, 2016
    Co-Authors: Yahui Ding, Huier Gao, Yu Zhang, Neil Vasdev, Yingdai Gao, Yue Chen, Quan Zhang
    Abstract:

    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

  • Additional file 1: of Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cells
    , 2016
    Co-Authors: Yahui Ding, Huier Gao, Yu Zhang, Neil Vasdev, Yingdai Gao, Yue Chen, Quan Zhang
    Abstract:

    Copies of NMR, MS, HPLC spectra of Alantolactone and copies of NMR spectra of DMA-Alantolactone. (DOCX 533 kb

  • Alantolactone selectively ablates acute myeloid leukemia stem and progenitor cells
    'Springer Science and Business Media LLC', 2016
    Co-Authors: Ding Yahui, Yu Zhang, Gao Huier, Vasdev Neil, Gao Yingdai, Chen Yue, Zhang Quan
    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. 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

Kwangho Song – One of the best experts on this subject based on the ideXlab platform.

  • Alantolactone improves prolonged exposure of interleukin 6 induced skeletal muscle inflammation associated glucose intolerance and insulin resistance
    Frontiers in Pharmacology, 2017
    Co-Authors: Minjee Kim, Kwangho Song, Yeong Shik Kim
    Abstract:

    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.

  • Alantolactone Improves Prolonged Exposure of Interleukin-6-Induced Skeletal Muscle Inflammation Associated Glucose Intolerance and Insulin Resistance
    Frontiers Media S.A., 2017
    Co-Authors: Minjee Kim, Kwangho Song, Yeong Shik Kim
    Abstract:

    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

  • 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, 2016
    Co-Authors: Jaemoo Chun, Kwangho Song, Sukjae Chung, Insoo Yoon
    Abstract:

    : 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.

  • targeting apoptosis pathways in cancer with Alantolactone and isoAlantolactone
    The Scientific World Journal, 2013
    Co-Authors: Muhammad Rashid Khan, Azhar Rasul, Muhammad Ali
    Abstract:

    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 chemchemotherapy.

  • Alantolactone induces apoptosis in hepg2 cells through gsh depletion inhibition of stat3 activation and mitochondrial dysfunction
    BioMed Research International, 2013
    Co-Authors: Muhammad Rashid Khan, Meiyan Sun, Azhar Rasul, Muhammad Khalil Khan, Faisal Nawaz, Yongchen Zheng
    Abstract:

    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.

  • Alantolactone induces apoptosis in glioblastoma cells via gsh depletion ros generation and mitochondrial dysfunction
    Iubmb Life, 2012
    Co-Authors: Muhammad Rashid Khan, Azhar Rasul, Nan Wang, Hongwen Gao, Rong Gao
    Abstract:

    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.

Minjee Kim – One of the best experts on this subject based on the ideXlab platform.

  • Alantolactone improves prolonged exposure of interleukin 6 induced skeletal muscle inflammation associated glucose intolerance and insulin resistance
    Frontiers in Pharmacology, 2017
    Co-Authors: Minjee Kim, Kwangho Song, Yeong Shik Kim
    Abstract:

    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.

  • Alantolactone Improves Prolonged Exposure of Interleukin-6-Induced Skeletal Muscle Inflammation Associated Glucose Intolerance and Insulin Resistance
    Frontiers Media S.A., 2017
    Co-Authors: Minjee Kim, Kwangho Song, Yeong Shik Kim
    Abstract:

    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