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1.
J Neurooncol ; 160(3): 677-689, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36396930

ABSTRACT

PURPOSE: Limited treatment options are currently available for glioblastoma (GBM), an extremely lethal type of brain cancer. For a variety of tumor types, bioenergetic deprivation through inhibition of cancer-specific metabolic pathways has proven to be an effective therapeutic strategy. Here, we evaluated the therapeutic effects and underlying mechanisms of dual inhibition of carnitine palmitoyltransferase 1A (CPT1A) and glucose-6-phosphate dehydrogenase (G6PD) critical for fatty acid oxidation (FAO) and the pentose phosphate pathway (PPP), respectively, against GBM tumorspheres (TSs). METHODS: Therapeutic efficacy against GBM TSs was determined by assessing cell viability, neurosphere formation, and 3D invasion. Liquid chromatography-mass spectrometry (LC-MS) and RNA sequencing were employed for metabolite and gene expression profiling, respectively. Anticancer efficacy in vivo was examined using an orthotopic xenograft model. RESULTS: CPT1A and G6PD were highly expressed in GBM tumor tissues. Notably, siRNA-mediated knockdown of both genes led to reduced viability, ATP levels, and expression of genes associated with stemness and invasiveness. Similar results were obtained upon combined treatment with etomoxir and dehydroepiandrosterone (DHEA). Transcriptome analyses further confirmed these results. Data from LC-MS analysis showed that this treatment regimen induced a considerable reduction in the levels of metabolites associated with the TCA cycle and PPP. Additionally, the combination of etomoxir and DHEA inhibited tumor growth and extended survival in orthotopic xenograft model mice. CONCLUSION: Our collective findings support the utility of dual suppression of CPT1A and G6PD with selective inhibitors, etomoxir and DHEA, as an efficacious therapeutic approach for GBM.


Subject(s)
Glioblastoma , Animals , Humans , Mice , Carnitine O-Palmitoyltransferase/antagonists & inhibitors , Carnitine O-Palmitoyltransferase/genetics , Carnitine O-Palmitoyltransferase/metabolism , Cell Line, Tumor , Dehydroepiandrosterone/therapeutic use , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/metabolism , Glucosephosphate Dehydrogenase/antagonists & inhibitors , Glucosephosphate Dehydrogenase/genetics , Glucosephosphate Dehydrogenase/metabolism , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology
2.
Cancer Cell Int ; 22(1): 309, 2022 Oct 11.
Article in English | MEDLINE | ID: mdl-36221088

ABSTRACT

INTRODUCTION: The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM. METHODS: The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO. RESULTS: GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group. CONCLUSION: ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM.

3.
Adv Healthc Mater ; 11(21): e2201586, 2022 11.
Article in English | MEDLINE | ID: mdl-36047642

ABSTRACT

Patient-specific cancer therapies can evolve by vitalizing the mother tissue-like cancer niche, cellular profile, genetic signature, and drug responsiveness. This evolution has enabled the elucidation of a key mechanism along with development of the mechanism-driven therapy. After surgical treatment, glioblastoma (GBM) patients require prompt therapy within 14 days in a patient-specific manner. Hence, this study approaches direct culture of GBM patient tissue (1 mm diameter) in a microchannel network chip. Cancer vasculature-mimetic perfusion can support the preservation of the mother tissue-like characteristic signatures and microenvironment. When temozolomide and radiation are administered within 1 day, the responsiveness of the tissue in the chip reflected the clinical outcomes, thereby overcoming the time-consuming process of cell and organoid culture. When the tissue chip culture is continued, the intact GBM signature gets lost, and the outward migration of stem cells from the tissue origin increases, indicating a leaving-home effect on the family dismantle. Nanovesicle production using GBM stem cells enables self-chasing of the cells that escape the temozolomide effect owing to quiescence. The anti-PTPRZ1 peptide display and temozolomide loading to nanovesicles awakes cancer stem cells from the quiescent stage to death. This study suggests a GBM clinic-driven avatar platform and mechanism-learned nanotherapy for translation.


Subject(s)
Brain Neoplasms , Glioblastoma , Nanomedicine , Humans , Brain Neoplasms/therapy , Cell Line, Tumor , Glioblastoma/therapy , Neoplastic Stem Cells , Temozolomide/pharmacology , Tumor Microenvironment
4.
Sci Rep ; 12(1): 13990, 2022 08 17.
Article in English | MEDLINE | ID: mdl-35978012

ABSTRACT

Forkhead Box M1 (FOXM1) is known to regulate cell proliferation, apoptosis and tumorigenesis. The lignan, (-)-(2R,3R)-1,4-O-diferuloylsecoisolariciresinol (DFS), from Alnus japonica has shown anti-cancer effects against colon cancer cells by suppressing FOXM1. The present study hypothesized that DFS can have anti-cancer effects against glioblastoma (GBM) tumorspheres (TSs). Immunoprecipitation and luciferase reporter assays were performed to evaluate the ability of DFS to suppress nuclear translocation of ß-catenin through ß-catenin/FOXM1 binding. DFS-pretreated GBM TSs were evaluated to assess the ability of DFS to inhibit GBM TSs and their transcriptional profiles. The in vivo efficacy was examined in orthotopic xenograft models of GBM. Expression of FOXM1 was higher in GBM than in normal tissues. DFS-induced FOXM1 protein degradation blocked ß-catenin translocation into the nucleus and consequently suppressed downstream target genes of FOXM1 pathways. DFS inhibited cell viability and ATP levels, while increasing apoptosis, and it reduced tumorsphere formation and the invasiveness of GBM TSs. And DFS reduced the activities of transcription factors related to tumorigenesis, stemness, and invasiveness. DFS significantly inhibited tumor growth and prolonged the survival rate of mice in orthotopic xenograft models of GBM. It suggests that DFS inhibits the proliferation of GBM TSs by suppressing FOXM1. DFS may be a potential therapeutic agent to treat GBM.


Subject(s)
Alnus , Glioblastoma , Lignans , Animals , Carcinogenesis/genetics , Cell Line, Tumor , Cell Proliferation , Forkhead Box Protein M1/genetics , Forkhead Box Protein M1/metabolism , Gene Expression Regulation, Neoplastic , Glioblastoma/metabolism , Humans , Lignans/pharmacology , Lignans/therapeutic use , Mice , beta Catenin/metabolism
5.
Yonsei Med J ; 62(10): 936-942, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34558873

ABSTRACT

PURPOSE: A critical indicator of the overall survival of patients with high-grade glioma is the successful isolation of tumor mesenchymal stem-like cells (tMSLCs), which play important roles in glioma progression. However, attempts to isolate tMSLCs from surgical specimens have not always been successful, and the reasons for this remain unclear. Considering that the amount of surgical high-grade glioma specimens varies, we hypothesized that larger surgical specimens would be better for tMSLC isolation. MATERIALS AND METHODS: We assessed 51 fresh, high-grade glioma specimens and divided them into two groups according to the success or failure of tMSLC isolation. The success of tMSLC isolation was confirmed by plastic adherence, presenting antigens, tri-lineage differentiation, and non-tumorigenicity. Differences in characteristics between the two groups were tested using independent two sample t-tests, chi-square tests, or Kaplan-Meier survival analysis. RESULTS: The mean specimen weights of the groups differed from each other (tMSLC-negative group: 469.9±341.9 mg, tMSLC positive group: 546.7±618.9 mg), but the difference was not statistically significant. The optimal cut-off value of specimen weight was 180 mg, and the area under the curve value was 0.599. CONCLUSION: Our results suggested a minimum criterion for specimen collection, and found that the specimen amount was not deeply related to tMSLC detection. Collectively, our findings imply that the ability to isolate tMSLCs is determined by factors other than the specimen amount.


Subject(s)
Brain Neoplasms , Glioma , Mesenchymal Stem Cells , Cell Differentiation , Humans , Neoplastic Stem Cells
6.
iScience ; 24(9): 103080, 2021 Sep 24.
Article in English | MEDLINE | ID: mdl-34585118

ABSTRACT

Resistance to current therapies is common for pancreatic cancer and hence novel treatment options are urgently needed. In this work, we developed and validated a computational method to select synergistic compound combinations based on transcriptomic profiles from both the disease and compound side, combined with a pathway scoring system, which was then validated prospectively by testing 30 compounds (and their combinations) on PANC-1 cells. Some compounds selected as single agents showed lower GI50 values than the standard of care, gemcitabine. Compounds suggested as combination agents with standard therapy gemcitabine based on the best performing scoring system showed on average 2.82-5.18 times higher synergies compared to compounds that were predicted to be active as single agents. Examples of highly synergistic in vitro validated compound pairs include gemcitabine combined with Entinostat, thioridazine, loperamide, scriptaid and Saracatinib. Hence, the computational approach presented here was able to identify synergistic compound combinations against pancreatic cancer cells.

7.
Front Pharmacol ; 12: 618773, 2021.
Article in English | MEDLINE | ID: mdl-33643049

ABSTRACT

Shexiang Baoxin Pill (SBP) is an oral formulation of Chinese materia medica for the treatment of angina pectoris. It displays pleiotropic roles in protecting the cardiovascular system. However, the mode of action of SBP in promoting angiogenesis, and in particular the synergy between its constituents is currently not fully understood. The combination of ginsenosides Rb2 and Rg3 were studied in human umbilical vein endothelial cells (HUVECs) for their proangiogenic effects. To understand the mode of action of the combination in more mechanistic detail, RNA-Seq analysis was conducted, and differentially expressed genes (DEGs), pathway analysis and Weighted Gene Correlation Network Analysis (WGCNA) were applied to further identify important genes that a play pivotal role in the combination treatment. The effects of pathway-specific inhibitors were observed to provide further support for the hypothesized mode of action of the combination. Ginsenosides Rb2 and Rg3 synergistically promoted HUVEC proliferation and tube formation under defined culture conditions. Also, the combination of Rb2/Rg3 rescued cells from homocysteine-induced damage. mRNA expression of CXCL8, CYR61, FGF16 and FGFRL1 was significantly elevated by the Rb2/Rg3 treatment, and representative signaling pathways induced by these genes were found. The increase of protein levels of phosphorylated-Akt and ERK42/44 by the Rb2/Rg3 combination supports the notion that it promotes endothelial cell proliferation via the PI3K/Akt and MAPK/ERK signaling pathways. The present study provides the hypothesis that SBP, via ginsenosides Rb2 and Rg3, involves the CXCR1/2 CXCL8 (IL8)-mediated PI3K/Akt and MAPK/ERK signaling pathways in achieving its proangiogenic effects.

8.
J Cancer Res Clin Oncol ; 146(11): 2817-2828, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32712753

ABSTRACT

PURPOSE: Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs. METHODS: GBM TSs (TS15-88, GSC11) were treated with niclosamide and/or temozolomide. Combined effects of two drugs were evaluated by measuring viability, neurosphere formation, and 3D-invasion in collagen matrix. Transcriptional profiles of GBM TS were analyzed using RNA sequencing. In vivo anticancer efficacy of combined drugs was tested in a mouse orthotopic xenograft model. RESULTS: Combination treatment of niclosamide and temozolomide significantly inhibited the cell viability, stemness, and invasive properties of GBM TSs. This combined treatment significantly down-regulated the expression of epithelial mesenchymal transition-related markers, Zeb1, N-cadherin, and ß-catenin. The combined treatment also significantly decreased tumor growth in orthotopic xenograft models. CONCLUSION: The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Brain Neoplasms/pathology , Glioblastoma/pathology , Animals , Cell Line, Tumor , Cell Survival/drug effects , Epithelial-Mesenchymal Transition/drug effects , Humans , Mice , Neoplastic Stem Cells/drug effects , Niclosamide/pharmacology , Temozolomide/pharmacology , Xenograft Model Antitumor Assays
9.
Mol Cell ; 78(6): 1224-1236.e5, 2020 06 18.
Article in English | MEDLINE | ID: mdl-32442398

ABSTRACT

Strand selection is a critical step in microRNA (miRNA) biogenesis. Although the dominant strand may change depending on cellular contexts, the molecular mechanism and physiological significance of such alternative strand selection (or "arm switching") remain elusive. Here we find miR-324 to be one of the strongly regulated miRNAs by arm switching and identify the terminal uridylyl transferases TUT4 and TUT7 to be the key regulators. Uridylation of pre-miR-324 by TUT4/7 re-positions DICER on the pre-miRNA and shifts the cleavage site. This alternative processing produces a duplex with a different terminus from which the 3' strand (3p) is selected instead of the 5' strand (5p). In glioblastoma, the TUT4/7 and 3p levels are upregulated, whereas the 5p level is reduced. Manipulation of the strand ratio is sufficient to impair glioblastoma cell proliferation. This study uncovers a role of uridylation as a molecular switch in alternative strand selection and implicates its therapeutic potential.


Subject(s)
MicroRNAs/metabolism , UDPglucose-Hexose-1-Phosphate Uridylyltransferase/metabolism , Animals , Cell Line, Tumor , Cell Proliferation , DEAD-box RNA Helicases/metabolism , DNA-Binding Proteins/metabolism , Female , Humans , Mice , MicroRNAs/genetics , Primary Cell Culture , RNA Nucleotidyltransferases/metabolism , Ribonuclease III/metabolism
10.
J Korean Neurosurg Soc ; 63(1): 26-33, 2020 Jan.
Article in English | MEDLINE | ID: mdl-31592000

ABSTRACT

Glioblastoma (GBM) is a disease without any definite cure. Numerous approaches have been tested in efforts to conquer this brain disease, but patients invariably experience recurrence or develop resistance to treatment. New surgical tools, carefully chosen samples, and experimental methods are enabling discoveries at single-cell resolution. The present article reviews the cell-of-origin of isocitrate dehydrogenase (IDH)-wildtype GBM, beginning with the historical background for focusing on cellular origin and introducing the cancer genesis patterned on firework. The authors also review mutations associated with the senescence process in cells of the subventricular zone (SVZ), and biological validation of somatic mutations in a mouse SVZ model. Understanding GBM would facilitate research on the origin of other cancers and may catalyze the development of new management approaches or treatments against IDH-wildtype GBM.

11.
J Ethnopharmacol ; 190: 219-30, 2016 Aug 22.
Article in English | MEDLINE | ID: mdl-27275774

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Ginsenosides are natural product steroid glycosides and triterpene saponins obtained from the Panax species. Panax ginseng has been widely used as a traditional Chinese medicine (TCM) for around a thousand years, especially in East Asian countries. Ginseng, the root and rhizome of the most popular species P. ginseng, used as tonic, prophylactic agent and restorative. In TCM, ginseng is highly valued herb and has been applied to a variety of pathological conditions and illnesses such as hypodynamia, anorexia, shortness of breath, palpitation, insomnia, impotence, hemorrhage and diabetes. AIM OF THE STUDY: The basic aim of this study was to evaluate the anti-Alzheimer's disease activities of selected ginsenosides (Rb1, Rb2, Rc, Re, Rg1, and Rg3) according to peroxynitrite (ONOO(‒)) scavenging activity and inhibitory activity of ONOO(-)-mediated nitrotyrosine formation as a measure of changes in oxidative stress. In addition, molecular docking simulation studies were performed to predict binding energies of the ginsenosides with ß-site amyloid precursor protein cleaving enzyme 1 (BACE1, ß-secretase) and identify the interacting residues. MATERIALS AND METHODS: In vitro cholinesterase enzyme assays by using acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and BACE1 were performed. In vitro authentic peroxynitrite scavenging activity and inhibitory activity against ONOO(-)-mediated nitrotyrosine formation were also performed. Molecular docking simulation studies were performed with Autodock Vina software and Discovery studio 4.1. RESULTS: In vitro enzyme assays demonstrated that ginsenosides have significant inhibitory potential against AChE, BChE, and BACE1, as well as ONOO(-) and nitrotyrosine formation. Most importantly, significant AChE inhibitory activities were observed for Re; BChE for Rg3; and BACE1 for Rc, with IC50 values of 29.86±3.20, 16.80±0.36, and 59.81±2.74µg/mL, respectively. Among the tested ginsenosides, Rb1 exhibited a higher scavenging activity against ONOO(-) with an IC50 value of 27.86±1.34µg/mL, while Rc and Rg3 exhibited impressive inhibitory activity against the formation of nitrotyrosine. In addition, molecular docking studies revealed potential BACE1 inhibitory activity of ginsenosides, especially Rb1 and Rb2, which exhibited good binding affinities towards BACE1, with docking scores of -10kcal/mol. CONCLUSION: The findings of the present study suggest the potential of ginsenosides (Rb1, Rb2, Rc, Re, Rg1, and Rg3) for use in the development of therapeutic or preventive agents for Alzheimer's disease, especially through inhibition of AChE, BChE and BACE1 activities, as well as scavenging of ONOO(-) and inhibition of nitrotyrosine formation.


Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Ginsenosides/pharmacology , Molecular Docking Simulation , Protease Inhibitors/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/enzymology , Amyloid Precursor Protein Secretases/chemistry , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/chemistry , Aspartic Acid Endopeptidases/metabolism , Binding Sites , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Dose-Response Relationship, Drug , Ginsenosides/chemistry , Ginsenosides/metabolism , Oxidative Stress/drug effects , Peroxynitrous Acid/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protein Binding , Protein Conformation , Structure-Activity Relationship , Tyrosine/analogs & derivatives , Tyrosine/metabolism
12.
Asian Pac J Trop Med ; 9(2): 103-11, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26919937

ABSTRACT

OBJECTIVE: To use structure-activity analysis to study the anti-Alzheimer's disease (anti-AD) activity of natural coumarins isolated from Angelica decursiva and Artemisia capillaris, along with one purchased coumarin (daphnetin). METHODS: Umbelliferone, umbelliferone 6-carboxylic acid, scopoletin, isoscopoletin, 7-methoxy coumarin, scoparone, scopolin, and esculetin have been previously isolated; however 2'-isopropyl psoralene was isolated from Angelica decursiva for the first time to evaluate their inhibitory effects against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) enzyme activity. We scrutinized the potentials of coumarins as cholinesterase and BACE1 inhibitors via enzyme kinetics and molecular docking simulation. RESULTS: Among the test compounds, umbelliferone 6-carboxylic acid, esculetin and daphnetin exhibited potent inhibitory activity against AChE, BChE and BACE1. Both esculetin and daphnetin have a catechol group and exhibit significant anti-AD activity against AChE and BChE. In contrast, presence of a sugar moiety and methoxylation markedly reduced the anti-AD activity of the coumarins investigated in this study. With respect to BACE1 inhibition, umbelliferone 6-carboxylic acid, esculetin and daphnetin contained carboxyl or catechol groups, which significantly contributed to their anti-AD activities. To further investigate these results, we generated a 3D structure of BACE1 using Autodock 4.2 and simulated binding of umbelliferone 6-carboxylic acid, esculetin and daphnetin. Docking simulations showed that different residues of BACE1 interacted with hydroxyl and carboxylic groups, and the binding energies of umbelliferone 6-carboxylic acid, esculetin and daphnetin were negative (-4.58, -6.25 and -6.37 kcal/mol respectively). CONCLUSIONS: Taken together, our results suggest that umbelliferone 6-carboxylic acid, esculetin and daphnetin have anti-AD effects by inhibiting AChE, BChE and BACE1, which might be useful against AD.

13.
Eur J Pharmacol ; 774: 95-104, 2016 Mar 05.
Article in English | MEDLINE | ID: mdl-26849943

ABSTRACT

The present study investigated the neuropathic pain, anti-neuroinflammatory and neuroprotective properties of a pyranocoumarin derivative (anomalin) in in vivo and in vitro models. An in vivo streptozotocin (STZ)-induced diabetic neuropathic pain model demonstrated that anomalin significantly suppressed neuropathic pain in mice. To identify the molecular mechanism of the anti-neuropathic pain activity of anomalin, sodium-nitroprusside (SNP)-induced neuroinflammation in neuro-2a (N2a) cells was further investigated in signaling pathways. The effects of anomalin against SNP-induced toxicity, nitrite production and related mRNA gene expression (iNOS and COX-2) were considerably reduced by anomalin in the SNP-induced N2a cells. In the molecular signaling pathway, anomalin effectively blocked the SNP-induced activation of the IKKα/ß, IκBα, ERK1/2 and p38 MAPK pathways. Furthermore, anomalin remarkably reduced the increase in the SNP-induced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. Additionally, the pro-inflammatory cytokines level was remarkably inhibited by anomalin in high glucose-induced DRG primary neurons and SNP-induced N2a cells. These findings indicate that anomalin has anti-neuropathic pain, anti-neuroinflammatory and neuroprotective effects against STZ-induced diabetic type I neuropathic pain and SNP-induced in neuronal cell models via the inactivation of the NF-κB, Nrf2 and MAPK signaling pathways.


Subject(s)
Antioxidants/chemistry , Antioxidants/pharmacology , Coumarins/chemistry , Coumarins/pharmacology , Neuralgia/drug therapy , Pyranocoumarins/chemistry , Animals , Antioxidants/therapeutic use , Cell Line, Tumor , Cold Temperature/adverse effects , Coumarins/therapeutic use , Cyclooxygenase 2/genetics , Cytokines/metabolism , Diabetes Mellitus, Type 1/complications , Disease Models, Animal , Ganglia, Spinal/drug effects , Ganglia, Spinal/pathology , Gene Expression Regulation, Enzymologic/drug effects , Inflammation/drug therapy , MAP Kinase Signaling System/drug effects , Male , Mice , Mice, Inbred ICR , NF-kappa B/metabolism , Neuralgia/complications , Neuralgia/metabolism , Neuralgia/pathology , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Nitric Oxide/biosynthesis , Nitric Oxide Synthase Type II/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats
14.
Arch Pharm Res ; 39(3): 340-9, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26832324

ABSTRACT

Caffeoylquinic acids, flavonoids, and coumarins isolated from Artemisia capillaris have recently emerged as therapeutic candidates for diabetes and diabetic complications; however, there have been very few studies of the anti-diabetic potential of polyacetylenes. In the present study, we investigated the anti-diabetic potential of two polyacetylenes isolated from A. capillaris, namely capillin and capillinol by investigating their ability to inhibit α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), and rat lens aldose reductase (RLAR). Capillin displayed potent inhibitory activity against α-glucosidase, PTP1B, and RLAR, while capillinol showed moderate inhibitory activity against α-glucosidase and PTP1B at the concentrations tested. In addition, a kinetic study revealed that capillin inhibited α-glucosidase and RLAR in a noncompetitive manner, while inhibited PTP1B in a mixed-type manner. Capillinol inhibited α-glucosidase and PTP1B in a mixed-type manner. Docking simulations of these compounds demonstrated negative binding energies and close proximity to residues in the binding pocket of PTP1B, indicating that these polyacetylenes have a high affinity and tight binding capacity for the active site of the enzyme. Furthermore, capillin dose-dependently inhibited peroxynitrite (ONOO(-))-mediated tyrosine nitration. The results clearly demonstrate the promising potential of capillin and capillinol as therapeutic interventions for the management of diabetes as well as diabetes-associated complications.


Subject(s)
Alkynes/pharmacology , Artemisia/chemistry , Diynes/pharmacology , Hexanols/pharmacology , Aldehyde Reductase/antagonists & inhibitors , Alkynes/isolation & purification , Animals , Diynes/isolation & purification , Glycoside Hydrolase Inhibitors/isolation & purification , Glycoside Hydrolase Inhibitors/pharmacology , Hexanols/isolation & purification , Hypoglycemic Agents/isolation & purification , Hypoglycemic Agents/pharmacology , Lens, Crystalline/enzymology , Molecular Docking Simulation , Peroxynitrous Acid/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Rats
15.
Food Chem Toxicol ; 89: 104-11, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26825629

ABSTRACT

Since the action of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is strongly correlated with the onset of Alzheimer's disease (AD), the development of BACE1 inhibitors as therapeutic agents is being vigorously pursued. In our ongoing research aimed at identifying anti-AD remedies derived from maritime plants, we evaluated the BACE1 inhibitory activities of fucosterol and fucoxanthin from Ecklonia stolonifera and Undaria pinnatifida. In vitro anti-AD activities were performed via BACE1 inhibition assays, as well as enzyme kinetic and molecular docking predictions. Based on enzyme-based assays, fucosterol and fucoxanthin showed noncompetitive and mixed-type inhibition, respectively, against BACE1. In addition, docking simulation results demonstrated that the Lys224 residue of BACE1 interacted with one hydroxyl group of fucosterol, while two additional BACE1 residues (Gly11 and Ala127) interacted with two hydroxyl groups of fucoxanthin. Moreover, the binding energy of fucosterol and fucoxanthin was negative (-10.1 and -7.0 kcal/mol), indicating that hydrogen bonding may stabilize the open form of the enzyme and potentiate tight binding of the active site of BACE1, resulting in more effective BACE1 inhibition. The results suggest that fucosterol and fucoxanthin may be used beneficially in the treatment of AD and provide potential guidelines for the design of new BACE1 inhibitors.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Phaeophyceae/chemistry , Stigmasterol/analogs & derivatives , Xanthophylls/chemistry , Hydrogen Bonding , Kinetics , Molecular Docking Simulation , Stigmasterol/chemistry , Stigmasterol/isolation & purification , Xanthophylls/isolation & purification
16.
J Sci Food Agric ; 96(6): 1856-66, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26455344

ABSTRACT

Seaweeds belong to a group of marine plants known as algae, which are consumed as sea vegetables in several Asian countries. Recent studies have focused on the biological and pharmacological activities of seaweeds and their highly bioactive secondary metabolites because of their potential in the development of new pharmaceutical agents. Although several varieties of bioactive novel compounds such as phlorotannins, diterpenes and polysaccharides from seaweeds have already been well scrutinized, fucosterol as a phytosterol still needs to reinvent itself. Fucosterol (24-ethylidene cholesterol) is a sterol that can be isolated from algae, seaweed and diatoms. Fucosterol exhibits various biological therapeutics, including anticancer, antidiabetic, antioxidant, hepatoprotective, antihyperlipidemic, antifungal, antihistaminic, anticholinergic, antiadipogenic, antiphotodamaging, anti-osteoporotic, blood cholesterol reducing, blood vessel thrombosis preventive and butyrylcholinesterase inhibitory activities. In this review, we address some potential approaches for arbitrating novel fucosterol biologics in the medical field, focusing on the selection of personalized drug candidates and highlighting the challenges and opportunities regarding medical breakthroughs. We also highlight recent advances made in the design of this novel compound, as the significant health benefits from using these optimized applications apply to the nutraceutical and pharmaceutical fields.


Subject(s)
Seaweed/chemistry , Stigmasterol/analogs & derivatives , Aquatic Organisms/chemistry , Humans , Molecular Structure , Stigmasterol/chemistry , Stigmasterol/pharmacology
17.
Arch Pharm Res ; 39(1): 115-26, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26474585

ABSTRACT

Angelica decursiva has long been used in Korean traditional medicine as an antitussive, analgesic, antipyretic, and cough remedy. In this study, the anti-inflammatory activity of 9 coumarin derivatives isolated from a 90 % methanol fraction was evaluated via inhibition of production of nitric oxide (NO) and tumor necrosis factor-α (TNF-α), as well as the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Among the tested compounds, edulisin II (1) exhibited the most potent NO production inhibitory activity, followed by decursidin (2), Pd-C-III (3), 4-hydroxy Pd-C-III (4), Pd-C-I (5), and Pd-C-II (6). In contrast, (+)-trans-decursidinol (7) did not exhibit NO suppressive effects on LPS-stimulated RAW 264.7 cells. Structure-activity relationships revealed that esterification of the hydroxyl at C-3' or C-4' of 7 with an angeloyl/senecioyl/acetyl group is essential for its inhibitory activity against NO production, while the number of angeloyl or senecioyl groups, and their positions greatly affect the potency of these coumarins. Coumarins 1-6 also inhibited TNF-α production and iNOS protein expression, while compounds 1-4 inhibited COX-2 protein expression in LPS-stimulated RAW 264.7 cells. These results suggest that coumarins isolated from A. decursiva might be used as potential leads for the development of therapeutic agents for inflammation-associated disorders.


Subject(s)
Angelica , Coumarins/isolation & purification , Lipopolysaccharides/antagonists & inhibitors , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/biosynthesis , Plant Extracts/isolation & purification , Animals , Coumarins/pharmacology , Lipopolysaccharides/toxicity , Mice , Plant Extracts/pharmacology , RAW 264.7 Cells
18.
Arch Pharm Res ; 38(12): 2153-62, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26119076

ABSTRACT

It has been reported that alkaloids derived from Coptis chinensis exert anti-adipogenic activity on 3T3-L1 adipocytes by downregulating peroxisome proliferation-activity receptor-γ (PPAR-γ) and CCAAT/enhancer binding protein-α (C/EBP-α). However, the signaling-based mechanism of the inhibitory role of epiberberine in the early stages of 3T3-L1 adipocyte differentiation is uncharacterized. Here, we show that epiberberine had inhibitory effects on adipocyte differentiation and significantly decreased lipid accumulation by downregulating an adipocyte-specific transcription factor, sterol regulatory element-binding protein-1 (SREBP-1). Furthermore, we observed that epiberberine markedly suppressed the differentiation-mediated phosphorylation of components of both the Raf/mitogen-activated protein kinase 1 (MEK1)/extracellular signal-regulated protein kinase 1/2 (ERK1/2) and AMP-activated protein kinase-α1 (AMPKα)/Akt pathways. In addition, gene expression of fatty acid synthase (FAS) was significantly inhibited by treatment with epiberberine during adipogenesis. These results indicate that the anti-adipogenic mechanism of epiberberine is associated with inhibition of phosphorylation of Raf/MEK1/ERK1/2 and AMPKα/Akt, followed by downregulation of the major transcription factors of adipogenesis, such as PPAR-γ, C/EBP-α, and SREBP-1, and FAS. Taken together, this study suggests that the anti-adipogenic effect of epiberberine is mediated by downregulation of the Raf/MEK1/ERK1/2 and AMPKα/Akt pathways during 3T3-L1 adipocyte differentiation. Moreover, the anti-adipogenic effects of epiberberine were not accompanied by modulation of ß-catenin.


Subject(s)
AMP-Activated Protein Kinases/physiology , Adipogenesis/physiology , Berberine/analogs & derivatives , MAP Kinase Signaling System/physiology , Mitogen-Activated Protein Kinases/physiology , Oncogene Protein v-akt/physiology , raf Kinases/physiology , 3T3-L1 Cells , AMP-Activated Protein Kinases/antagonists & inhibitors , Adipogenesis/drug effects , Animals , Anti-Obesity Agents/pharmacology , Berberine/pharmacology , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/pharmacology , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 1/physiology , MAP Kinase Kinase 2/antagonists & inhibitors , MAP Kinase Kinase 2/physiology , MAP Kinase Signaling System/drug effects , Mice , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Oncogene Protein v-akt/antagonists & inhibitors , Signal Transduction/drug effects , Signal Transduction/physiology , raf Kinases/antagonists & inhibitors
19.
J Ethnopharmacol ; 171: 28-36, 2015 Aug 02.
Article in English | MEDLINE | ID: mdl-26027757

ABSTRACT

ETHNOPHARMACOLOGIC RELEVANCE: Rhizoma Coptidis (the rhizome of Coptis chinensis Franch) has commonly been used for treatment of diabetes mellitus in traditional Chinese medicine due to its blood sugar-lowering properties and therapeutic benefits which highly related to the alkaloids therein. However, a limited number of studies focused on the Coptis alkaloids other than berberine. MATERIALS AND METHODS: In the present study, we investigated the anti-diabetic potential of Coptis alkaloids, including berberine (1), epiberberine (2), magnoflorine (3), and coptisine (4), by evaluating the ability of these compounds to inhibit protein tyrosine phosphatase 1B (PTP1B), and ONOO(-)-mediated protein tyrosine nitration. We scrutinized the potentials of Coptis alkaloids as PTP1B inhibitors via enzyme kinetics and molecular docking simulation. RESULTS: The Coptis alkaloids 1-4 exhibited remarkable inhibitory activities against PTP1B with the IC50 values of 16.43, 24.19, 28.14, and 51.04 µM, respectively, when compared to the positive control ursolic acid. These alkaloids also suppressed ONOO(-)-mediated tyrosine nitration effectively in a dose dependent manner. In addition, our kinetic study using the Lineweaver-Burk and Dixon plots revealed that 1 and 2 showed a mixed-type inhibition against PTP1B, while 3 and 4 noncompetitively inhibited PTP1B. Moreover, molecular docking simulation of these compounds demonstrated negative binding energies (Autodock 4.0=-6.7 to -7.8 kcal/mol; Fred 2.0=-59.4 to -68.2 kcal/mol) and a high proximity to PTP1B residues, including Phe182 and Asp181 in the WPD loop, Cys215 in the active sites and Tyr46, Arg47, Asp48, Val49, Ser216, Ala217, Gly218, Ile219, Gly220, Arg221 and Gln262 in the pocket site, indicating a higher affinity and tighter binding capacity of these alkaloids for the active site of the enzyme. CONCLUSION: Our results clearly indicate the promising anti-diabetic potential of Coptis alkaloids as inhibitors on PTP1B as well as suppressors of ONOO(-)-mediated protein tyrosine nitration, and thus hold promise as therapeutic agents for the treatment of diabetes and related disease.


Subject(s)
Alkaloids/pharmacology , Coptis , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Alkaloids/isolation & purification , Hypoglycemic Agents/isolation & purification , Hypoglycemic Agents/pharmacology , Molecular Docking Simulation , Peroxynitrous Acid/metabolism , Plant Extracts/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Rhizome/chemistry , Tyrosine/metabolism
20.
J Ethnopharmacol ; 152(3): 478-86, 2014 Mar 28.
Article in English | MEDLINE | ID: mdl-24495472

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia capillaris has widespread traditional and pharmacological applications such as analgesic, anti-inflammatory, anti-pyretic, enhance immunity and anti-tumor activity properties. To evaluate the pharmacological activities of this plant, capillarisin, one of the potent constituent of Artemisia capillaris was studied based on anti-hyperalgesic and anti-allodynic effects with detailed mechanism. It can be assumed that measurement of anti-nociceptive effects of capillarisin is one of the parameter for the evaluation of this herb. Capillarisin has extensive pharmacological properties and has been considered to have promising ant-inflammatory and anti-nociceptive activities. The aim of the current study is to investigate the effect of capillarisin and underlying molecular mechanisms of action in preventing acute and subchronic inflammatory pain. MATERIALS AND METHODS: The inflammatory pain was induced after 40 min or 1h of administration of vehicle, 70% EtOH extract of Artemisia capillaris (100mg/kg) or capillarisin (20 and 80 mg/kg) by intraplantar (i.p.l.) injections of CFA and carrageenan in ICR mice, respectively. Mechanical hyperalgesia and allodynia were evaluated in both acute and subchronic models. Further analysis was performed in CFA-induced mice exploring various molecular and signaling pathways such as NF-κB, AP-1, and ERK-CREB involved in the persistent pain sensations. RESULTS: In acute model, mechanical hyperalgesia and allodynia were evaluated after every 2h until 6h of CFA and after 4h of carrageenan injections. Whereas, in subchronic inflammatory pain model, mechanical hyperalgesia and paw edema were measured after 4h of CFA injection and every day after 4h of daily treatment until 5 days with interval of day four in order to assess the tolerance effect of capillarisin. Further analysis was performed in CFA-induced mice exploring various molecular and signaling pathways such as NF-κB, AP-1 and ERK-CREB involved in the persistent of pain sensations. Pre-treatment of capillarisin strongly inhibited NF-κB mediated genes (iNOS, COX-2), involved in pain. The plasma leading nitrite production was significantly reduced by capillarisin. Moreover, i.p. administration of capillarisin markedly suppressed the adenosine 5׳-triphosphate (ATP) in plasma and substance P in CFA-induced paw tissue. CONCLUSIONS: The present study indicates that capillarisin possessed promising anti-hyperalgesic and anti-allodynic effects through the inhibition of various inflammatory pain signaling, suggesting that capillarisin constitutes a significant component for the treatment of inflammatory pain.


Subject(s)
Artemisia/chemistry , Chromones/pharmacology , Inflammation/drug therapy , Plant Extracts/pharmacology , Analgesics/administration & dosage , Analgesics/isolation & purification , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Carrageenan/toxicity , Chromones/administration & dosage , Chromones/isolation & purification , Disease Models, Animal , Dose-Response Relationship, Drug , Edema/drug therapy , Edema/pathology , Hyperalgesia/drug therapy , Hyperalgesia/pathology , Inflammation/pathology , Male , Mice , Mice, Inbred ICR , Pain/drug therapy , Pain/pathology , Plant Extracts/administration & dosage , Signal Transduction/drug effects
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