179 results on '"Gan LS"'
Search Results
2. Case Studies: Masked read-only memory failure fault isolation without bitmapping
- Author
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Yeoh, BL, primary, Thor, MH, additional, Gan, LS, additional, Goh, SH, additional, Chan, YH, additional, Soh, WF, additional, Shaalini, C., additional, and Naradha, Wiswa, additional
- Published
- 2021
- Full Text
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3. Anti-coronavirus and anti-pulmonary inflammation effects of iridoids, the common component from Chinese herbal medicines for the treatment of COVID-19.
- Author
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Huang DY, Luo YX, Zheng WD, Wu SY, Huang PQ, Jin JW, Wu PP, and Gan LS
- Subjects
- Humans, A549 Cells, HEK293 Cells, COVID-19, Coronavirus 3C Proteases metabolism, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents chemistry, Anti-Inflammatory Agents therapeutic use, Coronavirus OC43, Human drug effects, Iridoids pharmacology, Iridoids chemistry, Antiviral Agents pharmacology, Antiviral Agents chemistry, Drugs, Chinese Herbal pharmacology, Drugs, Chinese Herbal chemistry, Drugs, Chinese Herbal therapeutic use, SARS-CoV-2 drug effects, COVID-19 Drug Treatment, Molecular Docking Simulation
- Abstract
The practice of Chinese herbal medicines for the treatment of COVID-19 in China played an essential role for the control of mortality rate and reduction of recovery time. The iridoids is one of the main constituents of many heat-clearing and detoxifying Chinese medicines that were largely planted and frequently used in clinical practice. Twenty-three representative high content iridoids from several staple Chinese medicines were obtained and tested by a SARS-CoV-2 pseudo-virus entry-inhibition assay on HEK-293 T/ACE2 cells, a live HCoV-OC43 virus infection assay on HRT-18 cells, and a SARS-CoV-2 3CL protease inhibitory FRET assay followed by molecular docking simulation. The anti-pulmonary inflammation activities were further evaluated on a TNF-α induced inflammation model in A549 cells and preliminary SARs were concluded. The results showed that specnuezhenide (7), cornuside (12), neonuezhenide (15), and picroside III (21) exhibited promising antiviral activities, and neonuezhenide (15) could inhibit 3CL protease with an IC
50 of 14.3 μM. Docking computation showed that compound 15 could bind to 3CL protease through a variety of hydrogen bonding and hydrophobic interactions. In the anti-pulmonary inflammation test, cornuside (12), aucubin (16), monotropein (17), and shanzhiside methyl ester (18) could strongly decrease the content of IL-1β and IL-8 at 10 μM. Compound 17 could also upregulate the expression of the anti-inflammatory cytokine IL-10 significantly. The iridoids exhibited both anti-coronavirus and anti-pulmonary inflammation activities for their significance of existence in Chinese herbal medicines, which also provided a theoretical basis for their potential utilization in the pharmaceutical and food industries., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)- Published
- 2024
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4. Isolation, structure modification, and anti-rheumatoid arthritis activity of isopimarane-type diterpenoids from Orthosiphon aristatus .
- Author
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Luo YX, Gong X, Su ZC, Mo JF, Li DL, Wu RH, Jin JW, Lang M, Wang JP, Xu XT, and Gan LS
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- Humans, Abietanes, Tumor Necrosis Factor-alpha, NF-kappa B metabolism, Orthosiphon chemistry, Orthosiphon metabolism, Arthritis, Rheumatoid drug therapy, Diterpenes pharmacology, Diterpenes chemistry
- Abstract
Orthosiphon aristatus is a well-known folkloric medicine and herb for Guangdong soup for the treatment of rheumatism in China. Eight isopimarane-type and migrated pimarane-type diterpenoids ( 1 - 8 ), including a new one with a rarely occurring α,β-unsaturated diketone C-ring, were isolated from O. aristatus . Their structures were determined by spectroscopic methods and quantum chemical calculations. Furthermore, the most abundant compound, orthosiphol K, was structurally modified by modern synthetic techniques to give seven new derivatives ( 9-15 ). The anti-rheumatoid arthritis activity of these diterpenoids were evaluated on a TNF-α induced MH7A human rheumatoid fibroblast-like synoviocyte model. Compound 10 showed the most potent activity among these compounds. Based on their inhibitory effects on the release levels of IL-1β, the preliminary structure-activity relationships were concluded. Furthermore, western blot analysis revealed that 10 could increase the expression of IκBα and decrease the expression of NF-κB p65, and the expression levels of COX-2 and NLRP3 proteins were consequently down-regulated.
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- 2024
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5. [A new benzopyran glycoside from Gentiana macrophylla].
- Author
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Huang PQ, Kang KW, Liao ZB, Wen Y, and Gan LS
- Subjects
- Glycosides pharmacology, Benzopyrans, Glucosides, Gentiana chemistry, Cardiac Glycosides, Ethers
- Abstract
Thirteen compounds were isolated and identified from 70% ethanol extract of the roots of Gentiana macrophylla by multi-chromatographic methods, including microporous resin, silica gel, and C_(18) reversed-phase column chromatography, as well as HPLC as follows: macrophylloside G(1), macrophylloside D(2), 5-formyl-2,3-dihydroisocoumarin(3),(+)-medicarpin(4),(+)-syringaresinol(5), liquiritigenin(6),(3R)-sativanone(7),(3R)-3'-O-methylviolanone(8), 4,2',4'-trihydroxychalcone(9), latifolin(10), gentioxepine(11), 6α-hydroxycyclonerolidol(12), and ethyl linoleate(13). Compound 1 was a new benzopyran glycoside. Compounds 4, 6-10, 12, and 13 were isolated for the first time from Gentiana plants. Compounds 1 and 2 showed promising hepatoprotective activity against D-GalN-induced AML12 cell damage at the concentration of 10 μmol·L~(-1), and compound 2 exhibited more significant activity than silybin at the same concentration.
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- 2024
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6. Lignan glucosides from Gentiana macrophylla with potential anti-arthritis and hepatoprotective activities.
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Huang PQ, Kang KW, Huang DY, Zhao CL, Zheng H, Luo YX, Wen Y, Zou MF, Li DL, Wu RH, Tian YC, Tian Y, Zhang WH, Jin JW, Yin S, and Gan LS
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- Humans, Glucosides pharmacology, Glucosides chemistry, Inflammation, Gentiana chemistry, Lignans pharmacology, Drugs, Chinese Herbal pharmacology
- Abstract
Ten lignans, including six previously undescribed phenolic ester glycosyl lignans (1-6), were isolated from a well-known traditional Chinese medicine, Qin-Jiao, which is the dry root of Gentiana macrophylla Pall. (Gentianaceae). Their structures were determined by spectroscopic and chemical methods, especially 2D NMR techniques. Quantum chemical calculations of theoretical ECD spectra allowed the determination of their absolute configurations. Refer to its traditional applications for the treatment of rheumatic arthralgia and hepatopathy, these compounds were evaluated on a TNF-α induced MH7A human synoviocyte inflammation model and a D-GalN induced AML12 hepatocyte injury model. Compounds 1, 2, 5, and 6 significantly reduced the release of proinflammatory cytokine IL-1β in MH7A cells at 15 μM and they also could strongly protect AML12 cells against D-GalN injury at 30 μM. Flow cytometry and Western blot analysis showed that compound 5 ameliorated D-GalN induced AML12 cell apoptosis by upregulating the expression of anti-apoptotic Bcl-2 protein and down-regulating the expression of pro-apoptotic Bax protein., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Li-She Gan reports financial support was provided by National Natural Science Foundation of China. Li-She Gan reports financial support was provided by Department of Education of Guangdong Province., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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7. Terpenoid Glucosides from Gentiana macrophylla That Attenuate TNF-α Induced Pulmonary Inflammation in A549 Cells.
- Author
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Huang PQ, Luo YX, Zhang YJ, Li ZX, Wen Y, Zhang K, Li DL, Jin JW, Wu RH, and Gan LS
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- Humans, Terpenes pharmacology, Tumor Necrosis Factor-alpha, Glucosides pharmacology, A549 Cells, Cytokines, Plant Extracts pharmacology, Gentiana, Pneumonia
- Abstract
Four previously undescribed terpenoid glucosides, including one sesquiterpenoid di-glucoside ( 1 ), two new iridoid glucosides ( 2 , 3 ), and a new triterpenoid tri-glucoside ( 4 ), were isolated from a 70% ethanol extract of the root of Gentiana macrophylla (Gentianaceae), along with eight known terpenoids. Their structures were determined by spectroscopic techniques, including 1D, 2D NMR, and HRMS (ESI), as well as chemical methods. The absolute configuration of compound 1 was determined by quantum chemical calculation of its theoretical electronic circular dichroism (ECD) spectrum. The sugar moieties of all the new compounds were confirmed to be D-glucose by GC analysis after acid hydrolysis and acetylation. Anti-pulmonary inflammation activity of the iridoids were evaluated on a TNF-α induced inflammation model in A549 cells. Compound 2 could significantly alleviate the release of proinflammatory cytokines IL-1β and IL-8 and increase the expression of anti-inflammatory cytokine IL-10.
- Published
- 2023
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8. Enantiomeric N-acetyldopamine trimers from Cicadae Periostracum and their absolute configurations.
- Author
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Mei F, Nie J, Wen Y, Li Z, Zhang D, Gan LS, Li W, and Guo DA
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- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Nitric Oxide, Dopamine pharmacology, Molecular Structure, Drugs, Chinese Herbal chemistry
- Abstract
Six previously undescribed N-acetyldopamine (NADA) trimmer racemates, percicamides A-F (1-6), were isolated from a 70% ethanol extract of Cicadae Periostracum. Subsequent chiral-phase separation afforded six pairs of enantiomers, (+)- and (-)-percicamides A-F (1a/1b-6a/6b). Their structures including absolute configurations were elucidated by combined extensive spectroscopic data and quantum chemical calculations. Compounds 1-6 represent the first examples of NADA trimmers with a cis-relationship of H-7'/H-8' or H-7''/H-8''. Bioassays verified that all isolated compounds showed weak inhibitory effects on nitric oxide production in RAW 264.7 cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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9. Rare diphenylheptanoid-phenylheptanoid hybrids with α-glucosidase inhibitory effects from the pollen of Typha angustifolia .
- Author
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Wang C, Li YP, Gong X, Gan LS, and Zhang H
- Abstract
Two rarely occurring diphenylheptanoid-phenylheptanoid hybrid dimers ( 1 and 2 ) and one new oxygenated fatty acid ( 3 ), as well as two known fatty acid analogues ( 4 and 5 ), were isolated from the 70% EtOH extract of the pollen of Typha angustifolia . Their planar structures were established by interpretation of MS and NMR spectroscopic data, and the absolute configurations of 1 and 2 were determined by Mosher's method and quantum chemical TD-DFT calculations of ECD spectra. An in vitro anti-diabetic evaluation of these isolates revealed that compounds 1 and 2 exhibited promising inhibitory activity against α-glucosidase with IC
50 values of 11.85 ± 0.69 and 17.06 ± 3.08 μM, respectively. It is the first report on both diphenylheptanoid constituents and α-glucosidase inhibitors from the title plant, which represents a significant phytochemical progress of this herbal species and may serve as a reference for its future medicinal applications.- Published
- 2023
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10. Cerebellar Brain Inhibition Is Associated With the Severity of Cervical Dystonia.
- Author
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Sondergaard RE, Strzalkowski NDJ, Gan LS, Jasaui Y, Furtado S, Pringsheim TM, Sarna JR, Avanzino L, Kiss ZHT, and Martino D
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- Humans, Brain, Cerebellum physiology, Transcranial Magnetic Stimulation methods, Muscle, Skeletal, Evoked Potentials, Motor physiology, Neural Inhibition physiology, Torticollis
- Abstract
Purpose: Cerebellar connectivity is thought to be abnormal in cervical dystonia (CD) and other dystonia subtypes, based on evidence from imaging studies and animal work. The authors investigated whether transcranial magnetic stimulation-induced cerebellar brain inhibition (CBI), a measure of cerebellar efficiency at inhibiting motor outflow, is abnormal in patients with CD and/or is associated with clinical features of CD. Because of methodological heterogeneity in CBI reporting, the authors deployed additional controls to reduce potential sources of variability in this study., Methods: Cerebellar brain inhibition was applied in 20 CD patients and 14 healthy control subjects. Cerebellar brain inhibition consisted of a cerebellar conditioning stimulus delivered at four different interstimulus intervals (ISIs) before a test stimulus delivered to hand muscle representation in the motor cortex. The average ratio of conditioned to unconditioned motor evoked potential was computed for each ISI. Cervical dystonia clinical severity was measured using the Toronto Western Spasmodic Torticollis Rating Scale. Control experiments involved neuronavigated transcranial magnetic stimulation, neck postural control in patients, and careful screening for noncerebellar pathway inhibition via cervicomedullary evoked potentials., Results: There was no difference between CBI measured in healthy control subjects and CD patients at any of the four ISIs; however, CBI efficiency was significantly correlated with worsening CD clinical severity at the 5 ms ISI., Conclusions: Cerebellar brain inhibition is a variable measure in both healthy control subjects and CD patients; much of this variability may be attributed to experimental methodology. Yet, CD severity is significantly associated with reduced CBI at the 5 ms ISI, suggestive of cerebello-thalamo-cortical tract dysfunction in this disorder., Competing Interests: R. E. Sondergaard holds a Natural Sciences and Engineering Research Council of Canada (NSERC) studentship and N. D. J. Strzalkowski held University of Calgary Eyes High, Parkinson Alberta and Parkinson Foundation postdoctoral fellowships. Funding was also provided by NSERC (RGPIN/04126-2017) to Z. H. T. Kiss and Dystonia Medical Research Foundation of Canada grant (Z.H.T.K. and D.M.). The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 by the American Clinical Neurophysiology Society.)
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- 2023
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11. Six pairs of phenylpropanoid enantiomers from Cinnamomum mollifolium.
- Author
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Wen Y, Rao L, Xu F, Li Y, Luo YX, Gong X, Wu RH, Zhang CR, and Gan LS
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- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Benzoates, Circular Dichroism, Stereoisomerism, Cinnamomum
- Abstract
Six pairs of undescribed phenylglycerol benzoate enantiomers, (±)-mollifolines A-F, which can also be categorized into three two-pairs of epimers, were isolated from Cinnamomum mollifolium H. W. Li (Lauraceae). The relative configurations (threo or erythro) of the epimers were determined by conformational searching of the lowest energy conformers and analyses of the relationship between the dihedral angle of H-7'─C-7'─C-8'─H-8' and the
3 JH-7', H-8' coupling constant according to the Karplus equation. Furthermore, intramolecular hydrogen bonds were proved to play an important role in stabilizing the lowest conformations by using reduced density gradient (RDG) method for noncovalent interactions. Chiral resolutions of these enantiomer pairs were accomplished by immobilized polysaccharide derivative-based chiral HPLC columns. Absolute configurations of the 12 optically pure isomers were finally determined by quantum chemical time-dependent density functional theory (TDDFT) calculations of their electronic circular dichroism (ECD) spectra., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Li-She Gan reports financial support was provided by National Natural Science Foundation of China. Li-She Gan reports financial support was provided by Department of Education of Guangdong Province. Li-She Gan reports financial support was provided by Jiangmen Program for Innovative Research Team. Chuan-Rui Zhang reports financial support was provided by China Pharmaceutical University State Key Laboratory Of Natural Medicines., (Copyright © 2022. Published by Elsevier Ltd.)- Published
- 2022
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12. Robotic mapping of motor cortex in children with perinatal stroke and hemiparesis.
- Author
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Kuo HC, Zewdie E, Giuffre A, Gan LS, Carlson HL, Wrightson J, and Kirton A
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- Adolescent, Child, Evoked Potentials, Motor physiology, Humans, Paresis etiology, Transcranial Magnetic Stimulation, Cerebral Palsy, Motor Cortex physiology, Robotic Surgical Procedures, Stroke complications, Stroke diagnostic imaging, Stroke Rehabilitation
- Abstract
Brain stimulation combined with intensive therapy may improve hand function in children with perinatal stroke-induced unilateral cerebral palsy (UCP). However, response to therapy varies and underlying neuroplasticity mechanisms remain unclear. Here, we aimed to characterize robotic motor mapping outcomes in children with UCP. Twenty-nine children with perinatal stroke and UCP (median age 11 ± 2 years) were compared to 24 typically developing controls (TDC). Robotic, neuronavigated transcranial magnetic stimulation was employed to define bilateral motor maps including area, volume, and peak motor evoked potential (MEP). Map outcomes were compared to the primary clinical outcome of the Jebsen-Taylor Test of Hand Function (JTT). Maps were reliably obtained in the contralesional motor cortex (24/29) but challenging in the lesioned hemisphere (5/29). Within the contralesional M1 of participants with UCP, area and peak MEP amplitude of the unaffected map were larger than the affected map. When comparing bilateral maps within the contralesional M1 in children with UCP to that of TDC, only peak MEP amplitudes were different, being smaller for the affected hand as compared to TDC. We observed correlations between the unaffected map when stimulating the contralesional M1 and function of the unaffected hand. Robotic motor mapping can characterize motor cortex neurophysiology in children with perinatal stroke. Map area and peak MEP amplitude may represent discrete biomarkers of developmental plasticity in the contralesional M1. Correlations between map metrics and hand function suggest clinical relevance and utility in studies of interventional plasticity., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)
- Published
- 2022
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13. (±)-Heterocageflavone, anti-inflammatory isoprenylated flavonoids with a tricyclo[5.3.1.0 3,8 ]undecane moiety from Artocarpus heterophyllus.
- Author
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Ren G, Gan LS, Zhu LZ, Zeng HT, Xu F, and Yuan T
- Subjects
- Alkanes, Anti-Inflammatory Agents pharmacology, Flavonoids chemistry, Flavonoids pharmacology, Artocarpus chemistry
- Abstract
(±)-Heterocageflavone (1), a pair of enantiomeric isoprenylated flavonoids, were isolated from Artocarpus heterophyllus. Compound 1 incorporates an unusual tricyclo[5.3.1.0
3,8 ]undecane moiety, forming a unique caged polycyclic system. The structures of the pair were determined by spectroscopic analysis, ECD calculations, and single-crystal X-ray diffraction. Compound 1 showed significant inhibitory activity against LPS-induced NO production in RAW264.7 cells with an IC50 value of 49.2 μM., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2022
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14. α-Pyrones with glucose uptake-stimulatory activity from the twigs of Cryptocarya wrayi.
- Author
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Wang XN, Kuang XD, Wang Y, Sun P, He XR, Peng YA, Liu LH, Gu JL, Gan LS, Wang XN, Shu JC, and Zhou ZW
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- Glucose, Molecular Structure, Pyrones pharmacology, Cryptocarya chemistry
- Abstract
Five new α-pyrones, cryptowratones A-E (1-5), and five known congeners (6-10), together with four other known compounds 11-14 were isolated from the twigs of Cryptocarya wrayi. The structures of the new compounds were elucidated on the basis of extensive spectroscopic data analysis and ECD calculations. All α-pyrones except 6 were evaluated for their stimulatory effects on glucose uptake in vitro with CHO-K1/GLUT4 cells. The positive control insulin displayed an approximate 42 ± 0.14% promotion on glucose uptake at 25 μM, compared with the CHO-K1/GLUT4 group. Compounds 1a/2a, 2, 3, and 10 showed a more significant stimulation of glucose uptake than insulin (25 μM) by 36 ± 0.08%, 27 ± 0.12%, 28 ± 0.12%, and 25 ± 0.12% at 1.5 μM, respectively. Immunofluorescence assays indicated the glucose uptake-stimulatory activity of α-pyrones might be correlated with increased GLUT4 translocation., (Copyright © 2021. Published by Elsevier B.V.)
- Published
- 2022
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15. Two new isoquinoline alkaloids from Cryptocarya wrayi and their biological activities.
- Author
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Liu YL, Wang Y, He XR, Gan LS, Xu F, Xu YJ, Wang XN, Shen T, and Zhou ZW
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- Alkaloids chemistry, Alkaloids metabolism, Glucosidases antagonists & inhibitors, Glycoside Hydrolase Inhibitors chemistry, Glycoside Hydrolase Inhibitors isolation & purification, Glycoside Hydrolase Inhibitors metabolism, Inhibitory Concentration 50, Isoquinolines chemistry, Isoquinolines metabolism, Magnetic Resonance Spectroscopy, Molecular Structure, NAD(P)H Dehydrogenase (Quinone) analysis, Optical Rotation, Alkaloids isolation & purification, Cryptocarya chemistry, Isoquinolines isolation & purification
- Abstract
Two new isoquinoline alkaloids, cryptowrayines A (1) and B (2), along with one known pavine alkaloid (-)-12-hydroxyeschscholtzidine (3), were isolated from the twigs of Cryptocarya wrayi. The structures of new compounds were elucidated by extensive spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Both compounds 1 and 2 exhibited moderate quinone reductase inducing activity in Hepa 1c1c7 cells., (Copyright © 2021. Published by Elsevier B.V.)
- Published
- 2022
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16. A Cryptic Plant Terpene Cyclase Producing Unconventional 18- and 14-Membered Macrocyclic C 25 and C 20 Terpenoids with Immunosuppressive Activity.
- Author
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Chen YG, Li DS, Ling Y, Liu YC, Zuo ZL, Gan LS, Luo SH, Hua J, Chen DY, Xu F, Li M, Guo K, Liu Y, Gershenzon J, and Li SH
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- Humans, Immunosuppressive Agents chemistry, Immunosuppressive Agents metabolism, Interferon-gamma biosynthesis, Interleukin-2 biosynthesis, Lamiaceae chemistry, Lamiaceae metabolism, Macrocyclic Compounds chemistry, Macrocyclic Compounds metabolism, Molecular Structure, T-Lymphocytes drug effects, T-Lymphocytes metabolism, Terpenes chemistry, Terpenes metabolism, Alkyl and Aryl Transferases metabolism, Immunosuppressive Agents pharmacology, Interferon-gamma antagonists & inhibitors, Interleukin-2 antagonists & inhibitors, Macrocyclic Compounds pharmacology, Terpenes pharmacology
- Abstract
A versatile terpene synthase (LcTPS2) producing unconventional macrocyclic terpenoids was characterized from Leucosceptrum canum. Engineered Escherichia coli and Nicotiana benthamiana expressing LcTPS2 produced six 18-/14-membered sesterterpenoids including five new ones and two 14-membered diterpenoids. These products represent the first macrocyclic sesterterpenoids from plants and the largest sesterterpenoid ring system identified to date. Two variants F516A and F516G producing approximately 3.3- and 2.5-fold, respectively, more sesterterpenoids than the wild-type enzyme were engineered. Both 18- and 14-membered ring sesterterpenoids displayed significant inhibitory activity on the IL-2 and IFN-γ production of T cells probably via inhibition of the MAPK pathway. The findings will contribute to the development of efficient biocatalysts to create bioactive macrocyclic sesterterpenoids, and also herald a new potential in the well-trodden territory of plant terpenoid biosynthesis., (© 2021 Wiley-VCH GmbH.)
- Published
- 2021
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17. Discovery of a Potential Liver Fibrosis Inhibitor from a Mushroom Endophytic Fungus by Genome Mining of a Silent Biosynthetic Gene Cluster.
- Author
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Cheng JT, Wang HM, Yu JH, Sun CF, Cao F, Jiang XH, Chen XA, Zhao QW, Gan LS, Xie RR, Wang SL, Li J, Zang Y, and Mao XM
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- Humans, Liver Cirrhosis genetics, Multigene Family, Agaricales genetics, Hypocreales genetics
- Abstract
Liver fibrosis has accounted for liver diseases and overall mortality, but no relevant drug has been developed. Filamentous fungi are important resources of natural products for pharmaceutical development. Calcarisporium arbuscula is a mushroom endophytic fungus, which primarily produces aurovertins. Here, in an aurovertin null-production mutant, one silent gene cluster ( mca17 ) was activated by overexpression of a pathway-specific zinc finger transcriptional regulator, and a tetramic acid-type compound ( 1 , MCA17-1) was identified. Along with detailed structural characterization, its biosynthesis was proposed to be produced from the core PKS-NRPS hybrid enzyme. Moreover, 1 suppressed the activation of LX-2 upon transforming growth factor-β (TGF-β) challenge and had stronger bioactivity than the positive control obeticholic acid (OCA) against liver fibrosis. Our work suggested that this engineered fungus could be a producer of 1 for promising pharmaceutical development, and alternatively, it would be developed as a mushroom ingredient in dietary therapy to prevent liver fibrosis.
- Published
- 2021
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18. [A new phenylethanol glycoside from Baphicacanthis Cusiae Rhizoma et Radix].
- Author
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Xu F, Zhou CX, Mo JX, and Gan LS
- Subjects
- Flavonoids, Glycosides, Molecular Structure, Rhizome, Cardiac Glycosides, Phenylethyl Alcohol
- Abstract
The 95% ethanol extract of Baphicacanthis Cusiae Rhizoma et Radix was purified by multi-chromatographic methods including microporous resin, silica gel, Sephadex LH-20, and C_(18) reversed-phase column chromatography. Fourteen compounds were isolated and structurally identified, including five phenylethanoid glycosides, five phenylpropanoids, one lupinane triterpene, two alkaloids, and one flavonoid, listed as follows: 2-(4-hydroxy-3-methoxyphenyl)-3-(2-hydroxy-5-methoxyphenyl)-3-oxo-1-propanol B(1), threo-2,3-bis-(4-hydroxy-3-methoxybenzene)-3-methoxypropanol(2), 2-(3-hydroxy-4-methoxyphenyl)-ethanol-1-O-[3,4-O-di-acetyl-(1→3)-O-α-L-rhamnopyranosyl]-β-D-glucopyranoside(3), verbascoside(4), 2″,3″-di-O-acetyl martynoside(5),(+)-pinore-sinol(6), diospyrosin(7), daidzein(8), wiedemannioside B(9), buddlenol A(10), 2″-O-acetyl martyonside(11), lupeol(12), indirubin(13), and tryptanthrin(14). Compound 3 was a new phenylethanoid glycoside, and the other 10 compounds were isolated for the first time from Baphicacanthis Cusiae Rhizoma et Radix except compounds 12, 13, and 14.
- Published
- 2021
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19. Horienoids A and B, Two Heterocoupled Sesquiterpenoid Dimers from Hedyosmum orientale .
- Author
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Fan YY, Gan LS, Chen SX, Gong Q, Zhang HY, and Yue JM
- Subjects
- Sesquiterpenes pharmacology
- Abstract
Two eudesmane-guaiane/lindenane heterocoupled sesquiterpenoid dimers, horienoids A ( 1 ) and B ( 2 ) with new carbon skeletons, from Hedyosmum orientale were characterized by a combined method. Compound 1 featured a unique 2,10-dioxabicyclo[6.2.1]undecane core moiety with an anti-Bredt bridgehead double bond. Their biogenetic pathways were proposed to involve Diels-Alder and cascade rearrangement reactions as the key steps. Compound 2 exhibited a potent anti-inflammatory effect on LPS-induced BV-2 microglial cells.
- Published
- 2021
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20. Pseudosterins A-C, Three 1-Ethyl-3-formyl-β-carbolines from Pseudostellaria heterophylla and Their Cardioprotective Effects.
- Author
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Xu GB, Zhu QF, Wang Z, Zhang CL, Yang X, Zhang JJ, Wang FR, Liu J, Zhou M, Wang YL, He X, Gan LS, and Liao SG
- Subjects
- Alkaloids chemistry, Animals, Carbolines chemistry, Cardiotonic Agents chemistry, Cell Line, China, Glycosides chemistry, Glycosides pharmacology, Hypoxia drug therapy, Plant Extracts chemistry, Plant Roots chemistry, Rats, Alkaloids pharmacology, Carbolines pharmacology, Cardiotonic Agents pharmacology, Caryophyllaceae chemistry, Plant Extracts pharmacology
- Abstract
Pseudostellaria heterophylla is used in China not only as a functional food but also as an herb to tonify the spleen, enhance immunity, and treat palpitation. Our previous investigation showed that a fraction enriched in glycosides obtained from the roots of P. heterophylla possessed pronounced protective effects on H9c2 cells against CoCl
2 -induced hypoxic injury. However, the active compounds responsible for the observed effects were still unknown. In the current investigation, pseudosterins A-C ( 1 - 3 ), three new alkaloids with a 1-ethyl-3-formyl-β-carboline skeleton, together with polydatin, have been isolated from the active fraction. Their structures were elucidated on the basis of spectroscopic analysis and quantum chemical calculations. The four compounds showed cardioprotective effects against sodium hydrosulfite-induced hypoxia-reoxygenation injury in H9c2 cells, with the three alkaloids being more potent. This is also the first report of alkaloids with a β-carboline skeleton isolated from P. heterophylla as cardioprotective agents.- Published
- 2021
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21. Structural Elucidation of Three 9,11- Seco Tetracyclic Triterpenoids Enables the Structural Revision of Euphorol J.
- Author
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Yuan FY, Xu F, Fan RZ, Li W, Huang D, Tang GH, Yuan T, Gan LS, and Yin S
- Subjects
- Crystallography, X-Ray, Molecular Structure, Steroids, Euphorbia, Triterpenes pharmacology
- Abstract
Compounds 1 - 3 , the rare examples of 9,11- seco euphane or lanostane triterpenoids featuring an enol-hemiacetal functionality, were isolated from Euphorbia stracheyi . Their structures were elucidated by a combination of spectroscopic, computational, chemical, and single-crystal X-ray diffraction means, which enables the structure of previously published euphorol J to be revised as 1 . 1 - 3 showed significant cytotoxicities on the breast cancer cell line MDA-MB-468 with IC
50 values in the range of 2.9-3.9 μM.- Published
- 2021
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22. An Efficient Regioselective Synthesis of 8-Formylhomoisoflavonoids with Neuroprotective Activity by Enhancing Autophagy.
- Author
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Li J, Yang F, Zeng LW, Zhang FM, Zhou CX, and Gan LS
- Subjects
- Cell Line, Tumor, Humans, Isoflavones chemical synthesis, Molecular Docking Simulation, Molecular Structure, Ophiopogon chemistry, Autophagy drug effects, Isoflavones pharmacology, Neuroprotective Agents pharmacology, Signal Transduction drug effects
- Abstract
6-Formylisoophiopogonone B ( 7a ) and 8-formylophiopogonone B ( 7b ), two natural products isolated from Ophiopogon japonicus , represent a subgroup of rare 6/8-formyl/methyl-homoisoflavonoid skeletons. Herein we report an efficient method for the synthesis of these formyl/methyl-homoisoflavonoids. The synthesized compounds were evaluated for their neuroprotective effects on the MPP
+ -induced SH-SY5Y cell injury model and showed marked activity. Exploration of the neuroprotective mechanisms of compound 7b led to an increased expression of autophagy marker LC3-II and down-regulation of autophagy substrate p62/SQSTM1. Molecular docking studies showed that 7b may prevent the inhibition of the classic PI3K-AKT-mTOR signaling pathway by interfering with the human HSP90AA1.- Published
- 2021
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23. A Cell Factory of a Fungicolous Fungus Calcarisporium arbuscula for Efficient Production of Natural Products.
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Cheng JT, Yu JH, Sun CF, Cao F, Ying YM, Zhan ZJ, Li WJ, Chen XA, Zhao QW, Li YQ, Gan LS, and Mao XM
- Subjects
- Aspergillus genetics, Hypocreales genetics, Multigene Family genetics, Multigene Family physiology, Penicillium genetics, Biological Products metabolism, Hypocreales metabolism
- Abstract
Fungal natural products are rich sources of clinical drugs. Particularly, the fungicolous fungi have a large number of biosynthetic gene clusters (BGCs) to produce numerous bioactive natural products, but most BGCs are silent in the laboratory. We have shown that a fungicolous fungus Calcarisporium arbuscula NRRL 3705 predominantly produces the highly reduced polyketide-type mycotoxins aurovertins. Here after evaluation of the aurovertin-null mutant ΔaurA as an efficient host, we further screened two strong promoters aurBp and A07068p based on RNA-Seq, and successfully activated an endogenous gene cluster from C. arbuscula as well as three additional exogenous BGCs from other fungi to produce polyketide-type natural products. Thus, we showed an efficient expression system from the fungicolous fungus C. arbuscula , which will be highly beneficial and complementary to the conventional Aspergillus and Penicillium fungal cell factories, and provides a useful toolkit for genome-wide mining of bioactive natural products from fungicolous fungi.
- Published
- 2021
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24. Theta-Burst Stimulation for Cognitive Enhancement in Parkinson's Disease With Mild Cognitive Impairment: A Randomized, Double-Blind, Sham-Controlled Trial.
- Author
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Lang S, Gan LS, Yoon EJ, Hanganu A, Kibreab M, Cheetham J, Hammer T, Kathol I, Sarna J, Martino D, and Monchi O
- Abstract
Background: Mild cognitive impairment is a common non-motor symptom of Parkinson's disease (PD-MCI) and has minimal treatment options. Objective: In this double-blind, randomized, sham-controlled trial, we assessed the effect of repeated sessions of intermittent theta-burst stimulation over the left dorsolateral prefrontal cortex on cognition and brain connectivity in subjects with PD-MCI. Methods: Forty-one subjects were randomized to receive real ( n = 21) or sham stimulation ( n = 20). All subjects underwent neuropsychological assessments before, 1 day, and 1 month after stimulation. Subjects also underwent resting-state functional magnetic resonance imaging before and 48 h after stimulation. The primary outcome was the change in the cognitive domain (executive function, attention, memory, language, and visuospatial abilities) z-scores across time. Results: There was an insignificant effect on cognitive domain z-scores across time when comparing real with sham stimulation and correcting for multiple comparisons across cognitive domains ( p > 0.05 Bonferroni correction). However, the real stimulation group demonstrated a trend toward improved executive functioning scores at the 1-month follow-up compared with sham ( p < 0.05 uncorrected). After real stimulation, the connectivity of the stimulation site showed decreased connectivity to the left caudate head. There was no change in connectivity within or between the stimulation network (a network of cortical regions connected to the stimulation site) and the striatal network. However, higher baseline connectivity between the stimulation network and the striatal network was associated with improved executive function scores at 1 month. Conclusions: These results suggest that intermittent theta-burst stimulation over the dorsolateral prefrontal cortex in subjects with PD-MCI has minimal effect on cognition compared with sham, although there were trends toward improved executive function. This intervention may be more effective in subjects with higher baseline connectivity between the stimulation network and the striatal network. This trial supports further investigation focusing on executive function and incorporating connectivity-based targeting. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03243214., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Lang, Gan, Yoon, Hanganu, Kibreab, Cheetham, Hammer, Kathol, Sarna, Martino and Monchi.)
- Published
- 2020
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25. Impact of Peritumoral Edema During Tumor Treatment Field Therapy: A Computational Modelling Study.
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Lang ST, Gan LS, McLennan C, Monchi O, and Kelly JJP
- Subjects
- Edema therapy, Electrodes, Head, Humans, Brain Neoplasms therapy, Electric Stimulation Therapy, Glioblastoma complications, Glioblastoma therapy
- Abstract
Background: Tumor treatment fields (TTFie-lds) are an approved adjuvant therapy for glioblastoma (GBM). The magnitude of applied electrical field has been shown to be related to the anti-tumoral response. However, peritumoral edema may result in shunting of electrical current around the tumor, thereby reducing the intra-tumoral electric field. In this study, we systematically address this issue with computational simulations., Methods: Finite element models are created of a human head with varying amounts of peritumoral edema surrounding a virtual tumor. The electric field distribution was simulated using the standard TTFields electrode montage. Electric field magnitude was extracted from the tumor and related to edema thickness. Two patient specific models were created to confirm these results., Results: The inclusion of peritumoral edema decreased the average magnitude of the electric field within the tumor. In the model considering a frontal tumor and an anterior-posterior electrode configuration, ≥6 mm of peritumoral edema decreased the electric field by 52%. In the patient specific models, peritumoral edema decreased the electric field magnitude within the tumor by an average of 26%. The effect of peritumoral edema on the electric field distribution was spatially heterogenous, being most significant at the tissue interface between edema and tumor., Conclusions: The inclusion of peritumoral edema during TTFields modelling may have a dramatic effect on the predicted electric field magnitude within the tumor. Given the importance of electric field magnitude for the anti-tumoral effects of TTFields, the presence of edema should be considered both in future modelling studies and when planning TTField therapy.
- Published
- 2020
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26. Preoperative Transcranial Direct Current Stimulation in Glioma Patients: A Proof of Concept Pilot Study.
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Lang S, Gan LS, McLennan C, Kirton A, Monchi O, and Kelly JJP
- Abstract
Background: Transcranial direct current stimulation (tDCS) has been used extensively in patient populations to facilitate motor network plasticity. However, it has not been studied in patients with brain tumors. We aimed to determine the feasibility of a preoperative motor training and tDCS intervention in patients with glioma. In an exploratory manner, we assessed changes in motor network connectivity following this intervention and related these changes to predicted electrical field strength from the stimulated motor cortex. Methods: Patients with left-sided glioma (n=8) were recruited in an open label proof of concept pilot trial and participated in four consecutive days of motor training combined with tDCS. The motor training consisted of a 60-min period where the subject learned to play the piano with their right hand. Concurrently, they received 40 min of 2 mA anodal tDCS of the left motor cortex. Patients underwent task and resting state fMRI before and after this intervention. Changes in both the connectivity of primary motor cortex (M1) and general connectivity across the brain were assessed. Patient specific finite element models were created and the predicted electrical field (EF) resulting from stimulation was computed. The magnitude of the EF was extracted from left M1 and correlated to the observed changes in functional connectivity. Results: There were no adverse events and all subjects successfully completed the study protocol. Left M1 increased both local and global connectivity. Voxel-wide measures, not constrained by a specific region, revealed increased global connectivity of the frontal pole and decreased global connectivity of the supplementary motor area. The magnitude of EF applied to the left M1 correlated with changes in global connectivity of the right M1. Conclusion: In this proof of concept pilot study, we demonstrate for the first time that tDCS appears to be feasible in glioma patients. In our exploratory analysis, we show preoperative motor training combined with tDCS may alter sensorimotor network connectivity. Patient specific modeling of EF in the presence of tumor may contribute to understanding the dose-response relationship of this intervention. Overall, this suggests the possibility of modulating neural networks in glioma patients., (Copyright © 2020 Lang, Gan, McLennan, Kirton, Monchi and Kelly.)
- Published
- 2020
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27. Acid/Base-Tunable Unimolecular Chirality Switching of a Pillar[5]azacrown Pseudo [1]Catenane.
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Liang H, Hua B, Xu F, Gan LS, Shao L, and Huang F
- Abstract
Stimuli-responsive unimolecular chirality switching is a highly intriguing topic because the molecular structure as well as its function can be adjusted simultaneously by a switching process. Herein, a novel acid/base-tunable unimolecular chirality switching system based on a pillar[5]azacrown pseudo [1]catenane is reported. The bicyclic pillar[5]azacrown pseudo [1]catenane PN4 is synthesized through fusing an azacrown ring onto one repeating unit of a pillar[5]arene. Protonation and deprotonation can reversibly regulate the conformational transformations of PN4 between self-inclusion and self-exclusion structures, which results in the chiroptical inversions of the pseudo [1]catenane. NMR spectra, circular dichroism spectra, and single-crystal structures demonstrate these processes. This pseudo [1]catenane is a novel pillararene-based unimolecular chirality switching system driven by acid/base responsiveness and reveals a new perspective on the supramolecular chirality chemistry of macrocycles.
- Published
- 2020
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28. Case studies in neuroscience: deep brain stimulation changes upper limb cortical motor maps in dystonia.
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Strzalkowski NDJ, Sondergaard RE, Gan LS, and Kiss ZHT
- Subjects
- Brain Mapping, Female, Globus Pallidus, Humans, Middle Aged, Neurosciences, Torticollis physiopathology, Torticollis therapy, Transcranial Magnetic Stimulation, Deep Brain Stimulation, Motor Cortex physiopathology, Muscle, Skeletal physiopathology, Tremor physiopathology, Tremor therapy, Upper Extremity physiopathology
- Abstract
Deep brain stimulation of the globus pallidus pars interna (GPi-DBS) is an effective treatment for primary dystonia; however, its therapeutic mechanism is poorly understood. Because improvement is gradual, GPi-DBS treatment likely involves short- and long-term mechanisms. Abnormal plasticity resulting in somatotopic reorganization is involved in the development of dystonia and has been proposed as a possible mechanism for this gradual improvement, yet it has not been directly investigated. We hypothesized that GPi-DBS will lead to progressive changes in the cortical representations (motor maps) of upper limb muscles. Neuronavigated robotic transcranial magnetic stimulation was used to map the cortical representation of five upper limb muscles in six healthy controls and a 45-yr-old female cervical dystonia patient before (Pre) and at four time points (Post5 to Post314), 5 to 314 days after GPi-DBS. Motor map area and volume decreased in all muscles following GPi-DBS, while changes in overlap and center of gravity distance between muscles were variable. Despite these motor map changes, only dystonic tremor improved after a year of DBS; neck position worsened slightly. These preliminary findings suggest that GPi-DBS may reduce the cortical representation and excitability of upper limb muscles in dystonia and that these changes can occur without clinical improvement. NEW & NOTEWORTHY Neuronavigated robotic transcranial magnetic stimulation was used to investigate changes in upper limb muscle representation in a cervical dystonia patient before and at four time points up to 314 days after globus pallidus pars interna deep brain stimulation (GPi-DBS). GPi-DBS altered excitability and motor cortical representation of upper limb muscles; however, these changes were not associated with clinical improvement.
- Published
- 2020
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29. Classification of Flavonoid Metabolomes via Data Mining and Quantification of Hydroxyl NMR Signals.
- Author
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Yu Y, Pauli GF, Huang L, Gan LS, van Breemen RB, Li D, McAlpine JB, Lankin DC, and Chen SN
- Subjects
- Magnetic Resonance Spectroscopy, Molecular Structure, Data Mining, Flavonoids analysis, Flavonoids metabolism, Hydroxides chemistry
- Abstract
Utilizing the distinct HMBC cross-peak patterns of l ower- f ield r ange (LFR; 11.80-14.20 ppm) hydroxyl singlets, presented NMR methodology characterizes flavonoid metabolomes both qualitatively and quantitatively. It enables simultaneous classification of the structural types of 5-OH flavonoids and biogenetically related 2'-OH chalcones, as well as quantification of individual metabolites from
1 H NMR spectra, even in complex mixtures. Initially, metabolite-specific LFR 1D1 H and 2D HMBC patterns were established via literature mining and experimental data interpretation, demonstrating that LFR HMBC patterns encode the different structural types of 5-OH flavonoids/2'-OH chalcones. Taking advantage of the simplistic multiplicity of the H,H-uncoupled LFR 5-/2'-OH singlets, individual metabolites could subsequently be quantified by peak fitting quantitative1 H NMR (PF-qHNMR). Metabolomic analysis of enriched fractions from three medicinal licorice ( Glycyrrhiza ) species established proof-of-concept for distinguishing three major structural types and eight subtypes in biomedical applications. The method identified 15 G. uralensis (GU) phenols from the six possible subtypes of 5,7-diOH (iso)flav(an)ones with 6-, 8-, and nonprenyl substitution, including the new 6-prenyl-licoisoflavanone ( 1 ) and two previously unknown compounds ( 4 and 7 ). Relative (100%) qNMR established quantitative metabolome patterns suitable for species discrimination and plant metabolite studies. Absolute qNMR with combined external and internal (solvent) calibration (ECIC) identified and quantified 158 GU metabolites. HMBC-supported qHNMR analysis of flavonoid metabolomes ("flavonomics") empowers the exploration of structure-abundance-activity relationships of designated bioactivity. Its ability to identify and quantify numerous metabolites simultaneously and without identical reference materials opens new avenues for natural product discovery and botanical quality control and can be adopted to other flavonoid- and chalcone-containing taxa.- Published
- 2020
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30. Daphnillonins A and B: Alkaloids Representing Two Unknown Carbon Skeletons from Daphniphyllum longeracemosum .
- Author
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Zhang DD, Xu JB, Fan YY, Gan LS, Zhang H, and Yue JM
- Subjects
- Carbon, Molecular Structure, Skeleton, Alkaloids, Daphniphyllum
- Abstract
Two highly rearranged daphniphyllum alkaloids, daphnillonins A ( 1 ) and B ( 2 ), were isolated from Daphniphyllum longeracemosum and structurally characterized by a combination of diverse methods, including the calculation of electronic circular dichroism. Compound 1 possesses an unprecedented carbon architecture with a very unique 8-methyl-6-azabicyclo[3.2.1]octane moiety, and compound 2 represents a new carbon skeleton with an uncommon 7/6/5/7/5/5-fused ring system. The biosynthetic pathways for the two alkaloids were proposed with the concurrent major alkaloids as the precursors.
- Published
- 2020
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31. Morindolestatin, Naturally Occurring Dehydromorpholinocarbazole Alkaloid from Soil-Derived Bacterium of the Genus Streptomyces .
- Author
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Zhang SY, Zhan ZJ, Zhang H, Qi H, Zhang LQ, Chen SX, Gan LS, Wang JD, and Ma LF
- Subjects
- Alkaloids chemistry, Alkaloids metabolism, Biological Products chemistry, Biological Products metabolism, Carbazoles chemistry, Molecular Structure, Stereoisomerism, Streptomyces metabolism, Alkaloids isolation & purification, Biological Products isolation & purification, Carbazoles isolation & purification, Streptomyces chemistry
- Abstract
Novel antilipid peroxidative carbazole alkaloids, antiostatin A
5 ( 1 ), antiostatin A6 ( 2 ), and (±)-morindolestatin ( 3 ), were isolated from a new soil-derived Streptomyces sp. Compound 2 possesses an unusual cyclohexene side chain. Compound 3 was a pair of enantiomers featuring an unprecedented [1,4]oxazino[2,3- c ]carbazole ring system. The absolute configuration of 3 was determined by online HPLC-ECD and ECD calculation. A racemization mechanism and putative biosynthetic pathway are discussed.- Published
- 2020
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32. Treatment of Persistent Post-Traumatic Headache and Post-Concussion Symptoms Using Repetitive Transcranial Magnetic Stimulation: A Pilot, Double-Blind, Randomized Controlled Trial.
- Author
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Stilling J, Paxman E, Mercier L, Gan LS, Wang M, Amoozegar F, Dukelow SP, Monchi O, and Debert C
- Subjects
- Adolescent, Adult, Aged, Double-Blind Method, Female, Humans, Male, Middle Aged, Pilot Projects, Young Adult, Post-Concussion Syndrome therapy, Post-Traumatic Headache therapy, Transcranial Magnetic Stimulation methods, Treatment Outcome
- Abstract
Persistent post-traumatic headache (PTH) after mild traumatic brain injury is one of the most prominent and highly reported persistent post-concussion symptoms (PPCS). Non-pharmacological treatments, including non-invasive neurostimulation technologies, have been proposed for use. Our objective was to evaluate headache characteristics at 1 month after repetitive transcranial magnetic stimulation (rTMS) treatment in participants with PTH and PPCS. A double-blind, randomized, sham-controlled, pilot clinical trial was performed on 20 participants (18-65 years) with persistent PTH (International Classification of Headache Disorders, 3rd edition) and PPCS (International Classification of Diseases, Tenth Revision). Ten sessions of rTMS therapy (10 Hz, 600 pulses, 70% resting motor threshold amplitude) were delivered to the left dorsolateral pre-frontal cortex. The primary outcome was a change in headache frequency or severity at 1 month post-rTMS. Two-week-long daily headache diaries and clinical questionnaires assessing function, PPCS, cognition, quality of life, and mood were completed at baseline, post-treatment, and at 1, 3, and 6 months post-rTMS. A two-way (treatment × time) mixed analyisis of variance indicated a significant overall time effect for average headache severity ( F
(3,54) = 3.214; p = 0.03) and a reduction in headache frequency at 1 month post-treatment (#/2 weeks, REAL -5.2 [standard deviation {SD} = 5.8]; SHAM, -3.3 [SD = 7.7]). Secondary outcomes revealed an overall time interaction for headache impact, depression, post-concussion symptoms, and quality of life. There was a significant reduction in depression rating in the REAL group between baseline and 1 month post-treatment, with no change in the SHAM group (Personal Health Questionnaire - 9; REAL, -4.3 [SD = 3.7[ p = 0.020]; SHAM, -0.7 [SD = 4.7; p = 1.0]; Bonferroni corrected). In the REAL group, 60% returned to work whereas only 10% returned in the SHAM group ( p = 0.027). This pilot study demonstrates an overall time effect on headache severity, functional impact, depression, PPCS, and quality of life after rTMS treatment in participants with persistent PTH; however, findings were below clinical significance thresholds. There was a 100% response rate, no dropouts, and minimal adverse effects, warranting a larger phase II study. Clinicaltrials.gov: NCT03691272.- Published
- 2020
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33. [A new spirocyclic cycloartane triterpenoid from Souliea vaginata].
- Author
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Zhang SY, Fang ZJ, Wang YL, Zhou CX, Mo JX, and Gan LS
- Subjects
- Actaea chemistry, Glycosides, Lipopolysaccharides, Molecular Structure, Triterpenes analysis, Actaea metabolism, Triterpenes metabolism
- Abstract
The 70% ethanol extract of the whole plant of Souliea vaginata was purified by multi-chromatographic methods including macroporous resin,silica gel,Sephadex LH-20,and C18-reversed-phase column chromatography. A new spirocyclic cycloartane triterpenoid was isolated and identified as( 16 R*,20 R*,23 S*,24 R*,25 S*)-16,23: 23,26-diepoxy-15α,24,25-trihydroxy-9,19-cycloart-3β-O-β-D-xylopyranoside( 1),and named as soulieoside S. Its planar structure and relative configuration were determined by spectroscopic techniques including 2 D NMR and HRESI-MS. As one of the main components of S. vaginata,compound 1 was evaluated for its anti-inflammatory activity by a lipopolysaccharide( LPS)-stimulated NO production model in RAW264. 7 macrophages,but it didn't show NO production inhibitory effect.
- Published
- 2019
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34. Proanthocyanidin Dimers and Trimers from Vitis vinifera Provide Diverse Structural Motifs for the Evaluation of Dentin Biomodification.
- Author
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Phansalkar RS, Nam JW, Leme-Kraus AA, Gan LS, Zhou B, McAlpine JB, Chen SN, Bedran-Russo AK, and Pauli GF
- Subjects
- Biopolymers chemistry, Biotin chemistry, Proanthocyanidins chemistry
- Abstract
Aimed at exploring the dentin biomodification potential of proanthocyanidins (PACs) for the development of dental biomaterials, this study reports the phytochemical and dental evaluation of nine B-type PACs from grape seed extract (GSE). Out of seven isolated dimers ( 1 - 7 ), four new compounds ( 2 , 3 , 5 , and 6 ) involved relatively rare ent -catechin or ent -epicatechin monomeric flavan-3-ol units. Low-temperature NMR analyses conducted along with phloroglucinolysis and electronic circular dichroism enabled unequivocal structural characterization and stereochemical assignment. Additionally, one known ( 8 ) and one new ( 9 ) B-type trimer were characterized. Differential
13 C NMR chemical shifts (Δδ) were used to determine the absolute configuration of 9 , relative to the dimers 1 and 2 as the possible constituent subunits. Compared to the dimers, the trimers showed superior dentin biomodification properties. The dimers, 1 - 7 , exhibited pronounced differences in their collagenase inhibitory activity, while enhancing dentin stiffness comparably. This suggests that PAC structural features such as the degree of polymerization, relative and absolute configuration have a differential influence on enhancement of dentin biomechanical and biostability. As mechanical enhancement to dentin and resistance to proteolytic biodegradation are both essential properties functional and stable dentin substrate, the structurally closely related PACs suggest a new metric, the dentin biomodification potential (DBMP) that may rationalize both properties.- Published
- 2019
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35. Theta band high definition transcranial alternating current stimulation, but not transcranial direct current stimulation, improves associative memory performance.
- Author
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Lang S, Gan LS, Alrazi T, and Monchi O
- Subjects
- Adolescent, Adult, Female, Humans, Male, Middle Aged, Neurodegenerative Diseases therapy, Pilot Projects, Memory, Neurodegenerative Diseases physiopathology, Temporal Lobe physiopathology, Theta Rhythm, Transcranial Direct Current Stimulation
- Abstract
Associative memory (AM) deficits are common in neurodegenerative disease and novel therapies aimed at improving these faculties are needed. Theta band oscillations within AM networks have been shown to be important for successful memory encoding and modulating these rhythms represents a promising strategy for cognitive enhancement. Transcranial alternating current stimulation (TACS) has been hypothesized to entrain and increase power of endogenous brain rhythms. For this reason, we hypothesized that focal delivery of theta band electrical current, using high-definition TACS, would result in improved AM performance compared to sham stimulation or transcranial direct current stimulation (TDCS). In this pilot study, 60 healthy subjects were randomized to receive high definition TACS, high definition TDCS, or sham stimulation delivered to the right fusiform cortex during encoding of visual associations. Consistent with our hypothesis, improved AM performance was observed in the TACS group, while TDCS had no effect. However, TACS also resulted in improved correct rejection of never seen items, reduced false memory, and reduced forgetting, suggesting the effect may not be specific for AM processes. Overall, this work informs strategies for improving associative memory and suggests alternating current is more effective than direct current stimulation in some contexts.
- Published
- 2019
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36. Euphorkanlide A, a Highly Modified Ingenane Diterpenoid with a C 24 Appendage from Euphorbia kansuensis.
- Author
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Yan XL, Sang J, Chen SX, Li W, Tang GH, Gan LS, and Yin S
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Antineoplastic Agents, Phytogenic isolation & purification, Apoptosis drug effects, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Diterpenes chemistry, Diterpenes isolation & purification, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm drug effects, Drug Screening Assays, Antitumor, Humans, Molecular Conformation, Structure-Activity Relationship, Antineoplastic Agents, Phytogenic pharmacology, Diterpenes pharmacology, Euphorbia chemistry
- Abstract
Euphorkanlide A (1), a highly modified ingenane diterpenoid with a C
24 appendage forming an additional hexahydroisobenzofuran-fused 19-membered macrocyclic bis-lactone ring system was isolated from the roots of Euphorbia kansuensis. Its structure was determined by extensive spectroscopic analysis and quantum-chemical calculations. Compound 1 showed significant cytotoxicities against a panel of cancer cell lines (IC50s < 5 μM). Mechanistic study revealed that 1 could induce the generation of ROS, leading to cell cycle arrest and cell apoptosis in drug-resistant cancer cell line HCT-15/5-FU.- Published
- 2019
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37. Network basis of the dysexecutive and posterior cortical cognitive profiles in Parkinson's disease.
- Author
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Lang S, Hanganu A, Gan LS, Kibreab M, Auclair-Ouellet N, Alrazi T, Ramezani M, Cheetham J, Hammer T, Kathol I, Sarna J, and Monchi O
- Subjects
- Aged, Brain Mapping, Cognition physiology, Cognition Disorders etiology, Cognition Disorders psychology, Executive Function physiology, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuropsychological Tests, Parkinson Disease complications, Parkinson Disease psychology, Brain diagnostic imaging, Cognition Disorders diagnostic imaging, Nerve Net diagnostic imaging, Parkinson Disease diagnostic imaging
- Abstract
Background: The dual syndrome hypothesis of cognitive impairment in PD suggests that two cognitive profiles exist with distinct pathological mechanisms and a differential risk for further cognitive decline. How these profiles relate to network dysfunction has never been explicitly characterized., Objective: First, to assess intranetwork functional connectivity while considering global connectivity, and second, to relate network connectivity with measures of the dysexecutive and posterior cortical profiles., Methods: Eighty-two subjects with idiopathic PD and 37 age-matched controls underwent resting-state functional MRI and comprehensive neuropsychological assessment. Intranetwork and global connectivity was compared between groups. Measures of the dysexecutive and posterior cortical profiles were related to network connectivity while considering demographic and disease-related covariates., Results: PD subjects show decreased connectivity within several cortical networks. However, only the sensorimotor network displayed a loss of connectivity independent of the observed decreased global connectivity. The dysexecutive factor was independently related to increased motor severity, less education, and decreased connectivity in the sensorimotor network. The posterior cortical factor was related to increased age, less education, decreased connectivity in the central executive network, as well as increased connectivity in the temporal network., Conclusions: Our results provide evidence supporting a network-specific process of degeneration in the sensorimotor network which contributes to the dysexecutive cognitive profile. In contrast, connectivity of the temporal and central executive network is related to the posterior cortical profile, representing a distinct network signature of this syndrome. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)
- Published
- 2019
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38. Cycloartane triterpenoids from Actaea vaginata with anti-inflammatory effects in LPS-stimulated RAW264.7 macrophages.
- Author
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Fang ZJ, Zhang T, Chen SX, Wang YL, Zhou CX, Mo JX, Wu YJ, Xu YK, Lin LG, and Gan LS
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Macrophages cytology, Macrophages metabolism, Mice, Models, Molecular, Molecular Conformation, NF-kappa B metabolism, Nitric Oxide biosynthesis, RAW 264.7 Cells, Signal Transduction drug effects, Actaea chemistry, Lipopolysaccharides pharmacology, Macrophages drug effects, Triterpenes chemistry, Triterpenes pharmacology
- Abstract
Five undescribed cycloartane triterpenoids, including two cycloartane trinor-triterpenoids, were isolated from a 70% ethanol extract of the whole plant of Actaea vaginata (Ranunculaceae), together with thirteen known cycloartane triterpenoids. Their structures were determined by spectroscopic techniques and quantum chemical calculations for intramolecular noncovalent interactions with reduced density gradient method. All compounds were evaluated for their anti-inflammatory effects by a lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production model in RAW264.7 macrophage cells, and some showed potent inhibitory effects with IC
50 values ranging from 5.0 to 24.4 μM. Further mechanism studies showed that one compound dose-dependently suppressed LPS-induced NO production and pro-inflammatory cytokines secretion, and decreased the expression of iNOS, through inhibiting NF-κB activation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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39. Benzofurans from Eupatorium chinense enhance insulin-stimulated glucose uptake in C2C12 myotubes and suppress inflammatory response in RAW264.7 macrophages.
- Author
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Ke JH, Zhang LS, Chen SX, Shen SN, Zhang T, Zhou CX, Mo JX, Lin LG, and Gan LS
- Subjects
- Animals, China, DNA-Binding Proteins metabolism, Glucose metabolism, Insulin, Mice, Molecular Structure, Nitric Oxide Synthase Type II metabolism, Phytochemicals isolation & purification, Phytochemicals pharmacology, Plant Roots chemistry, RAW 264.7 Cells, Signal Transduction drug effects, Transcription Factors metabolism, Benzofurans pharmacology, Eupatorium chemistry, Macrophages drug effects, Muscle Fibers, Skeletal drug effects
- Abstract
Fourteen acetylbenzofuran derivatives, including three undescribed carbon skeletons with a newly formed hexane or benzene ring on the other side of the benzofuran ring, (±)-eupatonin A (1), (±)-eupatonin B (2), and eupatonin C (3), two new benzofurans (-)-12β-hydroxygynunone (4) and (+)-12-hydroxyl-13-noreuparin (5), as well as 9 known ones (6-14), were isolated from 95% ethanol extract of the roots of Eupatorium chinense. Their structures were determined by spectroscopic methods and quantum chemical DFT and TDDFT calculations of the NMR chemical shifts and ECD spectra, which helped in the determination of the relative configurations of 1 and 2 and the absolute configurations of 4 and 5, respectively. 1 and 2 were further identified to be racemic mixtures by chiral HPLC analysis. All compounds were evaluated for insulin-stimulated glucose uptake in differentiated C2C12 myotubes. Compounds 1, 3, 4, 5, 11, 12, and 13 markedly enhanced insulin-mediated glucose uptake. (±)-Eupatonin A (1) activated the IRS-1/Akt/GSK-3β signaling pathway and enhanced insulin stimulated GLUT4 membrane translocation in C2C12 myotubes. On LPS stimulated RAW264.7 macrophages, several compounds exhibited significant inhibitory effect on NO production with IC
50 values ranging from 4.94 to 9.70 μΜ. (±)-Eupatonin A (1) again dose-dependently suppressed LPS-induced NO production and decreased the expression of inducible NO synthase (iNOS), through inhibiting NF-κB activity., (Copyright © 2019 Elsevier B.V. All rights reserved.)- Published
- 2019
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40. Both 50 and 30 Hz continuous theta burst transcranial magnetic stimulation depresses the cerebellum.
- Author
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Strzalkowski NDJ, Chau AD, Gan LS, and Kiss ZHT
- Subjects
- Adult, Cerebral Cortex physiology, Evoked Potentials, Motor physiology, Female, Hand, Humans, Male, Muscle, Skeletal physiology, Neural Pathways physiology, Thalamus physiology, Young Adult, Cerebellum physiology, Neural Inhibition physiology, Transcranial Magnetic Stimulation methods
- Abstract
The cerebellum is implicated in the pathophysiology of numerous movement disorders, which makes it an attractive target for noninvasive neurostimulation. Continuous theta burst stimulation (cTBS) can induce long lasting plastic changes in human brain; however, the efficacy of different simulation protocols has not been investigated at the cerebellum. Here, we compare a traditional 50-Hz and a modified 30-Hz cTBS protocols at modulating cerebellar activity in healthy subjects. Seventeen healthy adults participated in two testing sessions where they received either 50-Hz (cTBS
50 ) or 30-Hz (cTBS30 ) cerebellar cTBS. Cerebellar brain inhibition (CBI), a measure of cerebello-thalamocortical pathway strength, and motor evoked potentials (MEP) were measured in the dominant first dorsal interosseous muscle before and after (up to ~ 40 min) cerebellar cTBS. Both cTBS protocols induced cerebellar depression, indicated by significant reductions in CBI (P < 0.001). No differences were found between protocols (cTBS50 and cTBS30 ) at any time point (P = 0.983). MEP amplitudes were not significantly different following either cTBS protocol (P = 0.130). The findings show cerebellar excitability to be equally depressed by 50-Hz and 30-Hz cTBS in heathy adults and support future work to explore the efficacy of different cerebellar cTBS protocols in movement disorder patients where cerebellar depression could provide therapeutic benefits.- Published
- 2019
- Full Text
- View/download PDF
41. Tautomerism and bioactivities of curcumenol, a common sesquiterpenoid widely existing in edible plants.
- Author
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Zhang LS, Shen SN, Gao YL, Shi SY, Zhou CX, Mo JX, Xu YK, Lin LG, and Gan LS
- Subjects
- Animals, Cell Line, Isomerism, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Structure, Cell Differentiation drug effects, Muscle Development drug effects, Muscle Fibers, Skeletal drug effects, Plants, Edible chemistry, Sesquiterpenes chemistry
- Abstract
Curcumenol was firstly revealed as a pair of hemiacetal-ketone tautomers in solutions by using temperature variation 1H-NMR experiments, 2D NMR, and chemical methods. Quantum chemical calculation allowed the explanation of its spectroscopic behavior. An antioxidative SAR study on its derivatives verified the tautomeric bio-significance. Curcumenol also remarkably enhanced myogenic differentiation and mitochondrial function.
- Published
- 2019
- Full Text
- View/download PDF
42. Euphorhelipanes A and B, Triglyceride-Lowering Euphorbia Diterpenoids with a Bicyclo[4.3.0]nonane Core from Euphorbia helioscopia.
- Author
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Li W, Tang YQ, Chen SX, Tang GH, Gan LS, Li C, Rao Y, Huang ZS, and Yin S
- Subjects
- Cell Line, Tumor, Diterpenes chemistry, Diterpenes pharmacology, Humans, Hypolipidemic Agents chemistry, Hypolipidemic Agents pharmacology, Oleic Acid pharmacology, Diterpenes isolation & purification, Euphorbia chemistry, Hypolipidemic Agents isolation & purification, Triglycerides blood
- Abstract
Euphorhelipanes A (1) and B (2), two Euphorbia diterpenoids with a new 4-(5,5-dimethylheptan-2-yl)-2,7-dimethylbicyclo[4.3.0]nonane skeleton, were isolated from a 95% ethanol extract of the whole plants of Euphorbia helioscopia. Their structures were elucidated by spectroscopic data analysis, quantum chemical calculations, and single-crystal X-ray diffraction data. Compounds 1 and 2 represent the first examples of Euphorbia diterpenoids with a 5/6 fused carbon ring system, and their plausible biosynthetic pathways originating from jatrophanes are proposed. Compounds 1 and 2 showed a triglyceride-lowering effect in oleic-acid-stimulated HuH7 cells at concentrations of 1-50 μM.
- Published
- 2019
- Full Text
- View/download PDF
43. Triterpenoids from Cyclocarya paliurus that Enhance Glucose Uptake in 3T3-L1 Adipocytes.
- Author
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Fang ZJ, Shen SN, Wang JM, Wu YJ, Zhou CX, Mo JX, Lin LG, and Gan LS
- Subjects
- 3T3-L1 Cells, AMP-Activated Protein Kinase Kinases, Adipocytes cytology, Animals, Biological Transport, Cell Survival drug effects, Drug Discovery, Glycosides chemistry, Insulin, Mice, Molecular Structure, Phytochemicals isolation & purification, Phytochemicals pharmacology, Plant Extracts chemistry, Plant Leaves chemistry, Protein Kinases metabolism, Signal Transduction, Structure-Activity Relationship, Terpenes isolation & purification, Adipocytes drug effects, Glucose metabolism, Juglandaceae chemistry, Terpenes pharmacology
- Abstract
Four previously undescribed compounds, including three rarely occurring seco -dammarane triterpenoid glycosides and a pentacyclic triterpenic acid, were isolated from a 70% ethanol extract of the leaves of Cyclocarya paliurus (Juglandaceae), along with eleven known triterpenoids. Their structures were determined by spectroscopic techniques, including 2D NMR and HRESIMS, as well as chemical methods. Among them, several triterpenoids enhanced insulin stimulated glucose uptake in both 3T3-L1 adipocytes and C2C12 myotubes. Furthermore, compound 1 dose-dependently increased glucose uptake through activating AMP-activated protein kinase (AMPK)-p38 pathway. Collectively, triterpenoids from C. paliurus could be developed as insulin sensitizers, which might have therapeutic potential for insulin resistance and hyperglycemia.
- Published
- 2019
- Full Text
- View/download PDF
44. Maximumins A-D, Rearranged Labdane-Type Diterpenoids with Four Different Carbon Skeletons from Amomum maximum.
- Author
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Ji KL, Fan YY, Ge ZP, Sheng L, Xu YK, Gan LS, Li JY, and Yue JM
- Subjects
- Models, Molecular, Molecular Conformation, Amomum chemistry, Carbon chemistry, Diterpenes chemistry
- Abstract
Four highly rearranged labdane-type diterpenoids, maximumins A-D (1-4) possessing different new carbon skeletons, together with a biosynthetically related known analog 5 were isolated from Amomum maximum. The structures of new compounds with absolute configurations were characterized by spectroscopic and computational approaches. The plausible biogenetic pathways for 1-4 were proposed. These compounds showed moderate to weak activities against nuclear factor kappa B (NF-κB).
- Published
- 2019
- Full Text
- View/download PDF
45. Colocynthenins A-D, Ring-A seco-Cucurbitane Triterpenoids from the Fruits of Citrullus colocynthis.
- Author
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Liu Y, Chen G, Chen X, Chen SX, Gan LS, and Yuan T
- Subjects
- Cholinesterase Inhibitors pharmacology, Fruit chemistry, Triterpenes chemistry, Triterpenes pharmacology, Citrullus colocynthis chemistry, Triterpenes isolation & purification
- Abstract
Four ring-A seco-cucurbitane triterpenoids, colocynthenins A-D (1-4), together with seven known cucurbitane triterpenoids (5-11), were isolated from the fruits of Citrullus colocynthis. Their structures and absolute configurations were elucidated based on spectroscopic analysis and quantum chemical ECD calculations. Compound 1 possesses an unprecedented 2,11-lactone moiety, while compound 2 is the first reported cucurbitane triterpenoid with an unusual cyano group. Compounds 1 and 3 showed acetylcholinesterase inhibitory activities in a standard in vitro assay, with IC
50 values of 2.6 and 3.1 μM, respectively.- Published
- 2018
- Full Text
- View/download PDF
46. New podolactones from the seeds of Podocarpus nagi and their anti-inflammatory effect.
- Author
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Feng ZL, Zhang T, Liu JX, Chen XP, Gan LS, Ye Y, and Lin LG
- Subjects
- Anti-Inflammatory Agents pharmacology, Drugs, Chinese Herbal pharmacology, Anti-Inflammatory Agents therapeutic use, Drugs, Chinese Herbal chemistry, NF-kappa B metabolism, Nitric Oxide metabolism, Seeds chemistry
- Abstract
Podolactones are a class of structural diverse diterpenoid lactones, mainly isolated from the Podocarpus species. Several bioactivities have been disclosed for podolactones, including cytotoxicity and anti-atherosclerosis. In this study, the seeds of P. nagi were isolated by comprehensive chromatographic methods to obtain three new podolatones, named nagilactone B 1-O-β-D-glucoside (1), nagilactone N3 3-O-β-D-glucoside (2), and 2-epinagilactone B (3), as well as a known compound, nagilactone B (4). Their structures were determined by analyses of NMR and HRESIMS data. Compounds 1 and 2 significantly inhibited nitric oxide (NO) production on LPS-stimulated RAW264.7 macrophages, with IC
50 values of 0.18 ± 0.04 and 0.53 ± 0.03 μM, respectively. Indomethacin (IC50 4.21 ± 0.32 μM) was used as a positive control. Compound 1 suppressed the expression of inducible NO synthase (iNOS) in a concentration-dependent manner, mediating through inhibiting nuclear factor-κB (NF-κB) activity. This is the first report regarding the anti-inflammatory effect of podolactones, which could be potential anti-inflammatory agents.- Published
- 2018
- Full Text
- View/download PDF
47. Fampridine is a Substrate and Inhibitor of Human OCT2, but not of Human MATE1, or MATE2K.
- Author
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Xiao G, Rowbottom C, Boiselle C, and Gan LS
- Subjects
- 4-Aminopyridine metabolism, 4-Aminopyridine pharmacology, Biological Transport drug effects, HEK293 Cells, Humans, Hypoglycemic Agents metabolism, Hypoglycemic Agents pharmacokinetics, Metformin metabolism, Metformin pharmacokinetics, Organic Cation Transporter 2 antagonists & inhibitors, Potassium Channel Blockers metabolism, Potassium Channel Blockers pharmacology, 4-Aminopyridine pharmacokinetics, Organic Cation Transport Proteins metabolism, Organic Cation Transporter 2 metabolism, Potassium Channel Blockers pharmacokinetics
- Abstract
Purpose: The renal clearance of fampridine (Fampyra®, or Ampyra®) significantly exceeds the glomerular filtration rate, suggesting active renal secretion is likely the major elimination pathway. The goal of this study was to identify the renal transporters that are involved in the renal active secretion, and elucidate the active renal secretion mechanism of fampridine., Methods: The uptake of fampridine to HEK-293 cells overexpressing human OCT2, MATE1 or MATE2K was determined in the absence and presence of Cimetidine, the prototypical inhibitor of the transporters. The inhibition potential of fampridine on the renal transporters was evaluated by determining the uptake of TEA and Metformin, the probe substrates of the transporters of OCT2 and MATEs, respectively, in the absence or presence of fampridine., Results: Significant time- and concentration-dependent uptake of fampridine by human OCT2 was observed. The K
m and Vmax were determined as 51.0 ± 17.1 μM and 1107 ± 136 pmole/min/106 cells, respectively. Fampridine also inhibited OCT2 mediated uptake of Metformin with estimated IC50 of 66.8 μM. In contrast, there was not significant uptake of fampridine by human MATE1 or MATE2K, and fampridine did not inhibit MATE1 or MATE2K mediated uptake of TEA., Conclusion: The studies indicated fampridine is a substrate and inhibitor of OCT2, but not MATE1 or MATE2K. Results from the study suggested the active renal secretion of fampridine is mediated by human OCT2 but not MATE1 or MATE2K. To our knowledge, fampridine is the first reported substrate specific to OCT2 but not to MATE1 or MATE2K.- Published
- 2018
- Full Text
- View/download PDF
48. Monoclonal antibody exposure in rat and cynomolgus monkey cerebrospinal fluid following systemic administration.
- Author
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Wang Q, Delva L, Weinreb PH, Pepinsky RB, Graham D, Veizaj E, Cheung AE, Chen W, Nestorov I, Rohde E, Caputo R, Kuesters GM, Bohnert T, and Gan LS
- Subjects
- Administration, Intravesical, Animals, Antibodies, Monoclonal blood, Brain metabolism, Cerebrospinal Fluid metabolism, Humans, Kinetics, Macaca fascicularis, Male, Rats, Sprague-Dawley, Spinal Cord metabolism, Time Factors, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal cerebrospinal fluid
- Abstract
Background: Many studies have focused on the challenges of small molecule uptake across the blood-brain barrier, whereas few in-depth studies have assessed the challenges with the uptake of antibodies into the central nervous system (CNS). In drug development, cerebrospinal fluid (CSF) sampling is routinely used as a surrogate for assessing CNS drug exposure and biomarker levels. In this report, we have studied the kinetic correlation between CSF and serum drug concentration-time profiles for five humanized monoclonal antibodies in rats and cynomolgus monkeys and analyzed factors that affect their CSF exposure., Results: Upon intravenous (IV) bolus injection, antibodies entered the CNS slowly and reached maximum CSF concentration (
CSF Tmax ) in one to several days in both rats and monkeys. Antibody serum and CSF concentration-time curves converged until they became parallel afterCSF Tmax was reached. Antibody half-lives in CSF (CSF t½ ) approximated their serum half-lives (serum t½ ). Although the intended targets of these antibodies were different, the steady-state CSF to serum concentration ratios were similar at 0.1-0.2% in both species. Independent of antibody target and serum concentration, CSF-to-serum concentration ratios for individual monkeys ranged by up to tenfold from 0.03 to 0.3%., Conclusion: Upon systemic administration, average antibodies CSF-to-serum concentration ratios in rats and monkeys were 0.1-0.2%. TheCSF t½ of the antibodies was largely determined by their long systemic t½ (systemic t½ ).- Published
- 2018
- Full Text
- View/download PDF
49. Forces of Tool-Tissue Interaction to Assess Surgical Skill Level.
- Author
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Sugiyama T, Lama S, and Gan LS
- Subjects
- Adult, Female, Humans, Internship and Residency, Male, Microsurgery instrumentation, Middle Aged, Clinical Competence, Microsurgery standards, Neurosurgical Procedures standards, Pressure
- Published
- 2018
- Full Text
- View/download PDF
50. Cascarinoids A-C, a Class of Diterpenoid Alkaloids with Unpredicted Conformations from Croton cascarilloides.
- Author
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Gao XH, Xu YS, Fan YY, Gan LS, Zuo JP, and Yue JM
- Subjects
- Diterpenes, Molecular Conformation, Molecular Structure, Alkaloids chemistry, Croton
- Abstract
Cascarinoids A-C (1-3), a new class of diterpenoid alkaloids with unpredicted conformations, were isolated and structurally characterized from Croton cascarilloides. It was demonstrated that the dispersion interaction might be one of the main contributors that stabilized the folded conformations for compounds 1-3. Compounds 2 and 3 showed moderate immunosuppressive activity against T and/or B lymphocyte cells.
- Published
- 2018
- Full Text
- View/download PDF
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