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osthole treatment ameliorates Th2-mediated allergic asthma and exerts immunomodulatory effects on dendritic cell maturation and function

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Cellular & Molecular Immunology 2017年第11期14卷 935-947页

作者： Chen-Yuan Chiang Chen-Chen Lee Chia-Kwung Fan Huei-Mei Huang Bor-Luen Chiang Yueh-Lun Lee Division of Pulmonary Medicine Department of Internal MedicineWan Fang HospitalTaipei Medical UniversityTaipei 11031TaiwanChina Department of Internal Medicine School of MedicineCollege of MedicineTaipei Medical UniversityTaipei 11031TaiwanChina Department of Microbiology and Immunology School of MedicineCollege of MedicineChina Medical UniversityTaichung 40402TaiwanChina Department of Parasitology School of MedicineCollege of MedicineTaipei Medical UniversityTaipei 11031TaiwanChina Graduate Institute of Medical Sciences College of MedicineTaipei Medical UniversityTaipei 11031TaiwanChina Graduate Institute of Clinical Medicine College of MedicineNational Taiwan UniversityTaipei 10048TaiwanChina Department of Microbiology and Immunology School of MedicineCollege of MedicineTaipei Medical UniversityTaipei 11031TaiwanChina

osthole,an active component of Chinese herbal medicines,reportedly possesses various pharmacological properties and has potential therapeutic applications.This study explored the anti-allergic effects of osthole in asthmatic mice and investigated the immunomodulatory actions of osthole on dendritic cells(DCs)and T cells.Herein,we show that oral administration of osthole to BALB/c mice after ovalbumin(OVA)sensitization ameliorated all of the cardinal features of T helper 2(Th2)-mediated allergic asthma;namely,the production of OVA-specific immunoglobulin E,airway hyperresponsiveness,airway inflammation and the production of Th2-type cytokines including interleukin(IL)-4,IL-5 and IL-13.Surprisingly,IL-10 production was not inhibited and was even enhanced by osthole treatment.We observed a significant increase in the percentages of IL-10-producing DCs and forkhead box P3-positive regulatory T(Treg)cells in osthole-treated asthmatic mice.Additionally,in vitro analyses revealed that osthole-treated bone-marrow-derived DCs had a partial maturation phenotype,secreting large amounts of IL-10 and low levels of proinflammatory cytokines,such as IL-12,IL-6 and tumor necrosis factor-α,and displaying reduced levels of MHC class II surface molecules.These DCs displayed immunosuppressive capacity by directly inhibiting effector T-cell responses or inducing Treg cells.In addition,osthole directly inhibited the activated CD4+T-cell proliferation and Th1/Th2-type cytokine production in this system.Collectively,these results suggest that DCs and T cells are potential target cells responsible for the action of osthole against allergic asthma.

关键词： asthma dendritic cell osthole T cell

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osthole attenuates pulmonary arterial hypertension by the regulation of sphingosine 1-phosphate in rats

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Chinese Journal of Natural Medicines 2020年第4期18卷 308-320页

作者： YAO Li YANG Yu-Xia CAO Hui REN Huan-Huan NIU Zheng SHI Ling Department of Medicinal Chemistry and Natural Medicine Chemistry Department of PharmacognosyCollege of PharmacyHarbin Medical UniversityHarbin 150081China State-Province Key Laboratory of Biomedicine-Pharmaceutics of China Harbin Medical UniversityHarbin 150081China Department of Pharmacology College of PharmacyHarbin Medical UniversityHarbin 150081China

osthole is observed to have the capacity to treat pulmonary arterial hypertension(PAH) in rats, but molecular mechanism is still unknown. The present study aims to discover therapeutic targets and explore therapeutic mechanism of osthole against PAH from metabolic perspective. A rat model with PAH was successfully established with MCT, following osthole administration, then untargeted metabolomics assay was performed using UPLC-Q-TOF-MS to identify differential metabolites and associated metabolic pathways, at last mechanism investigation was done by qRT-PCR, Western blot and ELISA. Differential metabolites characterized in rats with PAH were mostly assigned to sphingolipid metabolism, synthesis of unsaturated fatty acids, glycolysis, nucleotide metabolism, steroid hormone biosynthesis. Furthermore, osthole reversed high level of S1 P by modulating metabolic enzyme Sphk1 in rats with PAH. In addition, osthole inhibited the expression of Sphk1 by downregulating microRNA-21, phosphorylation of Akt, phosphorylation of mTOR in vivo and in vitro. These results demonstrated that metabolomics is a promising approach to discover potential drug target for PAH treatment. Importantly, our findings further elucidated therapeutic mechanism of osthole, a natural product, having a role of metabolic regulator to potentially treat PAH by targeting inhibition of Sphk1/S1 P via microRNA-21-PI3 K/Akt/mTOR signal pathway. Altogether, this discovery paves a critical foundation for enabling osthole to be a candidate compound to treat PAH.

关键词： Pulmonary arterial hypertension osthole Metabolomics Sphk1/S1P MicroRNA-21-PI3K/Akt/mTOR Therapeutic mechanism

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osthole improves synaptic plasticity in the hippocampus and cognitive function of Alzheimer's disease rats via regulating glutamate

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Neural Regeneration Research 2012年第30期7卷 2325-2332页

作者： Xiaohua Dong Li Zhang Wei Li Xianyong Meng Department of Pharmacology College of Pharmacy Hebei Medical University Shijiazhuang 050017 Hebei Province China Department of Pharmacology School of Medicine Hebei North University Zhangjiakou 075000 Hebei Province China Department of Orthopedics the First Attached Hospital Hebei North University Zhangjiakou 075000 Hebei Province China

osthole, an effective monomer in Chinese medicinal herbs, can cross the blood-brain barrier and protect against brain injury, with few toxic effects. In this study, a rat model of Alzheimer＇s disease was established after intracerebroventricular injection of β-amyloid peptide （25-35）. Subsequently the rats were intraperitoneally treated with osthole （12.5 or 25.0 mg/kg） for 14 successive days. Results showed that osthole treatment significantly improved cognitive impairment and protected hippocampal neurons of AIzheimer＇s disease rats. Also, osthole treatment alleviated suppressed long-term potentiation in the hippocampus of Alzheimer＇s disease rats. In these osthole-treated Alzheimer＇s disease rats, the level of glutamate decreased, but there was no significant change in y-amino-butyric acid. These experimental findings suggest that osthole can improve learning and memory impairment, and increase synaptic plasticity in Alzheimer＇s disease rats. These effects of osthole may be because of its regulation of central glutamate and y-amino-butyric acid levels.

关键词： osthole Alzheimer＇s disease learning and memory long-term potentiation glutamate y-amino-butyric acid β-amyloid peptide brain hippocampus neural regeneration

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osthole decreases collagen Ⅰ/III contents and their ratio in TGF-β1-overexpressed mouse cardiac fibroblasts through regulating the TGF-β/Smad signaling pathway

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Chinese Journal of Natural Medicines 2018年第5期16卷 321-329页

作者： LIU Jin-Cheng ZHOU Lei WANG Feng CHENG Zong-Qi RONG Chen Clinic Pharmacology Laboratory Department of Pharmacy The First Affiliated Hospital of Soochow University Suzhou 215006 China Department of Pharmacology Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases College of Pharmaceutical Sciences Soochow University Suzhou 215123 China Laboratory Department Wuxi Center for Disease Control and Prevention Wuxi 214023 China

The present study was designed to elucidate whether the mechanism by which osthole decreases collagenⅠ/III contents and their ratio is regulating the TGF-β/Smad signaling pathway in TGF-β1-overexpressed mouse cardiac fibroblasts(CFs). These CFs were cultured and treated with different concentrations of osthole. Our results showed that the TGF-β1 expression in the CFs transfected with that the recombinant expression plasmids pc DNA3.1(+)-TGF-β1 was significantly enhanced. After the CFs were treated with 1.25-5 μg·m L^(-1) of osthole for 24 h, the m RNA and protein expression levels of collagensⅠand III were reduced. The collagen Ⅰ/III ratio was also reduced. The m RNA and protein expression levels of TGF-β1, TβRⅠ, Smad2/3, P-Smad2/3, Smad4, and α-SMA were decreased, whereas the expression level of Smad7 was increased. These effects suggested that osthole could inhibit collagen Ⅰ and III expression and reduce their ratio via the TGF-β/Smad signaling pathway in TGF-β1 overexpressed CFs. These effects of osthole may play beneficial roles in the prevention and treatment of myocardial fibrosis.

关键词： osthole TGF-β1 Collagen Mouse cardiac fibroblasts

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osthole inhibits proliferation of human breast cancer cells by inducing cell cycle arrest and apoptosis

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The Journal of Biomedical Research 2015年第2期29卷 132-138页

作者： Lintao Wang Yanyan Peng Kaikai Shi Haixiao Wang Jianlei Lu Yanli Li Changyan Ma Department of Biochemistry and Molecular Biology Nanjing Medical University Department of Developmental Genetics Nanjing Medical University Department of General Surgery Huaian No.1 People's Hospital Affiliated to Nanjing Medical University

Recent studies have revealed that osthole,an active constituent isolated from the fruit of Cnidium monnieri（L.） Cusson,a traditional Chinese medicine,possesses anticancer activity.However,its effect on breast cancer cells so far has not been elucidated clearly.In the present study,we evaluated the effects of osthole on the proliferation,cell cycle and apoptosis of human breast cancer cells MDA-MB 435.We demonstrated that osthole is effective in inhibiting the proliferation of MDA-MB 435 cells,The mitochondrion-mediated apoptotic pathway was involved in apoptosis induced by osthole,as indicated by activation of caspase-9 and caspase-3 followed by PARP degradation.The mechanism underlying its effect on the induction of G1 phase arrest was due to the up-regulation of p53 and p21 and down-regulation of Cdk2 and cyclin D1 expression.Were observed taken together,these findings suggest that the anticancer efficacy of osthole is mediated via induction of cell cycle arrest and apoptosis in human breast cancer cells and osthole may be a potential chemotherapeutic agent against human breast cancer.

关键词： osthole breast cancer proliferation cell cycle apoptosis

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Therapeutic effect of osthole on hyperlipidemic fatty liver in rats

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Acta Pharmacologica Sinica 2007年第3期28卷 398-403页

作者： Yan ZHANG Mei-lin XIE~2 Lu-jia ZHU Zhen-lun GU Department of Pharmacology,Medical School of Soochow University Suzhou 215123,China Department of Pharmacology Medical School of Soochow University Suzhou China

Aim:To study the effects of osthole on hyperlipidemic fatty liver and investigatethe possible mechanisms.Methods:A rat model with hyperlipidemic fatty liverwas successfully established by feeding fatty milk for 6 weeks.The experimentalrats were then treated with 5-20 mg/kg osthole for 6 weeks.The mouse hyperlipi-demic model was induced by feeding fatty milk when they were treated with 10-20mg/kg osthole for 3 weeks.Results:After treatment with osthole,the levels of ratserum total cholesterol(TC),triglyceride(TG)and low density lipoprotein-choles-terol significantly decreased as compared with the fatty liver model group(Posthole for 3 weeks(Postholedramatically decreased lipid accumulation(Posthole wasfound to have therapeutic effects on fatty milk-induced rat fatty liver;the mecha-nisms might be associated with its anti-oxidation and the elevation of the activi-ties of LPL and HL.

关键词： osthole hyperlipidemic fatty liver pharmacology

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Estrogenic activity of osthole and imperatorin in MCF-7 cells and their osteoblastic effects in Saos-2 cells

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Chinese Journal of Natural Medicines 2016年第6期14卷 413-420页

作者： JIA Min LI Yuan XIN Hai-Liang HOU Ting-Ting ZHANG Nai-Dai XU Hong-Tao ZHANG Qiao-Yan QIN Lu-Ping Department of Pharmacognosy School of Pharmacy Second Military Medical University

There is an increasing interest in phytoestrogens due to their potential medical usage in hormone replacement therapy(HRT). The present study was designed to investigate the in vitro effects of estrogen-like activities of two widespread coumarins, osthole and imperatorin, using the MCF-7 cell proliferation assay and their alkaline phosphatase(ALP) activities in osteoblasts Saos-2 cells. The two compounds were found to strongly stimulate the proliferation of MCF-7 cells. The estrogen receptor-regulated ERα, progesterone receptor(PR) and PS2 m RNA levels were increased by treatment with osthole and imperatorin. All these effects were significantly inhibited by the specific estrogen receptor antagonist ICI182, 780. Cell cycle analysis revealed that their proliferation stimulatory effect was associated with a marked increase in the number of MCF-7 cells in S phase, which was similar to that observed with estradiol. It was also observed that they significantly increased ALP activity, which was reversed by ICI182,780. These results suggested that osthole and imperatorin could stimulate osteoblastic activity by displaying estrogenic properties or through the ER pathway. In conclusion, osthole and imperatorin may represent new pharmacological tools for the treatment of osteoporosis.

关键词： osthole Imperatorin MCF-7 Estrogenic activity Estrogen receptors Osteoblasts Alkaline phosphatase

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Vasorelaxant effect of osthole on isolated thoracic aortic rings in rats

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Journal of Traditional Chinese Medicine 2019年第4期39卷 492-501页

作者： Huang Ying Kong Liting Wang Yanping Sun Mingjie Cui Haifeng Zhai Huaqiang LüCheng Fan Danping Experimental Research Center China Academy of Chinese Medical SciencesBeijing 100700China School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 100029China Institute of Basic Research in Clinical Medicine China Academy of Chinese Medical SciencesBeijing 100700China

OBJECTIVE: To investigate the effect of osthole on isolated thoracic aortic rings, and to determine the potential mechanism of action.METHODS: Thoracic aortas were isolated from Wistar rats, and were suspended in tissue organ chambers for vascular tension measurement. The effect of cumulative osthole(10-9, 10-8, 10-7, 10-6, and 10-5 mol/L) on endothelium-intact and endothelium-denuded thoracic aortic rings pre-contracted with phenylephrine(PE, 10-6 mol/L) or KCl(6 × 10-2 mol/L) was recorded. Histomorphological changes of thoracic aorta were analyzed by hematoxylin-eosin. The effects of different osthole concentrations on endothelium-intact aortic rings, which were pre-inhibited with the non-selective nitric oxide synthase inhibitor L-Arg(NO2)-OMe·HCl(3 × 10-4 mol/L), endothelium-derived nitric oxide synthase inhibitor Nω-nitro-L-arginine(3 × 10-4 mol/L), guanylate cyclase inhibitor 1 H-[1,2,4] oxadiazolo [4,3-α]quinoxaline-1-one(10-5 mol/L), cyclooxygenase inhibitor indometacin(10-5 mol/L), and the Ca2+-activated potassium channel inhibitor tetraethylammonium nitrate(10-5 mol/L), and then contracted with PE, were examined. Aortic rings incubated with osthole(10-5 mol/L), phentolamine(10-5 mol/L), or verapamil(10-5 mol/L) in Ca2+-free Krebs-Henseleit solution(KHS) were stimulated with PE or KCl.RESULTS: There was a dose-dependent increase in vasorelaxation of isolated thoracic aortic rings(both with and without endothelium) with increasing osthole concentration. Hematoxylin-eosin staining showed that osthole significantly improved thoracic aorta ring morphology. Compared with the control group, there were also significant differences after incubation with L-Arg(NO2)-OMe ω-nitro-L-arginine, and 1 H-[1,2,4] oxadiazo·lo HCl,N [4,3-α] quinoxaline-1-one(P osthole group incubated with indometacin and tetraethylammonium nitrate were similar to controls. In Ca2+-free KHS, the PE-induced contraction was similar between the osthole(4.37% ± 0.41%) and control(4.21% ± 1

关键词： Aorta,thoracic osthole Phentolamine Verapamil Vasorelaxation Calcium Nitric oxide

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Pharmacological Effects and Molecular Mechanism of osthole

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Medicinal Plant 2023年第2期14卷 93-96页

作者： Yannan LI Wenshuang HOU Jinglong CAO Anqi WANG Yinghua LUO Chenghao JIN College of Life Science and Biotechnology Heilongjiang Bayi Agricultural UniversityDaqing 163319China College of Animal Science and Veterinary Medicine Heilongjiang Bayi Agricultural UniversityDaqing 163319China

osthole has various pharmacological effects such as anti-cancer,anti-inflammation,prevention and treatment of cardiovascular diseases and neuroprotection.This paper reviews the advances in the research of the pharmacological effects and molecular mechanisms of osthole,in order to provide new ideas for further research and clinical application of osthole.

关键词： osthole Pharmacological effects Anti-cancer Anti-inflammation Prevention and treatment of cardiovascular diseases Neuroprotection

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Fluorescence spectroscopy of osthole binding to human serum albumin

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Journal of Pharmaceutical Analysis 2013年第3期3卷 200-204页

作者： Guang-De Yang Cong Li Ai-Guo Zeng Yuan Zhao Rong Yang Xiao-Li Bian School of Medicine Xi'an Jiaotong University Xi'an Tuberculosis and Thoracic Tumor Hospital

The interaction of human serum albumin （HSA） with osthole was investigated by fluorescence spectroscopy. osthole can quench the fluorescence of HSA and the quenching mechanism is a static process. The binding site number n and apparent binding constant K were measured at different temperatures. The thermodynamic parameters △H^0, △G^0 and △S^0 were calculated at different temperatures. The results indicated that electrostatic forces played a major role in the interaction of osthole with HSA. Results of osthole synchronous fluorescence and UV absorption spectra showed that the microenvironment and conformation of HSA were changed.

关键词： osthole Human serum albumin Fluorescence quenching

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