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    Effects of sesquiterpenes and amino acid-sesquiterpene conjugates from the roots of Saussurea lappa on inducible nitric oxide synthase and heat shock protein in lipopolysaccharide-activated macrophages. Matsuda Hisashi,Toguchida Iwao,Ninomiya Kiyofumi,Kageura Tadashi,Morikawa Toshio,Yoshikawa Masayuki Bioorganic & medicinal chemistry The methanolic extract of the roots of Saussurea lappa CLARKE, a Chinese medicinal herb Saussureae Radix, was found to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-activated mouse peritoneal macrophages. Among the constituents from the methanolic extract, two sesquiterpene lactones (costunolide and dehydrocostus lactone) and two amino acid-sesquiterpene conjugates (saussureamines A and B) potently inhibited LPS-induced NO production (IC(50)=1.2-2.8 microM). Saussureamines A and B in addition to costunolide and dehydrocostus lactone did not inhibit iNOS enzyme activity, but they inhibited both induction of inducible NO synthase and activation of nuclear factor-kappaB in accordance with induction of heat shock protein 72.
    Saussurea costus: botanical, chemical and pharmacological review of an ayurvedic medicinal plant. Pandey Madan Mohan,Rastogi Subha,Rawat Ajay Kumar Singh Journal of ethnopharmacology Saussurea costus (Falc.) Lipschitz, syn Saussurea lappa C.B. Clarke is a well known and important medicinal plant widely used in several indigenous systems of medicine for the treatment of various ailments, viz. asthma, inflammatory diseases, ulcer and stomach problems. Sesquiterpene lactones have been reported as the major phytoconstituents of this species. Different pharmacological experiments in a number of in vitro and in vivo models have convincingly demonstrated the ability of Saussurea costus to exhibit anti-inflammatory, anti-ulcer, anticancer and hepatoprotective activities, lending support to the rationale behind several of its traditional uses. Costunolide, dehydrocostus lactone and cynaropicrin, isolated from this plant, have been identified to have potential to be developed as bioactive molecules. Due to the remarkable biological activity of Saussurea costus and its constituents it will be appropriate to develop them as a medicine. The present review is an up-to-date and comprehensive analysis of the botany, chemistry, pharmacology and traditional and folkloric uses of Saussurea costus. 10.1016/j.jep.2006.12.033
    Effects of sesquiterpenoids from "Oriental incenses" on acetic acid-induced writhing and D2 and 5-HT2A receptors in rat brain. Okugawa H,Ueda R,Matsumoto K,Kawanishi K,Kato K Phytomedicine : international journal of phytotherapy and phytopharmacology Six sesquiterpenoids, namely jinkoh-eremol, agarospirol, alpha- and beta-santalols, dehydrocostus lactone and costunolide, isolated from oriental incenses inhibited acetic acid-induced writhing in mice. The incidence of writhing produced by jinkoh-eremol, alpha-santalol and costunolide were revealed by administration of naloxone (mu-, kappa- and delta-antagonists). Inhibitory activities of alpha-santalol on opioid receptors were shown only by the delta antagonist, but not by the mu- and kappa-antagonists. The delta2-antagonist, but not the delta-antagonist, inhibited the activity of alpha santalol. The mechanism of inhibitory activity on the opioid receptor by alpha-santalol was different from that of morphine. Alpha-santalol was shown to be the most potent of the six as an antagonist of dopamine D2 and serotonine 5-HT2A receptor binding. The effect of alpha-santalol, was the same as that of chlorpromazine as an antipsychotic agent, although alpha-santalol was less potent than chlorpromazine. 10.1016/S0944-7113(00)80063-X
    UPLC/MS/MS method for quantification and cytotoxic activity of sesquiterpene lactones isolated from Saussurea lappa. Kumar Ashish,Kumar Shiv,Kumar Dharmesh,Agnihotri Vijai K Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Saussurea lappa (Asteraceae) roots have been reputed for the usage in traditional medicinal systems of India, China and Japan for the treatment of various kinds of disorders such as anti-ulcer, anti-convulsant, anti-cancer, hepatoprotective, anti-arthritic and anti-viral activities. MATERIALS AND METHODS:Compounds were isolated using a column chromatographic technique. The root extract, fractions and isolated compounds were tested for cytotoxicity against A549 (human lung carcinoma) and C-6 (rat glioma) cells using the Sulphorhodamine B assay. Chromatographic separations of active sesquiterpene lactones were accomplished on BEH-HSS-T3 column at 25°C. RESULTS:Phytochemical investigation of Saussurea lappa root extract resulted in the isolation of isoalantolactone (1), β-cyclocostunolide (2) α-cyclocostunolide (3), 4-hydroxy-3,5-dimethoxycinnamyl-9-O-β-D-glucopyranoside (4), sucrose (5), and alantolactone (6). Their structures were determined by spectroscopic means. Ethanolic extract, chloroform fraction, compounds 1, 2, 3 and 6 possessed significant activity against both tested cells. The quantification was performed using the transitions of m/z 233/105 for isoalantolactone and m/z 233/105 for alantolactone respectively. Costunolide and dehydrocostus lactone were also characterised by comparison of MS/MS fragmentation pattern. CONCLUSIONS:This is the first study on simultaneous quantification of isoalantolactone and alantolactone by the UPLC/MS/MS method in Saussurea lappa. Our study against A549 and C-6 cells showed higher cytotoxicity. It is suggested that roots of Saussurea lappa might be a potential source of anticancer compounds. 10.1016/j.jep.2014.07.037
    The Genome-Wide Expression Profile of Saussurea lappa Extract on House Dust Mite-Induced Atopic Dermatitis in Nc/Nga Mice. Lim Hye-Sun,Ha Hyekyung,Shin Hyeun-Kyoo,Jeong Soo-Jin Molecules and cells Saussurea lappa has been reported to possess anti-atopic properties. In this study, we have confirmed the S. lappa's anti-atopic properties in Nc/Nga mice and investigated the candidate gene related with its properties using microarray. We determined the target gene using real time PCR in in vitro experiment. S. lappa showed the significant reduction in atopic dermatitis (AD) score and immunoglobulin E compared with the AD induced Nc/Nga mice. In the results of microarray using back skin obtained from animals, we found that S. lappa's properties are closely associated with cytokine-cytokine receptor interaction and the JAK-STAT signaling pathway. Consistent with the microarray data, real-time RT-PCR confirmed these modulation at the mRNA level in skin tissues from S. lappa-treated mice. Among these genes, PI3Kca and IL20Rβ were significantly downregulated by S. lappa treatment in Nc/Nga mouse model. In in vitro experiment using HaCaT cells, we found that the S. lappa components, including alantolactone, caryophyllene, costic acid, costunolide and dehydrocostus lactone significantly decreased the expression of PI3Kca but not IL20Rβ in vitro. Therefore, our study suggests that PI3Kca-related signaling is closely related with the protective effects of S. lappa against the development of atopic-dermatitis. 10.14348/molcells.2015.0062
    Anti-allergic effects of sesquiterpene lactones from the root of Aucklandia lappa Decne. Seo Chang-Seob,Lim Hye-Sun,Jeong Soo-Jin,Shin Hyeun-Kyoo Molecular medicine reports Aucklandia lappa Decne, a well-known traditional herbal medicine, is used for the treatment of asthma, rheumatism, coughs, tuberculosis and numerous other diseases. The present study evaluated the inhibitory effects of the three sesquiterpene lactones costunolide, dehydrocostus lactone, and alantolactone, isolated from a 70% methanolic extract of Aucklandia lappa, on the expression of chemokine mRNA in HaCaT human keratinocyte cells. The cytotoxicities of the compounds on HaCaT cells were evaluated using a Cell Counting Kit8 assay. Furthermore, the inhibitory effects of the three compounds on chemokine expression in tumor necrosis factor (TNF)‑α‑ and interferon (IFN)‑γ‑stimulated HaCaT cells were analyzed by reverse transcription-polymerase chain reaction analysis. Treatment with the compounds caused a significant reduction in the mRNA expression of a range of chemokines, including TARC/CCL17, MDC/CCL22, RANTES/CCL5 and interleukin‑8 in TNF-α and IFN-γ-stimulated HaCaT cells. The present study indicated that costunolide, dehydrocostus lactone and alantolactone may have the potential to be used for treating inflammatory skin disorders by suppressing chemokine expression. 10.3892/mmr.2015.4342
    Aucklandia costus (Syn. Saussurea costus): Ethnopharmacology of an endangered medicinal plant of the himalayan region. Nadda Rohit Kumar,Ali Aaliya,Goyal Renu Chib,Khosla Prem Kumar,Goyal Rohit Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Aucklandia costus Falc. a medicinal plant is native to the Himalayan region and synonymous with Saussurea costus, Saussurea lappa, and Aucklandia lappa. It has an ancient background of being used ethnopharmacologically for various body ailments. According to Ayurveda, Unani, Siddha, and Traditional Chinese Medicine, Costus roots are recommended for leukoderma, liver, kidney, blood disorders, Qi stagnation, and tridosha. Root and powder are used orally with warm water to cure gastric problems, and the paste is applied to the inflamed area to relieve pain. Root paste is applied on the skin to cure boils, blisters, and leprosy. AIM OF THE STUDY:The aim of the present review is to establish a correlation among the ethnopharmacological uses and scientific studies conducted on A. costus with chemical constituents, safety & toxicity data including future directions for its conservation with higher yield and effect. MATERIALS AND METHODS:The study was conducted by studying books, research papers, and literature in history, agroforestry, phytopharmacology of Himalayan plants using international databases, publication, Red data book, and reports. The search engines: Pubmed, Scopus, Wiley Inter-science, Indian Materia Medica, Science Direct, and referred journals are referenced. RESULTS:The literature collected from databases, journals, websites, and books mentioned the use of costus roots in local and traditional practices. CITES included A. costus in a critically endangered category due to lack of cultural practices and overexploitation from wild. A. costus roots are known since 13th century for use in ancient Ayurvedic products but the scientific evaluation is of future research interest. A correlation of traditional uses with scientific studies has been explored to assess the effect of root powder, extract, oil and isolated constituents: Costunolids, Saussureamine B and Dehydrocostus lactone etc. in gastric ulceration and lesions; inhibition of antigen-induced degranulation, mucin production, number of immune cells, eosinophils, and expression and secretion of Th2 cytokines (IL-4 and IL-13) in asthma. The inhibition of pro-inflammatory mediators is also reported by Cynaropicrin, Alantolactone, Caryophyllene, Costic acid. Also, the sesquiterpene lactones has profound effect in inhibition of inflammatory stages and induced apoptotic cascades in cancer. Very few data on the safety and toxicity of plant parts have been noted which needs to be evaluated scientifically. CONCLUSION:A. costus have been noted to have remarkable effect for gastric, hepatic, inflammatory, respiratory, cancer, skin problems but there were several errors in selection of plant material, authentification, selection of dose, assessment, selection of standard and control have been identified. Therefore, a schematic drug development and research strategy exploiting the potential of plant extract, fraction, products and probable constituents, costunolide, dehydrocostus lactone, cynaropicrin, saussureamine assuring dose-response relationship and safety may be determined under pre-clinical which may be extrapolated to clinical level. An evaluation of phytochemicals in A. costus collected from different geographical location in Himalayas may be drawn to identify and conserve the higher yielding plant. 10.1016/j.jep.2020.113199
    Effect of dehydrocostus lactone and costunolide from Saussurea root on the central nervous system in mice. Okugawa H,Ueda R,Matsumoto K,Kawanishi K,Kato A Phytomedicine : international journal of phytotherapy and phytopharmacology Saussurea root (Mokko in Japanese; root of Saussurea lappa, Compositae) is an aromatic stomachic and sedative in Oriental medicine. Four extracts of saussurea root were obtained by successively extracting with benzene, chloroform, methanol and water. Each of these extracts was tested for effects on the central nervous system (CNS) of mice by intraperitoneal administration, i. e. potentiation of hexobarbital sleeping time, body temperature alterations, antinociceptive effects, and spontaneous locomotor activity changes. The benzene extract was the most active and was then separated further into five fractions, 1,2,3,4, and 5 by column chromatography. Fraction 2 was shown to be the most active in the aforementioned assays. From this fraction dehydrocostus lactone and costunolide were isolated as the CNS active constituents. They were both active by the intraperitoneal, intragastric and intracerebroventricular routes of administration. They decreased both methamphetamine- and apomorphine-induced spontaneous motility. The level of homovanillic acid in the brain was increased following their administration, while the levels of monoamines and other metabolites were unchanged. Similar results were seen in chlorpromazine-treated mice. These results show that dehydrocostus lactone and costunolide can be considered as neuroleptics by resemblance of their pharmacological activities to chlorpromazine. 10.1016/S0944-7113(96)80028-6
    Sesquiterpene lactones derived from Saussurea lappa induce apoptosis and inhibit invasion and migration in neuroblastoma cells. Tabata Keiichi,Nishimura Yuki,Takeda Taiji,Kurita Masahiro,Uchiyama Taketo,Suzuki Takashi Journal of pharmacological sciences Neuroblastoma is among the most fatal of solid tumors in the pediatric age group, even when treated aggressively. Therefore, a new effective therapeutic drug(s) for neuroblastoma is urgently needed. To clarify the anticancer effects of the sesquiterpene lactones dehydrocostus lactone and costunolide, derived from Saussurea lappa, we examined the cytotoxic and migration/invasion-inhibitory effects of these compounds against neuroblastoma cell lines. Both the compounds exerted significant cytotoxicity against the neuroblastoma cell lines IMR-32, NB-39, SK-N-SH, and LA-N-1. Evidence of cellular apoptosis, such as nuclear condensation and membrane inversion, were observed after treatment with these compounds. Both compounds induced caspase-7 activation and PARP cleavage as confirmed by Western blotting. Furthermore, the sesquiterpene lactones also suppressed invasion and migration of the neuroblastoma cells. These results suggest that dehydrocostus lactone and costunolide are promising candidates for being developed into novel anticancer drugs effective against neuroblastoma. 10.1016/j.jphs.2015.01.002
    Costunolide and dehydrocostus lactone as inhibitors of killing function of cytotoxic T lymphocytes. Taniguchi M,Kataoka T,Suzuki H,Uramoto M,Ando M,Arao K,Magae J,Nishimura T,Otake N,Nagai K Bioscience, biotechnology, and biochemistry Costunolide and dehydrocostus lactone were isolated from an extract of mokko (Saussurea lappa Clarke) as inhibitors of killing activity of cytotoxic T lymphocytes (CTL). Mokko lactone was also isolated as an inactive compound from the extract. The structure-activity relationship indicated that alpha-methylene-gamma-butyrolactone is required for the inhibitory effect. Costunolide markedly inhibited the granule exocytosis and the production of inositol phosphates in response to anti-CD3 monoclonal antibody (mAb) stimulation at a concentration that did not affect the binding of anti-CD3 mAb. Tyrosine phosphorylation induced by crosslinking of CD3 molecules was significantly inhibited by costunolide in a dose-dependent manner. These results suggest that costunolide inhibits the killing activity of CTL through preventing the increase in tyrosine phosphorylation in response to the crosslinking of T-cell receptors. 10.1271/bbb.59.2064
    Inhibition of TNF-α-Induced Inflammation by Sesquiterpene Lactones from Saussurea lappa and Semi-Synthetic Analogues. Choodej Siwattra,Pudhom Khanitha,Mitsunaga Tohru Planta medica We investigated the tumor necrosis factor-alpha (TNF-) inhibitory activity of sesquiterpenes from root extracts. According to the hexane and EtOAc extracts showing significant activity with IC values of 0.5 and 1.0 µg/mL, respectively, chromatographic fractionation of the extracts was performed and led to the isolation of 10 sesquiterpenes (1: -10: ). Costunolide (1: ), a major compound, and dehydrocostus lactone (4: ) exhibited high efficiency in decreasing TNF- levels, with IC values of 2.05 and 2.06 µM, respectively. In addition, sesquiterpene analogues were synthesized to establish their structure-activity relationship (SAR) profile. Among the semi-synthetic analogues, compounds 6A: and 16: showed the most potent activity with IC values of 1.84 and 1.97 µM, respectively. More importantly, compound 6A: showed less toxicity than costunolide and 16: . These results provided the first SAR profile of sesquiterpene lactones and indicated that the -methylene--lactone moiety plays a crucial role in TNF- inhibition. Additionally, the epoxide derivative 6A: might represent a lead compound for further anti-TNF- therapies, owing to its potent activity and reduced toxicity. 10.1055/s-0043-120115
    Sesquiterpene lactones downregulate G2/M cell cycle regulator proteins and affect the invasive potential of human soft tissue sarcoma cells. Lohberger Birgit,Rinner Beate,Stuendl Nicole,Kaltenegger Heike,Steinecker-Frohnwieser Bibiane,Bernhart Eva,Bonyadi Rad Ehsan,Weinberg Annelie Martina,Leithner Andreas,Bauer Rudolf,Kretschmer Nadine PloS one Soft tissue sarcomas (STS) represent a rare group of malignant tumors that frequently exhibit chemotherapeutic resistance and increased metastatic potential. Many studies have demonstrated the great potential of plant-derived agents in the treatment of various malignant entities. The present study investigates the effects of the sesquiterpene lactones costunolide and dehydrocostus lactone on cell cycle, MMP expression, and invasive potential of three human STS cell lines of various origins. Both compounds reduced cell proliferation in a time- and dose-dependent manner. Dehydrocostus lactone significantly inhibited cell proliferation, arrested the cells at the G2/M interface and caused a decrease in the expression of the cyclin-dependent kinase CDK2 and the cyclin-dependent kinase inhibitor p27(Kip1). In addition, accumulation of cells at the G2/M phase transition interface resulted in a significant decrease in cdc2 (CDK1) together with cyclin B1. Costunolide had no effect on the cell cycle. Based on the fact that STS tend to form daughter cell nests and metastasize, the expression levels of matrix metalloproteinases (MMPs), which play a crucial role in extracellular matrix degradation and metastasis, were investigated by Luminex® technology and real-time RT-PCR. In the presence of costunolide, MMP-2 and -9 levels were significantly increased in SW-982 and TE-671 cells. Dehydrocostus lactone treatment significantly reduced MMP-2 and -9 expression in TE-671 cells, but increased MMP-9 level in SW-982 cells. In addition, the invasion potential was significantly reduced after treatment with both sesquiterpene lactones as investigated by the HTS FluoroBlock™ insert system. 10.1371/journal.pone.0066300
    Anti-allergic effects of sesquiterpene lactones from Saussurea costus (Falc.) Lipsch. determined using in vivo and in vitro experiments. Lee Bo-Kyung,Park Soo-Jin,Nam So-Yeon,Kang Saeromi,Hwang Jin,Lee Seung-Jin,Im Dong-Soon Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Saussurea costus (Falc.) Lipsch. root has been used in Asian traditional medicine for the treatment of asthma, rheumatism, and other conditions. S. costus extracts were shown to alleviate house dust mite-induced atopic-like dermatitis in Nc/Nga mice; besides, sesquiterpene lactones were isolated from S. costus extracts. AIMS OF THE STUDY:We aimed to investigate the effects of sesquiterpene lactones (alantolactone, costunolide, and dehydrocostuslactone) in allergic asthma using female Balb/c mice and rat RBL-2H3 mast cells. MATERIALS AND METHODS:Antigen-induced degranulation was assessed by measuring β-hexosaminidase activity in vitro. In addition, a murine ovalbumin-induced allergic asthma model was used to test the in vivo efficacy of sesquiterpene lactones. RESULTS:Sesquiterpene lactones inhibited antigen-induced degranulation, wherein dehydrocostuslactone > costunolide > alantolactone in potency. Administration of sesquiterpene lactones decreased the number of immune cells, particularly eosinophils, and reduced the expression and secretion of Th2 cytokines (IL-4 and IL-13) in the bronchoalveolar lavage fluid and lung tissues of mice with ovalbumin-induced allergic asthma. Histological studies showed that sesquiterpene lactones reduced inflammation and mucin production in the lungs. Similar to the in vitro study, dehydrocostuslactone showed the highest potency, followed by costunolide and alantolactone. CONCLUSION:These findings provide evidence that sesquiterpene lactones might be potential anti-allergic therapeutics. 10.1016/j.jep.2017.11.018
    Two naturally occurring terpenes, dehydrocostuslactone and costunolide, decrease intracellular GSH content and inhibit STAT3 activation. Butturini Elena,Cavalieri Elisabetta,de Prati Alessandra Carcereri,Darra Elena,Rigo Antonella,Shoji Kazuo,Murayama Norie,Yamazaki Hiroshi,Watanabe Yasuo,Suzuki Hisanori,Mariotto Sofia PloS one The main purpose of the present study is to envisage the molecular mechanism of inhibitory action of dehydrocostuslactone (DCE) and costunolide (CS), two naturally occurring sesquiterpene lactones, towards the activation of signal transducer and activator of transcription 3 (STAT3). We report that, in human THP-1 cell line, they inhibit IL-6-elicited tyrosine phosphorylation of STAT3 and its DNA binding activity with EC(50) of 10 µM with concomitant down-regulation of the phosphorylation of the tyrosine Janus kinases JAK1, JAK2 and Tyk2. Furthermore, these compounds that contain an α-β-unsaturated carbonyl moiety and function as potent Michael reaction acceptor, induce a rapid drop in intracellular glutathione (GSH) concentration by direct interaction with it, thereby triggering S-glutathionylation of STAT3. Dehydrocostunolide (HCS), the reduced form of CS lacking only the α-β-unsaturated carbonyl group, fails to exert any inhibitory action. Finally, the glutathione ethylene ester (GEE), the cell permeable GSH form, reverts the inhibitory action of DCE and CS on STAT3 tyrosine phosphorylation. We conclude that these two sesquiterpene lactones are able to induce redox-dependent post-translational modification of cysteine residues of STAT3 protein in order to regulate its function. 10.1371/journal.pone.0020174
    Inhibition of inflammatory and proliferative responses of human keratinocytes exposed to the sesquiterpene lactones dehydrocostuslactone and costunolide. Scarponi Claudia,Butturini Elena,Sestito Rosanna,Madonna Stefania,Cavani Andrea,Mariotto Sofia,Albanesi Cristina PloS one The imbalance of the intracellular redox state and, in particular, of the glutathione (GSH)/GSH disulfide couple homeostasis, is involved in the pathogenesis of a number of diseases. In many skin diseases, including psoriasis, oxidative stress plays an important role, as demonstrated by the observation that treatments leading to increase of the local levels of oxidant species ameliorate the disease. Recently, dehydrocostuslactone (DCE) and costunolide (CS), two terpenes naturally occurring in many plants, have been found to exert various anti-inflammatory and pro-apoptotic effects on different human cell types. These compounds decrease the level of the intracellular GSH by direct interaction with it, and, therefore, can alter cellular redox state. DCE and CS can trigger S-glutathionylation of various substrates, including the transcription factor STAT3 and JAK1/2 proteins. In the present study, we investigated on the potential role of DCE and CS in regulating inflammatory and proliferative responses of human keratinocytes to cytokines. We demonstrated that DCE and CS decreased intracellular GSH levels in human keratinocytes, as well as inhibited STAT3 and STAT1 phosphorylation and activation triggered by IL-22 or IFN-γ, respectively. Consequently, DCE and CS decreased the IL-22- and IFN-γ-induced expression of inflammatory and regulatory genes in keratinocytes, including CCL2, CXCL10, ICAM-1 and SOCS3. DCE and CS also inhibited proliferation and cell-cycle progression-related gene expression, as well as they promoted cell cycle arrest and apoptosis. In parallel, DCE and CS activated the anti-inflammatory EGFR and ERK1/2 molecules in keratinocytes, and, thus, wound healing in an in vitro injury model. In light of our findings, we can hypothesize that the employment of DCE and CS in psoriasis could efficiently counteract the pro-inflammatory effects of IFN-γ and IL-22 on keratinocytes, revert the apoptosis-resistant phenotype, as well as inhibit hyperproliferation in the psoriatic epidermis. 10.1371/journal.pone.0107904
    Growth inhibitory, bactericidal, and morphostructural effects of dehydrocostus lactone from Magnolia sieboldii Leaves on antibiotic-susceptible and -resistant strains of Helicobacter pylori. Lee Hyun-Kyung,Song Ha Eun,Lee Haeng-Byung,Kim Cheol-Soo,Koketsu Mamoru,Ngan Luong Thi My,Ahn Young-Joon PloS one Helicobacter pylori is associated with various diseases of the upper gastrointestinal tract, such as gastric inflammation and duodenal and gastric ulcers. The aim of the study was to assess anti-H. pylori effects of the sesquiterpene lactone dehydrocostus lactone (DCL) from Magnolia sieboldii leaves, compared to commercial pure DCL, two previously known sesquiterpene lactones (costunolide and parthenolide), (-)-epigallocatechin gallate, and four antibiotics. The antibacterial activity of natural DCL toward antibiotic-susceptible H. pylori ATCC 700392 and H. pylori ATCC 700824 strains (MIC, 4.9 and 4.4 mg/L) was similar to that of commercial DCL and was more effective than costunolide, parthenolide, and EGCG. The activity of DCL was slightly lower than that of metronidazole (MIC, 1.10 and 1.07 mg/L). The antibacterial activity of DCL was virtually identical toward susceptible and resistant strains, even though resistance to amoxicillin (MIC, 11.1 mg/L for PED 503G strain), clarithromycin (49.8 mg/L for PED 3582GA strain), metronidazole (21.6 mg/L for H. pylori ATCC 43504 strain; 71.1 mg/L for 221 strain), or tetracycline (14.2 mg/L for B strain) was observed. This finding indicates that DCL and the antibiotics do not share a common mode of action. The bactericidal activity of DCL toward H. pylori ATCC 43504 was not affected by pH values examined (4.0-7.0). DCL caused considerable conversion to coccoid form (94 versus 49% at 8 and 4 mg/L of DCL for 48 h). The Western blot analysis revealed that urease subunits (UreA and UreB) of H. pylori ATCC 43504 were not affected by 10 mM of DCL, whereas UreA monomer band completely disappeared at 0.1 mM of (-)-epigallocatechin gallate. Global efforts to reduce the level of antibiotics justify further studies on M. sieboldii leaf-derived materials containing DCL as potential antibacterial products or a lead molecule for the prevention or eradication of drug-resistant H. pylori. 10.1371/journal.pone.0095530
    Costunolide and Dehydrocostuslactone, two natural sesquiterpene lactones, ameliorate the inflammatory process associated to experimental pleurisy in mice. Butturini Elena,Di Paola Rosanna,Suzuki Hisanori,Paterniti Irene,Ahmad Akbar,Mariotto Sofia,Cuzzocrea Salvatore European journal of pharmacology The aim of this study was to investigate the effect of costunolide (CS) and dehydrocostuslactone (DCE) a well-known sesquiterpene lactones contained in many plants, in a model of lung injury induced by carrageenan administration in the mice. Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by fluid accumulation in the pleural cavity which contained a large number of polymorphonuclear cells (PMNs) as well as an infiltration of PMNs in lung tissues and increased production of tumour necrosis factor α (TNF-α). All parameters of inflammation were attenuated by CS and DCE (15mg/kg 10% DMSO i.p.) administered 1h before carrageenan. Carrageenan induced an up regulation of the intracellular adhesion molecules-1 (ICAM-1) and P-selectin, as well as nitrotyrosine and poly (ADP-ribose) (PAR) as determined by immunohistochemical analysis of lung tissues. The degree of staining for the ICAM-1, P-selectin, nitrotyrosine and PAR was reduced by CS and DCE. Additionally we show that this inflammatory events were associated with NF-κB and STAT3 activation and these sesquiterpenes down-regulated it. Taken together, ours results clearly shown that CS and DCE may offer a novel therapeutic approach for the management of inflammatory diseases. 10.1016/j.ejphar.2014.02.031
    Costunolide and dehydrocostuslactone combination treatment inhibit breast cancer by inducing cell cycle arrest and apoptosis through c-Myc/p53 and AKT/14-3-3 pathway. Peng Zhangxiao,Wang Yan,Fan Jianhui,Lin Xuejing,Liu Chunying,Xu Yang,Ji Weidan,Yan Chao,Su Changqing Scientific reports Our previous studies demonstrated that volatile oil from saussurea lappa root (VOSL), rich in two natural sesquiterpene lactones, costunolide (Cos) and dehydrocostuslactone (Dehy), exerts better anti-breast cancer efficacy and lower side effects than Cos or Dehy alone in vivo, however, their anti-cancer molecular mechanisms were still unknown. In this study, we investigated the underlying mechanisms of Cos and Dehy combination treatment (CD) on breast cancer cells through proteomics technology coupled with Western blot validation. Ingenuity Pathways Analysis (IPA) results based on the differentially expressed proteins revealed that both VOSL and CD affect the 14-3-3-mediated signaling, c-Myc mediated apoptosis signaling and protein kinase A (PKA) signaling. Western blot coupled with cell cycle and apoptosis analysis validated the results of proteomics analysis. Cell cycle arrest and apoptosis were induced in a dose-dependent manner, and the expressions of p53 and p-14-3-3 were significantly up-regulated, whereas the expressions of c-Myc, p-AKT, p-BID were significantly down-regulated, furthermore, the ratio of BAX/BCL-2 were significantly increased in breast cancer cells after CD and VOSL treatment. The findings indicated that VOSL and CD could induce breast cancer cell cycle arrest and apoptosis through c-Myc/p53 and AKT/14-3-3 signaling pathways and may be novel effective candidates for breast cancer treatment. 10.1038/srep41254
    Potential anti-cancer activities and mechanisms of costunolide and dehydrocostuslactone. Lin Xuejing,Peng Zhangxiao,Su Changqing International journal of molecular sciences Costunolide (CE) and dehydrocostuslactone (DE) are derived from many species of medicinal plants, such as Saussurea lappa Decne and Laurus nobilis L. They have been reported for their wide spectrum of biological effects, including anti-inflammatory, anticancer, antiviral, antimicrobial, antifungal, antioxidant, antidiabetic, antiulcer, and anthelmintic activities. In recent years, they have caused extensive interest in researchers due to their potential anti-cancer activities for various types of cancer, and their anti-cancer mechanisms, including causing cell cycle arrest, inducing apoptosis and differentiation, promoting the aggregation of microtubule protein, inhibiting the activity of telomerase, inhibiting metastasis and invasion, reversing multidrug resistance, restraining angiogenesis has been studied. This review will summarize anti-cancer activities and associated molecular mechanisms of these two compounds for the purpose of promoting their research and application. 10.3390/ijms160510888
    [Pharmacokinetics study on costunolide and dehydrocostuslactone after administration of traditional Chinese medicine Weichang'an pills]. Zhang Jing-ze,Wang Lei,Jin Zhao-xiang,Qu Zhuo,Chen Yu-ling,Gao Wen-yuan Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica A HPLC-MS/MS multiple-reaction monitoring (MRM) quantitative analysis was made to establish a determination method for drug concentrations of costunolide (Co) and dehydrocostuslactone (De) in blood samples in the positive ion mode, with diazepam as the internal standard substance, in order to study the pharmacokinetic process of sesquiterpene lactones costunolide and dehydrocostuslactone after the oral administration of Weichang'an pills, and provide an theoretical basis for further studies on the substance basis for the anti-diarrhea effect of Weichang'an pills. In the blood samples, Co and De showed a good linearity within concentration ranges 0.700 0-769.7, 2.510-956.0 μg x L(-1), respectively. The results of precision, stability and recovery experiences proved the stability and reliability of the plasma concentration determination method. After the oral administration, the concentrations of Co and De in plasma increased with the increase in dose, with T(max) between 10.65-12.98 h, indicating a long time to reach peak plasma concentrations; C(max) of costunolide and dehydrocostuslactone ranged between 3.750-5.450,15.34-44.52 μg x L(-1), respectively. The in vivo adsorption of Co and De conformed to the one-compartment model, with a longer time to attain the peak plasma concentrations. These results provided an experimental basis for revealing the active substance basis and clinical medication of Weichang'an pills.
    Evaluation of protective effects of costunolide and dehydrocostuslactone on ethanol-induced gastric ulcer in mice based on multi-pathway regulation. Zheng Hong,Chen Yuling,Zhang Jingze,Wang Lei,Jin Zhaoxiang,Huang Hanhan,Man Shuli,Gao Wenyuan Chemico-biological interactions The aim of the present study was to evaluate the anti-ulcerogenic activity of costunolide (Co) and dehydrocostuslactone (De) on ethanol-induced gastric ulcer in mice and to elucidate the potential mechanisms of the action involved. Mice were pretreated orally with Co (5 or 20 mg/kg), De (5 or 20 mg/kg) and omeprazole (OME, 20 mg/kg) for 7 consecutive days, followed by ulcer induction using absolute ethanol (0.2 mL/20 g body weight). Treatment with Co had a remarkable gastroprotection compared to the ethanol-ulcerated mice that significantly reduced the ulcerative lesion index (ULI) and histopathological damage. Daily intragastric administration of Co exerted a powerful anti-inflammatory activity as evidenced by the suppression of nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α, nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, as well as increased interleukin (IL)-10. Also, pretreatment with Co effectively inhibited ethanol-induced malondialdehyde (MDA) overproduction, increased the depleted superoxide dismutase (SOD) and promoted gastric mucosa epithelial cell proliferation by up-regulating proliferating cell nuclear antigen (PCNA) expression. Similarly, De had a protective effect on ethanol-induced ulcer, which was dependent on the inhibition of inflammatory cytokines and MDA generation, but independent of IL-10, SOD and PCNA improvement. Conclusively, the results have clearly demonstrated the anti-ulcerogenic potential of Co and De on ethanol-induced gastric ulcer; nevertheless, the gastroprotective activity of Co was superior to De due to more multi-pathway regulation than De. These findings suggested that Co or De could be a new useful natural gastroprotective tool against gastric ulcer, which provided a scientific basis for the gastroprotection of sesquiterpene lactones. 10.1016/j.cbi.2016.03.003
    Costunolide and dehydrocostuslactone from Saussurea lappa root inhibit autophagy in hepatocellular carcinoma cells. Okubo Shinya,Ohta Tomoe,Fujita Hideaki,Shoyama Yukihiro,Uto Takuhiro Journal of natural medicines Autophagy is a catabolic process for degradation of intracellular components and plays an important role in the development and growth of cancer. Our preliminary screening confirmed that an extract from the root of Saussurea lappa remarkably suppressed the proliferation of HepG2 hepatocellular carcinoma cells and inhibited autophagy. In this study, we explored the effects of costunolide (CL) and dehydrocostuslactone (DCL), which are bioactive sesquiterpene lactones in this extract, on autophagy modulation in HepG2 cells. An analysis of autophagy-related proteins demonstrated that CL and DCL blocks the autophagy process that leads to the accumulation of microtubule-associated protein 1 light chain 3 (LC3) and SQSTM1/p62 (p62). LC3 turnover assays indicated that CL and DCL trigger autophagy inhibition by blocking the autophagic flux, thereby resulting in the accumulation of LC3-II and p62. These results are encouraging and warrant further study of CL and DCL for potential use as autophagy inhibiting agents for liver cancer therapy. 10.1007/s11418-020-01462-1
    Study on the pharmacokinetics and metabolism of costunolide and dehydrocostus lactone in rats by HPLC-UV and UPLC-Q-TOF/MS. Peng Zhangxiao,Wang Yan,Gu Xue,Guo Xiaojie,Yan Chao Biomedical chromatography : BMC A method based on high-performance liquid chromatography coupled with ultraviolet detection was developed for studying the pharmacokinetics of costunolide (Cos) and dehydrocostus lactone (Dehy) in rats after intravenous (i.v.) administration. Following i.v. administration, the maximum plasma concentrations of Cos and Dehy were observed to be 12.29 ± 1.47 and 5.79 ± 0.13 µg/mL, respectively. The bioavailability of Cos was larger than that of Dehy; however, the clearance and the volume of distribution of Dehy were much larger than those of Cos. An ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry system with automated MS(E) (E represents collision energy) data analysis software (MetaboLynx(TM)) was used to analyze and identify the metabolites of Cos and Dehy in vivo. Four metabolites of Cos and six metabolites of Dehy were discovered from the plasma, urine and feces of rats. The main metabolic pathway of Cos was phase II biotransformation, but the main metabolic pathways of Dehy was phase І biotransformation. Two sequential desaturations and N-acetylcysteine conjugation were the common metabolic pathways of Cos and Dehy in rats. This information may be useful for the further development of the two drug candidates. 10.1002/bmc.3167
    Effect of costunolide and dehydrocostus lactone on cell cycle, apoptosis, and ABC transporter expression in human soft tissue sarcoma cells. Kretschmer Nadine,Rinner Beate,Stuendl Nicole,Kaltenegger Heike,Wolf Elisabeth,Kunert Olaf,Boechzelt Herbert,Leithner Andreas,Bauer Rudolf,Lohberger Birgit Planta medica Human soft tissue sarcomas represent a rare group of malignant tumours that frequently exhibit chemotherapeutic resistance and increased metastatic potential following unsuccessful treatment. In this study, we investigated the effects of costunolide and dehydrocostus lactone, which have been isolated from Saussurea lappa using activity-guided isolation, on three soft tissue sarcoma cell lines of various origins. The effects on cell proliferation, cell cycle distribution, apoptosis induction, and ABC transporter expression were analysed. Both compounds inhibited cell viability dose- and time-dependently. IC50 values ranged from 6.2 µg/mL to 9.8 µg/mL. Cells treated with costunolide showed no changes in cell cycle, little in caspase 3/7 activity, and low levels of cleaved caspase-3 after 24 and 48 h. Dehydrocostus lactone caused a significant reduction of cells in the G1 phase and an increase of cells in the S and G2/M phase. Moreover, it led to enhanced caspase 3/7 activity, cleaved caspase-3, and cleaved PARP indicating apoptosis induction. In addition, the influence of costunolide and dehydrocostus lactone on the expression of ATP binding cassette transporters related to multidrug resistance (ABCB1/MDR1, ABCC1/MRP1, and ABCG2/BCRP1) was examined using real-time RT-PCR. The expressions of ABCB1/MDR1 and ABCG2/BCRP1 in liposarcoma and synovial sarcoma cells were significantly downregulated by dehydrocostus lactone. Our data demonstrate for the first time that dehydrocostus lactone affects cell viability, cell cycle distribution and ABC transporter expression in soft tissue sarcoma cell lines. Furthermore, it led to caspase 3/7 activity as well as caspase-3 and PARP cleavage, which are indicators of apoptosis. Therefore, this compound may be a promising lead candidate for the development of therapeutic agents against drug-resistant tumours. 10.1055/s-0032-1315385
    Inhibition of Wnt/β-Catenin Pathway by Dehydrocostus Lactone and Costunolide in Colon Cancer Cells. Dong Guang-Zhi,Shim Ah-Ram,Hyeon Jin Seong,Lee Hwa Jin,Ryu Jae-Ha Phytotherapy research : PTR Abnormal activation of β-catenin has been reported in 90% in the sporadic and hereditary colorectal cancer. The suppression of abnormally activated β-catenin is one of the good strategies for chemoprevention and treatment of colorectal cancer. In this study, we have isolated two main compounds from root of Saussurea lappa, dehydrocostus lactone (DCL) and costunolide (CL), and investigated their anti-colorectal cancer activities. DCL and CL suppressed cyclin D1 and survivin through inhibiting nuclear translocation of β-catenin. They also suppressed the nuclear translocation of galectin-3 that is one of the coactivators of β-catenin in SW-480 colon cancer cells. Furthermore, DCL and CL suppressed proliferation and survival of SW-480 colon cancer cells through the induction of cell cycle arrest and cell death. Taken together, DCL and CL from root of S. lappa have anti-colorectal cancer activities through inhibiting Wnt/β-catenin pathway. 10.1002/ptr.5299
    Amelioration of Benign Prostatic Hyperplasia by Costunolide and Dehydrocostus Lactone in Wistar Rats. Choi Dohyun,Kim Jiyeon,An Jinho,Hong Seonhwa,Song Youngcheon,Kong Hyunseok The world journal of men's health PURPOSE:Sesquiterpene lactones, which are found in plants of the Asteraceae family, contain costunolide (CO) and dehydrocostus lactone (DCL) as indicator material. CO, in particular, has been reported to possess varied pharmacological activity, including anti-inflammatory, antibacterial, and antioxidant effects. This study was designed to characterize the effects of CO and DCL on benign prostate hyperplasia (BPH). MATERIALS AND METHODS:Rats were injected subcutaneously daily for 8 weeks with 5 mg/kg testosterone to induce prostatic hyperplasia. Wistar rats were randomly divided into 5 groups of 10 animals each and received the following treatment: I. Normal control group; II. BPH-induced group; III. CO group (0.075 mg/kg); IV. DCL group (0.075 mg/kg); and V. Finasteride group (0.8 mg/kg). After treatment, changes in prostate weight and serum biochemical indices, serum dihydrotestosterone level, and mRNA levels of were measured and histological examinations performed. RESULTS:Absolute and relative prostate weight in the indicator material treated groups, as well as prostate volume, decreased compared to those in the disease-induced group. Epithelial cell thickness increased significantly in the disease-induced group, with a significant decrease being observed in the CO group. The level of the anti-apoptotic protein (B-cell lymphoma 2) tended to decrease to a greater extent in the DCL group than in the disease-induced group. CONCLUSIONS:In this study, we confirmed that the indicator materials (CO and DCL) can help suppress the development of BPH. 10.5534/wjmh.190053
    Antitumor activity and mechanism of costunolide and dehydrocostus lactone: Two natural sesquiterpene lactones from the Asteraceae family. Li Qijuan,Wang Zhanguo,Xie Yu,Hu Huiling Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Costunolide (COS) and dehydrocostus lactone (DEH) are two natural sesquiterpene lactones with potential antitcancer activity against a range of cancer cell types both in vitro and in vivo, particularly for breast cancer and leukemia. There are many researches that have been taken to characterize these pathways and to reveal their anticancer mechanisms of action of COS and DEH. However, while there is a great deal of evidence detailing the effects of COS and DEH on considerable signaling pathways and cellular functions, a global view of their mechanism of action remains elusive. This review systematically summarizes the antitumor activity and mechanism of COS and DEH in the recent reports, and discusses the effect of the key active part (α-methylene-γ-butyrolactone) of COS and DEH against cancer. Moreover, we also discuss the antineoplastic activity of COS and DEH derivatives to improve the cytotoxicity and safety index. We believe this review can provide a systemic reference to develop COS and DEH as anticancer agents. 10.1016/j.biopha.2020.109955
    Analysis of the similarities and differences between Auclandia and Vladimirae rhizomes by chemical profiling and chemometric analysis. Chen Ziqiang,Li Qijuan,Yu Ziwei,Yan Xiaomin,Wang Wenjun,Xie Yu,Hu Huiling,Wang Zhanguo Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Aucklandiae Radix (AR) and Vladimiriae Radix (VR), as traditional Chinese medicine, have been included in many editions of Chinese Pharmacopoeia with similar efficacy such as promoting qi and relieving pain, which are used to treat chest, hypochondriac, abdominal fullness and pain, diarrhea and tenesmus. In most conditions, VR is used to be a substitute of AR or a local habit. However, whether VR could substitute for AR to play a same role in the formulation and clinical applications needs further study. AIM OF THE STUDY:In this study, similarities and differences between AR and VR would be assessed, and possible reasons that may influence the efficacy of the AR and VR would be explained from the perspective of chemical composition. MATERIALS AND METHODS:HPLC-PDA was used to obtain the data of 10 batches of AR and VR, and to establish chemical fingerprint and chemometric analysis. UPLC-ESI-Q-TOF-MS was used to identify the structure of chemical compounds which contributed to the differences between AR and VR. RESULTS:The chemical fingerprint analysis results showed that 20 peaks in common for AR and 26 peaks in common for VR both presented a good similarity (>0.9), and 15 peaks in common for AR and VR also showed a good similarity (>0.9). Nevertheless, chemometric showed AR was distinct from VR and three chemical compounds, which leading to their differences, were identified by UPLC-ESI-Q-TOF-MS. The three chemical compounds were 3β-acetoxy-11β-guaia-4 (15),10 (14)-diene-12,6α-olide, 10α,14-epoxy-11β-guaia-4 (15)-ene-12,6α-olide and costunolide, respectively. CONCLUSION:In general, AR and VR were highly similar, but their differences were deserved to be paid attention to. This research could provide reference for quality control and set a foundation for clinical applications of AR and VR. 10.1016/j.jep.2020.112719
    Sequential loading of inclusion complex/nanoparticles improves the gastric retention of Vladimiriae Radix essential oil to promote the protection of acute gastric mucosal injury. Yan Xiaomin,Huang Zecheng,Wu Yuyi,Yu Ziwei,Yang Ke,Chen Ziqiang,Wang Wenjun,Hu Huiling,Wang Zhanguo International journal of pharmaceutics The essential oil from Vladimiriae Radix (VEO) is a medicinal natural product with anti-ulcer activity. A novel gastroretentive drug delivery system was developed by preparing the hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex incorporated into chitosan nanoparticles (V-CD/NPs), to improve the bioavailability of VEO and its protective effect on gastric mucosa. The optimum preparation process of V-CD/NPs was obtained by Plackett-Burman and Box-Behnken response surface methodology. The resulting V-CD/NPs gained a suitable positive potential and small particle size, and showed stability in simulated gastric fluid, whose morphology and in vitro drug release profiles had a pH-sensitivity. Besides, V-CD/NPs was proved to strongly bind with mucin, and in vivo imaging revealed that it could be retained in the stomach for more than 8 h. The results of drug concentration in gastric tissues showed that the sequential loading of inclusion complex/nanoparticles promoted the local absorption of VEO in gastric tissues, which was favorable to reach the effective therapeutic concentration in the lesioned mucosa area. In comparison to VEO and V-CD, the callback effect of V-CD/NPs on 1L-1β, 1L-6, TNF-α, NF-κB, MDA and SOD was comparable to cimetidine, and V-CD/NPs outperformed in gastric mucosal protection. Therefore, the gastroretentive drug delivery system developed in our study effectively enhanced the anti-ulcer activity of VEO, which could be a promising strategy for the prevention and treatment of the acute gastric mucosal injury. 10.1016/j.ijpharm.2021.121234
    Comparative study of raw and processed Vladimiriae Radix on pharmacokinetic and anti-acute gastritis effect through anti-oxidation and anti-inflammation. Wang Wenjun,Li Qijuan,Yan Xiaomin,Chen Ziqiang,Xie Yu,Hu Huiling,Wang Zhanguo Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Vladimiriae Radix (VR) is the dry root of Vladimiria souliei (Franch.) Ling or Vladimiria souliei (Franch.) Ling var. cinerea Ling. Costunolide (CO) and dehydrocostus lactone (DE) are the two most effective active ingredients of VR. Raw Vladimiriae radix (rVR) and processed Vladimiriae radix (pVR) are the two most common forms. They have been used for hundreds of years to treat gastritis, gastric ulcer and gastrointestinal pain, but their protective effects on gastric mucosa have been widely considered to be different, and the mechanism is not clear. PURPOSE:A comparative study of in vivo process and efficacy difference of raw and processed Vladimiriae Radix was carried out to explore the treatment mechanism and to provide reference for the rationality of clinical usage. METHODS:In this study, multi-batch rVR and pVR were used to establish the characteristic chromatograms through high performance liquid chromatography (HPLC) to control the qualities of their extracts. A rapid and accurate ultra-high performance liquid chromatography - mass spectrometry (UPLC-MS) method was established and verified, and the concentrations of CO and DE in plasma of rats after oral administration were determined to analyze the pharmacokinetics. The anti-inflammatory and antioxidant activities of ethanol-induced acute gastric mucosa injury (AGMI) in rats were quantitatively analyzed by ELISA and Westernblot methods. RESULTS:Characteristic chromatograms study showed that there were 9 common characteristic peaks between the chromatograms of rVR and pVR, and there was a high level (> 0.90) of the similarity between batches (only one batch less than 0.90). The increased levels of T, T and MRT were found in rats treated with the pVR. Animal model studies indicated that both the two forms of VR could relieve AGMI, but pVR could more effectively reduce the content of ethanol in blood and lower the levels of TNF-α, IL-6, IL-1β, NO, iNOS and MDA, and increase the level of SOD. Results of Westernblot proved that pVR also could inhibit the expression of NF-κB p65, IκBα and up-regulate the expression of HO-1 and NRF2 more operatively to protect gastric mucosa through anti-inflammatory and antioxidant stress mechanisms. CONCLUSION:Compared with rVR, pVR has an accelerated absorption in vivo and its effect time was prolonged, and the observed improvement of anti-AGMI effect was achieved through anti-oxidation and anti-inflammation regulation. 10.1016/j.phymed.2020.153224
    Study of the therapeutic effect of raw and processed Vladimiriae Radix on ulcerative colitis based on intestinal flora, metabolomics and tissue distribution analysis. Yu Zi-Wei,Xie Yu,Huang Ze-Cheng,Yang Ke,Wang Zhan-Guo,Hu Hui-Ling Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:The intestinal flora imbalance and metabolic disorders are closely related to the pathogenesis of ulcerative colitis (UC). As a commonly used herb for the treatment of gastrointestinal diseases, Vladimiriae Radix (VR) has been used for hundreds of years, and its main active ingredients are costunolide (COS) and dehydrocostus lactone (DEH). Clinical usage habits and previous studies have shown that the processed Vladimiriae Radix (pVR) seems to be more suitable for treating bowel disease than the raw Vladimiriae Radix (rVR), but there is still no relevant comparative study. PURPOSE:To investigate the therapeutic effect of rVR and pVR on UC by analyzing the intestinal flora, metabolomics and tissue distribution. METHODS:UC rat models were established to investigate the anti-inflammatory activities of rVR and pVR by enzyme-linked immunosorbent assay (ELISA), and to study their regulation of intestinal flora and metabolism by 16s rRNA gene analysis and Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). Moreover, the distribution of COS and DEH in UC mouse tissues were also observed by High Performance Liquid Chromatography Mass Spectrometry (HPLC-MS). RESULTS:rVR and pVR reduced tissue damage and the levels of TNF-α, IL-6, IL-1β, IL-10, TGF-β and MPO, especially pVR. 16s rRNA gene analysis showed that rVR superior in ameliorating species evenness and restoring the abundance of Lachnospiraceae and Ruminococcaceae, while pVR is better at increasing the richness and the abundance of Prevotellaceae. Metabolomics analysis suggested that rVR regulates the β-alanine, pantothenic acid and coenzyme A biosynthesis, but pVR regulates more abundant metabolic pathways. The tissue distribution data indicated the accumulation of COS and DEH in the gastrointestinal tract. CONCLUSION:rVR and pVR had obvious therapeutic effect on UC. The potential mechanisms might be regulating abnormal metabolism, affecting the diversity and structure of intestinal flora, and accumulation of COS and DEH in colon. 10.1016/j.phymed.2021.153538
    Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo. Huang Hai,Park Song,Zhang Haibo,Park Sijun,Kwon Wookbong,Kim Enugyung,Zhang Xiujuan,Jang Soyoung,Yoon Duhak,Choi Seong-Kyoon,Yi Jun-Koo,Kim Sung-Hyun,Dong Zigang,Lee Mee-Hyun,Ryoo Zaeyoung,Kim Myoung Ok Journal of experimental & clinical cancer research : CR BACKGROUND:Colorectal cancer (CRC) is a clinically challenging malignant tumor worldwide. As a natural product and sesquiterpene lactone, Costunolide (CTD) has been reported to possess anticancer activities. However, the regulation mechanism and precise target of this substance remain undiscovered in CRC. In this study, we found that CTD inhibited CRC cell proliferation in vitro and in vivo by targeting AKT. METHODS:Effects of CTD on colon cancer cell growth in vitro were evaluated in cell proliferation assays, migration and invasion, propidium iodide, and annexin V-staining analyses. Targets of CTD were identified utilizing phosphoprotein-specific antibody array; Costunolide-sepharose conjugated bead pull-down analysis and knockdown techniques. We investigated the underlying mechanisms of CTD by ubiquitination, immunofluorescence staining, and western blot assays. Cell-derived tumour xenografts (CDX) in nude mice and immunohistochemistry were used to assess anti-tumour effects of CTD in vivo. RESULTS:CTD suppressed the proliferation, anchorage-independent colony growth and epithelial-mesenchymal transformation (EMT) of CRC cells including HCT-15, HCT-116 and DLD1. Besides, the CTD also triggered cell apoptosis and cell cycle arrest at the G2/M phase. The CTD activates and induces p53 stability by inhibiting MDM2 ubiquitination via the suppression of AKT's phosphorylation in vitro. The CTD suppresses cell growth in a p53-independent fashion manner; p53 activation may contribute to the anticancer activity of CTD via target AKT. Finally, the CTD decreased the volume of CDX tumors without of the body weight loss and reduced the expression of AKT-MDM2-p53 signaling pathway in xenograft tumors. CONCLUSIONS:Our project has uncovered the mechanism underlying the biological activity of CTD in colon cancer and confirmed the AKT is a directly target of CTD. All of which These results revealed that CTD might be a new AKT inhibitor in colon cancer treatment, and CTD is worthy of further exploration in preclinical and clinical trials. 10.1186/s13046-021-01895-w
    Costunolide ameliorates intestinal dysfunction and depressive behaviour in mice with stress-induced irritable bowel syndrome colonic mast cell activation and central 5-hydroxytryptamine metabolism. Li Xi,Liu Qingqing,Yu Jiaoyan,Zhang Ruitao,Sun Ting,Jiang Wei,Hu Na,Yang Peng,Luo Li,Ren Jing,Wang Qinhui,Wang Yan,Yang Qi Food & function Irritable bowel syndrome (IBS) is a common chronic functional bowel disease, associated with a high risk of depression and anxiety. The brain-gut axis plays an important role in the pathophysiological changes involved in IBS; however, an effective treatment for the same is lacking. The natural compound costunolide (COS) has been shown to exert gastroprotective, enteroprotective, and neuroprotective effects, but its therapeutic effects in IBS are unclear. Our study explored the effect of COS on intestinal dysfunction and depressive behaviour in stress-induced IBS mice. Mice were subjected to chronic unpredictable mild stress to trigger IBS, and some were administered COS. Behavioural tests, histochemical assays, western blotting, and measurement of 5-hydroxytryptamine (5-HT) levels in the colon and hippocampus were applied to monitor the physiological and molecular consequences of COS treatment in IBS mice. COS administration relieved intestinal dysfunction and depression-like behaviours in IBS mice. Improvements in low-grade colon inflammation and intestinal mucosal permeability, inhibition of the activation of mast cells, upregulation of colonic Occludin expression, and downregulation of Claudin 2 expression were also observed. COS was also found to upregulate GluN2A, BDNF, p-ERK1/2, and p-CREB expression and 5-HT levels in hippocampal cells but inhibited 5-HT metabolism. Molecular docking showed that COS could form hydrogen bonds with the serotonin transporter (SERT) to affect the reuptake of 5-HT in the intercellular space. In conclusion, COS alleviates intestinal dysfunction and depressive behaviour in stress-induced IBS mice by inhibiting mast cell activation in the colon and regulating 5-HT metabolism in the central nervous system. 10.1039/d0fo03340e
    Costunolide-Induced Apoptosis via Promoting the Reactive Oxygen Species and Inhibiting AKT/GSK3β Pathway and Activating Autophagy in Gastric Cancer. Xu Cuixiang,Huang Xiaoyan,Lei Xiaohua,Jin Zhankui,Wu Min,Liu Xiao,Huang Yubin,Zhao Xiangrong,Xiong Yue,Sun Jingying,Duan Xianglong,Wang Jianhua Frontiers in cell and developmental biology Costunolide (Cos) is a sesquiterpene lactone extracted from chicory. Although it possesses anti-tumor effects, the underlying molecular mechanism against gastric cancer cells remains unclear. This study aimed to explore the effect and potential mechanism of Cos on gastric cancer. The effect of Cos on HGC-27 and SNU-1 proliferation was detected by CCK-8 and clone formation assay. The changes in cell apoptosis were determined using Hoechst 33258 and tunel staining. The morphology of autophagy was analyzed by autophagosomes with the electron microscope and LC3-immunofluorescence with the confocal microscope. The related protein levels of the cell cycle, apoptosis, autophagy and AKT/GSK3β pathway were determined by Western blot. The anti-tumor activity of Cos was evaluated by subcutaneously xenotransplanting HGC-27 into Balb/c nude mice. The Ki67 and P-AKT levels were examined by immunohistochemistry. Cos significantly inhibited HGC-27 and SNU-1 growth and induced cell cycle arrest in the G2/M phase. Cos activated intrinsic apoptosis and autophagy through promoting cellular reactive oxygen species (ROS) levels and inhibiting the ROS-AKT/GSK3β signaling pathway. Moreover, preincubating gastric carcinoma cells with 3-methyladenine (3-MA), a cell-autophagy inhibitor, significantly alleviated the effects of Cos in inducing cell apoptosis. Cos induced apoptosis of gastric carcinoma cells via promoting ROS and inhibiting AKT/GSK3β pathway and activating pro-death cell autophagy, which may be an effective strategy to treat gastric cancer. 10.3389/fcell.2021.722734
    Cardiorenal Protective Effect of Costunolide against Doxorubicin-Induced Toxicity in Rats by Modulating Oxidative Stress, Inflammation and Apoptosis. Molecules (Basel, Switzerland) Doxorubicin (DXB) is one of the most commonly used anticancer agents for treating solid and hematological malignancies; however, DXB-induced cardiorenal toxicity presents a limiting factor to its clinical usefulness in cancer patients. Costunolide (COST) is a naturally occurring sesquiterpene lactone with excellent anti-inflammatory, antioxidant and antiapoptotic properties. This study evaluated the effect of COST on DXB-induced cardiorenal toxicity in rats. Rats were orally treated with COST for 4 weeks and received weekly 5 mg/kg doses of DXB for three weeks. Cardiorenal biochemical biomarkers, lipid profile, oxidative stress, inflammatory cytokines, histological and immunohistochemical analyses were evaluated. DXB-treated rats displayed significantly increased levels of lipid profiles, markers of cardiorenal dysfunction (aspartate aminotransferase, creatine kinase, lactate dehydrogenase, troponin T, blood urea nitrogen, uric acid and creatinine). In addition, DXB markedly upregulated cardiorenal malondialdehyde, tumor necrosis factor-α, interleukin-1β, interleukin-6 levels and decreased glutathione, superoxide dismutase and catalase activities. COST treatment significantly attenuated the aforementioned alterations induced by DXB. Furthermore, histopathological and immunohistochemical analyses revealed that COST ameliorated the histopathological features and reduced p53 and myeloperoxidase expression in the treated rats. These results suggest that COST exhibits cardiorenal protective effects against DXB-induced injury presumably via suppression of oxidative stress, inflammation and apoptosis. 10.3390/molecules27072122
    Sesquiterpene lactones-rich fraction from Aucklandia lappa Decne. alleviates dextran sulfate sodium induced ulcerative colitis through co-regulating MAPK and Nrf2/Hmox-1 signaling pathway. Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Aucklandia lappa Decne. (ALDE) is the general name for Asteraceae plants Yunmuxiang, which has traditionally been proven to have the efficacy in relieving depression by regulating qi, alleviating cold by warming, attenuating pain in stomach and relieving diarrhea in intestines. Therefore, ALDE is always recommended as an herbal remedy for gastrointestinal dysfunction. AIM OF THE STUDY:The purpose of this study was to explore the therapeutic potential and mechanism of action of the sesquiterpene lactone-rich fraction (SLRF) of ALDE extracts in vivo and in vitro. MATERIALS AND METHODS:An aqueous extract (AE) and SLRF of ALDE were prepared and the contents of the main components were quantified by high performance liquid chromatography (HPLC). The therapeutic effects of the extracts were evaluated in C57BL/6 mice with dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). Body weight, disease activity index (DAI), and colon length were recorded, and histopathological changes in the colon were characterized using hematoxylin and eosin (H&E) staining. The in vitro anti-inflammatory activity and possible mechanisms of the two main sesquiterpene lactones in ALDE (costunolide and dehydrocostus lactone) were studied by quantitative proteomic analysis. Finally, based on bioinformatic analysis, we used polymerase chain reaction (PCR), immunofluorescence, and western blot experiments to verify the anti-inflammatory mechanism of the extracts in C57BL/6 mice. RESULTS:The SLRF of ALDE significantly improved the pathological symptoms and inflammatory pathology of UC, whereas the AE had a weak protective effect. In RAW264.7 cells stimulated with lipopolysaccharide (LPS), costunolide and dehydrocostus lactone significantly reduced the mRNA levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, suggesting that these two sesquiterpene lactones had strong anti-inflammatory activity. Quantitative proteomics results indicated that the anti-inflammatory mechanism of these lactones was associated with the NF-κB/MAPK and Nrf2-Hmox-1 pathways. These results were further validated in SLRF-treated mice. CONCLUSION:This study confirmed that the SLRF of ALDE exerted protective activity against UC by regulating the Nrf2-Hmox-1, NF-κB, and MAPK pathways. 10.1016/j.jep.2022.115401
    [Study of the effect of exceed critical extracts from Radix Aucklandiae on experimental gastric ulcer model]. Han Jian,Lin Huangquan,Zhong Zhiyong,Rong Xianglu Zhong yao cai = Zhongyaocai = Journal of Chinese medicinal materials OBJECTIVE:To study the effect of exceed critical extracts from Radix Aucklandiae (MXY for short) on many kinds of experimental gastric ulcer model. METHODS:The effect of MXY to the mice's gastric ulcer induced by hydrochloric acid-ethanol, reserpine, and chronic gastric ulcer induced by acetic acid were observed. RESULTS:Compared with model group, MXY had remarkable inhibition activity on the hydrochloirc acid-ethanol type acute gastric ulcer (P < 0.01). It also could obviously reduce the index of gastric ulcer induced by reserpine and chronic gastric ulcer induced by acetic acid (P < 0.05 - 0.01).
    Pharmacokinetic study on costunolide and dehydrocostuslactone after oral administration of traditional medicine Aucklandia lappa Decne. by LC/MS/MS. Zhang Jingze,Hu Xiao,Gao Wenyuan,Qu Zhuo,Guo Huimin,Liu Zhen,Liu Changxiao Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Radix Aucklandiae (RA), a well known traditional Chinese medicine, is widely used for treating various problems in digestive system. A selective and sensitive high-performance liquid chromatography coupled with mass spectrometry method was first developed and validated for simultaneous quantification of costunolide and dehydrocostuslactone in rat plasma with diazepam as internal standard after oral administration of RA extraction. MATERIALS AND METHODS:Plasma samples were extracted via solid-phase extraction and detected by multiple-reaction monitoring mode under positive electrospray. Chromatographic separation was accomplished on an Agilent C18 column (2.1 mm × 150 mm, 5 µm), with 0.1% formic acid and acetonitrile (1:1) as the mobile phase at a flow rate of 0.5 mL/min. RESULTS:The quantification was performed using the transitions of m/z 233/187 for costunolide, m/z 231/185 for dehydrocostuslactone and m/z 285/193 for diazepam, respectively. Calibration curves were linear over the concentration range of 0.7-769.7 ng/mL for costunolide and 0.9-956.0 ng/mL for dehydrocostuslactone. The intra-day and inter-day precisions (RSD%) for two compounds was less than 8.76% and 9.70% and the accuracy (RE%) range from 6.14% to 5.35%. The time to reach the maximum plasma concentration (Tmax) was 10.46 h for costunolide, 12.39 h dehydrocostuslactone. The elimination half-time (t1/2) of costunolide and dehydrocostuslactone was 5.54 ± 0.81 and 4.32 ± 0.71 (h). The AUC of costunolide and dehydrocostuslactone was 308.83 and 7884.51 respectively (ngh/mL). CONCLUSIONS:It was the first report for the study of pharmacokinetic profile of costunolide and dehydrocostuslactone in rat plasma after oral administration of RA extract. These results provided a meaningful basis for better understanding the absorption of traditional medicine, RA, and provide useful scientific data for clinical application. 10.1016/j.jep.2013.10.024
    Topical treatments of Saussurea costus root and Thuja orientalis L. synergistically alleviate atopic dermatitis-like skin lesions by inhibiting protease-activated receptor-2 and NF-κB signaling in HaCaT cells and Nc/Nga mice. Yang Hye Jeong,Kim Min Jung,Kang Suna,Moon Na Rang,Kim Da Sol,Lee Na Ra,Kim Kang Sung,Park Sunmin Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:The root of Saussurea costus (Aucklandia lappa Decne, Aucklandiae Radix, SC) and Thuja orientalis L. (TOL) have been traditionally used as anti-inflammatory agents in Korea. However, they have not been studied for the efficacy of atopic dermatitis (AD) treatment, a chronic inflammatory skin disease. We investigated the efficacy of topical applications with 1,3-butyleneglycol extracts of SC and TOL to alleviate the symptoms of AD. MATERIALS AND METHODS:HaCaT cells and the dorsal skin of Nc/Nga mice had a local exposure of house mite extracts and 2,4-dinitrochlorobenzene (DNCB), respectively. After lesions developed, we topically applied 1,3-butylen glycol (vehicle; control), SC (30%), TOL (30%), or SC (15%)+TOL (15%) to the skin lesions for 5 weeks. The normal-control was not exposed to DNCB. The skin thickness, mast cell infiltration, serum immunoglobulin E (IgE) and IgG1 and gene expressions of interleukin (IL)-4, IL-13, and IFN-γ in the dorsal skin and HaCaT cells were measured. RESULTS:Chlorogenic acid (129.6±10.2μg/g) for SC and catechin and apigenin (93.4±13.2 and 16.9±1.3μg/g, respectively) for TOL were used as indicator compounds for the strength of the extracts. SC+TOL decreased the expression of protease-activated receptor-2 and ICAM-1 and the release of TNF-α and IL-6 in HaCaT cells activated by 3μg/mL house mite extracts in comparison to either of SC or TOL alone. In Nc/Nga mice challenged with DNCB, SC+TOL synergistically attenuated clinical symptoms of AD such as erythema, hemorrhage, edema, excoriation and dryness in the dorsal skin better than either SC or TOL alone. Histological analysis of the dorsal skin also showed that SC+TOL treatment significantly and additively decreased the inflammatory cellular infiltrate, including mast cells and eosinophils in comparison to either of SC or TOL. SC+TOL also decreased serum IgE and IgG1 levels and the expression of IFN-γ, IL-4, and IL-13 mRNA in dorsal skin in DNCB-treated Nc/Nga mice. CONCLUSION:SC+TOL relieved the symptoms of AD by reducing pro-inflammatory activity and over-activated immune responses. These data suggest that SC+TOL may be an effective alternative intervention for the management of AD. 10.1016/j.jep.2017.01.055
    Costunolide induces mitochondria-mediated apoptosis in human gastric adenocarcinoma BGC-823 cells. Yan Zhanpeng,Xu Tingting,An Zhentao,Hu Ying,Chen Wanzhen,Ma Jinxia,Shao Changle,Zhu Fangshi BMC complementary and alternative medicine BACKGROUND:Costunolide, a sesquiterpene lactone extracted from Radix Aucklandiae, has the activity against multiple cancers. However, the effect of costunolide on gastric cancer (GC) have remained to be ambiguous. In this study, we investigated the underlying mechanisms of apoptosis induced by costunolide in human gastric adenocarcinoma BGC-823 cells in vitro and in vivo. METHODS:The viability of BGC-823 cells was detected by MTT assay. The apoptosis and mitochondrial membrane potential (ΔΨm) of BGC-823 cells induced by costunolide were analyzed by flow cytometry. The inhibiton of costunolide on human gastric adenocarcinoma was estimated in xenografts in nude mice. Apoptosis related proteins and genes were detected by Western blot and Q-PCR. RESULTS:Costunolide inhibited the viability of BGC-823 cells in a time and concentration dependent manner. Costunolide induced the apoptosis and lowered the ΔΨm of BGC-823 cells significantly. Costunolide increased the expression of Bax, cleaved caspase 9, cleaved caspase 7, cleaved caspase 3 and cleaved poly ADP ribose polymerase (PARP) proteins and decreased the expression of Bcl-2, pro-caspase 9, pro-caspase 7, pro-caspase 3 and PARP proteins. Costunolide upregulated the expression of puma, Bak1 and Bax mRNA and downregulated the expression of Bcl-2 mRNA. In addition, we demonstrated that costunolide inhibited the growth and induced apoptosis of BGC-823 cells xenografted in athymic nude mice. Costunolide increased the expression of cleaved caspase 9, cleaved caspase 3 and Bax proteins and decreased the expression of Bcl-2 protein in xenografted tumor. Costunolide upregulated the expression of puma and Bax mRNA and decreased the expression of Bcl-2 mRNA in xenografted tumor. CONCLUSIONS:Collectively, our results suggested that costunolide induced mitochondria-mediated apoptosis in human gastric adenocarcinoma BGC-823 cells and could be the candidate drug against GC in clinical practice. 10.1186/s12906-019-2569-6
    Costunolide improved dextran sulfate sodium-induced acute ulcerative colitis in mice through NF-κB, STAT1/3, and Akt signaling pathways. Xie Fan,Zhang Hai,Zheng Chuan,Shen Xiao-Fei International immunopharmacology Costunolide (CTL) is the major sesquiterpene lactone from Radix Aucklandiae, which is widely used on the treatment of gastrointestinal diseases. However, the therapeutic effect of costunolide in ulcerative colitis (UC) is still unknown. Herein, we sought to evaluate the therapeutic effects and underlying mechanisms of costunolide on UC. ICR mice were intraperitoneally administered with costunolide (10 mg/kg) for 10 days. Beginning on the 4th day of drug administration, acute colitis was induced by feeding 4% dextran sulfate sodium (DSS) for additional 7 days. Costunolide markedly attenuated DSS-induced body weight loss, colonic shortening, elevation in disease activity index, and pathological damage of colon, and decreased the number of CD4 T cells in colon tissues. Furthermore, costunolide significantly inhibited myeloperoxidase (MPO) activity and nitric oxide (NO) level in colon tissues in DSS-exposed mice. Meanwhile, costunolide also suppressed DSS-induced expression of induced nitric oxide synthase (iNOS), interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) in both mRNA and protein levels. Mechanistically, costunolide repressed the phosphorylation of nuclear factor kappa-B (NF-κB) p65 and degradation of inhibitor of NF-κB (IκB), as well as the excessive activation of signal transducers and activators of transcription 1/3 (STAT1/3) and serine/threonine protein kinase Akt (Akt) in colon tissues in DSS-challenged mice. These findings successfully demonstrated that costunolide ameliorated DSS-induced murine acute colitis by suppressing inflammation through inactivation of NF-κB, STAT1/3, and Akt pathways. These results also suggested that costunolide may be a potential therapeutic agent for the treatment of acute UC. 10.1016/j.intimp.2020.106567
    Costunolide ameliorates colitis via specific inhibition of HIF1α/glycolysis-mediated Th17 differentiation. Lv Qi,Xing Yao,Dong Dong,Hu Yang,Chen Qingzhu,Zhai Linhui,Hu Lihong,Zhang Yinan International immunopharmacology Ulcerative colitis (UC) is a chronic idiopathic inflammatory disorder of colon. Costunolide, the main active constituent of Radix Aucklandiae, has been demonstrated to possess anti-inflammatory and immunomodulation activities. The aim of this study is to investigate the effect of costunolide on UC induced by dextran sulfate sodium (DSS). Results showed that oral administration of costunolide significantly improved the disease active index (DAI), rescued the reduction of colon length, downregulated myeloperoxidase (MPO) activity, alleviated the pathological changes, and decreased the levels of proinflammatory cytokines in colons of colitis mice. Costunolide also rebalanced Th17/Treg cells in colons, mesenteric lymph nodes and spleen, as indicated by decreased percentages of Th17 cells and reduced mRNA expressions of Rorc, Il17a. Interestingly, the in vitro experiment showed that no significant change in dendritic cell maturation, mRNA expressions of Ifng, Il6 and Treg cell differentiation, but a significant decreased Th17 cell differentiation was observed upon costunolide treatment. Deeper mechanistic studies showed that costunolide triggered the prolyl hydroxylase 2 (PHD2)-triggered proline hydroxylation-ubiquitination-proteasome degradation of HIF-1α, which in turn inactivated glycolytic process in Th17 rather than Treg cells. These findings clearly suggest that inhibition of HIF-1α-mediated glycolysis by costunolide is specifically responsible for Th17 cell differentiation and subsequent alleviation of UC and sets the stage for a new perspective on immune-metabolism therapy for colitis. 10.1016/j.intimp.2021.107688
    A comprehensive chemical and pharmacological review of three confusable Chinese herbal medicine-Aucklandiae radix, Vladimiriae radix, and Inulae radix. Zhuang Kaiyan,Xia Qing,Zhang Shanshan,Maharajan Kannan,Liu Kechun,Zhang Yun Phytotherapy research : PTR Aucklandiae radix (AR, Muxiang), vladimiriae radix (VR, Chuanmuxiang), and inulae radix (IR, Tumuxiang) are widely used in clinical or folk medicine in China. Their Chinese names all have the Chinese character "Muxiang," which makes it confusable in usage, especially AR and VR, because VR was used as a substitute for AR during a historical period. The National Health Commission of the People's Republic of China has approved AR as a functional food. However, VR and IR are not listed. Many research articles on three kinds of "Muxiang" have been published. However, no review was appeared to compare similarities and differences among the three kinds of "Muxiang." Here, the morphological characterization, phytochemistry, and pharmaceutical effects of AR, VR, and IR were reviewed. We found that only six compounds were common in the three species. Twenty-six compounds were common to AR and VR. Twenty-two compounds were common to AR and IR. Only seven compounds were common to VR and IR. The extracts of AR, VR, and IR were all reported with antiinflammatory effects, which is the most important activity of "Muxiang" species. The volatile oil of AR, VR, and IR had antibacterial activities. Extracts of AR and VR showed anti-gastric ulcers and anti-diarrhea effects. Extracts of AR and IR exhibited anticancer effects. In addition, AR extract had liver protective effect. It is worth mentioning that costunolide and dehydrocostus lactone, which were the common representative compounds of "Muxiang" species, showed antiinflammatory, anticancer, anti-gastric ulcers, and liver protective effects. This review will be a benefit reference for correct understanding and application of the three "Muxiang" species. 10.1002/ptr.7250
    [Screening and identifying hepatotoxic components in Aucklandiae Radix with GC-MS]. Zhao Xiao-ping,Lu Lin,Hu Bin,Wang Shu-fang Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences OBJECTIVE:To screen the potential hepatotoxic components in Chinese herb medicine Aucklandiae Radix. METHODS:The potential hepatotoxic components were screened using HepG2 cells labeled with fluorescein diacetate from 25 fractions of Aucklandiae Radix, in which the hepatotoxic compounds were further identified with GC-MS. RESULTS:Ten potential hepatotoxic fractions were screened. The identification results by GC-MS indicated that the main compounds in C09 were dehydrocostuslactone, santamarine (or magnolialide) and reynosin, and in C11 were α-costol and elemol. CONCLUSION:Dehydrocostuslactone, santamarine (or magnolialide), reynosin, α-costol and elemol are potential hepatotoxic compounds in Aucklandiae Radix. 10.3785/j.issn.1008-9292.2012.01.007
    Gastrointestinal effect of methanol extract of Radix Aucklandiae and selected active substances on the transit activity of rat isolated intestinal strips. Guo Huimin,Zhang Jingze,Gao Wenyuan,Qu Zhuo,Liu Changxiao Pharmaceutical biology CONTEXT:Radix Aucklandiae, the dry rhizome of Aucklandia lappa Decne (Asteraceae), enjoyed traditional popularity for its antidiarrheal effects. Although there are many investigations on its chemical constituents and pharmacologic actions, few studies explaining its activity and mechanism in gastrointestinal disorders are available. OBJECTIVE:In this paper, we focused on the effects of the methanol extract of R. Aucklandiae (RA ext) on gastrointestinal tract, so as to assess some of the possible mechanisms involved in the clinical treatment. MATERIALS AND METHODS:In vivo, in neostigmine-induced mice and normal mice, after intragastric administration, RA ext (100, 200, 300, and 400 mg/kg) was studied on gastrointestinal transit including gastric emptying and small intestinal motility. Meanwhile, in vitro, the effect of it (0.1, 0.2, 0.3, and 0.4 mg/mL) on the isolated tissue preparations of rat jejunum was also investigated, as well as costunolide and dehydrocostuslactone which were the main constituents. RESULTS:In vivo, the gastric emptying increased and intestinal transit decreased after the administration of RA ext in normal mice. However, RA ext inhibited the gastric emptying and the intestinal transit throughout the concentrations in neostigmine-induced mice. In vitro, RA ext caused inhibitory effect on the spontaneous contraction of rat-isolated jejunum in a dose-dependent manner ranging from 0.1 to 0.4 mg/mL, and it also relaxed the acetylcholine chloride (Ach, 10(-5) M), 5-hydroxytryptamine (5-HT, 200 μM)-induced, and K(+) (60 mM)-induced contractions. RA ext shifted the Ca(2+) concentration-response curves to right, similar to that caused by verapamil (0.025 mM). The Ca(2+) concentration-response curves were shifted by costunolide (CO) (5.4, 8.1, and 10.8 μg/mL), dehydrocostuslactone (DE) (4.6, 6.9, and 9.2 μg/mL), costunolide-dehydrocostuslactone (CO-DE) (5.4-4.6, 8.1-6.9, and 10.8-9.2 μg/mL) to the right, similar to that caused by verapamil (0.01 mM). DISCUSSION AND CONCLUSION:These results indicate that RA ext played a spasmolytic role in gastrointestinal motility, which is probably mediated through the inhibition of muscarinic receptors, 5-HT receptors, and calcium influx. The presence of cholinergic and calcium antagonist constituents may be the compatibility of CO and DE. All these results provide a pharmacological basis for its clinical use in the gastrointestinal tract. 10.3109/13880209.2013.879601
    Effect and mechanism of ethanol extracts of muxiang (Radix Aucklandiae) on gastric ulcers in rats. Xu Yuannan,Guo Peixin,Wang Yulian,Xia Tingting,Shen Yue,Zhang Qing,Huang Jinhong,Chen Haifeng,Lei Na,Xie Yuhuan Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan OBJECTIVE:To investigate the effect of ethanol extracts of Muxiang (Radix Aucklandiae) (RA) on gastric ulcers in rats and explore the potential mechanisms. METHODS:A model was established by ethanol (0.75 mL/kg). According to body weight, rats were pretreated with RA extracts (2.5 or 5 g/kg). The rats were administered 95% ethanol orally after 1 h. The effects of ethanol were evaluated by measuring the gastric secretion volume, pH, pepsin activity, and ulcer area. Histological analysis and immunohistochemistry were also conducted. Furthermore, the effect of the ethanol extract of RA on transiting activity of the gastrointestinal tract was observed in mice. RESULTS:Intragastric administration of RA extracts protected the gastric mucosa from ethanol-induced gastric ulcers, while reducing submucosal edema and preventing hemorrhagic damage. Moreover, the extracts increased the production of gastric mucus, upregulated Bcl-2, and downregulated Bax expression. Importantly, pretreated rats exhibited no significant change in the gastric secretion volume, gastric juice acidity, or pepsin. Furthermore, pretreatment prominently (P < 0.05) enhanced propulsive movement of the gastrointestinal tract in normal mice and mice with gastrointestinal motility disorders. CONCLUSION:Ethanol extracts of RA ameliorated gastric lesions in the gastric ulcer rat model. The mechanisms of action were related to improvement of gastrointestinal dynamics, maintenance of mucus integrity, and inhibition of apoptosis by downregulating proapoptotic Bax protein and upregulating anti-apoptotic Bcl-2 protein.
    Pharmacokinetics of costunolide and dehydrocostuslactone after oral administration of Radix aucklandiae extract in normal and gastric ulcer rats. Dong Shu,Ma Li-Yan,Liu Yue-Tao,Yu Meng,Jia Hong-Mei,Zhang Hong-Wu,Yu Chang-Yuan,Zou Zhong-Mei Journal of Asian natural products research Costunolide and dehydrocostuslactone are the main active ingredients of Radix Aucklandiae (RA). An accurate and sensitive LC-MS/MS method was established to simultaneously determine contents of costunolide and dehydrocostuslactone in plasma. There were significant differences in pharmacokinetic parameters (AUC, C, C, T, Vd, and CL) of costunolide and dehydrocostuslactone between RA group and costunolide group or dehydrocostuslactone group. The relative bioavailability of costunolide or dehydrocostuslactone of RA extract was improved. As compared to normal group, the T values of dehydrocostuslactone of RA in gastric ulcer group were prolonged, while the C, C, and AUC values decreased. 10.1080/10286020.2018.1489379
    An effective method for preventing cholestatic liver injury of Aucklandiae Radix and Vladimiriae Radix: Inflammation suppression and regulate the expression of bile acid receptors. Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Aucklandiae Radix (AR) and Vladimiriae Radix (VR) were used to treat gastrointestinal, liver and gallbladder diseases at practice. In most conditions, VR was used to be a substitute of AR or a local habit may attribute to the same main active ingredients Costunolide and Dehydrocostus lactone, which presented many similar pharmacological activities. However, other different lactone compounds in AR and VR also play a role in disease treatment, so the difference in therapeutic effects of AR and VR in related diseases needs to be further studied. AIMS OF THE STUDY:Revealing the differences between the chemical compounds of the total lactone extracts of AR and VR (TLE of AR and VR) and the differences in the protective effects of cholestatic liver injury to ensure rational use of AR and VR. STUDY DESIGN AND METHODS:The macroporous adsorption resin was used to purify and enrich the lactone compounds to obtain the total lactone extracts of AR and VR. HPLC-PDA was used to obtain the data to establish chemical fingerprint and chemometric analysis to compare similarities and differences between TLE of AR and VR. The pharmacodynamic experiment revealed how TLE of AR and VR to show protect effects on cholestatic liver injury. RESULTS:Similarity analysis results showed TLE of AR and VR had a high similarity (>0.9). Nevertheless, difference analysis results showed 4 compounds, Costunolide, Dehydrocostus lactone, 3β-acetoxy-11β-guaia-4 (15), 10 (14)-diene-12,6α-olide and vladinol F may contribute to the differences between them. The pharmacodynamics experiments results showed the TLE of AR and VR affected the different liver cholate-associated transporters mRNA expression (TLE of AR up-regulated CYP7A1, TLE of VR down-regulated FXR and BSEP), the TLE of AR and VR had an effect to regulate biochemical indicators (AST, ALT, ALP, TBA) of liver function, and TLE of VR was better than TLE of AR in reducing the expression of inflammatory factors (IL-6 and IL-1β). CONCLUSION:The liver protection of AR and VR have been confirmed, but the differences of material basis and mechanism of drug efficacy needed further study to guarantee formulation research and provide theoretical references for clinical rational applications of AR and VR. 10.1016/j.jep.2022.115330
    Anti-inflammatory effects of Radix Aucklandiae herbal preparation ameliorate intestinal mucositis induced by 5-fluorouracil in mice. Liu Ju-Han,Hsieh Chen-Hsi,Liu Chia-Yuan,Chang Ching-Wei,Chen Yu-Jen,Tsai Tung-Hu Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:5-Fluorouracil (5-FU) is a chemotherapy agent that is widely used in clinical oncologic practice. However, intestinal mucositis is the most frequently occurring side effect of cancer therapy with 5-FU. Based on a literature survey, Radix Aucklandiae herbal preparation potentially ameliorates intestinal mucositis in 5-FU-treated mice. AIM OF THE STUDY:The aim of this study was to investigate the inflammation and gastrointestinal regulation of intestinal mucositis induced by 5-FU, including the intestinal morphology, as well as the reduction in food intake, body weight loss, and diarrhea. MATERIALS AND METHODS:Intestinal mucositis was induced in mice by 5-FU (30 mg/kg, i.p., for 5 consecutive days). The dose-dependent Radix Aucklandiae herbal preparation (0.3, 1, and 3 g/kg/day, p.o.), loperamide (3 mg/kg/day, p.o.) or celecoxib (40 mg/kg/day, p.o.) was concurrently administered until the 7th day. Physical status observation, diarrhea assessment, serum proinflammatory cytokine levels, intestinal villus height and crypt depth, and total goblet cells from tissues were assessed. RESULTS:The dosage regimen of 5-FU administration caused severe intestinal mucositis in mice, including damage to the intestinal morphology, accompanied by a reduction in food intake, body weight loss, and diarrhea. The high-dose Radix Aucklandiae herbal preparation significantly relieves 5-FU-induced intestinal mucositis by enhancing proliferative activity in epithelial crypts; improving anepithymia, body weight loss, and diarrhea; and displaying protective effects on goblet cells in intestinal mucosal epithelia. Activation of NF-κB in the intestinal mucositis model was also suppressed by the Radix Aucklandiae herbal preparation, suggesting that it is a potent inhibitor of NF-κB and proinflammatory cytokines, such as IL-1β, IL-6, TNF-α, and COX-2. CONCLUSIONS:Our data support the conclusion that the Radix Aucklandiae herbal preparation could effectively ameliorate 5-FU-induced gastrointestinal toxicity and be applied clinically for the prevention of intestinal mucositis during chemotherapy. 10.1016/j.jep.2021.113912
    Antimicrobial Effects and Active Compounds of the Root of Decne (Radix Aucklandiae). Frontiers in chemistry The development of new biological fungicides using plant metabolites has become an important direction for pesticide development, and previous studies found that Radix Aucklandiae had a certain inhibitory effect on plant pathogens. In this study, we systematically studied the antimicrobial activity of extracts of Radix Aucklandiae, and the active compounds were isolated, purified and structurally identified. Ethanol extracts of Radix Aucklandiae had different inhibitory effects on seven common plant-pathogenic fungi, with EC (concentration for 50% of maximal effect) values ranging from 114.18 mg/L to 414.08 mg/L. The extract at concentration of 1,000 mg/L had a significant control effect on strawberry grey mould and wheat powdery mildew of more than 90%. Three active compounds were isolated and purified from the extract, which were identified as alantolactone, dehydrocostus lactone and costunolide. All three compounds showed significant inhibitory effects on , and the MIC (minimal inhibitory concentration) values were 15.63 mg/L, 3.91 mg/L and 15.63 mg/L. Dehydrocostus lactone also showed obvious inhibitory effect on with an MIC value of 62.25 mg/L. The extract of Radix Aucklandiae has high antimicrobial activity against some common plant-pathogenic fungi, and the work lays a foundation for the development of extracts of Radix Aucklandiae as botanical fungicides. 10.3389/fchem.2022.872480
    Aucklandiae Radix and Vladimiriae Radix: A systematic review in ethnopharmacology, phytochemistry and pharmacology. Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Aucklandiae Radix (AR) and Vladimiriae Radix (VR), as commonly used traditional Chinese herbal medicine, were widely used in the treatment of gastrointestinal diseases. The two herbal medicines were warm, pungent and bitter. They entered the spleen, stomach, large intestine and gallbladder meridians, and had the effect of promoting qi circulation to relieve pain. It is usually used for chest and hypochondrium, abdominal fullness and pain, tenesmus, indigestion, and warming the middle to harmonize the stomach in clinically. AIM OF THIS REVIEW:To provide a reference for the identification of traditional use, the material basis of efficacy and preclinical research between AR and VR, this review systematically summarized the similarities and differences in ethnopharmacology, phytochemistry and modern pharmacology. MATERIALS AND METHODS:The literature information was collected systematically from the electronic scientific databases, including PubMed, Science Direct, Google Scholar, Web of Science, Geen Medical, China National Knowledge Infrastructure, as well as other literature sources, such as classic books of herbal medicine, master's thesis, doctoral thesis. RESULTS:In the plateau areas of Sichuan Province, VR used to be regarded as substitute or local habit for AR, which is regularly used for chest, abdominal fullness and pain, diarrhea, and other related diseases. In Chinese Pharmacopoeia (ChP) 2020 edition, 145 prescription preparations with AR were collected, such as Xianglian Wan, Muxiang Shunqi Wan, Liuwei Muxiang San. However, only one prescription preparation (Jiuxiang Zhitong Wan) contained VR. Additionally, 237 and 254 chemical components were separately isolated and identified from AR and VR, 69 kinds of compounds were common among them, and the significant differences were presented in sesquiterpene lactones, monoterpenoids, triterpenoids and phenylpropanoids. Moreover, Costunolide (COS) and Dehydrocostus lactone (DEH), two main research objects of modern pharmacology, showed multiple pharmacological activities. Not only could they inhibit the activity of some cancer cells (such as breast cancer and leukemia cells), but they regulated the levels of various inflammatory factors (including TNF-α, NF-κB, IL-1β, IL-6) and repressed the growth and reproduction of various microorganisms (like Helicobacter pylori, Staphylococcus aureus). CONCLUSION:COS and DEH as the common active components, provide a certain basis for local medicine about the substitution of VR for AR in Sichuan province of China in the past. In addition, the sesquiterpenoids are the main common compounds in AR and VR by collecting and collating a large number of literature and various data websites. Furthermore, AR and VR have significant differences in ethnopharmacology and phytochemistry, especially in sesquiterpene lactones, monoterpenoids, triterpenoids and phenylpropanoids, and are probably viewed as reference of a separate list of AR and VR in Chinese Pharmacopoeia. 10.1016/j.jep.2021.114372
    Quality assessment and differentiation of Aucklandiae Radix and Vladimiriae Radix based on GC-MS fingerprint and chemometrics analysis: basis for clinical application. Yan Xiaomin,Wang Wenjun,Chen Ziqiang,Xie Yu,Li Qijuan,Yu Ziwei,Hu Huiling,Wang Zhanguo Analytical and bioanalytical chemistry Vladimiriae Radix, a geo-authentic medicinal herb found in Sichuan Province in China, is highly similar in chemical composition and pharmacological activity to Aucklandiae Radix. It is often used in local practice and as a substitute for Aucklandiae Radix in the treatment of gastrointestinal tract diseases. However, Vladimiriae Radix is preferred to Aucklandiae Radix in traditional Chinese medicine in Sichuan. In order to compare the difference in quality between the two species and differentiate them according to their chemical profiles, and further to explain the rationality of using Vladimiriae Radix as a substitute and explore the reason for the medication preference in Sichuan, similarity was evaluated using gas chromatography-mass spectrometry (GC-MS) fingerprinting and chemometric analysis. Volatile compounds were identified by comparing mass spectra with spectral data from the National Institute of Standards and Technology library 14.L (NIST 14.L) and the linear retention indices (RI) with those previously reported. The results showed that the similarity between the samples from Aucklandiae Radix (>96%) was greater than that of Vladimiriae Radix (>80%). In addition, 41 and 38 compounds were identified in 10 batches of Vladimiriae Radix and Aucklandiae Radix, respectively, and 21 compounds were common to both species, of which dehydrocostus lactone and aplotaxene were abundant in both. However, γ-patchoulene, longicyclene, β-gurjunene, humulene1,2-epoxide, and β-patchoulene were unique to Vladimiriae Radix, while 4-terpineol, α-ionone, trans-α-bergamotene, γ-selinene, and camphene were characteristic compounds of Aucklandiae Radix. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) suggested that the two species were well differentiated with regard to the level of essential oils. Orthogonal partial least squares discriminant analysis (OPLS-DA) further showed that compounds including costol, aplotaxene, caryophyllene, humulene, and β-eudesmol, together with the characteristic compounds of the two species, could be regarded as potential markers for differentiation, among which β-eudesmol, which is richer in Vladimiriae Radix, and β-patchoulene, which is unique to Vladimiriae Radix, have potential therapeutic effects on gastrointestinal diseases. The results obtained in this study distinguished Vladimiriae Radix and Aucklandiae Radix on a chemical level, and the similarity in chemical constituents may provide a basis for the rationality of Vladimiriae Radix as a substitute, while β-patchoulene and β-eudesmol existing in Vladimiriae Radix provide a theoretical basis for its preferential use in Sichuan. The analysis method established here has important implications for the quality control and differentiation of Vladimiriae Radix and Aucklandiae Radix, which can also serve as a reference for the identification of similar species. Graphical abstract. 10.1007/s00216-019-02380-2