Hydroethanolic extract of Cirsium setidens ameliorates doxorubicin-induced cardiotoxicity by AMPK-PGC-1α-SOD-mediated mitochondrial protection.

BACKGROUND: Doxorubicin (DOX) is an effective anticancer agent. However, the clinical outcomes of DOX-based therapies are severely hampered by their significant cardiotoxicity. PURPOSE: We investigated the beneficial effects of an ethanol extract of Cirsium setidens (CSE) on DOX-induced cardiomyotoxicity (DICT). METHODS: UPLC-TQ/MS analysis was used to identify CSE metabolite profiles. H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells were used to evaluate the effects of CSE on DICT-induced cell death. To elucidate the mechanism underlying it, AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma co-activator l-alpha (PGC1-α), nuclear respiratory factor 1 (NRF1), NRF2, superoxide dismutase (SOD1), and SOD2 expression was detected using western blot analysis. The oxygen consumption rate (OCR), cellular ROS, and mitochondrial membrane potential were measured. Finally, we confirmed the cardioprotective effect of CSE against DICT in both C57BL/6 mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) by observing various parameters, such as electrophysiological changes, cardiac fibrosis, and cardiac cell death. RESULTS: Chlorogenic acid and nicotiflorin were the major compounds in CSE. Our data demonstrated that CSE blocked DOX-induced cell death of H9c2 cells without hindrance of its apoptotic effects on MDA-MB-231 cells. DOX-induced defects of OCR and mitochondrial membrane potential were recovered in a CSE through upregulation of the AMPK-PGC1-α-NRF1 signaling pathway. CSE accelerated NRF1 translocation to the nucleus, increased SOD activity, and consequently blocked apoptosis in H9c2 cells. In mice treated with 400 mg/kg CSE for 4 weeks, electrocardiogram data, creatine kinase and lactate dehydrogenase levels in the serum, and cardiac fibrosis, were improved. Moreover, various electrophysiological features indicative of cardiac function were significantly enhanced following the CSE treatment of hiPSCCMs. CONCLUSION: Our findings demonstrate CSE that ameliorates DICT by protecting mitochondrial dysfunction via the AMP- PGC1α-NRF1 axis, underscoring the therapeutic potential of CSE and its underlying molecular pathways, setting the stage for future investigations into its clinical applications.

Seco-nortriterpenoids from Cirsium setosum and their anti-inflammatory activity.

Five unusual seco-nortriterpenoids, 3ß-hydroxy-20,21-seco-30-nortaraxastan-20,21-dioic acid (1), 3ß-hydroxy-20,21-seco-30-nortaraxastan-20-oic-21-oate (2), 3ß-hydroxy-20-oxo-21,22-seco-30-nortaraxastan-22-oic acid (3), 3ß-hydroxy-19-oxo-20,21-seco-29,30-nortaraxastan-21-oic acid (4) and 3ß-hydroxy-19-oxo-20,21-seco-19-norlupan-21-oic acid (5) were isolated and elucidated from the anti-inflammatory activity fraction of the ethanol extract of Cirsium setosum. The structures of these compounds were established through spectroscopic methods. Preliminary biological assays showed that compounds 1-5 had significant inhibitory effect on NO production on lipopolysaccharide-stimulated RAW 264.7 cells, and compound 1 showed the strongest anti-inflammatory activity. This type of ring-opening compound is the first seco-triterpenoid structure discovered from the genus of Cirsium.

Comparative Contents of Polyphenolic Compounds in Aerial Parts of Cirsium esculentum, C. serratuloides, and Ancathia igniaria (Asteraceae).

Because Ancathia igniaria (Spreng.) DC. (Cirsium igniarium Spreng.) has been segregated as a monotypic genus from the genus Cirsium on the basis of phylogenetic data, chemotaxonomic differences are of interest to detect in the composition of polyphenolic components of aerial plant parts. Phenolic compounds are of chemotaxonomic significance in a number of genera and families. The polyphenolic profile of aerial parts was therefore compared for Cirsium esculentum (Siev.) C.A. Mey., Cirsium serratuloides (L.) Hill, and A. igniaria. The last two species were for the first time examined in this context. The compounds were identified against known standard via high-performance liquid chromatography (HPLC). The species of the genus Cirsium were found to have similar compositions of simple phenols, but differ in the set of flavonoids. Six to eight phenolic compounds were detected in the species, and three simple polyphenols (syringin, chlorogenic acid, and ethyl gallate) proved to be common. The flavonoid profiles of aerial parts included rutin in both Cirsium species. Cymaroside and quercetin-3-O-ß-D-diglucoside-O-α-L-rhamnoside were species specific for C. serratuloides; salipurposide and hyperoside, for C. esculentum. An extract of A. igniaria aerial parts contained cinaroside (like in C. serratuloides), chrysin 7-O-glucoside, and eriodictyol. A greater difference in flavonoid composition was observed between the genera Cirsium and Ancathia. Data on phenolic compound composition are of importance for chemosystematics and use of plants as medicinal raw materials. The total content of coumarins, aglycones, and flavonoid glycosides in the species was determined by a spectrophotometric method. The contents of flavonoids and coumarins in C. esculentum and C. serratuloides were comparable and exceeded their contents in A. igniaria. Thus, A. igniaria proved to differ from the genus Cirsium in the quantitative and qualitative composition of phenolic compounds.

Antimicrobial and Antioxidant Efficacy of the Lipophilic Extract of Cirsium vulgare.

The aim of this study was to investigate the compounds in the hexane extract of Cirsium vulgare (Savi.) Ten. and to determine the antibacterial, antifungal, and antioxidant activities of different extracts. The Cirsium vulgare (NGBB 7229) plant was collected from Turkey's Trakya region. Crude extracts were obtained using different solvents. The chemical composition of Cirsium vulgare was determined in hexane extract using gas chromatography mass spectrometry. The antioxidant activities of the extracts were evaluated by Trolox equivalent antioxidant activity (TEAC), ferric-reducing antioxidant power (FRAP), cupric-reducing antioxidant capacity (CUPRAC), the ß-carotene bleaching method, and the determination of superoxide anion scavenging activities. The antibacterial activity was tested against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, and Salmonella typhimurium, whereas the antifungal activity was tested against Candida albicans, Candida glabrata, Candida parapsilosis, Candida krusei, Penicillium chrysogenum, and Aspergillus fumigatus by applying microdilution methods. A total of 41 bioactive compounds were identified using the GC-MS library. Terpenoids were found to be dominant (52.89%), and lup-20(29)-en-3-yl-acetate and lupeol were the most abundant terpenoids. The highest total flavonoid content (25.73 mg catechin/g) and antioxidant capacity were found in the methanolic extract. The highest antibacterial activity was detected against Bacillus subtilis in the ethyl acetate extract, and the highest antifungal activity was found against Candida krusei and Aspergillus fumigatus in the hexane extract. The observed antioxidant characteristics of the C. vulgare extracts could be attributed to the presence of flavonoids. The high antifungal activity of the hexane extract against all fungal strains can be attributed to its constituents, i.e., terpenoids. This study discloses the potential antioxidant and antimicrobial activities, including some bioactive components, of Cirsium vulgare and implies that Cirsium vulgare holds possible applications in the food and pharmaceutical industries as an antioxidant, antibacterial, and antifungal agent.

Biologically synthesis of gold nanoparticles using Cirsium japonicum var. maackii extract and the study of anti-cancer properties on AGS gastric cancer cells.

Plant extract-mediated synthesis of metal nanoparticles (NPs) is an eco-friendly and cost-effective biosynthesis method that is more suitable for biological applications than chemical ones. We prepared novel gold NPs (AuNPs), Cirsium japonicum mediated-AuNPs (CJ-AuNPs), using a biosynthetic process involving Cirsium japonicum (Herba Cirsii, CJ) ethanol extract. The physicochemical properties of CJ-AuNPs were characterized using spectrometric and microscopic analyses. The in vitro stability of CJ-AuNPs was studied for 3 months. Moreover, the selective human gastric adenocarcinoma (AGS) cell killing ability of CJ-AuNPs was verified in cancer and normal cells. An in vitro study revealed that CJ-AuNPs trigger oxidative stress and iron-dependent ferroptosis in AGS cells. Mechanistically, CJ-AuNPs induced mitochondrial reactive oxygen species (ROS), Fe2+, and lipid peroxidation accumulation, and mitochondrial damage by destroying the glutathione peroxidase-4 (GPX4)-dependent antioxidant capacity. Furthermore, in a xenograft mouse model implanted with AGS cells, treatment with 2.5, 5, and 10 mg/kg CJ-AuNPs for 16 days reduced tumor xenograft growth in a dose dependent manner in vivo without systemic toxicity. These results demonstrate that CJ-AuNPs exert anticancer effects in vitro and in vivo by inducing ferroptosis-mediated cancer cell death. This study, based on green-synthesized nanodrug-induced ferroptosis, provides new insight into potential developments in cancer therapies.

Effect of Cirsium japonicum Flower Extract on Skin Aging Induced by Glycation.

Advanced glycation end products (AGEs) have recently been increasingly discussed as one factor of skin aging. In this study, we investigated the effects of Cirsium japonicum flower (CFE) extract on glycation in relation to skin aging and skin elasticity. Moreover, we learned the main active constituent of CFE that has effects against glycation. To demonstrate the effects of CFE on glycation, we carried out an in vitro glycation study, 3-dimensional culture, and clinical study. As a result, CFE inhibited formation of AGEs in both bovine serum albumin (BSA)/glucose glycation system and aldehyde-derived glycation system. Moreover, CFE reduced Nε-(carboxymethyl), lysine (CML), and carbonylated proteins that increased by glycation. Furthermore, CFE broke crosslinks of collagen-AGEs and inhibited the increase of matrix metalloproteinase-1 (MMP-1) gene expression by AGEs. In the 3D culture condition, CFE restored the reduction of collagen gel contraction by glycation. Moreover, apigenin was detected as the main active constituent in CFE that has anti-glycation effects. In the clinical study, we confirmed that CFE has effects on skin wrinkles and skin elasticity. Our findings suggest that CFE can be used as a cosmetic or cosmeceutical ingredient for improving skin elasticity and wrinkles. Regulation of AGEs can be an interesting target for anti-aging.

A Complex of Cirsium japonicum var. maackii (Maxim.) Matisum. and Thymus vulgaris L. Improves Menopausal Symptoms and Supports Healthy Aging in Women.

We evaluated the efficacy and safety of MS-10® for the treatment of menopausal symptoms. A double-blind randomized placebo-controlled clinical trial was performed in 71 premenopausal women for 4 and 12 weeks. A total of 12 individual menopausal symptom scores were assessed using the Kupperman index. MS-10 treatment effectively improved the symptoms by ∼48%. In addition, the quality of life of the women improved by 36% from four perspectives: vasomotor, psychosocial, physical, and sexual symptoms as evaluated using the menopause-specific quality of life (MenQoL) questionnaire. Our results show that MS-10 improves insulin-like growth factor-1 (IGF-1) and estrogen utilization through receptor activation, which are thought to have causative therapeutic effects on menopause and aging inhibition in women. Improvement of Enthotheline-1 (ET-1) in the blood after MS-10 intake led to an improvement in menopausal vascular symptoms. Improvements in bone formation and absorption markers such as osteocalcin, bone-specific alkaline phosphatase (BSALP), C-telopeptides of type I collagen (CTx), deoxypyridinoline (deoxyPYD), and N-telopeptides of type I collagen (NTx) in blood or urine indicate that MS-10 fundamentally improves bone health in women. By confirming the improvement of the psychological well-being index based on the improvement of stress hormone cortisol, MS-10 can solve causative psychological and physical stress-related symptoms. Moreover, various safety tests, such as those for female hormones, were confirmed. Therefore, it can be confirmed that MS-10 is a natural pharmaconutraceutical that causatively and safely improves health of women and aids in antiaging processes.

Cirsium japonicum var. Maackii Improves Cognitive Impairment under Amyloid Beta25-35-Induced Alzheimer's Disease Model.

Abnormal production and degradation of amyloid beta (Aß) in the brain lead to oxidative stress and cognitive impairment in Alzheimer's disease (AD). Cirsium japonicum var. maackii (CJM) is widely used as an herbal medicine and has antibacterial and anti-inflammatory properties. This study focused on the protective effect of the ethyl acetate fraction from CJM (ECJM) on Aß 25-35-induced control mice. In the T-maze and novel object recognition test, ECJM provided higher spatial memory and object recognition compared to Aß 25-35 treatment alone. In the Morris water maze test, ECJM-administered mice showed greater learning and memory abilities than Aß 25-35-induced control mice. Additionally, ECJM-administered mice experienced inhibited lipid peroxidation and nitric oxide production in a dose-dependent manner. The present study indicates that ECJM improves cognitive impairment by inhibiting oxidative stress in Aß 25-35-induced mice. Therefore, CJM may be useful for the treatment of AD and may be a potential material for functional foods.

Network Pharmacology-Based Study to Uncover Potential Pharmacological Mechanisms of Korean Thistle (Cirsium japonicum var. maackii (Maxim.) Matsum.) Flower against Cancer.

Cirsium japonicum var. maackii (Maxim.) Matsum. or Korean thistle flower is a herbal plant used to treat tumors in Korean folk remedies, but its essential bioactives and pharmacological mechanisms against cancer have remained unexplored. This study identified the main compounds(s) and mechanism(s) of the C. maackii flower against cancer via network pharmacology. The bioactives from the C. maackii flower were revealed by gas chromatography-mass spectrum (GC-MS), and SwissADME evaluated their physicochemical properties. Next, target(s) associated with the obtained bioactives or cancer-related targets were retrieved by public databases, and the Venn diagram selected the overlapping targets. The networks between overlapping targets and bioactives were visualized, constructed, and analyzed by RPackage. Finally, we implemented a molecular docking test (MDT) to explore key target(s) and compound(s) on AutoDockVina and LigPlot+. GC-MS detected a total of 34 bioactives and all were accepted by Lipinski's rules and therefore classified as drug-like compounds (DLCs). A total of 597 bioactive-related targets and 4245 cancer-related targets were identified from public databases. The final 51 overlapping targets were selected between the bioactive targets network and cancer-related targets. With Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, a total of 20 signaling pathways were manifested, and a hub signaling pathway (PI3K-Akt signaling pathway), a key target (Akt1), and a key compound (Urs-12-en-24-oic acid, 3-oxo, methyl ester) were selected among the 20 signaling pathways via MDT. Overall, Urs-12-en-24-oic acid, 3-oxo, methyl ester from the C. maackii flower has potent anti-cancer efficacy by inactivating Akt1 on the PI3K-Akt signaling pathway.

Effects of ethanolic extracts of Quercus, Cirsium vulgare, and Falcaria vulgaris on gastric ulcer, antioxidant and inflammatory indices, and gene expression in rats.

INTRODUCTION: Gastric ulcer is a multifaceted process and is usually caused by mucosal damage. Herbal medicines have received much attention considering the side effects of chemical drugs. Nowadays, the use of herbal medicines has received much attention considering the side effects of chemical drugs. Quercus brantii Lindl, Cirsium vulgare (Savi) Ten, and Falcaria vulgaris Bernh are plants used as traditional phytomedicine for gastric ulcer diseases. AIM OF THE STUDY: This study was aimed to investigate the protective effects of hydroalcoholic extracts of these herbs on ethanol-induced gastric ulceration, in addition, to investigate the antioxidant, anti-inflammatory, and gene expression. MATERIALS AND METHODS: Thirty Sprague Dawley rats, (200-250 g), were divided into six groups: Control: intact animals; sham: gavaged with distilled water (14 days); negative control: gavaged with 20 mg/kg of omeprazole (14 days); experimental groups I, II, and III: gavaged with 500 mg/kg of the extract of Falcaria vulgaris, Quercus brantii, and Cirsium vulgare, respectively, (14 days). The number of ulcers and pathological parameters were assessed. The serum superoxide dismutase, catalase, glutathione peroxidase, malondialdehyde, total antioxidant capacity, albumin, total protein, haptoglobin, alpha-1-acid glycoprotein, total globulin, alpha-2-macroglobulin, C-fos, C-myc, and Caspase-9 were measured by ELISA and RT-PCR. RESULTS: The extracts significantly reduced gastric ulcer (52.33%). The results showed that the Quercus brantii extract was more effective. There were significant differences between the serum levels of alpha-1-acid glycoprotein and those of alpha-2-macroglobulin. Also, there was a significant difference in the serum level of antioxidant parameters. Changes in the expression of the genes also confirmed the results suggested by other parameters. The expression levels of C-fos, C-myc, and caspase-9 were decreased, but the Bcl-2 expression increased. CONCLUSION: The hydro-alcoholic extracts revealed various protection and noticeable change in the expression of caspase-9, C-myc, C-fos, and Bcl-2 genes in rats.

Recent research progress of Cirsium medicinal plants in China.

ETHNOPHARMACOLOGICAL RELEVANCE: The species of the genus Cirsium have been used as traditional Chinese medicine for hundreds of years. It is believed that Cirsium has the efficacies of cooling blood and stopping bleeding, dispelling blood stasis, detoxifying and eliminating carbuncle. At present, they are mainly used in treatment of the hemoptysis, hematemesis, hemoptysis, hematuria, traumatic bleeding and Henoch-Schonlein purpura. They are widely used in traditional Chinese medicine. AIM: This paper systematically collated the classification, traditional use, pharmacological action, phytochemistry and clinical application of Cirsium plants in the past ten years, intending to provide a critical appraisal of current knowledge for future in-depth study and rational development and utilization of Cirsium plants. MATERIAL AND METHODS: This paper searched various databases (SciFinder, Science Direct, CNKI, Wiley online library, Spring Link, Web of Science, PubMed, Wanfang Data, Weipu Data), Chinese Pharmacopoeia 2020 Edition, Chinese Flora, Chinese Materia Medica and some local books on ethnopharmacology. RESULTS: More than ten species of Cirsium have been used as folk medicine, and modern pharmacological studies have shown that Cirsium has the effects of protecting liver, antioxidation, anti-tumor, anti-inflammation, antibacterial, etc. More than 200 chemical constituents such as flavonoids, triterpenes, sterols, phenylpropanoids have been isolated from Cirsium. Some ingredients show a wide variety of bioactivities including hepatoprotective, anti-inflammatory, antioxidant, anti-tumor and other activities. At present, Cirsium medicinal plants, as traditional Chinese medicine, were mainly used to treat nephritis, Henoch-Schonlein purpura and hemorrhage, although some species used in folk lack of quality control systems. CONCLUSION: Cirsium plants are a safe and effective medicine for cooling blood and hemostasis. Recent studies on pharmacology and phytochemistry also provide solid scientific evidences for the traditional application of this genus. It also shows significant hepatoprotective activity and may be a potential clinical candidate for the treatment of liver disease. However, the qualitative and quantitative analysis, pharmacokinetics-pharmacodynamics and mechanism of action also need in-depth study.

Antioxidant Effects and Phytochemical Properties of Seven Taiwanese Cirsium Species Extracts.

In the present investigation, we compared the radical-scavenging activities and phenolic contents of seven Taiwanese Cirsium species with a spectrophotometric method. We further analyzed their phytochemical profiles with high-performance liquid chromatography-photodiode array detection (HPLC-DAD). We found that the flower part of Cirsium japonicum var. australe (CJF) showed the best radical-scavenging activities against 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and the hypochlorite ion, for which the equivalents were 6.44 ± 0.17 mg catechin/g, 54.85 ± 0.66 mmol Trolox/g and 418.69 ± 10.52 mmol Trolox/g respectively. CJF also had the highest contents of total phenolics (5.23 ± 0.20 mg catechin/g) and phenylpropanoids (29.73 ± 0.72 mg verbascoside/g). According to the Pearson's correlation coefficient, there was a positive correlation between the total phenylpropanoid content and ABTS radical-scavenging activities (r = 0.979). The radical-scavenging activities of the phenylpropanoids are closely related to their reducing power (r = 0.986). HPLC chromatograms obtained in validated HPLC conditions confirm that they have different phytochemical profiles by which they can be distinguished. Only CJF contained silicristin (0.66 ± 0.03 mg/g) and silydianin (9.13 ± 0.30 mg/g). CJF contained the highest contents of apigenin (5.56 ± 0.09 mg/g) and diosmetin (2.82 ± 0.10 mg/g). Among the major constituents, silicristin had the best radical-scavenging activities against DPPH (71.68 ± 0.66 mg catechin/g) and ABTS (3.01 ± 0.01 mmol Trolox/g). However, diosmetin had the best reducing power and radical-scavenging activity against the hypochlorite anion (41.57 ± 1.14 mg mmol Trolox/g). Finally, we found that flavonolignans (especial silicristin and silydianin) and diosmetin acted synergistically in scavenging radicals.

Effects of Cirsium setidens (Dunn) Nakai on the osteogenic differentiation of stem cells.

Cirsium setidens (Dunn) Nakai, commonly known as gondre, is a perennial herb that grows predominantly in South Korea. It contains several bioactive phytochemicals with antioxidant, anti­cancer, anti­tumor and anti­inflammatory properties. The present study aimed to investigate the effects of methanolic extracts of gondre on osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs). As characterized by nuclear magnetic resonance spectroscopy and matrix­assisted laser deposition/ionization (time­of­flight) mass spectrometry, the methanol extract of gondre was found to be enriched with pectolinarin. After 48 h, enhanced viability of hPDLSCs was observed in the presence of gondre compared with under control conditions, suggesting the biocompatibility of gondre. Notably, biocompatibility was markedly affected by gondre concentration in cultured media. Relatively high cell viability was observed in medium containing 0.05% gondre. Furthermore, mineralization was significantly higher in hPDLSCs in the presence of gondre compared with that in control cells, indicating their mineralization potential. Increased expression of various transcription markers, such as collagen 1, runt­related transcription factor 2, bone sialoprotein and alkaline phosphatase, was also detected when hPDLSCs were stimulated with gondre compared with in the control groups, further confirming the superior osteogenic potential of gondre extract for tissue engineering applications, particularly in bone tissues.

A new pyran derivative analog from the whole plant of Cirsium italicum.

The aim of the present article was to analyze the phytochemical composition of EtOAc extract of Cirsium italicum (Savi) DC. and to determine the antioxidant activity of a new compound 1. The EtOAc extract of C. italicum was purified by different chromatographic methods. Compound 1 was isolated from the whole plant of C. italicum. Its structure was established on the basis of UV, IR, 1 D, 2 D NMR, and HRESI-MS methods and antioxidant activities of this compound were investigated using TEAC, FRAP, and CUPRAC assays. According to the ABTS assays, the TEAC capacity of compound 1 was determined as 0.186 mmol TE/g.

Plant cell culture extract of Cirsium eriophorum with skin pore refiner activity by modulating sebum production and inflammatory response.

Facial pore enlargement is considered a significant esthetic and health concern in skincare cosmetics. The pores fulfill the critical function of keeping the skin surface hydrated and protected against microbial infections. The hyperseborrhea, the stress factors, and the hormonal triggers can cause pore size enlargement, causing higher susceptibility of the skin to microbe aggressions and inflammatory reactions. Thus, reducing excessive sebum production and keeping functional pores are two of the most requested activities in skincare cosmetics. A Cirsium eriophorum cell culture extract was investigated for its role in sebum regulation, stratum corneum desquamation, and anti-inflammation. The extract was able to regulate essential markers associated with sebum secretion and pore enlargements, such as the enzyme 5α-reductase, which plays a central role in sebum production, and the trypsin-like serine protease Kallikrein 5, which promotes skin exfoliation and antimicrobial response. Moreover, the extract showed a sebum-normalizing and pore refining activity in individuals having seborrheic or acne-prone skins, suggesting a role of the C. eriophorum extract in rebalancing altered skin conditions responsible for pore enlargement.

Luteolin, a Potent Human Monoamine Oxidase-A Inhibitor and Dopamine D4 and Vasopressin V1A Receptor Antagonist.

Luteolin, a flavonoid widely distributed in the plant kingdom, contains two benzene rings and hydroxyl groups, and this structural specificity contributes to its diverse biological activities. However, no previous studies have simultaneously investigated the therapeutic potency of luteolin isolated from a plant as an antipsychotic and antidepressant. Here, luteolin exhibited selective inhibition of hMAO-A (IC50 = 8.57 ± 0.47 µM) over hMAO-B (IC50 > 100 µM). In silico proteochemometric modeling predicted promising targets of luteolin, and verification via cell-based G protein-coupled receptor functional assays showed that luteolin is a selective antagonist of the vasopressin receptor V1AR (IC50 = 19.49 ± 6.32 µM) and the dopamine D4 receptor (IC50 = 39.59 ± 1.46 µM). Molecular docking showed the tight binding of luteolin with a low binding score and the high stability of the luteolin-receptor complex, corroborating its functional effect. Thus, hMAO-A, hD4R, and hV1AR are prime targets of luteolin and potential alternatives for the management of neurodegenerative diseases.

Linarin and its aglycone acacetin abrogate actin ring formation and focal contact to bone matrix of bone-resorbing osteoclasts through inhibition of αvß3 integrin and core-linked CD44.

BACKGROUND: Since enhanced bone resorption due to osteoclast differentiation and activation cause skeletal diseases, there is a growing need in therapeutics for combating bone-resorbing osteoclasts. Botanical antioxidants are being increasingly investigated for their health-promoting effects on bone. Edible Cirsium setidens contains various polyphenols of linarin, pectolinarin, and apigenin with antioxidant and hepatoprotective effects. PURPOSE: This study aimed to determine whether linarin present in Cirsium setidens water extracts (CSE) and its aglycone acacetin inhibited osteoclastogenesis of RANKL-exposed RAW 264.7 murine macrophages for 5 days. METHODS: This study assessed the osteoprotective effects of CSE, linarin and acacetin on RANKL-induced differentiation and activation of osteoclasts by using MTT assay, TRAP staining, Western blot analysis, bone resorption assay actin ring staining, adhesion assay and immunocytochemical assay. This study explored the underlying mechanisms of their osteoprotection, and identified major components present in CSE by HPLC analysis. RESULTS: Linarin and pectolinarin were identified as major components of CSE. Nontoxic linarin and acacetin as well as CSE, but not pectolinarin attenuated the RANKL-induced macrophage differentiation into multinucleated osteoclasts, and curtailed osteoclastic bone resorption through reducing lacunar acidification and bone matrix degradation in the osteoclast-bone interface. Linarin and acacetin in CSE reduced the transmigration and focal contact of osteoclasts to bone matrix-mimicking RGD peptide. Such reduction was accomplished by inhibiting the induction of integrins, integrin-associated proteins of paxillin and gelsolin, cdc42 and CD44 involved in the formation of actin rings. The inhibition of integrin-mediated actin ring formation by linarin and acacetin entailed the disruption of TRAF6-c-Src-PI3K signaling of bone-resorbing osteoclasts. The functional inhibition of c-Src was involved in the loss of F-actin-enriched podosome core protein cortactin-mediated actin assembly due to linarin and acacetin. CONCLUSION: These observations demonstrate that CSE, linarin and acacetin were effective in retarding osteoclast function of focal adhesion to bone matrix and active bone resorption via inhibition of diffuse cloud-associated αvß3 integrin and core-linked CD44.

Bioassay-Guided Isolation of Triterpenoids as α-Glucosidase Inhibitors from Cirsium setosum.

Cirsium setosum (C. setosum) has a potential antihyperglycemic effect, but it is unclear what bioactive components play a key role. According to the α-glucosidase inhibition activity, three new taraxastane-type triterpenoids of 3ß-hydroxy-30-hydroperoxy-20-taraxastene (1), 3ß-hydroxy-22α-methoxy-20-taraxastene (2), and 30-nor-3ß,22α-dihydroxy-20-taraxastene (3), as well as five known taraxastane triterpenoids of 3ß,22-dihydroxy-20-taraxastene (4), 20-taraxastene-3,22-dione (5), 3ß-acetoxy-20-taraxasten-22-one (6), 3ß-hydroxy-20-taraxasten-22-one (7), and 30-nor-3ß-hydroxy-20-taraxastene (8) were obtained from the petroleum ether-soluble portion of the ethanol extract from C. setosum. All chemical structures of the compounds were elucidated by spectroscopic data analysis and compared with literature data. Compounds 4-8 were identified for the first time from this plant, and compounds 1, 2, 4, and 7 exhibited more potent α-glucosidase inhibitory activity-with IC50 values of 18.34 ± 1.27, 26.98 ± 0.89, 17.49 ± 1.42, and 22.67 ± 0.25 µM, respectively-than acarbose did (positive control, IC50 42.52 ± 0.32 µM).

Korean Thistle (Cirsium japonicum var. maackii (Maxim.) Matsum.): A Potential Dietary Supplement against Diabetes and Alzheimer's Disease.

In the search for natural products having a dual inhibitory action on diabetes and Alzheimer's disease, this study investigated the activity of different parts of Korean thistle (Cirsium japonicum var. maackii (Maxim.) Matsum), and its fractional constituents by in vitro enzymatic and in silico molecular docking studies. Cirsium maackii has been used as a traditional medicine for the treatment of several diseases. The ethyl acetate and dichloromethane fractions of a leaf extract showed α-glucosidase and BACE1 inhibitory activity, respectively. Furthermore, the isolated compound, luteolin, exhibited concentration-dependent non-competitive inhibition against both α-glucosidase and BACE1 (IC50 = 51.27 ± 1.23 and 13.75 ± 0.26 µM; Ki value = 52.04 and 14.76 µM, respectively). Moreover, docking studies showed that luteolin formed a strong hydrogen bond with the peripheral binding amino acid residues, and hydrophobic interactions with the α-glucosidase and BACE1 enzymes. Therefore, Korean thistle may act as an important dietary supplement against diabetes and Alzheimer's disease, especially the leaves, because of the preponderance of the active component, luteolin, making Korean thistle a promising candidate for more detailed in vitro and in vivo studies.

Taraxastane-type triterpenoids from the medicinal and edible plant Cirsium setosum.

Guided by TNF-α secretion inhibitory activity assay, four taraxastane-type triterpenoids, including two new ones, 22-oxo-20-taraxasten-3ß, 30-diol (1) and 22α-hydroxy-20-taraxasten-30ß, 30-triol (2), have been obtained from an active fraction of the petroleum ether-soluble extract of the the medicinal and edible plant Cirsium setosum. Their structures were elucidated by spectroscopic data and CD data analysis. In the TNF-α secretion inhibitory activity assay, compounds 1 and 2 were active with the IC50 of 2.6 and 3.8 µmol·L-1, respectively. In addition, compounds 1 and 2 showed moderately selective cytotoxicity against the human ovarian cancer (A2780) and colon cancer (HCT-8) cell lines.