Cimicifuga Simplex Research Articles

Prim-O-glucosylcimifugin alleviates influenza virus-induced pneumonia in mice by inhibiting the TGF-β1/PI3KCD/MSK2/RELA signalling pathway.

Prim-O-glucosylcimifugin (POG) is a chromone derived primarily from Saposhnikovia divaricata (Turcz) Schischk and Cimicifuga simplex. Previous research has shown that POG possesses antibacterial, anticancer, anti-inflammatory, antioxidant, anticonvulsant, antipyretic, and analgesic properties. However, the specific impact of POG on influenza-virus-induced pneumonia is not well understood. In this study, we investigated the protective effects and underlying mechanisms of POG in pneumonia caused by influenza A virus (IAV). In vitro, POG was found to have a protective effect against infections caused by the respiratory viruses respiratory syncytial virus (RSV), human coronavirus OC43, and influenza A virus. POG inhibited A/FM/1/1947(H1N1) infection with an EC50 ranging from 3.01 to 10.43 in vitro. Intraperitoneal infection of mice with POG at a dose of 5 or 10 mg/kg resulted in a reduction in IAV-induced pneumonia, as evidenced by decreased pulmonary edema, improved lung histopathology, and reduced inflammatory cell accumulation. At the higher dose (10 mg/kg), POG treatment significantly increased survival rates, decreased viral titres in the lungs, improved lung histology, and reduced lung inflammation in IAV-infected mice. POG also effectively alleviated pulmonary fibrosis by reducing the levels of fibrotic markers (hydroxyproline [Hyp] and transforming growth factor β1 [TGF-β1]) and suppressing the expression of alpha smooth muscle actin (α-SMA), p focal adhesion kinase (p-FAK), and TGF-β1 in lung tissues. In addition, POG inhibited the expression of the RELA proto-oncogene (RELA), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD), and mitogen- and stress-activated protein kinase 2 (MSK2) in lung tissues. These results indicate that POG may have a protective effect against IAV-induced pneumonia by downregulating the TGF-β1/PI3KCD/MSK2/RELA signalling pathway in the lungs.

Secondary Metabolites with Anti-Inflammatory from the Roots of Cimicifuga taiwanensis.

The genus Cimicifuga is one of the smallest genera in the family Ranunculaceae. Cimicifugae Rhizoma originated from rhizomes of Cimicifuga simplex, and C. dahurica, C. racemosa, C. foetida, and C. heracleifolia have been used as anti-inflammatory, analgesic and antipyretic remedies in Chinese traditional medicine. Inflammation is related to many diseases. Cimicifuga taiwanensis was often used in folk therapy in Taiwan for inflammation. Phytochemical investigation and chromatographic separation of extracts from the roots of Cimicifuga taiwanensis has led to the isolation of six new compounds: cimicitaiwanins A–F (1–6, respectively). The structures of the new compounds were unambiguously elucidated on the basis of extensive spectroscopic data analysis (1D- and 2D-NMR, MS, and UV) and comparison with the literature data. The effect of some isolates on the inhibition of NO production in lipopolysaccharide-activated RAW 264.7 murine macrophages was evaluated. Of the isolates, 3–6 exhibited potent anti-NO production activity, with IC50 values ranging from 6.54 to 24.58 μM, respectively, compared with that of quercetin, an iNOS inhibitor with an IC50 value of 34.58 μM. This is the first report on metabolite from the endemic Taiwanese plant-C. taiwanensis.

Discovery of cryptic diversity in phytophagous gall midges (Diptera: Cecidomyiidae) associated with different ecotypes of the perennial herb Cimicifuga simplex

• We collected gall midges (Cecidomyiidae) from Cimicifuga simplex herbs. • Gall midges belonging to five clades were collected from three C . simplex ecotypes. • The cryptic diversity of phytophagous insects was nested within that of the plants. • Plant diversification spurs further diversification of phytophagous insects. Studying the diversification patterns of species-rich phytophagous insect taxa can help us understand the factors that cause species diversification. We conducted a molecular phylogenetic analysis of the mitochondrial COI gene of larvae of gall midges (Diptera: Cecidomyiidae) using three genetically differentiated morphs of Cimicifuga simplex plants and found that the gall midges could be divided into five major clades. Gall midges collected from morph I of C. simplex belonged to four Schizomyia clades. Gall midges collected from morph II of C. simplex belonged to one of the four Schizomyia clades collected from morph I. Gall midges collected from morph III belonged one Contarinia clade. On morphs I and II of C. simplex , the Schizomyia species induced galls on the flower bud, whereas on morph III of C. simplex , the Contarinia species was collected from normal fruits (not gall inducer); thus, morph III plants were used differently by gall midges than plants of morphs I and II. These results indicate that the cryptic diversity of these phytophagous insects correspond to that of plant ecotypes, and suggests that the diversification of the host plant contributed to parallel diversification of the phytophagous gall midges.

Differences in the flower visitor behaviour on female and hermaphroditic flowers of Cimicifuga simplex

ABSTRACT The behavioural patterns of flower-visiting insects are influenced by floral display size, floral reward, etc. We tested whether insects of various taxa visiting Cimicifuga simplex would change their behaviour between hermaphroditic and female flowers. Male-phase flowers of hermaphroditic ramets provide flower visitors with nectar and pollen as rewards, whereas female flowers of female ramets provide flower visitors with only nectar. The appearance of the both sexes in C. simplex is different with hermaphrodite being relatively large and female ramet being relatively small. Therefore, to investigate how sexual differences in floral rewards and conspicuousness affect flower visitor behaviour, we compared flower visitor behaviour between male-phase hermaphroditic ramets and female ramets. C. simplex was visited by the bumblebee Bombus beaticola beaticola (Hymenoptera), Vespula flaviceps (Hymenoptera), Anthomyiidae spp. (Diptera), Episyrphus balteatus (Diptera), and Pidonia aegrota (Coleoptera). The visitation frequency of all visitors, especially of bumblebees and dipteran insects, to male-phase hermaphroditic ramets was higher than that to female ramets. The number of flowers contacted per single visit to an inflorescence was significantly higher for hermaphroditic ramets than for female ramets in bumblebees, but no difference was found in other insect groups. These results suggest that bumblebees visit the low-reward female ramets less often than male-phase hermaphroditic ramets, and they stay on female ramets for a shorter time. In contrast, insects other than bumblebees seem to decide which flowers to visit according to how conspicuous the flowers are, but once they visit a ramet they continue to visit flowers on the ramet even if no pollen rewards there are.

Differences in sex expression and mating systems in three pollination morphs of Cimicifuga simplex

AbstractCimicifuga simplex (Ranunculaceae) has three genetically distinct pollination morphs. Here, we report that each of the three pollination morphs of C. simplex differs from the others with regard to sex expression and mating system: morph I consists mostly of ramets with hermaphroditic flowers and ramets with only female flowers, morph II consists of ramets with hermaphroditic flowers and ramets with hermaphroditic and male flowers, and morph III consists mostly of ramets with hermaphroditic flowers. A microsatellite analysis of seed DNA showed that morph III has a high self‐fertilization rate. Flowering season and flower visitor assemblages, which also differ among the three morphs, may influence the evolution and maintenance of the differences in sex expression and mating systems in the morphs.

Development and Characterization of Microsatellite Markers for Three Pollination Morphs of <i>Cimicifuga simplex</i> (Ranunculaceae)

Cimicifuga simplex Wormsk. (Ranunculaceae) is a perennial herb distributed in eastern and northeastern Asia for which at least three different pollination morphs have been reported. It is classified as endangered or near threatened in some Japanese regions, and its rhizome is commercially used as a crude drug. To examine genetic differentiation and gene flow among the three morphs, we developed eight microsatellite markers by using next-generation sequencing and estimated the genetic structure of C. simplex. We tested eight primer pairs on 93 individuals from six populations of C. simplex in Nagano, central Japan, and found that heterozygosity in morphs I and III was low compared to expected heterozygosity. Bayesian clustering performed with the STRUCTURE program clearly distinguished the three morphs of C. simplex, and only a little gene flow was detected among the morphs. These eight microsatellite markers are expected to be useful in conservation genetic studies of this species and for future conservation planning.

9,19-Cycloartenol glycoside G3 from Cimicifuga simplex regulates immune responses by modulating Th17/Treg ratio

Cimicifuga simplex is a medicinal herb which has a wide range of biological activities. We isolated seven 9,19-cycloartenol glycosides from the roots of C. simplex, and among the glycosides, G3 exhibited the strongest inhibitory effect on immune responses, including suppressing the differentiation of CD4+ T cells and directly suppressing the cytokine-induced JAK/STAT signaling pathways. In the IL-23-induced mouse ear model of skin disease, G3 repressed disease development by inhibiting the expression of pro-inflammatory mediators in murine ear skin. Moreover, G3 affected the maturation of DCs in vitro, thereby inducing T cell differentiation, resulting in an increased Treg phenotype and decreased Th17 phenotype. This study provides new evidence that G3 might ameliorate chronic inflammatory skin diseases by suppressing pathogenic CD4+ T cell differentiation and the IL-17+RORγt+/IL-10+FoxP3+ ratio. These findings suggest that G3 might mediate the therapeutic effects observed in psoriasis patients following treatment with C. simplex.

Hydroxyshengmanol-type triterpenoids from the aerial parts of Cimicifuga simplex Wormsk

New hydroxyshengmanol-type triterpenoids (1–8) were identified from the aerial parts of cimicifuga simplex Wormsk by comprehensive 1D and 2D NMR, MS, and single-crystal X-ray diffraction analyses. The absolute configuration of the himeketal carbon (C-16) in hydroxyshengmanol-type constituents from cimicifuga spp. was initially determined as R using X-ray diffraction. All compounds were evaluated for their cytotoxicity in a panel of cancer cell lines and acetylcholinesterase inhibitory activity.

Cycloartenol triterpenoid saponins from Cimicifuga simplex (Ranunculaceae) and their biological effects

The constituents of Cimicifuga plants have been extensively investigated, and the principal metabolites are 9,19-cyclolanostane triterpenoid glycosides, which are distributed widely in Cimicifuga plants, but not in other members of the Ranunculaceae family, and are considered to be characteristics of the Cimicifuga genus. This type of triterpenoid glycoside possesses several important biological activities. More than 120 cycloartane triterpene glycosides have been isolated from Cimicifuga simplex Wormsk. The aim of this review article is to summarize all the major findings based on the available scientific literatures on C. simplex, with a focus on the identified 9,19-cyclolanostane triterpenoid glycosides. Biological studies of cycloartane triterpene glycosides from Cimicifuga spp. are also discussed.

New 9,19-cycloartenol glycosides isolated from the roots of Cimicifuga simplex and their anti-inflammatory effects

Two new cycloartenol triterpene saponins, 3β,16α-dihydroxy-12-acetoxy-16,22-cyclo-23-ketone-24R,25-epoxy-cycloartane-3-O-β-d-galactopyranoside (1), 3β,16α-dihydroxy-12-acetoxy-16,22-cyclo-23-ketone-24R,25-epoxy-cycloartane-7-ene-3-O-β-d-xylopyranoside (2), were isolated from the ethyl acetate soluble fraction of the roots of Cimicifuga simplex Wormsk. Their structures were established by detailed spectroscopic analysis, including extensive 2D NMR data. Their anti-proinflammatory activities were also carried out by LPS-stimulated IL-6, IL-23 and TNF-α genes expression in RAW cells in vitro using Q-PCR method.

Two new 9,19-cycloartenol glycosides from the roots of Cimicifuga simplex Wormsk

Two new cycloartenol triterpene saponins, 7,8,16,17-tetrahydro-23R,24R-O-acetyl-hydroshengmanol-3-O-β-d-galactopyranoside (1), 16,17-didehydro-23R,24R-O-acetyl-hydroshengmanol-3-O-β-d-galactopyranoside (2), were isolated from the ethyl acetate soluble fraction of Cimicifuga simplex Wormsk. Their structures were established by detailed spectroscopic analysis, including extensive 2D NMR data. This is the first time to report 16,17-double bond type glycosidesaponin from Cimicifuga species. Their immunosuppressive activities were also carried out by ConA-stimulated T splenocyte proliferation assay in vitro.

Three New Cycloartenol Glycosides from the Roots ofCimicifuga simplex

Three new cycloartenol triterpene saponins, 3 β,16 α-dihydroxy-12-acetoxy-16,22-cyclo-23-ketone-24 R,25-epoxy-cycloartane-7-ene 3- O- β-D-galactopyranoside ( 1), 24- O-hydroxy-7,8-didehydrohydroshengmanol 3- O- β-D-galactopyranoside ( 2), and 24-epi-24- O-hydroxy-7,8-didehydrohydroshengmanol 3- O- β-D-galactopyranoside ( 3), were isolated from the ethyl acetate soluble fraction of Cimicifuga simplex. Their structures were established by detailed spectroscopic analysis, including extensive 2D-NMR data. This is the first time that a 16,22-cyclo type glycosidesaponin from aCimicifuga species was reported. The immunosuppressive activities of the new compounds were evaluated by a ConA-stimulated T splenocyte proliferation assay in vitro.

Three New Cycloartenol Triterpenoid Saponins from the Roots of Cimicifuga simplex Wormsk

Three new cycloartenol triterpene saponins, named shengmaxinsides A-C, have been isolated from the ethyl acetate soluble fraction of an ethanol extract of Cimicifuga simplex Wormsk roots. Their structures were established by chemical tests and detailed spectroscopic analysis as 25-O-acetyl-7,8-didehydrocimigenol-3-O-β-D-galactopyranoside (1), 7,8-didehydrocimigenol-3-O-β-D-galactopyranoside (2) and 7,8-didehydro-24S-O-acetylhydroshengmanol-3-O-β-D-galactopyranoside (3), respectively.

Cell-specific Synergic Effect of Cimicifugoside on Cytotoxicity of Methotrexate

Cimicifugoside is a triterpenoid originating from the rhizomes of Cimicifuga simplex, and acts to inhibit the subcellular transport of nucleosides. Cimicifugoside, when used in combination with methotrexate, showed a cell-specific synergic effect on the promonocytic leukemia cell line U937, but not on the chronic myelogenetic leukemia cell line K562. Thymidine uptake was more severely inhibited by cimicifugoside in a dose-dependent fashion in U937 than in K562. The mRNA expression of one of the equilibrative Na+-independent nucleoside transporters, ENT2, was lower in U937 than in K562. This suggests that the thymidine uptake by ENT2 of U937 is more severely affected by cimicifugoside than that of K562, resulting in a decrease in DNA synthesis by methotrexate. In addition, cimicifugoside more efficiently stimulated the activity of thymidine kinase (TK) in K562 than in U937, suggesting that K562 resisted the decrease in DNA synthesis caused by the inhibition of nucleoside transporters. Cimicifugoside bifunctionally potentiated the cell-specific cytotoxicity of methotrexate by inhibiting ENT2 and activating TK.

Phenolic Constituents of the Aerial Parts of Cimicifuga simplex and Cimicifuga japonica

Chemical investigation of the aerial parts of Cimicifuga simplex afforded four new fukinolic acid analogues, cimicifugic acids K-N (1-4), and 10 known compounds, and C. japonica afforded three new fukinolic acid analogues, cimicifugic acids K-M (1-3), a new phenolic glycoside, shomaside F (5), and 10 known compounds. Cimicifugic acids K-N showed more potent hyaluronidase inhibitory activities than rosmarinic acid.

Inhibition of nucleoside transport and synergistic potentiation of methotrexate cytotoxicity by cimicifugoside, a triterpenoid from Cimicifuga simplex

Cimicifugoside, a triterpenoid isolated from Cimicifuga simplex, which has been used as a traditional Chinese medicine due to its anti-inflammatory, analgesic or anti-pyretic action, was examined for inhibition of nucleoside transport and synergistic potentiation of methotrexate cytotoxicity. Cimicifugoside inhibited uptake of uridine, thymidine and adenosine in human leukemia U937 cells with the low nanomolar IC 50 values, but did not affect that of uracil, leucine or 2-deoxyglucose at ≤100 nM. Cimicifugoside analogs differentially inhibited uridine uptake in the order cimicifugoside > cimicifugenin (aglycon of cimicifugoside) > bugbanoside B > cimicifugenin A, O-methyl cimicifugenin and bugbanoside A. Cimicifugoside had less affinity for the binding site of nitrobenzylthioinosine (typical high-affinity inhibitor of equilibrative nucleoside transporter-1) in U937 cells, K562 cells and human erythrocyte membranes compared with the prototype nucleoside transport inhibitor dipyridamole. Cimicifugoside markedly potentiated methotrexate cytotoxicity in a culture of U937 cells and human carcinoma KB cells. Potentiation of methotrexate cytotoxicity by cimicifugoside analogs in U937 cells was in proportion to their inhibitory activity against uridine uptake. The present study demonstrates that cimicifugoside is a novel specific nucleoside transport inhibitor that displays synergistic potentiation of methotrexate cytotoxicity.

Composition of the essential oil of rootstock from Cimicifuga simplex

The composition of the essential oils from rootstock of Cimicifuga simplex has been investigated by capillary GC and GC/MS. The main components in essential oil were m-acetanisole (27.57%), (E)-cinnamaldehyde (6.84%), paeonol (5.58%), caproic acid (5.07%) and atractylone (3.10%). The oil was characterized by a high content of aromatic components (52.59%).

Cimicifuga species identification by high performance liquid chromatography–photodiode array/mass spectrometric/evaporative light scattering detection for quality control of black cohosh products

Black cohosh has become one of the most important herbal products in the US dietary supplements market. It is manufactured from roots and rhizomes of Cimicifuga racemosa (Ranunculaceae). Botanical identification of the raw starting material is a key step in the quality control of black cohosh preparations. The present report summarizes a fingerprinting approach based on high performance liquid chromatography–photodiode array/mass spectrometric/evaporative light scattering detection (HPLC–PDA/MS/ELSD) that has been developed and validated using a total of 10 Cimicifuga species. These include three North American species, Cimicifuga racemosa, Cimicifuga americana, Cimicifuga rubifolia, and seven Asian species, Cimicifuga acerina, Cimicifuga biternat, Cimicifuga dahurica, Cimicifuga heracleifolia, Cimicifuga japonica, Cimicifuga foetida, and Cimicifuga simplex. The chemotaxonomic distinctiveness of the HPLC fingerprints allows identification of all 10 Cimicifuga species. The triterpene glycoside cimigenol-3- O-arabinoside ( 3), cimifugin ( 12), and cimifugin-3- O-glucoside ( 18) were determined to be suitable species-specific markers for the distinction of C. racemosa from the other Cimicifuga species. In addition to identification, the fingerprint method provided insight into chemical interconversion processes occurring between the diverse triterpene glycosides contained in black cohosh. The reported method has proven its usefulness in the botanical standardization and quality control of black cohosh products.

LC/TIS-MS Fingerprint Profiling of Cimicifuga Species and Analysis of 23-Epi-26-deoxyactein in Cimicifuga racemosa Commercial Products

In this study, a liquid chromatography (LC)/turbo ion spray (TIS)-mass spectrometry (MS) method was developed to examine the chromatography or "fingerprint profile" of seven Cimicifuga herbs and six Cimicifuga racemosa (black cohosh) commercial products. Triterpene glycoside components were selected as chemical markers for analysis because they have appeared as a major compound group in Cimicifuga species. LC/MS chromatograms unveiled the patterns of C. racemosa, Cimicifuga dahurica, Cimicifuga foetida, Cimicifuga heracleifolia, Cimicifuga japonica, Cimicifuga acerina, and Cimicifuga simplex, which are very different from each other. 23-Epi-26-deoxyactein was found only in C. racemosa, C. dahurica, and C. foetida. A highly selective and sensitive LC/MS/MS method for quantitative analysis of 23-epi-26-deoxyactein with detection levels up to 2.5 ng in these samples was also developed and was applied to six commercial C. racemosa products. C. racemosa and its six commercial products contained about 6-15% of 23-epi-26-deoxyactein in total triterpene glycosides. On the other hand, the estimated amount of total triterpene glycosides in other commercial products was either greater or lesser than what the manufacturers claimed. The technique and LC/MS profiles generated in this study provide a reliable and reproducible method that can be readily utilized for botanical identification of Cimicifuga plants, for examination and validation of its commercial products, and for "chemical" quality control in the manufacture of black cohosh products.

ChemInform Abstract: Studies on the Constituents of Cimicifuga Species. Part 28. Four New Cycloart‐7‐enol Glycosides from the Underground Parts of Cimicifuga simplex WORMSK.

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