Sesquiterpene dimers with a rare skeleton from Chloranthus holostegius exhibiting multidrug resistance reversal activity in vitro and in vivo.

Two previously unreported lindenane sesquiterpene dimers (1 and 2) with a rare skeleton containing an oxaspiro[4.5]decane moiety were isolated from the roots of Chloranthus holostegius var. trichoneurus. Their structures were elucidated by HRESIMS, NMR, ECD, and NMR quantum chemical calculations, along with DP4+ probability analysis. In bioassay, compound 1 exhibited significant activity to reverse the MDR in MCF-7/ADR cells, with an IC50 value of 4.4 µM. Further mechanistic studies revealed that compound 1 combined with doxorubicin could induce apoptosis of MCF-7/ADR cells and block the cell cycle in the G2/M phase. Mechanistically, compound 1 could inhibit the efflux function of P-glycoprotein (P-gp) using the zebrafish model. Finally, the enhanced chemotherapeutic effects of doxorubicin were further confirmed by in vivo zebrafish xenograft experiments.

Sarcanoids A and B, two new lindenane-type sesquiterpenoid dimers from the aerial parts of Sarcandra glabra.

Sarcanoids A and B (1 and 2), two new lindenane-type sesquiterpenoid dimers with a γ-hydroxysenecioate moiety at C-15', were isolated from the ethyl acetate extract of Sarcandra glabra. The structures were elucidated by extensive analysis of spectroscopic data, and their absolute configurations were determined by single-crystal X-ray crystallography. Compounds 1 and 2 showed moderate inhibitory activities on the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophages.

Isolation and biomimetic synthesis of phenylpropionyl phenylethylamines from Chloranthus henryi.

In this study, ten phenylpropionyl phenylethylamines, including five previously undescribed ones (1a/b, 2a/b, and 3), five known analogues (4-8), and two established phenylpropanoids precursors (9, 10) were isolated from the aerial parts of Chloranthus henryi Hemsl. Their structures, including absolute configurations, were determined by high-resolution mass spectrometry, enantio-separation, electronic circular dichroism calculation, and single crystal diffraction. Compounds 1a and 1b were the first examples of natural hetero-[2 + 2] cycloaddition products between phenylpropionyl phenylethylamine and phenylpropene. The plausible hetero-[2 + 2] biosynthesis pathway was confirmed by a photocatalytic biomimetic synthesis in eight steps, which also led to the production of three other potential natural homo-[2 + 2] adducts (1'a/b, 2', and 3'). Bioactivity screening indicated that these adducts bear medium inhibitory activity on nitric oxide generation, with IC50 values of 6-35 µM in RAW 264.7 macrophages.

Cretaceous chloranthoids: early prominence, extinct diversity and missing links.

BACKGROUND: The Chloranthaceae comprise four extant genera (Hedyosmum, Ascarina, Chloranthus and Sarcandra), all with simple flowers. Molecular phylogenetics indicates that the Chloranthaceae diverged very early in angiosperm evolution, although how they are related to eudicots, magnoliids, monocots and Ceratophyllum is uncertain. Fossil pollen similar to that of Ascarina and Hedyosmum has long been recognized in the Early Cretaceous, but over the last four decades evidence of extinct Chloranthaceae based on other types of fossils has expanded dramatically and contributes significantly to understanding the evolution of the family. SCOPE: Studies of fossils from the Cretaceous, especially mesofossils of Early Cretaceous age from Portugal and eastern North America, recognized diverse flowers, fruits, seeds, staminate inflorescences and stamens of extinct chloranthoids. These early chloranthoids include forms related to extant Hedyosmum and also to the Ascarina, Chloranthus and Sarcandra clade. In the Late Cretaceous there are several occurrences of distinctive fossil androecia related to extant Chloranthus. The rich and still expanding Cretaceous record of Chloranthaceae contrasts with a very sparse Cenozoic record, emphasizing that the four extant genera are likely to be relictual, although speciation within the genera might have occurred in relatively recent times. In this study, we describe three new genera of Early Cretaceous chloranthoids and summarize current knowledge on the extinct diversity of the group. CONCLUSIONS: The evolutionary lineage that includes extant Chloranthaceae is diverse and abundantly represented in Early Cretaceous mesofossil floras that provide some of the earliest evidence of angiosperm reproductive structures. Extinct chloranthoids, some of which are clearly in the Chloranthaceae crown group, fill some of the morphological gaps that currently separate the extant genera, help to illuminate how some of the unusual features of extant Chloranthaceae evolved and suggest that Chloranthaceae are of disproportionate importance for a more refined understanding of ecology and phylogeny of early angiosperm diversification.

Structurally diverse amides from Chloranthus henryi var. hupehensis and their anti-inflammatory activities by blocking Akt phosphorylation.

Eleven new amides, four racemic pairs of (±)-chlorahupetamides A, B, D, E (1, 2, 4, 5) and chlorahupetamides C, F, G (3, 6, 7), have been isolated from Chloranthus henryi var. hupehensis. Compounds 1-3 are the first naturally occurring dimers via an unprecedented [2 + 2] cycloaddition derived from two dissimilar cinnamic acid amides, while compounds 4 and 5 represent the first examples of lignanamides in Chloranthus; together with two new hydroxycinnamic acid amide monomers (6-7), these compounds were obtained. Their structures were characterized by nuclear magnetic resonance (NMR), electronic circular dichroism (ECD), and X-ray diffraction analysis. Meanwhile, an LPS-induced BV-2 cell inflammatory model was used to determine the potential anti-inflammatory activity of all the isolated compounds. Intriguingly, compound -1 treatment showed a much greater inhibition of TNF-α expression with an EC50 value of 1.80 µM, while compound + 1 had more advantages in reducing IL-1ß expression with an EC50 value of 19.93 µM. Moreover, compounds + 1 and -1 could significantly suppress inflammation and inhibit the Akt signaling pathway by decreasing the phosphorylated protein levels of Akt.

Lindenane sesquiterpenoid dimers from Chloranthus holostegius with anti-neuroinflammatory activities in BV-2 microglia.

Fifteen undescribed lindenane-type sesquiterpenoid dimers, designated chloranholides F-T (1-15), together with twenty-five known analogs (16-40), were isolated from the whole plants of Chloranthus holostegius. The isolate structures were elucidated by analysis of spectroscopic data and chemical methods, and their absolute configurations were determined by X-ray crystallography and electronic circular dichroism spectra. In anti-neuroinflammatory assays, all isolates were evaluated by examination of their inhibitory effect on nitric oxide (NO) in LPS-stimulated BV-2 cells, and the results showed that 21-24, 26, 30, 32 and 36 significantly inhibited the production of the inflammatory mediator NO, with IC50 values ranging from 3.18 to 11.46 µM, which was better than that of quercetin. Structure-activity relationship analysis revealed that two essential functional groups played an indispensable role in the anti-inflammatory effects. Moreover, 22 and 24 inhibited the LPS-induced upregulation of iNOS and COX-2 enzymes in BV-2 microglia at the protein level.

Lindenane sesquiterpenoid monomers and oligomers: Chemistry and pharmacological activities.

Lindenane sesquiterpenoid monomers and oligomers, characterized by a sterically congested cyclopentane and an unusual trans-5/6 ring junction, are mainly found in Chloranthaceae species and the genus Lindera Thunb (Lauraceae). Numerous studies have shown that lindenane sesquiterpenoid monomers and oligomers exhibit a broad range of biological activities, such as cytotoxicity, anti-inflammation, neuroprotection, antifungal, and anti-malarial activities. This review covers publications from the first identification of lindeneol in 1925-2023 and classifies the lindenane sesquiterpenoid derivatives into sesquiterpenoid monomers, sesquiterpenoid-monoterpene conjugates, sesquiterpenoid homodimers, sesquiterpenoid heterodimers, and trimeric sesquiterpenoids. In addition, their biological activities are summarized. This review will establish a scientific basis and provide guidance for utilizing this unique class of natural products as potential lead compounds to develop their application in treating diseases corresponding to inflammation, cancer, and plasmodium.

Lindenane-Type Sesquiterpene Dimers Mitigate Lipopolysaccharide-Induced Inflammation by Inhibiting Toll-Like Receptor Signaling.

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns and trigger an inflammatory response via the myeloid differential factor 88 (MyD88)-dependent and toll-interleukin-1 receptor domain-containing adapter-inducing interferon-ß (TRIF)-dependent pathways. Lindenane type sesquiterpene dimers (LSDs) are characteristic metabolites of plants belonging to the genus Sarcandra (Chloranthaceae). The aim of this study was to evaluate the potential anti-inflammatory effects of the LSDs shizukaol D (1) and sarcandrolide E (2) on lipopolysaccharides (LPS)-stimulated RAW264.7 macrophages in vitro, and explore the underlying mechanisms. Both LSDs neutralized the LPS-induced morphological changes and production of nitric oxide (NO), as determined by CCK-8 assay and Griess assay, respectively. Furthermore, shizukaol D (1) and sarcandrolide E (2) downregulated interferon ß (IFNß), tumor necrosis factor α (TNFα) and interleukin-1ß (IL-1ß) mRNA levels as measured by reverse transcription polymerase chain reaction (RT-PCR), and inhibited the phosphorylation of nuclear factor kappa B p65 (p65), nuclear factor kappa-Bα (IκBα), Jun N-terminal kinase (JNK), extracellular regulated kinase (ERK), mitogen-activated protein kinase p38 (p38), MyD88, IL-1RI-associated protein kinase 1 (IRAK1), and transforming growth factor-ß-activated kinase 1 (TAK1) proteins in the Western blotting assay. In conclusion, LSDs can alleviate the inflammatory response by inhibiting the TLR/MyD88 signalling pathway.

Anti-neuroinflammatory sesquiterpenoids from Chloranthus henryi.

Hupelactones A (1) and B (2), two new eudesmanolide-type enantiomers of the corresponding compounds, along with four mono- (3-6) and nine dimeric- (7-15) known sesquiterpenoids were isolated from the whole plant of Chloranthus henryi var. hupehensis (syn. C. henryi). The new structures including the absolute configurations were determined by comparison with previously reported enantiomers, extensive spectroscopic methods in combination with electronic circular dichroism (ECD) calculations. All the isolates were evaluated for their inhibitory activities against the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in murine BV-2 microglial cells. Among them, the dimeric lindenane sesquiterpenoids shizukaols F (8) and G (11) exhibited the most potent activities, with IC50 values of 2.65 and 4.60 µM, respectively.

The complete plastid genome sequence of Chloranthus fortunei (A. Gray) Solms-Laub. in Chloranthaceae.

Chloranthus fortunei (A. Gray) Solms-Laub. is a perennial herb in a basal angiosperm family Chloranthaceae. Here, we reported the complete plastid genome of C. fortunei using Illumina short-read data. The total genome size was 157,063 bp in length, containing 79 protein-coding genes, 30 tRNA genes, and four rRNA genes. The gene content and order were consistent with previously reported Chloranthus plastid genomes. The overall GC content of the C. fortunei plastid genome was 39.0%. In the phylogenetic result, genus Chloranthus was monophyletic and divided into two subclades: C. japonicus+C. angustifolius+C. fortunei, and C. henryi+C. spicatus+C. erectus. Our phylogenetic result was consistent with previous phylogenetic studies, and was supported by a previously proposed infrageneric classification of the genus Chloranthus.

Sesquiterpene dimers from Chloranthus fortunei and their protection activity against acute lung injury.

Chloranthus fortunei (family Chloranthaceae), a perennial herb, widely distributed in south China with an altitude of 170-340 m. The whole plants were used as an anti-inflammatory agent for the treatment of cough, arthritis and tumor. Five previously unreported compounds fortulactones A-E were isolated from the aerial part of Chloranthus fortunei. Their structures were elucidated using 1D/2D NMR and HRESIMS and their absolute configuration were determined using the ECD excitron chirality method. All isolates were tested for inhibitory effects on the NO production of liposaccharide (LPS)-induced RAW 264.7 macropahges. The most potent compound 1 was further evaluated its protective activity against LPS stimulated A549 cells, the ELISA kits results showed the abnormal states of MDA and SOD were corrected to a certain extent. Meanwhile, the pro-inflammatory cytokine, such as TNF-α, IL-6 and IL-1ß were also attenuated. In conclusion, these results showed that 1 exhibited therapeutic potential for ameliorating ALI.

Two new dinor-eudesmane sesquiterpenoids from the roots of Chloranthus multistachys.

Two new dinor-eudesmane sesquiterpenoids, named multistalin A (1), and multistalin B (2), together with three sesquiterpene glycosides (3-5), and a norlabdane-type diterpene (6) were isolated from the root extract of Chloranthus multistachys Pei. Their structures were elucidated on the basis of spectroscopic analysis including 1D, 2D NMR techniques and HR-ESI-MS. In addition, the cytotoxicity activities of the isolated compounds against selected cancer cells (Hela and A-549) were evaluated by MTT assay.

Further terpenoids from the Chloranthaceae plant Chloranthus multistachys and their anti-neuroinflammatory activities.

Three labdane-type [multisins A-C (1-3)], two guaiane-type [multisins D (4) and E (5)], and one eudesmane-type [multisin F (6)] previously undescribed terpenoids, together with 14 mono- (7-20) and seven dimeric- (21-27) known terpenoids, were isolated from the 90% MeOH extract of the whole plant of Chloranthus multistachys. Their structures and absolute configurations were determined by extensive spectroscopic methods and electronic circular dichroism (ECD) calculations. Compounds 4 and 5 are rare trinor-sesquiterpenes with a de-isopropyl guaiane skeleton, whereas compound 6 is a rearranged dinor-eudesmene featuring an uncommon octahydro-1H-indene ring system. Among the isolates, the dimeric lindenane sesquiterpenoid shizukaol C (25) exhibited the most potent (IC50 = 8.04 µM) anti-neuroinflammatory activity by inhibiting the nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated murine BV-2 microglial cells.

Chlomultiols A-L, sesquiterpenoids from Chloranthus multistachys and their anti-inflammatory activities.

Twelve undescribed sesquiterpenoids, named chlomultiols A-L, involving three lindenane sesquiterpenoid dimers, three eudesmane sesquiterpenoids, three guaiane sesquiterpenoids, and three cadinane sesquiterpenoids, along with four known compounds, were obtained from the whole plant of Chloranthus multistachys. Their structures were determined through spectroscopic techniques (HRESIMS, 1D and 2D NMR). In addition, the absolute and relative configurations of the undescribed compounds were established by using single crystal X-ray crystallography, NOESY and CD spectroscopy. The inhibitory effects of chlomultiols A-M on the production of nitric oxide in RAW 264.7 cells induced by lipopolysaccharide were evaluated. Chlomultiols A-C, and chlomultiols K-L showed moderate anti-inflammatory activities with IC50 values of 3.34 ± 0.73, 15.06 ± 1.08, 13.13 ± 3.99, 6.63 ± 1.11, and 16.16 ± 1.88 µM, respectively.

Oxidative stress-mediated hepatotoxicity in rats induced by ethanol extracts of different parts of Chloranthus serratus.

CONTEXT: Chloranthus serratus (Thunb.) Roem. et Schult. (Chloranthaceae) is an herb widely used as a folk medicine treating inflammatory diseases, although it is toxic. OBJECTIVE: To investigate hepatotoxicity and related mechanisms induced by ethanol extracts of different parts of C. serratus in rats. MATERIALS AND METHODS: Sprague Dawley rats were divided into control (Con), ethanol extract of roots (ER), stems (ES), and leaves (EL) groups, and acute oral toxicity studies were conducted. The rats received doses of 4.14, 3.20, and 1.16 g/kg/d extracts for 14 days, respectively. Liver index, liver function and oxidative stress biomarkers, liver pathology, ultrastructure, TNF-α, ICAM-1, and Nrf2/HO-1 proteins expression levels were determined. RESULTS: The LD50 of ER, ES, and EL were higher than 10.35, 8.05, and 2.90 g/kg/p.o., respectively. The liver indexes in the extract groups increased significantly. EL dramatically increased TP, GLB, AST, ALT, ALP, TBA, MDA, ICAM-1, and TNF-α levels (p < 0.01), and induced the most obvious pathological and ultrastructural changes. ES and EL obviously decreased the T-SOD, GSH, CAT, and CHOL levels. Nrf2 and HO-1 proteins expression was reduced significantly in ES (0.77 ± 0.06, 2.33 ± 0.20) and EL (0.23 ± 0.04, 2.14 ± 0.16) groups, and reduced slightly in ER (1.08 ± 0.10; 3.39 ± 0.21) group. DISCUSSION AND CONCLUSION: ES and EL induce stronger hepatotoxicity than ER through oxidative stress and the Nrf2/HO-1 pathway, and the root is a better medicinal part, which provides a basis for clinical research, safe applications, and reasonable development of C. serratus.

A new lindenane-type sesquiterpenoid lactone from Chloranthus japonicus.

Chromatographic fractionation of the EtOH extracts of the Traditional Chinese Medicine (TCM) Chloranthus japonicus, has led to the isolation of a new lindenane-type sesquiterpenoid lactone derivative (1). Rosmarylchloranthalactone E (1), which consists of lindenane sesquiterpenoid lactone and rosmarinic acid moieties linked via an ester bridge, was structurally elucidated by 1D and 2D NMR and HRMS data. Compound 1 was a potent phosphodiesterase-4 (PDE4) inhibitor with an IC50 value of 0.96 ± 0.04 µM.

Complete chloroplast genome of Chloranthus henryi (chloranthaceae).

The complete chloroplast genome of Chloranthus henryi, an important traditional Chinese herbal medicine, was sequenced and characterized in this study. The genome size is 157,990 bp in length with 37.3% GC content. Two inverted repeats of 26,151 bp are separated by a large single-copy region (87,148 bp), and a small single-copy region (18,569 bp). A total of 131 genes were identified, including 86 protein-coding genes, 37 tRNA genes and 8 rRNA genes. Eight plastome accessions from Chloranthales, Austrobaileyales, Nymphaeales, and Amborellales were selected to assess the phylogenetic placement of genus.

[Scientific research on selection of medicinal herbs of Chloranthaceae based on materia medica theory].

The plants of Chloranthaceae are widely distributed and rich in resources in our country, records of ancient herbs indicaded that various species of plants of Chloranthaceae can be used for medicinal purposes, especially the Sarcandra glabra which with the least toxicity and possessed the function of clearing heat and cooling blood, activating blood to eliminate spots and removing wind and dredging collaterals. Based on the theory of herbage and by the method of consulting the past herbal literature, we summarized and analyzed the medicinal history, distribution characteristics of herbage geography, characteristics of herbage ecology, standard collection situation and the modern toxicology research of Chloranthaceae plants. Therefore we explained the scientificity for selection of medicinal herbs of Chloranthaceae plants, and provided a theoretical and scientific basis for further research of Chloranthaceae plants.

Scientific research on selection of medicinal herbs of Chloranthaceae based on materia medica theory / 中国中药杂志

The plants of Chloranthaceae are widely distributed and rich in resources in our country, records of ancient herbs indicaded that various species of plants of Chloranthaceae can be used for medicinal purposes, especially the Sarcandra glabra which with the least toxicity and possessed the function of clearing heat and cooling blood, activating blood to eliminate spots and removing wind and dredging collaterals. Based on the theory of herbage and by the method of consulting the past herbal literature, we summarized and analyzed the medicinal history, distribution characteristics of herbage geography, characteristics of herbage ecology, standard collection situation and the modern toxicology research of Chloranthaceae plants. Therefore we explained the scientificity for selection of medicinal herbs of Chloranthaceae plants, and provided a theoretical and scientific basis for further research of Chloranthaceae plants.

Sesquiterpene dimers from the roots of Chloranthus holostegius with moderate anti-inflammatory activity.

Eight lindenane dimers, chololactones A-H, along with two known compounds, were isolated from the roots of Chloranthus holostegius. Their structures were elucidated using 1D/2D NMR and HRESIMS, and their absolute configurations were determined using the ECD exciton chirality method. All isolates were tested for inhibitory effects on the NO production of the liposaccharide (LPS)-induced RAW 264.7 macrophages, and showed moderate activity with IC50 values at 3.5-35.4 µM.