Ent-eudesmane sesquiterpenoids with anti-neuroinflammatory activity from the marine-derived fungus Eutypella sp. F0219.

In this study, twenty-three ent-eudesmane sesquiterpenoids (1-23) including fifteen previously undescribed ones, named eutypelides A-O (1-15) were isolated from the marine-derived fungus Eutypella sp. F0219. Their planar structures and relative configurations were established by HR-ESIMS and extensive 1D and 2D NMR investigations. The absolute configurations of the previously undescribed compounds were determined by single-crystal X-ray diffraction analyses, modified Mosher's method, and ECD calculations. Structurally, eutypelide A (1) is a rare 1,10-seco-ent-eudesmane, whereas 2-15 are typically ent-eudesmanes with 6/6/-fused bicyclic carbon nucleus. The anti-neuroinflammatory activity of all isolated compounds (1-23) was accessed based on their ability to NO production in LPS-stimulated BV2 microglia cells. Compound 16 emerged as the most potent inhibitor. Further mechanistic investigation revealed that compound 16 modulated the inflammatory response by decreasing the protein levels of iNOS and increasing ARG 1 levels, thereby altering the iNOS/ARG 1 ratio and inhibiting macrophage polarization. qRT-PCR analysis showed that compound 16 reversed the LPS-induced upregulation of pro-inflammatory cytokines, including iNOS, TNF-α, IL-6, and IL-1ß, at both the transcriptional and translational levels. These effects were linked to the inhibition of the NF-κB pathway, a key regulator of inflammation. Our findings suggest that compound 16 may be a potential structure basis for developing neuroinflammation-related disease therapeutic agents.

Discovery of eudesmane-type sesquiterpenoids with neuroprotective effects from the roots of Chloranthus serratus.

Seven eudesmane-type sesquiterpenoids, including three pairs of racemic compounds (1a-3a and 1b-3b) and a sesquiterpenoid lactone (4), were obtained from the roots of Chloranthus serratus. The structures of these sesquiterpenoids were characterized based on spectroscopic analyses, ECD calculations, and X-ray diffraction experiment. Neuroprotection assays of the isolated eudesmane-type sesquiterpenoids were conducted on H2O2 damaged PC12 cells. At the concentration of 10 µM, compounds 1b and 4 increased cell viability from 54.8 ± 3.3% to 76.8 ± 2.3 and 72.7 ± 8.2%, respectively.

Anti-inflammatory Eudesmane Sesquiterpenoids from Artemisia hedinii.

Fourteen new eudesmane sesquiterpenoids (1, 3-5, 7-16) and seven known analogues were isolated from the whole plant of Artemisia hedinii. Their structures were elucidated by spectroscopic data analysis and comparison with published NMR data, and their absolute configurations were confirmed by X-ray diffraction experiments and TDDFT ECD calculation. Compounds 1-15 were identified as eudesmane acids, which represent a kind of lactone ring-opening eudesmane-type sesquiterpenes with an acetoxyl or a hydroxy group attached to C-9. Compounds 1 and 2, 5 and 6, and 7 and 8 are three pairs of epimers isomerized at C-3, C-5, and C-11, respectively. Compounds 1-9, 11-13, 15-19, and 21 could influence the proinflammatory phenotype of the M1 macrophage. Among them, compounds 5, 8, 9, 12, 16, and 19 consistently exhibited anti-inflammatory effects, as evidenced by downregulating classic pro-inflammatory cytokines TNF-α, IL-12, IL-6, and IFN-γ in LPS-induced primary bone marrow derived M1 macrophages.

Alantolactone alleviates collagen-induced arthritis and inhibits Th17 cell differentiation through modulation of STAT3 signalling.

CONTEXT: Alantolactone, the bioactive component in Inula helenium L. (Asteraceae), exhibits multiple biological effects. OBJECTIVE: We aimed to determine the anti-inflammatory effect of alantolactone in a collagen-induced arthritis (CIA) mouse model and its immunomodulatory effects on Th17 differentiation. MATERIALS AND METHODS: A CIA mouse model was established with DBA/1 mice randomly divided into four groups (n = 6): healthy, vehicle and two alantolactone-treated groups (25 or 50 mg/kg), followed by oral administration of alantolactone to mice for 21 consecutive days after arthritis onset. The severity of CIA was evaluated by an arthritic scoring system and histopathological examination. Levels of cytokines and anti-CII antibodies as well as percentages of splenic Th17 and Th17 differentiation with or without alantolactone treatments (0.62, 1.2 or 2.5 µM) were detected with ELISA and flow cytometry, respectively. Western blot analysis was used to evaluate intracellular signalling in alantolactone-treated spleen cells. RESULTS: In CIA mice, alantolactone at 50 mg/kg attenuated RA symptoms, including high arthritis scores, infiltrating inflammatory cells, synovial hyperplasia, bone erosion and levels of the proinflammatory cytokines TNF-α, IL-6 and IL-17A, but not IL-10 in paw tissues. Alantolactone also reduced the number of splenic Th17 cells and the capability of naïve CD4+ T cells to differentiate into the Th17 subset by downregulating STAT3/RORγt signalling by as early as 24 h of treatment. DISCUSSION AND CONCLUSIONS: Alantolactone possesses an anti-inflammatory effect that suppresses murine CIA by inhibiting Th17 cell differentiation, suggesting alantolactone is an adjunctive therapeutic candidate to treat rheumatoid arthritis.

Therapeutic potential and pharmacological activities of ß-eudesmol.

Herbal medicines are attracting the attention of researchers worldwide. ß-Eudesmol is one of the most studied and major bioactive sesquiterpenes, mainly extracted from Atractylodes lancea (Thunb) DC. rhizomes. It has potential anti-tumor and anti-angiogenic activities and is an inhibitor of tumor growth by inhibiting angiogenesis by suppressing CREB activation of the growth factor signaling pathway. It also stimulates neurite outgrowth in rat pheochromocytoma cells with activation of mitogen-activated protein kinases. It may be a promising lead compound for enhancing neural function, and it may help to explain the underlying mechanisms of neural differentiation. In this review, we summarized the currently available clinical and preclinical studies describing the therapeutic applications of ß-eudesmol.

Inhibition of Growth of Esophageal Cancer by Alantolactone via Wnt/ß- Catenin Signaling.

BACKGROUND: Alantolactone (AL) is a natural compound extracted from the roots of Inula Helenium L, which exerts an anti-tumor effect in a variety of cancer cell lines; however, its effect on esophageal cancer, a common malignancy with poor prognosis, remains unclear. Therefore, we aim to evaluate the effect of AL on esophageal cancer and to explore its underlying mechanism. OBJECTIVE: This study aims to determine whether AL has an anti-cancer effect on esophageal cancer cells and to explore its underlying mechanism. METHODS: The effect of AL on the proliferation and apoptosis of esophageal cancer cells was detected by MTT assay, colony formation assay, crystal violet assay, flow cytometry and hoechst apoptosis staining. The wound healing and Transwell invasion assay were performed to examine the effect of AL on the migration and invasion of esophageal cancer cells. Luciferase reporter system and Western blot were used to study the anti-tumor mechanism of AL on esophageal cancer cells. The subcutaneous murine xenograft model was employed to verify the effects of AL on esophageal cancer cells. RESULTS: MTT assay, colony formation assay and crystal violet assay found that AL inhibited the growth of esophageal cancer cells. Hoechst staining and flow cytometry analysis showed that AL induced apoptosis in esophageal cancer through mitochondrial pathway. Transwell assay and wound healing assays showed that AL inhibited the metastasis and invasion of esophageal cancer cells. Wnt/ ß-catenin signaling may contribute to the mechanism of the inhibition. The anti-tumor effect of AL on esophageal cancer cells was validated on murine xenograft model. CONCLUSION: Our data indicate that AL inhibits proliferation, migration, and invasion of esophageal cancer cells, and promote apoptosis of esophageal cancer cells through the Wnt/ß-catenin signaling pathway.

Structurally diverse sesquiterpenoids from the aerial parts of Artemisia annua (Qinghao) and their striking systemically anti-inflammatory activities.

Thirteen new sesquiterpenoids, arteannoides F-R (1-13), along with 13 known analogues (14-26), were isolated from the dried aerial parts of Artemisia annua L. Their structures, including absolute configurations, were unambiguously determined by a combination of physical data analyses (HRESIMS, 1D and 2D NMR, and ECD) as well as the crystal structures of 1, 5, 6, 15, 19, and 23. Among the isolated compounds, 1 features an unusual 11-oxatricyclo[6.2.1.04,9]undecan-2-ene ring system, 5 possesses an uncommon 4,11-ether bridged tricyclic framework, whereas 6 is a new eudesmane-type sesquiterpenoid formed via rearrangement of its carbon backbone. The systemically anti-inflammatory activities of all isolates were evaluated by measuring their inhibitory effects on PGE2, NO, TNF-α, and IL-6 production in LPS-stimulated RAW 264.7 macrophages. Moreover, the structure activity relationships of some compounds are summarized, this study will provide new structural templates for discovering potential anti-inflammatory agents.

Oxygenated Geosmins and Plant-like Eudesmanes from a Bacterial Mangrove Endophyte.

Geosmin (1) is a microbial terpene metabolite that is responsible for the typical smell of soil and causes an off-odor of food and water. Eudesmane sesquiterpenes are commonly found in plant essential oils. Here we describe the discovery of four geosmin-type metabolites, 7R-hydroxygeosmin (2), 3-oxogeosmin (3), 2R-hydroxy-7-oxogeosmin (4), 5-deoxy-7ß,9ß-dihydroxygeosmin (5), the plant-like eudesmanes 4ß,10α-eudesmane-5ß,11-diol (6) and (1S,5S,6S,7S,10S)-10α-eudesm-4(15)-ene-1α,6α-diol (7), and the known 1(10)E,5E-germacradiene-2,11-diol (8) from a bacterial endophyte (Streptomyces sp. JMRC:ST027706) of the mangrove plant Bruguiera gymnorrhiza. By means of NMR, MS, and ECD spectroscopy, all chemical structures as well as the absolute configurations for the new compounds were elucidated. Compounds 2-5 represent the first geosmin-related metabolites directly as bacterial natural products. The plant-derived eudesmane-5ß,11-diol (6) and (1S,5S,6S,7S,10S)-10α-eudesm-4(15)-ene-1α,6α-diol (7) are also now reported as bacterial products. The broad antimicrobial activities of 6 against a suite of fungal and bacterial pathogens including methicillin-resistant Staphylococcus aureus suggest that this terpene could be an important active principle of the medicinal plant Cymbopogon distans. The discovery of geosmin metabolites from one actinomycete indicated that these bacteria could possess enzymes for modifying geosmin and offer a possibility for bioremediation.

2-Hydroxysorangiadenosine: Structure and Biosynthesis of a Myxobacterial Sesquiterpene-Nucleoside.

Myxobacteria represent an under-investigated source for biologically active natural products featuring intriguing structural moieties with potential applications, e.g., in the pharmaceutical industry. Sorangiadenosine and the here-discovered 2-hydroxysorangiadenosine are myxobacterial sesquiterpene-nucleosides with an unusual structural moiety, a bicyclic eudesmane-type sesquiterpene. As the biosynthesis of these rare terpene-nucleoside hybrid natural products remains elusive, we investigated secondary metabolomes and genomes of several 2-hydroxysorangiadenosine-producing myxobacteria. We report the isolation and full structure elucidation of 2-hydroxysorangiadenosine and its cytotoxic and antibiotic activities and propose a biosynthetic pathway in the myxobacterium Vitiosangium cumulatum MCy10943T.

The characteristic smell emitted from two scale insects, Ceroplastes japonicus and Ceroplastes rubens.

The volatile components emitted from two scale insects, Ceroplastes japonicus and Ceroplastes rubens, were identified using GC-MS analysis. The major volatile components of the solvent extract from C. japonicus were α-humulene (35.8%) and δ-cadinene (17.0%), while those of C. rubens were ß-selinene (10.3%) and ß-elemene (5.1%). In GC/olfactometry, linalool, butyric acid, 3-methylbutyric acid, 2-methylbutyric acid, and vanillin were identified as the odor-active components of the extract from C. japonicus, in addition to trace amounts of trans-4,5-epoxy-(2E)-decenal, 4-methyl-(3E)-hexenoic acid, and phenylacetic acid. With regard to C. rubens, trans-4,5-epoxy-(2E)-decenal, 3-methylbutyric acid, and phenylacetic acid were identified as the odor-active components. Besides, decan-1,4-olide (γ-decalactone) with milky cherry-like note and 3-hydroxy-4,5-dimethylfuran-2(5H)-one (sotolone) with brown sugar-like note were also detected as the characteristic cherry-like sweet-and-sour note of these two scale insects. ABBREVIATIONS: GC: Gas chromatography; GC/O: gas chromatography/olfactometry.

Nitric Oxide Production Inhibitory Eudesmane-Type Sesquiterpenoids from Artemisia argyi.

Six new eudesmane-type sesquiterpene derivatives, artemargyinins A-F were isolated from the leaves of Artemisia argyi. Their structures were elucidated based on the extensive analysis of spectroscopic data. Artemargyinins A-F feature a lactone ring-opening eudesmane-type sesquiterpene with an isoprenoid group at C(8). All compounds were tested for their inhibitory effects on lipopolysaccharide-induced nitric oxide (NO) production in RAW264.7 macrophages. Artemargyinins A-F showed more potent NO production inhibitory activity with IC50 values ranging from 7.66±0.53 to 61.19±2.54 µM than the positive control quercetin (IC50 =74.34±1.39 µM). Among them, artemargyinins C and D exhibited strong inhibitory activity with IC50 values of 8.08±0.21 and 7.66±0.53 µM, respectively.

2α-Hydroxyeudesma-4,11(13)-Dien-8ß,12-Olide Isolated from Inula britannica Induces Apoptosis in Diffuse Large B-cell Lymphoma Cells.

2α-Hydroxyeudesma-4,11(13)-dien-8ß,12-olide (HEDO), a eudesmane-type sesquiterpene lactone belonging to large group of plant terpenoids isolated from Inula britannica, displays cytotoxic activity against diffuse large B cell lymphoma cells in vitro. However, the molecular mechanism of the anticancer effect remains unclear. In this study, we showed that HEDO inhibits cell growth by inducing apoptosis in lymphoma cell lines through its antiproliferative activity. HEDO increases the depolarization of mitochondrial membrane potential and upregulated intracellular reactive oxygen species (ROS). Furthermore, we examined the cell cycle effect, and our results provided evidence that the arrest of the cell cycle at the SubG0/G1 phase plays an important role in the ability of HEDO to inhibit cell growth in Ontario Cancer Institute (OCI)-LY3 lymphoma cells by preventing nuclear factor-kappa B (NF-κB) signaling. In addition, HEDO induced apoptosis by instigating the activation of Bcl-2-associated X (BAX) and cleaved caspase-3, decreasing B-cell lymphoma 2 (BCL2), B-cell lymphoma-extra large (BCL-XL), and procaspase 3 expression levels. Based on these findings, we suggest that HEDO has potential as an anticancer drug of lymphoma by inducing ROS-dependent accumulation of SubG0/G1 arrest and apoptosis in OCI-LY3 cells.

Anti-Trypanosoma cruzi activity of costic acid isolated from Nectandra barbellata (Lauraceae) is associated with alterations in plasma membrane electric and mitochondrial membrane potentials.

As part of our continuous studies on prospecting metabolites from Brazilian plant species with pharmacologic activity against Trypanosoma cruzi, the n-hexane extract from twigs of Nectandra barbellata (Lauraceae) was subjected to a bioactivity-guided fractionation to afford the sesquiterpene costic acid. As results, costic acid induced a trypanocidal effect with IC50 of 37.8 and 7.9 µM to trypomastigotes and intracellular amastigotes, respectively. When tested in L929 cells, no cytotoxicity was detected in the highest tested concentration (CC50 > 200 µM), resulting in SI values >5 and >25 to trypomastigotes and amastigotes, respectively. Based on these promising results against T. cruzi, a mechanistic study of the parasite death was investigated. The flow cytometry analysis of costic acid-treated parasites showed depolarization of the plasma membrane electric potential. Spectrofluorimetrical analysis and transmission electron microscopy showed no evidence of plasma membrane permeability alteration of trypomastigotes, but strong ultrastructural damage, evidenced by large vacuoles. Although Ca2+ and reactive oxygen species (ROS) levels were unaltered after short time incubation with costic acid, it rapidly affected the mitochondria, leading to a depolarized potential of the membrane, reducing the ATP levels. In silico studies of costic acid showed good predictions for drug-likeness, with adherence to Lipinskís rules of five (RO5), good ADMET properties and no alerts for Pan-Assay Interference Compounds (PAINS). Therefore, costic acid demonstrated promising activity against T. cruzi parasites, with high selectivity to intracellular amastigotes. Considering the lethal action of costic acid in affecting a vital and unique organelle as the mitochondria, it could be considered a new hit compound for future drug design studies for Chagas disease.

Dodelates A-E: Five dimeric eudesmane sesquiterpenoids from Dobinea delavayi.

Dodelates A-E (1-5), five angeloylated eudesmane sesquiterpenoid dimers were isolated from the roots of Dobinea delavayi. Their structures were elucidated by extensive spectroscopic data and single-crystal X-ray diffraction analyses. A possible biosynthetic pathway of these five compounds was proposed. Compounds 1 and 3 exhibited moderate antimalarial activities against Plasmodium yoelii BY265RFP.

Bioactive Eudesmane sesquiterpenes from Artabotrys hongkongensis Hance.

A new naturally occurring trinoreudesmane sesquiterpene, artahongkongol A (1), together with seven known eudesmane sesquiterpenes (2-8), was isolated from the stems and leaves of Artabotrys hongkongensis Hance. Among them, 1 is a rare trinoreudesmane sesquiterpene containing 12 carbon atoms on the carbon skeleton. All known compounds (2-8) were isolated from the genus Artabotrys for the first time. The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1-8 showed significant inhibitory effects against various human cancer cell lines with IC50 values ranging from 0.57 to 15.68 µM.

Sesquiterpenoids from the herbs of Solanum lyratum and their cytotoxicity on human hepatoma cells.

Eleven sesquiterpenoids including four new eudesmane sesquiterpenoids, solanoids A-D (1-4), and seven known compounds (5-11) were isolated from the herbs of Solanum lyratum. By analyzing the UV, MS and NMR data, the gross structures of all isolates were established. The absolute configurations of these new compounds were determined by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. The in vitro cytotoxicity of all isolates against the hepatocellular carcinoma Hep3B and HepG2 cell lines was evaluated. Among them, compounds 7 and 11 exhibited moderate cytotoxicity against two cell lines.

Apoptosis-promoting and migration-suppressing effect of alantolactone on gastric cancer cell lines BGC-823 and SGC-7901 via regulating p38MAPK and NF-κB pathways.

BACKGROUND: Gastric cancer is a malignant tumor with high incidence rate and mortality rate. PURPOSE: In this study, we investigated the anti-cancer effect of alantolactone, a sesquiterpene lactone, on gastric cancer cell lines BGC-823 and SGC-7901. METHODS: BGC-823 and SGC-7901 cells were treated with different concentrations of alantolactone, Hoechst 33258 staining, flow cytometry, wound healing assay, invasion assay, colony forming assay, quantative polymerase chain reaction, and western blot analysis were used to evaluate the anticancer activity of alantolactone to gastric cancer. RESULTS: Alantolactone induced apoptosis of gastric cancer cells by regulating the expression of Bax, Bcl-2, and p53, which related to intrinsic apoptotic pathway, and suppressed colony formation, migration, and invasion by mediating the expression of matrix metalloproteinase (MMP)-2, MMP-7, and MMP-9. Cell signaling pathway analysis showed that alantolactone enhanced the phosphorylation of p38 and decreased the translocation of nucleus p65, suggesting that the apoptosis-promoting and migration-suppressing effect of alantolactone might at least partially rely on regulating p38 mitogen-activated protein kinase (p38MAPK) pathway and nuclear factor-κB (NF-κB) pathway. CONCLUSIONS: Alantolactone can be used as a potential therapeutic agent for treating gastric cancer.

Eudesmane Glycosides from Ambrosia artemisiifolia (Common Ragweed) as Potential Neuroprotective Agents.

In Alzheimer's disease, amyloid-ß (Aß) accumulation in the brain results in neuronal cell death and is one of the major causes of dementia. Because the current therapeutic agents are not yet sufficiently effective or safe, there have been attempts to find new neuroprotective chemicals against Aß-induced cytotoxicity. A 70% EtOH extract of whole plants of Ambrosia artemisiifolia (common ragweed) was selected after the screening of a natural extract library. Seven new eudesmane-type glycosides (1-7) and seven known compounds (8-14) were obtained through bioactivity-guided fractionation from the aerial parts of this plant. Their structures were determined on the basis of their nuclear magnetic resonance spectra, high-resolution electrospray ionization mass spectrometry analysis, and electronic circular dichroism calculations. Among them, compounds 1, 2, 4-6, 8, 9, 11, 13, and 14 showed protective effects against Aß-induced cytotoxicity in Aß42-transfected HT22 cells. The most active compounds, 5 and 6, exhibited moderate protective activity dose-dependently (10, 20, and 40 µM).

[A new eudesmane type sesquiterpene from cultivated Clerodendranthus spicatus in Hainan].

Six compounds were isolated from the aerial part of cultivated Clerodendranthus spicatus in Hainan with various chromatographic techniques,and their structures were determined as:1-dehydroxy-1-oxo-rupestrinol(1),N-trans-feruloyltyramine(2),methyl 3,4-dihydroxyphenyllactate(3),caffein acid(4),methyl caffeate(5) and ethyl caffeate(6),via analysis of physicochemical properties and spectroscopic evidence.Compound 1 was a new compound,while compounds 2 and 3 were isolated from C.spicatus for the first time.Biological activity results showed that compounds 2-4 exhibited α-glucosidase inhibitory activity with different inhibition ratio.

Potent inhibition of gastric cancer cells by a natural compound via inhibiting TrxR1 activity and activating ROS-mediated p38 MAPK pathway.

Thioredoxin reductase 1 (TrxR1) has emerged as a potential target for cancer therapy, because it is overexpressed in several types of cancers and associated with increased tumour growth and poor patient prognosis. Alantolactone (ALT), a natural sesquiterpene lactone originated from traditional folk medicine Inula helenium L., has been reported to exert antitumor activity in various tumours. However, the effect of ALT on human gastric cancer cells and its underlying mechanism remains unknown. In this study, we showed that ALT inhibited cell proliferation and induced cell apoptosis in gastric cancer cells. Mechanistically, our data found that ALT induced reactive oxygen species (ROS) production by inhibiting TrxR1 activity, resulting in the activation of p38 mitogen-activated protein kinase (MAPK) pathway and eventually cell apoptosis in gastric cancer cells. And the effects of ALT were reversed by pre-treatment with NAC (a scavenger of ROS). Further investigation revealed that ALT displayed synergistic lethality with erastin against gastric cancer cells, which demonstrating combined inhibition of TrxR1 and glutathione (GSH) leads to a synergistic effect in gastric cancer cells. More importantly, ALT treatment markedly reduced the activity of TrxR1 in vivo and inhibited the growth of gastric cancer xenografts without exhibiting significant toxicity. Taken together, these findings suggest that ALT may be used as a novel therapeutic agent against human gastric cancer.