Loliolide in Sargassum horneri Alleviates Ultrafine Urban Particulate Matter (PM 0.1)-Induced Inflammation in Human RPE Cells.

Owing to increasing air pollution due to industrial development, fine dust has been associated with threatening public health. In particular, ultrafine urban particulate matter (uf-UP, PM 0.1) can easily enter our bodies, causing inflammation-related diseases. Therefore, in the present study, we evaluated the effects of hydrothermal extracts of Sargassum horneri and its bioactive compound, loliolide, on uf-UP-induced inflammation as a potential treatment strategy for retinal disorders. Human retinal pigment epithelial cells (ARPE-19) stimulated with TNF-α or uf-UPs were treated with S. horneri extract and loliolide. S. horneri extracts exhibited anti-inflammatory effects on uf-UP-induced inflammation without cell toxicity through downregulating the mRNA expression of MCP-1, IL-8, IL-6, and TNF-α. UPLC-QTOF/MS analysis confirmed that the hydrothermal extract of S. horneri contained loliolide, which has anti-inflammatory effects. Loliolide effectively reduced the mRNA expression and production of proinflammatory chemokines (IL-8) and cytokines (IL-1ß and IL-6) by downregulating the MAPK/NF-ĸB signaling pathway on TNF-α-stimulated inflammatory ARPE-19 cells. These effects were further confirmed in inflammatory ARPE-19 cells after stimulation with uf-UPs. Collectively, these results suggested the application of S. horneri as a functional ingredient for treating ocular disorders caused by particular matters.

Anti-Inflammatory Activity of Cajanin, an Isoflavonoid Derivative Isolated from Canavalia lineata Pods.

The bioactive components of Canavalia lineata (Thunb.) DC pods were investigated using bioactivity-guided isolation, and the chemical structures of flavonoids 1-3, isoflavonoid derivatives 4-11, and phenolic compounds 12 and 13 were identified by comparing NMR, MS, and CD spectral data with previously reported spectroscopic data. Compounds 1-13 were evaluated for their anti-inflammatory effects on LPS-stimulated RAW264.7 macrophages. Among these compounds, the isoflavonoid derivative cajanin (7) exhibited the most potent anti-inflammatory activity (IC50 of NO = 19.38 ± 0.05 µM; IC50 of IL-6 = 7.78 ± 0.04 µM; IC50 of TNF-α = 26.82 ± 0.11 µM), exerting its anti-inflammatory effects by suppressing the activation and nuclear translocation of the transcription factor NF-κB by phosphorylating IκB and p65. These results suggested that cajanin (7) may be a potential candidate for improving the treatment of inflammatory diseases.

Medicarpin and Homopterocarpin Isolated from Canavalia lineata as Potent and Competitive Reversible Inhibitors of Human Monoamine Oxidase-B.

Thirteen compounds were isolated from the Canavalia lineata pods and their inhibitory activities against human monoamine oxidase-A (hMAO-A) and -B (hMAO-B) were evaluated. Among them, compounds 8 (medicarpin) and 13 (homopterocarpin) showed potent inhibitory activity against hMAO-B (IC50 = 0.45 and 0.72 µM, respectively) with selectivity index (SI) values of 44.2 and 2.07, respectively. Most of the compounds weakly inhibited MAO-A, except 9 (prunetin) and 13. Compounds 8 and 13 were reversible competitive inhibitors against hMAO-B (Ki = 0.27 and 0.21 µM, respectively). Structurally, the 3-OH group at A-ring of 8 showed higher hMAO-B inhibitory activity than 3-OCH3 group at the A-ring of 13. However, the 9-OCH3 group at B-ring of 13 showed higher hMAO-B inhibitory activity than 8,9-methylenedioxygroup at the B-ring of 12 (pterocarpin). In cytotoxicity study, 8 and 13 showed non-toxicity to the normal (MDCK) and cancer (HL-60) cells and moderate toxicity to neuroblastoma (SH-SY5Y) cell. Molecular docking simulation revealed that the binding affinities of 8 and 13 for hMAO-B (-8.7 and -7.7 kcal/mol, respectively) were higher than those for hMAO-A (-3.4 and -7.1 kcal/mol, respectively). These findings suggest that compounds 8 and 13 be considered potent reversible hMAO-B inhibitors to be used for the treatment of neurological disorders.

The Anti-Tumor Effects of Oenothera odorata Extract Are Mediated by Inhibition of Glycolysis and Cellular Respiration in Cancer Cells.

Cancer is caused by uncontrolled cell division and is a leading cause of mortality worldwide. Oenothera odorata (O. odorata) extract is used in herbal medicine to inhibit inflammation, but its potential anti-tumor properties have not been fully evaluated. Here, we demonstrated that O. odorata extract inhibits the proliferation of lung adenocarcinoma and melanoma cell lines In Vitro, and also inhibits the growth of melanoma cells In Vivo. After partitioning the extract with n-hexane, chloroform, ethyl acetate, and n-butanol, it was found that the butanol-soluble (OOB) and water-soluble (OOW) fractions of O. odorata extract are effective at inhibiting tumor cell growth In Vivo although OOW is more effective than OOB. Interestingly, these fractions did not inhibit the growth of non-cancerous cells. The anti-proliferative effects of the OOW fraction were found to be mediated by inhibition of glycolysis and cellular respiration. UPLC of both fractions showed two major common peaks, which were predicted to be hydrolyzable tannin-related compounds. Taken together, these data suggest that O. odorata extract has anti-tumor properties, and the molecular mechanism involves metabolic alterations and inhibition of cell proliferation. O. odorata extract therefore holds promise as a novel natural product for the treatment of cancer.

Optogenetic activation of parvalbumin and somatostatin interneurons selectively restores theta-nested gamma oscillations and oscillation-induced spike timing-dependent long-term potentiation impaired by amyloid ß oligomers.

BACKGROUND: Abnormal accumulation of amyloid ß1-42 oligomers (AßO1-42), a hallmark of Alzheimer's disease, impairs hippocampal theta-nested gamma oscillations and long-term potentiation (LTP) that are believed to underlie learning and memory. Parvalbumin-positive (PV) and somatostatin-positive (SST) interneurons are critically involved in theta-nested gamma oscillogenesis and LTP induction. However, how AßO1-42 affects PV and SST interneuron circuits is unclear. Through optogenetic manipulation of PV and SST interneurons and computational modeling of the hippocampal neural circuits, we dissected the contributions of PV and SST interneuron circuit dysfunctions on AßO1-42-induced impairments of hippocampal theta-nested gamma oscillations and oscillation-induced LTP. RESULTS: Targeted whole-cell patch-clamp recordings and optogenetic manipulations of PV and SST interneurons during in vivo-like, optogenetically induced theta-nested gamma oscillations in vitro revealed that AßO1-42 causes synapse-specific dysfunction in PV and SST interneurons. AßO1-42 selectively disrupted CA1 pyramidal cells (PC)-to-PV interneuron and PV-to-PC synapses to impair theta-nested gamma oscillogenesis. In contrast, while having no effect on PC-to-SST or SST-to-PC synapses, AßO1-42 selectively disrupted SST interneuron-mediated disinhibition to CA1 PC to impair theta-nested gamma oscillation-induced spike timing-dependent LTP (tLTP). Such AßO1-42-induced impairments of gamma oscillogenesis and oscillation-induced tLTP were fully restored by optogenetic activation of PV and SST interneurons, respectively, further supporting synapse-specific dysfunctions in PV and SST interneurons. Finally, computational modeling of hippocampal neural circuits including CA1 PC, PV, and SST interneurons confirmed the experimental observations and further revealed distinct functional roles of PV and SST interneurons in theta-nested gamma oscillations and tLTP induction. CONCLUSIONS: Our results reveal that AßO1-42 causes synapse-specific dysfunctions in PV and SST interneurons and that optogenetic modulations of these interneurons present potential therapeutic targets for restoring hippocampal network oscillations and synaptic plasticity impairments in Alzheimer's disease.

Kurarinone Attenuates BLM-Induced Pulmonary Fibrosis via Inhibiting TGF-ß Signaling Pathways.

Idiopathic pulmonary fibrosis (IPF) is a refractory interstitial lung disease for which there is no effective treatment. Although the pathogenesis of IPF is not fully understood, TGF-ß and epithelial-mesenchymal transition (EMT) have been shown to be involved in the fibrotic changes of lung tissues. Kurarinone is a prenylated flavonoid isolated from Sophora Flavescens with antioxidant and anti-inflammatory properties. In this study, we investigated the effect of kurarinone on pulmonary fibrosis. Kurarinone suppressed the TGF-ß-induced EMT of lung epithelial cells. To assess the therapeutic effects of kurarinone in bleomycin (BLM)-induced pulmonary fibrosis, mice were treated with kurarinone daily for 2 weeks starting 7 days after BLM instillation. Oral administration of kurarinone attenuated the fibrotic changes of lung tissues, including accumulation of collagen and improved mechanical pulmonary functions. Mechanistically, kurarinone suppressed phosphorylation of Smad2/3 and AKT induced by TGF-ß1 in lung epithelial cells, as well as in lung tissues treated with BLM. Taken together, these results suggest that kurarinone has a therapeutic effect on pulmonary fibrosis via suppressing TGF-ß signaling pathways and may be a novel drug candidate for pulmonary fibrosis.

Rugosic acid A, derived from Rosa rugosa Thunb., is novel inhibitory agent for NF-κB and IL-6/STAT3 axis in acute lung injury model.

Rosa rugosa Thunb., is as a medicinal plant known for anti-diabetic, and anti-inflammatory activities. However, the specific active compounds responsible for the individual pharmacological effects of in R. rugosa extract (95% EtOH) remain unknown. Here, we hypothesized that terpenoid structure, the most abundant constituents in R. rugosa extract, are responsible for its anti-inflammatory activity. We investigated the phytochemical substituents (compounds 1-13) and newly purified 11-methoxy polisin A, and 13-methoxy bisaborosaol F using NMR and ESI-MS and to screened their effects on NO production in LPS-induced macrophages. Rugosic acid A (RA) induced to ameliorate NO production, iNOS, and pro-inflammatory cytokines associated with the NF-κB. And, RA suppressed IL-6 secretion and IL-6-mediated STAT3 activation in LPS-mediated inflammation. In addition, RA was evaluated in LPS-mediated acute lung injury (ALI) model similar to acute pneumonia. Our results suggested that RA was suppressed to translocate nuclear NF-κB and IL-6-mediated STAT3 activation. Finally, RA led to amelioration of ALI by decreasing myeloperoxidase (MPO) and inhibiting phosphorylation of NF-κB and STAT3. Our group originally found that R. rugosa extract had new methoxy compounds and RA may be alternative natural agent for acute pneumonia similar to severe acute respiratory syndrome by coronavirus.

Bioactive triterpene glycosides from the fruit of Stauntonia hexaphylla and insights into the molecular mechanism of its inflammatory effects.

Chromatography of the ethanol extract of the medicinal fruit Stauntonia hexaphylla resulted in the purification of 26 compounds (1-26), including two undescribed triterpene saponins 1 and 2 (hexaphylosides A and B). Their structures were confirmed by spectroscopic data, including IR, HR QTOF MS, 1H, 13C NMR, COSY, HMQC, HMBC, and TOCSY, and HPLC sugar analysis after acid hydrolysis. The anti-inflammatory effects of the high-purity constituents (1-26) on lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells were investigated by screening nitric oxide production. The NO inhibitory activity of compounds 6 and 10 with the IC50 values of 1.33 and 1.10 µM, respectively. The structure-activity relationships (SAR) of the isolated compounds were also analyzed. Furthermore, compounds 6 and 10 inhibited the protein expression inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2 via Western blotting analysis. This showed that compounds 6 and 10 contributed to the anti-inflammatory effects of S. hexaphylla fruit, which could be developed as a natural nutraceutical and functional food ingredient.

In vitro inhibitory effects of cirsiliol on IL-6-induced STAT3 activation through anti-inflammatory activity.

Many studies have identified and described various medicinal effects of cirsiliol. Here, we investigated the signaling pathway involved in the anti-inflammatory effects of cirsiliol on IL-6-induced activity. Cirsiliol showed no cytotoxicity and inhibited pSTAT3-induced luciferase activity. At the molecular level, cirsiliol suppressed the expression of IL-6-induced inflammatory marker genes such as CRP, IL-1ß, ICAM-1 and SOCS3, IL-6-induced activation of Jak2, gp130, STAT3 and ERK and nuclear translocation of STAT3, as measured by PCR, immunofluorescence staining and western blot analysis. However, the interaction between IL-6 and its receptor was not affected by cirsiliol treatment. These results indicate that cirsiliol attenuates IL-6-induced cellular signaling by regulating Jak2 phosphorylation. Therefore, cirsiliol could be a therapeutic agent for IL-6-related inflammatory diseases.

Isolation, structural elucidation, and insights into the anti-inflammatory effects of triterpene saponins from the leaves of Stauntonia hexaphylla.

Using various chromatographic techniques, 23 triterpene saponins (1-23) were isolated from an ethanol extract of Stauntonia hexaphylla, including two new compounds (12 and 15). Their chemical structures were established by comprehensive spectroscopic methods such as 1D- and 2D-NMR, and HR-ESI-MS, and chemical reactions. The anti-inflammatory activities of the isolated saponins were determined using the nitric oxide (NO) assay. Compound 13 exhibited the greatest inhibitory effect (IC50 = 0.59 µM). In addition to NO, compound 13 suppressed the secretion of PGE2, IL-1ß, and IL-6, but not TNF-α, and inhibited the protein expression of iNOS and COX-2 in LPS-activated RAW264.7 cells. The chemical derivatives of the isolated compounds were studied using structure-activity relationships. The results suggested that compound 13 isolated from S. hexaphylla might be useful for treating inflammation. This is the first comprehensive study of saponins from the leaves of S. hexaphylla based on anti-inflammatory extract screening guidelines.

Anti-inflammatory Potential of Saponins from Aster tataricus via NF-κB/MAPK Activation.

Four new aster saponins (1-4) together with five known analogues (5-9) were isolated from Aster tataricus. The chemical structures of 1-4 were elucidated based on spectrometric and spectroscopic analysis and comparison with reported data. The potential anti-inflammatory activities of aster saponins 1-9 were evaluated subsequently by measuring lipopolysaccharide (LPS)-enhanced nitric oxide (NO) formation in murine macrophages. Among these, aster saponin B (6) exhibited the most potent inhibitory activity (IC50: 1.2 µM). Additionally, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein levels were dose-dependently suppressed by 6 in LPS-activated RAW 264.7 cells. Investigation of the anti-inflammatory mechanism indicated that 6 attenuated the phosphorylation and degradation of the inhibitor of NF-κB (IκB), which led to the blocking of NF-κB p65 translocation to the nucleus.

Identification of potential inflammatory inhibitors from Aster tataricus.

Aster tataricus L.f. is a traditional Eastern Asian herbal medicine used for the relief of cough-related illnesses. In this study, 32 known compounds and two novel monoterpene glycosides were isolated from the roots of A. tataricus. With the aid of reported data, elucidation of the root-extract components was carried out using a multitude of spectroscopic techniques. All isolates were investigated for their ability to inhibit nitric oxide (NO) secretion in lipopolysaccharide-activated RAW264.7 cells. Compound 7 remarkably suppressed NO production with an IC50 value of 8.5 µM. In addition, compound 7 exhibited significant inhibitory activity against the production of inflammatory cytokines (prostaglandin E2, interleukin-6, and interleukin-1 beta) and the expression of inflammatory enzymes (inducible nitric oxide synthase and cyclooxygenase-2) via inhibition of nuclear factor-kappa B activation. Moreover, compound 7 effectively prevented the downstream activation of the mitogen-activated protein kinase signaling pathway by inhibiting phosphorylation of c-Jun N-terminal kinases, extracellular signal-regulated kinases, and p38. These results outline compound 7 as a potential inhibitor for the broad treatment of inflammatory diseases, such as atopic dermatitis, asthma, and various allergies.

STAT3-inhibitory activity of sesquiterpenoids and diterpenoids from Curcuma phaeocaulis.

Three new sesquiterpenoids (compounds 4, 5, and 26), along with 23 known sesquiterpenoids (compounds 1-3 and 6-25) and two diterpenoids (compounds 27 and 28), were obtained from Curcuma phaeocaulis, and their chemical structures were determined through nuclear magnetic resonance (NMR), circular dichroism (CD), and high-resolution electrospray ionization (HRESIMS) spectroscopic data, which were compared to the data from previous studies. All isolates were tested for inhibitory activity against interleukin (IL)-6-stimulated STAT3 expression using a luciferase reporter assay, and curzerenone (21) and 8-epi-galanolactone (28) displayed promising signal transducer and activator of transcription (STAT3)-inhibitory activities with IC50 values of 4.8 and 4.1 µM, respectively. In addition, these candidates significantly suppressed the mRNA expression levels of the proinflammatory genes IL-1ß and C-reactive protein (CRP) via blockade of the IL-6-activated Janus kinase 2 (JAK2)/STAT3 and ERK-MAPK signaling pathways. These results suggest that curzerenone (21) and 8-epi-galanolactone (28) may be potential candidates for ameliorating severe inflammatory diseases.

Chemical constituents from Vietnamese mangrove Calophyllum inophyllum and their anti-inflammatory effects.

In a search for anti-inflammatory activity in resources from Vietnamese mangroves, we found that a methanolic extract from the leaves of Calophyllum inophyllum (CIL) showed significant anti-inflammatory effects in vitro. Using various chromatographic techniques, we subsequently isolated 12 compounds (1-12) from a methanolic extract of CIL, including two novel compounds (1-2). The inhibitory effects of these compounds on lipopolysaccharide-induced nitric oxide (NO) production in RAW264.7 cells were also evaluated. Compound 1 significantly suppressed NO production (IC50 = 2.44 ±â€¯0.88 µM), the secretion of pro-inflammatory cytokines (including interleukin-1 beta and tumor necrosis factor alpha), and the expression of inducible nitric oxide synthase through downregulation of nuclear factor-kappa-B signaling cascades. These results suggest that C. inophyllum leaves might be a useful resource for the development of drugs for the treatment of inflammation.

Diarylheptanoids from Curcuma phaeocaulis Suppress IL-6-Induced STAT3 Activation.

Three undescribed diarylheptanoids (3: -5: ) and six known curcuminoids (1, 2: , and 6: -9: ) were obtained from the ethyl acetate-soluble fraction of an ethanolic extract of Curcuma phaeocaulis. Their chemical structures and absolute configurations were elucidated by high-resolution electrospray ionization mass spectrometry, nuclear magnetic resonance spectroscopy, circular dichroism spectroscopy, and the modified Mosher's method. Previous studies constructed Hep3B cells stably transfected with pSTAT3-Luc plasmid containing STAT3 binding site to discover STAT3 inhibitors from natural products. The STAT3 inhibitory activities of all isolates were measured in transfected Hep3B cells after treatment with IL-6. Compound 5: ((5R)-1,7-Bis(3,4-dimethoxyphenyl)-3-methoxy-1-hepten-5-ol), demethoxycurcumin (7: ), and curcumin (8: ) exhibited significant inhibitory activity (IC50 values: 11.1, 1.9, and 1.6 µM, respectively). Furthermore, IL-6-induced phosphorylation of STAT3, and the mRNA expression levels of inflammation-related genes such as CRP, IL-1ß, ICAM-1, and SOCS3 were significantly reduced by exposure to compound 5: . These data suggested that the inhibitory activity of 5: is associated with the suppression of STAT3 phosphorylation. Thus, compound 5: may be a promising candidate for the treatment of cancer or inflammatory diseases related to the IL-6/STAT3 signaling pathway.

Inhibition potential of phenolic constituents from the aerial parts of Tetrastigma hemsleyanum against soluble epoxide hydrolase and nitric oxide synthase.

The aerial parts of Tetrastigma hemsleyanum (APTH) have been used as a functional tea in China. The purpose of the current study was to identify the bioactive constituents with inhibitory activity against soluble epoxide hydrolase (sEH) and inducible nitric oxide synthase (iNOS), which are jointly considered potential therapeutic targets for vascular system diseases. In the present study, 39 compounds (1-39) were isolated from the APTH. Among them, compounds 8, 10, 12, 16, 17, 19, and 32 displayed potential activities, with IC50 values ranging from 4.5 to 9.5 µM, respectively, and all in non-competitive inhibition mode. Compounds 5, 10, 12, 19, and 32 displayed potent iNOS inhibitory effects, with IC50 values ranging from 15.6 to 47.3 µM. The results obtained in this work contribute to a better understanding of the pharmacological activities of T. hemsleyanum and its potential application as a functional food.

Oleanolic Acid Acetate Exerts Anti-Inflammatory Activity via IKKα/ß Suppression in TLR3-Mediated NF-κB Activation.

Oleanolic acid acetate (OAA), a major triterpenoid compound of Vigna angularis (azuki bean, V. angularis), has been shown to downregulate inflammatory responses in macrophages. Here, we show the molecular basis for the effect of OAA on Toll-like receptor (TLR) downstream signaling. OAA treatment significantly inhibited the secretion of embryonic alkaline phosphatase (SEAP) induced by polyinosinic acid (poly(I), TLR3 ligand) in a dose-dependent manner and without cytotoxicity in THP1-XBlue cells. In addition, OAA downregulated the gene expression of poly(I) induced pro-inflammatory cytokines and chemokines genes such as MCP-1, IL-1ß, IL-8, VCAM-1 and ICAM-1. Furthermore, we found that the inhibition activity of OAA was accompanied by decreased activation of not only nuclear factor-kappa B (NF-κB) signaling but also mitogen-activated protein kinase (MAPK) signaling upon stimulation with the TLR3 agonist. Interestingly, the interaction of OAA with IκB kinase α/ß (IKKα/ß) strongly attenuated the production of certain proteins and inflammatory cytokines in the TLR3 signaling pathway, such as nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkBα), extracellular regulated kinases (ERK), and p38, in an in vitro model. The action of OAA was regulated by TLR3, demonstrating that TLR3 plays a critical role in mediating the physiologically-relevant anti-inflammatory action of OAA and that the interaction with IKKα/ß is modulated through TLR3. These results reveal new insight into the understanding of the regulatory mechanisms of the downstream TLR3 signaling pathway and consequent inflammatory responses that are involved in the development and progression of inflammatory diseases.

1-Carbomethoxy-ß-Carboline, Derived from Portulaca oleracea L., Ameliorates LPS-Mediated Inflammatory Response Associated with MAPK Signaling and Nuclear Translocation of NF-κB.

Portulaca oleracea is as a medicinal plant known for its neuroprotective, hepatoprotective, antidiabetic, antioxidant, anticancer, antimicrobial, antiulcerogenic, and anti-inflammatory activities. However, the specific active compounds responsible for the individual pharmacological effects of P. oleracea extract (95% EtOH) remain unknown. Here, we hypothesized that alkaloids, the most abundant constituents in P. oleracea extract, are responsible for its anti-inflammatory activity. We investigated the phytochemical substituents (compounds 1-22) using nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESI-MS) and screened their effects on NO production in lipopolysaccharide (LPS)-induced macrophages. Compound 20, 1-carbomethoxy-ß-carboline, as an alkaloid structure, ameliorated nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and proinflammatory cytokines associated with the mitogen-activated protein kinase (MAPK) pathways, p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). Subsequently, we observed that compound 20 suppressed nuclear translocation of nuclear factor κB (NF-κB) using immunocytochemistry. Moreover, we recently reported that compound 8, trans-N-feruloyl-3', 7'-dimethoxytyramine, was originally purified from P. oleracea extracts. Our results suggest that 1-carbomethoxy-ß-carboline, the most effective anti-inflammatory agent among alkaloids in the 95% EtOH extract of P. oleracea, was suppressing the MAPK pathway and nuclear translocation of NF-κB. Therefore, P. oleracea extracts and specifically 1-carbomethoxy-ß-carboline may be novel therapeutic candidates for the treatment of inflammatory diseases associated with the activation of MAPKs and NF-κB.

Alkaloids from Tetrastigma hemsleyanum and Their Anti-Inflammatory Effects on LPS-Induced RAW264.7 Cells.

Alkaloids 1⁻10 were isolated from the aerial parts of Tetrastigma hemsleyanum (APTH) and obtained from species of the genus Tetrastigma for the first time. The chemical structures of the isolated compounds were identified by NMR, UV, and MS analyses. Their anti-inflammatory activities were investigated by measuring nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Among all the isolates, compounds 6, 7 and 10 showed potent inhibitory activity against LPS-stimulated NO production in RAW264.7 cells (IC50: 31.9, 25.2 and 6.3 µM, respectively). Furthermore, APTH and S-(−)-trolline (10) inhibited induction of inflammatory cytokines or mediators such as interleukin-1ß (IL-1ß) and inducible nitric oxide synthase (iNOS) via suppression of nuclear factor κB (NF-κB) translocation into the nucleus. In addition, 10 suppressed extracellular signal-regulated protein kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) phosphorylation in a dose-dependent manner. These results conclusively demonstrated that compound 10 displays anti-inflammatory activity via suppression of NF-κB activation and the ERK-MAPK signaling pathway in LPS-stimulated RAW264.7 cells.

Anti-inflammatory Activity of Eudesmane-Type Sesquiterpenoids from Salvia plebeia.

Nine new sesquiterpenoid lactones and 11 known analogues were isolated from the aerial parts of Salvia plebeia R.Br. Their structures were elucidated via HRESIMS and NMR data, and their absolute configurations were defined via electronic circular dichroism data, X-ray crystallographic analysis, and the modified Mosher's ester method. Compounds 1-20 were investigated for their ability to inhibit LPS-stimulated nitric oxide production in murine macrophage cells. Of the isolates, epi-eudebeiolide C (20) showed the highest inhibitory effect (IC50 of 17.9 µM). mRNA and protein expression of inducible nitric oxide synthase (iNOS), but not that of cyclooxygenase-2 (COX-2), was dose-dependently decreased by 20 in LPS-activated RAW 264.7 cells. Based on a mechanistic study involving the nuclear factor-κB (NF-κB) signaling pathway, the anti-inflammatory effect of 20 was attributed to NF-κB activation blockade via inhibition of NF-κB (IκB) phosphorylation. Therefore, 20 might be a potential candidate for relieving inflammatory diseases.