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Aging is associated with immune disregulation and oxidative stress which lead to inflammation and neurodegenerative diseases. We have tried to identify the anti-neuroinflammatory and anti-inflammatory components of Coreopsis lanceolata L. The dried flowers of C. lanceolata were extracted with 70% EtOH, and the obtained extract was divided into CH2Cl2, EtOAc, n-BuOH, and H2O fractions. The CH2Cl2 fraction was separated using silica gel and C-18 column chromatography to yield phenylheptatriyne (1), 2′-hydroxy-3,4,4′-trimethoxychalcone (2), and 4′,7-dimethoxyflavanone (3). Additionally, the EtOAc fraction was subjected to silica gel, C-18, and Sephadex LH-20 column chromatography to yield 8-methoxybutin (4) and leptosidin (5). All the compounds isolated from C. lanceolata inhibited the production of nitric oxide (NO) in LPS-induced BV2 and RAW264.7 cells. In addition, phenylheptatriyne and 4′,7-dimethoxyflavanone reduced the secretion of inflammatory cytokines, tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6. Among them, phenylheptatriyne was significantly downregulated in the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Subsequently, phenylheptatriyne also effectively inhibited nuclear factor-kappa B (NF-κB) activation in LPS-stimulated BV2 and RAW264.7 cells. Based on these results, the anti-neuroinflammatory effect of phenylheptatriyne isolated from C. lanceolata was confirmed, which may exert a therapeutic effect in treatment of neuroinflammation-related diseases.

A prenylated flavonoid, cudraflavanone B, is isolated from Cudrania tricuspidata. In this study, we investigated its anti-inflammatory and anti-neuroinflammatory effects in lipopolysaccharide (LPS)-induced RAW264.7 and BV2 cells. In our initial study of the anti-inflammatory effects of cudraflavanone B the production of nitric oxide and prostaglandin E2 was attenuated in LPS-stimulated RAW264.7 and BV2 cells. These inhibitory effects were related to the downregulation of inducible nitric oxide synthase and cyclooxygenase-2. In addition, cudraflavanone B suppressed the production of pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-α in LPS-induced RAW264.7 and BV2 cells. Moreover, the evaluation of the molecular mechanisms underlying the anti-inflammatory effects of cudraflavanone B revealed that the compound attenuated the nuclear factor-kappa B signaling pathway in LPS-induced RAW264.7 and BV2 cells. In addition, cudraflavanone B inhibited the phosphorylation of extracellular signal-regulated kinase mitogen-activated protein kinase signaling pathways in these LPS-stimulated cells. Thus, cudraflavanone B suppressed nuclear factor-κB, and extracellular signal-regulated kinase mitogen-activated protein kinase mediated inflammatory pathways, demonstrating its potential in the treatment of neuroinflammatory conditions.

Heme oxygenase (HO)-1 is a detoxifying phase II enzyme that plays a role in both inflammatory and oxidative stress responses. Curdrania tricuspidata is widespread throughout East Asia and is used as a therapeutic agent in traditional medicine. We investigated whether treatment with sixteen flavonoid or xanthone compounds from C. tricuspidata could induce HO-1 expression in HT22 hippocampal cells, RAW264.7 macrophage, and BV2 microglia. In these compounds, kuwanon C showed the most remarkable HO-1 expression effects. In addition, treatment with kuwanon C reduced cytoplasmic nuclear erythroid 2-related factor (Nrf2) expression and increased Nrf2 expression in the nucleus. Significant inhibition of glutamate-induced oxidative injury and induction of reactive oxygen species (ROS) occurred when HT22 hippocampal cells were pretreated with kuwanon C. The levels of inflammatory mediator and cytokine, which increased following lipopolysaccharide (LPS) stimulation, were suppressed in RAW264.7 macrophage and BV2 microglia after kuwanon C pretreatment. Kuwanon C also attenuated p65 DNA binding and translocation into the nucleus in LPS-induced RAW264.7 and BV2 cells. The anti-inflammatory, anti-neuroinflammatory, and neuroprotective effects of kuwanon C were reversed when co-treatment with HO-1 inhibitor of tin protoporphyrin-IX (SnPP). These results suggest that the neuroprotective and anti-inflammatory effects of kuwanon C are regulated by HO-1 expression.

We previously reported that desoxo-narchinol A and narchinol B from Nardostachys jatamansi DC (Valerianaceae) inhibited the production of nitric oxide (NO) and prostaglandin E2 (PGE2), and the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 protein in lipopolysaccharide (LPS)-stimulated BV2 and primary microglial cells. In this study, we aimed to elucidate the molecular mechanism underlying the anti-neuroinflammatory effects of desoxo-narchinol A and narchinol B. These two compounds inhibited the nuclear factor (NF)-κB pathway, by repressing the phosphorylation and degradation of inhibitor kappa B (IκB)-α, nuclear translocation of the p65/p50 heterodimer, and DNA-binding activity of the p65 subunit. Furthermore, both compounds induced heme oxygenase-1 (HO-1) protein expression, which was mediated by the activation of nuclear transcription factor erythroid-2-related factor 2 (Nrf2). Activation of the Nrf2/HO-1 pathway by desoxo-narchinol A was shown to be regulated by increased phosphorylation of p38 and extracellular signal-regulated kinase (ERK), whereas only p38 was involved in narchinol B-induced activation of the Nrf2/HO-1 pathway. In addition, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling was also involved in the activation of HO-1 by desoxo-narchinol A and narchinol B. These compounds also increased the phosphorylation of glycogen synthase kinase 3 beta (GSK3β) at serine-9 residue, following phosphorylation of Akt. The anti-neuroinflammatory effect of desoxo-narchinol A and narchinol B was partially blocked by a selective HO-1 inhibitor, suggesting that this effect is partly mediated by HO-1 induction. In addition, both compounds also induced HO-1 protein expression in rat-derived primary microglial cells, which was correlated with their anti-neuroinflammatory effects in LPS-stimulated primary microglial cells. In conclusion, desoxo-narchinol A and narchinol B are potential candidates for the development of preventive agents for the regulation of neuroinflammation in neurodegenerative diseases.

Dalbergia odorifera T. Chen (Leguminosae) grows in Central and South America, Africa, Madagascar, and Southern Asia. D. odorifera possesses many useful pharmacological properties, such as antioxidative and anti-inflammatory activities in various cell types. 4-Methoxydalbergione (MTD) and 4'-hydroxy-4-methoxydalbergione (HMTD) were isolated from the EtOH extract of D. odorifera by several chromatography methods. The chemical structures were elucidated by nuclear magnetic resonance (NMR) and mass spectrum (MS). Anti-inflammatory and cytoprotective effects were examined using BV2 microglial cells and murine hippocampus. MTD and HMTD were demonstrated to induce heme oxygenase (HO)-1 protein levels through the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) in BV2 microglial cells, while only MTD upregulated HO-1 in HT22 cells. MTD and HMTD induced HO-1 expression through JNK MAPK pathway in BV2 cells, whereas only MTD activated the ERK and p38 pathways in HT22 cells. MTD was also shown to activated MTD and HMTD suppressed lipopolysaccharide-stimulated nitric oxide (NO) and prostaglandin E2 production by inhibiting inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in a dose-dependent manner. Furthermore, MTD and HMTD attenuated pro-inflammatory cytokine productions. These anti-inflammatory effects were found to be mediated through the nuclear factor-kappa B (NF-κB) pathway. MTD exhibited neuroprotective effects on glutamate-induced neurotoxicity by promoting HO-1 in HT22 cells. The anti-inflammatory and cytoprotective effects of MTD and HMTD were partially reversed by an HO inhibitor tin protoporphyrin IX. In addition, MTD and HMTD inhibited pro-inflammatory cytokines and NF-κB pathway in primary rat microglia. These findings suggest that MTD and HMTD have therapeutic potential against neurodegenerative diseases accompanied by microglial activation and/or oxidative cellular injury.

Through searching for anti‑neuroinflammatory metabolites from

Nardostachys jatamansi contains various types of sesquiterpenoids that may play an important role in the potency of plant&rsquo, s anti-inflammatory effects, depending on their structure. In this study, five new sesquiterpenoids, namely kanshone L (1), kanshone M (2), 7-methoxydesoxo-narchinol (3), kanshone N (4), and nardosdaucanol (5), were isolated along with four known terpenoids (kanshone D (6), nardosinanone G (7), narchinol A (8), and nardoaristolone B (9)) from the rhizomes and roots of Nardostachys jatamansi. Their structures were determined by analyzing 1D and 2D NMR and MS data. Among the nine sesquiterpenoids, compounds 3, 4, and 8 were shown to possess dose-dependent inhibitory effects against lipopolysaccharide (LPS)-stimulated nitric oxide (NO) production in BV2 microglial cells. Furthermore, compounds 3, 4, and 8 exhibited anti-neuroinflammatory effects by inhibiting the production of pro-inflammatory mediators, including prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) proteins, as well as pro-inflammatory cytokines, such as interleukin (IL)-1&beta, IL-12 and tumor necrosis factor-&alpha, (TNF-&alpha, ), in LPS-stimulated BV2 microglial cells. Moreover, these compounds were shown to inhibit the activation of the NF-&kappa, B signaling pathway in LPS-stimulated BV2 microglial cells by suppressing the phosphorylation of I&kappa, B-&alpha, and blocking NF-&kappa, B translocation. In conclusion, five new and four known sesquiterpenoids were isolated from Nardostachys jatamansi, and compounds 3, 4, and 8 exhibited anti-neuroinflammatory effects in LPS-stimulated BV2 microglial cells through inhibiting of NF-&kappa, B signaling pathway.

Two new meroterpenoid-type fungal metabolites, furanoaustinol (1) and 7-acetoxydehydroaustinol (2), were isolated from the ethyl acetate extract of a marine-derived fungal strain Penicillium sp. SF-5497, along with eight (3-10) known meroterpenoids. Their structures were elucidated mainly based on the analysis of their NMR (1D and 2D) and MS data. Particularly, the novel meroterpenoid, furanoaustinol (1), belonging to the austin group, was identified to possess an unprecedented hexacyclic ring system. Biological evaluation of these compounds revealed that furanoaustinol (1) weakly inhibited the activity of protein tyrosine phosphatase 1B in a dose-dependent manner with an IC50 value of 77.2 μM. In addition, 7-acetoxydehydroaustinol (2) and four other known meroterpenoids (5, 7, 9, and 10) weakly suppressed the overproduction of nitric oxide in lipopolysaccharide-challenged BV2 microglial cells with IC50 values of 61.0, 30.1, 58.3, 37.6, and 40.2 μM, respectively.

In the course of searching for bioactive secondary metabolites from marine fungi, TMC-256C1 was isolated from an ethyl acetate extract of the marine-derived fungus Aspergillus sp. SF6354. TMC-256C1 displayed anti-neuroinflammatory effect in BV2 microglial cells induced by lipopolysaccharides (LPS) as well as neuroprotective effect against glutamate-stimulated neurotoxicity in mouse hippocampal HT22 cells. TMC-256C1 was shown to develop a cellular resistance to oxidative damage caused by glutamate-induced cytotoxicity and reactive oxygen species (ROS) generation in HT22 cells, and suppress the inflammation process in LPS-stimulated BV2 cells. Furthermore, the neuroprotective and anti-neuroinflammatory activities of TMC-256C1 were associated with upregulated expression of heme oxygenase (HO)-1 and nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) in HT22 and BV2 cells. We also found that TMC-256C1 activated p38 mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways in HT22 and BV2 cells. These results demonstrated that TMC-256C1 activates HO-1 protein expression, probably by increasing nuclear Nrf2 levels via the activation of the p38 MAPK and PI3K/Akt pathways.

In Korea and China, Cudrania tricuspidata Bureau (Moraceae) is an important traditional medicinal plant used to treat lumbago, hemoptysis, and contusions. The C. tricuspidata methanol extract suppressed both production of NO and PGE2 in BV2 microglial cells. Cudraflavanone D (1), isolated from this extract, remarkably suppressed the protein expression of inducible NO synthase and cyclooxygenase-2, and decreased the levels of NO and PGE2 in BV2 microglial cells exposed to lipopolysaccharide. Cudraflavanone D (1) also decreased IL-6, TNF-α, IL-12, and IL-1β production, blocked nuclear translocation of NF-κB heterodimers (p50 and p65) by interrupting the degradation and phosphorylation of inhibitor of IκB-α, and inhibited NF-κB binding. In addition, cudraflavanone D (1) suppressed the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK pathways. This study indicated that cudraflavanone D (1) can be a potential drug candidate for the cure of neuroinflammation.

Kanjang (Korean soy sauce) is a byproduct of the production of the Korean fermented soybean. In the present study, seven indole alkaloid derivatives were isolated from methanol extract of kanjang. Their structures were identified as 1-propyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (1), 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (2), 1-methyl-1,2,3,4-tetrahydro-β-carboline-1-carboxylic acid (3), 3-indoleacetic acid (4), Nb-acetyltryptamine (5), 1-methyl-3,4-dihydro-β-carboline (6), and flazine (7) by NMR and MS analyses. Preliminary screening for anti-neuroinflammatory effects of isolated indole alkaloids in lipopolysaccharide (LPS)-stimulated BV2 cells revealed that these compounds inhibited the production of nitric oxide and prostaglandin E2. For the subsequent investigation of anti-neuroinflammatory action of these metabolites, compounds 4 and 7 were selected, and the results revealed that these inhibitory effects correlated with the suppressive effect of 4 and 7 on inducible nitric oxide synthase and cyclooxygenase-2 expression in LPS-stimulated BV2 cells. In regards to the mechanism of the anti-inflammatory effect, 4 and 7 significantly inhibited the nuclear factor-kappa B pathway.

Chemical investigation of the EtOAc extracts of marine-derived fungal isolates Aspergillus sp. SF-5974 and Aspergillus sp. SF-5976 yielded a new dihydroisocoumarin derivative (1) and 12 known metabolites. The structures of the isolated metabolites were established by extensive spectroscopic analyses, including 1D and 2D NMR spectra and MS data. Among the metabolites, the absolute configuration of 5'-hydroxyasperentin (6) was determined by single-crystal X-ray diffraction analysis. The in vitro antineuroinflammatory effects of the metabolites were also evaluated in lipopolysaccharide (LPS)-stimulated microglial cells. Among the isolated metabolites, dihydroisocoumarin derivatives 1-6 (10-80 μM) were shown to inhibit LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production by suppressing the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively, in LPS-stimulated BV2 microglia. Further, 1 (20-80 μM) was found to suppress the phosphorylation of the inhibitor of nuclear factor kappa B-α (IκB-α), interrupt the nuclear translocation of nuclear factor kappa B (NF-κB), and decrease the activation of p38 mitogen-activated protein kinase (MAPK).

In the course of a search for anti-neuroinflammatory metabolites from marine fungi, aurantiamide acetate (1) was isolated from marine-derived Aspergillus sp. as an anti-neuroinflammatory component. Compound 1 dose-dependently inhibited the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in BV2 microglial cells. It also attenuated inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and other pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). In a further study designed to elucidate the mechanism of its anti-neuroinflammatory effect, compound 1 was shown to block the activation of nuclear factor-kappa B (NF-κB) in lipopolysaccharide (LPS)-induced BV2 microglial cells by inhibiting the phosphorylation of the inhibitor kappa B-α (IκB)-α. In addition, compound 1 decreased the phosphorylation levels of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs). These results suggest that compound 1 has an anti-neuroinflammatory effect on LPS stimulation through its inhibition of the NF-κB, JNK and p38 pathways.