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• Two new coumarins (1 and 2) were established by extensive spectroscopic studies and chemical evidence. • Compounds 2 and 8 exhibited considerable HNE inhibitory activity, with IC 50 values of 3.6 and 9.6 μM. • Compounds 2 and 8 inhibited NO production as well as iNOS and COX-2 protein expression in RAW 264.7 cells. • Active coumarins from F. rhynchophylla are promising therapeutic agents for treating inflammation-related diseases. Two new coumarins (1 and 2), together with six known compounds (3 – 8), were isolated from the stem bark of Fraxinus rhynchophylla. The structures of these compounds were established by extensive spectroscopic studies and chemical evidence. The inhibitory activities of the isolated compounds (1 – 8) against human neutrophil elastase (HNE) were evaluated in vitro; all compounds tested exhibited inhibitory effects against HNE activity, with IC 50 values ranging from 3.6–74.3 μM. Among the compounds tested, compounds 2 and 8 exhibited considerable HNE inhibitory activity, with IC 50 values of 3.6 and 9.6 μM, respectively. The mechanism by which the two active compounds (2 and 8) inhibited HNE was noncompetitive inhibition, with inhibition constant (K i) values of 2.2 and 6.8 μM, respectively. Furthermore, compounds 2 and 8 dose-dependently inhibited LPS-induced NO production in RAW 264.7 cells. Consistent with these findings, they also suppressed LPS-induced expression of iNOS and COX-2 at the protein level in RAW 264.7 cells. [ABSTRACT FROM AUTHOR]

Microbial transformation of bavachin ( 1 ), one of the major bioactive components of Psoralea corylifolia L., was performed by using Absidia coerulea . Three oxidized metabolites were obtained in the biotransformation of 1 , and their structures were elucidated as bavachinone A ( 2 ), (2 S )-4′-hydroxy-6,7-[( R )-2-(1-hydroxy-1-methylethyl)-2,3-dihydrofurano]flavanone ( 3 ), and (2 S )-4′,7-dihydroxy-6-(2,3-dihydroxy-3-methylbutyl)flavanone ( 4 ) based on the spectroscopic analyses. Among them, metabolites 3 and 4 were new compounds. The biotransformation study suggested that 1 was fully oxidized to its metabolites within 5 days. Thus, biotransformation by A. coerulea can be used as a promising method for oxidation of bavachin. [ABSTRACT FROM AUTHOR]

6-Prenylapigenin ( 1 ) and 8-prenylapegenin ( 2 ) were semi-synthesized from apigenin by nuclear prenylation. Morusin ( 3 ) was isolated from the root bark of Morus alba L. The microbial transformation studies of these three bioactive prenylated apigenin derivatives were performed using eighteen cell cultures in order to select microorganisms capable of transforming them. It was identified that Mucor hiemalis (KCTC 26779) showed the ability to metabolize the parent compounds ( 1–3 ) into three new ( 4 – 6 ) and one known ( 7 ) glucosylated derivatives with high efficiency. Their structures were established as 6-prenylapigenin 7- O -β- d -glucopyranoside ( 4 ), 8-prenylapigenin 7- O -β- d -glucopyranoside ( 5 ), morusin 5- O -β- d -glucopyranoside ( 6 ), and morusin 4′- O -β- d -glucopyranoside ( 7 ) by the spectroscopic methods. [ABSTRACT FROM AUTHOR]

Background: Osteomeles schwerinae C. K. Schneid. (Rosaceae, OSSC) is a medicinal plant traditionally used to treat various diseases in Asia. The chemical constituents of OSSC have an inhibitory effect on aldose reductase activity, which has been implicated in the pathogenesis of diabetic complications. However, the protective effects of the pharmacological activity and potential mechanisms in diabetic nephropathy are still not known.Objective: In the present study, OSSC extracts and major compounds were examined for their effects on binding to the receptors of advanced glycation end products (RAGE) and on transforming growth factor-beta1 (TGF-β1) expression-related signal mechanisms in mouse glomerular mesangial cells (GMCs).Materials and Methods: A simple, rapid and efficient method was developed for the simultaneous determination of the marker compounds in the ethanol extract of the leaves and twigs of OSSC using HPLC-diode array detector (DAD). In this study, we determined the effects of OSSC extract and hyperoside on AGE and RAGE binding, and studied the mechanism of OSSC extract effects on AGE-bovine serum albumin (BSA)-treated GMCs. GMCs overexpressing human RAGE were cultured in AGE-BSA labeled with Alexa 488, and OSSC extract. AGE/RAGE binding were measured using fluorescence (excitation 485 nm/emission 528 nm). TGF-β1 protein expression levels were determined by western blot analyses.Results: OSSC extracts of leaves and twigs inhibited on AGE/RAGE binding and TGF-β1 protein expression in a dose-dependent manner in GMCs. Furthermore, OSSC extracts reduced the effects on AGE-BSA-induced reactive oxidative species (ROS) formation and nuclear translocalization of transcription factor NF-κB. OSSC extracts inhibited phosphorylation of extracellular signal-regulated protein kinases1/2 (ERK1/2), p38 mitogen-activated protein kinases (p38MAPK), and IκB. Hyperoside also inhibited AGE/RAGE binding and ROS formation, and reduced TGF-β1 expression and IkB phosphorylation.Conclusions: OSSC extracts and hyperoside may attenuate AGE/RAGE binding and expression of TGF-β1 by downregulating of pERK1/2, p38MAPK and IκB phosphorylations in GMCs under diabetic condition and retard the development of diabetic complications such as diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease represents one of the main neurological disorders in the aging population. Treatment options so far are only of symptomatic nature and efforts in developing disease modifying drugs by targeting amyloid beta peptide-generating enzymes remain fruitless in the majority of human studies. During the last years, an alternative approach emerged to target the physiological alpha-secretase ADAM10, which is not only able to prevent formation of toxic amyloid beta peptides but also provides a neuroprotective fragment of the amyloid precursor protein - sAPPalpha. Purpose: To identify novel alpha-secretase enhancers from a library of 313 extracts of medicinal plants indigenous to Korea, a screening approach was used and hits were further evaluated for their therapeutic value. Methods: The extract library was screened for selective enhancers of ADAM10 gene expression using a luciferase-based promoter reporter gene assay in the human neuroblastoma cell line SH-SY5Y. Candidate extracts were then tested in wild type mice for acute behavioral effects using an open field paradigm. Brain and liver tissue from treated mice was biochemically analyzed for ADAM10 gene expression in vivo. An in vitro blood-brain barrier model and an in vitro ATPase assay were used to unravel transport properties of bioactive compounds from extract candidates. Finally, fractionation of the most promising extract was performed to identify biologically active components. Results: The extract of Caragana sinica (Buc'hoz) Rehder was identified as the best candidate from our screening approach. We were able to demonstrate that the extract is acutely applicable in mice without obvious side effects and induces ADAM10 gene expression in peripheral tissue. A hindered passage across the blood-brain barrier was detected explaining lack of cerebral induction of ADAM10 gene expression in treated mice. By fractionating C. sinica extract we identified alpha-viniferin as one of the biologically active components. Conclusion: The extract of C. sinica and alpha-viniferin as one of its bioactive constituents might serve as novel therapeutic options for treating Alzheimer's disease by increasing ADAM10 gene expression. The identification of alpha-viniferin represents a promising starting point to achieve blood-brain barrier penetrance in the future. [ABSTRACT FROM AUTHOR]

Highlights: [•] Chalcone, 2-hydroxychalcone, and xanthohumol showed cytotoxicity in breast cells. [•] 2-Hydroxychalcone and xanthohumol induced apoptosis by Bcl-2 downregulation. [•] 2-Hydroxychalcone and xanthohumol exerted potent inhibitory effects on invasion. [•] Chalcones are potential anticancer agents which alleviate breast cancer progression. [Copyright &y& Elsevier]

Abstract: Chronic inflammatory response in the brain is a characteristic etiopathology of various neurodegenerative diseases; consequently increasing the intrinsic anti-inflammatory potency could be an especially desirable strategy to prevent inflammation-related neuronal injuries. Transcription factor NF-E2-related factor-2 (Nrf2)-mediated control of redox homeostasis may participate in the modulation of microglial responses by regulating expression of important antioxidant and phase II detoxification genes. In our present work, we show that artesunate, a semi-synthetic derivative of anti-malarial agent artemisinin, attenuates LPS-induced inflammatory responses in microglial BV2 cells. Artesunate activates Nrf2-ARE system, and leads to an increase in the level of downstream heme oxygenase-1. Artesunate also activates PI3K/Akt, ERK, and JNK MAPKs signaling, but artesunate-induced activation of Nrf2 signaling and up-regulation of heme oxygenase-1 are ERK pathway-dependent. Collectively, this study demonstrates that artesunate is a potential activator of the Nrf2/ARE-dependent pathway and is therapeutically relevant to inflammatory responses of microglial cells. [Copyright &y& Elsevier]

Abstract: Xanthohumol (2′,4′,4-trihydroxy-6′-methoxy-3′-prenylchalcone) is a major chalcone derivative isolated from hop (Humulus lupulus L.) commonly used in brewing due to its bitter flavors. Xanthohumol has anti-carcinogenic, free radical-scavenging, and anti-inflammatory activities, but its precise mechanisms are not clarified yet. The basic leucine zipper (bZIP) protein NRF2 is a key transcription factor mediating the antioxidant and anti-inflammatory responses in animals. Therefore, we tested whether xanthohumol exerts anti-inflammatory activity in mouse microglial BV2 cells via NRF2 signaling. Xanthohumol significantly inhibited the excessive production of inflammatory mediators NO, IL-1β, and TNF-α, and the activation of NF-κB signaling in LPS-induced stimulated BV2 cells. Xanthohumol up-regulated the transcription of NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), and increased the level of the endogenous antioxidant GSH. In addition, xanthohumol induced nuclear translocation of NRF2 and further activation of ARE promoter-related transcription. The anti-inflammatory response of xanthohumol was attenuated by transfection with NRF2 siRNA and in the presence of the HO-1 inhibitor, ZnPP, but not the NQO1 inhibitor, dicoumarol. Taken together, our study suggests that xanthohumol exerts anti-inflammatory activity through NRF2-ARE signaling and up-regulation of downstream HO-1, and could be an attractive candidate for the regulation of inflammatory responses in the brain. [ABSTRACT FROM AUTHOR]

Background: Moutan radicis cortex (MRC) and Cinnamomi ramulus (CR) are commonly used in eastern Asian traditional medicine to treat various diseases including cerebrovascular and cardiovascular, and have wide spectrum of pharmacological activities. However, the effect against laser-induced choroidal neovascularization (CNV) of extract of MRC and CR (1:1) (MRCCR) has not yet been studied.Purpose: Our aim was to investigate the inhibitory effect of MRCCR on pathological CNV in laser-treated Brown-Norway (BN) rats.Methods: MRCCR (60, 90 mg/kg) was orally administered twice per day for 15 days from the day of CNV formation in laser-treated BN rats. Effects of MRCCR or its constituents on cell migration, tube formation, hyperpermeability and phosphorylation of FAK/p38 MAPK were confirmed in humane retinal microvascular endothelial cells or human retinal pigment epithelial cells.Results: MRCCR significantly reduced the CNV lesions areas and the extent of fluorescein leakage. MRCCR and its constituents such as ellagic acid, paeonol or gallic acid decreased cell migration, tube formation or hyperpermeability. MRCCR inhibited the phosphorylation of FAK and p38 MAPK.Conclusion: Combining the oral MRCCR and intravitreal injection of anti-VEGF medicine may result in a more potent therapeutic effect and consequently bring the reduction in eye injection numbers for patients with wet AMD. [ABSTRACT FROM AUTHOR]

Chalcones, the biosynthetic precursors of flavonoids and isoflavonoids abundant in edible plants, possess a number of pharmacological properties, and there is growing evidence that chalcone derivatives inhibit TNF-α mediated insulin resistance. The aim of the present study was to define the effects of 4-methoxychalcone (4-MC) on adipocyte differentiation and to determine the underlying molecular mechanism. We investigated the effects of 4-MC on adipocyte differentiation and lipid accumulation, and expression of adipogenic genes in 3T3-L1 cells. Additionally, treatment with 4-MC significantly increased the PPARγ-induced transcriptional activity and 4-MC also enhanced the DNA binding affinity of PPARγ to the proliferator-activated receptor response elements (PPRE) at target promoters. Next, we tested the effect of 4-MC on the inhibition induced by TNF-α on adipocyte differentiation. Treatment with 4-MC enhanced the lipid accumulation and strongly up-regulated the expression of adipogenic markers, including PPARγ, aP2, FAS, and adiponectin during adipocyte differentiation. Finally, 4-MC attenuated the inhibitory effect of TNF-α on adipocyte differentiation and adiponectin expression and subsequently regulated the expression and secretion of various adipokines that are involved in insulin sensitivity. This study clearly demonstrates that 4-MC enhanced adipocyte differentiation, in part, by its potent effects on PPARγ activation and by its reverse effect on TNF-α. [ABSTRACT FROM AUTHOR]

Abstract: Microbial transformation of silybin A (1) and silybin B (2), the major hepatoprotective flavonolignan diastereomers from the fruits of Silybum marianum, with the culture broth of Trichoderma koningii gave two pairs of glucosylated derivatives. Their structures were identified as silybin A 3-O-β-d-glucopyranoside (3), silybin A 7-O-β-d-glucopyranoside (4), silybin B 3-O-β-d-glucopyranoside (5) and silybin B 7-O-β-d-glucopyranoside (6) by spectroscopic methods. [Copyright &y& Elsevier]

Colon cancer is a common and deadly malignancy of the gastrointestinal tract. Targeting proteins that inhibit tumor proliferation could lead to innovative treatment strategies for this disease. Demethylzeylasteral, extracted naturally from Tripterygium wilfordii Hook. f., demonstrates incredible anti-colon cancer activity. However, the molecular mechanism behind this requires further investigation. This study aims to identify crucial targets and mechanisms of demethylzeylasteral in treating colon cancer, making it a promising candidate for anti-tumor therapy. Through gene knockout, overexpression techniques, and double Luciferase experiments, we confirmed that demethylzeylasteral reduces S100A11 expression in HT29 cells and in vivo tumor models to anti-colon cancer. By conducting Surface Plasmon Resonance, immunofluorescence staining, and confocal laser microscopy observations, we verified the direct interaction between demethylzeylasteral and S100A11, and explored the impact of S100A11's subcellular localization on cell proliferation. Demethylzeylasteral inhibited S100A11 expression and exhibited anti-cancer activity in both in vitro and in vivo colon cancer models. Conversely, overexpression of S100A11 hindered apoptosis induced by demethylzeylasteral. Additionally, we found that knockdown or overexpression of NF-κB respectively decreased or increased S100A11 expression, subsequently affecting cell proliferation. The dual Luciferase reporting experiment revealed that NF-κB is an upstream transcription factor regulating S100A11 expression. And Surface plasmon resonance confirmed that S100A11 can directly interact with demethylzeylasteral, this interaction limited the transport of S100A11 from the cytoplasm to nucleus, attenuation S100A11 mediated cell proliferation effect. [Display omitted] • Demethylzeylasteral's new mechanism: NF-κB-S100A11 signaling against colon cancer. • The first discovery of small molecule inhibitors targeting S100A11. • S100A11 nuclear transfer promotes colon cancer cell proliferation. [ABSTRACT FROM AUTHOR]

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator for the protection of cells against oxidative and xenobiotic stresses. Recent studies have demonstrated that high constitutive expression of Nrf2 is observed in many types of cancer cells showing resistance to anti-cancer drugs, suggesting that the suppression of overexpressed Nrf2 could be an attractive therapeutic strategy to overcome cancer drug resistance. In the present study, we aimed to find small molecule compounds that enhance the sensitivity of tumor cells to cisplatin induced cytotoxicity by suppressing Nrf2-mediated defense mechanism. A549 lung cancer cells were shown to be more resistant to the anti-cancer drug cisplatin than HEK293 cells, with higher Nrf2 signaling activity; constitutively high amounts of Nrf2-downstream target proteins were observed in A549 cells. Among the three chalcone derivatives 4-methoxy-chalcone (4-MC), hesperidin methylchalcone, and neohesperidin dihydrochalcone, 4-MC was found to suppress transcriptional activity of Nrf2 in A549 cells but to activate it in HEK293 cells. 4-MC was also shown to down-regulate expression of Nrf2 and the downstream phase II detoxifying enzyme NQO1 in A549 cells. The PI3K/Akt pathway was found to be involved in the 4-MC-induced inhibition of Nrf2/ARE activity in A549 cells. This inhibition of Nrf2 signaling results in the accelerated generation of reactive oxygen species and exacerbation of cytotoxicity in cisplatin-treated A549 cells. Taken together, these results suggest that the small molecule compound 4-MC could be used to enhance the sensitivity of tumor cells to the therapeutic effect of cisplatin through the regulation of Nrf2/ARE signaling. [ABSTRACT FROM AUTHOR]

Abstract: Benzo[3,4]azepino[1,2-b]isoquinolinones were designed and developed as constraint forms of 3-arylisquinolines with an aim to inhibit topoisomerase I (topo I). Ring closing metathesis (RCM) of 3-arylisoquinolines with suitable diene moiety provided seven membered azepine rings of benzoazepinoisoquinolinones. Spectral analyses of these heterocyclic compounds demonstrated that the methylene protons of the azepine rings are nonequivalent. The shielding environment experienced by these geminal hydrogens differs unusually by 2.21ppm. As expected, benzoazepinoisoquinolinones displayed potent cytotoxicity. However, cytotoxic effects of the compounds were not related to topo I inhibition which is explained by non-planar conformation of the rigid compounds incapable of intercalating between DNA base pairs. In contrast, flexible 3-arylisoquinoline 8d attains active conformation at drug target site to exhibit topo I inhibition identical to cytotoxic alkaloid, camptothecin (CPT). [Copyright &y& Elsevier]

Abstract: Xanthohumol (XN) and its related compounds were evaluated for their effects on modulating the production of interleukin (IL)-12, the most important factor driving T helper 1 immune responses. XN showed the strongest inhibitory effect on IL-12 production in macrophages stimulated by lipopolysaccharide (LPS) or LPS/interferon-γ. Xanthohumol 4′-O-β-D-glucopyranoside (XNG) inhibited IL-12 production less effectively than XN. Isoxanthohumol and 8-prenylnaringenin showed comparatively lower inhibitory effects on IL-12 production than XNG. (2S)-5-methoxy-8-prenylnaringenin 7-O-β-D-glucopyranoside did not exert any effect on IL-12 production. We then tested how these compounds affected NF-κB binding activity to the κB site in the nucleus. The compounds inhibited κB binding in macrophages with the same potency order as IL-12 inhibition. Furthermore, we investigated whether XN, which showed the most effective reduction of IL-12 production, attenuated skin inflammation. Chronic allergic contact dermatitis, an experimental model for psoriasis, was used to determine the anti-inflammatory effects of XN in vivo. XN treatment reduced the degree of ear thickening induced by oxazolone. Taken together, XN might be effective as an anti-inflammatory agent to reduce skin inflammation by inhibiting IL-12 production. [Copyright &y& Elsevier]

Abstract: Xanthohumol (XN) is a major chalcone found in hop, which is used to add bitterness and flavor to beer. In this study, we investigated the effects of XN on the production of interlukin-2 (IL-2), a potent T cell growth factor. Treatment with XN significantly increased IL-2 production in mouse EL-4 T cells activated with phorbol 12-myristate 13-acetate (PMA) plus ionomycin (Io) in a dose-dependent manner. To further characterize its regulatory mechanism of XN on increased IL-2 production, the effects of XN on IL-2 promoter activity and the activity of several transcription factors modulating IL-2 expression were analyzed. XN enhanced activity of the IL-2 promoter, which contains distal and proximal regulatory elements in PMA/Io-activated EL-4 T cells. Furthermore, the activity of NF-AT and AP-1 was enhanced but NF-κB activity was not influenced by XN in PMA/Io-activated EL-4 T cells. These results suggest that XN increased IL-2 production at the transcriptional levels via the up-regulation of NF-AT and AP-1 in PMA/Io-activated EL-4 T cells. [Copyright &y& Elsevier]

Abstract: Macrophages are the main cells responsible for the innate immunity, and their activation by lipopolysaccharide (LPS) from Gram-negative bacteria or interferon (IFN)-γ from host immune cells is important for controlling infections. However, the overwhelming activation of macrophages can cause a severe inflammatory state. This study investigated the inhibitory mechanism of xanthohumol (XN) against the inflammatory effectors (IL-1β, TNF-α, and iNOS) in activated RAW264.7 macrophages by using different stimuli such as LPS, IFN-γ, or LPS plus IFN-γ. XN is a major prenylated chalcone found in hops, which is used to add bitterness and flavor to beer. XN reduced the expression of the LPS receptor components such as TLR4 and MD2 resulting in the suppression of NF-κB activation in LPS-activated RAW264.7 cells. In the IFN-γ stimulated RAW264.7 cells, the binding activity of STAT-1α and IRF-1 was inhibited by XN. This suggests that differential signaling pathways are used by XN for the inhibition of excess inflammatory mediators depending on the stimuli in macrophages. [Copyright &y& Elsevier]

A new ergostane-type steroid, 3β-hydroxy-1,11-dioxo-ergosta-8,24(28)-diene-4α-carboxylic acid (1) was isolated from the mold Hormoconis resinae as a cholesterol biosynthesis inhibitor in the Chang liver cell. The absolute stereostructure of 1 was established based on the spectroscopic analyses and modified Mosher''s method. [Copyright &y& Elsevier]