Kushenol C from Sophora flavescens protects against UVB-induced skin damage in mice through suppression of inflammation and oxidative stress.

Sophora flavescens has been used in traditional medicine for the treatment of various diseases such as viral hepatitis, fever, cancer, and pain. It is known to contain many bioactive compounds including prenylated flavonoids such as kurarinone, sophoraflavanone G, kuraridine and isoxanthohumol. These flavonoids have been confirmed to have anti-inflammatory, α-glucosidase inhibitory and antioxidant performances. However, the protective activities against UV-induced skin damage of kushenol C from S. flavescens have not yet been elucidated. In this study, we explored the protective effect of kushenol C against the skin damage induced by UVB in mice. Our results showed that kushenol C treatment significantly recovered UVB-induced skin damage, the degradation of collagen, mast cell infiltration, together with epidermal hyperplasia in mice. Furthermore, the treatment of kushenol C remarkably suppressed the generation of pro-inflammatory mediators in the mice irradiated by UVB. More so, treatment with kushenol C suppressed the oxidative stress in mice irradiated by UVB. In conclusion, these results showed that kushenol C from S. flavescens has potentialities to treat skin injury via suppressing skin damage induced by UVB and oxidative stress.

Anti-inflammatory of disenecionyl cis-khellactone in LPS-stimulated RAW264.7 cells and the its inhibitory activity on soluble epoxide hydrolase.

The objective of the present study was to investigate anti-inflammatory effects of disenecionyl cis-khellactone (DK) isolated from Peucedanum japonicum Thunberg, a traditional edible plant, in RAW264.7 cells stimulated with lipopolysaccharide (LPS). Anti-inflammatory effects of DK were analyzed using various techniques, including NO assay, Western blot analysis, enzyme-linked immunosorbent assay (ELISA), real-time PCR, and immunofluorescence staining. It was revealed that DK reduced the production of pro-inflammatory cytokines including Monocyte chemoattractant protein-1 (MCP-1), Tumor necrosis factor-α (TNF-α), Interleukin 1ß (IL-1ß), and Interleukin 6 (IL-6) in RAW264.7 cells stimulated with LPS. It was revealed that DK effectively downregulated expression levels of iNOS and COX-2 due to inhibition of NF-κB activation and suppressing the phosphorylation of p38 and jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) phosphorylation. Also, soluble epoxide hydrolase activity and expression were decreased by the proinflammatory inhibitor, DK. Finally, findings of this study suggest that DK isolated from P. japonicum might have potential as a therapeutic candidate for inflammatory diseases.

Anti-inflammatory effects of Peucedanum japonicum Thunberg leaves extract in Lipopolysaccharide-stimulated RAW264.7 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Peucedanum japonicum Thunberg are perennial herbaceous plants known to be cultivated for food and traditional medicinal purposes. P. japonicum has been used in traditional medicine to soothe coughs and colds, and to treat many other inflammatory diseases. However, there are no studies on the anti-inflammatory effects of the leaves. AIM OF THE STUDY: Inflammation plays an important role in our body as a defense response of biological tissues to certain stimuli. However, the excessive inflammatory response can lead to various diseases. This study aimed to investigate the anti-inflammatory effects of P. japonicum leaves extract (PJLE) in LPS-stimulated RAW 264.7 cells. MATERIAL AND METHODS: Nitric Oxide (NO) production assay measured by NO assay. Inducible NO synthase (iNOS), COX-2, MAPKs, AKT, NF-κB, HO-1, Nrf-2 were examined by western blotting. PGE2, TNF-α, and IL-6 were analyzed by ELSIA. Nuclear translocation of NF-κB was detected by immunofluorescence staining. RESULTS: PJLE suppressed inducible nitric oxygen synthase (iNOS) and prostaglandin-endoperoxide synthase 2 (cyclooxygenase-2, COX-2) expression, increased heme oxygenase 1 (HO-1) expression, and decreased nitric oxide production. And PJLE inhibited the phosphorylation of AKT, MAPK, and NF-κB. Taken together, PJLE down-regulated inflammatory factors such as iNOS and COX-2 by inhibiting the phosphorylation of AKT, MAPK, and NF-κB. CONCLUSIONS: These results suggest that PJLE can be used as a therapeutic material to modulate inflammatory diseases.

Antimelanogenic activity of patuletin from Inula japonica flowers in B16F10 melanoma cells and zebrafish embryos.

During the search for natural melanogenesis inhibitors, patuletin, a flavonoid, was isolated from Inula japonica flowers. We investigated the antimelanogenic effects of patuletin on B16F10 melanoma cells and zebrafish embryos. Patuletin dose-dependently reduced melanocyte-stimulating hormone-induced melanogenesis and L-DOPA oxidation in B16F10 cells. Western blot analysis showed that patuletin reduced cellular tyrosinase expression in a dose-dependent manner. Patuletin treatment significantly decreased melanin pigmentation in the embryo compared to the untreated controls.

Inhibitory Activity of 4-O-Benzoyl-3'-O-(OMethylsinapoyl) Sucrose from Polygala tenuifolia on Escherichia coliß-Glucuronidase.

Bacterial ß-glucuronidase in the intestine is involved in the conversion of 7-ethyl-10- hydroxycamptochecin glucuronide (derived from irinotecan) to 7-ethyl-10-hydroxycamptothecin, which causes intestinal bleeding and diarrhea (side effects of anti-cancer drugs). Twelve compounds (1-12) from Polygala tenuifolia were evaluated in terms of ß-glucuronidase inhibition in vitro. 4-O-Benzoyl-3'-O-(O-methylsinapoyl) sucrose (C3) was highly inhibitory at low concentrations. C3 (an uncompetitive inhibitor) exhibited a ki value of 13.4 µM; inhibitory activity increased as the substrate concentration rose. Molecular simulation revealed that C3 bound principally to the Gln158-Tyr160 enzyme loop. Thus, C3 will serve as a lead compound for development of new ß- glucuronidase inhibitors.

Inhibitory Effects of Cucurbitane-Type Triterpenoids from Momordica charantia Fruit on Lipopolysaccharide-Stimulated Pro-Inflammatory Cytokine Production in Bone Marrow-Derived Dendritic Cells.

The bitter melon, Momordica charantia L., was once an important food and medicinal herb. Various studies have focused on the potential treatment of stomach disease with M. charantia and on its anti-diabetic properties. However, very little is known about the specific compounds responsible for its anti-inflammatory activities. In addition, the in vitro inhibitory effect of M. charantia on pro-inflammatory cytokine production by lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells (BMDCs) has not been reported. Phytochemical investigation of M. charantia fruit led to the isolation of 15 compounds (1-15). Their chemical structures were elucidated spectroscopically (one- and two-dimensional nuclear magnetic resonance) and with electrospray ionization mass spectrometry. The anti-inflammatory effects of the isolated compounds were evaluated by measuring the production of the pro-inflammatory cytokines interleukin IL-6, IL-12 p40, and tumor necrosis factor α (TNF-α) in LPS-stimulated BMDCs. The cucurbitanes were potent inhibitors of the cytokines TNF-α, IL-6, and IL-12 p40, indicating promising anti-inflammatory effects. Based on these studies and in silico simulations, we determined that the ligand likely docked in the receptors. These results suggest that cucurbitanes from M. charantia are potential candidates for treating inflammatory diseases.

Kushenol C Prevents Tert-Butyl Hydroperoxide and Acetaminophen-Induced Liver Injury.

Sophora flavescens, also known as Kushen, has traditionally been used as a herbal medicine. In the present study we evaluated the ameliorative effects of kushenol C (KC) from S. flavescens against tBHP (tert-Butyl hydroperoxide)-induced oxidative stress in hepatocellular carcinoma (HEPG2) cells and acetaminophen (APAP)-induced hepatotoxicity in mice. KC pretreatment protected the HEPG2 cells against oxidative stress by reducing cell death, apoptosis and reactive oxygen species (ROS) generation. KC pretreatment also upregulated pro-caspase 3 and GSH (glutathione) as well as expression of 8-Oxoguanine DNA Glycosylase (OGG1) in the HEPG2 cells. The mechanism of action was partly related by KC's activation of Akt (Protein kinase B (PKB)) and Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) in the HepG2 cells. In in vivo investigations, coadministration of mice with KC and APAP significantly attenuated APAP-induced hepatotoxicity and liver damage, as the serum enzymatic activity of aspartate aminotransferase and alanine aminotransferase, as well as liver lipid peroxidation and cleaved caspase 3 expression, were reduced in APAP-treated mice. Coadministration with KC also up-regulated antioxidant enzyme expression and prevented the production of proinflammatory mediators in APAP-treated mice. Taken together, these results showed that KC treatment has potential as a therapeutic agent against liver injury through the suppression of oxidative stress.

Lower risk of subarachnoid haemorrhage in diabetes: a nationwide population-based cohort study.

BACKGROUND AND PURPOSE: Diabetes mellitus (DM) is a common metabolic disorder with increased risk of cardiovascular and cerebrovascular complications. However, its relationship with risk of subarachnoid haemorrhage (SAH), the most devastating form of stroke, remains controversial. METHODS: To evaluate the relationship between DM and risk of SAH, we performed a retrospective cohort study using a nationwide, population-based, health screening database in Korea. We included participants without history of stroke who underwent a nationwide health screening programme between 2003 and 2004. Primary outcome was occurrence of SAH. Participants were followed up until development of SAH or December 2015. Multivariate Cox proportional hazards regression analysis was performed with adjustments for age, sex, systolic blood pressure, total cholesterol, body mass index, physical activity, smoking status, alcohol habit, household income and treatment with antihypertensive agents and statins. RESULTS: Among 421 768 study participants, prevalence of DM was 9.6%. During a mean follow-up period of 11.6±1.9 years, 1039 patients developed SAH. Presence of DM was significantly associated with decreased risk of SAH (adjusted HR 0.68; 95% CI 0.53 to 0.86; p<0.001). Elevated level of fasting blood glucose was also negatively associated with risk of SAH (adjusted HR per 1 mmol/L increase 0.90; 95% CI 0.86 to 0.95; p<0.001). CONCLUSION: DM and elevated level of fasting blood glucose were inversely associated with risk of SAH. Further studies may elucidate the possibly protective, pathophysiological role played by hyperglycaemia in patients at risk of SAH.

In vitro Anti-Inflammatory and Anti-Oxidative Stress Activities of Kushenol C Isolated from the Roots of Sophora flavescens.

Kushenol C (KC) is a prenylated flavonoid isolated from the roots of Sophora flavescens aiton. Little is known about its anti-inflammatory and anti-oxidative stress activities. Here, we investigated the anti-inflammatory and anti-oxidative stress effects of KC in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, and tert-butyl hydroperoxide (tBHP)-induced oxidative stress in HaCaT cells. The results demonstrated that KC dose-dependently suppressed the production of inflammatory mediators, including NO, PGE2, IL-6, IL1ß, MCP-1, and IFN-ß in LPS-stimulated RAW264.7 macrophages. The study demonstrated that the inhibition of STAT1, STAT6, and NF-κB activations by KC might have been responsible for the inhibition of NO, PGE2, IL-6, IL1ß, MCP-1, and IFN-ß in the LPS-stimulated RAW264.7 macrophages. KC also upregulated the expression of HO-1 and its activities in the LPS-stimulated RAW264.7 macrophages. The upregulation of Nrf2 transcription activities by KC in the LPS-stimulated RAW264.7 macrophages was demonstrated to be responsible for the upregulation of HO-1 expression and its activity in LPS-stimulated RAW264.7 macrophages. In HaCaT cells, KC prevented DNA damage and cell death by upregulating the endogenous antioxidant defense system involving glutathione, superoxide dismutase, and catalase, which prevented reactive oxygen species production from tert-butyl hydroperoxide (tBHP)-induced oxidative stress in HaCaT cells. The upregulated activation of Nrf2 and Akt in the PI3K-Akt signaling pathway by KC was demonstrated to be responsible for the anti-oxidative stress activity of KC in HaCaT cells. Collectively, the study suggests that KC can be further investigated as a potential anti-inflammatory candidate for the treatment of inflammatory diseases.

Cerebrospinal fluid from Alzheimer's disease patients as an optimal formulation for therapeutic application of mesenchymal stem cells in Alzheimer's disease.

Mesenchymal stem cells (MSCs) have emerged as one of the promising treatment options for Alzheimer's disease (AD). Although many studies have investigated on the efficacy of MSCs in AD, how MSCs actually change following exposure to the AD environment has not been studied extensively. In this study, we investigated on the potential of AD patient-cerebrospinal fluid (CSF) samples to be used as a formulation of MSCs and its application in AD therapeutics. When Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) were stored in the CSF of AD patients, the stemness of WJ-MSCs was preserved. Furthermore, several genes were upregulated following storage in AD CSF. This signified the therapeutic potential of CSF formulation for AD therapy. Overall, these findings suggest that CSF from AD patients can be an optimal source for MSC formulation.

Cytotoxic triterpene saponins from the mangrove Aegiceras corniculatum.

Using various chromatographic separations, sixteen compounds, including one new triterpene saponin named aegicoroside A (1), were isolated from the leaves of the Vietnamese mangrove Aegiceras corniculatum. Their structures were determined by spectroscopic methods such as 1D and 2D NMR and HR-ESI-MS. The cytotoxic activities of the isolated compounds against MCF7 (breast), HCT116 (colon), B16F10 (melanoma), and A549 (adenocarcinoma) cancer cell lines were also evaluated. Strong cytotoxicity was observed for sakurasosaponin (2) against all four cancer cell lines and for sakurasosaponin methyl ester (3) against MCF7, A549, and HCT116 cell lines with IC50 values ranging from 2.89 ± 0.02 to 9.86 ± 0.21 µM.

Kushenol A and 8-prenylkaempferol, tyrosinase inhibitors, derived from Sophora flavescens.

Tyrosinase is known for an enzyme that plays a key role in producing the initial precursor of melanin biosynthesis. Inhibition of the catalytic reaction of this enzyme led to some advantage such as skin-whitening and anti-insect agents. To find a natural compound with inhibitory activity towards tyrosinase, the five flavonoids of kushenol A (1), 8-prenylkaempferol (2), kushenol C (3), formononetin (4) and 8-prenylnaringenin (5) were isolated by column chromatography from a 95% methanol extract of Sophora flavescens. The ability of these flavonoids to block the conversion of L-tyrosine to L-DOPA by tyrosinase was tested in vitro. Compounds 1 and 2 exhibited potent inhibitory activity, with IC50 values less than 10 µM. Furthermore, enzyme kinetics and molecular docking analysis revealed the formation of a binary encounter complex between compounds 1-4 and the enzyme. Also, all of the isolated compounds (1-5) were confirmed to possess antioxidant activity.

Tyrosinase inhibitory components from the seeds of Cassia tora.

Ten compounds (1-10) isolated from the seeds of Cassia tora were evaluated for tyrosinase inhibition. Compounds 3, 4, and 7 inhibited tyrosinase enzymatic activity in a dose-dependent manner, with IC50 values of 3.0 ± 0.8, 7.0 ± 0.4, and 9.2 ± 3.4 µM, respectively. Kinetic analyses revealed a mechanism consistent with competitive inhibition. In silico molecular docking showed that compounds 3 and 4 docked in the active site of tyrosinase, whereas 7 interacted with Ala246 and Val248 at outside of the active site, and His244 and Glu256 at inside. Additionally, compounds 3, 4, and 7 suppressed melanogenesis in α-MSH-treated B16F10 melanoma cells at a concentration of 10 µM.

Anti-Inflammatory Effect of Lupinalbin A Isolated from Apios americana on Lipopolysaccharide-Treated RAW264.7 Cells.

Apios americana, a leguminous plant, is used as food in some countries. Although the biological activities of Apios extract have been reported, there have been no reports about the anti-inflammatory mechanism of lupinalbin A on the RAW264.7 cells. In this study, we investigated the anti-inflammatory effect of A. americana lupinalbin A on lipopolysaccharide (LPS)-treated RAW264.7 cells. Lupinalbin A significantly inhibited nitric oxide production and inducible nitric oxide synthase expression in LPS-treated RAW264.7 cells. The expression of cytokines, including interleukin-6, tumor necrosis factor-α, and chemokine of monocyte chemoattractant protein, was reduced under lupinalbin A exposure in LPS-treated RAW264.7 cells. In addition, lupinalbin A significantly decreased LPS-induced interferon (IFN)-ß production and STAT1 protein levels in RAW264.7 cells. Taken together, these results suggest that A. americana lupinalbin A exerts anti-inflammatory effects via the inhibition of pro-inflammatory cytokines and blocking of IFN-ß/STAT1 pathway activation.

Quinoxaline-, dopamine-, and amino acid-derived metabolites from the edible insect Protaetia brevitarsis seulensis.

Edible insects have been reported to produce metabolites showing various pharmacological activities, recently emerging as rich sources of health functional food. In particular, the larvae of Protaetia brevitarsis seulensis (Kolbe) have been used as traditional Korean medicines for treating diverse diseases, such as breast cancer, inflammatory disease, hepatic cancer, liver cirrhosis, and hepatitis. However, only few chemical investigations were reported on the insect larvae. Therefore, the aim of this study was to discover and identify biologically active chemical components of the larvae of P. brevitarsis seulensis. As a result, a quinoxaline-derived alkaloid (1) was isolated, which was not reported previously from natural sources. In addition, other related compounds (2, 4-10, 15, 16) were also encountered for the first time from the larvae. The structures of all the isolated compounds were established mainly by analysis of HRESIMS, NMR, and electronic circular dichroism data. Compound 5 exhibited inhibition of tyrosinase with IC50 value of 44.8 µM.

Inhibitory Components from Glycosmis stenocarpa on Pepper Mild Mottle Virus.

The goal of this study was to identify a source of natural plant compounds with inhibitory activity against pepper mild mottle virus (PMMoV). We showed, using a half-leaf assay, that murrayafoline-A (1) and isomahanine (2) isolated from the aerial parts of Glycosmis stenocarpa have inhibitory activity against PMMoV through curative, inactivation, and protection effects. Using a leaf-disk assay, we confirmed that 2 inhibited virus replication in Nicotiana benthamiana. Using electron microscopy, we found that a mixture of the virus with 2 resulted in damage to the rod-shaped virus.

(-)-Epicatechin derivate from Orostachys japonicus as potential inhibitor of the human butyrylcholinesterase.

Cholinesterase inhibitors block the bioconversion of neurotransmitters by cholinesterase in the nervous system. Epicatechin derivatives (1, 3 and 5), polyphenols (6 and 7) from Orostachys japonicus, and catechin derivatives (2 and 4) from our in-house library were evaluated for their inhibitory activity on cholinesterase. Compound 5 exhibited IC50 values of 58.3±2.4 and 17.8±3.8µg/mL on AChE and BuChE, respectively. Compound 5 inhibited BuChE more strongly than AChE through a competitive behavior. In silico binding positions of 5 in the active site were predicted using Autodock 4.2 and processed in a 10000-ps molecular dynamics simulation to assess the stability of compound 5 binding.

Solitary Fibrous Tumor of Central Nervous System: A Case Report.

Solitary fibrous tumor (SFT) is a rare neoplasm of mesenchymal origin, especially in the central nervous system (CNS). Reported herein is a case of SFT of CNS in a 63-year-old female patient who had confused mentality, without other neurological deficit. The brain MRI showed an ovoid mass in the right frontal lobe. The tumor was surgically removed grossly and totally, and the pathologic diagnosis was SFT. At 55 months after the surgery, the tumor recurred at the primary site and at an adjacent area. A second operation was thus done, and the tumor was again surgically removed grossly and totally. The pathologic diagnosis was the same as the previous, but the Ki-67 index was elevated. Ten months later, two small recurring tumors in the right frontal skull base were found in the follow-up MRI. It was decided that radiation therapy be done, and MRI was done again 3 months later. In the follow-up MRI, the size of the recurring mass was found to have decreased, and the patient did not manifest any significant symptom. Follow-up will again be done 18 months after the second surgery.

Anterior Cervical Discectomy and Fusion Alters Whole-Spine Sagittal Alignment.

PURPOSE: Anterior cervical discectomy and fusion (ACDF) has become a common spine procedure, however, there have been no previous studies on whole spine alignment changes after cervical fusion. Our purpose in this study was to determine whole spine sagittal alignment and pelvic alignment changes after ACDF. MATERIALS AND METHODS: Forty-eight patients who had undergone ACDF from January 2011 to December 2012 were enrolled in this study. Cervical lordosis, thoracic kyphosis, lumbar lordosis, sagittal vertical axis (SVA), and pelvic parameters were measured preoperatively and at 1, 3, 6, and 12 months postoperatively. Clinical outcomes were assessed using Visual Analog Scale (VAS) scores and Neck Disability Index (NDI) values. RESULTS: Forty-eight patients were grouped according to operative method (cage only, cage & plate), operative level (upper level: C3/4 & C4/5; lower level: C5/6 & C6/7), and cervical lordosis (high lordosis, low lordosis). All patients experienced significant improvements in VAS scores and NDI values after surgery. Among the radiologic parameters, pelvic tilt increased and sacral slope decreased at 12 months postoperatively. Only the high cervical lordosis group showed significantly-decreased cervical lordosis and a shortened SVA postoperatively. Correlation tests revealed that cervical lordosis was significantly correlated with SVA and that SVA was significantly correlated with pelvic tilt and sacral slope. CONCLUSION: ACDF affects whole spine sagittal alignment, especially in patients with high cervical lordosis. In these patients, alteration of cervical lordosis to a normal angle shortened the SVA and resulted in reciprocal changes in pelvic tilt and sacral slope.

Soluble epoxide hydrolase inhibitory and anti-inflammatory components from the leaves of Eucommia ulmoides Oliver (duzhong).

Eucommia ulmoides leaves have been used as a functional food and drink in China. The purpose of this study was to identify the bioactive constituents with soluble epoxide hydrolase (sEH) inhibitory activity and anti-inflammatory properties. Twenty-seven known compounds (1-27) were isolated from the leaves of E. ulmoides Oliver, and their structures were identified by NMR and ESIMS analysis; three of these, 2,5-dimethoxy-3-glucopyranosyl cinnamic alcohol (11), foliasalacioside E2 (26), and icariside F2 (27), were obtained from this plant for the first time. Compounds 1-7 exhibited soluble epoxide hydrolase (sEH) inhibitory activity at 100 µM; among them, quercetin (1) and kaempferol (5) displayed potential activities with IC50 values of 22.5 ± 0.9 and 31.3 ± 2.6 µM, respectively, with noncompetitive inhibition mode. Nuclear factor kappa B (NF-κB) inhibitory activity of the isolated compounds was evaluated by the NF-κB liciferase assay in HepG2 cells. Compounds 1, 9, 20, and 27 displayed potent NF-κB inhibitory effects, with IC50 values of 15.14 ± 2.29, 15.23 ± 2.34, 16.88 ± 2.17, and 16.25 ± 2.19 µM, respectively, whereas other compounds showed weak inhibition of NF-κB transcriptional activity ranging from 17.54 to 92.6 µM. A structure-activity relationship of flavonoids 1-9 was also discussed. The results obtained in this work might contribute to the understanding of pharmacological activities of E. ulmoides leaves and further investigation on its potential application values for food and drug.