Potential Phytotherapy of DSS-Induced Colitis: Ameliorating Reactive Oxygen Species-Mediated Necroptosis and Gut Dysbiosis with a New Crataegus pinnatifida Bunge Variety-Daehong.

Developing new plant varieties plays a crucial role in competitiveness in the agricultural and food industries and enhancing food security. Daehong (DH) is a new variety of Crataegus pinnatifida Bunge (CP); however, its physiological functions and potential as a nutraceutical ingredient remain unknown. Here, the efficacy of DH on inflammatory bowel disease (IBD) was investigated using dextran sulfate sodium (DSS)-induced colitis mice, and its relative pharmacological effects were analyzed against CP. DH improved colitis-induced weight loss, colon shortening, and inflammatory responses and reduced intestinal permeability. The reactive oxygen species (ROS)-mediated necroptotic signal that triggers enterocyte cell death in DSS-induced colitis was effectively controlled by DH, attributed to epicatechin. DSS-induced gut dysbiosis was recovered into a healthy gut microbiome environment by DH, increasing beneficial bacteria, like Akkermansia muciniphila, and changing harmful bacteria, including Bacteroides vulgatus and Peptostreptococcaceae. DH shows potential as a dietary or pharmaceutical ingredient to promote gut health and to prevent and treat IBD.

Securinega suffruticosa extract alleviates atopy-like lesions in NC/Nga mice via inhibition of the JAK1-STAT1/3 pathway.

Securinega suffruticosa (SS) has well-known antioxidant, anti-vascular inflammation, and anti-bone resorption effects; however, the effects of SS in atopic dermatitis (AD) remain unknown. We examined the effects of SS on AD via application of Dermatophagoides farinae extract (DfE) to the ears and skin of NC/Nga mice. As a result of SS administration, DfE-induced AD mice had reduced ear thickness, epidermal thickness, scratching behavior, and transepidermal water loss. The serum levels of immunoglobulin E and thymic interstitial lymphopoietin (TSLP) were reduced by SS application. SS decreased mast cell and eosinophil recruitment to skin lesions. Phosphorylation of signal transducer and activation of transcription (STAT)1, STAT3, and Janus kinase 1 were reduced in the skin tissue of SS-administered mice, and downregulated filaggrin was restored. SS reduced the levels of interleukin-6, regulated on activation, normal T cell expressed and secreted chemokine, and TSLP in interferon-γ/tumor necrosis factor-α-induced keratinocytes. The main components of SS were rutin and geraniin. These study results indicated that SS extract attenuated AD and has potential as a therapeutic natural product candidate for AD.

Potent Xanthine Oxidase Inhibitory Activity of Constituents of Agastache rugosa (Fisch. and C.A.Mey.) Kuntze.

The aerial parts of Agastache rugosa are used as a food material and traditional medicine in Asia. A 50% ethanol extract exhibited potent xanthine oxidase (XO) inhibitory activity (IC50 = 32.4 µg/mL). To investigate the major components responsible for this effect, seven known compounds were identified from A. rugosa; among these, salvianolic acid B (2) was isolated from this plant for the first time. Moreover, acacetin (7) exhibited the most potent inhibitory activity with an IC50 value of 0.58 µM, lower than that of allopurinol (IC50 = 4.2 µM), which is commonly used as a XO inhibitor. Comparative activity screening revealed that the C6-bonded monosaccharides (3) or sugars substituted with acetyl or malonyl groups (4-6) are critical for XO inhibition when converted to aglycone (7). The most potent inhibitor (7) in the A. rugosa extract (ARE) exhibited mixed-type inhibition kinetics and reversible inhibition toward XO. Furthermore, the hydrolysis of ARE almost converted to an inhibitor (7), which displayed the highest efficacy; UPLC-qTof MS revealed an increased content, up to five times more compared with that before treatment. This study will contribute to the enhancement in the industrial value of ARE hydrolysates as a functional ingredient and natural drug toward the management of hyperuricemia and treatment of gout.

Duchesnea indica Extract Ameliorates LPS-Induced Septic Shock in Mice.

Objective: Duchesnea indica has been reported for its anti-inflammatory properties. However, its efficacy in sepsis has yet to be reported. In this study, we studied the ability of Duchesnea indica extract (DIE) to rescue mice from septic shock and sepsis. Methods: In vitro studies included the measurement of secreted nitric oxide, cell viability, gene and protein expression via real-time polymerase chain reaction and western blot, and confocal microscopy in RAW 264.7 cells. In vivo studies include a model of septic shock and sepsis in BALB/c mice induced by a lethal and sub-lethal dose of lipopolysaccharide (LPS). Results: DIE suppressed the expression of proinflammatory cytokines induced by LPS and prevented the translocation of NFκB into the nucleus of RAW 264.7 cells. It also prevented reactive oxygen species damage induced by LPS in murine bone marrow-derived macrophages. Models of sepsis and septic shock were established in BALB/c mice and DIE-rescued mice from septic shock. DIE also reversed the increase in tumor necrosis factor-α and nitrite levels in the serum of mice induced with sepsis. DIE also prevented the translocation of NFκB from the cytosol into the nucleus in murine lungs. Histopathological damage induced by sepsis was reversed in the testis, liver, and lungs of mice. Conclusion: In conclusion, DIE is a suitable candidate for development as a therapeutic agent for sepsis.

Saengmaeksan, a traditional herbal formulation consisting of Panax ginseng, ameliorates hyperuricemia by inhibiting xanthine oxidase activity and enhancing urate excretion in rats.

BACKGROUND: Saengmaeksan (SMS) is a traditional Korean medicine composed of three herbs, Panax ginseng, Schisandra chinensis, and Liriope platyphylla. SMS is used to treat respiratory and cardiovascular disorders. However, whether SMS exerts antihyperuricemic effects is unknown. METHODS: Effects of the SMS extract in water (SMS-W) and 30% ethanol (SMS-E) were studied in a rat model of potassium oxonate-induced hyperuricemia. Uric acid concentrations and xanthine oxidase (XO) activities were evaluated in the serum, urine, and hepatic tissue. Using renal histopathology to assess kidney function and uric acid excretion, we investigated serum creatinine and blood urea nitrogen concentrations, as well as protein levels of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), and organic anion transporter 1 (OAT1). The effects of SMS on in vitro XO activity and uric acid uptake were also evaluated. The components of SMS were identified using Ultra Performance Liquid Chromatography (UPLC). RESULTS: SMS-E reduced serum uric acid and creatinine concentrations, and elevated urine uric acid excretion. SMS-E lowered XO activities in both the serum and liver, and downregulated the expression of renal URAT1 and GLUT9 proteins. SMS-E reduced renal inflammation and IL-1ß levels in both the serum and kidneys. SMS-E inhibited both in vitro XO activity and urate uptake in URAT1-expressing oocytes. Using UPLC, 25 ginsenosides were identified, all of which were present in higher levels in SMS-E than in SMS-W. CONCLUSION: SMS-E exhibited antihyperuricemic effects by regulating XO activity and renal urate transporters, providing the first evidence of its applicability in the treatment of hyperuricemia and gout.

Rapid identification of isoprenylated flavonoids constituents with inhibitory activity on bacterial neuraminidase from root barks of paper mulberry (Broussonetia papyrifera).

This study was to assess the possibility of using competitive and slow binding experiments with affinity-based ultrafiltration UPLC-QTof-MS analysis to identify potent bacterial neuraminidase (bNA) inhibitors from the Broussonetia papyrifera roots extract. To isolate unbound compounds from the enzyme-binding complex, the root bark extracts were either incubated in the absence of bNA, in the presence of bNA, or with the time-dependent bNA before the ultrafiltration was performed. Thirteen flavonoids were separated from the target extract, and their inhibitory activities were tested against bNA. The isolated flavonoids exhibited potent inhibition against NA (IC50 = 0.7-54.0 µM). Our kinetic analysis of representative active flavonoids (1, 2, and 6) showed slow and time-dependent reversible inhibition. Additionally, chalcones exhibited noncompetitive inhibition characteristics, whereas flavonols and flavans showed mixed-type behavior. The computational results supported the experimental behaviors of flavonoids 2, 6, 10, and 12, indicating that bounded to the active site, but flavonoids 6 and 10 binds near but not accurately at the active site. Although this is mixed-type inhibition, their binding can be considered competitive.

Effect of Jakyakgamcho-Tang Extracts on H2O2-Induced C2C12 Myoblasts.

Oxidative stress is a major contributor to muscle aging and loss of muscle tissue. Jakyakgamcho-tang (JGT) has been used in traditional Eastern medicine to treat muscle pain. Here, we compared the total phenolic and flavonoid contents in 30% ethanol and water extracts of JGT and tested the preventive effects against oxidative stress (hydrogen peroxide)-induced cell death in murine C2C12 skeletal muscle cells. The total phenolic content and total flavonoid content in 30% ethanol extracts of JGT were higher than those of water extracts of JGT. Ethanol extracts of JGT (JGT-E) had stronger antioxidant activities of 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and 2,2'-diphenyl-1-picrylhydrazyl-scavenging activity (DPPH) than water extracts of JGT (JGT-W). JGT-E contained 19-53% (1.8 to 4.9-fold) more active compounds (i.e., albiflorin, liquiritin, pentagalloylglucose, isoliquiritin apioside, isoliquiritin, liquiritigenin, and glycyrrhizin) than JGT-W. The ethanol extracts of JGT inhibited hydrogen peroxide-induced cell death and intracellular reactive oxygen species generation more effectively than the water extract of JGT in a dose-dependent manner. For the first time, these results suggest that ethanol extract of JGT is relatively more efficacious at protecting against oxidative stress-induced muscle cell death.

Siraitia grosvenorii Residual Extract Attenuates Atopic Dermatitis by Regulating Immune Dysfunction and Skin Barrier Abnormality.

Atopic dermatitis is a persistent inflammatory skin disorder. Siraitia grosvenorii fruits (monk fruit or nahangwa in Korean, NHG) are used as a natural sweetener and as a traditional medicine for the treatment of asthma and bronchitis. We evaluated the activity of S. grosvenorii residual extract (NHGR) on allergic inflammation of atopic dermatitis in a Dermatophagoides farinae mite antigen extract (DfE)-treated NC/Nga murine model and in vitro. Oral administration of NHGR significantly reduced epidermal hyperplasia and inflammatory cell infiltration in the skin lesions of DfE-induced atopic dermatitis, as well as the dermatitis severity score. NHGR reduced serum immunoglobulin E levels. Splenic concentrations of IFN-γ, interleukin (IL)-4, IL-5, and IL-13 were reduced by NHGR administration. Immunohistofluorescence staining showed that NHGR administration increased the protein levels of claudin-1, SIRT1, and filaggrin in atopic dermatitis skin lesions. In addition, NHGR inhibited the phosphorylation of mitogen-activated protein kinases and decreased filaggrin and chemokine protein expression in TNF-α/IFN-γ-induced human keratinocytes. Moreover, NHGR also inhibited histamine in mast cells. The quantitative analysis of NHGR revealed the presence of grosvenorine, kaempferitrin, and mogrosides. These results demonstrate that NHGR may be an efficient therapeutic agent for the treatment of atopic dermatitis.

Ulmus parvifolia Jacq. Exhibits Antiobesity Properties and Potentially Induces Browning of White Adipose Tissue.

The bark of Ulmus parvifolia Jacq. (UP) was traditionally used as a diuretic and to treat intestinal inflammation. With modern evidence of the correlation of diuretics, gut inflammation, and obesity, our study has shown the antiobesity effects of the bark of UP. UP treatment reduced lipid production and adipogenic genes in vitro. In vivo studies revealed that UP 100 mg/kg and UP 300 mg/kg treatment significantly reduced mouse weight without reducing food intake, indicating increased energy expenditure. UP significantly reduced the weight of epididymal and subcutaneous adipose tissue and decreased liver weight. Histological analysis revealed improvement in the progression of nonalcoholic fatty liver disease and epididymal white adipose tissue hypertrophy induced by a HFD. Real-Time PCR of epididymal adipose tissue revealed significant increases of uncoupling protein-1 (UCP-1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression after UP 300 mg/kg treatments. Phosphorylation of AMP-activated protein α (AMPKα) was increased, while phosphorylation of Acetyl-CoA Carboxylase (ACC) was reduced. Our findings reveal the ability of UP to reduce the occurrence of obesity through increased browning of white adipose tissue via increased AMPKα, PPARγ, PGC-1α, and UCP-1 expression.

Phloroglucinol Derivatives from Dryopteris crassirhizoma as Potent Xanthine Oxidase Inhibitors.

Dryopteris crassirhizoma rhizomes are used as a traditional medicine in Asia. The EtOAc extract of these roots has shown potent xanthine oxidase (XO) inhibitory activity. However, the main phloroglucinols in D. crassirhizoma rhizomes have not been analyzed. Thus, we investigated the major constituents responsible for this effect. Bioassay-guided purification isolated four compounds: flavaspidic acid AP (1), flavaspidic acid AB (2), flavaspidic acid PB (3), and flavaspidic acid BB (4). Among these, 1 showed the most potent inhibitory activity with a half-maximal inhibitory concentration (IC50) value of 6.3 µM, similar to that of allopurinol (IC50 = 5.7 µM) and better than that of oxypurinol (IC50 = 43.1 µM), which are XO inhibitors. A comparative activity screen indicated that the acetyl group at C3 and C3' is crucial for XO inhibition. For example, 1 showed nearly 4-fold higher efficacy than 4 (IC50 = 20.9 µM). Representative inhibitors (1-4) in the rhizomes of D. crassirhizoma showed reversible and noncompetitive inhibition toward XO. Furthermore, the potent inhibitors were shown to be present in high quantities in the rhizomes by a UPLC-QTOF-MS analysis. Therefore, the rhizomes of D. crassirhizoma could be used to develop nutraceuticals and medicines for the treatment of gout.

Corrigendum to "Zanthoxylum ailanthoides Suppresses Oleic Acid-Induced Lipid Accumulation through an Activation of LKB1/AMPK Pathway in HepG2 Cells".

[This corrects the article DOI: 10.1155/2018/3140267.].

Anti-hyperuricemic effect of Alpinia oxyphylla seed extract by enhancing uric acid excretion in the kidney.

BACKGROUND: Alpinia oxyphylla is a well-known traditional medicine used in China and Korea to treat intestinal disorders, urosis, diuresis, and chronic glomerulonephritis. PURPOSE: We investigated the anti-hyperuricemic effects of Alpinia oxyphylla seed extract (AE), and the underlying mechanisms of action through in vitro and in vivo studies. METHODS: We evaluated levels of uric acid in the serum and urine, the expression of renal urate transport proteins, and levels of inflammatory cytokines in potassium oxonate (PO)-induced hyperuricemic rats. Xanthine oxidase activity was analyzed in vitro, while cellular uric acid uptake was assessed in oocytes expressing the human urate transporter 1 (hURAT1). Moreover, the main components of AE were analyzed using UPLC. RESULTS: In PO-induced hyperuricemic rats, 200 and 400 mg/kg of AE significantly decreased levels of uric acid in serum, while 400 mg/kg of AE increased uric acid levels in urine. AE did not inhibit xanthine oxidase in vitro; however, 1, 10, and 100 µg/ml of AE significantly decreased uric acid uptake into oocytes expressing hURAT1. Furthermore, 400 mg/kg of AE increased levels of organic anion transporter (OAT) 1 protein, while 200 and 400 mg/kg of AE decreased the protein content of urate transporter, URAT1 and inflammatory cytokines in the kidneys. Nootkatone was identified as one the main chemical components in AE from UPLC analysis. CONCLUSIONS: These findings suggest that AE exerts anti-hyperuricemic and uricosuric effects, which are related to the promotion of uric acid excretion via enhanced secretion and inhibition of uric acid reabsorption in the kidneys. Thus, AE may be a potential treatment for hyperuricemia and gout.

Siraitia grosvenorii residual extract attenuates ovalbumin-induced lung inflammation by down-regulating IL-4, IL-5, IL-13, IL-17, and MUC5AC expression in mice.

BACKGROUND: Siraitia grosvenorii fruits are used in traditional medicine to treat cough, sore throat, bronchitis, and asthma. PURPOSE: This study aimed to investigate the anti-inflammatory and anti-asthmatic effects of S. grosvenorii residual extract (SGRE) on ovalbumin (OVA)-induced asthma in mice. METHODS: Asthma was induced in BALB/c mice by systemic sensitization to OVA, followed by intratracheal, intraperitoneal, and aerosol allergen challenges. SGRE was orally administered for four weeks. We investigated the effects of SGRE on airway hyper-responsiveness, OVA-specific IgE production, histological analysis of lung and trachea, immune cell phenotyping, Th1/Th2 cytokine production in bronchoalveolar lavage fluid (BAL) fluid and splenocytes, and gene expression in the lung. RESULTS: SGRE ameliorated OVA-driven airway hyper-responsiveness, serum IgE production, and histopathological changes in the lung and trachea. SGRE reduced the total number of cells in the lung and BAL, the total number of lymphocytes, neutrophils, monocytes, and eosinophils in the lung and BAL, the absolute number of CD4+/CD69+ T cells in the lung, and the absolute number of CD4+/CD8+ T cells and CD11b+/Gr-1+ granulocytes in the lung and BAL. SGRE also reduced Th2 cytokines (IL-4, IL-5, and IL-13) and increased the Th1 cytokine IFN-γ in the BAL fluid and supernatant of splenocyte cultures. SGRE decreased the OVA-induced increase of IL-13, TARC, MUC5AC, TNF-α, and IL-17 expression in the lung. CONCLUSION: SGRE exerts anti-asthmatic effects via the inhibition of Th2 and Th17 cytokines and the increase of Th1 cytokines, suggesting that SGRE may be a potential therapeutic agent for allergic lung inflammation, such as asthma.

Biofunctional soyasaponin Bb in peanut (Arachis hypogaea L.) sprouts enhances bone morphogenetic protein-2-dependent osteogenic differentiation via activation of runt-related transcription factor 2 in C2C12 cells.

Improvement of bone formation is necessary for successful treatment of the bone defects associated with osteoporosis. In this study, we sought to elucidate the osteogenic activity of peanut sprouts and their bioactive components. We found that peanut sprout water extract (PSWE) enhanced bone morphogenetic protein-2-mediated osteoblast differentiation in a dose-dependent manner by stimulating expression of runt-related transcription factor 2 (Runx2) via activation of AKT/MAP kinases. We identified a major component of PSWE, soyasaponin Bb, as the bioactive compound responsible for improvement of anabolic activity. Soyasaponin Bb from PSWE enhanced expression of the osteogenic transcription factor Runx2 and alkaline phosphatase. The soyasaponin Bb content depended on sprouting time of peanut, and the anabolic action of PSWE was dependent on soyasaponin Bb content. Thus, PSWE and soyasaponin Bb have the potential to protect against bone disorders, including osteoporosis.

Effects of Toona sinensis Leaf Extract and Its Chemical Constituents on Xanthine Oxidase Activity and Serum Uric Acid Levels in Potassium Oxonate-Induced Hyperuricemic Rats.

Toona sinensis leaf is used as a seasonal vegetable in Korea. A 70% ethanol extract of these leaves exhibited potent xanthine oxidase (XO) inhibition, with a 50% inhibitory concentration (IC50) of 78.4 µM. To investigate the compounds responsible for this effect, bioassay-guided purification led to the isolation of five constituents, identified as quercetin-3-O-rutinoside, quercetin-3-O-ß-d-glucopyranoside, 1,2,3,4,6-penta-O-galloyl-ß-d-glucopyranose (compound 3), quercetin-3-O-α-l-rhamnopyranoside, and kaempferol-3-O-α-l-rhamnopyranoside. Compound 3 showed the most potent inhibition of XO, with an IC50 of 2.8 µM. This was similar to that of allopurinol (IC50 = 2.3 µM), which is used clinically to treat hyperuricemia. Kinetic analyses found that compound 3 was a reversible noncompetitive XO inhibitor. In vivo, the T. sinensis leaf extract (300 mg/kg), or compound 3 (40 mg/kg), significantly decreased serum uric acid levels in rats with potassium oxonate-induced hyperuricemia. Furthermore, ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry analysis identified a high level of compound 3 in the leaf extract. These findings suggest that T. sinensis leaves could be developed to produce nutraceutical preparations.

DKB114, A Mixture of Chrysanthemum Indicum Linne Flower and Cinnamomum Cassia (L.) J. Presl Bark Extracts, Improves Hyperuricemia through Inhibition of Xanthine Oxidase Activity and Increasing Urine Excretion.

Chrysanthemum indicum Linne flower (CF) and Cinnamomum cassia (L.) J. Presl bark (CB) extracts have been used as the main ingredients in several prescriptions to treat the hyperuricemia and gout in traditional medicine. In the present study, we investigated the antihyperuricemic effects of DKB114, a CF, and CB mixture, and the underlying mechanisms in vitro and in vivo. DKB114 markedly reduced serum uric acid levels in normal rats and rats with PO-induced hyperuricemia, while increasing renal uric acid excretion. Furthermore, it inhibited the activity of xanthine oxidase (XOD) in vitro and in the liver in addition to reducing hepatic uric acid production. DKB114 decreased cellular uric acid uptake in oocytes and HEK293 cells expressing human urate transporter (hURAT)1 and decreased the protein expression levels of urate transporters, URAT1, and glucose transporter, GLUT9, associated with the reabsorption of uric acid in the kidney. DKB114 exerts antihyperuricemic effects and uricosuric effects, which are accompanied, partially, by a reduction in the production of uric acid and promotion of uric acid excretion via the inhibition of XOD activity and reabsorption of uric acid. Therefore, it may have potential as a treatment for hyperuricemia and gout.

Tetragonia tetragonoides (Pall.) Kuntze (New Zealand Spinach) Prevents Obesity and Hyperuricemia in High-Fat Diet-Induced Obese Mice.

Tetragonia tetragonoides (Pall.) Kuntze, called New Zealand spinach (NZS), is an edible plant used in salad in Western countries and has been used to treat gastrointestinal diseases in traditional medicine. We examined the anti-obesity and anti-hyperuricemic effects of NZS and the underlying mechanisms in high-fat diet (HFD)-induced obese mice. Mice were fed a normal-fat diet (NFD); high-fat diet (HFD); HFD with 75, 150, or 300 mg/kg NZS extract; or 245 mg/kg Garcinia cambogia (GC) extract. NZS decreased body weight gain, total white adipose tissue (WAT), liver weight, and size of adipocytes and improved hepatic and plasma lipid profiles. With NZS, the plasma levels of the leptin and uric acid were significantly decreased while the levels of the adiponectin were increased. Furthermore, NZS decreased the expression levels of adipogenesis-related genes and xanthine oxidoreductase (XOR), which is involved in uric acid production, while increasing that of proteins associated with fatty acid oxidation. UPLC analysis revealed that NZS contained 6-methoxykaempferol-3-O-ß-d-glucosyl(1'''→2'')-ß-d-glucopyranoside, 6-methoxykaempferol-3-O-ß-d-glucosyl(1'''→2'')-ß-d-glucopyranosyl-(6''''-caffeoyl)-7-O-ß-d-glucopyranoside, and 6,4'-dimethoxykaempferol-3-O-ß-d-glucosyl(1'''→2'')-ß-d-glucopyranosyl-(6''''-caffeoyl)-7-O-ß-d-glucopyranoside. These results suggest that NZS exerts anti-obesity, anti-hyperlipidemia, and anti-hyperuricemic effects in HFD-induced obese mice, which are partly explained by regulation of lipid-metabolism-related genes and proteins and decreased expression of XOR.

Zanthoxylum ailanthoides Suppresses Oleic Acid-Induced Lipid Accumulation through an Activation of LKB1/AMPK Pathway in HepG2 Cells.

Zanthoxylum ailanthoides (ZA) has been used as folk medicines in East Asian and recently reported to have several bioactivity; however, the studies of ZA on the regulation of triacylglycerol (TG) biosynthesis have not been elucidated yet. In this study, we examined whether the methanol extract of ZA (ZA-M) could reduce oleic acid- (OA-) induced intracellular lipid accumulation and confirmed its mode of action in HepG2 cells. ZA-M was shown to promote the phosphorylation of AMPK and its upstream LKB1, followed by reduction of lipogenic gene expressions. As a result, treatment of ZA-M blocked de novo TG biosynthesis and subsequently mitigated intracellular neutral lipid accumulation in HepG2 cells. ZA-M also inhibited OA-induced production of reactive oxygen species (ROS) and TNF-α, suggesting that ZA-M possess the anti-inflammatory feature in fatty acid over accumulated condition. Taken together, these results suggest that ZA-M attenuates OA-induced lipid accumulation and inflammation through the activation of LKB1/AMPK signaling pathway in HepG2 cells.

Piscroside C inhibits TNF-α/NF-κB pathway by the suppression of PKCδ activity for TNF-RSC formation in human airway epithelial cells.

BACKGROUND: Piscroside C, isolated from Pseudolysimachion rotundum var. subintegrum, is a novel iridoid glycoside with therapeutic efficacy in a mouse model of chronic obstructive pulmonary disease (COPD). Piscroside C has been reported as a constituent of YPL-001 (under Phase 2a study, ClinicalTrials.gov identifier NCT02272634). PURPOSE: To investigate the mechanisms behind piscroside C therapeutic effects on COPD in human airway epithelial NCI-H292 cells. METHODS: We tested if piscroside C effectively suppresses MUC5AC gene expression and TNF-RSC/IKK/NF-κB cascades in TNF-α-stimulated NCI-H292 cells by employing, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, luciferase reporter assays, chromatin immunoprecipitation assays and immunoprecipitation. RESULTS: Piscroside C markedly suppressed the expression of TNF-α-induced MUC5AC mucus protein by inhibiting the transcriptional activity of NF-κB in NCI-H292 cells. Indeed, piscroside C negatively regulated the function of TNF receptor 1 signaling complex (TNF-RSC, an upstream regulator of the NF-κB pathway) without affecting its extracellular interaction with the TNF-α ligand. This inhibitory effect by piscroside C is mediated by the inactivation of protein kinase C (PKC), an essential regulator of TNF-RSC. PKC inactivation by piscroside C results in decreased PKCδ binding to a TRAF2 subunit of TNF-RSC and subsequent reduced IKK phosphorylation, resulting in NF-κB inactivation. CONCLUSION: We propose that piscroside C is a promising therapeutic constituent of YPL-001 through its inhibition of PKCδ activity in the TNF-RSC/IKK/NF-κB/MUC5AC signaling cascade.

Anti-inflammatory effect of stem bark of Paulownia tomentosa Steud. in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and LPS-induced murine model of acute lung injury.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaves, bark, and flowers of Paulownia tomentosa Steud. have been widely used as a traditional medicine in East Asia to treat inflammatory and infectious diseases. AIM OF THE STUDY: We investigated the protective effect of the methanol stem bark extract of P. tomentosa using an animal model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). MATERIALS AND METHODS: The UPLC Q-TOF-MS profiles for the methanol extract of P. tomentosa stem bark showed that verbascoside and isoverbascoside were the predominant compounds. Raw 264.7 cells were used for inhibitory effects of cytokine production in vitro. C57BL/6N mice were administered intranasally with LPS (10µg/per mouse) to induce ALI. H&E staining was used to evaluate histological changes in the lung. RESULTS: Treatment with P. tomentosa stem bark extract (PTBE) suppressed the production of IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophages, and the recruitment of neutrophils and macrophages in the BALF of mice with LPS-induced ALI. PTBE also decreased the levels of reactive oxygen species (ROS) and pro-inflammatory cytokines in the BALF. PTBE reduced the levels of nitric oxide (NO) in the serum and of inducible nitric oxide synthase (iNOS) in the lung of ALI mice. PTBE also attenuated the infiltration of inflammatory cells and the expression of monocyte chemoattractant protein-1 (MCP-1) in the lung. In addition, PTBE suppressed the activation of NF-κB and the reduced expression of superoxide dismutase 3 (SOD3) in the lung. CONCLUSION: The results suggest that PTBE has a protective effect on LPS-induced ALI.