Mechanism of anti-hyperuricemia of isobavachin based on network pharmacology and molecular docking.

BACKGROUND: Hyperuricemia is a more popular metabolic disease caused by a disorder of purine metabolism. Our previous study firstly screened out a natural product Isobavachin as anti-hyperuricemia targeted hURAT1 from a Chinese medicine Haitongpi (Cortex Erythrinae). In view of Isobavachin's diverse pharmacological activities, similar to the Tranilast (as another hURAT1 inhibitor), our study focused on its potential targets and molecular mechanisms of Isobavachin anti-hyperuricemia based on network pharmacology and molecular docking. METHODS: First of all, the putative target genes of compounds were screen out based on the public databases with different methods, such as SwissTargetPerdiction, PharmMapper and TargetNet,etc. Then the compound-pathways were obtained by the compounds' targets gene from David database for Gene Ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis. The cross pathways of compound-pathways and the diseases pathways of hyperuricemia from Comparative Toxicogenomics Database were be considered as the compound-disease pathways. Next, based on the compound-disease pathways and the PPI network, the core targets were identified based on the retrieved disease-genes. Finally, the compound-target-pathway-disease network was constructed by Cytoscape and the mechanism of isobavachin anti-hyperuricemia was discussed based on the network analysis. RESULTS: Our study demonstrated that there were five pathways involved in Isobavachin against hyperuricemia, including Drug metabolism-other enzymes, Metabolic pathways, Bile secretion, Renin-angiotensin system and Renin secretion. Among the proteins involved in these pathways, HPRT1, REN and ABCG2 were identified as the core targets associated with hyperuricemia, which regulated the five pathways mentioned above. It is quite different from that of Tranilast, which involved in the same pathways except Bile secretion instead of purine metabolism. CONCLUSION: This study revealed Isobavachin could regulate the pathways including Drug metabolism-other enzymes, Metabolic pathways, Bile secretion, Renin-angiotensin system, Renin secretion by core targets HPRT1, REN and ABCG2, in the treatment of hyperuricemia effect. Among them, the Bile secretion regulated by ABCG2 probably would be a novel pathway. Our work provided a theoretical basis for the pharmacological study of Isobavachin in lowering uric acid and further basic research.

Standardized myrtol attenuates lipopolysaccharide induced acute lung injury in mice.

CONTEXT: Standardized myrtol, an essential oil containing primarily cineole, limonene and α-pinene, has been used for treating nasosinusitis, bronchitis and chronic obstructive pulmonary disease (COPD). OBJECTIVE: To investigate the effects of standardized myrtol in a model of acute lung injury (ALI) induced by lipopolysaccharides (LPS). MATERIALS AND METHODS: Male BALB/c mice were treated with standardized myrtol for 1.5 h prior to exposure of atomized LPS. Six hours after LPS challenge, lung injury was determined by the neutrophil recruitment, cytokine levels and total protein concentration in the bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in the lung tissue. Additionally, pathological changes and NF-κB activation in the lung were examined by haematoxylin and eosin staining and western blot, respectively. RESULTS: In LPS-challenged mice, standardized myrtol at a dose of 1200 mg/kg significantly inhibited the neutrophile counts (from 820.97 ± 142.44 to 280.42 ± 65.45, 103/mL), protein concentration (from 0.331 ± 0.02 to 0.183 ± 0.01, mg/mL) and inflammatory cytokines level (TNF-α: from 6072.70 ± 748.40 to 2317.70 ± 500.14, ng/mL; IL-6: from 1184.85 ± 143.58 to 509.57 ± 133.03, ng/mL) in BALF. Standardized myrtol also attenuated LPS-induced MPO activity (from 0.82 ± 0.04 to 0.48 ± 0.06, U/g) and pathological changes (lung injury score: from 11.67 ± 0.33 to 7.83 ± 0.79) in the lung. Further study demonstrated that standardized myrtol prevented LPS-induced NF-κB activation in lung tissues. DISCUSSION AND CONCLUSION: Together, these data suggest that standardized myrtol has the potential to protect against LPS-induced airway inflammation in a model of ALI.

Mollugin inhibits the inflammatory response in lipopolysaccharide-stimulated RAW264.7 macrophages by blocking the Janus kinase-signal transducers and activators of transcription signaling pathway.

Mollugin, a kind of naphthohydroquinone, is a major constituent isolated from Rubia cordifolia L. and demonstrated to possess anti-inflammatory activity in recent reports. However, the effects and mechanism of action of mollugin in inflammation have not been fully defined. The present study was therefore designed to investigate whether mollugin suppresses the inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Mollugin attenuated the LPS-induced expression of nitric oxide (NO), inducible nitric oxide synthase (iNOS), interleukin (IL)-1ß and IL-6 but augmented the expression of tumor necrosis factor (TNF)-α. Mollugin did not inhibit the degradation of inhibitory kappa B (IκB)-α or the nuclear translocation of p65 nuclear factor-kappa B (NF-κB) but rather enhanced the phosphorylation of p65 subunits evoked by LPS. Mollugin did not inhibit the phosphorylation of extracellular-signal-related kinase (ERK) 1/2, p38, and c-Jun N-terminal kinase (JNK) 1/2 either. Mollugin significantly reduced the LPS-mediated phosphorylation of Janus kinase (JAK) 2, signal transducers and activators of transcription (STAT) 1 and STAT3. Molecular docking analysis showed that mollugin binds to JAK2 in a manner similar to that of AG490, a specific JAK2 inhibitor. We conclude that mollugin may be a JAK2 inhibitor and inhibits LPS-induced inflammatory responses by blocking the activation of the JAK-STAT pathway.

Pyranocoumarins isolated from Peucedanum praeruptorum Dunn suppress lipopolysaccharide-induced inflammatory response in murine macrophages through inhibition of NF-κB and STAT3 activation.

Praeruptorin C, D, and E (PC, PD, and PE) are three pyranocoumarins isolated from the dried root of Peucedanum praeruptorum Dunn of Umbelliferae. In the present study, we investigated the anti-inflammatory effect of these compounds in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Pyranocoumarins significantly inhibited LPS-induced production of nitric oxide, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). The mRNA and protein expressions of inducible nitric oxide synthase, IL-6, and TNF-α were also suppressed by these compounds. Both PD and PE exhibited greater anti-inflammatory activities than PC. Further study showed that pyranocoumarins suppressed the cytoplasmic loss of inhibitor κB-α protein and inhibited the translocation of NF-κB from cytoplasm to nucleus. In addition, pyranocoumarins suppressed LPS-induced STAT3 tyrosine phosphorylation. Taken together, the results suggest that pyranocoumarins may exert anti-inflammatory effects in LPS-stimulated RAW 264.7 macrophages through the inhibition of NF-κB and STAT3 activation.

Praeruptorin A inhibits lipopolysaccharide-induced inflammatory response in murine macrophages through inhibition of NF-κB pathway activation.

Praeruptorin A (PA) is a pyranocoumarin compound isolated from the dried root of Peucedanum praeruptorum Dunn (Umbelliferae). However, the antiinflammatory effect of PA has not been reported. The present study investigated the antiinflammatory effect of PA in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. PA significantly inhibited the LPS-induced production of nitric oxide (NO), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). The mRNA and protein expressions of inducible nitric oxide synthase (iNOS), IL-1ß and TNF-α were also suppressed by this compound. Further study showed that PA decreased the cytoplasmic loss of inhibitor κB-α (IκB-α) protein and inhibited the translocation of NF-κB from cytoplasm to nucleus. Taken together, the results suggest that PA may exert antiinflammatory effects in vitro in LPS-stimulated RAW 264.7 macrophages through inhibition of NF-κB signal pathway activation.

Effect of astragaloside IV on hepatic glucose-regulating enzymes in diabetic mice induced by a high-fat diet and streptozotocin.

AIM: Hepatic glycogen phosphorylase (GP) and glucose-6-phosphatase (G6Pase) are important in control of blood glucose homeostasis, and are considered to be potential targets for antidiabetic drugs. Astragaloside IV has been reported to have a hypoglycemic effect. However, the biochemical mechanisms by which astragaloside IV regulates hepatic glucose-metabolizing enzymes remain unknown. The present study examines whether GP and G6Pase mediate the hypoglycemic effect of astragaloside IV. METHODS: Type 2 diabetic mice were treated with astragaloside IV for 2 weeks. Blood glucose and insulin levels were measured by a glucometer and the ELISA method, respectively. Total cholesterol (TC) and triglyceride (TG) levels were determined using Labassay kits. Activities of hepatic GP and G6Pase were measured by the glucose-6-phosphate dehydrogenase-coupled reaction. The mRNA and protein levels of both enzymes were determined by real-time RT-PCR and Western blotting. RESULTS: Astragaloside IV at 25 and 50 mg/kg significally decreased the blood glucose, TG and insulin levels, and inhibited the mRNA and protein expression as well as enzyme activity of GP and G6Pase in diabetic mice. CONCLUSIONS: Astragaloside IV exhibited a hypoglycemic effect in diabetic mice. The hypoglycemic effect of this compound may be explained, in part, by its inhibition of hepatic GP and G6Pase activities.

[Evaluation of Amberlite XAD-1600 resin-based purification of the bioactive components from Radix Paeoniae Alba and Rhizoma Curcumae Longae extracts by pharmacodynamic and toxicological models].

OBJECTIVE: To evaluate the pharmacodynamics and toxicicity of the major bioactive components extracted and purified from Radix Paeoniae Alba and Rhizoma Curcumae Longae using Amberlite XAD-1600 resin. METHODS: Amberlite XAD-1600 was used to purify the bioactive components from the crude 75% ethanol extracts of the two herbs. The pharmacodynamic and toxic effects of the crude extracts and extract purified using XAD-1600 resin were comparatively examined with two acute inflammatory models, two pain models and acute toxicity test in vivo. RESULTS: The anti-inflammatory and analgesic effects of the purified extract were significant stronger with lower toxicity than those of the crude ethanol extract. CONCLUSION: Amberlite XAD-1600 resin allows efficient extraction and purification of the bioactive components from the two herbs.

Ellagitannin (BJA3121), an anti-proliferative natural polyphenol compound, can regulate the expression of MiRNAs in HepG2 cancer cells.

MicroRNAs (miRNAs) play an important role in cancers. A number of miRNA expression-profiling studies have been done to identify the miRNA signatures of cancers from different cellular origin. There is, however, relatively little information on how anticancer agents regulate miRNA expression. Ellagitannin (BJA3121), 1,3-Di-O-galloyl-4,6-(s)-HHDP-b-D-glucopyranose, is a new natural polyphenol compound isolated from Balanophora Japonica MAKINO. Our preliminary results have shown that BJA3121 had antiproliferative effect and modified the expression of different genes in human HepG(2) cancer cells. In this study, we further evaluate whether this antineoplastic compound is able to alter miRNA expression in HepG(2) cells. We demonstrated for the first time that BJA3121 can regulate the expression of 25 miRNAs, including 17 upregulated and 8 downregulated miRNAs in HepG(2) cells. Our results suggested that BJA3121-modifed miRNA expression can mediate, at least in part, the antiproliferative and multigene regulatory action induced by the compound on HepG(2) cancer cells.