Integration of network pharmacology, transcriptomics and molecular docking reveals two novel hypoglycemic components in snow chrysanthemum.

Our previous studies uncovered the glucose-lowering properties of snow chrysanthemum tea, however, the active ingredients and underlying mechanisms were yet to be uncovered. Flavonoids are the most active and abundant components in snow chrysanthemum tea. In this study, we treated leptin-deficient diabetic ob/ob or high-fat diet (HFD)-induced C57BL/6 J obese mice with or without total flavonoids of snow chrysanthemum (TFSC) for 14 weeks. Results indicated that TFSC ameliorated dyslipidemia and fatty liver, thereby reducing hyperlipidemia. Further mechanism experiments, including RNA-seq and experimental validation, revealed TFSC improved glycolipid metabolism primarily by activating the AMPK/Sirt1/PPARγ pathway. Additionally, by integrating UPLC, network pharmacology, transcriptomics, and experimental validation, we identified two novel hypoglycemic compounds, sulfuretin and leptosidin, in TFSC. Treatment with 12.5 µmol/L sulfuretin obviously stimulated cellular glucose consumption, and sulfuretin (3.125, 6.25 and 12.5 µmol/L) significantly mitigated glucose uptake damage and reliably facilitated glucose consumption in insulin-resistant HepG2 cells. Remarkably, sulfuretin interacted with the ligand-binding pocket of PPARγ via three hydrogen bond interactions with the residues LYS-367, GLN-286 and TYR-477. Furthermore, a concentration of 12.5 µmol/L sulfuretin effectively upregulated the expression of PPARγ, exhibiting a comparable potency to a renowned PPARγ agonist at 20 µmol/L. Taken together, our findings have identified two new hypoglycemic compounds and revealed their mechanisms, which significantly expands people's understanding of the active components in snow chrysanthemum that have hypoglycemic effects.

Cells-Micropatterning Biomaterials for Immune Activation and Bone Regeneration.

Natural tissues are composed of ordered architectural organizations of multiple tissue cells. The spatial distribution of cells is crucial for directing cellular behavior and maintaining tissue homeostasis and function. Herein, an artificial bone bioceramic scaffold with star-, Tai Chi-, or interlacing-shaped multicellular patterns is constructed. The "cross-talk" between mesenchymal stem cells (MSCs) and macrophages can be effectively manipulated by altering the spatial distribution of two kinds of cells in the scaffolds, thus achieving controllable modulation of the scaffold-mediated osteo-immune responses. Compared with other multicellular patterns, the Tai Chi pattern with a 2:1 ratio of MSCs to macrophages is more effective in activating anti-inflammatory M2 macrophages, improving MSCs osteogenic differentiation, and accelerating new bone formation in vivo. In brief, the Tai Chi pattern generates a more favorable osteo-immune environment for bone regeneration, exhibiting enhanced immunomodulation and osteogenesis, which may be associated with the activation of BMP-Smad, Oncostatin M (OSM), and Wnt/ß-catenin signaling pathways in MSCs mediated by macrophage-derived paracrine signaling mediators. The study suggests that the manipulation of cell distribution to improve tissue formation is a feasible approach that can offer new insights for the design of tissue-engineered bone substitutes with multicellular interactions.

Traditional uses, ten-years research progress on phytochemistry and pharmacology, and clinical studies of the genus Scutellaria.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria (Lamiaceae), which includes approximately 360-469 accepted species, is widespread in Europe, North America, East Asia, and South America. Several species have a long history being used as traditional medicines to treat respiratory, peptic, neurological, and hepatic and gall diseases. The phytochemistry and pharmacology of the genus Scutellaria have been developed dramatically in the past ten years, and the traditional uses and clinical studies of the genus have not been systematically summarized. Therefore, it is especially valuable to review the current state of knowledge to provide a basis for further exploration of its medicinal potential. AIM OF THE REVIEW: The review aims to provide updated information on the ethnopharmacology, the ten-year research progress of phytochemistry and pharmacology, and clinical studies of Scutellaria and to explore the potential medicinal values and further studies of Scutellaria. MATERIALS AND METHODS: This review is based on published studies and books from the library and electronic sources, including SciFinder, Scopus, PubMed, Web of Science, Baidu Scholar, CNKI, the online ethnobotanical database, and ethnobotanical monographs. This literature is related to ethnopharmacology, the ten-year research progress on the phytochemistry and pharmacology, and clinical studies of Scutellaria. RESULTS: A total of 50 species, 5 subspecies and 17 varieties of the genus Scutellaria are used as traditional medicine with various biological activities. In the past ten years, 208 chemical constituents have been identified from 16 species and 1 variety of the genus Scutellaria, such as neo-clerodane diterpenoids, sesterterpenoids, terpenoids, flavonoids. Pharmacological research has demonstrated that the extracts and compounds identified from this genus exhibit extensive biological activities, including anticancer, antioxidant, anti-inflammatory, antiviral and antibacterial activities, effects on cardiovascular, cerebrovascular diseases as well as hepatoprotective and neuroprotective effects. The species S. baicalensis, S. barbata, and S. lateriflora and the main compounds baicalein, baicalin and wogonin are involved in clinical trials, which point the way for us to conduct further studies, such as study on the anticancer, antihypertensive, anti-infective, anti-inflammatory, neuroprotective and other effects of Scutellaria. CONCLUSIONS: The species included in the genus Scutellaria can be used to treat cancer, infection, hepatic disorders, cardiovascular and cerebrovascular diseases, neurodegenerative diseases, and other diseases. Some indications in traditional medicines have been confirmed by modern pharmacological studies, such as anticancer, anti-inflammatory, anti-infective activity, and hepatoprotective and neuroprotective effects. The available literature indicated that most of the bioactivities could be attributed to flavonoids and neo-clerodane diterpenoids. Although there are some uses of Scutellaria in clinical practice, the existing research on this genus is still limited. In order to expand the development of medicinal resources of Scutellaria, the already studied species in this genus are recommended for more comprehensive investigation on their active substances, pharmacological mechanisms, quality control, clinical use and new drug research. Additionally, it is necessary to study species that their chemical composition or pharmacological activity have not yet been investigated, especially those used in folk medicine.

Traditional uses, phytochemistry, pharmacology, and toxicology of Coreopsis tinctoria Nutt.: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Coreopsis tinctoria Nutt. (family Asteraceae) is an important traditional medicine in North America, Europe, and Asia for quite a long historical period, which has received great attention due to its health-benefiting activities, including disinfection, treatment sexual infection, diarrhoea, acute and chronic dysentery, red-eye swelling as well as pain, heat, thirst, hypertension, palpitation, gastrointestinal discomfort, and loss of appetite. AIM OF THE REVIEW: The purpose of this review is to give an overview of the current phytochemistry and pharmacological activities of C. tinctoria, and reveals the correlation among its traditional uses, phytochemistry, pharmacological profile, and potential toxicity. MATERIALS AND METHODS: This review is based on published studies and books from electronic sources and library, including the online ethnobotanical database, ethnobotanical monographs, Scopus, SciFinder, Baidu Scholar, CNKI, and PubMed. These reports are related to the traditional uses, phytochemistry, pharmacology, and toxicology of C. tinctoria. RESULTS: Coreopsis tinctoria is traditionally used in diarrhoea, infection, and chronic metabolic diseases. From 1954 to now, more than 120 chemical constituents have been identified from C. tinctoria, such as flavonoids, polyacetylenes, polysaccharides, phenylpropanoids, and volatile oils. Flavonoids are the major bioactive components in C. tinctoria. Current research has shown that its extracts and compounds possess diverse biological and pharmacological activities such as antidiabetes, anti-cardiovascular diseases, antioxidant, anti-inflammatory, protective effects on organs, neuroprotective effects, antimicrobial, and antineoplastic. Studies in animal models, including acute toxicity, long-term toxicity, and genotoxicity have demonstrated that Snow Chrysanthemum is a non-toxic herb, especially for its water-soluble parts. CONCLUSIONS: Recent findings regarding the main phytochemical and pharmacological properties of C. tinctorial have confirmed its traditional uses in anti-infection and treatment of chronic metabolic disease and, more importantly, have revealed the plant as a valuable medicinal plant resource for the treatment of a wide range of diseases. The available reports indicated that most of the bioactivities in C. tinctorial could be attributed to flavonoids. However, higher quality studies on animals and humans studies are required to explore the efficacy and mechanism of action of C. tinctoria in future.

The chemopreventive effects of Huangqin-tea against AOM-induced preneoplastic colonic aberrant crypt foci in rats and omics analysis.

Despite that colorectal cancer (CRC) is a severe global health problem, effective chemopreventive strategies against CRC are still lacking. Huang-qin tea (HQT), a healthy herbal tea, is prepared from the aerial parts of Scutellaria baicalensis Georgi and has been consumed in China for thousands of years. HQT contains abundant flavonoids, which display potent anticancer effects, but no research studies have investigated the cancer-preventive effects of HQT on CRC in vivo. Here, we found that HQT inhibits azoxymethane-induced aberrant crypt foci (ACF) formation in a preneoplastic colonic ACF rat model. The essential role of the gut microbiota in the chemopreventive effect of HQT on CRC in a pseudo-germ-free rat model was confirmed. Besides, HQT modulates inflammatory cytokine expression by significantly decreasing IL-1ß, IL-6, IL-10, and TNF-α expression, and elevating IFN-γ production. 16S rDNA sequencing analysis indicated that HQT regulated the gut microbiota by increasing the abundance of beneficial bacteria (Lachnoclostridium, Alistipes, Roseburia, and Lactococcus) and reducing the levels of Bacteroides, Parasutterella, and unidentified_Clostridiales. Fecal metabolomics showed that HQT modulated the AOM-induced metabolomic disorder, and these altered metabolites were almost involved in the lipid metabolic pathways. The Spearman correlation analysis revealed a correlation between the gut microbiota and fecal metabolites. Collectively, these results suggested that HQT exerted beneficial effects on host health by inhibiting inflammation, and by regulating the gut microbiota profile and certain metabolic pathways. In conclusion, HQT inhibits AOM-induced ACF formation by modulating the gut microbiota composition and improving metabolomic disorders, indicating the potential of HQT as a functional beverage candidate for the prevention and treatment of CRC.

JAX2, an ethanol extract of Hyssopus cuspidatus Boriss, can prevent bronchial asthma by inhibiting MAPK/NF-κB inflammatory signaling.

BACKGROUND: Hyssopus cuspidatus Boriss has been used to treat bronchial asthma for many years in Uighur medicine. JAX2, an ethanol extract from this plant, has effectiveness against bronchial asthma. However, the molecular basis for the anti-inflammatory effects of JAX2 remains unclear. PURPOSE: This study aimed to evaluate the mechanism of JAX2 against bronchial asthma. METHODS: We established an asthma model in rats using ovalbumin (OVA), and an inflammatory model in RAW264.7 cells using lipopolysaccharide (LPS) stimulation. To evaluate the anti-inflammatory effects of JAX2, the concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, IL-17, eotaxin and immunoglobulin (Ig)E were measured by enzyme-linked immunosorbent assay (ELISA). Cell viability was investigated by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)2H-tetrazolium, inner salt (MTS) assay. Further, nitric oxide (NO) and reactive oxygen species (ROS) were determined using Griess reagent and 2,7-dichlorofluorescein diacetate. The phosphorylation of p-extracellular signal-regulated kinase (ERK), p-Jun-NH2-terminal kinase (JNK), p38 kinases (p38) and p-inhibitor of nuclear factor kappa-B kinase (IKK), and nuclear translocation of p-p65 kinases (p-p65) were determined by immunofluorescence to uncover the effects of JAX2 on the Mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways. RESULTS: After JAX2 administration to rats, Interferon (IFN)-γ concentrations in BALF increased significantly. Further, the concentrations of TNF-α, IL-4, IL-6, IL-17 and eotaxin in BALF, and IgE in serum decreased. JAX2 decreased TNF-α, IL-6 and NO in cell supernatant, and reduced ROS intracellularly. Concurrently, IFN-γ concentrations increased in cell supernatant significantly. In LPS-induced RAW264.7 cells, JAX2 inhibited phosphorylation of p-ERK, p-JNK and p-38 MAPK. The subsequent phosphorylation of p-IKK and nuclear translocation of the p-p65 subunit of NF-κB were also suppressed. CONCLUSION: Based on these findings, we believe that JAX2 has both preventive and treatment effects in bronchial asthma. Furthermore, in the RAW264.7 cell inflammatory model, JAX2 also inhibited NF-κB and MAPK signaling pathways.

Vasorelaxant effects of the extracts and some flavonoids from the buds of Coreopsis tinctoria.

CONTEXT: The buds of Coreopsis tinctoria Nutt (Compositae) are used in the treatment of hypertension in the Uyghur folk medicine in China. OBJECTIVE: To investigate vasorelaxant properties of extracts and some flavonoids from C. tinctoria (CT) and their underlying mechanisms in isolated rat thoracic aortic rings. MATERIALS AND METHODS: Vasorelaxant effects of ethanol extracts of CT (CTA) and its flavonoids as well as water-ethanol eluates from CTA by AB-8 resins (CTAA∼CTAF) were evaluated on rat aortic rings pre-contracted with phenylephrine (PE, 1 µM) or high KCl (60 µM). We evaluated the effect of CTA, CTAD and CTAE on PE-induced contraction in a Ca²âº-free medium and a dose-effect curve of Ca²âº in pre-contracted ring with high KCl. RESULTS: Endothelial removal did not modify the effect of CTAD and CTAE (3.00 g/L) neither on PE-pre-contracted rings (164.78 ± 21.44 and 191.47 ± 16.75%) nor on KCl-pre-contracted rings (75.68 ± 10.76 and 125.14 ± 17.41%) compared with intact-endothelium rings pre-contracted with high KCl (100.49 ± 17.30 and 110.81 ± 16.33%). CTAD and CTAE (3.00 g/L) down-regulated the dose-effect curve of Ca²âº in pre-contraction with high KCl, and inhibited the pre-contraction with PE in a Ca²âº-free medium (p < 0.05). Seven flavonoids were obtained from CTAD, of which luteolin (5) and quercetin (6) were found to be the most effective relaxation in rings precontracted with PE (EC50: 0.006 and 0.039 g/L, p < 0.05) or high KCl (EC50: 0.023 and 0.045 g/L, p < 0.05). DISCUSSION AND CONCLUSION: These data demonstrated the vasorelaxant effect of CT, and its mechanism is likely due to an inhibitory effect on calcium movements through cell membranes.

[Study on new extraction technology and protective effect of hugan buzure granule on liver injury in mice].

OBJECTIVE: To study on the new preparation technology of Hugan Buzure granule and to compare protective effect on liver injury in rats by different extraction processes. METHOD: Volatile oil extraction technology, inclusion condition and ethanol extraction condition were selected by orthogonal experiments. The experiment models of liver injury were induced by carbon tetrachloride, bacillus calmette-guerin (BCG) and plus lipolysaccharides (LPS) in rats, respectively. ALT, AST in serum, and MDA, SOD in liver were measured and the rats were killed to calculate the liver coefficient to evaluate the protective effect of Hugan Buzure granule on experimental injury in rats. RESULT: The optimum conditions of volatile oil extraction were 1:12 of solid-liquid ratio, 2 h of soaking time, and 8 h of extracting time. The optimal beta-cyclodextrin inclusion complex condition was as follows: the volatile oils formed complex with the beta-CD in a ratio of 1: 6 and stirring for 1 h at 40 degrees C. The optimum ethanol extraction was as follows: refluxing and extracting 3 times with 10-fold 50% ethanol, 2 h for each time. Compared with the model group, the new technology extraction of Hugan Buzure granule could obviously inhibite the elevation of serum ALT (P < 0.01), AST (P < 0.05) of liver injury induced by BCG + LPS, and elevate the contents of SOD, and obviously inhibite the elevation of serum AST (P < 0.01) of liver injury induced by carbon tetrachloride. CONCLUSION: The new preparation technology was feasible. The new extraction could protect the liver injury in rats, which was better than extraction of current preparation technology.

[Studies on chemical constituents in seeds of Cicer arietinum].

OBJECTIVE: To study the chemical constituents in seeds of Cicer arietinum, so that to find bioactive natural products. METHOD: Dried and sprouted seeds of C. arietinum were extracted with ethanol of various concentrations respectively, then isolated and purified by silica gel, macroreticular resin D 101, Sephadex LH -20 gel column chromatography, and structures of compounds were identified by spectral analysis. RESULT: Nine compounds have been isolated and identified: 3-hydroxy-olean-12-ene (1), biochanin A-7-O-beta-D-glucoside (2), cerebroside (3), 1-ethyl-alpha-L-galactoside (4), uridine (5), adenosine (6), trytophan (7), biochanin A (8), fomononetin (9). CONCLUSION: Compounds 1, 3, 4, 6, 7 were isolated from genus Cicer for the first time.

[Studies on chemical constituents in herbs of Dracocephalum moldavica II].

OBJECTIVE: To study the chemical constituents of Dracocephalum moldavica. METHOD: The compounds were isolated by using RA polystyrene resin, polyamide and silica gel column chromatography, The structures of the compounds were elucidated on the basis of physic-chemical properties and spectra data. RESULT: Six compounds were identified as syringaresinol4-O-beta-D-monoglucoside (I), sy-ringaresinol-4,4'-O-bis-beta-D-glucoside (II), kaempferol-3-O-beta-D-(6"-O-p-coumaroyl)-galactopyranoside (III), 2"-p-coumarylastragalin (IV), takakin-8-O-beta-D-glucopyranoside (V), beta-daucosterol (VI). CONCLUSION: Compounds I-V were obtained from genus Dracocephalum for the first time.

[Studies on chemical constituents from herb of Dracocephalum moldavica].

OBJECTIVE: To study the chemical constituents from the whole plant of Dracocephalum moldavica. METHOD: The compounds were isolated by using column chromatography with RA polystyrene resin, polyamide and silica gel as packing materials, and the structures of the compounds were identified by means of spectral data. RESULT: eight compounds were identified as apigenin(I), luteolin(II), kaempferol(III), isorhamnetin(IV), tilianin(V), agastachoside(VI), acacetin-7-O-(6-O-Malonyl-beta-D-glucopyranoside) (VII) and syringaresinol(VIII). CONCLUSION: Compounds I, II and III were isolated from genus Dracocephalum for the first time and compounds IV, VII and VIII were isolated from Dracocephalum moldavuca for the first time.