DT-010 Exerts Cardioprotective Effects by Regulating the Crosstalk between the AMPK/PGC-1α Pathway and ERp57.

The AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway performs a crucial role in energy metabolism and mitochondrial network. Our previous study found that DT-010, a novel danshensu (DSS) and tetramethylpyrazine (TMP) conjugate, had significant cardioprotective properties in vitro and in vivo. We also reported that ERp57 served as a major target of DSS using the chemical proteomics approach. In this article, we focus on exploring the interrelationship between the regulation of the AMPK/PGC-1α pathway and promoting ERp57 expression induced by DT-010 in tert-butylhydroperoxide- (t-BHP-) induced H9c2 cell injury. The results showed that DT-010 activated the AMPK/PGC-1α pathway and increased ERp57 protein expression. Importantly, the above phenomenon as well as the mitochondrial function can be partially reversed by siRNA-mediated ERp57 suppression. Meanwhile, silencing AMPK significantly inhibited the ERp57 expression induced by DT-010. In addition, molecular docking and kinase assay in vitro revealed that DT-010 had no direct regulation effects on AMPK activity. Taken together, DT-010 exerted cardioprotective effects by regulating the crosstalk of AMPK/PGC-1α pathway and ERp57, representing a potential therapeutic agent for ischemic heart disease.

New furofuran and tetrahydrofuran lignans from the flower buds of Magnolia biondii Pamp and their antiallergic effects.

The dried flower buds of Magnolia biondii Pamp (herbal name, Xin-Yi) are a traditional Chinese medicine with a long history of clinical use in the treatment of allergic rhinitis and sinusitis. However, the constituents responsible for its antiallergic effects remain clearly unidentified. In the present study, totally 33 lignans were obtained from M. biondii. Among them, two novel furofuran lignans (1 and 2), two novel tetrahydrofuran lignans (3 and 4), and other 16 known lignans were isolated first time from M. biondii. The antiallergic effects of compounds 1-33 on mouse bone marrow-derived mast cells (BMMCs) degrunaliton were evaluated and results showed that compounds 7, 8, 13, 15 and 18 could significantly inhibited ß-hex release on BMMCs. The results proved that furofuran and tetrahydrofuran lignans were the main constituents in M. biondii and their antiallergic effects were related with suppressing mast cell activation.

LDICDL: LncRNA-Disease Association Identification Based on Collaborative Deep Learning.

It has been proved that long noncoding RNA (lncRNA) plays critical roles in many human diseases. Therefore, inferring associations between lncRNAs and diseases can contribute to disease diagnosis, prognosis and treatment. To overcome the limitation of traditional experimental methods such as expensive and time-consuming, several computational methods have been proposed to predict lncRNA-disease associations by fusing different biological data. However, the prediction performance of lncRNA-disease associations identification needs to be improved. In this study, we propose a computational model (named LDICDL) to identify lncRNA-disease associations based on collaborative deep learning. It uses an automatic encoder to denoise multiple lncRNA feature information and multiple disease feature information, respectively. Then, the matrix decomposition algorithm is employed to predict the potential lncRNA-disease associations. In addition, to overcome the limitation of matrix decomposition, the hybrid model is developed to predict associations between new lncRNA (or disease) and diseases (or lncRNA). The ten-fold cross validation and de novo test are applied to evaluate the performance of method. The experimental results show LDICDL outperforms than other state-of-the-art methods in prediction performance.

Four new indole alkaloids from the roots of Isatis tinctoria.

Chemical fractionation of the ethanolic extract of the roots of Isatis tinctoria L. (I. tinctoria) yielded fourteen indole alkaloids including four new ones, isatisindigoticanine L-N and isatindigoside M. Their structures were established on the basis of extensive spectroscopic techniques including NMR, HRESIMS and IR as well as chemical methods. The absolute configuration of 1 was confirmed by ECD experiments. All the compounds were tested for their inhibitory effects on NO production in mouse mononuclear macrophages (RAW264.7) induced by lipopolysaccharide (LPS). The results showed that only compound 5 exhibited inhibitory effects with IC50 value of 18.5 µM.

Synthesis of Four Pentacyclic Triterpene-Sialylglycopeptide Conjugates and Their Affinity Assays with Hemagglutinin.

Influenza outbreaks pose a serious threat to human health. Hemagglutinin (HA) is an important target for influenza virus entry inhibitors. In this study, we synthesized four pentacyclic triterpene conjugates with a sialylglycopeptide scaffold through the Cu(I)-catalyzed alkyne-azide cycloaddition reaction (CuAAC) and prepared affinity assays of these conjugates with two HAs, namely H1N1 (A/WSN/1933) and H5N1 (A/Hong Kong/483/97), respectively. With a dissociation constant (KD) of 6.89 µM, SCT-Asn-betulinic acid exhibited the strongest affinity with the H1N1 protein. Furthermore, with a KD value of 9.10 µM, SCT-Asn-oleanolic acid exhibited the strongest affinity with the H5N1 protein. The conjugates considerably enhanced antiviral activity, which indicates that pentacyclic triterpenes can be used as a ligand to improve the anti-influenza ability of the sialylglycopeptide molecule by acting on the HA protein.

Isatisindigoticanine A, a novel indole alkaloid with an unpresented carbon skeleton from the roots of Isatis tinctoria.

Isatisindigoticanine A (1), a new indole alkaloid with an unusual carbon skeleton of a benzofuran-3-one unit connected with a 1H-indole-3-yl unit and a 4-(1,2-dihydroxyethyl)-6-oxa-3-azabicyclo[3.1.0]hexan-2-one unit via a C-3－C-8'' bond and a C-4'－C-8'' bond, was obtained from the roots of Isatis tinctoria. Its structure was determined by physicochemical properties and spectroscopic methods including 1 D, 2 D NMR, IR, HRESIMS data. The absolutely configurations were deduced by comparison of its experimental CD and calculated ECD spectra. Nitric oxide (NO) inhibitory activities of isatisindigoticanine A was also evaluated in the LPS-stimulated RAW 264.7 cells, however, no inhibitory effect was presented.

ILDMSF: Inferring Associations Between Long Non-Coding RNA and Disease Based on Multi-Similarity Fusion.

The dysregulation and mutation of long non-coding RNAs (lncRNAs) have been proved to result in a variety of human diseases. Identifying potential disease-related lncRNAs may benefit disease diagnosis, treatment and prognosis. A number of methods have been proposed to predict the potential lncRNA-disease relationships. However, most of them may give rise to incorrect results due to relying on single similarity measure. This article proposes a novel framework (ILDMSF) by fusing the lncRNA similarities and disease similarities, which are measured by lncRNA-related gene and known lncRNA-disease interaction and disease semantic interaction, and known lncRNA-disease interaction, respectively. Further, the support vector machine is employed to identify the potential lncRNA-disease associations based on the integrated similarity. The leave-one-out cross validation is performed to compare ILDMSF with other state of the art methods. The experimental results demonstrate our method is prospective in exploring potential correlations between lncRNA and disease.

Inferring LncRNA-disease associations based on graph autoencoder matrix completion.

Accumulating studies have indicated that long non-coding RNAs (lncRNAs) play crucial roles in large amount of biological processes. Predicting lncRNA-disease associations can help biologist to understand the molecular mechanism of human disease and benefit for disease diagnosis, treatment and prevention. In this paper, we introduce a computational framework based on graph autoencoder matrix completion (GAMCLDA) to identify lncRNA-disease associations. In our method, the graph convolutional network is utilized to encode local graph structure and features of nodes for learning latent factor vectors of lncRNA and disease. Further, the inner product of lncRNA factor vector and disease factor vector is used as decoder to reconstruct the lncRNA-disease association matrix. In addition, the cost-sensitive neural network is utilized to deal with the imbalance between positive and negative samples. The experimental results show GAMLDA outperforms other state-of-the-art methods in prediction performance which is evaluated by AUC value, AUPR value, PPV and F1-score. Moreover, the case study shows our method is the effectively tool for potential lncRNA-disease prediction.

[Study on chemical constituents of Cinnamomi Ramulus].

The chemical constituents of Cinnamomi Ramulus were investigated in this study. Twenty-two compounds were isolated by silica gel, Sephadex LH-20 gel column chromatographies and preparative HPLC and their structures were identified by various spectral analyses as dihydrorosavin(1), rosavin(2), 1-phenyl-propane-1,2,3-triol(3), patchoulol(4), graphostromane B(5),(+)-lyoniresinol-3 a-O-ß-D-glucopyranoside(6),(-)-lyoniresinol-3 a-O-ß-D-glucopyranoside(7), cinnacaside(8), subaveniumin A(9), 3-phenyl-2-propenyl-6-O-L-arabinopyranosyl-ß-glucopyranoside(10), 2-phenylethyl-ß-vicianoside(11), cinnacasol(12), [(2R,3S,4S,5R,6R)-6-(benzyloxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl] methyl hydrogen sulfate(13), coniferyl aldehyde(14),(2R,3R)-5,7-dimethoxy-3',4'-methylenedioxyflavan-3-ol(15), cinnacassin L(16), E-cinnamic alcohol(17),(E)-3-(2-methoxyphenyl)-2-propen-1-ol(18), 2-hydroxyphenylpropanol(19), cinnamomulactone(20),(+)-syringaresinol(21) and cinnamomumolide(22), respectively. Among them, 1 is a new compound and 3-7, 9-11, 13, 15, 18 and 19 were isolated from the plant for the first time.

Buyang Huanwu Decoction Attenuates Infiltration of Natural Killer Cells and Protects Against Ischemic Brain Injury.

BACKGROUND/AIMS: Natural killer (NK) cells are among the first immune cells that respond to an ischemic insult in human brains. The infiltrated NK cells damage blood-brain barrier (BBB) and exacerbate brain infarction. Buyang Huanwu Decoction (BHD), a classic Chinese traditional herbal prescription, has long been used for the treatment of ischemic stroke. The present study investigated whether BHD can prevent brain infiltration of NK cells, attenuate BBB disruption and improve ischemic outcomes. METHODS: Transient focal cerebral ischemia was induced in rats by a 60-minute middle cerebral artery occlusion, and BHD was orally administrated at the onset of reperfusion, 12 hours later, then twice daily. Assessed parameters on Day 3 after ischemia were: neurological and motor functional deficits through neurological deficit score and rotarod test, respectively; brain infarction through TTC staining; BBB integrity through Evans blue extravasation; matrix metalloproteinase-2/9 activities through gelatin zymography; tight junction protein, nuclear factor-kB (NF-kB) p65 and phospho-p65 levels through Western blotting; NK cell brain infiltration and CXCR3 levels on NK cells through flow cytometry; interferon-γ production through ELISA; CXCL10 mRNA levels through real-time PCR; CXCL10 expression and p65 nuclear translocation through immunofluorescence staining. RESULTS: BHD markedly reduced brain infarction, improved rotarod performance, and attenuated BBB breakdown. Concurrently, BHD attenuated the upregulation of matrix metalloproteinase-2/9 activities and the degradation of tight junction proteins in the ischemic brain. Infiltration of NK cells was observed in the ischemic hemisphere, and this infiltration was blunted by treatment with BHD. BHD suppressed brain ischemia-induced interferon-γ and chemokine CXCL10 production. Furthermore, BHD significantly reduced the expression of CXCR3 on brain-infiltrated NK cells. Strikingly, BHD did not affect NK cell levels or its CXCR3 expression in the spleen or peripheral blood after brain ischemia. The nuclear translocation of NF-kB p65 and phospho-p65 in the ischemic brain was inhibited by BHD. CONCLUSION: Our findings suggest that BHD prevents brain infiltration of NK cells, preserves BBB integrity and eventually improves ischemic outcomes. The inhibitory effects of BHD on NK cell brain invasion may involve its ability of suppressing NF-kB-associated CXCL10-CXCR3-mediated chemotaxis. Notably, BHD only suppresses NK cells and their CXCR3 expression in the ischemic brain, but not those in periphery.

Total Flavonoids from Radix Glycyrrhiza Exert Anti-Inflammatory and Antitumorigenic Effects by Inactivating iNOS Signaling Pathways.

Inducible nitric oxide synthase (iNOS) plays an important role in inflammation, which has also been considered as a major driver of breast cancer disease progression. Radix Glycyrrhiza (RG) has been broadly used for its anti-inflammatory and antitumorigenic effects. However, the mechanisms of regulation of iNOS in inflammation and cancer have not been fully explored. Total flavonoids isolated from RG (TFRG) exhibited anti-inflammatory activity through the regulation of ERK/NF-κB/miR-155 signaling and suppression of iNOS expression in LPS/IFN-γ stimulated RAW264.7 macrophages without cytotoxicity. TFRG also markedly reduced tumor mass of breast cancer cell MDA-MB-231 xenografts with suppression of iNOS expression, formation of 3-nitrotyrosine (3-NT), and inactivation of protumorigenic JAK2/STAT3 signaling pathway. These results suggested that TFRG limited the development of breast cancer and inflammation due to its property of iNOS inhibition.

A new iridoid derivative from the roots of Scrophularia buergeriana.

Phytochemical investigation of the roots of Scrophularia buergeriana Miq. (Scrophulariaceae), resulted in the isolation of a new iridoid derivative named as buergerinin (1). Its structure was elucidated as rel-(1R, 5R, 6R)-(2-oxa-bicyclo[3.3.0]oct-7-en-6, 7-diyl)dimethoxypropane based mainly on MS and 1D and 2D NMR spectroscopic analyses.

Extract of okra lowers blood glucose and serum lipids in high-fat diet-induced obese C57BL/6 mice.

Okra is an important tropical vegetable and source of dietary medicine. Here, we assayed the effects of an ethanol extract of okra (EO) and its major flavonoids isoquercitrin and quercetin 3-O-gentiobioside on metabolic disorders in high-fat diet-induced obese mouse. We found that treatment with EO, isoquercitrin and quercetin 3-O-gentiobioside reduced blood glucose and serum insulin levels and improved glucose tolerance in obese mice. Meanwhile, serum triglyceride levels and liver morphology in the mice were significantly ameliorated by EO and isoquercitrin treatment. Total cholesterol levels in isoquercitrin and quercetin 3-O-gentiobioside treated mice were also reduced. We also found that EO inhibited the expression of nuclear receptor transcription factor PPARγ, which is an important regulator of lipid and glucose homeostasis. Furthermore, we determined that EO and quercetin 3-O-gentiobioside have antioxidant activity in vitro. Our results indicate that okra may serve as a dietary therapy for hyperglycemia and hypertriglyceridemia.

[Effects of extracts of Radix Scrophulariae on blood pressure in spontaneously hypertensive rats and the underlying mechanisms].

OBJECTIVE: To explore the effects of extracts of Radix Scrophulariae (ERS) on blood pressure, vasoconstrictors and morphology of artery in spontaneously hypertensive rats (SHRs). METHODS: Fifty SHRs were randomly divided into SHR, SHR plus 40 mg/kg of captopril, SHR plus 70 mg/kg of ERS, SHR plus 140 mg/kg of ERS and SHR plus 280 mg/kg of ERS groups. Wistar-Kyoto (WKY) rats were randomly divided into two groups, namely, WKY and WKY plus 140 mg/kg of ERS groups. The rats were orally administered with the corresponding drugs or drinking water once a day for 20 weeks. The blood pressure was determined every three weeks. At the 21st week, the concentrations of noradrenaline (NA), angiotensin II (Ang II), thromboxane B(2) (TXB(2)) and 6-keto-prostaglandin F(1α) in serum and endothelin-1 (ET-1) were detected by enzyme-linked immunosorbent assay. The morphological changes in abdominal aorta were observed under an optical microscope with hematoxylin and eosin staining. The ratio of intima-media thickness/lumen radius of abdominal aorta was calculated. RESULTS: ERS significantly lowered the blood pressure of SHRs from the 3rd to the 21st week; ERS also reduced the levels of NA, Ang II, ET-1 and TXB(2), decreased the intima-media thickness of abdominal aortal wall and improved the morphological changes in abdominal aorta in SHRs. In addition, ERS did not significantly change blood pressure and vasoactive substances in WKY rats. CONCLUSION: ERS possesses beneficial effects in inhibiting hypertension and attenuating arteriosclerosis. The underlying mechanism may be associated with restraining the release of vasoconstrictors, such as NA, Ang II, ET-1 and TXB(2).

[Simultaneous determination of five constituents in Scrophularia ningpoensis by HPLC].

OBJECTIVE: To develop an HPLC method for the simultaneous quantitation of five constituents in Scrophularia ningpoensis. METHOD: Samples were analyzed on an Agilent SB-C18 column(4.6 mm x 250 mm, 5 microm) eluted with acetonitrile and water containing 0.03% phosphate acid as mobile phases in a linear gradient mode. The flow rate was kept at 1.0 mL x min(-1), and the column temperature was set to 30 degrees C. The DAD detector wavelengths were 210, 280, 330 nm. RESULT: The linear ranges were 50-400 mg x L(-1) for harpagide, 1-40 mg x L(-1) for harpagoside, 1-20 mg x L(-1) for cinnamic acid, 0.5-4.5 mg x L(-1) for acteoside,1-60 mg x L(-1) for angoroside C, respectively. The average recoveries of the five constituents were 100.8% (RSD 0.62%), 101.7% (RSD 0.32%), 98.8% (RSD 0.48%), 99.9% (RSD 1.4%), 99.2% (RSD 1.1%), respectively. CONCLUSION: Through the validation, the method was proved to be sensitive, accurate, repeatable, and can be used for quality control of the roots of S. ningpoensis.

Hypoglycemic activities of A- and B-type procyanidin oligomer-rich extracts from different Cinnamon barks.

Procyanidin oligomers in Cinnamon are thought to be responsible for the biological activity in the treatment of diabetes mellitus (DM). To clarify types of procyanidin oligomers in different Cinnamon species and investigate their different effects, the present study investigated procyanidin oligomers in polyphenolic oligomer-rich extracts of three Cinnamon samples by LC-MS methods, and their hypoglycemic activities were detected in vivo and in vitro. The results showed that two of the three samples from Cinnamomum cassia were rich in B-type procyanidin oligomers, and the other sample was rich in A-type procyanidin oligomers. The Cinnamon extracts were administered at doses of 200 and 300 mg/kg body wt. in high-fat diet-fed and low-dose streptozotocin (STZ)-induced diabetic mice for 14 days. The results showed that blood glucose concentrations were significantly decreased in all Cinnamon extract groups compared with the control group (p<0.05). Administration of the Cinnamon extracts significantly increased the consumption of extracellular glucose in insulin-resistant HepG2 cells and normal HepG2 cells compared with the control group. These results suggest that both A- and B-type procyanidin oligomers in different Cinnamon species have hypoglycemic activities and may improve insulin sensitivity in type 2 DM.