Wei-Dong Zhang

Therapeutic effects of astragaloside IV on myocardial injuries: multi-target identification and network analysis.

Astragaloside IV (AGS-IV) is a main active ingredient of Astragalus membranaceus Bunge, a medicinal herb used for cardiovascular diseases (CVD). In this work, we investigated the therapeutic mechanisms of AGS-IV at a network level by computer-assisted target identification with the in silico inverse docking program (INVDOCK). Targets included in the analysis covered all signaling pathways thought to be implicated in the therapeutic actions of all CVD drugs approved by US FDA. A total of 39 putative targets were identified. Three of these targets, calcineurin (CN), angiotensin-converting enzyme (ACE), and c-Jun N-terminal kinase (JNK), were experimentally validated at a molecular level. Protective effects of AGS-IV were also compared with the CN inhibitor cyclosporin A (CsA) in cultured cardiomyocytes exposed to adriamycin. Network analysis of protein-protein interactions (PPI) was carried out with reference to the therapeutic profiles of approved CVD drugs. The results suggested that the therapeutic effects of AGS-IV are based upon a combination of blocking calcium influx, vasodilation, anti-thrombosis, anti-oxidation, anti-inflammation and immune regulation.

Sesquiterpene lactones from Inula falconeri, a plant endemic to the Himalayas, as potential anti-inflammatory agents

A phytochemical investigation of Inula falconeri, a plant endemic to the Himalayas, afforded 10 new sesquiterpenoids and 26 known sesquiterpene lactones, including those bearing guaiane, pseudoguaiane, xanthane, eudesmane, germacrane, rare secocaryophyllane, chromolaevane, and carabrane frameworks. The structures were elucidated via spectroscopic analysis and compared with data from literature. All the isolates were assessed for their inhibitory effects against LPS-induced nitric oxide production in RAW264.7 macrophages. Compounds 4, 11, 24, and 31 showed stronger inhibitory activities than the positive control with IC(50) values of 0.13, 0.07, 0.11, and 0.11 μM, respectively. These studies also led to a better understanding of the structure-activity relationships for the sesquiterpene lactone family of compounds.

The inhibitory activities of the components of Huang-Lian-Jie-Du-Tang (HLJDT) on eicosanoid generation via lipoxygenase pathway.

AIM OF THE STUDY Huang-Lian-Jie-Du-Tang (HLJDT) is a traditional Chinese medicine with anti-inflammatory use. In the present study, the effects of its component herbs and pure components were observed on eicosanoid generation to find out the contributory components and their precise targets on arachidonic acid (AA) cascade. MATERIALS AND METHODS By monitoring leukotriene B(4) (LTB(4)), 5-hydroxyeicosatetraenoic acid (5-HETE), and 12-hydroxy-5,8,10-heptadecatrienoic acid (12-HHT), we compared the effects of HLJDT, HLJDT free of one or two component herbs, and water extract of four single component herbs of HLJDT (Rhizoma coptidis, Radix scutellariae, Cortex phellodendri and Fructus gardeniae) on eicosanoid generation in rat elicited peritoneal macrophages. In addition, thirteen pure compounds from HLJDT (baicalin, baicalein, wogonoside, wogonin, berberine, magnoflorine, phellodendrine, coptisine, palmatine, jateorrhizine, crocin, chlorogenic acid, and geniposide) were tested in the macrophages. Furthermore, the efficacies of these thirteen compounds were evaluated on cell-free purified enzymes: leukotriene A(4) hydrolase (LTA(4)H), 5-, 15-lipoxygenase (5-, 15-LO), and cyclo-oxygenase-1/2 (COX-1/2). Moreover, the possible synergetic effect on LO pathway derived LTB(4) generation between the active components was also tested in rat peritoneal macrophages. RESULTS Our experiments showed that Rhizoma coptidis and Radix scutellariae were responsible for the suppressive effect of HLJDT on eicosanoid generation. Some of the pure components including baicalein, baicalin, wogonoside, wogonin, coptisine, and magnoflorine inhibited eicosanoid generation in rat macrophages via LO pathway of AA cascade. Further experiments on cell-free purified enzymes confirmed that Radix scutellariae derived baicalein and baicalin showed significant inhibition on 5-LO and 15-LO, while Rhizoma coptidis derived coptisine showed medium inhibition on LTA(4)H. On the other hand, no significant inhibition of thirteen components on COX-1/2 was observed. Moreover, the slight synergetic inhibition on LTB(4) between baicalein and coptisine was proved in the rat peritoneal macrophages. CONCLUSIONS Baicalein and coptisine, the active components of HLJDT, for the first time are found to interfere with arachidonic acid cascade via inhibition on different points of LO pathway. This finding makes the mechanism of HLJDT clearer and achieves its safer therapeutic application.

Sesquiterpenoids and triterpenoids from Abies holophylla and their bioactivities.

Six previously unreported and 11 known terpenoids were isolated from Abies holophylla. The structures of the six compounds were established as two unusual bisabolane sesquiterpenoids, three nortriterpenoids, and one 3,4-seco-triterpenoid based on the detailed analysis of their 1D and 2D NMR spectroscopic data. In addition, electronic circular dichroism (ECD) calculations and molecular orbital (MO) analysis were used to assign the absolute configuration of one bisabolane sesquiterpenoid, abiesesquine A. Abiesesquine A showed the strongest inhibitory effects against LPS-induced nitric oxide (NO) production in RAW264.7 macrophages with an IC(50) value of 113.1 μM. Lanosta-7,9(11),24-trien-26-oic acid showed potent cytotoxic activity against COLO-205, LOVO, and QGY-7703 tumor cells with IC(50) values of 0.9, 4.2, and 2.0 μM, respectively. (23R,25R)-3,4-seco-9βH-Lanosta-4(28),7-dien-26,23-olid-3-oic acid, exhibited a significant antiproliferation effect against A549 cells (IC(50)=14.7 μM).

Incarvilleatone, a new cyclohexylethanoid dimer from Incarvillea younghusbandii and its inhibition against nitric oxide (NO) release.

Incarvilleatone (1), an unprecedented dimeric cyclohexylethanoid analog with a racemic nature, was isolated from the whole plant of Incarvillea younghusbandii. HPLC chiral separation of 1 gave two enantiomers (-)-incarvilleatone and (+)-incarvilleatone. The structure of 1 was established by spectroscopic methods and single crystal X-ray diffraction. The absolute configurations of enantiomers were determined by quantum mechanical calculation. (-)-Incarvilleatone exhibited a potent inhibitory effect against NO production in LPS-induced RAW264.7 macrophages.

Pharmacokinetics and tissue distribution of five bufadienolides from the Shexiang Baoxin pill following oral administration to mice

ETHNOPHARMACOLOGICAL RELEVANCE Shexiang Baoxin Pill (SBP) is a well-known composite formula of traditional Chinese medicine (TCM), widely used to treat cardiovascular diseases such as angina pectoris and myocardial infarction. Bufadienolides are major active compounds of Venenum Bufonis, which is one of the seven materiamedicas that comprise the Shexiang Baoxin Pill. Previous pharmacokinetics studies of bufadienolides have typically used a single medicinal material delivered to rats. In this study, we have chosen the mouse, a more proper animal model than the rat, to investigate the in vivo pharmacokinetics and tissue distribution of bufadienolides from the Shexiang Baoxin Pill. MATERIALS AND METHODS The concentrations of bufadienolides in plasma and tissues were identified using high performance liquid chromatography-tandem mass spectrometry (HPLC-ESI-MS/MS). The samples were prepared by liquid-liquid extraction with ethyl acetate, and the separation of bufadienolides was achieved using an ACQUITY HSS T3 column by gradient elution using water (containing 0.1% formic acid) and acetonitrile as the mobile phase at a flow rate of 0.3 mL/min. The pharmacokinetic parameters were determined using non-compartmental analysis. RESULTS The results showed that the five bufadienolides were rapidly absorbed and distributed into the body. The pharmacokinetic curve showed double peaks after oral administration. The major tissue depots for resibufogenin, bufalin, and bufotalin in mice were the intestines, lung and kidney, whereas the major tissue depots of gamabufotalin and arenobufagin were the intestines, liver and kidney. CONCLUSION The information gained from this research provides a meaningful insight for the clinical applications of the Shexiang Baoxin Pill.

Sesquiterpenoids from Inula racemosa Hook. f. Inhibit Nitric Oxide Production

A novel trinorsesquiterpene (1), three new (2-4), and 10 known sesquiterpenes were isolated from the roots of Inula racemosa Hook. f. The structures and absolute configurations of the new sesquiterpenes were elucidated by extensive spectroscopic and computational methods. All compounds were evaluated for their inhibition of LPS-induced nitric oxide production in RAW264.7 macrophages, and the results indicated that compounds 9, 12, and 13 moderately inhibited nitric oxide production with IC₅₀ values of 7.39 ± 0.36, 6.35 ± 0.26, and 5.39 ± 0.18 µM, respectively.

Compounds from Platycladus orientalis and Their Inhibitory Effects on Nitric Oxide and TNF-α Production

Four new compounds: an abietane (1), two isopimarane (2 and 3) diterpenes, and a dihydrobenzofuran neolignan (5), together with a sesquiterpene glycoside (6) firstly isolated from a natural source, and a known phenol glycoside (4) were isolated from leaves of Platycladus orientalis. The structures and relative configurations of these compounds were assigned on the basis of MS, IR, 1D and 2D NMR data. The absolute configuration of compound 1 was determined via density functional theory calculations of its electronic circular dichroism. In addition, the results of bioassays indicated that compounds 4 and 6 showed a potent inhibitory effect on NO production with IC₅₀ values of 24.4 and 11.9 µM, respectively. Meanwhile, compounds 1, 2, and 3 moderately inhibited TNF- α release.

A new flavonol from Oxytropis ochrocephala Bunge

A new acylated flavonoid, 3-O-rhamnocitrin-6-O-benzoyl-β-D-glucopyranoside (1), together with five known flavonoids, rhamnocitrin (2), pratensein (3), (3R)-7,3′-dihydroxy-2′,4′-dimethoxyisoflavan (4), (3R)-7,2′-dihydroxy-3′,4′-dimethoxyisoflavan (5) and isoliquiritigenin (6), was isolated from Oxytropis ochrocephala Bunge. The structural elucidation of the isolated compounds was primarily based on HRESIMS, IR and 1-D- and 2-D-NMR analyses.