Type II cGMP-dependent protein kinase inhibits epidermal growth factor-induced phosphatidylinositol-3-kinase/Akt signal transduction in gastric cancer cells.

Our previous study revealed that Type II cGMP-dependent protein kinase (PKG II) inhibits epidermal growth factor (EGF)-induced MAPK/ERK and MAPK/JNK-mediated signal transduction through the inhibition of the phosphorylation/activation of the EGF receptor (EGFR). As EGFR also mediates several other signal transduction pathways besides MAPK-mediated pathways, the present study was designed to investigate whether PKG II was able to inhibit EGF/EGFR-induced phosphatidylinositol-3-kinase (PI3K)/Akt-mediated signal transduction. The AGS human gastric cancer cell line was infected with adenoviral constructs encoding a cDNA of PKG II (Ad-PKG II) to increase the expression of PKG II, and treated with 8-pCPT-cGMP to activate the enzyme.

Design, synthesis, and biological evaluation of andrographolide derivatives as potent hepatoprotective agents.

Poor water solubility limits the clinical use of andrographolide and its derivatives. In an attempt to develop potent hepatoprotective drugs, a strategy was proposed to improve the aqueous solubility of andrographolide. Ten andrographolide derivatives were designed, synthesized, evaluated for aqueous solubility and in vivo hepatoprotective activity against CCl4 -induced liver injury in mice.

Novel fatty chain-modified glucagon-like peptide-1 conjugates with enhanced stability and prolonged in vivo activity.

A series of fatty chain conjugates of glucagon-like peptide-1(GLP-1) were designed and synthesized. First, eleven cysteine modified peptides (1-11) were prepared using Gly8-GLP-1(7-36)-NH2 peptide as a starting point. Peptides 1, 6, 9, and 11 which showed comparable GLP-1 receptor activate potency and glucose-lowering effect in vivo with Gly8-GLP-1(7-36)-NH2 were selected for second step modifications to yield conjugates 12-23.

Adenylyl cyclase anchoring by a kinase anchor protein AKAP5 (AKAP79/150) is important for postsynaptic β-adrenergic signaling.

Recent evidence indicates that the A kinase anchor protein AKAP5 (AKAP79/150) interacts not only with PKA but also with various adenylyl cyclase (AC) isoforms. However, the physiological relevance of AC-AKAP5 binding is largely unexplored. We now show that postsynaptic targeting of AC by AKAP5 is important for phosphorylation of the AMPA-type glutamate receptor subunit GluA1 on Ser-845 by PKA and for synaptic plasticity.

Cyanide detection using a triazolopyridinium salt.

A triazolopyridinium salt chemodosimeter has been developed that displays a 60-fold enhancement in fluorescence upon reaction with cyanide. The novel, fast, selective and sensitive reaction-based indicator relies on the pseudopericyclic ring opening of the bridgehead nitrogen-containing detector.

PKG II inhibits EGF/EGFR-induced migration of gastric cancer cells.

Background: Our previous research results showed that Type II cGMP dependent protein kinase (PKG II) could block the activation of epidermal growth factor receptor (EGFR) and consequently inhibit the proliferation and the related MAPK/ERK-mediated signal transduction of gastric cancer cell line BGC-823, suggesting that PKG II might inhibit other EGFR-triggered signal transduction pathways and related biological activities of gastric cancer cells. This paper was designed to investigate the potential inhibition of PKG II on EGF/EGFR-induced migration activity and the related signal transduction pathways.

Methodology/principal Findings: In gastric cancer cell line AGS, expression and activity of PKG II were increased by infecting the cells with adenoviral construct encoding PKG II cDNA (Ad-PKG II) and treating the cells with cGMP analogue 8-pCPT-cGMP.

Acrylonitrile has Distinct Hormetic Effects on Acetyl-Cholinesterase Activity in Mouse Brain and Blood that are Modulated by Ethanol.

Acrylonitrile(AN) is a neurotoxin both in animals and humans, but its effects on acetylcholinesterase (AChE) activity remain controversial. This study aimed to determine the dose-response effects of AN on AChE activity and the modulatory role of ethanol pre-treatment. A total of 144 Kunming mice were randomly divided into 18 groups: nine groups received 5% ethanol in their drinking water, and the remaining nine groups received regular tap water.

Hormetic effects of acute methylmercury exposure on grp78 expression in rat brain cortex.

This study aims to explore the expression of GRP78, a marker of endoplasmic reticulum (ER) stress, in the cortex of rat brains acutely exposed to methylmercury (MeHg). Thirty Sprague-Dawley (SD) rats were randomly divided into six groups, and decapitated 6 hours (h) after intraperitoneal (i.p.

Evaluation of hypoglycemic and antioxidative effects of synthesized peptide MC62.

Diabetes mellitus has been considered as a major health problem in the world today. This study aimed to investigate the hypoglycemic and antioxidative effects of peptide MC62 which was synthesized by solid-phase peptide synthesis method against diabetes induced by streptozotocin. MC62 was administered daily and injected intraperitoneally to the diabetic mice at a dose of 1 μmol/kg body weight for 20 days.

Surgical management of vertebral and basilar artery aneurysms: a single center experience in 41 patients.

Objective: To study an effective method for surgical management of vertebral and basilar artery aneurysms.

Methods: Forty-one patients with 43 aneurysms of the vertebral and basilar arteries were managed by microsurgical clipping. Cerebral angiography revealed basilar apex aneurysms in 17 patients, basilar trunk in six patients, vertebrobasilar (VB) junction aneurysms in three patients and vertebral aneurysms in 15 patients.

Endogenous cGMP-dependent protein kinase reverses EGF-induced MAPK/ERK signal transduction through phosphorylation of VASP at Ser239.

In our previous study, we demonstrated that type II cGMP-dependent protein kinase (PKG II) was expressed at lower levels in different human cancer cell lines and that exogenous PKG II inhibited epidermal growth factor (EGF)-induced MAPK/ERK signaling. In order to investigate its functions further in this signaling pathway, it is necessary to elucidate whether endogenous PKG has the same effect or not. This study aimed to investigate the possible inhibitory effect of endogenous PKG activity on EGF-induced MAPK/ERK signal transduction in human lung cancer cells and its mechanism.

A novel supramolecular ternary polymer with two orthogonal host-guest interactions.

A linear supramolecular ternary polymer based on two host-guest interactions in an orthogonal way was constructed, by taking advantage of the distinguishable binding properties between cyclodextrin and calixarene.

Embolic middle cerebral artery occlusion model using thrombin and fibrinogen composed clots in rat.

Ischemic stroke accounts for over 80% in total human stroke which mostly affect middle cerebral artery (MCA) territory. Embolic stroke models induced by injection of homologous clots into the internal carotid artery and MCA closely mimic human stroke and have been commonly used in stroke research. Studies indicate that the size and composition of clots are critical for the reproducibility of the stroke model.

LPS-induced nuclear translocation of RhoA is dependent on NF-κB in the human lung cancer cell line A549.

RhoA, an extensively studied member of the Rho GTPase family, has been identified as a mediator of pro-inflammatory responses and aggressive carcinogenesis. Bacterial lipopolysaccharide (LPS) is known to be a potent stimulator of inflammatory cytokine production. LPS is able to alter the activity of RhoA and the subcellular distribution of RhoA is altered according to its activity.

3D QSAR pharmacophore modeling for c-Met kinase inhibitors.

The receptor tyrosine kinase c-Met has multiple roles during cancer development and is currently considered as a promising target for cancer therapies. Pharmacophore models of c-Met kinase inhibitors have been developed based on 22 diverse compounds by using HypoGen algorithm implemented in Discovery studio program package. The best quantitative pharmacophore model, Hypo 1, which had the highest correlation coefficient (0.

[The expression and correlation of inducible nitric oxide synthase, Bax and Bcl-2 in nasal polyps].

Objective: To detect the expressions of inducible nitric oxide synthase (iNOS), apoptosis-related gene Bax, Bcl-2 in nasal polyps,and discuss the their relationship.

Method: The apoptosis of 30 cases of nasal polyps was detected by TUNEL assay. The expressions of iNOS and Bax, Bcl-2 was detected by immunohistochemical SABC method.

TNF-α inhibitors with anti-oxidative stress activity from natural products.

Tumor necrosis factor-α (TNF-α) is a major cytokine involved in the inflammatory response. Elevated TNF-α expression has been found to be associated with the development of diabetes, septic shock, tumorigenesis, cardiovascular diseases, rheumatoid arthritis and inflammatory bowel disease. In the past decade, the success of anti-TNF-α biologics has valuated the importance of the blockade of TNF-α production in the treatment of patients with various inflammatory diseases.

Discovery, synthesis and evaluation of novel cholesterol absorption inhibitors.

Chemical-based common feature pharmacophore modelling of Niemann Pick C1 Like 1 inhibitors was performed to provide some insights on the important pharmacophore features essential for Niemann Pick C1 Like 1 inhibition using Discovery Studio V2.5. After in-house database screening, a new series of substituted oxazolidinones, selected from the top ranked hits, have been synthesized and evaluated as novel cholesterol absorption inhibitors.

Synthesis and biological evaluation of andrographolide derivatives as potent anti-HIV agents.

In an attempt to develop potent anti-HIV drugs, 20 andrographolide derivatives were designed, synthesized, and evaluated for their in vitro anti-HIV activity. The screening results revealed that five compounds showed potent anti-HIV activities with therapeutic indices (TI) above 10. The most promising compound 6f shows a significant TI close to 34.

Design, synthesis and antiproliferative activity of 2-acetamidothiazole-5-carboxamide derivatives.

In order to develop a new series of dual inhibitors of SRC and ABL, and to investigate whether the pyrimidin- 4-ylamino moiety is critical for dasatinib's activity, acetyl substitution was adopted as alternate scaffold at the 2-amino group. Eighteen novel dasatinib derivatives were developed by a parallel synthesis approach and evaluated for their antiproliferative effects. Preliminary tests showed that some of the target compounds IId, IIe and IIf manifested strong antiproliferative activity against MCF-7, MDA-MB 231 and HT-29 cells.

Synthesis and biological evaluation of a series of 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-substituted tetrahydroisoquinoline derivatives.

Multidrug resistance in cancer is a major cause of failure in cancer chemotherapy. In search of new compounds with strong reversal activity and simple molecular structure, we have synthesized a series of compounds in which different substituents were linked to the 2-position of the 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)- tetrahydroisoquinoline system. Compounds were analyzed for their cytotoxicity by MTT in K562 cell line in vitro, all of the derivatives exhibited little cytotoxic activity.

Two immunogenic passenger dendritic cell subsets in the rat liver have distinct trafficking patterns and radiosensitivities.

Unlabelled: The aim of this study was to investigate the trafficking patterns, radiation sensitivities, and functions of conventional dendritic cell (DC) subsets in the rat liver in an allotransplantation setting. We examined DCs in the liver, hepatic lymph, and graft tissues and recipient secondary lymphoid organs after liver transplantation from rats treated or untreated by sublethal irradiation. We identified two distinct immunogenic DC subsets.

Design and synthesis of thiourea derivatives containing a benzo[5,6]cyclohepta[1,2-b]pyridine moiety as potential antitumor and anti-inflammatory agents.

Thiourea derivatives (6a-e) were developed and screened for antitumor and anti-inflammatory activity. Most of the compounds exhibited growth inhibitory effects comparable to 5-fluorouracil in vitro against mammary (MCF-7 and MDA-MB 231) as well as colon (HT-29) carcinoma cells. They also showed stronger anti-inflammatory activity than ibuprofen in vivo in the xylene-induced ear swelling assay in mice.

Cucurbituril-modulated supramolecular assemblies: from cyclic oligomers to linear polymers.

Employing bis(p-sulfonatocalix[4]arenes) (bisSC4A) and N',N''hexamethylenebis(1-methyl-4,4'-bipyridinium) (HBV(4+)) as monomer building blocks, the assembly morphologies can be modulated by cucurbit[n]uril (CB[n]) (n = 7, 8), achieving the interesting topological conversion from cyclic oligomers to linear polymers. The binary supramolecular assembly fabricated by HBV(4+) and bisSC4A units, forms an oligomeric structure, which was characterized by NMR spectroscopy, atomic force microscopy (AFM), transmission electron microscopy (TEM), dynamic light scattering (DLS), isothermal titration calorimetry (ITC), and gel permeation chromatography (GPC) experiments. The ternary supramolecular polymer participated by CB[8] is constructed on the basis of host-guest interactions by bisSC4A and the [2]pseudorotaxane HBV(4+)@CB[8], which is characterized by means of AFM, DLS, NMR spectroscopy, thermogravimetric analysis (TGA), UV/Vis spectroscopy, and elemental analysis.

Synthesis and preliminary antihyperlipidaemic activities evaluation of andrographolide derivatives.

Recent studies indicated that andrographolide was a potential antihyperlipidaemic therapeutic agent. In the paper, the synthesis of a series of andrographolide derivatives was described and their antihyperlipidaemic activities were evaluated in vivo. As compared with TG, TC, HDL-C and LDL-C concentrations, some of the derivatives exhibited better antihyperlipidaemic effects than positive control atromide.