A glutamate-gated chloride channel as the mite-specific target-site of dicofol and other diphenylcarbinol acaricides.

Dicofol has been widely used to control phytophagous mites. Although dicofol is chemically related to DDT, its mode of action has remained elusive. Here, we mapped dicofol resistance in the spider mite Tetranychus urticae to two genomic regions. Each region harbored a glutamate-gated chloride channel (GluCl) gene that contained a mutation-G314D or G326E-known to confer resistance against the unrelated acaricide abamectin. Using electrophysiology assays we showed that dicofol and other diphenylcarbinol acaricides-bromopropylate and chlorobenzilate-induce persistent currents in Xenopus oocytes expressing wild-type T. urticae GluCl3 receptors and potentiate glutamate responses. In contrast, the G326E substitution abolished the agonistic activity of all three compounds. Assays with the wild-type Drosophila GluClα revealed that this receptor was unresponsive to dicofol. Homology modeling combined with ligand-docking confirmed the specificity of electrophysiology assays. Altogether, this work elucidates the mode of action of diphenylcarbinols as mite-specific agonists of GluCl.

Controlled Release of Growth Factor from Heparin Embedded Poly(aldehyde guluronate) Hydrogels and Its Effect on Vascularization.

To deliver growth factors controllably for tissue regeneration, poly(aldehyde guluronate) (PAG) was obtained from alginate and covalently cross-linked with aminated gelatin (AG) to form PAG/AG hydrogel as a growth factors carrier. The prepared hydrogel exhibits a slow degradation rate and excellent cytocompatibility. Heparin was conjugated with gelatin and embedded into the hydrogel to reserve and stabilize growth factors. Basic fibroblast growth factor (bFGF) was immobilized into the hydrogel and performed sustained release as the hydrogel degraded. The bFGF loaded hydrogel can improve vascularization effectively in a rat dorsal sac model. To summarize, heparin embedded PAG/AG hydrogels would serve as a promising biodegradable vehicle for the controlled delivery of growth factors and promoting vascularization in regenerative medicine.

Research Progress of Epigenetic Modification on the Regulation of Transporters Under Hypoxia.

Epigenetic modification refers to the heritable changes caused by chromosomal changes without changing the DNA sequence. Epigenetics runs through the entire growth and differentiation process of the body, which causes varied diseases. Hypoxia is a physiological astate of lowered partial oxygen partial pressure that affects cell and tissue function. Transporters are proteins that maintain a normal and stable state of cells. Transporter's expression levels when hypoxia occurs influence the absorption, distribution, metabolism, and excretion of drugs, thereby affecting the utilization and efficacy of drugs. Epigenetic modification is assumed to play an important role in the metabolism of drugs. Changes in epigenetic modification and transporter expression levels under hypoxia are explored in our work, and the effect of epigenetic modification on transporter expression and how this regulatory mechanism works and affects drugs under hypoxia are questioned. It is important for drug development, treatment of diseases and rational use of drugs.

Research progress on the mechanism of intestinal barrier damage and drug therapy in a high altitude environment.

The plateau is a typical extreme environment with low temperature, low oxygen and high ultraviolet rays. The integrity of the intestinal barrier is the basis for the functioning of the intestine, which plays an important role in absorbing nutrients, maintaining the balance of intestinal flora, and blocking the invasion of toxins. Currently, there is increasing evidence that high altitude environments can enhance intestinal permeability and disrupt intestinal barrier integrity. This article mainly focuses on the regulation of the expression of HIF and tight junction proteins in the high altitude environment, which promotes the release of pro-inflammatory factors, especially the imbalance of intestinal flora caused by the high altitude environment. The mechanism of intestinal barrier damage and the drugs to protect the intestinal barrier are reviewed. Studying the mechanism of intestinal barrier damage in high altitude environment is not only conducive to understanding the mechanism of high altitude environment affecting intestinal barrier function, but also provides a more scientific medicine treatment method for intestinal damage caused by the special high altitude environment.

Exploration of N-Arylsulfonyl-indole-2-carboxamide Derivatives as Novel Fructose-1,6-bisphosphatase Inhibitors by Molecular Simulation.

A series of N-arylsulfonyl-indole-2-carboxamide derivatives have been identified as potent fructose-1,6-bisphosphatase (FBPase) inhibitors (FBPIs) with excellent selectivity for the potential therapy of type II diabetes mellitus. To explore the structure-activity relationships (SARs) and the mechanisms of action of these FBPIs, a systematic computational study was performed in the present study, including three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, pharmacophore modeling, molecular dynamics (MD), and virtual screening. The constructed 3D-QSAR models exhibited good predictive ability with reasonable parameters using comparative molecular field analysis (q2 = 0.709, R2 = 0.979, rpre2 = 0.932) and comparative molecular similarity indices analysis (q2 = 0.716, R2 = 0.978, rpre2 = 0.890). Twelve hit compounds were obtained by virtual screening using the best pharmacophore model in combination with molecular dockings. Three compounds with relatively higher docking scores and better ADME properties were then selected for further studies by docking and MD analyses. The docking results revealed that the amino acid residues Met18, Gly21, Gly26, Leu30, and Thr31 at the binding site were of great importance for the effective bindings of these FBPIs. The MD results indicated that the screened compounds VS01 and VS02 could bind with FBPase stably as its cognate ligand in dynamic conditions. This work identified several potential FBPIs by modeling studies and might provide important insights into developing novel FBPIs.

Protective effects of areca nut polyphenols on hypoxic damage of rat pulmonary microvascular endothelial cells.

OBJECTIVE: To investigate the protective effects of areca nut polyphenols on hypoxic damage of rat pulmonary microvascular endothelial cells (PMVECs). METHODS: Malondialdehyde and superoxide dismutase (SOD) were used to determine the optimal modeling of lung hypoxic injury cells. CCK-8 method was used to detect cell viability for determining the effective dose of areca nut polyphenols. Rat PMVECs were divided into control group, hypoxia model group and areca nut polyphenols group. BCA method was used to detect the protein concentration of each group, and the oxidative stress level in PMVECs was measured. Western blotting was used to detect the expression of inflammatory and apoptosis-related proteins. Immunofluorescence staining was used to detect the expression of occludin and zonula occludens (ZO) 1. Transwell chamber was used to detect transendothelial electrical resistance, and rhodamine fluorescent dye was used to detect PMVECs barrier permeability. RESULTS: The hypobaric hypoxia-induced cell injury model was established by culturing PMVECs for 48 h at 1% oxygen concentration. The 20 µg/mL areca nut polyphenols significantly reversed the survival rate and the oxidative stress of PMVECs in hypoxia model group (all P<0.05). Areca nut polyphenols had significant inhibitory effect on the up-regulation of inflammation-related proteins, including nuclear factor-κB (NF-κB) and nuclear factor-E2-related factor (Nrf) 2 in hypoxia model group (all P<0.05). And areca nut polyphenols could reduce hypoxia-induced PMVECs apoptosis by down-regulating the expressions of apoptosis-related proteins, including cysteine aspartic acid specific protease (caspase) 3, Bcl-2 associated X protein (Bax) in PMVECs (all P<0.05). In addition, areca nut polyphenols effectively improves the transendothelial electrical resistance and barrier permeability of PMVECs through elevating the expression of occludin and ZO-1 (all P<0.05). CONCLUSION: Areca nut polyphenols can inhibit the hypoxic damage of PMVECs by reducing oxidative stress and apoptosis down-regulating the expression of inflammatory proteins and reducing membrane permeability.

[Evaluation of regional wall movement abnormalities in coronary artery disease by quantitative tissue velocity imaging].

OBJECTIVE: To evaluate the clinical value of quantitative tissue velocity imaging (QTVI) in detection of regional wall movement abnormalities in patients with coronary artery disease (CAD). METHODS: The segmental left ventricular wall motion velocity was measured in 45 normal subjects and 48 patients with CAD, and the parameters of QTVI were analyzed between the two groups. RESULTS: Velocity decrement and wave form alterations were shown in abnormal segmental movements in the CAD group. There were obvious differences in the velocity between normal and abnormal segment. CONCLUSION: QTVI is valuable in quantitative and sensitive evaluation of regional wall movement abnormalities for non-invasive diagnosis of CAD.