Efficacy of brain-computer interfaces on upper extremity motor function rehabilitation after stroke: A systematic review and meta-analysis.

BACKGROUND: The recovery of upper limb function is crucial to the daily life activities of stroke patients. Brain-computer interface technology may have potential benefits in treating upper limb dysfunction. OBJECTIVE: To systematically evaluate the efficacy of brain-computer interfaces (BCI) in the rehabilitation of upper limb motor function in stroke patients. METHODS: Six databases up to July 2023 were reviewed according to the PRSIMA guidelines. Randomized controlled trials of BCI-based upper limb functional rehabilitation for stroke patients were selected for meta-analysis by pooling standardized mean difference (SMD) to summarize the evidence. The Cochrane risk of bias tool was used to assess the methodological quality of the included studies. RESULTS: Twenty-five studies were included. The studies showed that BCI had a small effect on the improvement of upper limb function after the intervention. In terms of total duration of training, < 12 hours of training may result in better rehabilitation, but training duration greater than 12 hours suggests a non significant therapeutic effect of BCI training. CONCLUSION: This meta-analysis suggests that BCI has a slight efficacy in improving upper limb function and has favorable long-term outcomes. In terms of total duration of training, < 12 hours of training may lead to better rehabilitation.

Characterizing ammonia emissions from water bodies using dynamic floating chambers.

Ammonia (NH3) is the most important alkaline gas in the atmosphere and plays a central role in atmospheric pollution and the global N cycle. Water bodies receive increasing nitrogen inputs from effluents and atmospheric deposition due to anthropogenic activities and are regarded as the major natural NH3 and NH4+ sinks. In this work, floating dynamic flux chambers were deployed at four types of freshwater (rivers, large reservoirs, medium-sized reservoirs and ponds) systems and a coastal seawater system to estimate the water-air NH3 emission fluxes. The NH3 emission fluxes of rivers (26.4 µg NH3 m-2 h-1) were significantly higher than those of other types of freshwater systems, and the NH3 flux of offshore water was unexpectedly high (3.9 µg NH3 m-2 h-1). The ammonium content and water temperature were the most important factors driving NH3 emissions from water bodies. The global NH3 emissions from water bodies reached 8.88 TgN a-1, and this value will increase persistently with global warming and water quality deterioration. Water bodies that are relatively eutrophic and directly affected by anthropogenic activities should be considered reservoirs of inputted N instead of permanent sinks.

The synthesis of puerarin derivatives and their protective effect on the myocardial ischemia and reperfusion injury.

Puerarin is a naturally occurring isoflavone and is frequently used for the treatment of cardiovascular symptoms in China. By the structural modification of the puerarin molecule at different positions, seven new puerarin derivatives were obtained, and their cardioprotective activities (in vitro and in vivo) were respectively evaluated. The finding that the activities of 3 and 8 markedly exceeded puerarin suggested that the acylated modification of phenolic hydroxyl at C-7 in the puerarin molecule may improve the cardioprotective activity, which will be an important reference for further structural optimization.

Synthesis and anti-inflammatory activity of the major metabolites of imrecoxib.

We have developed a novel and moderately selective COX-2 inhibitor, imrecoxib, as a new anti-inflammatory drug. We describe herein the preparation of the major metabolites M2 and M4 of imrecoxib, as well as the in vitro and in vivo activities of the two compounds. The results showed that both M2 and M4 are potential COXs inhibitors with a moderate COX-1/COX-2 selectivity, and their anti-inflammatory activity in vivo was equal to or slightly higher than the clinical celecoxib.

Formation of 4'-carboxyl acid metabolite of imrecoxib by rat liver microsomes.

AIM: Imrecoxib is a novel and moderately selective COX-2 inhibitor. The aim of the present in vitro investigation was to study the formation of the major metabolite 4'-carboxylic acid imrecoxib (M2) and identify the enzyme(s) involved in the reaction. METHODS: The formation of M2 was studied in rat liver cytosol in the absence or presence of liver microsome. The formed metabolite was identified and quantified by LC/MS(n). In addition, to characterize the cytochrome P450 (CYP) isozymes involved in M2 formation, the effects of typical CYP inhibitors (such as ketoconazle, quinine, alpha-naphthoflavone, methylpyrazole, and cimetidine) on the formation rate of M2 were investigated. RESULTS: The formation of M2 from 4-hydroxymethyl imrecoxib (M4) was completely dependent on rat liver microsomes and NADPH. Enzyme kinetic studies demonstrated that the formation rate of M2 conformed to monophasic Michaelis-Menten kinetics. Additional experiments showed that the formation of M2 was induced significantly by dexamethasone and lowered by ketoconazole strongly and concentration-dependently. By comparison, other CYP inhibitors, such as alpha-naphthoflavone, cimetidine, quinine, and methylpyrazole had no inhibitory effects on this metabolic pathway. CONCLUSION: These biotransformation studies of imrecoxib in rat liver at the subcellular level showed that the formation of M2 occurs in rat liver microsomes and is NADPH-dependent. The reaction was mainly catalyzed by CYP 3A in untreated rats and in dexamethasone-induced rats. Other CYP, such as CYP 1A, 2C, 2D, and 2E, seem unlikely to participate in this metabolic pathway.

Role of rat liver cytochrome P450 3A and 2D in metabolism of imrecoxib.

AIM: To investigate the in vitro metabolism of imrecoxib in rat liver microsomes and to identify the cytochrome P450 (CYP) forms involved in its metabolism. METHODS: Liver microsomes of Wistar rats were prepared using an ultracentrifuge. The in vitro metabolism of imrecoxib was studied by incubation with rat liver microsomes. To characterize the CYP forms involved in the 4 '-methyl hydroxylation of imrecoxib, the effects of typical CYP inducers (such as dexamethasone, isoniazid and beta-naphthoflavone) and of CYP inhibitors (such as ketoconazole, quinine, alpha-naphthoflavone, methylpyrazole, and cimetidine) on the formation rate of 4 '-hydroxymethyl imrecoxib were investigated. RESULTS: Imrecoxib was metabolized to 3 metabolites by rat liver microsomes: 4'-hydroxymethyl imrecoxib (M4), 4'-hydroxymethyl-5-hydoxyl imrecoxib (M3), and 4 '-hydroxymethyl-5-carbonyl imrecoxib (M5). Over the imrecoxib concentration range studied (5-600 micromol/L), the rate of 4'-methyl hydroxylation conformed to monophasic Michaelis-Menten kinetics. Dexamethasone significantly induced the formation of M4. Ketoconazole markedly lowered the metabolic rate of imrecoxib in a concentration-dependent manner. Moreover, a significant inhibitory effect of quinine on the formation of M4 was observed in microsomes obtained from control rats, isoniazid-induced rats, and b-naphthoflavone-induced rats. In contrast, a-naphthoflavone, cimetidine, and methylpyrazole had no inhibitory effects on this metabolic pathway. CONCLUSION: Imrecoxib is metabolized via 4'-methyl hydroxylation in rat liver microsomes. The reaction is mainly catalyzed by CYP 3A. CYP 2D also played a role in control rats, in isoniazid-induced rats and in beta-naphthoflavone-induced rats.

Computational study of human phosphomannose isomerase: Insights from homology modeling and molecular dynamics simulation of enzyme bound substrate.

Phosphomannose isomerase is a zinc metalloenzyme that catalyzes the reversible isomerization of mannose-6-phosphate and fructose-6-phosphate, and the three-dimensional (3D) structure of human phosphomannose isomerase has not been reported. In order to understand the catalytic mechanism, the 3D structure of the protein is built by using homology modeling based on the known crystal structure of mannose-6-phosphate isomerase from (PDB code 1PMI). The model structure is further refined by energy minimization and molecular dynamics methods. The mannose-6-phosphate-enzyme complex is developed by molecular docking and the key residues involved in the ligand binding are determined, which will facilitate the understanding of the action mode of the ligands and guide further genetic studies. Our results suggest a hydride transfer mechanism of alpha-hydrogen between the C1 and C2 positions but do not support the cis-enediol mechanism. The detailed mechanism involves, on one side, Zn2+ mediating the movement of a proton between O1 and O2, and, on the other side, the hydrophobic environment formed in part by Tyr278 promoting transfer of a hydride ion.

Inhibitory mode of N-phenyl-4-pyrazolo[1,5-b] pyridazin-3-ylpyrimidin-2-amine series derivatives against GSK-3: molecular docking and 3D-QSAR analyses.

Glycogen synthase kinase 3 (GSK-3) inhibition is an important research topic because of its wide range of associated health implications. The interaction mode of a series of N-phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine compounds with human GSK-3 has been studied using molecular docking and 3D-QSAR approaches. In the 3D-QSAR studies, the molecular alignment and conformation determination are so important that they affect the success of a model. Flexible docking (AutoDock3.0.5) was used for the determination of 'active' conformation and molecular alignment. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to develop 3D-QSAR models of 80 N-phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine compounds. The r(2) values were 0.870 and 0.861 for CoMFA and CoMSIA models, respectively. The predictive ability of these models was validated by 10 compounds of the test set. Mapping these models back to the topology of the active site of GSK-3 led to a better understanding of the vital N-phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amines-GSK-3 interactions. The results demonstrate that combination of ligand-based and receptor-based modeling is a powerful approach to build 3D-QSAR models. The interaction mode from this study may be helpful for the design of a novel inhibitor and guide the selection of candidate sites for further experimental studies on site-directed mutagenesis.

Synthesis and evaluation of azaindole-alpha-alkyloxyphenylpropionic acid analogues as PPARalpha/gamma agonists.

A series of azaindole-alpha-alkyloxyphenylpropionic acid analogues was synthesized and evaluated for PPAR agonist activities. Structure-activity relationship was developed for PPARalpha/gamma dual agonism. One of the synthesized compound 7a was identified as a potent, selective PPARalpha/gamma dual agonist.

Acryloylamino-salicylanilides as EGFR PTK inhibitors.

A series of acryloylamino-salicylanilides were synthesized as inhibitors of EGFR PTK. A strategy of pseudo six-membered ring formed through intramolecular hydrogen bonding in salicylanilides is employed to mimic the planar pyrimidine ring of quinazoline EGFR inhibitors. Acrylamido moiety is incorporated to target the Cys-773 of EGFR specifically. Some of the obtained compounds exhibited good activity as EGFR inhibitors.

Design, synthesis, and evaluation of 2-alkoxydihydrocinnamates as PPAR agonists.

A series of 2-alkoxydihydrocinnamates were synthesized as PPARgamma and PPARalpha dual agonists. In vitro studies in cell model showed that these compounds were efficacious. Compound 1g was found to be a potent PPARalpha/gamma dual agonist and will be further evaluated for the treatment of type II diabetes.

Exploration of a binding mode of indole amide analogues as potent histone deacetylase inhibitors and 3D-QSAR analyses.

Docking simulations and three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses were conducted on a series of indole amide analogues as potent histone deacetylase inhibitors. The studies include comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Selected ligands were docked into the active site of human HDAC1. Based on the docking results, a novel binding mode of indole amide analogues in the human HDAC1 catalytic core is presented, and enzyme/inhibitor interactions are discussed. The indole amide group is located in the open pocket, and anchored to the protein through a pair of hydrogen bonds with Asp99 O-atom and amide NH group on ligand. Based on the binding mode, predictive 3D-QSAR models were established, which had conventional r2 and cross-validated coefficient values (r(cv)2) up to 0.982 and 0.601 for CoMFA and 0.954 and 0.598 for CoMSIA, respectively. A comparison of the 3D-QSAR field contributions with the structural features of the binding site showed good correlation between the two analyses. The results of 3D-QSAR and docking studies validate each other and provided insight into the structural requirements for activity of this class of molecules as HDAC inhibitors. The CoMFA and CoMSIA PLS contour maps and MOLCAD-generated active site electrostatic, lipophilicity, and hydrogen-bonding potential surface maps, as well as the docking studies, provided good insights into inhibitor-HDAC interactions at the molecular level. Based on these results, novel molecules with improved activity can be designed.

[Using distance comparison method to build pharmacophore model of epidermal growth factor receptor inhibitors].

OBJECTIVE: To build 3D-pharmacophore model of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors using distance comparisons method and design novel EGFR inhibitors. METHODS: Thirteen typical EGFR inhibitors were selected, and their biologically active conformations were obtained by using DOCK5.0 program, then 3D-pharmacophore model of EGFR inhibitors was built using distance comparisons method. RESULTS: Validation of the 3D-pharmacophore model was carried out and novel structures with potential inhibitory activity were selected by means of 3D-searching and docking method. CONCLUSION: This method can improve hit rate of lead compounds discovery and can be used to design novel EGFR inhibitors.

Microdialysis combined with liquid chromatography-tandem mass spectrometry for the determination of 6-aminobutylphthalide and its main metabolite in the brains of awake freely-moving rats.

6-Aminobutylphthalide (ABP) is a new drug candidate which is currently being developed for the treatment of cerebral ischemia. The pharmacokinetics and metabolism of ABP were studied using in situ microdialysis sampling in the brains of awake freely-moving rats. Two LC-MS/MS methods were used for the quantitative and qualitative analysis of microdialysate. For comparison and confirmation, brain tissue samples were also analyzed by LC-MS/MS and GC/MS. The results described provide more authentic information in pharmacokinetics and metabolism at the site of action by using the coupling of microdialysis to LC-MS/MS technique than the traditional sampling methods.

Discovery of 2-phenyl-3-sulfonylphenyl-indole derivatives as a new class of selective COX-2 inhibitors.

2-Sulfonylphenyl-3-phenyl-indole derivatives have been reported to be highly potent and selective COX-2 inhibitors previously. In this paper, the regio-isomeric analogues-2-phenyl-3-sulfonylphenyl-indoles were identified as potent and selective COX-2 inhibitors. This work led to the discovery of compounds 4a and 8a possessing higher activity than Celecoxib on cellular assay.

Synthesis and biological evaluation of substituted 2-sulfonyl-phenyl-3-phenyl-indoles: a new series of selective COX-2 inhibitors.

A new series of substituted 2-sulfonyphenyl-3-phenyl-indole derivatives were synthesized and evaluated for their ability to inhibit COX-2 and COX-1enzymes. Most of the compounds synthesized were found to be highly potent and selective inhibitors of COX-2. This work led to the discovery of 2-aminosulfonylphenyl-3-phenyl-indole 5a which possesses higher activity and selectivity for COX-2 than Celecoxib both in vitro and in vivo.

7-imidazolylalkanamido-1-carboxylalkylbenzo-diazepine, a novel series of farnesyltransferase inhibitors.

AIM: Design, synthesis and evaluation of a series of 7-imidazolylalkanamido-1-carboxylalkylbenzodiazepine farnesyltransferase (FTase) inhibitors. METHODS AND RESULTS: Coupling of imidazolylalkylcarboxylic acids and 1-substituted 7-aminobenzodiazepines (5a-5c) yielded 10 new compounds (6-12, 16-18) which were biologically tested against FTase using scintillation proximity assay method. CONCLUSION: Five target compounds were found to be potential farnesyltransferase inhibitors.

Partial synthesis of harringtonine.

The partial synthesis of harringtonine from cephaltotaxine has been described. A key intermediate, 5, 5-dimethyl-2-hydroxytetrahydrofuran-2-carboxylic acid (V), prepared from 4-methyl-1, 4-valerolactone, was dehydrated smoothly to give 5, 5-dihydrofuran-2-carboxylic acid (VI), Through its sodium salt, VI was converted into the corresponding acyl chloride VIII, which reacted with cephalotaxine in the presence of pyridine to give ester IX. After being treated with hydrichloric-acetic acid, ester IX unerwent Reformatsky reaction to give a mixture (XIV) of harringtonine and its diastereoisomer (epiharringtonine) as the final product which was purified either by countercurrent distribution or column chromatography on neutral alumina. The amounts of the two epimers in the mixture shown by TLC were roughly equal.