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OBJECTIVE To find a promising candidate for anti- Alzheimer disease (AD) with multiple targets in multiple pathways. METHODS A series of classifiers were constructed for predicting the active compounds against 51 key targets toward Alzheimer disease (AD) using the multitarget-quantitative structure- activity relationships (mt- QSAR) method. While drug screening assays were established to evaluate the predicted active molecules. In addition, various cellular models and animal models related with AD were set up to further study the effects of the active compounds. RESULTS A system for the discovery of Multitarget-Directed Ligands against AD was set up and applied, the predicted active compounds were validated by the drug screening assays, and several active compounds with multiple targets were discovered. Among them, DL0410 exerted high activity on H3R, α7nAChR, AChE and ERα, also displayed the most significant effect in improving the ability of memory and learning in several AD animal models. The study on its action mechanisms showed that it's effect may partially through increasing neurotransmitter, inhibiting oxidative emergency, inhibiting the expression of APP, and promoting long- term potentiation. Besides, DL0410 is of more safety than the first- line clinical medicines. CONCLUSION DL0410 is a promising candidate for further development for AD treatment.
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OBJECTIVE To investigate the anti- tremor effect and mechanism of baicalein on oxotremorine- induced muscle tremor in mice. METHODS The acute model of muscular tremor was induced by intraperitoneal injection of oxotremorine, and the latency, duration and frequency of muscle tremor in mice were measured immediately; the saliva of mice was measured to reflect the correlation between tremor and peripheral nerve function; the aim of this study was to determine the content of MDA and the activity of GSH-PX, and to investigate the anti-oxidation of mice with tremor model. The activity of acetylcholinesterase (AchE) and acetylcholine transferase (ChAT) can indirectly reflect the level of acetylcholine in the brain. The level of monoamine neurotransmitters in brain tissue was determined by high performance liquid chromatography (HPLC-ECD). RESULTS The animals in the model group appeared obvious tremoring, salivating and erecting and other symptoms. Compared to the model group, there was no obvious inhibitory effect on the administration of each dose. After 7, 14, 21 and 28 d of continuous administration, the latency, duration and tremor frequency of tremor mice were significantly shortened, the levels of acetylcholine were significantly decreased, the changes of DOPAC and DA neurotransmitters in the brain of model group were recovered, regulate the dynamic balance of acetylcholine and dopamine in the brain. CONCLUSION Long- term administration can improve the tremor behavior of mice, the mechanismmay be related to the regulation of neurotransmittersin brain.
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OBJECTIVE Diabetic nephropathy (DN) has been one of the most common complications of diabetes and the leading cause of end-stage renal disease. Glomerular hyperfiltrationis central in earlystage of DN and leads to the progression of renal architectonic and functional abnormalities. Salvi?anolic acid A (SalA) has been proved to protect diabetic complications such as hepatic fibrosis and neuropathy. The present study was designed to investigate the effects of SalAon glomerular endothelial dysfunctionand diabetic nephropathy. METHODS Primary glomerular endothelial cells were subjected to assess permeability under injury of advanced glycation end-products (AGEs). AGEs-induced changes of RhoA/ROCK pathway and cytoskeleton rearrangement were assessed bywestern blotandimmunoflu?orescence. The beneficial effects of SalA on diabetic nephropathy were investigated in a rat model induced by high-fat and high-glucose diet combined with low dose of streptozocin (35 mg·kg- 1, ip). Renal function and architectonic changes were evaluated by biochemical assay and PAS staining. RESULTS SalA 3μMameliorated AGEs- induced glomerular endothelial permeability (P<0.05) and suppressed rearrangement of cytoskeleton through inhibiting AGE-RAGE-RhoA/ROCK pathway. SalA 1 mg · kg- 1 markedly reduced endothelium loss (P<0.01) and glomerular hyperfiltration (P<0.05) in diabetic kidney. Subsequently,SalA 1 mg·kg-1 suppressed glomerular hypertrophy and mesangial matrix expansion, eventually reduced 24 h-urinary albumin and ameliorated renal function by decreasing blood urine nitrogen (BUN), serum creatinine (Scr) and serum n-acetyl-β-d-glucosaminidase (NAG). AGEs-RAGE-Nox4-induced oxidative stress was suppressed by the treatment of SalA 1 mg·kg-1. CONCLUSION SalA ameliorated AGEs-induced glomerular endothelial hyperpermeability, and effec?tively protected against early-stage diabetic nephropathy by reducing hyperfiltration and alleviating renal structural deterioration through inhibiting AGEs and its downstream pathway. Thus, SalA might be a promising therapeutic agent for the treatment of diabetic nephropathy.
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OBJECTIVE To evaluate the effect of Guizhi Fuling Capsule active pharmaceutical ingredient (API) and its fractions on human breast cancer cells proliferation by high-throughput screening assay. METHODS The crude fractions were obtained from the extraction and elution of the API of Guizhi Fuling Capsule, and 929 standard fractions were obtained by the optimal separation conditions. Sulforhodamine B (SRB) method was used to evaluate the effects of the Guizhi Fuling capsule API and 929 kinds of fractions on the proliferation of human breast cancer cells MCF- 7 and MDA- MB- 231. RESULTS The Guizhi Fuling capsule API had a strong ability to inhibit the proliferation of MCF-7 cells at high concentration and the ability to inhibit MDA-MB-231 cells' proliferate at low concentration follow?ing 72 h treatment;some samples of 929 fractions (5 μg·mL-1) was found to have a breast cancer cell growth inhibition rate above 50%, without toxicity on HUVECs proliferation. CONCLUSION The API of Guizhi Fuling capsule had significant cytotoxicity effects on these two human breast cancer cells, with significant concentration- and time-dependent manner.