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It is a significant challenge to improve the blood-brain barrier (BBB) permeability of central nervous system (CNS) drugs in their development. Compared with traditional pharmacokinetic property tests, machine learning techniques have been proven to effectively and cost-effectively predict the BBB permeability of CNS drugs. In this study, we introduce a high-performance BBB permeability prediction model named balanced-stacking-learning based BBB permeability predictor(BSL-B3PP). Firstly, we screen out the feature set that has a strong influence on BBB permeability from the perspective of medicinal chemistry background and machine learning respectively, and summarize the BBB positive(BBB+) quantification intervals. Then, a combination of resampling algorithms and stacking learning(SL) algorithm is used for predicting the BBB permeability of CNS drugs. The BSL-B3PP model is constructed based on a large-scale BBB database (B3DB). Experimental validation shows an area under curve (AUC) of 97.8% and a Matthews correlation coefficient (MCC) of 85.5%. This model demonstrates promising BBB permeability prediction capability, particularly for drugs that cannot penetrate the BBB, which helps reduce CNS drug development costs and accelerate the CNS drug development process.
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Blood-Brain Barrier , Algorithms , Area Under Curve , Databases, Factual , PermeabilityABSTRACT
Objective· To explore association between blood-brain barrier (BBB) permeability and physical disability in patients with neuromyelitis optica spectrum disorders (NMOSD).Methods· Clinical data of 105 patients with NMOSD was retrospectively analyzed in Department of Neurology at Changhai Hospital,Second Military Medical University and Renji Hospital,Shanghai Jiao Tong University School of Medicine from June 2009 to June 2016.According to the difference between the expanded disability status scale (EDSS) scores when discharged from hospital and when admitted to hospital,NMOSD patients were divided into disability-reduction group and disability-exacerbation group,and their clinical characteristics were compared between the two groups,then association between BBB permeability and physical disability was analyzed.Results · Between the disabilityreduction group and the disability-exacerbation group,there was no significant difference in gender,age,disease duration,inducing factor,clinical symptoms,and medication (all P＞0.05),and the abnormal rates of thoracic spinal cord in clinical examination were statistically different (P=0.023).There was no significant difference in biochemical data between the two groups (P＞0.05),and a statistically significant difference was observed in the rate of cerebrospinal/serum albumin ratio (QALB) in the cerebrospinal fluid examination (P=0.042).The percentages of exacerbation of disability in the QALB normal and high groups were 27.60％ (16/58) and 46.80％ (22/47),respectively,and there was a statistically significant difference between the two groups (x2=4.150,P=0.042).BBB permeability was positively correlated with physical disability (r=0.299,P=0.042).Conclnsion · The higher the BBB permeability of NMOSD patients on admission is,the higher the degree of physical disability is.The difference in BBB permeability provides key clues to the investigation of the immunological mechanisms of physical disability in NMOSD patients.
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Objective: To explore association between blood-brain barrier (BBB) permeability and physical disability in patients with neuromyelitis optica spectrum disorders (NMOSD). Methods: Clinical data of 105 patients with NMOSD was retrospectively analyzed in Department of Neurology at Changhai Hospital, Second Military Medical University and Renji Hospital, Shanghai Jiao Tong University School of Medicine from June 2009 to June 2016. According to the difference between the expanded disability status scale (EDSS) scores when discharged from hospital and when admitted to hospital, NMOSD patients were divided into disability-reduction group and disability-exacerbation group, and their clinical characteristics were compared between the two groups, then association between BBB permeability and physical disability was analyzed. Results: Between the disabilityreduction group and the disability-exacerbation group, there was no significant difference in gender, age, disease duration, inducing factor, clinical symptoms, and medication (all P>0.05), and the abnormal rates of thoracic spinal cord in clinical examination were statistically different (P=0.023). There was no significant difference in biochemical data between the two groups (P>0.05), and a statistically significant difference was observed in the rate of cerebrospinal/serum albumin ratio (QALB) in the cerebrospinal fluid examination (P=0.042). The percentages of exacerbation of disability in the QALB normal and high groups were 27.60% (16/58) and 46.80% (22/47), respectively, and there was a statistically significant difference between the two groups (χ2=4.150, P=0.042). BBB permeability was positively correlated with physical disability (r=0.299, P=0.042). Conclusion: The higher the BBB permeability of NMOSD patients on admission is, the higher the degree of physical disability is. The difference in BBB permeability provides key clues to the investigation of the immunological mechanisms of physical disability in NMOSD patients.
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Objective To analysis the effects of Ang-(1-7) on the blood brain barrier permeability after subarachnoid hemor-rhage .Methods SAH-rats were produced by two times injection of blood into cisterna magna .Evans blue was used to detect the the permeability of SAH-rats brains and brain water content .RT-PCR and Western blot were performed to measure the expression of adhesion protein ICAM-1 and VCAM-1 in brains of SAH-rats .The artificial hemorrhagic cerebrospinal fluid (BCSF) was used to stimulate vascular endothelial cells (HBMEC) ,and the proliferation and apoptosis of HBMEC cell were analyzed .Results Ang-(1-7) reduced the content of Evans blue and brain water in brains of SAH-rats in dose and time dependent manner with the most sig-nificant change under the treatment of 10 - 5 mol/L Ang-(1-7) for 24 h (P< 0 .05) .Under the above condition ,the mRNA and pro-tein levels of ICAM-1 and VCAM-1 in brains of SAH-rats were significantly up-regulated (P< 0 .05) ,while the content of Evans blue in HBMEC cells stimulated by BCSF was obviously reduced .Besides ,Ang-(1-7) was observed to increase the expression of ICAM-1 and VCAM-1 in BCSF-stimulated HBMEC cells ,enhance the proliferation of HBMEC cells but reduce their apoptosis . Conclusion Ang-(1-7) plays a protective role in the blood-brain barrier damage induced by subarachnoid hemorrhage .
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Objective To investigate the effect of hand twelve Jing-Well points bloodletting on blood-brain barrier (BBB) permeability in the early stage of focal cerebral ischemic injury in rats with permanent middle cerebral artery occlusion (pMCAO). Method Male Wister rats were randomized into sham operation, model and bloodletting groups. A model of middle cerebral artery occlusion was made by Longa's method. 2%Evans blue (EB) was injected into the caudal vein at three time points:5, 24 and 72 hrs after model making. EB exudation amount was assessed by measurement of EB absorbance in brain tissue to observe BBB permeability. Result Cerebral EB exudation amount was significantly higher in the model group of rats than in the sham operation group (P<0.01) and significantly lower in the bloodletting group than in the model group (P<0.01). Conclusion Hand twelve Jing-Well points bloodletting can reduce blood-brain barrier permeability in pMCAO rats. Its effect is highly significant at 24 and 72 hrs after ischemia.
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OBJECTIVE@#To evaluate the protective effect of Lavandula officinalis (L. officinalis) extract against blood-brain barrier (BBB) permeability and its possible mechanisms in an experimental model of stroke.@*METHODS@#Focal cerebral ischemia was induced by the transient occlusion of the middle cerebral artery for 1 h in rats. Lavender extract (100, 200 mg/kg i.p.) was injected for 20 consecutive days. BBB permeability and oxidative stress biomarkers were evaluated using standard methods.@*RESULTS@#The results of this study showed that L. officinalis ethanolic extract significantly reduced the BBB permeability in experimental groups when compared with ischemia group. The lavender extract significantly reduced malondialdehyde levels of plasma and brain tissue in intact group when compared with control group.@*CONCLUSIONS@#L. officinalis extract reduced blood brain barrier permeability and alleviated neurological function in rats, and the mechanism may be related to augmentation in endogenous antioxidant defense and inhibition of oxidative stress in the rat brain.
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Objective: To evaluate the protective effect of Lavandula officinalis (L. officinalis) extract against blood-brain barrier (BBB) permeability and its possible mechanisms in an experimental model of stroke. Methods: Focal cerebral ischemia was induced by the transient occlusion of the middle cerebral artery for 1 h in rats. Lavender extract (100, 200 mg/kg i.p.) was injected for 20 consecutive days. BBB permeability and oxidative stress biomarkers were evaluated using standard methods. Results: The results of this study showed that L. officinalis ethanolic extract significantly reduced the BBB permeability in experimental groups when compared with ischemia group. The lavender extract significantly reduced malondialdehyde levels of plasma and brain tissue in intact group when compared with control group. Conclusions: L. officinalis extract reduced blood brain barrier permeability and alleviated neurological function in rats, and the mechanism may be related to augmentation in endogenous antioxidant defense and inhibition of oxidative stress in the rat brain.