Accurate prediction of drug-target interactions (DTIs) plays a pivotal role in drug discovery, facilitating optimization of lead compounds, drug repurposing and elucidation of drug side effects. However, traditional DTI prediction methods are often limited by incomplete biological data and insufficient representation of protein features. In this study, we proposed KG-CNNDTI, a novel knowledge graph-enhanced framework for DTI prediction, which integrates heterogeneous biological information to improve model generalizability and predictive performance. The proposed model utilized protein embeddings derived from a biomedical knowledge graph via the Node2Vec algorithm, which were further enriched with contextualized sequence representations obtained from ProteinBERT. For compound representation, multiple molecular fingerprint schemes alongside the Uni-Mol pre-trained model were evaluated. The fused representations served as inputs to both classical machine learning models and a convolutional neural network-based predictor. Experimental evaluations across benchmark datasets demonstrated that KG-CNNDTI achieved superior performance compared to state-of-the-art methods, particularly in terms of Precision, Recall, F1-Score and area under the precision-recall curve (AUPR). Ablation analysis highlighted the substantial contribution of knowledge graph-derived features. Moreover, KG-CNNDTI was employed for virtual screening of natural products against Alzheimer's disease, resulting in 40 candidate compounds. 5 were supported by literature evidence, among which 3 were further validated in vitro assays.
Alzheimer Disease/drug therapy* ; Biological Products/therapeutic use* ; Humans ; Neural Networks, Computer ; Machine Learning ; Drug Discovery/methods* ; Algorithms ; Drug Evaluation, Preclinical/methods*

AIM:This study aimed to confirm the glycolytic inhibitory activity of 3-bromopyruvic acid(3BP)and to assess whether this inhibition could ameliorate hypoxia-induced pulmonary hypertension in rats.METHODS:PAH model rats were generated from normal SD rats via exposure to normal pressure and hypoxia.Intervention groups I and II(6 rats per group)were then intraperitoneally injected with 3BP(15 mg/kg),and the normal and hypoxia groups(6 rats per group)were given the same amount of normal saline for a total of 21 d.The average pulmonary artery pressure of the rats in each group was measured via right heart catheterisation,and hilar tissue measurements.The right ventricle(RV),left ventricle,and interventricular septum(LV+S)were weighed,and the ratio of RV/(LV+S)was calculated as an index of right ventricular hypertrophy.Right lower lung tissues were fixed in 4%paraformaldehyde-PBS buffer,sec-tioned in conventional paraffin(5 μm thick),stained with HE and Masson,photographed under a microscope.Then the thickness ratio of the tunica media and the area ratio of collagen fibres were calculated.The expression of pyruvate kinase isozyme type M2(PKM2),nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),and pyruvate de-hydrogenase(PDH)proteins in the hilar tissues of each group were detected by western blot,whereas interleukin-1β(IL-1β)and IL-18 contents were detected using ELISA,and lactic acid content was detected using a lactic acid kit.RE-SULTS:The results showed that 3-brpa effectively inhibited glycolysis and significantly improved hypoxia-induced pulmo-nary hypertension in rats.Compared with the hypoxia group,in intervention group II,PKM2 expression was decreased(P<0.05),PDH expression increased significantly(P<0.01),and NLRP3 expression was decreased(P<0.05).The IL-18 and IL-1β contents decreased(P<0.05 or P<0.01,respectively).Pulmonary hemodynamic indexes showed that the pro-portion of the right ventricle and the mean pressure of the pulmonary artery decreased(P<0.05 or P<0.01,respectively).The HE and Masson staining results showed that the thickness ratio of the tunica media and the area ratio of collagen fibres decreased significantly(P<0.01).Lactic acid content was significantly decreased(P<0.01).CONCLUSION:This study showed that 3BP can inhibit glycolysis and alleviate hypoxia-induced pulmonary hypertension in rats.

AIM:This study aimed to confirm the glycolytic inhibitory activity of 3-bromopyruvic acid(3BP)and to assess whether this inhibition could ameliorate hypoxia-induced pulmonary hypertension in rats.METHODS:PAH model rats were generated from normal SD rats via exposure to normal pressure and hypoxia.Intervention groups I and II(6 rats per group)were then intraperitoneally injected with 3BP(15 mg/kg),and the normal and hypoxia groups(6 rats per group)were given the same amount of normal saline for a total of 21 d.The average pulmonary artery pressure of the rats in each group was measured via right heart catheterisation,and hilar tissue measurements.The right ventricle(RV),left ventricle,and interventricular septum(LV+S)were weighed,and the ratio of RV/(LV+S)was calculated as an index of right ventricular hypertrophy.Right lower lung tissues were fixed in 4%paraformaldehyde-PBS buffer,sec-tioned in conventional paraffin(5 μm thick),stained with HE and Masson,photographed under a microscope.Then the thickness ratio of the tunica media and the area ratio of collagen fibres were calculated.The expression of pyruvate kinase isozyme type M2(PKM2),nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),and pyruvate de-hydrogenase(PDH)proteins in the hilar tissues of each group were detected by western blot,whereas interleukin-1β(IL-1β)and IL-18 contents were detected using ELISA,and lactic acid content was detected using a lactic acid kit.RE-SULTS:The results showed that 3-brpa effectively inhibited glycolysis and significantly improved hypoxia-induced pulmo-nary hypertension in rats.Compared with the hypoxia group,in intervention group II,PKM2 expression was decreased(P<0.05),PDH expression increased significantly(P<0.01),and NLRP3 expression was decreased(P<0.05).The IL-18 and IL-1β contents decreased(P<0.05 or P<0.01,respectively).Pulmonary hemodynamic indexes showed that the pro-portion of the right ventricle and the mean pressure of the pulmonary artery decreased(P<0.05 or P<0.01,respectively).The HE and Masson staining results showed that the thickness ratio of the tunica media and the area ratio of collagen fibres decreased significantly(P<0.01).Lactic acid content was significantly decreased(P<0.01).CONCLUSION:This study showed that 3BP can inhibit glycolysis and alleviate hypoxia-induced pulmonary hypertension in rats.

Objectives To analyze the spatial and temporal aggregation of multidrug resistant pulmonary tuberculosis (MDR-TB) incidence in Nanning at the township / street scale from 2017 to 2021, to explore the spatial and temporal characteristics of the spread of MDR-TB in Nanning, and to provide a scientific reference basis for the health administrative departments to achieve the precise implementation of MDR-TB prevention and control. Methods Based on the data of MDR-TB cases in Nanning from 2017 to 2021, the spatial-temporal scanning analysis software SaTScan v9.7 was used to retrospectively detect and analyze the areas where MDR-TB cases gathered. Results Through simple spatial scanning analysis, it was found that there were three first-class aggregation areas (the aggregation center was Fujiayuan Street, Jiangnan District, 2017, Xinyang Street, Xixiangtang District, 2019, and Zhonghe Town, Yongning District, 2020), and one second-class aggregation area (the aggregation center was Jinchai Town, Mashan County, 2020). Simple time scanning showed that the clustering occurred from May 2019 to December 2020. Temporal and spatial aggregation analysis showed that Xinyang Street in Xixiangtang District was the center of the first-class aggregation area, Zhonghe Town in Yongning District was the center of the second-class aggregation area, and Jinchai Town in Mashan County was the center of the third-class aggregation area. Conclusion The multidrug resistant pulmonary tuberculosis epidemic in Nanning is distributed in an aggregated manner, especially in Xinyang Street, Xixiangtang District, which has the highest spatial and temporal aggregation. It is necessary to focus on and take regional prevention and control measures to control the epidemic.

Objective To investigate the influence of one kind of defective gene NOTCH3 (R90C) of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in proliferation of oligodendrocyte lineage cells HS683 and their related molecular mechanism.Methods (1) A pCMV-Sport6.0 was chosen as the expression vector and site-directed mutation was used to construct the mutant NOTCH3 (p.R90C) expression vector;eukaryotic cell transfection technique was used to respectively transfect the pCMV-Sport6.0 empty vector,wild NOTCH3 vector (p.NOTCH3) and mutant NOTCH3 (p.R90C) expression vector to HS683 cells (blank control vector group,wild NOTCH3 vector group,and mutant NOTCH3 vector group);the protein expressions of NOTCH3,p53,phosphorylated p53 and p21 were detected by Westem blotting.(2) Wild NOTCH3 vector group,mutant NOTCH3 vector group and mutant NOTCH3 vector+pifithrin-α group were divided,and after wild NOTCH3 vector (p.NOTCH3) and mutant NOTCH3 (p.R90C) vector transfection,the latter two groups were added 0 or 1 μmol/L pifithrin-α,respectively;CCK-8 assay was employed to test the proliferation oftransfected HS683 cells 24,48 and 72,and 96 h after transfection.Results (1) As compared with wild NOTCH3 vector group,mutant NOTCH3 vector group had significantly lower absorbance value 24,48 and 72 h after transfection (P＜0.05);72 h after transfection,wild NOTCH3 vector group and mutant NOTCH3 vector group had significantly higher NOTCH3 protein expression as compared with blank control vector group (P＜0.05),and mutant NOTCH3 vector group had significantly higher p53,phosphorylated-p53 and p21 protein expressions as compared with wild NOTCH3 vector group and blank control vector group (P＜0.05).(2) The absorbance value in the mutant NOTCH3 vector+pifithrin-α group was significantly increased as compared with that in the mutant NOTCH3 vector group 48,72 and 96 h after transfection (P＜0.05).Conclusion Mutation of NOTCH3 (R90C) may inhibit the proliferation of oligodendrocyte cell lineage via p53 dependent way,which might play a direct role in demyelination pathology of CADASIL caused by NOTCH3(R90C).

AIM: To investigate effects of different therapeutic methods and typical recipes on activation of ERK1/2 in Kupffer cells of rats with fatty liver.METHODS: The rat model of fatty liver was established by feeding high fat diet combinated with distillate spirit.Meanwhile Chinese medicines Shugan fang,Jianpi fang,Huoxue fang,Qushi fang,and Zonghe fang were given to treat different groups respectively.12 weeks later,the Kupffer cells were isolated from livers of control group,model group and different treatment groups by sequential in situ perfusion with collagenaseⅣ and pronase E,density gradient centrifugation,selective adherence.The expression of total ERK1/2 and phospho-ERK1/2 in Kupffer cells of control group,model group and different treatment groups were detected by Western blotting.RESULTS: The expressions of total ERK1/2 and phospho-ERK1/2 were higher in Kupffer cells from model group than those in control group(P