iNGNN-DTI: prediction of drug-target interaction with interpretable nested graph neural network and pretrained molecule models.

MOTIVATION: Drug-target interaction (DTI) prediction aims to identify interactions between drugs and protein targets. Deep learning can automatically learn discriminative features from drug and protein target representations for DTI prediction, but challenges remain, making it an open question. Existing approaches encode drugs and targets into features using deep learning models, but they often lack explanations for underlying interactions. Moreover, limited labeled DTIs in the chemical space can hinder model generalization. RESULTS: We propose an interpretable nested graph neural network for DTI prediction (iNGNN-DTI) using pre-trained molecule and protein models. The analysis is conducted on graph data representing drugs and targets by using a specific type of nested graph neural network, in which the target graphs are created based on 3D structures using Alphafold2. This architecture is highly expressive in capturing substructures of the graph data. We use a cross-attention module to capture interaction information between the substructures of drugs and targets. To improve feature representations, we integrate features learned by models that are pre-trained on large unlabeled small molecule and protein datasets, respectively. We evaluate our model on three benchmark datasets, and it shows a consistent improvement on all baseline models in all datasets. We also run an experiment with previously unseen drugs or targets in the test set, and our model outperforms all of the baselines. Furthermore, the iNGNN-DTI can provide more insights into the interaction by visualizing the weights learned by the cross-attention module. AVAILABILITY AND IMPLEMENTATION: The source code of the algorithm is available at https://github.com/syan1992/iNGNN-DTI.

[Toxicokinetics of emodin-8-O-ß-D-glucoside in rats in vivo].

This study aims to establish an ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) method for the determination of emodin-8-O-ß-D-glucoside(EG) and its metabolites in plasma, and to investigate the toxicokinetics(TK) behavior of them in rats. To be specific, the TK of EG and its metabolites from the first to the last administration in the repeated dose toxicity study was determined, and the kinetic parameters were calculated. The exposure of EG prototype and metabolites in rat plasma after oral administration of different doses of EG was evaluated. The result showed that the prototype of EG and its metabolites aloe-emodin-8-O-ß-D-glucoside, emodin, aloe-emodin, and hydroxyemodin could be detected in rats after oral administration of high-, medium-, and low-dose EG. The area under the curve(AUC) of the prototype and metabolites after the first and last administration was in positive correlation with the dose. The time to the maximum concentration(T_(max)) of EG and metabolites in the three administration groups was <6 h, and the longest in vivo residence time was 12 h. The T_(max) and in vivo residence time of EG were prolonged with the increase in the dose. The metabolites emodin, aloe-emodin, and hydroxyemodin all had two peaks. Both hydroxyemodin and aloe-emodin exhibited increased plasma exposure, slow metabolism, and accumulation in vivo. In addition, aloe-emodin-8-O-ß-D-glucoside and emodin disappeared with the increase in dose, suggesting the change of the metabolic pathway of EG in vivo in the case of high-dose administration. The mechanism of high-dose EG in vivo needs to be further explored. This study preliminarily elucidates the TK behavior of EG in rats, which is expected to support clinical drug use.

Long noncoding RNA KTN1 antisense RNA 1exerts an oncogenic function in lung adenocarcinoma by regulating DEP domain containing 1 expression via activating epithelial-mesenchymal transition.

Long noncoding RNA (lncRNA) KTN1 antisense RNA 1 (KTN1-AS1) is a novel promoter in the progression of some cancers. However, the knowledge of its role in lung adenocarcinoma is still limited. The current study aimed to examine the biological functions of KTN1-AS1 and its coexpressed protein in lung adenocarcinoma. The RNA sequencing expression profiles from The Cancer Genome Atlas (TCGA) database were downloaded to evaluate the expression of KTN1-AS1 and its coexpressed protein, as well as assess their prognostic values. The correlation between DEP domain containing 1 (DEPDC1) and KTN1-AS1 levels was verified using Pearson's correlation coefficient. Real-time qPCR and western blot were adopted to determine the mRNA and protein levels of the corresponding molecules. Cell viability, invasiveness and motility were assayed by cell counting kit-8, clone formation and Transwell assays, appropriately. High levels of KTN1-AS1 were observed and led to a poorer prognosis in lung adenocarcinoma patients, according to the public dataset. DEPDC1 was found to be a downstream protein associated with KTN1-AS1. Moreover, DEPDC1 was also upregulated in lung adenocarcinoma tissues and can be seen as an independent prognosticator for patients with lung adenocarcinoma. Besides, DEPDC1 expression was positively correlated with KTN1-AS1 expression, which was verified by real-time qPCR and western blot. Functional experiments indicated that KTN1-AS1-knockdown inhibited cells proliferation, migration and invasion, whereas DEPDC1-overexpression could diminish this inhibition. Conversely, overexpression of KTN1-AS1 presented a promoting effect on these phenotypes, whereas silencing DEPDC1 could reduce these accelerations. Further evidence supported that KTN1-AS1/DEPDC1 plays the carcinogenic role by activating the epithelial-mesenchymal transition process and elevating MMP9 expression in lung adenocarcinoma cells. These data suggested that the KTN1-AS1/DEPDC1 axis may involve in the tumorigenesis in lung adenocarcinoma by activating the epithelial-mesenchymal transition process.

[Research progress on in vitro models of cardiomyocyte injury].

Cardiovascular diseases seriously endanger human health and life. The accompanying myocardial injury has been a focus of attention in society. Chinese medicine,serving as a natural and precious reservoir for the research and development of new drugs,is advantageous in resisting myocardial injury due to its multi-component,multi-pathway,and multi-target characteristics. In recent years,with the extensive application of culture method for isolated cardiomyocytes,a cost-effective,controllable in vitro model of cardiomyocyte injury with uniform samples is becoming a key tool for mechanism research on cardiomyocyte injury and drug development.A good in vitro model can reduce experimental and manpower cost,and also accurately stimulate clinical changes to reveal the mechanism. Therefore,the selection and establishment of in vitro model are crucial for the in-depth research. This study summarized the modeling principles,evaluation indicators,and application of more than ten models reflecting different clinical conditions,such as injuries induced by hypoxia-reoxygenation,hypertrophy,oxidative stress,inflammation,internal environmental disturbance,and toxicity. Furthermore,we analyzed advantages and technical difficulties,aiming to provide a reference for in-depth research on myocardial injury mechanism and drug development.

The J-protein AtDjB1 is required for mitochondrial complex I activity and regulates growth and development through ROS-mediated auxin signalling.

AtDjB1 is a mitochondria-located J-protein in Arabidopsis thaliana It is involved in the regulation of plant growth and development; however, the exact mechanisms remain to be determined. We performed comparison analyses of phenotypes, auxin signalling, redox status, mitochondrial structure and function using wild-type plants, AtDjB1 mutants, rescued AtDjB1 mutants by AtDjB1 or YUCCA2 (an auxin synthesis gene), and AtDjB1 overexpression plants. AtDjB1 mutants (atj1-1 or atj1-4) exhibited inhibition of growth and development and reductions in the level of IAA and the expression of YUCCA genes compared to wild-type plants. The introduction of AtDjB1 or YUCCA2 into atj1-1 largely rescued phenotypic defects and the IAA level, indicating that AtDjB1 probably regulates growth and development via auxin. Furthermore, atj1-1 plants displayed a significant reduction in amount/activity of mitochondrial complex I compared to wild-type plants; this resulted in the accumulation of reactive oxygen species (ROS). Moreover, exogenous H2O2 markedly inhibited the expression of YUCCA genes in wild-type plants. In contrast, the reducing agent ascorbate increased the expression of YUCCA genes and IAA level in atj1-1 plants, indicating that the low auxin level observed in atj1-1 was probably due to the high oxidation status. Overall, the data presented here suggest that AtDjB1 is required for mitochondrial complex I activity and regulates growth and development through ROS-mediated auxin signalling in Arabidopsis.

Immunological characterization and diagnostic models of RNA N6-methyladenosine regulators in Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia, and it displays both clinical and molecular variability. RNA N6-methyladenosine (m6A) regulators are involved in a wide range of essential cellular processes. In this study, we aimed to identify molecular signatures associated with m6A in Alzheimer's disease and use those signatures to develop a predictive model. We examined the expression patterns of m6A regulators and immune features in Alzheimer's disease using the GSE33000 dataset. We examined the immune cell infiltration and molecular groups based on m6A-related genes in 310 Alzheimer's disease samples. The WGCNA algorithm was utilized to determine differently expressed genes within each cluster. After evaluating the strengths and weaknesses of the random forest model, the support vector machine model, the generalized linear model, and eXtreme Gradient Boosting, the best machine model was selected. Methods such as nomograms, calibration curves, judgment curve analysis, and the use of independent data sets were used to verify the accuracy of the predictions made. Alzheimer's disease and non-disease Alzheimer's groups were compared to identify dysregulated m6A-related genes and activated immune responses. In Alzheimer's disease, two molecular clusters linked to m6A were identified. Immune infiltration analysis indicated substantial variation in protection between groups. Cluster 1 included processes like the Toll-like receptor signaling cascade, positive regulation of chromatin binding, and numerous malignancies; cluster 2 included processes like the cell cycle, mRNA transport, and ubiquitin-mediated proteolysis. With a lower residual and root mean square error and a larger area under the curve (AUC = 0.951), the Random forest machine model showed the greatest discriminative performance. The resulting random forest model was based on five genes, and it performed well (AUC = 0.894) on external validation datasets. Accuracy in predicting Alzheimer's disease subgroups was also shown by analyses of nomograms, calibration curves, and decision curves. In this research, we methodically outlined the tangled web of connections between m6A and AD and created a promising prediction model for gauging the correlation between m6A subtype risk and AD pathology.

The Impact of Rocuronium and Sugammadex on Length of Stay in Patients Undergoing Open Spine Surgery: A Propensity Score-Matched Analysis.

Enhanced Recovery After Surgery (ERAS), an all-encompassing perioperative care approach, has been demonstrated to enhance surgical results, mitigate postoperative issues, and decrease the length of hospital stay (LOS) in diverse surgical specialties. In this retrospective study, our objective was to examine the influence of muscle relaxant selection on LOS and perioperative results in adult patients undergoing open spine surgery. Specifically, we compared 201 patients who received cisatracurium and neostigmine with 201 patients who received rocuronium and sugammadex, after 1:1 propensity score matching. The utilization of the rocuronium and sugammadex combination in anesthesia for open spinal surgery did not lead to a reduction in the LOS but was associated with a decreased incidence of postoperative chest radiographic abnormalities, including infiltration, consolidation, atelectasis, or pneumonia (p = 0.027). In our secondary analysis, multivariate analysis revealed multiple determinants influencing the prolonged LOS (>7 days) during open spine surgery. Bispectral index-guided anesthesia emerged as a protective factor, while variables such as excessive intraoperative blood loss and fluid administration as well as postoperative chest radiographic abnormalities independently contributed to prolonged LOS.

Postoperative Vomiting Following Laparoscopic Cholecystectomy Is Associated with Intraoperative Fluid Administration: A Retrospective Cohort Study.

Potential risk factors for postoperative vomiting (POV) are important for daily anesthesia practice. To identify the risk factors associated with POV we retrospectively reviewed 553 adult patients who underwent scheduled simple laparoscopic cholecystectomy under sevoflurane-based general anesthesia between January and December 2018. Patients who experienced POV were predominantly women, had lower body weight, and higher ASA (American Society of Anesthesiologists) physical status. The POV group showed female sex predominance, lower body weight, and higher ASA physical status, with a significant difference when compared with the non-POV group. In univariate analysis, female sex and Apfel scores of 2, 3, and 4 were associated with a higher POV incidence. Age > 70 years, higher body weight, and ASA physical status III were associated with a lower POV incidence. In multivariate logistic regression, sex, age, Apfel score, and intraoperative crystalloid infusion rate were POV predictive factors. Receiver operating characteristic analysis showed a negative association between the intraoperative crystalloid infusion rate and POV occurrence with an area under the curve of 0.73 (p = 0.001). The cutoff intraoperative crystalloid infusion rate was 2 mL/kg/h with 82% sensitivity and 49% specificity (≥2 mL/kg/h was associated with a lower POV incidence vs. <2 mL/kg/h (OR, 95% CI; 0.52 [0.33-0.83])). To decrease POV in these patients, identifying high-risk factors and an intraoperative crystalloid administration of ≥2 mL/kg/h should be considered in patients undergoing LC under sevoflurane-based general anesthesia.

[Efficacy and mechanism of fire needling bloodletting for lower extremity varicose veins].

OBJECTIVE: To compare the clinical effect of lower extremity varicose veins between fire needling bloodletting and operation, and to explore the possible mechanism. METHODS: A total of 60 patients were randomized into an observation group and a control group, 30 cases in each one. In the control group，the operation was adopted. The fire needling bloodletting was applied in the observation group, twice a week for 4 weeks. Before and after treatment, the venous clinical severity score (VCSS) and venous disability score (VDS) were recorded, the hemorheological indexes [blood viscosity, plasma viscosity, hematocrit, fibrinogen and erythrocyte sedimentation rate (ESR)], immune inflammatory response indexes[serum C-reactive protein (CRP), tumor necrosis factor-α(TNF-α) and interleukin-6 (IL-6)], vascular endothelial cell function indexes [the number of circulatingendothelial cell (CEC), plasma endothelin (ET-1) and NO)] and apoptosis indexes (Bcl-2, Bax and Caspase-3) were detected in the two groups. RESULTS: Compared before treatment, the scores of VCSS and VDS, hemorheological indexes, immune inflammatory response indexes and levels of plasma NO after treatment were reduced in the two groups (P<0.05). The level of serum Bax after treatment was reduced in the observation group (P<0.05). The number of CEC and levels of plasma ET-1 after treatment were increased in the two groups (P<0.05). The levels of serum Bcl-2 and Caspase-3 after treatment were increased in the observation group (P<0.05). In the observation group, the scores of VCSS and VDS, hemorheological indexes，immune inflammatory response indexes, vascular endothelial cell function indexes and level of serum Bax after treatment were lower than the control group (P<0.05), and the levels of Bcl-2 and Caspase-3 were higher than the control group (P<0.05). CONCLUSION: Fire needling bloodletting could effectively treat lower extremity varicose veins, and the mechanism may be related to the improvement of hemorheology, downregulation of immune inflammatory response, improvement of vascular endothelial cell function and inhibition of apoptosis.

Design, synthesis and biological evaluation of non-secosteriodal vitamin D receptor ligand bearing double side chain for the treatment of chronic pancreatitis.

Chronic pancreatitis (CP) is a serious disease that characterized by the progressive replacement of functional pancreas tissue by fibrotic tissue. Vitamin D receptor (VDR) plays a critical role in the development of CP, since it inhibits excessive deposition of extracellular matrix (ECM) in activated pancreatic stellate cells (PSCs). Herein, a novel series of non-secosteriodal VDR ligands were designed and synthesized, and their VDR affinity and anti-fibrosis activity were evaluated. The identification of the potent compound 9c was found over structural optimization, which inhibited ECM deposition and fibrotic gene expression in the western blot and qPCR assays, respectively. Further investigation revealed that compound 9c inhibited pancreatic fibrosis in vivo without increase on serum calcium, which could cause hypercalcemia. These results provide novel insight in possible drug discovery for the treatment of CP using non-secosteroidal VDR modulators.

Sulfonyl-containing phenyl-pyrrolyl pentane analogues: Novel non-secosteroidal vitamin D receptor modulators with favorable physicochemical properties, pharmacokinetic properties and anti-tumor activity.

Modulating the vitamin D receptor (VDR) is an effective way to treat for cancer. We previously reported a potent non-secosteroidal VDR modulator (sw-22) with modest anti-tumor activity, which could be due to its undesirable physicochemical and pharmacokinetic properties. In this study, we investigated the structure-activity and structure-property relationships around the 2'-hydroxyl group of sw-22 to improve the physicochemical properties, pharmacokinetic properties and anti-tumor activity. Compounds 19a and 27b, the potent non-secosteroidal VDR modulators, were identified as the most effective molecules in inhibiting the proliferation of three cancer cell lines, particularly breast cancer cells, with a low IC50 via the distribution of cell cycle and induction of apoptosis by stimulating the expression of p21, p27 and Bax. Further investigation revealed that 19a and 27b possessed favorable rat microsomal metabolic stability (2.22 and 2.3 times, respectively, more stable than sw-22), solubility (43.9 and 50.2 times, respectively, more soluble than sw-22) and in vivo pharmacokinetic properties. In addition, 19a and 27b showed excellent in vivo anti-tumor activity without cause hypercalcemia, which is the main side effect of marketed VDR modulators. In summary, the favorable physicochemical properties, pharmacokinetic properties and anti-tumor activity of 19a and 27b highlight their potential therapeutic applications in cancer treatment.

Effect of different anesthetic methods on cellular immune functioning and the prognosis of patients with ovarian cancer undergoing oophorectomy.

The present study aimed to explore the effects of different anesthetic methods on cellular immune function and prognosis of patients with ovarian cancer (OC) undergoing oophorectomy. A total of 167 patients who received general anesthesia (GA) treatment (GA group) and 154 patients who received combined general/epidural anesthesia (GEA) treatment (GEA group) were collected retrospectively. Each group selected 124 patients that met the inclusion and exclusion criteria for further study. ELISA and radioimmunoassay were employed to detect levels of IL-2, TNF-α, and CA-125. The rates of tumor-red cell rosette (RTRR), red cell immune complex rosette (RRICR), and red cell C3b receptor rosette (RRCR) were also measured. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were determined by hemodynamics. The levels of tumor necrosis factor-α (TNF-α) and interleukin (IL)-2 decreased at 1 h intraoperation (T2), but increased 24-h post surgery (T3). The levels of TNF-α and IL-2 were recovered faster in the GEA group than in the GA group. The GA group exhibited greater levels of CA-125 expression than in the GEA group. The levels of RTRR, RRICR, and RRCR; ratios of CD3+, CD4+, CD4+/CD8+, CD16+, and CD56+ at 30 min after anesthesia (T1), T2, T3 and 48 h after the operation (T4) and levels of SBP, DBP, and HR at T1, T2, and T3 displayed increased levels in the GEA group than in the GA group. At 72-h post surgery (T5), the 5-year survival rate significantly increased in the GEA group compared with the GA group. GEA to be more suitable than GA for surgery on OC patients.

[Test-retest reliability of Mandarin monosyllable lists: a multi-center study in Chinese dialectal regions].

OBJECTIVE: To develop 22 Chinese Mandarin monosyllable lists with good psychometrical equivalence. This study was to evaluate the test-retest reliability of these lists when it was used in speech recognition test in normal hearing dialectal speakers. METHODS: Seven cities including Dalian, Shanghai, Hangzhou, Wuhan, Guangzhou, Fuzhou and Xiamen were selected as testing centers which contain 6 typical Chinese dialectal regions including north of China, East of China, north of Fujian, south of Fujian, Guangdong and mid-south of China. At each center, 22 local normal hearing people were selected to join this study. Every participant was tested by each recognition test of all 22 lists twice in two sessions and same test order respectively. The second run of testing was carried out within 10 days-1 month since first run of testing. RESULTS: There was a significant correlations between scores obtained at the two sessions (r = 0.682, P < 0.01). Paired student-t test had shown that a gross score of all dialectal participants was significantly higher than that of initial test to retest (P < 0.01). The mean increment of score was (2.7 +/- 10.1)%. A significant difference of test-retest score in 7 sites was 19.8% and it was equal to 5 test items. A one way ANOVA analysis had indicated that there were statistically significant difference between the score improvement of 7 test sites (P < 0.01). Another analysis had shown that there was no significant correlation between test-retest score improvement and intra-session intervals (P = 0.947). CONCLUSIONS: Mandarin monosyllabic recognition test seems to be more stable, and the present study has indicated a systematic differences in Chinese Mandarin monosyllable recognition scores between test and retest. Monosyllable recognition test is not susceptible to memory effect. Pearson's correction analysis is not suitable to evaluation for test-retest reliability.