Advancements in artificial intelligence (AI) and emerging technologies are rapidly expanding the exploration of chemical space, facilitating innovative drug discovery. However, the transformation of novel compounds into safe and effective drugs remains a lengthy, high-risk, and costly process. Comprehensive early-stage evaluation is essential for reducing costs and improving the success rate of drug development. Despite this need, no comprehensive tool currently supports systematic evaluation and efficient screening. Here, we present druglikeFilter, a deep learning-based framework designed to assess drug-likeness across four critical dimensions: 1) physicochemical rule evaluated by systematic determination, 2) toxicity alert investigated from multiple perspectives, 3) binding affinity measured by dual-path analysis, and 4) compound synthesizability assessed by retro-route prediction. By enabling automated, multidimensional filtering of compound libraries, druglikeFilter not only streamlines the drug development process but also plays a crucial role in advancing research efforts towards viable drug candidates, which can be freely accessed at https://idrblab.org/drugfilter/.

Drug development encompasses multiple processes, wherein protein subcellular localization is essential. It promotes target identification, treatment development, and the design of drug delivery systems. In this research, a deep learning framework called LocPro is presented for predicting protein subcellular localization. Specifically, LocPro is unique in (a) combining protein representations from the pre-trained large language model (LLM) ESM2 and the expert-driven tool PROFEAT, (b) implementing a hybrid deep neural network architecture that integrates convolutional neural network (CNN), fully connected (FC) layer, and bidirectional long short-term memory (BiLSTM) blocks, and (c) developing a multi-label framework for predicting protein subcellular localization at multiple granularity levels. Additionally, a dataset was curated and divided using a homology-based strategy for training and validation. Comparative analyses show that LocPro outperforms existing methods in sequence-based multi-label protein subcellular localization prediction. The practical utility of this framework is further demonstrated through case studies on drug target subcellular localization. All in all, LocPro serves as a valuable complement to existing protein localization prediction tools. The web server is freely accessible at https://idrblab.org/LocPro/.

Objective: To investigate the effect of G protein-coupled receptor 108(GPR108) gene knockout on systemic inflammation in lipopolysaccharide(LPS)-induced sepsis mice. Methods: Male C57BL/6 mice and GPR108 gene knockout mice were randomly divided into 4 groups: WT group, WT-LPS group, KO group, KO-LPS group. The physiological characteristics of mice in different groups were observed, and the morphological changes of liver and lung tissues were observed. Macrophages were extracted from bone marrow and subjected to flow cytometry to detect their M1 polarization status. The expression levels of IL-6 in liver and lung tissues, macrophages, and serum were also measured. Results: KO-LPS group mice showed significant liver and lung tissue damage, with a significantly greater number of bone marrow-derived macrophages polarizing towards M1 in the KO-LPS group compared to the WT-LPS group. Additionally, at the tissue, cellular, and serum levels, the expression of IL-6 in the KO-LPS group mice was significantly higher than that in the WT-LPS group mice(P<0.05). Conclusion During the systemic inflammatory infection induced by LPS in mice, the lack of GPR108 exacerbates the systemic inflammatory response. GPR108 has an inhibitory effect on the inflammatory response in mice with LPS-induced sepsis.

Objective: To establish a Tohoku hospital pediatrics-1 (THP-1) cell line with G protein-coupled recep- tor108 ( GPR108) deletion and explore its functions． Methods: According to the requirements of the clustered regularly interspaced short palindromic repeats ( CRISPR) / CRISPR-associated protein 9 ( Cas9 ) system ，two single guide RNAs (sgRNA1 and sgRNA2) paring to the flanking fragments of human GPR108 gene were designed and synthesized．The two oligonucleotides were inserted in the pL-CRISPR. EFS．GFP vector to generate the new recombinant vectors ( pL-CRISPR. EFS．GFP-sgRNA1 and pL-CRISPR. EFS．GFP-sgRNA2 ) ．The recombinant vectors and packaging plasmids (pMD2. G and psPAX2) ，were co-transfected into 293T cells to generate virus for infecting THP-1 cells．The GFP + cells were screened and isolated in 96-well culture plates by flow cytometry to obtain single-cell clones．PCR and Western blot were used to detect whether GPR108 was successfully knocked out in THP- 1 cells．Both GPR108 + / + and GPR108 －/ － THP-1 cells were treated with lipopolysaccharide (LPS) ．Interleukin 8 (IL-8) derived from the THP-1 cells，which were treated by LPS，was detected with Western blot and cytometric bead array ( CBA) analysis. Results: The recombinant lentiviral vector pL-CRISPR. EFS．GFP-sgRNA was successfully constructed and single-cell clone F9 was obtained by flow cytometric sorting after transfection of THP-1 cells．PCR and Western blot both confirmed that F9 was a GPR108 －/ － THP-1 single-cell clone． LPS stimulated GPR108 －/ － and GPR108 + / + THP-1 cells，both Western blot and CBA results showed a significant decrease in IL- 8 synthesis and secretion in GPR108 －/ － THP-1 cells． Conclusion The GPR108 －/ － THP-1 cell clone is success- fully obtained based on the CRISPR / Cas9 system．GPR108 deletion in THP-1 cells treated by LPS leads to a decrease of IL-8 expression and secretion．It lays the foundation for further research on the molecular mechanisms of GPR108 in the immune inflammatory response.

Objective:To compare the effect of local vibration and extracorporeal shock wave therapy (ESWT) on triceps spasticity and the walking ability of hemiplegic stroke survivors.Methods:Sixty-nine stroke survivors with hemiplegia were randomly divided into a control group, a vibration group and an ESWT group. The control group received 60 minutes of conventional Bobath rehabilitation treatment and motor relearning from Monday to Saturday for 4 weeks. For the vibration and ESWT groups, 10 minutes of that traditional therapy were replaced by either local vibration or extracorporeal shock wave treatment every Tuesday, Wednesday and Saturday. Before and after the treatment, the three groups were evaluated using the Comprehensive Spasticity Scale (CSS) and in terms of passive joint range of motion (PROM), ankle plantar flexion angle, 10m maximum walking speed, stride frequency, and stride length.Results:After the intervention the average CSS, PROM, and ankle plantar flexion angle were significantly better for all three groups than before the treatment. At that point the ESWT group′s averages were significantly better than those of the vibration group, and the vibration group′s averages were significantly superior to those of the control group. Walking speed, stride frequency and stride length had also improved significantly in all three groups, with those in the vibration and ESWT groups significantly outperforming the control group. There was no significant difference between the vibration and ESWT groups in terms of walking ability.Conclusions:Both local vibration and extracorporeal shock wave therapy improve triceps spasticity and the walking ability of hemiplegic stroke survivors. Shock waves are more effective for improving spasticity, but there is no significant difference between the therapies in terms of improving walking ability.

Objective:To investigate the expression and significance of human ether-a-go-go related gene (HERG) protein in interstitial cells of Cajal (ICC) in patients with gallbladder stones.Methods:The gallbladder tissues of 60 patients with gallbladder diseases who underwent cholecystectomy from January 2018 to December 2020 in the Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital were collected, including 36 males and 24 females, aged (46.0±14.0) years. They were divided into two groups according to whether there were gallstones: gallstone group and control group (patients with gallbladder polyps and gallbladder adenomyosis), with 30 cases in each group. Color ultrasound was used to detect and calculate the gallbladder contraction rate. The neck, body and bottom tissues of the gallbladder were excised and sectioned. The expression of HERG protein and CD117 ( marker of ICC) was detected by immunofluorescence staining, immunohistochemistry and Western blot.Results:The gallbladder contraction rate in the gallstone group was (65.8±4.1)%, lower than that in the control group (73.8±5.3)%, with a statistically significant difference ( t=4.14, P<0.001). Immunohistochemistry showed that HERG protein was mainly distributed in the mucosal layer of gallbladder tissue, which was pale brown. The relative expression of HERG protein at the bottom of gallbladder in the gallstone group was (0.293±0.102), lower than that in the control group (0.694±0.059), with a statistically significant difference ( t=3.38, P=0.027). Immunofluorescence staining showed that HERG protein was mainly distributed in ICC of gallbladder epithelium. HERG protein expression in ICC at the bottom of gallbladder in gallstone group was lower than that in control group, while HERG protein expression at the neck and body of gallbladder had no significant difference. Conclusion:There are ICC and HERG protein in gallbladder tissue of patients with gallstone. The decrease of gallbladder contraction rate may be related to the decrease of HERG protein expression in ICC in gallbladder bottom tissue.

Objective:To preliminarily study the feasibility, safety and efficacy of transcatheter arterial chemoembolization (TACE) combined with selective portal vein embolization (SPVE) before surgical resection in the treatment of large liver cancer.Methods:A retrospective study was conducted on the clinical data of 17 patients with large liver cancer treated with TACE combined with SPVE from January 2016 to December 2019 at the Department of Hepatobiliary Surgery, the Sixth Medical Center of PLA General Hospital. The study included 15 males and 2 females, aged (59.17±10.30) years. The levels of alanine aminotransferase, tumor changes and patient survival were analyzed before operation, after TACE, and after SPVE.Results:Among the 17 patients, the levels of alanine aminotransferase on the 1st and 3rd day after SPVE was significantly higher than those after TACE [191.4 (30.5-1966.4) IU/L vs 125.3 (35.7-846.2) IU/L on the first day, and 298.5 (24.6-1334.2) IU/L vs 208.6 (21.6-775.6) IU/L on the 3rd day], all P<0.05. One month after the two combined embolism, among the 6 patients with a tumor diameter of 5-10 cm, 2 patients (33.3%) had complete remission, 3 patients (50.0%) had partial remission, and 1 patients (16.6%) had stable disease. For the tumor’s longest diameter, among the 11 patients with tumors >10 cm, 1 patient had complete remission (9.1%), 4 patients had partial remission (36.4%), 5 patients had stable diseases (45.5%), and 1 patient had disease progression (9.1%). Eventually, 11 patients underwent surgical exploration. The median residual liver volume before treatment was 329.5 (284.9-365.7) ml, and after the combined procedure 415.6 (354.7-718.8) ml. The median hyperplasia ratio was 28.1% (14.1%-51.3%). Eight patients finally underwent surgical resection. There was no death in the perioperative periods. The median tumor-free survival time was 17 (7-42) months, and the median survival time was 27 (7-42) months. Conclusion:For patients with large liver cancer with insufficient remnant liver volume, preoperative TACE+ SPVE has certain value in controlling tumor progression, promoting remnant liver hyperplasia, increasing surgical resection rate and improving prognosis.

OBJECTIVE: To explore the effect and mechanism of miR-125a-5p targeted regulation of scavenger receptor B1 (Scarb1) gene on anoxia/reoxygenation injury of rat cardiomyocytes. METHODS: H9c2 rat cardiomyocytes were randomly divided into blank control group, hypoxia/reoxygenation group, transfection control group and mir-125a-5p transfection group. The expression of miR-125a-5p, cardiomyocyte viability, apoptosis rate, ATP content and the expression of Scarb1, Cyt C, Bax, Bcl-2 and NF-κB signaling pathway related proteins were determined. Target gene of miR-125a-5p was predicted with Targetscan software, and the targeting of miR-125a-5p on Scarb1 was verified by double luciferase reporter gene experiment. RESULTS: Compared with the blank control group, the expression of miR-125a-5p, Bax, Cyt C and the apoptotic rate of cardiomyocytes in the hypoxia/reoxygenation group were significantly increased (P<0.05), while the expression of Scarb1, Bcl-2 and the content of ATP were significantly decreased (P<0.05). Compared with the control group, the situation of mir-125a-5p transfection group was just the opposite. Double luciferase reporter gene experiment has confirmed Scarb1 to be the target of miR-125a-5p. Hypoxia/reoxygenation can promote the expression of NF-κB p65, C-myc and Cyclin D1 in cardiomyocytes, while down-regulating the expression of miR-125a-5p can inhibit the expression of such proteins. CONCLUSION Hypoxia/reoxygenation can induce the expression of miR-125a-5p in rat cardiomyocytes. Inhibition of miR-125a-5p can protect cardiomyocytes from hypoxia/reoxygenation by up-regulating the expression of Scarb1. The mechanism may be related to the inhibition of activation of NF-κB signaling pathway.

OBJECTIVE: To study the effects and mechanism of couplet medicines of Scutellaria baicalensis-Paeonia lactiflora on improving ulcerative colitis (UC) in mice. METHODS: A total of 70 mice were randomly divided into blank group, model group, S. baicalensis group (1. 5 g/kg), P. lactiflora group (1. 5 g/kg), S. baicalensis-P. lactiflora (2:1, 1:1, 1:2, m/m) groups (total amount of 1. 5 g/kg), with 10 mice in each group. Except for blank group, UC model of mice was induced in each group. The next day after modeling, treatment groups were given relevant medicine liquid 0. 2 mL/10 g (75 mg/mL, calculated by crude drug mass concentration), while blank group and model group were given constant volume of normal saline intragastrically, once a day, for consecutive 7 d. After administration, disease activity indexes (DAI) of rats were scored, and the serum levels of TNF-α, IL-1β, IL-6, D-LA and myeloperoxidase (DAO) were determined. The length of the colon was measured and the intestinal mass index was calculated in mice. The activities of medullary peroxide (MPO) and SOD, the levels of NO and MDA were determined in colon tissue. RESULTS: Compared with blank group, DAI score, serum levels of TNF-α, IL-1β, IL-6, D-LA and DAO, the levels of MPO, NO and MDA in colon were increased significantly in model group, while the length of colon, intestinal mass index and SOD level of colon tissue were decreased significantly, with statistical significance (P<0. 05 or P<0. 01). Compared with model group, DAI score, serum levels of TNF-α, IL-1β and DAO, the level of MDA in colon were decreased significantly in S. baicalensis group (P<0. 05 or P<0. 01). The serum levels of TNF-α and IL-1β, the level of MDA in colon were decreased significantly in P. lactiflora group (P<0. 05 or P<0. 01). Above indexes of S. baicalensis-P. lactiflora (2:1) group were improved significantly except for the length of colon (P<0. 05 or P<0. 01). Above indexes of S. baicalensis-P. lactiflora (1:1) group were improved significantly except for serum level of IL-6 and the level of SOD in colon (P<0. 05 or P<0. 01). Above indexes of S. baicalensis-P. lactiflora (1:2) group were improved significantly except for serum level of NO (P<0. 05 or P<0. 01). CONCLUSIONS: The couplet medicines of S. baicalensis-P. lactiflora can reduce the expression of proinflammatory factors, enhancing antioxidant activity of the body and decrease intestinal mucosal permeability so as to improve UC symptom of mice; and the effect of S. baicalensis-P. lactiflora (2:1) group is the best.