The glucagon receptor (GCGR) is a critical target for the treatment of metabolic disorders such as Type 2 Diabetes Mellitus (T2DM) and obesity. Activation of GCGR enhances systemic insulin sensitivity through paracrine stimulation of insulin secretion, presenting a promising avenue for treatment. However, the discovery of effective GCGR agonists remains a challenging and resource-intensive process, often requiring time-consuming wet-lab experiments to synthesize and screen potential compounds. Recent advances in artificial intelligence technologies have demonstrated great potential in accelerating drug discovery by streamlining screening and efficiently predicting bioactivity. In the present work, we propose DeepGCGR, a two-layer deep learning model that leverages graph convolutional networks (GCN) integrated with a multiple attention mechanism to expedite the identification of GCGR agonists. In the first layer, the model predicts the bioactivity of various compounds against GCGR, efficiently filtering large chemical libraries to identify promising candidates. In the second layer, DeepGCGR classifies high bioactive compounds based on their functional effects on GCGR signaling, identifying those with potential agonistic or antagonistic effects. Moreover, DeepGCGR was specifically applied to identify novel GCGR-regulating compounds for the treatment of T2DM from natural products derived from traditional Chinese medicine (TCM). The proposed method will not only offer an effective strategy for discovering GCGR-targeting compounds with functional activation properties but also provide new insights into the development of T2DM therapeutics.
Deep Learning ; Drug Discovery/methods* ; Humans ; Diabetes Mellitus, Type 2/metabolism* ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/pharmacology*

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

OBJECTIVES: Investigating the protective effect of naringenin (NAR) on the osteogenic potential of human periodontal ligament stem cells (hPDLSCs) under oxidative stress and its related mechanisms. METHODS: The oxidative damage model of hPDLSCs was established using hydrogen peroxide (H₂O₂) andthe hPDLSCs were treated with different concentrations of NAR and 0.5 μmol/L forkhead box protein O-1 (FOXO1) inhibitor AS1842856. After that, the cell counting kit-8 (CCK8) was used to determine the optimal concentrations of H₂O₂ and NAR. The alkaline phosphatase (ALP) staining and real time fluorescent quantitative reverse transcription polymerase chain reaction (qRT-PCR) were employed to assess the expression of ALP, runt-related transcription factor 2 (RUNX2) and osteocalcin (OCN) in hPDLSCs of each group. The enzyme-linked immunosorbent assay (ELISA) and 2',7'-dichlorofluorescin diacetate (DCFH-DA) staining were utilized to evaluate the expression of reactive oxygen species (ROS), malondialdehyde (MDA) and lactate dehydrogenase (LDH) in hPDLSCs. Meanwhile, qRT-PCR and western blot were used to detect the expression levels of FOXO1 and β-catenin, both are pathway related genes and proteins. RESULTS: H₂O₂ exposure led to an increase in oxidative damage in hPDLSCs, characterized by a rise in intracellular ROS levels and increased expression of MDA and LDH (P<0.05). At the same time, the osteogenic differentiation ability of hPDLSCs decreased, as evidenced by lighter ALP staining and reduced expression levels of osteogenic differentiation-related genes ALP, RUNX2 and OCN (P<0.05). Co-treatment with NAR alleviated the oxidative damage in hPDLSCs, enhanced their antioxidant capacity, and restored their osteogenic ability. The FOXO1 inhibitor AS1842856 downregulated the expression of β-catenin (P<0.05) and significantly diminished both the antioxidant effect of NAR and its ability to restore osteogenesis (P<0.05). CONCLUSIONS NAR can enhance the antioxidant capacity of hPDLSCs by activating the FOXO1/β-catenin signaling pathway within hPDLSCs, thereby mitigating oxidative stress damage and alleviating the loss of osteogenic capacity.
Humans ; Oxidative Stress/drug effects* ; Periodontal Ligament/cytology* ; Hydrogen Peroxide ; Forkhead Box Protein O1/metabolism* ; Stem Cells/cytology* ; Flavanones/pharmacology* ; beta Catenin/metabolism* ; Osteogenesis/drug effects* ; Signal Transduction ; Core Binding Factor Alpha 1 Subunit/metabolism* ; Alkaline Phosphatase/metabolism* ; Osteocalcin/metabolism* ; Cells, Cultured ; Cell Differentiation/drug effects*

AIM:To investigate the impact of aquaporin 4(AQP4)expression inhibition on autophagy and apoptosis in a mouse model of cerebral ischemia-reperfusion(I/R)injury,and to elucidate its underlying mechanism.METHODS:Cerebral I/R injury was induced in mice via transient middle cerebral artery occlusion(tMCAO).Totally 60 mice were randomly divided into sham group,I/R group,AQP4 inhibition group,and 3-methyladenine(3-MA)group,with 15 mice in each group.Among them,the mice in sham and I/R groups received intraperitoneal injections of normal saline,while those in AQP4 inhibition group and 3-MA group received intraperitoneal injections of AER-271(2 mg·kg-1·d-1)and AER-271+3-MA(2 mg·kg-1·d-1)for 3 d,respectively,once per day.Longa score was adopted to assess the neu-rological function,and to record changes in body weight.Cerebral infarction volume and histopathological alterations were evaluated using hematoxylin-eosin staining.Western blot analysis was performed to determine the levels of AQP4,LC3-Ⅱ,P62 and cleaved caspase-3,while the LC3-Ⅱ,P62,cleaved caspase-3 and NeuN(neuronal marker)colocalization and expression assessment were conducted with immunofluorescence.RESULTS:The mice in I/R and AQP4 inhibition groups exhibited extensive cerebral infarction,cerebral edema,and elevated Longa scores.However,in comparision to I/R group,the mice in AQP4 inhibition group showed significantly reduced cerebral infarct volume,cerebral edema vol-ume,and Longa score(P<0.05).Additionally,in contrast to sham group,the mice in I/R group displayed increased ex-pression of AQP4,LC3-Ⅱ and cleaved caspase-3(P<0.01),accompanied by decreased body weight and P62 expression(P<0.05 or P<0.01).Furthermore,compared with I/R group,the mice in both AQP4 inhibition group and 3-MA group demonstrated a decrease in the expression levels of AQP4,LC3-Ⅱ and cleaved caspase-3(P<0.05 or P<0.01),along with increased body weight and P62 expression(P<0.05 or P<0.01).Nonetheless,no significant differences were ob-served between AQP4 inhibition group and 3-MA group regarding Longa score,cerebral infarct volume,body weight,and the expression of AQP4,LC3-Ⅱ,cleaved caspase-3 and P62.CONCLUSION:Inhibition of AQP4 expression signifi-cantly reduces cerebral infarction area and nerve injury severity in tMCAO mice.Moreover,AQP4 expression inhibition decelerates autophagy and apoptosis after cerebral infarction,with the additional autophagy inhibitor showing no notable impact on the protective effect of AQP4 inhibition.

Objective To explore the characteristics of blood lipid metabolism indicators and risk factors of prognosis in children with systemic lupus erythematosus (SLE). Methods A total of 54 children who were diagnosed with SLE and hospitalized in Chengdu Women and Children’ s Central Hospital from January 2013 to August 2022 were selected. Clinical data of all children were collected and blood lipid metabolism indicators and biochemical indicators were detected , and binary logistic regression was used to analyze the prognosis risk factors in children with SLE. Results Among the 47 cases (87.04%) had abnormal blood lipid metabolism at admission, and is mainly manifested as elevated levels of LDL-C, TG and TC and decreased level of HDL-C. The proportion of cardiovascular system damage, hematological system damage, urinary protein positivity, and SLEDAI-2000 score in the group with good prognosis were lower than those in the group with poor prognosis, while the proportion of dsDNA positivity was higher in the group with poor prognosis. Binary Logistic regression analysis showed that the cardiovascular system damage and positive urinary protein were risk factors for poor prognosis, with statistically significant differences (P<0.05). Conclusion Abnormal blood lipid metabolism is common in children with SLE, and cardiovascular system damage and positive urinary protein may increase the risk of poor prognosis in young children.

Medical microbiology is one of the compulsory courses of basic medical sciences, which lays an important theoretical foundation for the follow-up study of infectious diseases, contagions, tumors, and so on. The course of medical microbiology in our college adhered to the concept of student-centered, diversified teaching, scientific evaluation, and continuous improvement. Teaching design was a cross-link of general theories, specific chapters, clinical cases, theory and practice, and the ideological and political education throughout the curriculum. Lectures adopted the mode of offline teaching (such as flipped classroom, case analysis, and comprehensive experimental design), online assistance (such as classroom test, stage test, extracurricular homework, and questionnaire survey), and combined process evaluation. This teaching mode also reflected the deep integration of information technology and classroom teaching. With the development and construction in these years, medical microbiology has completed the renewal of curriculum resources, the construction of online question bank, the construction and design of ideological and political case bank, and process evaluation (10 points of usual score + 10 points of case study + 10 points of experimental performance + 100 points of final examination multiplied by 70%). There was no significant difference in the results of qustionnaire survey in terms of the improvement of independent learning ability, curriculum evaluation system and satisfaction feedback. Students in Batch 2019 were most satisfied with the teaching of keeping pace with the times and the guidance of positive outlook on life and values.

Adolescent ; Adult ; Aged ; COVID-19 ; Child ; Child, Preschool ; China/epidemiology* ; Female ; Humans ; Male ; Middle Aged ; Quarantine ; SARS-CoV-2 ; Surveys and Questionnaires ; United States ; Young Adult

Objective:To investigate the correlations between perfused lung volumes, visual scores (using perfusion SPECT/CT) and right-heart catheter (RHC) hemodynamic parameters in patients with chronic thromboembolic pulmonary hypertension (CTEPH).Methods:A total of 51 consecutive CTEPH patients (17 males, 34 females, age (59±12) years) in the First Affiliated Hospital of Guangzhou Medical University between March 2015 and July 2019 were retrospectively analyzed. All patients underwent lung perfusion SPECT/CT imaging and RHC examinations. Perfused lung volumes were determined using threshold-based (15%-85%) segmentation. Visual semiquantitative scoring in each lung segment was performed using Begic method. RHC hemodynamic parameters including pulmonary artery systolic pressure (PASP), pulmonary arterial diastolic pressure (PADP), mean pulmonary artery pressure (mPAP), pulmonary arteriolar wedge pressure (PAWP), pulmonary vessel resistance (PVR), cardiac output (CO), cardiac index (CI) were recorded. Spearman correlation analysis was used to evaluate the correlations between perfused lung volumes, visual scores and hemodynamic parameters.Results:There were significant correlations between perfused lung volumes (30%-70% threshold) and mPAP ( rs values: from -0.414 to -0.302, all P<0.05). Among them, perfused lung volumes under the threshold of 40% and 45% were moderately correlated with mPAP ( rs values: -0.414, -0.412, both P<0.05). Perfused lung volume (40% threshold) was moderately negatively correlated with PASP, PADP ( rs values: -0.402, -0.440, both P<0.05), and slightly negatively correlated with PVR ( rs=-0.352, P<0.05). Visual scores were slightly positively correlated with the PADP ( rs=0.311, P<0.05), while there was no correlation between visual scores and other RHC hemodynamic parameters ( rs values: from -0.201 to 0.275, all P>0.05). Conclusion:Perfused lung volumes based on threshold-based segmentation in lung perfusion SPECT/CT imaging can accurately reflect hemodynamic status and may provide useful information for severity assessment of CTEPH.

Objective: To analyze the epidemiological and etiological characteristics of aggregation epidemics of infectious diarrhea induced by norovirus, and to provide the scientific basis for the prevention and control. Methods: A descriptive epidemiological analysis of aggregation epidemics events occurred during 2016-2018 in Longhua District of Shenzhen was carried out, with subtypes identified by real-time fluorescence quantitative PCR, Region B and Region C fragment sequence determination. Results: There were 34 aggregation epidemic events,including 448 cases, the mean attack rate was 18.26%(448/2 454). The median duration of aggregation epidemic was 3 days. The peak season appeared in autumn and winter, and the peak of epidemic emerged from December 2016 to April 2017. About 91.18% (31/34) of the epidemics occurred in schools and child care centers, and among children aged 3-6 years (78.79%, 353/448). The clinical symptoms were mainly nausea and vomiting (95.77%, 408/426) in children and adolescents but diarrhea in adult group (95.45%, 21/22). The differences between vomiting and diarrhea were both statistically significant in the two age groups (χ2=98.89，99.61，P<0.01). 29 cases were transmitted through interpersonal network, of which 21 cases were found to have unregulated treatment of vomit on campus. The detection rate of biological samples was 49.15% (203/413), all of which were G Ⅱ norovirus. The genotype was mainly GⅡ.P16-G Ⅱ.2(n=49)from November 2016 to April 2017. Conclusion Norovirus can cause large-scale outbreaks in child care centers and schools easily. Early standardized patient isolation and proper management of vomit and diarrhea are the key steps in prevention and control measures.

Objective:Taking medical microbiology in the pathogen biology as an example, to explore the effects of process evaluation in basic medicine teaching.Methods:Multiple methods, including classroom performance, stage test, case analysis, final examination, questionnaire survey and so on, were used in the study to systematically evaluate the teaching process. According to the students' suggestions, feedback problems and solutions were publically given to students in the form of PPT, forming a process evaluation with "evaluation-feedback-correction" loop as the core. Collected data were analyzed statistically with SPSS 16.0.Results:The students were impressed by the contents with various teaching methods and satisfied with the evaluation system. Most of them thought that their abilities had been improved in many ways during the learning process. 96.8% of the students supported the reform, and 88.6% of the students hoped to apply this system to other disciplines. The scores of case analysis, final examination and overall evaluation in the experimental group were significantly higher than those of the control group ( P<0.01). Conclusion:Both teachers and students got profit from the process evaluation based on feedback loop. The teaching quality of medical microbiology would be further improved by a constantly enhanced evaluation system.