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*

Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.

Although enteric glial cell (EGC) abnormal activation is reported to be involved in the pathogenesis of Parkinson's disease (PD), and inhibition of EGC gliosis alleviated gut and dopaminergic neuronal dysfunction was verified in our previous study, the potential role of gut microbiota on EGC function in PD still need to be addressed. In the present study, fecal microbiota transplantation revealed that EGC function was regulated by gut microbiota. By employing 16S rRNA and metabolomic analysis, we identified that 3-indolepropionic acid (IPA) was the most affected differential microbial metabolite that regulated EGC gliosis. The protective effects of IPA on PD were validated in rotenone-stimulated EGCs and rotenone (30 mg/kg i.g. for 4 weeks)-induced PD mice, as indicated by decreased inflammation, improved intestinal and brain barrier as well as dopaminergic neuronal function. Mechanistic study showed that IPA targeted pregnane X receptor (PXR) in EGCs, and inhibition of IL-13Rα1 involved cytokine-cytokine receptor interaction pathway, leading to inactivation of downstream JAK1-STAT6 pathway. Our data not only provided evidence that EGC gliosis was critical in spreading intestinal damage to brain, but also highlighted the potential role of microbial metabolite IPA in alleviating PD pathological damages through gut-brain axis.

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.

[This corrects the article DOI: 10.1016/j.apsb.2025.02.029.].

Objective To investigate the correlation between spread through air space (STAS) of sub-centimeter non-small cell lung cancer and clinical characteristics and radiological features, constructing a nomogram risk prediction model for STAS to provide a reference for the preoperative planning of sub-centimeter non-small cell lung cancer patients. Methods The data of patients with sub-centimeter non-small cell lung cancer who underwent surgical treatment in Nanjing Drum Tower Hospital from January 2022 to October 2023 were retrospectively collected. According to the pathological diagnosis of whether the tumor was accompanied with STAS, they were divided into a STAS positive group and a STAS negative group. The clinical and radiological data of the two groups were collected for univariate logistic regression analysis, and the variables with statistical differences were included in the multivariate analysis. Finally, independent risk factors for STAS were screened out and a nomogram model was constructed. The sensitivity and specificity were calculated based on the Youden index, and area under the curve (AUC), calibration plots and decision curve analysis (DCA) were used to evaluate the performance of the model. Results A total of 112 patients were collected, which included 17 patients in the STAS positive group, consisting of 11 males and 6 females, with a mean age of (59.0±10.3) years. The STAS negative group included 95 patients, with 30 males and 65 females, and a mean age of (56.8±10.3) years. Univariate logistic regression analysis showed that male, anti-GAGE7 antibody positive, mean CT value and spiculation were associated with the occurrence of STAS (P＜0.05). Multivariate regression analysis showed that associations between STAS and male (OR=5.974, 95%CI 1.495 to 23.872), anti-GAGE7 antibody positive (OR=11.760, 95%CI 1.619 to 85.408) and mean CT value (OR=1.008, 95%CI 1.004 to 1.013) were still significant (P＜0.05), while the association between STAS and spiculation was not significant anymore (P=0.438). Based on the above three independent predictors, a nomogram model of STAS in sub-centimeter non-small cell lung cancer was constructed. The AUC value of the model was 0.890, the sensitivity was 76.5%, and the specificity was 91.6%. The calibration curve was well fitted, suggesting that the model had a good prediction efficiency for STAS. The DCA plot showed that the model had a good clinically utility. Conclusion Male, anti-GAGE7 antibody positive and mean CT value are independent predictors of STAS positivity of sub-centimeter non-small cell lung cancer, and the nomogram model established in this study has a good predictive value and provides reference for preoperative planning of patients.

Objective:To evaluate the clinical efficacy of intervertebral disc radiofrequency(RF)ablation combined with dorsal medial branch(DMB)neurotomy in elderly patients suffering from chronic low back pain.Methods:A retrospective analysis was conducted on patients aged 60 years and older with chronic low back pain admitted to Beijing Hospital from March 2023 to September 2024.The combined treatment group underwent intervertebral disc radiofrequency ablation combined with radiofrequency treatment of the dorsal medial branch of the spinal nerve.The single treatment group underwent intervertebral disc radiofrequency ablation alone.Pain visual analogue scale(VAS)scores were assessed before treatment and on the first day, 3 months, and 6 months post-treatment.The Oswestry Disability Index(ODI)and Barthel Index were evaluated before treatment and at 3 months and 6 months post-treatment.Clinical efficacy was compared between the two groups.Results:A total of 115 elderly patients with chronic low back pain were enrolled, aged 61 to 72 years(mean 66.5 ± 5.6 years), with 44 males.The combined therapy group consisted of 71 patients, and the monotherapy group consisted of 44 patients.All patients were followed up continuously for 6 months.At all-time points post-treatment, the VAS scores in the combined therapy group were significantly lower than those in the monotherapy group( t=-4.887, -10.095, -7.687, all P<0.05); at 3 and 6 months post-treatment, the combined therapy group showed significantly greater improvements in ODI( t=-3.645, -9.451, both P<0.001)Barthel Index improvement were significantly greater than those in the monotherapy group( t=6.578, 8.530, both P<0.001); the overall good-to-excellent rate in the combined therapy group was 88.7%, higher than the 72.7% in the monotherapy group( χ2=4.85, P<0.05). Conclusions:Combined disc RF ablation and DMB neurotomy provide superior pain relief, functional recovery, and improvement in daily activities compared to single disc ablation in elderly patients with CLBP.This minimally invasive approach represents a safe and effective therapeutic strategy for managing chronic low back pain in the geriatric population.

Rhytidectomy, as the most effective method for improving facial aging at present, precisely restores the position of facial anatomical structures. However, for facial aging accompanied by soft tissue or bone atrophy, the improvement effect of rhytidectomy alone is inadequate, and simultaneous restoration of facial volume is required to achieve better facial rejuvenation results. Therefore, rhytidectomy combined with fat grafting has received increasing attention in facial rejuvenation in recent years. This paper reviewed the research progress of facial rhytidectomy, fat grafting, and their combined approaches.

Objective To investigate the effect of resveratrol on airway remodeling induced by ovalbumin(OVA)in asthmatic young mice based on the sphingosine-1-phosphate(S1P)/transforming growth factor-β1(TGF-β1)pathway.Methods Young mice were randomly assigned into normal group,model group,S1P group,resveratrol group,and resveratrol+S1P group,with 12 mice in each group.A mouse model of asthma induced by OVA was established.The Wright Giemsa staining was applied to detect the number of inflammatory cells in bronchoalveolar lavage fluid(BALF).ELISA was applied to detect the levels of interleukin-4(IL),IL-5,and IL-13 in BALF.The colorimetric method was applied to detect the activities of SOD and CAT and the content of MDA in lung tissue.HE staining was applied to observe pathological changes in lung tissue,and the wall area of bronchial tube(Wat)and perimeter of basement membrane(Pbm)were analyzed.Masson staining was applied to observe the area of collagen fibers in lung tissue.Immunohistochemistry was applied to detect the expression of α-SMA in lung tissue.Western blot was applied to detect the expression of E-cadherin,N-cadherin,Snail,SP1,and TGF-β1 proteins in lung tissue.Results Compared with the normal group,the number of eosinophils,lymphocytes,neutrophils,levels of IL-4,IL-5,and IL-13 in BALF,lung tissue MDA content,Wat/Pm ratio,collagen fiber area,α-SMA positive expression,the protein levels of N-cadherin,Snail,SP1,TGF-β1 increased in the model group,while the activities of SOD,CAT,and the protein level of E-cadherin in lung tissue decreased(P＜0.05).Compared to the model group,the number of eosinophils,lymphocytes,neutrophils,levels of IL-4,IL-5,and IL-13 in BALF,lung tissue MDA content,Wat/Pm ratio,collagen fiber area,α-SMA positive expression,the protein levels of N-cadherin,Snail,SP1,TGF-β1 decreased in the resveratrol group,while the activities of SOD,CAT,and the protein level of E-cadherin in lung tissue increased(P＜0.05).The S1P recombinant protein could weaken the inhibitory effect of resveratrol on airway remodeling in asthmatic young mice.Conclusion Resveratrol can inhibit oxidative stress,airway inflammation,and epithelial mesenchymal transition,thereby suppressing airway remodeling in asthmatic young mice.Its effect is related to the inhibition of the S1P/TGF-β1 signaling pathway.