The ambiguity of symptom information in traditional Chinese medicine （TCM） syndrome differentiation can be amplified in the direct reasoning process from symptoms to syndromes in the absence of constraints， which affects the accuracy and stability of intelligent syndrome differentiation. TCM disease concepts， while historically rational， are structurally ambiguous in both their connotation and extension， making it difficult to serve as stable prior knowledge in intelligent modeling. In contrast， modern medical diseases， based on objective testing and quantifiable indicators， have relatively clear boundaries and reproducible standards. This study proposes a disease-syndrome combination model， adopting modern medical diseases as structural prior variables to reconstruct the hierarchical relationships among disease， symptoms， and syndromes. By applying disease constraints， effective screening of information from the four examinations and compressing the reasoning space are achieved. Furthermore， by integrating artificial intelligence technologies， such as multimodal fusion and knowledge graphs， an intelligent syndrome differentiation model driven by both prior knowledge and clinical data is constructed， providing a feasible path to enhance the accuracy of syndrome differentiation and realize the intelligentization of TCM diagnosis and treatment.

ObjectiveTo explore the clinical and phenomics characteristics of patients with phlegm-stasis binding syndrome and its accompanied patterns in stable angina pectoris （SAP） of coronary heart disease （CHD）. MethodsA multicenter cross-sectional study design was adopted. A total of 300 patients with SAP of CHD were enrolled and classified into 120 cases of phlegm-stasis binding syndrome， 125 cases of qi deficiency-accompanied syndrome， 38 cases of qi stagnation-accompanied syndrome， and 17 cases of toxin accumulation-accompanied syndrome according to traditional Chinese medicine （TCM） patterns. Data of patients with different TCM patterns were collected， including general condition， TCM symptoms， blood lipids， coagulation function， immune indicators， and serum metabolomics. Metabolic pathway enrichment analysis was used to compare differences in phenomics characteristics among groups. Metabolites with variable importance in projection （VIP） ≥1 and fold change （FC） ≥2 were considered as representative differential metabolites. ResultsPatients in each TCM pattern type were most commonly in the 60-75 years age group， with a relatively high proportion of males. Regarding TCM symptoms， patients with phlegm-stasis binding syndrome most commonly presented with wiry-choppy or wiry-slippery pulse， chest pain， and chest tightness； in patients with qi deficiency-accompanied syndrome， fatigue， chest pain， and weak pulse were most common； in patients with qi stagnation-accompanied sydnrome， wiry-choppy or wiry-slippery pulse， chest pain， and symptoms that increase or decrease with emotional changes， belching， or flatulence were most common； in patients with toxin accumulation-accompanied syndrome， bitter taste in the mouth， chest tightness， irritability， restlessness or manic delirium， and dry and hard stools or foul-smelling diarrhea were most common. Comparisons among the different TCM patterns showed statistically significant differences in coagulation parameters （P＜0.05）， whereas no statistically significant difference was found in blood lipid levels and immune indicators （P＞0.05）.Metabolomics analysis suggested that disorders of glycerophosphate metabolism and valine， leucine， and isoleucine metabolism are characteristic features of phlegm-stasis binding syndrome and its accompanied patterns. The representative differential metabolites between phlegm-stasis binding syndrome and qi deficiency-accompanied syndrome were 7,8-dihydrobiopterin （FC = 3.58） and oxypurinol （FC = 124.50）. Those between phlegm-stasis binding syndrome and qi stagnation-accompanied syndrome were cytidine 5′-diphosphocholine （FC = 2.62） and D-mannosamine （FC = 2.99）. Those between phlegm-stasis binding syndrome and toxin accumulation-accompanied syndrome were anserine （FC = 7.83） and canrenone （FC = 8.94）. ConclusionThere are certain differences in the clinical characteristics and phenomics characteristics among patients with SAP due to CHD exhibiting phlegm-stasis binding syndrome and its accompanied patterns. The phenomics characteristics mainly involve biological alterations such as lipid metabolism disorders， amino acid metabolism abnormalities， and multiple immune indicators activation， which may provide a reference for precise differentiation and treatment of SAP of CHD in TCM clinical practice.

ObjectiveTo explore the clinical and phenomics characteristics of patients with phlegm-stasis binding syndrome and its accompanied patterns in stable angina pectoris （SAP） of coronary heart disease （CHD）. MethodsA multicenter cross-sectional study design was adopted. A total of 300 patients with SAP of CHD were enrolled and classified into 120 cases of phlegm-stasis binding syndrome， 125 cases of qi deficiency-accompanied syndrome， 38 cases of qi stagnation-accompanied syndrome， and 17 cases of toxin accumulation-accompanied syndrome according to traditional Chinese medicine （TCM） patterns. Data of patients with different TCM patterns were collected， including general condition， TCM symptoms， blood lipids， coagulation function， immune indicators， and serum metabolomics. Metabolic pathway enrichment analysis was used to compare differences in phenomics characteristics among groups. Metabolites with variable importance in projection （VIP） ≥1 and fold change （FC） ≥2 were considered as representative differential metabolites. ResultsPatients in each TCM pattern type were most commonly in the 60-75 years age group， with a relatively high proportion of males. Regarding TCM symptoms， patients with phlegm-stasis binding syndrome most commonly presented with wiry-choppy or wiry-slippery pulse， chest pain， and chest tightness； in patients with qi deficiency-accompanied syndrome， fatigue， chest pain， and weak pulse were most common； in patients with qi stagnation-accompanied sydnrome， wiry-choppy or wiry-slippery pulse， chest pain， and symptoms that increase or decrease with emotional changes， belching， or flatulence were most common； in patients with toxin accumulation-accompanied syndrome， bitter taste in the mouth， chest tightness， irritability， restlessness or manic delirium， and dry and hard stools or foul-smelling diarrhea were most common. Comparisons among the different TCM patterns showed statistically significant differences in coagulation parameters （P＜0.05）， whereas no statistically significant difference was found in blood lipid levels and immune indicators （P＞0.05）.Metabolomics analysis suggested that disorders of glycerophosphate metabolism and valine， leucine， and isoleucine metabolism are characteristic features of phlegm-stasis binding syndrome and its accompanied patterns. The representative differential metabolites between phlegm-stasis binding syndrome and qi deficiency-accompanied syndrome were 7,8-dihydrobiopterin （FC = 3.58） and oxypurinol （FC = 124.50）. Those between phlegm-stasis binding syndrome and qi stagnation-accompanied syndrome were cytidine 5′-diphosphocholine （FC = 2.62） and D-mannosamine （FC = 2.99）. Those between phlegm-stasis binding syndrome and toxin accumulation-accompanied syndrome were anserine （FC = 7.83） and canrenone （FC = 8.94）. ConclusionThere are certain differences in the clinical characteristics and phenomics characteristics among patients with SAP due to CHD exhibiting phlegm-stasis binding syndrome and its accompanied patterns. The phenomics characteristics mainly involve biological alterations such as lipid metabolism disorders， amino acid metabolism abnormalities， and multiple immune indicators activation， which may provide a reference for precise differentiation and treatment of SAP of CHD in TCM clinical practice.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Pulmonary infection is one of the infectious diseases that have long plagued human health.The receptor for advanced glycation end-products(RAGE)is a non-specific,multi-ligand pat-tern recognition receptor expressed on the surface of various tissues and cells.It can bind to a series of structurally different ligands,including pathogen-associated molecular patterns from pathogenic micro-organisms.Soluble receptor for advanced glycation end-products(sRAGE)is a soluble form generated when cell surface RAGE is excessively stimulated by inflammatory cytokines.As a competitive recep-tor,it inhibits multiple RAGE-dependent cellular signaling pathways and participates in the inflamma-tory response process.This review summarized the clinical significance of serum sRAGE levels in in-fection-related pulmonary diseases,explored the biological characteristics of sRAGE in these diseases,and evaluated its clinical application value.

Objective:To evaluate the efficacy and safety of combining third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) with brain radiotherapy in patients with newly diagnosed EGFR mutation-positive non-small cell lung cancer (NSCLC) with brain metastases. Methods:A retrospective analysis was performed on the clinical data of patients with newly diagnosed EGFR-mutant NSCLC with brain metastases who received first-line treatment with third-generation EGFR-TKI with or without brain radiotherapy at the Fourth Affiliated Hospital of Guangxi Medical University between January 2018 and December 2022. Patients treated with EGFR-TKI plus brain radiotherapy were assigned to the combination group, while those treated with EGFR-TKI alone were assigned to the monotherapy group. Intracranial progression-free survival (iPFS), progression-free survival (PFS), overall survival (OS), intracranial disease control rate (iDCR), intracranial objective response rate (iORR), and adverse events were compared between groups. Subgroup analyses were performed according to EGFR exon 19 deletion (19del) and exon 21L858R mutation status. Survival was estimated using the Kaplan-Meier method, with the log-rank test applied for group comparisons and univariate analysis, while multivariate analysis was conducted using Cox proportional hazards regression model. Results:A total of 107 patients were included: 57 (53%) in the monotherapy group and 50 (47%) in the combination group. The combination therapy significantly improved iORR (80% vs. 60%, P=0.023), prolonged median OS (37.7 vs. 31.6 months, P=0.004), and extended median iPFS (21.8 vs. 16.7 months, P=0.018). The iDCR was 100% in both groups, and the difference in median PFS was not statistically significant (18.6 vs. 15.2 months, P=0.086). In the 19del subgroup ( n=53), patients in the combination group had longer OS ( P=0.028) and iPFS ( P=0.028). In the 21L858R subgroup ( n=54), the median OS was also longer in the combination group ( P=0.050). Multivariate analysis identified TKI monotherapy and an Eastern Cooperative Oncology Group (ECOG) performance status score=2 as independent adverse prognostic factors for iPFS, while TKI monotherapy, age ≥65 years, ECOG score=2, and >3 brain metastases were the independent adverse prognostic factors for OS. The incidence of adverse events did not differ significantly between groups (all P>0.05). Conclusions:First-line combination therapy with third-generation EGFR-TKI and cranial radiotherapy provides superior efficacy and acceptable safety compared with EGFR-TKI monotherapy in patients with EGFR-mutant lung adenocarcinoma and brain metastases. Both EGFR 19del and 21L858R mutation subgroups benefit from the combined treatment approach.

Objective:To investigate the relationship between Triglyceride Glucose-WHR index and retinal arteriosclerosis.Methods:Retrospective longitudinal cohort research method. Using data from the Tongren Health Care Study of Beijing Tongren Hospital from March 2014 to June 2020. The TyG-WHR index was calculated, the restricted cubic spine regression model was used to explore the dose-response relationship between TyG-WHR index and the risk of retinal arteriosclerosis. Cox proportional regression model was implemented to estimate the impact on the risk of retinal arteriosclerosis associated with the different TyG-WHR groups. Receiver operating characteristic were used to explore the value of triglyceride glucose-WHR index for the risk of retinal arteriosclerosis.Results:A total of 8 215 subjects were included, including 3 334 (40.58%) males, 4 881 (59.42%) females;7 689 cases had normal fundus, 296 cases had newly developed retinal arteriosclerosis, and 230 cases had retinal arteriosclerosis. The median age is 45 years old, and the average age is (47.63±13.89) years old. The cumulative incidence rate of new retinal arteriosclerosis was 3.71%(296/7 985), and the cumulative incidence rate of women (3.31%,158/4 767) was lower than that of men (4.29%, 138/3 218) ( χ2=5.105, P<0.001); The cumulative incidence rate of new retinal arteriosclerosis increased with age ( χ2=365.133, P<0.001); The TyG-WHR index was divided into four groups according to the interquartile range, and the Q2- Q4 group had an increased risk of developing new retinal arteriosclerosis compared to Q1 ( χ2=132.887, P<0.001).In the restricted cubic spine regression model, the results showed a non-linear dose-response relationship ( χ2=54.27, P<0.001) between baseline TyG-WHR index and the new-onset of retinal arteriosclerosis. By the multivariate Cox Regression models, three models were constructed in this study. TyG-WHR index was positively correlated with the risk of retinal arteriosclerosis: the HR (95% CI) of model 1-3 was 1.534,1.517 and 1.502.The AUC curve analysis verified that the prediction AUC of the TyG-WHR index for new-onset retinal arteriosclerosis was 0.755, the best prediction value was 7.343, the sensitivity was 90.2%, and the specificity was 75.60%. Conclusion:TyG-WHR index may be an independent risk factor for new-onset retinal arteriosclerosis.

Objective To explore the regulatory role of N-methyl berbamine(N-MB)in intracellular calcium homeostasis in H9c2 car-diomyocytes,and,thereby,clarify the possible mechanism of the myocardial protective effect of N-MB.Methods Binding of N-MB to CaV1.2 channels was simulated using the MOE software,and the binding affinity and binding mode were determined.The hCaV1.2 gene was transfected into HEK293 cells,and the effect of N-MB(30 μmol/L)on the CaV1.2 current was detected using the whole-cell patch clamp technique.In addition,a Fluo 3-AM fluorescent probe was loaded into H9c2 cardiomyocytes,and the effect of N-MB(3,30 μmol/L)on intracellular calcium ion concentration was observed under a laser confocal microscope.The effect of N-MB(3,30 μmol/L)on the expression of Ca2+regulation-related genes Cacna1c,Cacnb2,Ryr2,Serca2a,and Ncx1 in H9c2 cardiomyocytes was examined using real-time quantitative PCR.Results N-MB was predicted to bind to CaV1.2 channels.The binding sites mainly involved Phe1191,Thr1420,and Asn771,and the binding modes were H-donor,pi-pi,and pi-H.N-MB(30 μmol/L)significantly inhibited CaV1.2 currents,with an inhibition rate of 76.09％±7.41％.The fluorescence intensity of intracellular Ca2+level in H9c2 cardiomyocytes was significantly enhanced with N-MB treatment(3,30 μmol/L,P＜0.01).Compared with the control group,differences in the expression of Cacna1c,Serca2a,and Ncx1 in H9c2 cardiomyocytes were not significant after N-MB(3,30 μmol/L)intervention(P＞0.05),whereas the expression of Cacnb2 significantly reduced(P＜0.001)and the expression of Ryr2 significantly increased(P＜0.05).Conclusion N-MB binds to CaV1.2 calcium channels.N-MB may regulate intracellular calcium homeostasis by inhibiting calcium currents by decreasing the gene expression of CaV1.2 calcium channels.Additionally,N-MB may also increase intracellular Ca2+concentration by promoting the expression of Ryr2,which could be the mechanism underlying the myocardial protective effect of N-MB.

Objective:To investigate the relationship between Triglyceride Glucose-WHR index and retinal arteriosclerosis.Methods:Retrospective longitudinal cohort research method. Using data from the Tongren Health Care Study of Beijing Tongren Hospital from March 2014 to June 2020. The TyG-WHR index was calculated, the restricted cubic spine regression model was used to explore the dose-response relationship between TyG-WHR index and the risk of retinal arteriosclerosis. Cox proportional regression model was implemented to estimate the impact on the risk of retinal arteriosclerosis associated with the different TyG-WHR groups. Receiver operating characteristic were used to explore the value of triglyceride glucose-WHR index for the risk of retinal arteriosclerosis.Results:A total of 8 215 subjects were included, including 3 334 (40.58%) males, 4 881 (59.42%) females;7 689 cases had normal fundus, 296 cases had newly developed retinal arteriosclerosis, and 230 cases had retinal arteriosclerosis. The median age is 45 years old, and the average age is (47.63±13.89) years old. The cumulative incidence rate of new retinal arteriosclerosis was 3.71%(296/7 985), and the cumulative incidence rate of women (3.31%,158/4 767) was lower than that of men (4.29%, 138/3 218) ( χ2=5.105, P<0.001); The cumulative incidence rate of new retinal arteriosclerosis increased with age ( χ2=365.133, P<0.001); The TyG-WHR index was divided into four groups according to the interquartile range, and the Q2- Q4 group had an increased risk of developing new retinal arteriosclerosis compared to Q1 ( χ2=132.887, P<0.001).In the restricted cubic spine regression model, the results showed a non-linear dose-response relationship ( χ2=54.27, P<0.001) between baseline TyG-WHR index and the new-onset of retinal arteriosclerosis. By the multivariate Cox Regression models, three models were constructed in this study. TyG-WHR index was positively correlated with the risk of retinal arteriosclerosis: the HR (95% CI) of model 1-3 was 1.534,1.517 and 1.502.The AUC curve analysis verified that the prediction AUC of the TyG-WHR index for new-onset retinal arteriosclerosis was 0.755, the best prediction value was 7.343, the sensitivity was 90.2%, and the specificity was 75.60%. Conclusion:TyG-WHR index may be an independent risk factor for new-onset retinal arteriosclerosis.

Objective To explore the regulatory role of N-methyl berbamine(N-MB)in intracellular calcium homeostasis in H9c2 car-diomyocytes,and,thereby,clarify the possible mechanism of the myocardial protective effect of N-MB.Methods Binding of N-MB to CaV1.2 channels was simulated using the MOE software,and the binding affinity and binding mode were determined.The hCaV1.2 gene was transfected into HEK293 cells,and the effect of N-MB(30 μmol/L)on the CaV1.2 current was detected using the whole-cell patch clamp technique.In addition,a Fluo 3-AM fluorescent probe was loaded into H9c2 cardiomyocytes,and the effect of N-MB(3,30 μmol/L)on intracellular calcium ion concentration was observed under a laser confocal microscope.The effect of N-MB(3,30 μmol/L)on the expression of Ca2+regulation-related genes Cacna1c,Cacnb2,Ryr2,Serca2a,and Ncx1 in H9c2 cardiomyocytes was examined using real-time quantitative PCR.Results N-MB was predicted to bind to CaV1.2 channels.The binding sites mainly involved Phe1191,Thr1420,and Asn771,and the binding modes were H-donor,pi-pi,and pi-H.N-MB(30 μmol/L)significantly inhibited CaV1.2 currents,with an inhibition rate of 76.09％±7.41％.The fluorescence intensity of intracellular Ca2+level in H9c2 cardiomyocytes was significantly enhanced with N-MB treatment(3,30 μmol/L,P＜0.01).Compared with the control group,differences in the expression of Cacna1c,Serca2a,and Ncx1 in H9c2 cardiomyocytes were not significant after N-MB(3,30 μmol/L)intervention(P＞0.05),whereas the expression of Cacnb2 significantly reduced(P＜0.001)and the expression of Ryr2 significantly increased(P＜0.05).Conclusion N-MB binds to CaV1.2 calcium channels.N-MB may regulate intracellular calcium homeostasis by inhibiting calcium currents by decreasing the gene expression of CaV1.2 calcium channels.Additionally,N-MB may also increase intracellular Ca2+concentration by promoting the expression of Ryr2,which could be the mechanism underlying the myocardial protective effect of N-MB.