Breast cancer prevention and treatment have become major issues that urgently need to be addressed in the field of global public health. As a key pathological transitional stage in the progression of breast cancer， preneoplastic breast cancer （PBC） carries a significant risk of clinical transformation. Effective intervention in the progression of PBC is of great clinical significance in preventing the occurrence of breast cancer. Pathological studies have shown that abnormal angiogenesis is a key mechanism driving the transformation of PBC into breast cancer. Vascular endothelial growth factor （VEGF）， as a core regulatory molecule that promotes angiogenesis， plays a pivotal role in this process. The malignant transformation of PBC is closely associated with the abnormal activation of the VEGF-mediated pro-angiogenic network. Although modern medicine has achieved certain therapeutic effects through surgery and endocrine therapy， clinical limitations such as invasiveness， drug resistance， and adverse reactions still exist. Recent studies have demonstrated that the VEGF signaling system mediates the phosphatidylinositol 3-kinase-protein kinase B （PI3K/Akt） signaling pathway and the mitogen-activated protein kinase （MAPK） pathway. In addition， the hypoxia-inducible factor-1α （HIF-1α）/VEGF signaling pathway and the delta-like ligand 4 （DLL4）/Notch receptor 1 （Notch1） signaling pathway， together with other pathways， form a complex regulatory network that plays a central role in angiogenesis during PBC. Traditional Chinese medicine （TCM）， characterized by multi-component synergy， multi-pathway regulation， and high safety， demonstrates significant advantages in inhibiting pathological angiogenesis and blocking PBC progression by targeting the VEGF signaling pathway. From the perspective of VEGF pathway regulation， this paper systematically reviews the latest research progress on TCM in inhibiting angiogenesis and intervening in PBC， and discusses its mechanisms and application value in the early prevention and treatment of PBC， with the aim of providing references for optimizing clinical intervention strategies for PBC.

Due to patient compliance and convenience, oral medication is likely the most common and acceptable method of drug administration. However, traditional dosage forms such as tablets or capsules may lead to low drug bioavailability and poor therapeutic efficiency. Therefore, with advancements in material science and micro/nano manufacturing technology, various carriers have been developed to enhance drug absorption in the gastrointestinal tract. In this context, we initially discuss the key biological factors that hinder drug transport and absorption (including anatomical, physical, and biological factors). Building on this foundation, recent progress in both conventional and innovative oral drug delivery routes aimed at improving drug bioavailability and targeting is reviewed. Finally, we explore future prospects for oral drug delivery systems as well as potential challenges in clinical translation.

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

Objective:By analyzing the genetic risk of triglyceride-glucose index(Tyg)and insulin resistance(IR)for cardiovascular disease(CVD), to elucidate the extent to which the contribution of Tyg to the risk of CVD development is influenced by IR genetic risk.Methods:In this study, we selected data from a cohort of elderly people in the Kunshan community, screened 7, 385 individuals with both clinical and genomic data, and calculated the polygenic risk score of insulin resistance(IRPRS)for each participant based on publicly available IR genome-wide association data, and assessed the effect of genetic risk and Tyg level on the risk of developing CVD using a multivariate Cox proportional risk model.Calculating interactions to assess the effects of genetic risk and Tyg levels on the risk of developing CVD, the effects of Tyg tertile grouping and IRPRS on the risk of developing CVD were assessed using a multivariate Cox proportional risk model, and subgroup analyses were performed for gender to assess the effects of Tyg tertile grouping and IRPRS on the risk of developing CVD by gender.Results:In the univariate Cox model, Q3 and IRPRS with the highest TYG levels were significantly associated with the risk of CVD, respectively( HR=1.59, 95% CI: 1.33-1.89; P<0.001; HR=1.61, 95% CI: 1.18-2.20; P=0.003).After adjusting for multiple confounders, the Q3 Group with the highest TYG level was still significantly associated with the risk of CVD( HR=1.28, 95% CI: 1.05-1.57; P=0.014), the Association of TYG with the risk of CVD did not change significantly( HR=1.29, 95% CI: 1.05-1.57; P=0.014).We conducted a subgroup analysis by sex and found that among older men, 13, the highest levels of TYG and IRPRS were significantly associated with CVD risk, respectively( HR=1.70, 95% CI: 1.31.2.20; P<0.001; HR=1.98, 95% CI: 1.24-3.15; P=0.004).After adding IRPRS to the model, the Association of TYG with the risk of CVD remained unchanged( HR=1.69, 95% CI: 1.31-2.19; P<0.001).After adjusting for various confounders, Tyg remained significantly associated with the risk of CVD( HR=1.39, 95% CI: 1.04-1.88; P=0.028), the results showed that TYG remained significantly associated with the risk of CVD( HR=1.41, 95% CI: 1.05-1.90; P=0.023), and the association did not decrease.No Association of IRPRS with CVD risk was found in older women. Conclusions:IRPRS and TYG are the risk factors of CVD, and diet, exercise, drugs and other external factors on TYG are the main risk factors of CVD.For individuals with high genetic factors, the risk of CVD can still be reduced by lifestyle adjustments such as diet, exercise and drug intervention.

Objective:By analyzing the genetic risk of triglyceride-glucose index(Tyg)and insulin resistance(IR)for cardiovascular disease(CVD), to elucidate the extent to which the contribution of Tyg to the risk of CVD development is influenced by IR genetic risk.Methods:In this study, we selected data from a cohort of elderly people in the Kunshan community, screened 7, 385 individuals with both clinical and genomic data, and calculated the polygenic risk score of insulin resistance(IRPRS)for each participant based on publicly available IR genome-wide association data, and assessed the effect of genetic risk and Tyg level on the risk of developing CVD using a multivariate Cox proportional risk model.Calculating interactions to assess the effects of genetic risk and Tyg levels on the risk of developing CVD, the effects of Tyg tertile grouping and IRPRS on the risk of developing CVD were assessed using a multivariate Cox proportional risk model, and subgroup analyses were performed for gender to assess the effects of Tyg tertile grouping and IRPRS on the risk of developing CVD by gender.Results:In the univariate Cox model, Q3 and IRPRS with the highest TYG levels were significantly associated with the risk of CVD, respectively( HR=1.59, 95% CI: 1.33-1.89; P<0.001; HR=1.61, 95% CI: 1.18-2.20; P=0.003).After adjusting for multiple confounders, the Q3 Group with the highest TYG level was still significantly associated with the risk of CVD( HR=1.28, 95% CI: 1.05-1.57; P=0.014), the Association of TYG with the risk of CVD did not change significantly( HR=1.29, 95% CI: 1.05-1.57; P=0.014).We conducted a subgroup analysis by sex and found that among older men, 13, the highest levels of TYG and IRPRS were significantly associated with CVD risk, respectively( HR=1.70, 95% CI: 1.31.2.20; P<0.001; HR=1.98, 95% CI: 1.24-3.15; P=0.004).After adding IRPRS to the model, the Association of TYG with the risk of CVD remained unchanged( HR=1.69, 95% CI: 1.31-2.19; P<0.001).After adjusting for various confounders, Tyg remained significantly associated with the risk of CVD( HR=1.39, 95% CI: 1.04-1.88; P=0.028), the results showed that TYG remained significantly associated with the risk of CVD( HR=1.41, 95% CI: 1.05-1.90; P=0.023), and the association did not decrease.No Association of IRPRS with CVD risk was found in older women. Conclusions:IRPRS and TYG are the risk factors of CVD, and diet, exercise, drugs and other external factors on TYG are the main risk factors of CVD.For individuals with high genetic factors, the risk of CVD can still be reduced by lifestyle adjustments such as diet, exercise and drug intervention.

Objective To investigate the therapeutic effect and mechanism of Jianwei Xiaozhang Tablets on rats with precancerous lesions of gastric cancer(PLGC).Methods Forty male SD rats were randomly divided into the normal group,the model group,the folic acid group and the Jianwei Xiaozhang Tablets group,with 10 rats in each group.In addition to the normal group,the other three groups of rats were prepared by gavage with Ranitidine Aqueous Solution combined with N-methyl-N'-nitro-N-nitrosoguanidine(MNNG)solution drinking method for the preparation of PLGC model.After successful modeling,drugs were administered accordingly for 7 weeks.The changes in body mass of rats during modeling and drug administration were recorded,the gross view of the stomach was observed and scored pathologically,the coefficients of spleen and liver were determined,the pathological changes in gastric tissue were observed by hematoxylin-eosin(HE)staining,enzyme-linked immunosorbent assay(ELISA)was used to measure serum gastrin(GAS),motilin(MTL)and glucagon(GC),Alisin Blue-Periodic Acid Schiff's(AB-PAS)staining was used to observe the thickness of the mucosal layer of gastric tissues,the expressions of phosphatidylinositol 3-kinase(PI3K),phosphorylated PI3K(p-PI3K),protein kinase B(Akt),phosphorylated Akt(p-Akt),and endothelial-type nitric oxide synthase(eNOS)proteins in gastric tissues were detected by protein immunoblotting(Western Blot),and the expression of vascular endothelial growth factor A(VEGFA)protein in gastric tissues was detected by immunofluorescence staining.Results Compared with the normal group,the body mass of rats in the model group grew slowly during the experimental period,gastric macroscopic pathological scores were significantly increased(P＜0.01),splenic coefficient and hepatic coefficient were significantly decreased(P＜0.01),the gastric tissues showed cuprocyte hyperplasia and intestinal chemotaxis,gastric tissues'inflammation scores were significantly increased(P＜0.01),the serum GAS content was significantly increased(P＜0.01),and the MTL,GC contents were significantly reduced(P＜0.05),and the thickness of the mucous membrane layer of gastric tissue was significantly reduced(P＜0.05),the protein expression levels of PI3K,p-PI3K,Akt,p-Akt and eNOS were reduced(P＜0.01),and the protein expression level of VEGFA was reduced(P＜0.01);compared with the model group,the above indexes of the Jianwei Xiaozhang Tablets group and the folic acid group were all significantly improved(P＜0.05 or P＜0.01),among which,the Jianwei Xiaozhang Tablets group had a better improvement effect in the proliferation of cup cells and intestinal chemotaxis in gastric tissues,the content of serum GAS,and the thickness of the mucous layer in gastric tissues.Conclusion The mechanism of the improvement of PLGC in rats by Jianwei Xiaozhang Tablets may be related to the activation of the PI3K-Akt-eNOS pathway,which in turn promotes the angiogenesis and repair of gastric damaged tissues.

Objective:Trigeminal neuralgia(TN)is a severe chronic neuropathic pain that mainly affects the distribution area of the trigeminal nerve with limited treating efficacy.There are numerous treatments for TN,but currently the main clinical approach is to suppress pain by carbamazepine(CBZ).Brain-derived neurotrophic factor(BDNF)is closely related to chronic pain.This study aims to determine the effects of CBZ treatment on BDNF expression in both the trigeminal ganglion(TG)and serum of TN via a chronic constriction injury of the infraorbital nerve(ION-CCI)rat model. Methods:The ION-CCI models were established in male Sprague-Dawley rats and were randomly divided into a sham group,a TN group,a TN+low-dose CBZ treatment group(TN+20 mg/kg CBZ group),a TN+medium-dose CBZ treatment group(TN+40 mg/kg CBZ group),and a TN+high-dose CBZ treatment group(TN+80 mg/kg CBZ group).The mechanical pain threshold in each group of rats was measured regularly before and after surgery.The expressions of BDNF and tyrosine kinase receptor B(TrkB)mRNA in TGs of rats in different groups were determined by real-time PCR,and the expression of BDNF protein on neurons in TGs was observed by immunofluorescence.Western Blotting was used to detect the protein expression of BDNF,TrkB,extracellular regulated protein kinases(ERK),and phospho-extracellular regulated protein kinases(p-ERK)in TGs of rats in different groups.The expression of BDNF in the serum of rats in different groups was detected by enzyme-linked immunosorbent assay(ELISA). Results:The results of mechanical pain sensitivity showed that there was no significant difference in the mechanical pain threshold in the right facial sensory area of the experimental rats in each group before surgery(all P>0.05).From the 3rd day after operation,the mechanical pain threshold of rats in the TN group was significantly lower than that in the sham group(all P<0.01),and the mechanical pain threshold of rats in the TN+80 mg/kg CBZ group,the TN+40 mg/kg CBZ group,and the TN+20 CBZ mg/kg group was higher than that in the TN group(all P<0.05).The BDNF and TrkB mRNA and protein expressions in TGs of rats in the TN group were higher than those in the sham group(all P<0.05),and those in the TN+80 mg/kg CBZ group,the TN+40 mg/kg CBZ group,and the TN+20 mg/kg CBZ group were lower than the TN group(all P<0.05).The p-ERK levels in TG of rats in the TN+80 mg/kg CBZ group,the TN+40 mg/kg CBZ group,and the TN+20 mg/kg CBZ group were significantly decreased compared with the TN group(all P<0.05).The BDNF and neuron-specific nuclear protein(NeuN)were mainly co-expressed in neuron of TGs in the TN group and they were significantly higher than those in the sham group(all P<0.05).The co-labeled expressions of BDNF and NeuN in TGs of the TN+ 80 mg/kg CBZ group,the TN+40 mg/kg CBZ group,and the TN+20 mg/kg CBZ group were lower than those in the TN group(all P<0.05).The results of ELISA showed that the level of BDNF in the serum of the TN group was significantly higher than that in the sham group(P<0.05).The levels of BDNF in the TN+80 mg/kg CBZ group,the TN+40 mg/kg CBZ group,and the TN+20 mg/kg CBZ group were lower than those in the TN group(all P<0.05).Spearman correlation analysis showed that the BDNF level in serum was negatively correlated with mechanical pain threshold(r=-0.650,P<0.01). Conclusion:CBZ treatment can inhibit the expression of BDNF and TrkB in the TGs of TN rats,reduce the level of BDNF in serum of TN rats and the phosphorylation of ERK signaling pathway,so as to inhibit TN.The serum level of BDNF can be considered as an indicator for the diagnosis and prognosis of TN.

Objective To investigate the expression of angiopoietin 1 and 2(Ang1,Ang2)in diffuse large B-cell lymphoma(DLBCL)and its survival prognosis analysis.Methods Peripheral blood was collected from 32 patients with initially diagnosed DLBCL and 30 healthy volunteers(the health control group),and the serum Ang1 and Ang2 levels were detected by ELISA.The biopsy tissues from DLBCL patients and the resec-ted normal lymph node biopsy tissues in neck surgery of 25 patients with non-tumor lesions(the control group)were taken as the specimens.The immunohistochemistry was used to detect the expression of CD34 in lymphoid tissues and the microvessel density was calculated;the statistical analyses were carried out by combi-ning with the clinical characteristics of the DLBCL patients and the follow-up data.Results The serum Ang1 level in initially diagnosed DLBCL was higher than that in the healthy control group[(36.22±9.12)ng/mL vs.(30.92±13.37)ng/mL],and the serum Ang2 level in initially diagnosed DLBCL was higher than that in the healthy control group[(28.42±10.78)ng/mL vs.(23.81±3.68))ng/mL],and the differences were sta-tistically significant(P＜0.05).CD34 was highly expressed in the lymphoma tissues of the patients with DL-BCL,whereas CD34 in normal lymph node tissues was weakly expressed;the microvessel density count in the DLBCL group was increased compared with the normal lymph node group(25.5±4.4 vs.13.2±3.0,P＜0.05).The Ang1 expression level had no significant correlation with the gender,age,IPI score,clinical stage and COO subtype.The Ang2 expression was correlated with the clinical stage,Ang2 was lowly expressed in the patients with stage Ⅰ-Ⅱ DLBCL,while which was highly expressed in the patients with stage Ⅲ-Ⅳ(P＜0.05);Ang2 had no significant correlation with the gender,age,IPI score and COO subtype.The OS time had no significant difference between the patients with Ang1 low expression and the patients with Ang1 high expression(25.86 months vs.23.11 months,P=0.722);the OS time in the patients with Ang2 low ex-pression was significantly higher than in the patients with high Ang2 expression(32.24 months vs.17.66 months,P=0.002).In the univariate analysis,Ann Arbor stage,IPI score and Ang2 all were the prognostic factors affecting the patients'OS,while gender,age and Ang1 had no significant correlation with the patients'OS.In Cox multifactorial analysis,the Ann Arbor stage,IPI score and Ang2 all were the independent prog-nostic factors affecting the patients'OS.prognostic factors.Conclusion Ang1 and Ang2 are highly expressed in DLBCL patients and promote lymphoma angiogenesis;Ang2 affects the survival prognosis of DLBCL patients.

Ameloblastoma is a benign tumor characterized by locally invasive phenotypes,leading to facial bone destruction and a high recurrence rate.However,the mechanisms governing tumor initiation and recurrence are poorly understood.Here,we uncovered cellular landscapes and mechanisms that underlie tumor recurrence in ameloblastoma at single-cell resolution.Our results revealed that ameloblastoma exhibits five tumor subpopulations varying with respect to immune response(IR),bone remodeling(BR),tooth development(TD),epithelial development(ED),and cell cycle(CC)signatures.Of note,we found that CC ameloblastoma cells were endowed with stemness and contributed to tumor recurrence,which was dominated by the EZH2-mediated program.Targeting EZH2 effectively eliminated CC ameloblastoma cells and inhibited tumor growth in ameloblastoma patient-derived organoids.These data described the tumor subpopulation and clarified the identity,function,and regulatory mechanism of CC ameloblastoma cells,providing a potential therapeutic target for ameloblastoma.