Arginine methylation is a critical post-translational modification that plays multifaceted biological functions. However, the manipulation of protein arginine methylation largely depends on genetic or pharmaceutic inhibition of the regulatory enzymes, protein arginine methyltransferases (PRMTs), or non-methylation substitution of corresponding arginine residue to lysine or alanine of protein of interest (POI), which inevitably affects other substrates, or disrupts the structure of POI. Thus, it urges an approach to specifically modulate the arginine methylation of a POI under physiological conditions. To this end, we report the discovery of a methylation tagging system (MeTAG), that enables targeted modification of protein arginine methylation. Through bridging the methyltransferase PRMT5 proximity to a POI, MeTAG facilitates the arginine methylation of POIs, including known arginine methylated proteins, androgen receptor (AR) and protein kinase B (AKT), as well as a neo-substrate E1A binding protein (p300), in a reversible and PRMT5-dependent manner. Moreover, MeTAG can regulate downstream signaling in a methylation dependent manner, leading to downregulation of PSMA mRNA level and activation of AKT. Therefore, MeTAG represents a feasible approach to modulate protein methylation and thereby perturbs protein function in biological and therapeutic contexts.

Objective:A C57/BL6 mouse model of traumatic temporomandibular joint ankylosis (TTMJA) was established through composite trauma to lay the foundation for studying the pathophysiology of TTMJA.Methods:This study was conducted from January 2024 to February 2025. Forty-two 4-weeks old C57/BL6 mice, numbered 1 to 42, are randomly assigned to a control group ( n=21) and an experimental group ( n=21) using a computer-generated random number sequence. The experimental group undergoes modeling surgery on the left temporomandibular joint (TMJ), while the control group is routinely raised without special treatment. At 12 weeks post-surgery, the TMJ complex of both groups is assessed via body weight and mouth opening measurements, gross observation, micro-CT, and histological staining to evaluate model establishment. Results:At 12 weeks post-operation, in the experimental group, the body weight of mice [(27.75±1.08) g] did not show a significant difference compared with that of the control group [(30.80±0.29) g]( t=0.54, P=0.610). The maximum vertical passive mouth opening [(1.70±0.26) mm] in the experimental group was significantly lower than that in the control group [(3.43±0.21) mm]( t=8.92, P<0.001). Gross observation indicated that the right TMJ structure of the experimental-group mice was normal, while irregular hyperplasia occurred in the left TMJ complex. Micro-CT revealed that at 12 weeks post-operation, the right joint structure of the experimental-group mice was normal, with regular condyles and glenoid fossae. On the left side, a large amount of bone hyperplasia occurred on the lateral side of the joint in the condyles and glenoid fossae, forming two irregular bone masses, and there was an uncalcified radiolucent zone between the bone masses. In histological staining, no new cartilage or bone tissue was observed in the left joint space of the control-group mice, and the articular disc structure was normal. In the experimental-group mice, obvious new cartilage and calcified bone tissue were visible on the lateral side of the left joint space. A bone bridge was formed between the condyles and glenoid fossae, the articular disc structure disappeared, and bony ankylosis occurred. Conclusions:In this experiment, a TTMJA model of C57/BL6 mice was initially established by removing the articular disc and damaging part of the fibrous cartilage of the glenoid fossae and condyles, providing an experimental platform for further research on the pathogenesis of TTMJA.

Objective:A C57/BL6 mouse model of traumatic temporomandibular joint ankylosis (TTMJA) was established through composite trauma to lay the foundation for studying the pathophysiology of TTMJA.Methods:This study was conducted from January 2024 to February 2025. Forty-two 4-weeks old C57/BL6 mice, numbered 1 to 42, are randomly assigned to a control group ( n=21) and an experimental group ( n=21) using a computer-generated random number sequence. The experimental group undergoes modeling surgery on the left temporomandibular joint (TMJ), while the control group is routinely raised without special treatment. At 12 weeks post-surgery, the TMJ complex of both groups is assessed via body weight and mouth opening measurements, gross observation, micro-CT, and histological staining to evaluate model establishment. Results:At 12 weeks post-operation, in the experimental group, the body weight of mice [(27.75±1.08) g] did not show a significant difference compared with that of the control group [(30.80±0.29) g]( t=0.54, P=0.610). The maximum vertical passive mouth opening [(1.70±0.26) mm] in the experimental group was significantly lower than that in the control group [(3.43±0.21) mm]( t=8.92, P<0.001). Gross observation indicated that the right TMJ structure of the experimental-group mice was normal, while irregular hyperplasia occurred in the left TMJ complex. Micro-CT revealed that at 12 weeks post-operation, the right joint structure of the experimental-group mice was normal, with regular condyles and glenoid fossae. On the left side, a large amount of bone hyperplasia occurred on the lateral side of the joint in the condyles and glenoid fossae, forming two irregular bone masses, and there was an uncalcified radiolucent zone between the bone masses. In histological staining, no new cartilage or bone tissue was observed in the left joint space of the control-group mice, and the articular disc structure was normal. In the experimental-group mice, obvious new cartilage and calcified bone tissue were visible on the lateral side of the left joint space. A bone bridge was formed between the condyles and glenoid fossae, the articular disc structure disappeared, and bony ankylosis occurred. Conclusions:In this experiment, a TTMJA model of C57/BL6 mice was initially established by removing the articular disc and damaging part of the fibrous cartilage of the glenoid fossae and condyles, providing an experimental platform for further research on the pathogenesis of TTMJA.

Objective To explore the relationship between the triglyceride-glucose(TyG)index,residual cholesterol(RC)and dia-betic nephropathy(T2DM).Methods A total of 410 patients with T2DM were consecutively selected from the Endocrinology Depart-ment of Jiangsu Provincial Traditional Chinese Medicine Hospital from March 2022 to March 2023.The patients were stratified into three groups based on their morning urinary albumin-to-creatinine ratio(UACR):269 patients were in simple diabetes mellitus(SDM)group,80 in early diabetic nephropathy(EDN)group and 61 in clinical diabetic nephropathy(CDN)group.Comparative an-alyses were conducted on the three groups in terms of gender,age,past medical history,body mass index(BMI),systolic blood pres-sure(SBP),diastolic blood pressure(DBP),fasting blood glucose(FBG),Urea,creatinine(Cr),urinary albumin(UA)total cholesterol(TC),triglycerides(TG),high-density lipoprotein cholesterol(HDL-C),and low-density lipoprotein cholesterol(LDL-C).Additionally,TyG index and RC were calculated.Spearman analysis was employed to evaluate the correlation between UACR and these various parameters.Binary Logistic regression was utilized to identify independent risk factors for diabetic nephropathy(DN).The diagnostic performances of Urea,Cr,TyG index and RC for type 2 diabetic nephropathy were assessed using receiver operating charac-teristic(ROC)curve analyses.Results Compared with SDM group,diabetes duration,SBP,Urea,UA,TG,TC,TyG index and RC showed significant increases in EDN group with statistically significant differences(P＜0.05),and diabetes duration,SBP,DBP,Urea,Cr,UA,TG,TC,LDL-C,TyG index and RC in CDN group also exhibited significant increases,with statistically significant differences(P＜0.05).Spearman rank correlation analysis revealed a positive correlation between RC and UACR(r=0.278,P＜0.001),a positive correlation between TyG index and UACR(r=0.239,P＜0.001)and a positive correlation between RC and TyG in-dex(r=0.562,P＜0.001).Binary logistic regression analysis showed that diabetes duration,SBP,Urea,Cr,TyG index(OR=2.815,95％CI:1.481-5.349,P=0.002),and RC(OR=2.179,95％CI:1.038-4.574,P=0.04)were independent risk factors for DN.The area under the ROC curve(AUCROC)for RC predicting DN occurrence was 0.670(95％CI:0.616-0.725),while the AUCROC for the TyG index was 0.620(95％CI:0.564-0.676).Conclusion TyG index and RC were significantly correlated with the development of DN in the patients with T2DM,which may early facilitate clinical identification and management for the patients in the risk ofr diabetic kidney disease.

Objective To explore the optimal postoperative adjuvant regimens for patients with stage IB lung adenocarcinoma.Methods We respectively analyzed the data of 653 patients undergoing surgery for stage IB lung adenocarcinoma in our hospital from January,2013 to December,2021.The 5-year disease-free survival(DFS)and overall survival(OS)rates were compared among the patients receiving postoperative adjuvant therapy with epidermal growth factor-tyrosine kinase inhibitors(EGFR-TKIs group,n=111),chemotherapy(CT group,n=108)and clinical observation(CO group,n=434).Results In TKIs,CT,and CO groups,the 5-year DFS rates were 92.8%,80.7%,and 81.7%,respectively,significantly higher in TKIs group than in CO group(P<0.01).The 3-year OS rates of the 3 groups were 96.8%,97.1%,and 91.7%,respectively.Subgroup analysis showed that in TKIs,CT,and CO groups,the 5-year DFS rates of patients with with T3-4 cmN0M0 were 92.6%,84.0%,and 81.4%,respectively,significantly higher in TKIs group than in CO group(P<0.05);the 5-year DFS rates of T2ViscPlN0M0 patients were 95.1%,71.4%,and 83.5%,respectively.Multivariate COX regression analysis showed that age(P<0.05;HR=0.631,95%CI:0.401-0.993),solid nodules(P<0.01;HR=7.620,95%CI:3.037-19.121),micropapillary or solid component(P<0.05;HR=1.776,95%CI:1.010-3.122),lymphovascular invasion(P<0.05;HR=2.981,95%CI:1.198-7.419),and adjuvant therapy(P<0.01)were independent predictors of DFS.The most common adverse effects included rashes,paronychia,and diarrhea for TKIs and hematological suppression and gastrointestinal reactions for chemotherapy,and TKIs were associated with a higher incidence of grade 3 or above adverse effects(44.4%vs 9.0%).Conclusion Adjuvant therapy with TKIs helps improve DFS in patients with stage IB(T3-4cmN0M0)lung adenocarcinoma but not in patients with T2ViscPlN0M0.Adjuvant chemotherapy does not improve DFS or OS in patients with stage IB lung adenocarcinoma.

Objective To explore the optimal postoperative adjuvant regimens for patients with stage IB lung adenocarcinoma.Methods We respectively analyzed the data of 653 patients undergoing surgery for stage IB lung adenocarcinoma in our hospital from January,2013 to December,2021.The 5-year disease-free survival(DFS)and overall survival(OS)rates were compared among the patients receiving postoperative adjuvant therapy with epidermal growth factor-tyrosine kinase inhibitors(EGFR-TKIs group,n=111),chemotherapy(CT group,n=108)and clinical observation(CO group,n=434).Results In TKIs,CT,and CO groups,the 5-year DFS rates were 92.8%,80.7%,and 81.7%,respectively,significantly higher in TKIs group than in CO group(P<0.01).The 3-year OS rates of the 3 groups were 96.8%,97.1%,and 91.7%,respectively.Subgroup analysis showed that in TKIs,CT,and CO groups,the 5-year DFS rates of patients with with T3-4 cmN0M0 were 92.6%,84.0%,and 81.4%,respectively,significantly higher in TKIs group than in CO group(P<0.05);the 5-year DFS rates of T2ViscPlN0M0 patients were 95.1%,71.4%,and 83.5%,respectively.Multivariate COX regression analysis showed that age(P<0.05;HR=0.631,95%CI:0.401-0.993),solid nodules(P<0.01;HR=7.620,95%CI:3.037-19.121),micropapillary or solid component(P<0.05;HR=1.776,95%CI:1.010-3.122),lymphovascular invasion(P<0.05;HR=2.981,95%CI:1.198-7.419),and adjuvant therapy(P<0.01)were independent predictors of DFS.The most common adverse effects included rashes,paronychia,and diarrhea for TKIs and hematological suppression and gastrointestinal reactions for chemotherapy,and TKIs were associated with a higher incidence of grade 3 or above adverse effects(44.4%vs 9.0%).Conclusion Adjuvant therapy with TKIs helps improve DFS in patients with stage IB(T3-4cmN0M0)lung adenocarcinoma but not in patients with T2ViscPlN0M0.Adjuvant chemotherapy does not improve DFS or OS in patients with stage IB lung adenocarcinoma.

Objective To investigate the role of immunoglobulin superfamily containing leucine-rich repeat protein(ISLR)in the malignant progression of osteosarcoma cells and its potential regulatory mechanism.Methods ISLR mRNA levels in osteosarcoma tissues and cells were detected by quantitative real time polymerase chain reaction(qRT-PCR).U2OS cells were transfected with ISLR short hairpin RNA(shRNA)sequence or negative-control shRNA(NC shRNA)sequence,thus the cells were treated with phosphatidylinositol 3 kinase(PI3K)activator 740 Y-P.The cell viability,invasion ability and apoptosis rate were detected by CCK-8 assay,Transwell assay and flow cytometry,respectively.Western blot was used to detect the expressions of ISLR protein,epithelial-mesenchymal transition(EMT)-related proteins[Epitheia-cadherin(E-cadherin),Nerve cadherin(N-cadherin),Vimentin,Snail],PI3K/protein kinase B(AKT)pathline-related proteins,apoptotic proteins[Cysteinyl aspartate-specific proteinase-3(Caspase-3),B cell lymphoma/leukemia-2(Bcl-2),Bcl-2 associated X protein(Bax)]and proliferation marker Ki67 protein.Lentivirus was used to transfect U2OS cells,and the cells were injected into nude mice to construct a xenograft tumor model,and tumor growth was monitored.Results ISLR mRNA level in osteosarcoma tissue(5.14±1.63)was up-regulated compared with para-cancerous tissue(1.01±0.02),and the difference was significant(t=-14.332,P＜0.001).Compared with normal osteoblasts hFOB1.19(1.01±0.01),osteosarcoma cells MG63(3.05±0.57),U2OS(4.55±0.79),HOS(2.46±0.41),the relative expression of ISLR mRNA in Saos-2(2.62±0.44)and 143B(3.62±0.51)were increased,and differences were significant(t=4.883,8.473,3.471,3.854,6.247,all P＜0.05).Silencing ISLR inhibited the proliferation of U2OS cells(t=6.593,6.835)and invasion(t=8.621,8.448),but promoted cell apoptosis(t=25.505,25.574),and the differences were significant(all P＜0.05).Silencing ISLR promoted Caspase-3 activity in U2OS cells(t=13.489,13.366)and Bax protein(t=8.628,8.524),but inhibited Bcl-2 protein expression(t=10.948,10.775),with significant differences(all P＜0.05).Silencing ISLR promoted EMT-related protein E-cadherin(t=15.168,15.087),inhibited N-cadherin(t=10.220,10.058),Vimentin(t=8.303,8.164)and Snail(t=9.211,9.384),but reduced the phosphorylation levels of PI3K and AKT(t=17.441,14.452),with significant differences(all P＜0.05).Additionally,740 Y-P treatment reversed the effect of silencing ISLR on U2OS cells.Experimental results in vivo showed that knockdown of ISLR significantly inhibited tumor growth.Conclusion ISLR could promote EMT,proliferation and invasion,but inhibit apoptosis of osteosarcoma cells by activating the PI3K/AKT pathway,there by promoting osteosarcoma progression.

Previous studies have found that As2 O3 can interfere with serum thyroid hormone TH levels in rats and cause chronic liver damage,but the mechanism remains unclear.In order to ex-plore the role of TH signaling pathway in As2 O3-induced chronic liver injury,qRT-PCR and West-ern blot techniques were used to detect the expression changes of genes and protein of TRβ1(a key regulator of TH signaling pathway in rat liver)and cyclin D1(the downstream factor of TRβ1 in nuclear pathway).Meanwhile,the changes in the protein of key factors(Bax,Bcl-2)of the TH sig-nal nuclear outside pathway were detected.The results indicated that:after As2 O3 treatment for 110 days,compared with the control group,the expression of TRβ1 protein in the liver of female mice significantly decreased(P＜0.01),the expression of cyclin D1 significantly increased in the 0.1 and 0.2 mg/L groups(P＜0.01).Meanwhile,the expression of TRβ1 protein in male mice sig-nificantly decreased in 0.4 mg/L group(P＜0.01),and the expression of cyclin D1 in each group significantly increased(P＜0.01).The mRNA expression results were basically the same as those of protein expression.After As2 O3 treatment for 194 days,compared with the control group,the expression of TRβ1 protein in each group significantly decreased(P＜0.01),and the expression of cyclin D1 significantly increased(P＜0.01).The mRNA expression results were basically consist-ent with the protein.As2 O3 interfered with the expression of Bcl-2 and Bax proteins in rats and in-duced the increase in the ratio of Bcl-2/Bax protein as the action time increased.Among them,the Bcl-2/Bax ratio of female rats in each group and male rats in the 0.4 mg/L group significantly in-creased(P＜0.01),and male rats in the 0.1 mg/L group significantly increased(P＜0.05).It shows that As2O3 can cause abnormal levels of TRβ1,cyclin D1 and the Bcl-2/Bax ratio in rat liv-er.

Harmine(HM)is a type of β-Carboline alkaloid abundant in nature and has many biological effects.In recent years.Studies have found that HM had a significant positive effect on Alzheimer's disease(AD)both in vivo and in vitro.Its mechanism may be related to the reduction of abnormal deposition of β-amyloid protein(Aβ),excessive phosphorylation of Tau protein,regulation of the cholinergic system,antioxidant stress,and antineuritis.This article reviews the research progress on the improvement effect and mechanism of HM in AD in order to provide an experimental basis for the clinical application of HM and the development of drugs in the area of AD the prevention and treatment.

Objective To investigate the causal association between bronchial asthma and bone mineral density at different sites using a two-sample Mendelian randomization (MR) approach. Methods Summary data for exposure factors and outcome were obtained from different genome-wide association studies.Single nucleotide polymorphisms strongly associated with bronchial asthma were selected as instrumental variables,and those in linkage disequilibrium were excluded.The inverse-variance weighted (IVW) method was used as the primary method for MR analysis,complemented by weighted median,simple mode,weighted mode,and MR-Egger regression methods.Sensitivity analyses were conducted to assess the stability of the results. Results The random-effects model of IVW analysis showed that heel bone mineral density (OR=0.986;95% CI,0.974 to 0.998;P=0.023) as the outcome dataset had a reverse causal effect with bronchial asthma,while lumbar spine bone mineral density (OR=1.031;95% CI,0.984 to 1.081;P=0.195),femoral neck bone mineral density (OR=1.014;95% CI,0.973 to 1.057;P=0.505),and forearm bone mineral density (OR=1.011;95% CI,0.935 to 1.094;P=0.775) as outcome datasets showed no causal effect with bronchial asthma.The MR-Egger intercept test results indicated that the P-values for the intercepts of lumbar bone mineral density,femoral neck bone mineral density,forearm bone mineral density,and calcaneal bone mineral density were all over 0.05,suggesting no horizontal pleiotropy and relatively stable results. Conclusion MR analysis reveals a reverse causal effect between bronchial asthma and heel bone mineral density,suggesting that clinicians should strengthen the monitoring of heel bone mineral density in patients with bronchial asthma to timely detect and intervene osteoporosis.