Diabetic cataract, a prevalent ocular complication of diabetes mellitus, arises from a complex interplay of pathological mechanisms, with oxidative stress and glycation stress playing central roles. Autophagy, a critical cellular self-protection mechanism, sustains intracellular homeostasis by selectively degrading damaged organelles and misfolded proteins, thereby counteracting the detrimental effects of oxidative and glycation stress under hyperglycemic conditions. Emerging evidence indicates a synergistic interaction between glycation stress and oxidative stress, which may exacerbate autophagic dysfunction and accelerate the onset and progression of diabetic cataract. However, the precise molecular mechanisms underlying this relationship remain incompletely understood. This review systematically examines the regulatory role of autophagy inthe pathogenesis of diabetic cataract, with a particular focus on how autophagic impairment influences disease progression under the combined effects of glycation and oxidative stress. By elucidating these mechanisms, the paper aims to provide novel insights into molecular diagnostic approaches and targeted therapeutic strategies for diabetic cataract.

Objective To investigate the role and mechanism of RNA-Specific adenosine deaminase 3 (Adar3) in regulating macrophage polarization during Coxsackievirus B3(CVB3)-induced viral myocarditis (VM). Methods Bone marrow-derived macrophages (BMDM) from mice were cultured in vitro and induced into M1/M2 macrophages using interferon-gamma (IFN-γ)/lipopolysaccharide (LPS) or interleukin 4 (IL-4), respectively. The mRNA expression levels of Adar1, Adar2, and Adar3 in each group of cells were assessed by real-time quantitative PCR (qRT-PCR). Specific siRNAs targeting the Adar3 gene were designed, synthesized, and transiently transfected into M2 macrophages. The mRNA levels of M2 polarization-related marker genes-including arginase 1 (Arg1), chitinase 3-like molecule 3 (YM1/Chi3l3), and resistin-like molecule alpha (RELMα/FIZZ1)-were detected by qRT-PCR. RNA sequencing was performed to analyze the signaling pathways affected by Adar3. The expression levels of Wnt/β-catenin signaling pathway were further validated using qRT-PCR and Western blot. The adeno-associated virus overexpressing Adar3 was designed, synthesized, and injected into mice via tail vein. Three weeks later, a myocarditis mouse model was established. After an additional week, the phenotype and function of cardiac macrophages, as well as multiple indicators of VM (including echocardiography, body weight, histopathology and serology) were examined. Additionally, the protein levels of the Wnt/β-catenin signaling pathway were assessed. Results Compared to M0-type macrophages, the expression level of Adar3 was significantly increased in M2-type macrophages. After transfection of Adar3 siRNA, the mRNA levels of Arg1, YM1 and FIZZ1 in M2 macrophages were downregulated. RNA sequencing revealed 149 upregulated genes and 349 downregulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and subsequent validation experiments indicated that Adar3 modulated the Wnt/β-catenin signaling pathway. In vivo experiments demonstrated that Adar3 overexpression alleviated the cardiac dysfunction of VM mice. The proportion of M1 macrophages in the heart decreased, while the proportion of M2 macrophages increased. At the same time, the Adar3 overexpression activated the Wnt/β-catenin signaling pathway. Conclusion Adar3 promotes macrophage polarization toward the M2 phenotype by activating the Wnt/β-catenin signaling pathway, thereby alleviating VM.
Animals ; Adenosine Deaminase/metabolism* ; Macrophages/immunology* ; Wnt Signaling Pathway/genetics* ; Myocarditis/immunology* ; Mice ; Coxsackievirus Infections/metabolism* ; Male ; Mice, Inbred BALB C ; Enterovirus B, Human/physiology* ; beta Catenin/genetics*

Most cancers are currently incurable, partly due to abnormal post-translational modifications (PTMs). In this study, we initially used multiple myeloma (MM) as a working model and found that SUMOylation activating enzyme subunit 1 (SAE1) promotes the malignancy of MM. Through proteome microarray analysis, SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine. Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo. Additionally, SAE1 directly SUMOylated and upregulated the total protein expression of p27, leading to LLPS-mediated nuclear export of p27. Our study also demonstrated the involvement of SAE1 in other types of cancer cells, and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine. Colchicine also showed promising results in the Patient-Derived Tumor Xenograft (PDX) model. Furthermore, a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine. Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export. SAE1 may serve as a promising therapeutic target, and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.

OBJECTIVE To clarify the institutional logics of the dilemma of the use of national medical insurance negotiation drugs（referred to as “national negotiation drugs”）， and promote the implementation and use of these drugs in medical institutions. METHODS Based on the complex institutional environment in which medical institutions were situated， the theory of multiple institutional logics was used to construct an analytical framework for the behavioral choices of medical institutions， and reveal the mechanism of the difficulty in the use of national negotiation drugs by clarifying the interaction and conflict of multiple logics in this process， so as to put forward some measures. RESULTS & CONCLUSIONS There were contradictions and coupling among the state logic， market logic， social logic and professional logic in the use of national negotiation drugs. In the game of multiple logics， the market logic and professional logic tended to be risk-averse， the failed “pressure-type system” of state logic， and the social logic was weakened， which caused the lack of action in the use of national negotiation drugs with the goal of completing performance evaluations in the current medical institutions. Thus， it is suggested to unbundle the invisible policy restrictions on the use of national negotiation drugs， form the pressure and motivation of medical institutions by incentive and constraint mechanisms， respond to the clinical demand by establishing a green procurement channel， and construct the supervision mechanism on the use of national negotiation drugs by social force， etc.， so as to enhance the effect of the national negotiation drugs.

Purpose To explore the predictive value of nomogram model for invasive breast cancer with axillary lymph node metastasis.Materials and Methods Retrospective analysis was made on 122 patients suspected to be breast cancer in the General Hospital of Ningxia Medical University from September 2020 to March 2022.According to whether there was axillary lymph node metastasis,all subjects were divided into 57 patients in the metastasis group and 65 patients in the non-metastasis group.All lesions were pathologically confirmed by surgery.The two groups received synthesis of magnetic resonance imaging(syMRI),dynamic contrast enhancement magnetic resonance imaging(DCE-MRI)and diffusion weighted imaging(DWI)scans.The syMRI parameters[including T1,T2,proton density(PD)],DCE-MRI time signal intensity curve,apparent diffusion coefficient(ADC)value of breast lesions were measured.Compared the difference of parameters between the two groups,and screened the independent risk factors of invasive breast cancer with axillary lymph node metastasis.Results Logistic regression results showed that Ki-67(OR=2.971,95%CI 1.306-6.762,P=0.009),lesion size(OR=1.652,95%CI 1.067-2.556,P=0.024),ADCratio(OR=1.685,95%CI 1.014-2.801,P=0.044),T2ratio(OR=3.015,95%CI 1.433-6.340,P=0.003),PDratio(OR=2.782,95%CI 1.471-5.262,P=0.002)were independent risk factors for invasive breast cancer with axillary lymph node metastasis.The comparison of the five models showed that the Logistic regression model had the best performance,with the area under curve of 0.729(95%CI 0.621-0.789),the accuracy,specificity and sensitivity were 70.65%,62.79%and 77.55%,respectively.The accuracy of the nomogram model was tested,and C-index=0.844,the accuracy of the nomogram model established was good,cut-off risk was 0.468,and the cut-off score was 143.50,which means that when the total score exceeds 143.50,the risk of axillary lymph node metastasis would be higher than 46.8%.Conclusion Nomogram model has a good predictive ability for invasive breast cancer patients with axillary lymph node metastasis.

Objective This study aimed to identify differentially methylated genes (DMGs) associated with natural killer cells in patients with autoimmune thyroiditis (AIT),focusing on the influence of varying water iodine exposure levels. Methods Participants were divided into categories based on median water iodine (MWI) concentrations:iodine-fortified areas (IFA,MWI<10 μg/L),iodine-adequate areas (IAA,40 ≤ MWI ≤ 100μg/L),and iodine-excessive areas (IEA,MWI>300 μg/L). A total of 176 matched AIT cases and controls were recruited and divided into 89,40,and 47 pairs for IFA,IAA,and IEA,respectively. DMGs were identified using 850K BeadChip analysis for 10/10 paired samples. Validation of DNA methylation and mRNA expression levels of the DMGs was conducted using MethylTarget? and QRT-PCR for 176/176 paired samples. Results KLRC1,KLRC3,and SH2D1B were identified as significant DMGs. Validation revealed that KLRC1 was hypomethylated and highly expressed,whereas KLRC3 was hypermethylated and highly expressed in individuals with AIT. Furthermore,KLRC1 was hypomethylated and highly expressed in both IFA and IEA. Conclusion The DNA methylation status of KLRC1 and KLRC3 may play crucial roles in AIT pathogenesis. Additionally,DNA methylation of KLRC1 seems to be influenced by different iodine concentrations in water.

Objective:To assess the association between short-term ambient air pollution exposure and arterial stiffness and whether obesity modifies these associations.Methods:A cross-sectional study was conducted based on Fangshan family cohort in Beijing. The 24 hours average air pollutant levels on the day cohort participants took baseline survey were calculated as short-term air pollution. A generalized additive model (GAM) with Gaussian links was used to estimate changes in typical carotid artery intima-media thickness (CIMT), brachial-ankle pulse wave velocity (BAPWV), pulse pressure (PP) and ankle-branchial index (ABI) after short-term exposure to each air pollution (PM 2.5, PM 10, SO 2, NO 2, CO). The cross-product terms of each air pollution, body mass index (BMI), and waist-to-hip ratio were included in the GAM model to test the interaction. Further, they conducted a stratified analysis to test their effects on the relationship between short-term exposure to each air pollution and the arterial stiffness indicators. Results:A total of 4 211 individuals were included in the analysis. Individuals' age was (58.9±8.7) years, of which 2 268 (53.9%) were female. Several covariates, including sociodemographic factors, lifestyle behaviors, and history of drugs, were included in the analysis. The results of the GAM analysis showed that an increase in PM 2.5 ( β=2.912×10 -4, 95% CI: 1.424×10 -4-4.400×10 -4, P<0.001), CO ( β=0.027, 95% CI: 0.011-0.043, P<0.001), SO 2 ( β=2.070×10 -3, 95% CI: 7.060×10 -4-3.430×10 -3, P=0.003), and NO 2 ( β=3.650×10 -4, 95% CI: 2.340×10 -5-7.060×10 -4, P=0.036) were associated with an increase in CIMT, while an increase in PM 10 ( β=0.018, 95% CI: 0.002-0.033, P=0.028) was associated with an increase in PP in the study population. Besides, the waist-to-hip ratio had an effect-modification on the correlation of short-term exposure of PM 2.5 (interaction P=0.015), NO 2 (interaction P=0.008), and CO (interaction P=0.044) with CIMT, and the correlation between short-term exposure of PM 2.5 (interaction P=0.002), NO 2 (interaction P=0.010), CO (interaction P=0.029), PM 10 (interaction P<0.001) with PP. The significant association between CIMT, PP, and air pollution concentrations was more visible in people with lower waist-to-hip ratios. Conclusions:Short-term ambient air pollution exposure was associated with arterial stiffness indicators, and there was an effect modification of waist-to-hip ratio on these associations, and lower waist-to-hip ratios may enhance the association between air pollution exposure and indicators.

This study was performed to investigate the features of HBV-specific CD8+T cell reactivity in patients with chronic hepatitis B(CHB),HBV-induced liver cirrhosis(LC)or hepatocellular carcinoma(HCC).A total of 124 CHB patients,36 LC patients,and 114 HCC patients were enrolled in this study.The reactive HBV-specific CD8+T cells in peripheral blood were enumerated using an innovative ELISPOT system.In addition,19 CHB patients and 20 HCC patients were longitudinally monitored with an interval of 3-5 months.Data showed that the numbers of reactive HBV-specific CD8+T cells in CHB group were not significantly different from that in LC group,but obviously lower than that in HCC group(P=0.009 9),especially HBsAg-,HBpol-and HBe/cAg-specific CD8+T cells.In CHB group,the patients with normal ALT level,AST level,or low HBV-DNA load showed significantly more reactive HBV-specific CD8+T cells than the patients with abnormal ALT level,abnormal AST level,or high HBV-DNA load.Furthermore,the duration of NUCs treatment had an impact on the HBV-specific CD8+T cell reactivity in CHB patients,while different NUCs at the same treatment duration did not bring different reactivity of HBV-specific T cells.In LC group,the HBeAg-positive patients presented much more reactive HBV-specific CD8+T cells than the HBeAg-negative patients did.In HCC group,the numbers of reactive HBV-specific CD8+T cells in the patients with normal AFP level or normal DCP level were significantly higher than that in the patients with abnormal AFP level or abnormal DCP level.Longitudinal monitoring results showed that HBV-specific CD8+T cell reactivity displayed a slow upward trend in the CHB patients undergoing NUCs treatment,and an obvious increasing in the HCC patients undergoing combined treatment of targeted drugs and immunotherapy.Taken together,the features of HBV-specific CD8+T cell reactivity are distinct among the CHB,LC and HCC patients,and are influenced by virological indicators,tumor markers and treatment regimens.Therefore,more attention should be paid to the changes of HBV-specific CD8+T cell reactivity during clinical treatment.

Objective To mine and analyze cutaneous adverse drug event(ADE)of eight antibody-drug conjugates(ADC),and to ensure the safe clinical use of ADC drugs.Methods The data was obtained from the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)for the period from the third quarter of 2011 to the fourth quarter of 2023.The cutaneous ADE associated with 8 eight ADC drugs were identified through the process of specification and standardization of nomenclature.The potential ADE signals were detected using the reporting odds ratio and Bayesian confidence propagation neural network methods.Results A total of 124 234 ADE reports were identified with the 8 ADC drugs as the first suspected drugs,including 5 184 reports of cutaneous ADEs adverse reactions,involving 3 225 patients.A total of 72 preferred term signals were detected for the 8 ADC drugs.The highest number of signals were detected for enfortumab vedotin,followed by ado-trastuzumab emtansine and brentuximab vedotin.Except for detrolizumab,the first-day incidence of cutaneous ADEs associated with the remaining 7 ADC drugs was less than 30％.The median time of occurrence for the 7 drugs,excluding brentuximab vedotin,was within one course of treatment(21 d).Conclusion The risks of cutaneous ADEs was variable with ADC drugs,occurs early in treatment and poses a potential life-threatening danger.Therefore,clinical vigilance and close monitoring of skin conditions are essential during ADC drug use.

Objective To provide pharmaceutical care for patients with hepatitis B cirrhosis by using the medication therapy management(MTM)model combined with Pharmaceutical Care Network Europe(PCNE),and to analyze the effectiveness of pharmaceutical care from clinical efficacy,safety,humanistic effect and drug-related problems(DRPs).Methods Patients with hepatitis B cirrhosis were randomly divided into the pharmaceutical care group and the control group who received only conventional treatment.Clinical pharmacists used MTM combined with PCNE to provide pharmaceutical care in the pharmaceutical care group.Economic effects,clinical indicators,safety,medication compliance and quality of life were compared between the two groups during the treatment and follow-up period.DRPs were analyzed in the pharmaceutical care group.Results The cost-utility ratio and clinical indicators in the pharmaceutical care group were better than those in the control group,and the adverse drug reactions of the former were statistically significant compared with the latter at the three months follow-up,and medication compliance and quality of life were statistically significant after intervention and during follow-up(P＜0.05).There were 52 DRPs in the pharmaceutical care group,mainly in the category of poor treatment outcome.The main reasons were poor drug selection and excessive usage and dosage.There were 46 DRPs accepted by intervention,and 45 DRPs were completely and partially solved.Conclusion The pharmaceutical care model of MTM combined with PCNE classification system for patients with hepatitis B cirrhosis played a positive role in the treatment and follow-up period.