[摘 要] 目的：构建负载STING激动剂DMXAA的锰卟啉金属有机框架纳米颗粒（DPM），探讨其对三阴性乳腺癌（TNBC）细胞4T1及其小鼠移植瘤的治疗效果。方法：通过物理吸附法制备 DPM 纳米颗粒，利用透射电镜、扫描电镜及纳米粒度电位仪表征其形貌与理化性质。常规培养4T1细胞，细胞实验分为对照组、超声辐照组（US组）、DPM治疗组（DPM组）和DPM治疗联合超声辐照组（DPM + US组），用CCK-8法检测细胞活性，免疫荧光法检测高迁移率族蛋白B1（HMGB1）和钙网蛋白（CRT）的表达，WB法检测STING通路相关蛋白的表达。构建4T1细胞移植瘤小鼠模型，分为四组，处理同细胞实验，测量肿瘤体积，免疫荧光法检测移植瘤组织中Ki-67、HMGB1、CRT和缺氧诱导因子-1ɑ（HIF-1ɑ）蛋白的表达，TUNEL法检测细胞凋亡，流式细胞术检测免疫细胞活化情况，对主要器官进行H-E染色，以评估纳米材料的体内安全性。结果：DPM呈梭形，平均粒径（268 ± 3.302）nm，电位（33.1 ± 0.87）mV。细胞实验中，DPM联合超声辐照可明显抑制4T1细胞的增殖（P < 0.001），提高4T1细胞中ROS水平（P < 0.001），诱导4T1细胞CRT表达上调（P < 0.001），HMGB1从细胞核中移至细胞质，激活STING信号通路[p-STING、p-TBK1、p-IRF3蛋白表达均显著增加（均P < 0.001）]。体内实验中，DPM联合超声辐照可显著抑制4T1细胞移植瘤生长（P < 0.001）并促进免疫细胞表型转化（P < 0.001），抑制移植瘤组织中Ki-67、HIF-1α蛋白表达（均P < 0.01），谷胱甘肽（GSH）产生（P < 0.01），促进CRT、HMGB1蛋白表达、ROS产生（P < 0.001），对主要器官结构无明显影响。结论： DPM联合超声辐照可通过激活STING通路显著抑制4T1细胞及其移植瘤的生长，诱导抗肿瘤免疫应答，且对主要器官无明显毒性。

Peri-implant diseases are characterized by the resorption of hard tissue and the inflammation of soft tissue. Epigenetics refers to alterations in the expression of genes that are not encoded in the DNA sequence, influencing diverse physiological activities, including immune response, inflammation, and bone metabolism. Epigenetic modifications can lead to tissue-specific gene expression variations among individuals and may initiate or exacerbate inflammation and disease predisposition. However, the impact of these factors on peri-implantitis remains inconclusive. To address this gap, we conducted a comprehensive review to investigate the associations between epigenetic mechanisms and peri-implantitis, specifically focusing on DNA methylation and microRNAs (miRNAs or miRs). We searched for relevant literature on PubMed, Web of Science, Scopus, and Google Scholar with keywords including "epigenetics," "peri-implantitis," "DNA methylation," and "microRNA." DNA methylation and miRNAs present a dynamic epigenetic mechanism operating around implants. Epigenetic modifications of genes related to inflammation and osteogenesis provide a new perspective for understanding how local and environmental factors influence the pathogenesis of peri-implantitis. In addition, we assessed the potential application of DNA methylation and miRNAs in the prevention, diagnosis, and treatment of peri-implantitis, aiming to provide a foundation for future studies to explore potential therapeutic targets and develop more effective management strategies for this condition. These findings also have broader implications for understanding the pathogenesis of other inflammation-related oral diseases like periodontitis.
Peri-Implantitis/genetics* ; Humans ; Epigenesis, Genetic ; DNA Methylation ; MicroRNAs/genetics*

The inherent clinical uncertainties, substantial costs, and small patient cohorts of orphan drugs limit the applicability of randomized controlled trial (RCT)-based health technology assessments (HTAs) in guiding coverage criteria, sustainable financing models, and equitable reimbursement frameworks for medical financial assistance policies for rare diseases.The digital transformation in healthcare system leads to solutions to the challenges in designing the policy by using data-driven decision-making. This article summarizes the decision-making issues in policy design, discusses the current status and trends of digital transformation, and analyzes the important new opportunities for AI-driven policy design for medical financial assistance policies for rare diseases. Decision-making that is digital intelligence driven and using techniques such as big data analytics and real-world research methods will enhance targeting efficiency, improve the quality of financing, and realize the performance-based reimbursement in the medical financial assistance, providing significant value in facilitating the policy reform and development for rare diseases healthcare.

Objective:To investigate the changes of home blood pressure from weekdays to weekends and its influencing factors.Methods:This study was a national multicenter prospective registry study. Data came from the registry study on the “Action of controlling home blood pressure to target in ten thousand patients”. Hypertension patients receiving antihypertensive drugs in the above study were included, and the general clinical data of the enrolled patients were collected. Patients′ office and home blood pressure were measured at baseline, followed by home blood pressure measurements for 7 consecutive days, and blood pressure trends over a one-week period were analyzed. Multivariate linear stepwise regression was used to investigate the influencing factors of blood pressure change from weekdays to weekends, and subgroup analysis was conducted according to body mass index, alcohol consumption, fasting blood glucose ≥6.1 mmol/L or diabetes mellitus. Kappa consistency test was used to analyze the influence of removing weekend blood pressure data on home blood pressure monitoring results. Results:A total of 3 228 hypertensive patients aged (66.2±7.6) years were included, including 1 612 (49.9%) males. The weekly blood pressure changes of the study subjects showed a trend of gradually increasing during working days (Monday to Friday) and decreasing during weekends (Saturday to Sunday). The blood pressure on weekends was lower than that on weekdays, but the difference was not statistically significant ((128.2±13.7)/(79.7±8.7) mmHg vs. (128.3±12.9)/(79.8±8.3) mmHg, all P>0.05; 1 mmHg=0.133 kPa). The blood pressure on Sunday was significantly lower than that on Friday ((127.9±13.3)/(79.6±9.1) mmHg vs. (128.5±13.3)/(80.0±9.0) mmHg, all P<0.05). Subgroup analysis showed that hypertensive patients who were overweight and obese, drank alcohol, and had fasting blood glucose≥6.1 mmol/L or combined diabetes mellitus had a smaller decrease or increasing trend in home blood pressure from weekdays to weekends. Consistency test results showed that the mean blood pressure after removing the 2-day home blood pressure data on weekends was consistent with the mean blood pressure of one week ( Kappa=0.90). The mean blood pressure after removing only the blood pressure data of Sunday was slightly less consistent with the mean blood pressure of one week ( Kappa=0.88). Conclusions:The home blood pressure level of hypertensive patients receiving antihypertensive drugs showed a trend of gradually increasing during working days and decreasing at weekends. People with hypertension who were overweight and obese, drank alcohol, had high fasting blood sugar, or had combined diabetes mellitus, and their home blood pressure decreased less or increased from weekdays to weekends. The removal of 1-day Sunday blood pressure data but not 2-day weekend blood pressure data had impact on the one-week home blood pressure monitoring results.

Objective To establish and evaluate a mouse model of chronic obstructive pulmonary disease(COPD)induced by cigarette smoke(CS).Methods Forty BALB/c mice were divided randomly into a control group and a CS group.Mice in the CS group were subjected to passive smoking for 20 weeks and a COPD model was established.Morphological changes in the organs and lung,heart,liver,and kidney fibrosis were observed by hematoxylin-eosin(HE)and Masson staining.Lung,cardiac,and brain cognitive function were evaluated by pulmonary function testing,small-animal ultrasound,and Morris water maze trials.Tumor necrosis factor-α(TNF-α),interleukin(IL)-6 and IL-1β levels in lung and brain tissues were detected by ELISA.Liver and renal functions were measured by biochemical method.Results The alveolar septum was narrowed or broken in mice in the CS group,and the adjacent alveolar cavity was enlarged and fused,consistent with the pathological changes of COPD.Neuronal degeneration and necrosis were observed in the hippocampus,but there were no significant morphological changes in other organs.Masson staining showed no obvious fibrosis in the lung,heart,liver,or kidney in CS-group mice.The result of pulmonary function tests showed that the forced expiratory volume in 0.1 second/forced vital capacity(FEV 0.1/FVC)and dynamic compliance were significantly decreased in the CS group compared with the control group,while airway resistance was obviously increased.Cognitive impairment in mice in the CS group was confirmed in the Morris water maze trial.TNF-α,IL-6,and IL-1β levels in lung and brain tissues were higher in the CS group compared with the control group.There were no significant differences in cardiac,liver,and renal functions between the groups.Conclusions A mouse model of COPD can be established by CS exposure for 20 weeks.Lung histomorphology,lung function,brain cognitive function,and levels of inflammatory factors can be used as indicators to evaluate the success of the model.

Objective:To explore the effect of social cognition and interaction training (SCIT) combined with transcranial magnetic stimulation (TMS) on intrinsic motivation and social cognition in patients with schizophrenia.Methods:Forty-two stable schizophrenia patients were randomly divided into the SCIT + TMS group( n=22) and the SCIT group( n=20). All the subjects received 20 sessions of SCIT treatment, and the SCIT+ TMS group simultaneously received 15 sessions of intermittent theta burst stimulation(iTBS) over the left dorsolateral prefrontal cortex(DLPFC). All the subjects were assessed by intrinsic motivation inventory for schizophrenia research(IMI-SR), Chinese version of the ambiguous intentions hostility questionnaire(AIHQ-C), theory of mind-picture sequencing task(ToM-PST), mentalization scale (MentS), Chinese version of interpersonal reactivity index (IRI-C) and positive and negative syndrome scale (PANSS) before and after intervention. SPSS 26.0 software was used for data analysis.Wilcoxon signed-rank test was used for intra-group comparison before and after treatment, while Mann-Whitney U test and covariance analysis were used for inter-group comparison.Spearman correlation analysis and Logistic regression analyses were used to explore the association between the intrinsic motivation and social cognition. Results:There were no significant differences on IMI-SR scores before and after treatment between the two groups(all P>0.05). In the SCIT+ TMS group, the total score of hostility bias (HB), HB scores in ambiguous scenes, HB scores in intentional scenes, and aggressive bias (AB) scores in ambiguous scenes of AIHQ-C scale after treatment were lower than those befor treatment( Z=-2.044--3.112, all P<0.05), while the total score of ToM-PST(18.50(16.00, 21.00) vs 15.50(11.75, 18.00), Z=-2.598, P=0.009) and IRI-C imagination score (12.18±3.79, 14.41±4.73, t=-2.694, P=0.014) were higher than those before treatment.In the SCIT group, the total score of ToM-PST after treatment was higher than that before treatment(21.00(20.00, 22.00) vs 17.00(14.50, 20.75), Z=-2.518, P=0.012).There was no significant statistical difference in MentS scores between after treatment and before treatment ( P>0.05). The difference in AIHQ-C intentional scenario AB score before and after treatment was higher in the SCIT+ TMS group than in the SCIT group ( Z=-1.996, P=0.046), while there was no statistically significant difference in the difference before and after treatment in social cognitive scores between the two groups (all P>0.05).In the combined two samples, Spearman correlation analysis showed that the total score of IMI-SR before treatment was positively correlated with the primary belief score of ToM-PST understanding, reciprocity score, MentS total score, other person mentalization score, motivation mentalization score, IRI-C total score, viewpoint taking score, and empathy concern score after treatment( r=0.341-0.509, all P<0.05), while negatively correlated with AIHQ-C total score and factor scores ( r=-0.434--0.645, P<0.05).Logistic regression analysis showed that the total score of IMI-SR had negative impact on AIHQ-C total HB score( B=-0.047, OR=0.954, 95% CI=0.917-0.993).The value score had a positive impact on the total score of MentS ( B=0.143, OR=1.154, 95% CI=1.043-1.277), other person mentalization score( B=0.166, OR=1.181, 95% CI=1.058-1.318), motivation mentalization score( B=0.111, OR=1.117, 95% CI=1.021-1.223), IRI-C total score ( B=0.138, OR=1.148, 95% CI=1.038-1.270), and viewpoint taking score( B=0.194, OR=1.214, 95% CI=1.076-1.369). Interest score had a positive impact on IRI-C empathy concern score ( B=0.098, OR=1.103, 95% CI=0.998-1.218) and ToM-PST understanding primary belief score( B=0.130, OR=1.138, 95% CI=1.010-1.283) and reciprocity score( B=0.189, OR=1.208, 95% CI=1.057-1.380). Conclusion:The research results did not confirm the effect of TMS over the DLPFC on enhancing intrinsic motivation, as well as the synergistic effect of SCIT treatment on social cognition. But the correlation results indicates that improving schizophrenia patients' intrinsic motivation level in cognitive training is meaningful for promoting social cognition.

Objective To investigate the effect of Jiawei Simiao powder on the Toll-like receptor 4(TLR4)/nuclear factor-κB(NF-κB)signaling pathway through miR-146a in monosodium urate(MSU)crystal-induced RAW264.7 macrophage inflammation models,and to explore its anti-inflammatory mechanism.Methods A cell model of gouty arthritis was established by inducing RAW264.7 cells with MSU crystals.Cells were divided into control,model,Jiawei Simiao powder,and colchicine groups and cell viability was assessed using the CCK-8 method.Levels of interleukin(IL)-1β,IL-6,and tumor necrosis factor(TNF)-α were measured by enzyme-linked immunosorbent assay.Expression levels of miR-146a miRNA and TLR4,myeloid differentiation factor 88(MyD88),TNF receptor-associated factor 6(TRAF6),and NF-κB p65 mRNA were detected by quantitative real-time polymerase chain reaction amplification technology,and protein expression levels of TLR4,MyD88,TRAF6,and phospho(p)-NF-κB p65 were evaluated by Western blot.Results miR-146a expression was significantly decreased in the model group compared with the control group(P＜0.01),while mRNA and protein expression levels of TLR4,MyD88,and TRAF6,and protein expression of p-NF-κB p65,IL-1β,IL-6,and TNF-α were significantly increased(P＜0.01).In contrast,miR-146a expression was significantly increased(P＜0.01)and mRNA and protein expression of TLR4,MyD88,and TRAF6,and p-NF-κB p65 protein expression(P＜0.01),as well as IL-1β,IL-6,and TNF-α levels(P＜0.05)were significantly decreased in the Jiawei Simiao powder and colchicine groups.Conclusions Jiawei Simiao powder may alleviate MSU crystal-induced macrophage inflammatory responses by upregulating miR-146a,suppressing TLR4/NF-κB signaling pathway activation,and decreasing secretion of inflammatory factors.

Objective The study aims to elucidate the inhibitory effects of curcumin on the proliferation of colon cancer RKO cells,focusing on the regulatory mechanisms of tripartite motif-containing protein 2(TRIM2)expression and the mammalian target of rapamycin(mTOR)signaling pathway.Methods Experimental concentrations of curcumin were determined by calculating the half maximal inhibitory concentration(IC50)value.Quantitative polymerase chain reaction(qPCR)was utilized to assess the level of TRIM2 expression in RKO and fetal human colon(FHC)cells.Western blotting analysis was conducted to investigate the level of TRIM2 expression and mTOR pathway-related proteins in curcumin-treated RKO cells.The impact of curcumin treatment,TRIM2-knockingdown,and mTOR signaling pathway on proliferation in RKO cells was quantified using the cell counting kit-8(CCK8)assay.Results The expression of TRIM2 was found to be elevated in RKO cells as determined by qPCR,compared to FHC cells.Curcumin suppressed the level of TRIM2 expression,and subsequent knockdown of TRIM2 resulted in decreased expression of mTOR-related proteins in RKO cells.Both curcumin and TRIM2-knockdown demonstrated significant inhibition of proliferation in RKO cells,with reversion upon activation of mTOR signaling pathway.Conclusion The study unveils the inhibitory effects of curcumin on RKO cells proliferation through modulation of TRIM2 expression and the mTOR signaling pathway.

Age-related macular degeneration(AMD)is one of the leading causes of blindness in the elderly.Wet AMD(nAMD)accounts for more than 90％of AMD-related vision loss.Pathologically,nAMD is defined by choroidal neovascu-larization(CNV)and chronic retinal inflammation driven by oxidative stress,complement activation,pro-inflammatory cy-tokines,and overexpression of vascular endothelial growth factor(VEGF).Yet anti-VEGF monotherapy often falls short.The nuclear factor kappa-B(NF-κB)signaling cascade,acting through both canonical and non-canonical pathways,or-chestrates the expression of genes governing immunity,inflammation,apoptosis,and angiogenesis.In nAMD,oxidative stress and complement fragments ignite NF-κB,unleashing a repertoire of pro-inflammatory and pro-angiogenic mediators that fuel CNV.Pharmacologic or genetic suppression of NF-κB dampens both inflammation and neovascularization,attenua-ting experimental CNV.Thus,dissecting the molecular machinery of NF-κB signaling in nAMD may uncover novel combina-tion strategies that enhance therapeutic efficacy and curb anti-VEGF resistance.

Objective:To understand the mental problem in elderly male prisoners and its related factors.Methods:A total of 289 elderly male prisoners from five prisons in Sichuan Province were selected.They were assessed with the self-compiled general situation questionnaire,12-item General Health Questionnaire(GHQ-12,with a total score ≥ 3 indicating a tendency towards mental problem),short-form UCLA Loneliness Scale(ULS-8)and Insomnia Severity Index-Chinese Version(ISI-C).Results:The detection rate of mental problem was 41.52％.Multiple factor logistic regression analysis indicated that having a remaining sentence of≥5 years,educa-tional levels of primary school and below,high school or technical secondary school and above,involvement in drug-related crimes,property crimes,violent crimes,good and poor relationships with spouses,average relationships with fellow inmates,self-assessed blood pressure levels that were low and high,and having insomnia were risk fac-tors for mental problem(OR=9.55,11.75,13.88,82.24,33.96,363.52,5.77,113.27,2.33,1.87,3.80,42.89).Conclusion:The mental problem among elderly male prisoners are related to their sentence,education lev-el,crime type,relationship with spouse and cellmates,self-rated blood pressure and sleep status.