Diabetic retinopathy(DR)is one of the most common and serious microvascular complications of diabetes, posing a significant threat to patients' visual health. In recent years, epigenetic mechanisms have garnered increasing attention in the scientific community for their pivotal role in the onset and progression of DR. This paper systematically examines the regulatory roles of epigenetic mechanisms in DR, covering key pathways such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs. Under hyperglycemic conditions in diabetes, these epigenetic mechanisms modulate gene expression, thereby influencing critical pathological processes such as oxidative stress, inflammatory responses, mitochondrial dysfunction, and metabolic memory. This article reviews recent advances in epigenetic regulation in DR, providing an in-depth analysis of its underlying molecular mechanisms and complex regulatory networks, and explores the potential of epigenetic markers as diagnostic biomarkers and therapeutic targets. Additionally, this article highlights emerging therapeutic strategies targeting epigenetic modifications, aiming to provide a theoretical foundation and research direction for the early diagnosis and precision treatment of this disease.

OBJECTIVE To compare the efficacy and safety of chemotherapy combined with tislelizumab or sintilimab in patients with advanced non-small cell lung cancer （NSCLC）， and to analyze the influential factors of prognostic. METHODS A retrospective study was conducted on 163 patients with advanced NSCLC who received chemotherapy combined with tislelizumab or sintilimab at the First People’s Hospital of Yunnan Province from September 1， 2021 to November 30， 2024. Among them， there were 90 patients in the tislelizumab group and 73 patients in the sintilimab group. The objective response rate （ORR）， disease control rate （DCR）， progression free survival （PFS）， and overall survival （OS） of two groups were observed， and the occurrence of adverse drug reactions in patients was evaluated. Kaplan-Meier method was used to plot PFS and OS survival curves， Log-rank test was applied for univariate analysis， and Cox regression model was used to evaluate the independent prognostic factors of PFS and OS. RESULTS The median PFS of patients in the tislelizumab group and the sintilimab group were 14.14 months （95%CI of 10.95-17.33） and 10.95 months （95%CI of 8.75-13.15）， respectively. The median OS was 25.89 months （95%CI of 22.67-29.11） and 24.25 months （95%CI of 19.34-29.16）， with ORR of 45.56% and 49.32%， DCR of 94.44% and 90.41%， and the incidence of adverse drug reactions of 84.44% and 79.45%， respectively， the differences were not statistically significant （P＞0.05）. Age ≥60 years （HR＝1.542， 95%CI of 1.044-2.278， P＝0.029） and systemic immune inflammatory nutritional index （SIINI）＞ 116.58 （HR＝1.541， 95%CI of 1.058-2.245， P＝0.024） were risk factors for PFS in NSCLC patients receiving immune checkpoint inhibitor therapy； the use of antibiotics may affect the overall survival of patients （P＝0.001）. CONCLUSIONS The efficacy and safety of chemotherapy combined with tislelizumab or sintilimab for advanced NSCLC are comparable； age≥60 years and SIINI ＞116.58 are risk factors for PFS in NSCLC patients， and the use of antibiotics may affect the patients’ OS.

BACKGROUND: Epoxyeicosatrienoic acids (EETs), which are metabolites of arachidonic acid catalyzed by cytochrome P450 epoxygenase, are degraded into inactive dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). Many studies have revealed that sEH gene deletion exerts protective effects against diabetes. Vascular calcification is a common complication of diabetes, but the potential effects of sEH on diabetic vascular calcification are still unknown. METHODS: The level of aortic calcification in wild-type and Ephx2-/- C57BL/6 diabetic mice induced with streptozotocin was evaluated by measuring the aortic calcium content through alizarin red staining, immunohistochemistry staining, and immunofluorescence staining. Mouse vascular smooth muscle cell lines (MOVAS cells) treated with β-glycerol phosphate (0.01 mol/L) plus advanced glycation end products (50 mg/L) were used to investigate the effects of sEH inhibitors or sEH knockdown and EETs on the calcification of vascular smooth muscle cells, which was detected by Western blotting, alizarin red staining, and Von Kossa staining. RESULTS: sEH gene deletion significantly inhibited diabetic vascular calcification by increasing levels of EETs in the aortas of mice. EETs (especially 11,12-EET and 14,15-EET) efficiently prevented the osteogenic transdifferentiation of MOVAS cells by decreasing nidogen-2 (NID2) expression. Interestingly, suppressing sEH activity by small interfering ribonucleic acid or specific inhibitors did not block osteogenic transdifferentiation of MOVAS cells induced by β-glycerol phosphate and advanced glycation end products. NID2 overexpression significantly abolished the inhibitory effect of sEH gene deletion on diabetic vascular calcification. Moreover, NID2 overexpression mediated by adeno-associated virus 9 vectors markedly increased insulin-like growth factor 2 (IGF2) and phospho-ERK1/2 expression in MOVAS cells. Overall, sEH gene knockout inhibited diabetic vascular calcification by decreasing aortic NID2 expression and, then, inactivating the downstream IGF2-ERK1/2 signaling pathway. CONCLUSIONS sEH gene deletion markedly inhibited diabetic vascular calcification through repressed osteogenic transdifferentiation of vascular smooth muscle cells mediated by increased aortic EET levels, which was associated with decreased NID2 expression and inactivation of the downstream IGF2-ERK1/2 signaling pathway.
Animals ; Mice ; Vascular Calcification/metabolism* ; Mice, Inbred C57BL ; Epoxide Hydrolases/metabolism* ; Diabetes Mellitus, Experimental/genetics* ; Male ; Gene Deletion ; MAP Kinase Signaling System/genetics* ; Cell Line ; Immunohistochemistry ; Muscle, Smooth, Vascular/metabolism* ; Signal Transduction/genetics* ; Mice, Knockout

Brain metastases are the most common intracranial tumors, and their incidence is increasing with the improvement of systemic treatments and survival rates. Optimal treatment usually requires a multidisciplinary approach, including radiotherapy, surgical resection, chemotherapy, targeted therapy, and immunotherapy. Stereotactic radiotherapy, compared to whole-brain radiotherapy, offers improved local control rates and reduced risk of neurocognitive impairment, and has become a new standard option for the treatment of brain metastases. Additionally, the widespread use of targeted and immune therapies in brain metastases has significantly improved the survival of some patients. This article reviews and integrates recent literature on the treatment of brain metastases and analyzes the role of stereotactic radiotherapy in comprehensive treatment, aiming to provide a reference for the selection of clinical treatment plans.

Ketone body metabolism plays a significant role in the development and progression of diabetic retinopathy(DR), which closely related to the system and local metabolic disorders as a major microvascular complication of diabetes mellitus. Previous research has established a close relationship between dyslipidemia and DR progression. Ketone bodies, comprising β-hydroxybutyrate, acetoacetate, and acetone, are metabolic products generated from fat breakdown when glucose metabolism is impaired. Studies have revealed that ketone body metabolism is intricately linked to multiple pathophysiological processes in DR, including oxidative stress, inflammatory responses, and neurodegeneration within retinal cells. This article provides a review exploring the impact of ketone body metabolism on the pathogenesis of DR, and systematically reviews the latest research progress on the impact of ketone bodies on the core pathological links such as retinal vascular barrier destruction, glial cell activation and angiogenesis through metabolic reprogramming, epigenetic modification and cell signal transduction, so as to provide a theoretical basis for in-depth understanding of the metabolic driving mechanism of DR.

ObjectiveThis study aims to reveal the mechanism of liver and kidney injuries caused by Dictamni Cortex and its interrelationship by metabonomics analysis of liver and kidney via ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry （UPLC-Q-TOF-MS）. MethodsThe content of the marker compounds of Dictamni Cortex was measured by high-performance liquid chromatography （HPLC） to carry out quality control. Sprague Dawley （SD） rats were randomly divided into a blank group （normal saline）， an administration group （0.9， 2.7， 8.1 g·kg^-1）， and a high-dose withdrawal control group， with eight rats in each group. Continuous administration was performed once daily for 28 days. The liver and kidney injuries caused by each administration group were assessed by organ indices， pathological observations， and serum and plasma biochemical indices measured by enzyme-linked immunosorbent assay （ELISA）. The potential biomarkers of liver and kidney injuries caused by Dictamni Cortex were screened， and pathway enrichment analysis and correlation analysis were performed based on UPLC-Q-TOF-MS. ResultsCompared with the blank group， both the medium- and low-dose groups showed insignificant damage to the liver and kidney of rats. The high-dose group exhibited the most serious damage， and the level of liver and kidney function indices ［alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， creatinine （Cr）， and blood urea nitrogen （BUN）］ and serum inflammatory indices （［interleukin 1β （IL-1β）， IL-6， and tumor necrosis factor-α （TNF-α）］ in the serum were significantly changed （P<0.01）. The liver and kidney metabolism pathways and differential metabolites were quite different. Among them， phenylalanine metabolism， niacin and nicotinamide metabolism， and glycerophospholipid metabolism were common pathways. Correlation analysis of differential metabolites showed that there were significant correlations among disorders of 4′-Phosphopantothenoylcysteine， PC （16∶0/15∶0）， phenylethylamine， arachidonic acid， and linoleic acid in liver and kidney tissue. ConclusionThe decoction of Dictamni Cortex can cause liver and kidney injuries， and its mechanism may be related to oxidative stress and lipid metabolism disorders. The correlation of differential metabolites indicates the interaction between liver and kidney injuries.

ObjectiveTo explore the mechanism of the immunotoxicity induced by dictamnine （DIC） in rats and the recovery effect after drug withdrawal by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry， thereby providing a theoretical basis for elucidating the toxic mechanism of DIC. MethodsSD rats were randomized into blank （normal saline）， DIC （10 mg·kg^-1）， and DIC withdrawal （recovery period） groups （n=8）. The rats were continuously treated for 7 days， once a day， and the body weight and organ weight were recorded. The levels of interleukin-1 （IL-1）， IL-6， and tumor necrosis factor-α （TNF-α） in the serum and immunoglobulin A （IgA）， immunoglobulin G （IgG）， and immunoglobulin M （IgM） in the spleen were determined by enzyme-linked immunosorbent assay. Hematoxylin-eosin staining was used to observe the pathological changes in the spleen. ultra performance liquid chromatography quadrupole time-of-flight mass spectrometry （UPLC-Q-TOF-MS） was employed to screen the potential biomarkers of immune inflammation caused by DIC， and pathway enrichment analysis and correlation analysis were performed. The mRNA levels of IL-1β， TNF-α， lysophosphatidylcholine acyltransferase 2 （LPCAT2）， and farnesoid X receptor （FXR） in the serum were determined by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. ResultsCompared with the blank group， the DIC group showed elevated levels of IL-1β， IL-6， and TNF-α in the serum （P<0.01）， and the DIC withdrawal group showcased lowered levels of IL-1β， IL-6， and TNF-α in the serum （P<0.01）. The levels of IgA， IgG， and IgM in the spleen of rats in the DIC group were decreased （P<0.01）， while those in the DIC withdrawal group were recovered （P<0.05， P<0.01）. Untargeted metabolomics of the serum and spleen screened out 14 common differential metabolites and 14 common metabolic pathways. The Spearman correlation analysis between differential metabolites and inflammatory factors identified PC （32∶0）， LysoPC （20∶4/0∶0）， LysoPC （P-18∶0/0∶0）， taurochenodeoxycholic acid， taurocholic acid， LysoPC ［20∶5（5Z，8Z，11Z，14Z，17Z）/0∶0］， chenodeoxycholic acid， arachidonic acid， LysoPC （18∶0/0∶0）， LysoPC （15∶0/0∶0）， LysoPC （16∶0/0∶0）， and LysoPC （17∶0/0∶0） as the biomarkers of immunotoxicity induced by DIC in SD rats. In the process of immunotoxicity caused by DIC， lipid metabolism disorders such as glycerophospholipid metabolism， primary bile acid metabolism， and arachidonic acid metabolism were enriched， which was consistent with the DIC-induced inflammatory factors and pathological characteristics of the spleen. Compared with the blank group， the DIC group exhibited up-regulated mRNA levels of IL-1β， TNF-α， LPCAT2， and FXR （P<0.01）， and the up-regulation was decreased in the withdrawal group （P<0.01）. ConclusionDIC can lead to immune and inflammatory disorders. DIC withdrawal can regulate the expression of biomarkers related to serum and spleen metabolites， regulate the inflammatory metabolic pathway， reduce the inflammation level， and alleviate the metabolic disorders， thus attenuating the potential toxicity induced by DIC.

Objective To develop the Ego Depletion Scale for Type 2 Diabetes Patients and evaluate its reliability and validity,and to provide a specific assessment tool for evaluating ego-depletion in self-management.Methods Guided by the self-control strength model,the initial scale was constructed through literature review,semi-structured interviews,2 rounds of expert consultation,and a pilot survey.A convenience sampling method was employed to recruit 460 patients with Type 2 Diabetes from the endocrinology department of a tertiary hospital in Wuhan,Hubei Province,between April and July 2024.They were randomly divided into 2 subsets for exploratory factor analysis and confirmatory factor analysis.Results A total of 451 valid questionnaires were collected.Exploratory factor analysis extracted 6 common factors,with a cumulative variance contribution of 73.231％.In confirmatory factor analysis,an item was deleted due to failing to meet the standardized loading value criterion.The revised Ego Depletion Scale for Type 2 Diabetes Patients comprised 6 dimensions and 22 items.The total Cronbach's α coefficient was 0.911;split-half reliability was 0.744;the content validity index was 0.860.Correlation coefficients between the total score and scores of each dimension of the scale and the total score of the Self-Regulatory Fatigue Scale ranged from 0.558 to 0.946(P＜0.001).Conclusion The scale exhibits robust reliability and validity,serving as a scientifically instrument for assessing ego depletion in patients with Type 2 Diabetes.

Objective To identify clinicopathological parameters that differentiate between very high-risk and ordinary high-risk gas-trointestinal stromal tumors(GISTs)to provide guidance for clinical treatment and follow-up monitoring.Methods A retrospective cohort study was conducted,collecting 174 cases of high-risk GISTs initially diagnosed and surgically resected at Tianjin Medical University Cancer Institute and Hospital between January 1st,2011,and December 31st,2019.Based on long-term follow-up data,the X-tile software was used to identify key parameters for screening very high-risk GISTs from ordinary high-risk GISTs,and the results were validated by using high-risk GIST cases from the cBioPortal database.Results Among the 174 high-risk GIST cases,the X-tile software indicat-ed that the maximum tumor diameter of 14 cm,the mitotic count of 14/5 mm2,and the Ki-67 proliferation index of 10%were the optimal cutoff values for distinguishing very high-risk GISTs from ordinary high-risk GISTs.Univariate survival analysis confirmed that these cutoff values were associated with progression free survival(PFS,all P<0.05).Multivariate survival analysis confirmed that the maximum tumor diameter≥14 cm(HR=5.727,P<0.01),mitotic count≥14/5 mm2(HR=2.454,P=0.047),and Ki-67 proliferation index≥10%(HR=2.275,P=0.047)were independent risk factors for tumor progression in high-risk GIST patients.High-risk GISTs with any one of the three parameters more than or equal to its optimal cutoff value were defined as very high-risk GISTs,and the other GISTs were defined as ordinary high-risk GISTs.Compared to very high-risk GIST patients,the ordinary high-risk GIST patients had superior PFS(P<0.01),and a trend toward better overall survival(OS,P=0.082).Stratified analysis showed that,in subgroups of patients with gastric or non-gas-tric primary tumors,those receiving or not receiving adjuvant therapy,and those with KIT proto-oncogene,receptor tyrosine kinase(KIT)gene mutations,ordinary high-risk GIST patients all exhibited superior PFS compared to very high-risk GIST patients(all P<0.05).Both PFS and OS of ordinary high-risk GIST patients in the cBioPortal database were better than those of very high-risk GIST patients(both P=0.001).Stratified analysis of the cBioPortal database data showed that,in subgroups of patients with gastric or non-gastric primary tu-mors,those who received adjuvant therapy,and those with KIT gene mutations,ordinary high-risk GIST patients all exhibited superior PFS compared to very high-risk GIST patients(all P<0.05);conversely,among patients who did not receive adjuvant therapy,very high-risk GIST patients showed a trend toward poorer PFS(P=0.366).Conclusions This study has established a method utilizing commonly used clinical parameters to distinguish very high-risk GISTs in clinical practice.However,further validation through multicenter studies with larger sample sizes is still required.

Objective:To investigate the role of WW domain containing E3 ubiquitin protein ligase 1 (WWP1) in enamel development of mice.Methods:Single-cell RNA sequencing data of incisor tissues of postnatal day 7 (P7) mice and mandibular first molar tooth germs of P3.5 mice were used to analyze the expression of Wwp1 in dental epithelial cells. Immunohistochemistry was performed to observe the distribution and expression levels of WWP1 in the epithelium of mouse incisors and mandibular first molar tooth germs. Wwp1 knockout (Wwp1 KO) mice were generated and collected with their control littermates at P1, P7, three mice per group, as well as at P14, P28, 2 months (2M), and 3M, six mice per group. The enamel volumes of molars and incisors were analyzed using micro-CT. Scanning electron microscopy was employed to examine the enamel cross-sections of Wwp1 KO and control mice. Energy dispersive spectroscopy (EDS) was used to analyze the calcium and phosphorus content of the enamel rod of incisors. Immunofluorescence was performed to detect the expression of amelogenin (AMELX) in the ameloblasts of Wwp1 KO and control mice. Additionally, LS-8 ameloblast-like epithelial cells were cultured, and Wwp1 siRNA or overexpression plasmids were transfected to knock down or overexpress WWP1. The protein levels of AMELX were then assessed by Western blotting.Results:Single-cell sequencing result showed a high Wwp1 mRNA expression level in the epithelial cells of mouse incisors and mandibular molar tooth germs. Immunohistochemistry revealed the expression of WWP1 in presecretory, secretory, transitional, and mature ameloblasts. Wwp1 KO mice exhibited enamel developmental defects. The enamel volumes of molars and incisors in Wwp1 KO mice [(0.155±0.016), (0.300±0.017) μm 3] were reduced by 23.95% ( P<0.001) and 28.31% ( P<0.001) compared with the control group [(0.203±0.062), (0.418±0.023) μm 3] respectively. Scanning electron microscopy showed disorganized enamel structures in Wwp1 KO incisors and molars. EDS results showed the weight percent of calcium in the enamel rod of incisors decreased in Wwp1 KO mice [(20.74±0.91)%] compared with the control group [(30.30±3.83)%] ( P<0.001), and the calcium-to-phosphorus ratio decreased in Wwp1 KO mice (1.93±0.01) compared with the control group (2.02±0.01) ( P<0.001). Immunofluorescence showed weaker AMELX expression in ameloblasts of mandibular first molar tooth germs from P1 and P7 Wwp1 KO mice compared with the control group ( P<0.001, P<0.001). In LS-8 cells, Wwp1 knocked-down led to a decrease of AMELX protein expression, while WWP1 overexpression resulted in an increased AMELX protein level. Conclusions:WWP1 promotes ameloblast differentiation and enamel matrix mineralization, playing a critical role in enamel formation.