Diabetic retinopathy (DR) is one of the most prevalent and vision-threatening microvascular complications of diabetes mellitus, yet its pathogenesis extends far beyond vascular injury alone. As the retina is among the most energy-demanding tissues in the body, its neurons, glial cells, pigment epithelial cells, pericytes, and endothelial cells are highly dependent on mitochondrial oxidative phosphorylation to maintain visual signal transduction, ionic homeostasis, and neurovascular integrity. This review summarizes current evidence indicating that mitochondrial dysfunction is not merely a downstream consequence of chronic hyperglycemia, but a central pathogenic hub that initiates, amplifies, and perpetuates retinal neurovascular degeneration in DR. Persistent hyperglycemia activates multiple abnormal metabolic pathways, including the polyol pathway, hexosamine pathway, protein kinase C signaling, advanced glycation end-product formation, and angiotensin II-related responses. Although these pathways differ mechanistically, they converge on excessive reactive oxygen species (ROS) generation, antioxidant depletion, and mitochondrial injury. Under diabetic stress, electron transport chain overload promotes mitochondrial ROS leakage, damages mitochondrial DNA, disrupts membrane potential, and impairs the transcription of key respiratory chain components. In parallel, mitochondrial quality-control systems become progressively compromised. The balance between fusion and fission shifts toward pathological fragmentation through reduced MFN1/2 and OPA1 activity and enhanced DRP1-mediated fission. Mitochondrial biogenesis is suppressed through inhibition of the AMPK/SIRT1/PGC-1α/NRF1/TFAM axis, while mitophagy changes from an early compensatory response to a later state of autophagic flux blockade and accumulation of dysfunctional mitochondria. Importantly, damaged mitochondria serve as signal amplifiers linking metabolic stress to inflammation and programmed cell death. Mitochondrial ROS, oxidized mitochondrial DNA, calcium overload, cardiolipin exposure, and membrane permeabilization activate interrelated death pathways, including intrinsic apoptosis, ferroptosis, and pyroptosis. Cytochrome C and apoptosis-inducing factor promote caspase-dependent and caspase-independent apoptosis; iron dyshomeostasis, glutathione depletion, GPX4 dysfunction, and lipid peroxidation drive ferroptosis; and mitochondrial danger signals activate the NLRP3 inflammasome and gasdermin-dependent pyroptosis. These pathways jointly damage the retinal neurovascular unit and contribute to pericyte loss, endothelial barrier breakdown, Müller cell dysfunction, retinal ganglion cell apoptosis, retinal pigment epithelial injury, and photoreceptor degeneration. This review also emphasizes the role of epigenetic regulation in stabilizing mitochondrial pathology. DNA methylation, histone modifications, and non-coding RNAs interact to silence mitochondrial protective genes, alter antioxidant responses, and maintain the “metabolic memory” of DR even after glycemic normalization. Therefore, mitochondrial dysfunction should be understood as a dynamic, multidimensional network rather than a single pathological event. Current clinical approaches, such as laser photocoagulation, intravitreal anti-VEGF therapy, and vitrectomy, mainly target advanced vascular lesions and are limited by invasiveness, incomplete responsiveness, recurrence, and potential adverse effects. Therapeutically, strategies targeting mitochondrial ROS, restoring mitochondrial dynamics, enhancing biogenesis, regulating mitophagy, inhibiting inflammasome activation, correcting epigenetic abnormalities, and improving targeted delivery systems show promising potential. However, major translational barriers remain, including retinal cell heterogeneity, stage-specific mitochondrial responses, insufficient organelle-specific drug delivery, and long-term safety concerns. A deeper understanding of mitochondrial regulatory networks may support earlier, more precise, and multi-target interventions for preventing or slowing DR progression.

The Type III Secretion System (T3SS) serves as a pivotal virulence apparatus for numerous Gram-negative bacterial pathogens, enabling them to infect both animal and plant hosts. Functioning as a molecular syringe, the T3SS directly translocates bacterial effector proteins from the bacterial cytoplasm into the interior of eukaryotic host cells. These effectors are central weapons that precisely manipulate a wide spectrum of host cellular physiological processes, ranging from cytoskeletal dynamics to immune signaling, to establish a favorable niche for bacterial survival and proliferation. Among the diverse arsenal of T3SS effectors, the YopJ family constitutes a critical group of virulence factors. Members of this family are characterized by a conserved catalytic triad structure—a hallmark of the CE clan of cysteine proteases that has been evolutionarily repurposed to confer acetyltransferase activity. A defining and intriguing feature of these enzymes is their stringent dependence on a host-derived eukaryotic cofactor, inositol hexakisphosphate (IP₆), for allosteric activation. This requirement acts as a sophisticated molecular safeguard, ensuring enzymatic activity only within the appropriate host environment, thereby preventing detrimental effects on the bacterium itself. While seminal studies on individual members such as Yersinia’s YopJ and Salmonella’s AvrA have provided deep mechanistic insights, a systematic and integrative understanding of the structure-function relationships across the entire family remains fragmented. Key questions persist regarding how a conserved catalytic core has diverged to recognize distinct host substrates in different kingdoms of life. To address this gap, this article provides a systematic review of the YopJ family, focusing on three interconnected aspects: their structural features, their catalytic mechanism, and their divergent immunosuppressive strategies in animal versus plant hosts. By conducting a comparative analysis of the sequences and resolved three-dimensional structures of three representative members (e.g., HopZ1a, PopP2, AvrA), we elucidate regions of significant variation embedded within the conserved core catalytic architecture. These variable regions, often involving surface loops and substrate-binding interfaces, are crucial determinants of target specificity and functional specialization. The functional divergence of this effector family is most apparent when comparing their modes of action in different hosts. In animal hosts, YopJ-family effectors primarily sabotage innate immune signaling pathways. They achieve this by acetylating key serine and threonine residues within the activation loops of critical kinases in the MAPK and NF‑κB pathways. This post-translational modification blocks the phosphorylation and subsequent activation of these kinases, leading to potent suppression of inflammatory cytokine production. Conversely, in plant hosts, the strategy broadens to dismantle the two-tiered plant immune system. YopJ homologs target a more diverse set of substrates, including immune-associated receptor-like cytoplasmic kinases (RLCKs), microtubule networks via tubulin acetylation (which disrupts cellular trafficking and signaling), and transcription factors central to defense gene regulation. This multi-target approach effectively suppresses both Pattern-Triggered Immunity (PTI) and Effector-Triggered Immunity (ETI). In conclusion, this synthesis aims to deepen the mechanistic understanding of YopJ family-mediated pathogenesis by integrating structural biology with cellular function across host kingdoms. Elucidating the precise molecular basis for substrate selection—how conserved platforms achieve target diversity—is a major frontier. Furthermore, this knowledge provides a vital theoretical foundation for developing novel anti-virulence strategies. Targeting the conserved IP₆-binding pocket or the catalytic acetyltransferase activity itself represents a promising avenue for designing broad-spectrum inhibitors that could disarm this critical family of bacterial effectors, potentially offering new therapeutic approaches against a range of pathogenic bacteria.

Objective: To explore the relationship of family function with sleep and externalizing problem behaviors of preschool children, so as to provide a guidance for externalizing problem prevention and intervention among preschool children. Methods: From October 2023 to January 2024, a convenience sampling method was used to select 5 138 preschool children from kindergartens in 8 districts of Wuhan City, Hubei Province. Parents completed the survey for Family Adaptability and Cohesion Scale, children s sleep habits and Child Behavior Checklist (CBCL). Spearman correlation analysis was used to examine the correlation of family function with scores of sleep quality and externalizing problem behaviors among preschool children. A mediation model analysis and bootstrap test were conducted to further investigate the mediating role of sleep quality between family function and externalizing problem behaviors. Mplus 8.7 software was used for latent profile analysis of family function. Results: The reported rates of poor sleep quality and externalizing problem behaviors among preschool children were 11.8% ( n =607), 20.0% ( n =1 026). The relevant analysis results showed that family function was negatively correlated with sleep quality and externalizing problem behaviors ( r = -0.20, -0.23), and sleep quality was positively correlated with externalizing problem behaviors ( r =0.27) ( P <0.01). The mediation effect test showed that family function negatively predicted externalizing problem behaviors ( β =-0.079) and sleep quality ( β = -0.075), while sleep quality positively predicted externalizing problem behaviors ( β =0.215) ( P <0.01). The latent profile analysis results showed that family function could be classified into 4 categories: high family function group (23.01%), upper middle family function group (44.65%), moderate family function group (26.24%) and low family function group (6.11%). Compared to high family function, the other three categories significantly positively predicted externalizing problem behaviors, and the mediating effects of sleep quality on different categories of family function were statistically significant [upper middle family function: mediation effect value was 0.022 (95% CI =0.004-0.041) and direct effect value was 0.329 (95% CI =0.263-0.396); middle family function: mediation effect value was 0.087 (95% CI =0.063-0.115) and direct effect value was 0.491 (95% CI =0.416-0.565); low family function: mediation effect value was 0.144 (95% CI =0.107-0.185) and direct effect 0.621 (95% CI =0.503-0.740)] ( P < 0.05 ). Conclusion Family function negatively predicts the externalizing problem behaviors of preschool children, and sleep quality plays a partial mediating role.

Objective To explore the value of prenatal ultrasound indicators in diagnosing fetal heart malformation during pregnancy.Methods A case-control study was conducted,and 76 fetuses with confirmed heart malformation during follow-up in the hospital were selected as case group,and another 76 fetuses without any heart malformation were selected as control group.The results of ultra-sound examinations during pregnancy for both groups were compared,including umbilical vein cathe-ter color Doppler ultrasonic blood flow spectral parameters,cardiac axis angle,and myocardial per-formance index(MPI).Receiver operating characteristic(ROC)curve was used to analyze the value of each indicator in auxiliary diagnosis of fetal congenital heart malformation during pregnancy.Results The ventricular systolic velocity,peak atrial systolic velocity,peak ventricular diastolic ve-locity,and maximum A-wave velocity in the case group were significantly lower than those in the con-trol group,while the pulsatility index,venous preload index,and venous peak flow index were signif-icantly higher than those in the control group(P＜0.05).Values of area under the curve(AUC)of ROC curves for ventricular systolic velocity,peak ventricular diastolic velocity,peak atrial systolic ve-locity,maximum A-wave velocity,pulsatility index,venous preload index,and venous peak flow index in diagnosing fetal heart malformation were 0.680,0.753,0.590,0.859,0.674,0.715 and 0.663,respectively.The left ventricular MPI,right ventricular MPI,and cardiac axis angle in the case group were significantly higher than those in the control group(P＜0.05).The values of AUC for left ventricular MPI,right ventricular MPI,and cardiac axis angle in diagnosing fetal heart malformation were 0.502,0.571 and 0.712,respectively.Conclusion Implementation of umbilical vein cathe-ter color Doppler ultrasonic blood flow spectral parameters,cardiac axis angle,and MPI screening during pregnancy has important reference value for auxiliary diagnosis of fetal heart malformation.

Breast cancer is one of the most common tumors worldwide.Despite significant pro-gress in diagnosis and treatment,the incidence and mortality rates remain high due to its highly inva-sive and metastatic characteristics.Trichorhinophalangeal syndrome type 1(TRPS1)is an atypical globin transcription factor-1(GATA).It plays an important role in regulating cell proliferation and differentiation and tissue growth.Studies have found that TRPS1 is significantly overexpressed in breast cancer and closely related to tumor invasion and metastasis.TRPS1 is specifically expressed in the ductal epithelial cells of breast tissue and closely associated with the differentiation of breast ducts.In recent years,scholars have mainly focused on the role and mechanisms of TRPS1 in the di-agnosis and treatment of breast cancer.This review summarized the research progress of TRPS1 in breast cancer,aiming to further analyze its clinical application value in the occurrence,development,diagnosis,and treatment of breast cancer.

The occurrence and development of type 2 diabetes mellitus(T2DM)are closely as-sociated with defects in insulin secretion.Synaptosomal-associated protein 25(SNAP25),as a core component of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor(SNARE)complex,directly mediates the fusion of insulin secretion granules with the cell membrane and regu-lates the dynamic balance of insulin secretion stimulated by glucose.The expression defect of SNAP25 in patients with T2DM and model animals directly leads to vesicle fusion disorder,constituting the core pathological link of insulin secretion disorder and exacerbating the deterioration of β-cell func-tion.SNAP25 may serve as a key hub for multi-target synergistic intervention,and its genetic poly-morphism and the plasticity of its regulatory network offer novel strategies for precision therapy.This article innovatively integrated multidimensional regulatory mechanisms,including calcium channel ac-tivity,G-protein-coupled signaling and epigenetic modifications,to systematically analyze the spatio-temporal-specific regulatory network of SNAP25 in insulin secretion,providing a theoretical basis for T2DM therapeutic strategies targeting vesicle fusion.

Objective To explore the neuroprotective effects of osteocalcin(OCN)on an Alzheimer's disease(AD)cell model and its potential mechanisms,providing a scientific basis for new therapeutic targets for AD.Methods Human neuroblastoma cell line SH-SY5Y was treated with 40 nmol/L okadaic acid(OA)for 24 h to establish an AD cell model.The cells were divided into a normal group(untreated SH-SY5Y cells),a model group(40 nmol/L OA intervention),and an OCN intervention group(intervention with various concentrations of OCN in the AD cell model),and AKT knockout/overexpression groups(AKT-KO group and AKT-OE group),and AKT-KO OCN group and AKT-OE OCN group.CCK-8 assay was used to detect the changes in cell viability.Wright's staining was employed to observe the morphological changes of AD cells.Western blotting was utilized to detect the protein levels of Tau,p-Tau,Bax,Bcl-2,Caspase-3 and their lytic types,as well as the expression of Tau,p-Tau,mTOR,AKT and p-AKT in each group after AKT knockout/overexpression.TUNEL staining and flow cytometry were applied to detect the changes in early and late apoptotic cells and the apoptotic rate in the OCN-treated AD cell model.Results ①Compared to the normal group,the model group exhibited a significant decrease in cell viability,noticeable morphological and structural damage,upregulation of p-Tau and Caspase-3,increased early and late apoptosis,and a significantly higher apoptotic rate(P<0.05).②After treatment of different concentrations of OCN for 24 h,cell viability was increased to varying degrees compared to the AD model group,with the 100 pg/mL OCN group showing a significant increase in cell viability(P<0.01)and marked improvement in cell number and morphology(P<0.01).③ Compared to the AD cell model group,the p-Tau/Tau ratio was decreased in all OCN treatment groups,particularly in the 100 pg/mL OCN intervention group,where the p-Tau/Tau ratio was significantly lower than that of the model group(P<0.01).④ Compared to the model group,a significant concentration-dependent decrease in the Cleaved Caspase-3/Caspase-3 ratio was observed when OCN concentrations ranged from 1 to 100 pg/mL,with a significant reduction in the Bax/Bcl-2 ratio in the 100 pg/mL group(P<0.000 1).⑤ The results of TUNEL staining and flow cytometry showed that,compared to the model group,all concentrations of OCN effectively inhibited the apoptosis in the AD model cells,with a significant reduction in early and late apoptotic cells and apoptotic rate in the 100 pg/mL OCN group.⑥ Compared with the control group and the model group,the P-AKT was significantly increased in the AKT-OE group after AKT overexpression(P<0.05).The expression level of AKT protein was decreased in the AKT-KO group after AKT knockout(P<0.05).When the AKT pathway was inhibited,the expression level of p-Tau was higher in the AKT-KO group than the control group(P<0.05),and when the AKT was overexpressed,the expression level was significantly inhibited(P<0.05).Conclusion OCN may inhibit cell apoptosis and reduce p-tau protein level by regulating the ratio of Caspase-3/Caspase-3 and Bax/Bcl-2,and thereby improve the morphology of AD model cells and effectively protect nerve cells,which may be related to the regulation of the AKT/mTOR pathway.

Cervical spine health issues not only seriously affect patients' quality of life but also impose a heavy burden on the social healthcare system. Existing guidelines lack sufficient clinical guidance on lifestyle and work habits, such as exercise, posture, daily routine, and diet, making it difficult to meet practical needs. To address this, relying on the China Association of Chinese Medicine, Wangjing Hospital of China Academy of Chinese Medical Sciences took the lead and joined hands with more than ten institutions to form a multidisciplinary guideline development group. For the first time, the group developed the Guidelines for Cervical Spine Health Intervention based on evidence-based medicine methods, strictly following the standardized procedures outlined in the World Health Organization Handbook for Guideline Development and the Guiding Principles for the Formulation/Revision of Clinical Practice Guidelines in China (2022 Edition). This proposal systematically explains the methods and steps for developing the guideline, aiming to make the guideline development process scientific, standardized, and transparent.
Humans ; Practice Guidelines as Topic/standards* ; Cervical Vertebrae ; China

BACKGROUND: Double-stranded RNA-specific adenosine deaminase 1 (ADAR1) binds to double-stranded RNA and catalyzes the deamination of adenosine (A) to inosine (I). The functional mechanism of ADAR1 in non-small cell lung cancer (NSCLC) remains incompletely understood. This study aimed to investigate the prognostic significance of ADAR1 in NSCLC and to elucidate its potential role in regulating tumor cell proliferation and migration. METHODS: Data from The Cancer Genome Atlas (TCGA) and cBioPortal were analyzed to assess the correlation between high ADAR1 expression and clinicopathological features as well as prognosis in lung cancer. We performed Western blot (WB), cell proliferation assays, Transwell invasion/migration assays, and nude mouse xenograft modeling to examine the phenotypic changes and molecular mechanisms induced by ADAR1 knockdown. Furthermore, the ADAR1 p150 overexpression model was utilized to validate the proposed mechanism. RESULTS: ADAR1 expression was significantly elevated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tissues compared with adjacent non-tumor tissues (LUAD: P=3.70×10-15, LUSC: P=0.016). High ADAR1 expression was associated with poor prognosis (LUAD: P=2.03×10-2, LUSC: P=2.81×10-2) and distant metastasis (P=0.003). Gene Set Enrichment Analysis (GSEA) indicated that elevated ADAR1 was associated with mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway activation, matrix metalloproteinase-9 (MMP-9) expression, and cell adhesion. ADAR1 and MMP-9 levels showed a strongly positive correlation (P=6.45×10-34) in 10 lung cancer cell lines, highest in H1581. Knockdown of ADAR1 in H1581 cells induced a rounded cellular morphology with reduced pseudopodia. Concomitantly, it suppressed cell proliferation, invasion, migration, and in vivo tumorigenesis. It also suppressed ERK phosphorylation and downregulated cellular Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog (c-FOS), MMP-9, N-cadherin, and Vimentin. Conversely, ADAR1 p150 overexpression in PC9 cells enhanced ERK phosphorylation and increased c-FOS and MMP-9 expression. CONCLUSIONS High ADAR1 expression is closely associated with poor prognosis and distant metastasis in NSCLC patients. Mechanistically, ADAR1 may promote proliferation, invasion, migration, and tumorigenesis in lung cancer cells via the ERK/c-FOS/MMP-9 axis.
Humans ; Lung Neoplasms/physiopathology* ; Adenosine Deaminase/genetics* ; Matrix Metalloproteinase 9/genetics* ; Cell Proliferation ; Carcinoma, Non-Small-Cell Lung/physiopathology* ; Cell Movement ; Animals ; Mice ; RNA-Binding Proteins/genetics* ; Female ; Male ; Cell Line, Tumor ; Proto-Oncogene Proteins c-fos/genetics* ; Middle Aged ; MAP Kinase Signaling System ; Gene Expression Regulation, Neoplastic ; Mice, Nude ; Extracellular Signal-Regulated MAP Kinases/genetics*

OBJECTIVE: To evaluate the protective effects of gentiopicroside (GPS) against reactive oxygen species (ROS)-induced NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in endothelial cells, aiming to reduce atherosclerosis. METHODS: Eight-week-old male ApoE-deficient mice were randomly divided into 2 groups (n=10 per group): the vehicle group and the GPS treatment group. Both groups were fed a high-fat diet for 16 weeks. GPS (40 mg/kg per day) was administered by oral gavage to the GPS group, while the vehicle group received an equivalent volume of the vehicle solution. At the end of the treatment, blood and aortic tissues were collected for assessments of atherosclerosis, lipid profiles, oxidative stress, and molecular expressions related to NLRP3 inflammasome activation, ROS production, and apoptosis. Additionally, in vitro experiments on human aortic endothelial cells treated with oxidized low-density lipoprotein (ox-LDL) were conducted to evaluate the effects of GPS on NLRP3 inflammasome activation, pyroptosis, apoptosis, and ROS production, specifically examining the role of the sirtuin 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. SIRT1 and Nrf2 inhibitors were used to confirm the pathway's role. RESULTS: GPS treatment significantly reduced atherosclerotic lesions in the en face aorta (P<0.01), as well as in the thoracic and abdominal aortic regions, and markedly decreased sinus lesions within the aortic root (P<0.05 or P<0.01). Additionally, GPS reduced oxidative stress markers and proinflammatory cytokines, including interleukin (IL)-1 β and IL-18, in lesion areas (P<0.05, P<0.01). In vitro, GPS inhibited ox-LDL-induced NLRP3 activation, as evidenced by reduced NLRP3 (P<0.01), apoptosis-associated speck-like protein containing a CARD, cleaved-caspase-1, and cleaved-gasdermin D expressions (all P<0.01). GPS also decreased ROS production, apoptosis, and pyroptosis, with the beneficial effects being significantly reversed by SIRT1 or Nrf2 inhibitors. CONCLUSION GPS exerts an antiatherogenic effect by inhibiting ROS-dependent NLRP3 inflammasome activation via the SIRT1/Nrf2 pathway.
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Reactive Oxygen Species/metabolism* ; Iridoid Glucosides/therapeutic use* ; NF-E2-Related Factor 2/metabolism* ; Animals ; Atherosclerosis/metabolism* ; Inflammasomes/drug effects* ; Male ; Sirtuin 1/metabolism* ; Signal Transduction/drug effects* ; Humans ; Endothelial Cells/pathology* ; Mice ; Oxidative Stress/drug effects* ; Apoptosis/drug effects* ; Lipoproteins, LDL ; Mice, Inbred C57BL