Objective To establish an oxidative stress mouse model of atopic dermatitis (AD) by applying 2,4-dinitrofluorobenzene (DNFB) to the back and post-auricular skin of KM mice, and to evaluate the regulatory role of the RAGE-NLRP3 axis (receptor for advanced glycation end products-NOD-like receptor family, pyrin domain containing 3 axis) in AD-related oxidative stress, thereby providing a potential therapeutic target for AD treatment. Methods Twenty SPF-grade female KM mice were randomly divided into a control group (Control group) and an experimental group (DNFB group), with 10 mice in each group. Mice in the Control group were treated with an acetone-olive oil vehicle (acetone: olive oil = 3:1) on their back and post-auricular skin. Mice in the DNFB group were treated with 0.5% DNFB (prepared by adding 0.5 g DNFB per 100 mL of acetone-olive oil vehicle) on the same areas, once daily for 14 consecutive days. The severity of skin lesions was scored on days 2, 4, 6, 9, 12, and 14 of treatment. On day 14, scratching behavior and ear thickness were evaluated. Ear swelling was evaluated on the final day by measuring bilateral ear thickness three times with a vernier caliper; the three measurements were averaged. HE staining was used to observe morphological and structural changes of cells in the back skin tissues. The mRNA and protein expression levels of RAGE (receptor for advanced glycation end products) in skin tissues were detected by quantitative real-time PCR, Western blot, and immunohistochemical staining. The mRNA expression levels of oxidative stress-related molecules, including NLRP3 (NOD-like receptor family, pyrin domain containing 3), caspase-1 (cysteine-dependent aspartate-specific protease 1), and IL-1β (Interleukin-1β), were detected by quantitative real-time PCR. Results On day 14, the back skin lesion scores of the Control group and DNFB group were (0.20±0.42) and (9.93±1.30) (P<0.000 1), respectively. Scratching behavior scores were (5.00±2.05) and (49.26±8.49) episodes, respectively (P<0.000 1), and ear thicknesses were (213.00±11.87) μm and (765.93±140.47) μm (P<0.000 1), respectively. The DNFB group exhibited marked skin dryness, desquamation, and thickening. HE staining results showed that skin inflammation was obvious in the DNFB group, consistent with the pathological features of AD. Quantitative real-time PCR and Western blot results showed that compared with the Control group, the mRNA expression level of RAGE in skin tissues of the DNFB group was significantly increased (P<0.05), and the protein expression level of RAGE was also significantly increased (P<0.01). Immunohistochemical staining results showed that compared with the Control group, skin tissue sections of the DNFB group exhibited thickened stratum corneum and fibrotic proliferation of fibroblasts in the interstitium under microscopic observation, with a significant increase in RAGE protein expression in the skin tissues (P<0.01). Quantitative real-time PCR results showed that the mRNA expression levels of NLRP3, caspase-1, and IL-1β in skin tissues of the DNFB group were all significantly increased (P<0.01). Conclusion The AD mouse oxidative stress model has been successfully established by topical DNFB application. RAGE may promote the development of AD by regulating the NLRP3 inflammasome and IL-1β release, forming an oxidative-inflammatory cascade, suggesting that it could be a potential therapeutic target for AD.

Objective To explore the feasibility and reference value of allogeneic lung transplantation and postoperative monitoring in miniature pigs for lung transplantation research. Methods Two miniature pigs (R1 and R2) underwent left lung allogeneic transplantation. Complement-dependent cytotoxicity tests and blood cross-matching were performed before surgery. The main operative times and partial pressure of arterial oxygen (PaO₂) after opening the pulmonary artery were recorded during surgery. Postoperatively, routine blood tests, biochemical blood indicators and inflammatory factors were detected, and pathological examinations of multiple organs were conducted. Results The complement-dependent cytotoxicity test showed that the survival rate of lymphocytes between donors and recipients was 42.5%-47.3%, and no agglutination reaction occurred in the cross-matching. The first warm ischemia times of D1 and D2 were 17 min and 10 min, respectively, and the cold ischemia times were 246 min and 216 min, respectively. Ultimately, R1 and R2 survived for 1.5 h and 104 h, respectively. Postoperatively, in R1, albumin (ALB) and globulin (GLB) decreased, and alanine aminotransferase increased; in R2, ALB, GLB and aspartate aminotransferase all increased. Urea nitrogen and serum creatinine increased in both recipients. Pathological results showed that in R1, the transplanted lung had partial consolidation with inflammatory cell infiltration, and multiple organs were congested and damaged. In R2, the transplanted lung had severe necrosis with fibrosis, and multiple organs had mild to moderate damage. The expression levels of interleukin-1β and interleukin-6 increased in the transplanted lungs. Conclusions The allogeneic lung transplantation model in miniature pigs may systematically evaluate immunological compatibility, intraoperative function and postoperative organ damage. The data obtained may provide technical references for subsequent lung transplantation research.

Objective To summarize the clinical efficacy of robotic-assisted left thoracic small-incision minimally invasive direct coronary artery bypass grafting(MIDCAB).Methods A retrospective analysis was conducted on the procedures and treatment outcomes of robotic-assisted MIDCAB in the Army Medical Center of PLA from October 2016 to June 2023.Baseline clinical information,MIDCAB-related data,perioperative conditions and data during follow-up were collected and analyzed.Results There were 23 patients subjected,including 21 males and 2 females,with a mean age of 58.17±7.49 years,and a body mass index(BMI)of 23.99±3.25 kg/m2.All of them experienced angina pectoris,and 1 had a history of myocardial infarction,1 had dilated cardiomyopathy,2 patients had chronic obstructive pulmonary disease(COPD),and 10 had a history of percutaneous coronary intervention(PCI).Robotic-assisted MIDCAB procedure was successfully completed.No internal mammary artery injury or transformation of the procedure occurred in these cases,and excellent bridging vessel flow was achieved after anastomosis of the internal mammary artery to left anterior descending branch.The incision length in the left chest was 8(8,8)cm,the operation time was 380(300,465)min,the intraoperative bleeding volume was 300(100,400)mL,the length of ICU stay was 3(2,3)d,the amount of thoracic drainage was 780(525,1 040)mL,and the postoperative length from surgery to discharge was 11.17±2.38 d.No mortality was observed during or within 30 d of hospitalization,and 1 patient was readmitted due to pericardial effusion within 30 d,and was discharged after symptomatic treatment including pericardiocentesis and drainage.No deaths,major adverse cardiovascular and cerebrovascular events(MACCE),or re-revascularization occurred in all patients during outpatient and telephone follow-up.Conclusion Robotic-assisted internal mammary artery dissection is a delicate and safe technique,and coronary artery bypass grafting in minimally invasive small-incision off-pump is effective,safe and feasible,with satisfactory short-and mid-term outcomes.The technique is suitable for minimally invasive coronary artery disease surgery and is worthy of popularization and application.

In the 1950s and 1960s,Japan's implementation of policies prioritizing economic develop-ment caused a lack of effective supervision over the discharge of industrial wastewater and exhaust gases,which led to the occurrence of the"Four Major Pollution Diseases",including Minamata disease,causing serious social and public health problems.To more effectively address public nuisances and pro-vide compensation to victims,the Japanese government gradually established an environmental damage compensation system with administrative relief characteristics since the 1970s.Through long-term prac-tice and system optimization,this system has evolved into a mature institutional framework with a clear division of labor and efficient collaboration.This paper systematically reviews the development process of Japan's environmental damage compensation system and deeply analyzes its legal frame-work and supporting policies,aiming to provide useful references for the construction and improve-ment of China's environmental damage compensation system.Meanwhile,through the case analysis of Minamata disease,the paper explores the specific mechanisms and effects in the compensation practices,further revealing the system's operational characteristics and implications,and providing a reference ba-sis for the construction of China's environmental governance legal system.

Flavoprotein monooxygenases(FPMOs) and cytochrome P450(CYP450) oxygenases are pivotal monooxygenases in nature, catalyzing crucial redox reactions in diverse biological processes and contributing to the synthesis of highly complex natural products. While CYP450 enzymes have been extensively reported and studied, numerous FPMOs have also been discovered in past research endeavors, yet their classification, catalytic reactions, and catalytic mechanisms remain to be systematically analyzed. This paper comprehensively reviews the latest advancements in FPMOs research, initiating with a classification based on sequence similarities and distinct structural features. It delves into the catalytic characteristics of three subfamilies(FMO, BVMO, and NMO) within Class B FPMOs of plants, which are integral to biosynthetic pathways of natural products. Class B FPMOs encompass two canonical Rossmann fold motifs(FAD-binding GxGxxG and NADPH-binding GxGxxA), along with a central FMO recognition motif FxGxxxHxxxF/Y/W. These enzymes play a key role in regulating various metabolic routes and precisely modulate plant growth and development. Furthermore, the review summarizes the applications of Class B FPMOs of plants, showcasing through concrete examples their potential in synthesizing natural products such as auxins, indigo, and cyanogenic glycosides. These insights will broaden and deepen our understanding of FPMOs, fostering their transition from fundamental research to practical applications. More optimized biosynthetic pathways can be devised by leveraging FPMOs, conducive to the development of novel strategies and tools for agriculture, plant protection, natural product biosynthesis, and synthetic biology.
Biological Products/metabolism* ; Mixed Function Oxygenases/chemistry* ; Flavoproteins/chemistry* ; Plants/metabolism* ; Plant Proteins/chemistry* ; Cytochrome P-450 Enzyme System/genetics*

BACKGROUND: Mild cognitive impairment (MCI) is common in atrial fibrillation (AF) patients and may develop earlier in those with multiple cardiovascular comorbidities, potentially impairing self-management and treatment adherence. This study aimed to characterize the prevalence and profile of MCI in AF patients, examine its associations with cardiovascular comorbidities, and assess how these comorbidities influence specific cognitive domains. METHODS: This cross-sectional study analyzed data from AF patients who underwent cognitive assessment between 2017 and 2021. Cognitive status was categorized as MCI or non-MCI based on the Montreal Cognitive Assessment. Associations between comorbidities and MCI were assessed by logistic regression, and cognitive domains were compared using the Mann-Whitney U test. RESULTS: Of 4136 AF patients (mean age: 64.7 ± 9.4 years, 64.7% male), 33.5% of patients had MCI. Among the AF patients, 31.2% of patients had coronary artery disease, 20.1% of patients had heart failure, and 18.1% of patients had hypertension. 88.7% of patients had left atrial enlargement, and 11.0% of patients had reduced left ventricular ejection fraction. Independent factors associated with higher MCI prevalence included older age (OR = 1.04, 95% CI: 1.03-1.05, P < 0.001), lower education level (OR = 1.51, 95% CI: 1.31-1.73, P < 0.001), hypertension (OR = 1.28, 95% CI: 1.07-1.52, P = 0.001), heart failure (OR = 1.24, 95% CI: 1.04-1.48, P = 0.020), and lower left ventricular ejection fraction (OR = 1.43, 95% CI: 1.04-1.98, P = 0.028). A higher CHA₂DS₂-VASc score (OR = 1.27, 95% CI: 1.22-1.33, P < 0.001; ≥ 2 points vs. < 2 points), and greater atherosclerotic cardiovascular disease burden (OR = 1.45, 95% CI: 1.02-2.08, P = 0.040; 2 types vs. 0 type) were linked to increased MCI risk. These above factors influenced various cognitive domains. CONCLUSIONS MCI is common in AF and closely associated with cardiovascular multimorbidity. Patients with multiple comorbidities are at higher risk, highlighting the importance of routine cognitive assessment to support self-management and integrated care.

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

Tailored lipid nanoparticles (LNPs)-mediated small interfering RNA (siRNA) nanomedicines show promise in treating liver disease, such as acute liver injury (ALI) and non-alcoholic steatohepatitis (NASH). However, constructing LNPs that address biosafety concerns, ensure efficient delivery, and target specific hepatic subcellular fractions has been challenging. To evade above obstacles, we develop three novel self-degradable "gemini-like" ionizable lipids (SS-MA, SS-DC, SS-MH) by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head. Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release, improving both biosafety and siRNA delivery efficiency. Furthermore, the distance of ester bond and tertiary amino head significantly influences the LNPs' pK _a, thereby affecting endosomal escape, hemolytic efficiency, absorption capacity of ApoE, uptake efficiency of hepatocytes and liver accumulation. We also develop the modified-mannose LNPs (M-LNP) to target liver macrophages specifically. The optimized M-MH_LNP@TNFα exhibits potential in preventing ALI by decreasing tumor necrosis factor α (TNFα) levels in the macrophages, while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-acyltransferase 2 (DGAT2) in the hepatocytes. Our findings provide new insights into developing novel highly effective and low-toxic "gemini-like" ionizable lipids for constructing LNPs, potentially achieving more effective treatment for hepatic diseases.

Spinal cord injury(SCI)is a central nervous system disease that can lead to motor,sensory,and autonomic dysfunction.Depending on the state of immune microenvironment,macrophage polarization can differentiate into M1/M2 phenotypes.The regulation of macrophage polarization by stem cells in many pathophysiological processes of SCI has become a hot topic of research in recent years.This review summarizes the relationship between macrophage polarization and SCI,and how mesenchymal stem cells(MSCs)and neural stem cells(NSCs)regulate macrophage polarization to improve SCI through paracrine secretion,delivery molecules,derived exosomes,and metabolic reprogramming pathways.It also summarizes the mechanism by which stem cells regulate the macrophage polarization phenotypes to promote SCI recovery through signaling pathways such as Janus tyrosine kinase/signal transducer and activator of transcription(JAK/STAT),Notch,Toll-like receptor 4/nuclear factor kappa-B(TLR4/NF-κB),phosphatidylinositol 3 kinase/protein kinase B(PI3K/Akt).The aim is to provide theoretical support for the treatment of SCI by regulating macrophage polarization with stem cells and to offer new perspectives for exploring the mechanism of stem cell therapy for SCI.

Atherosclerosis(AS)is an inflammatory cardiovascular disease characterized by plaque accumulation in the arterial wall,leading to increased morbidity and mortality of related cardiovascular disorders.The main pathological mechanisms of AS include lipid deposition,oxidative stress,and chronic inflammation,with disease progression involving endothelial cell dysfunction,macrophage polarization,foam cell formation,and smooth muscle cell proliferation or apoptosis.Mitochondria are essential organelles that provide energy for cellular metabolism,and the mitochondrial quality control(MQC)system is the fundamental mechanism maintaining mitochondrial functional homeostasis.MQC dysfunction can induce vascular phenotype changes through pathways such as oxidative stress,apoptosis,and inflammation,thereby promoting the progression of AS.Therefore,targeting MQC to regulate mitochondrial function may become a new direction for the treatment of AS.This review summarizes the molecular mechanisms of MQC,including mitochondrial biogenesis,mitochondrial dynamics,and mitochondrial autophagy(mitophagy),and further elucidates the role of abnormal MQC in the pathological processes of AS,aiming to provide a scientific basis for identifying potential targets to delay the progression of AS and developing related drugs.