Flap transplantation is a critical surgical strategy for the reconstruction of tissue defects caused by trauma, tumor resection, and congenital malformations, and its survival rate directly determines surgical efficacy and patient prognosis. Following transplantation, flaps inevitably undergo ischemia-reperfusion (I/R) injury, during which oxidative stress, inflammatory responses, and metabolic disturbances are intricately intertwined, ultimately leading to cellular injury and tissue necrosis. Recent studies have demonstrated that multiple forms of programmed cell death—including apoptosis, pyroptosis, ferroptosis, necroptosis, and PANoptosis—play central roles in flap I/R injury. The extensive crosstalk and molecular interactions among these pathways form a highly complex cell death network. Specifically, apoptosis is mediated by the imbalance of Bcl-2 family proteins and the activation of cysteine-dependent aspartate-specific protease (caspase) cascades; pyroptosis is driven by the NLRP3-caspase-1-GSDMD axis, resulting in membrane pore formation and the release of pro-inflammatory cytokines; ferroptosis is characterized by iron-dependent lipid peroxidation and dysfunction of glutathione peroxidase 4 (GPX4); necroptosis is triggered by the receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-RIPK3-MLKL signaling complex, leading to membrane rupture; and PANoptosis represents an integrated form of inflammatory cell death that coordinates multiple death pathways. Importantly, these forms of programmed cell death are not independent but are interconnected through extensive signaling crosstalk. Key regulatory molecules, including caspase-8, reactive oxygen species (ROS), nuclear factor-κB (NF-κB), and nuclear factor erythroid 2-related factor 2 (Nrf2), collectively modulate the dynamic balance among these pathways. Therefore, the multidimensional interplay and spatiotemporal dynamics of programmed cell death constitute a fundamental pathological basis of flap I/R injury. This review systematically summarizes the latest advances in the mechanisms and interactions of various programmed cell death pathways in flap I/R injury, aiming to elucidate the underlying regulatory network. These insights may provide novel theoretical foundations for optimizing flap protection strategies, improving flap survival, and promoting tissue repair.

Andrological diseases have become an important public health problem threatening men's health worldwide， which significantly affects the quality of life of patients and brings a heavy disease burden. Western medicine often faces the dilemma of obvious side effects and limited efficacy. Traditional Chinese medicine has unique advantages in the prevention and treatment of andrological diseases and has accumulated rich clinical experience. Epimedii Folium， as a traditional Chinese medicine for strengthening kidney and Yang， exerts a key therapeutic effect on andrology diseases through multi-component synergy， multi-target regulation， and multi-pathway intervention. Recent studies have found that the main active components of Epimedii Folium， such as icariin， icariside， and icaritin， are the key material basis for the treatment of andrological diseases. The active components of Epimedii Folium can play a role in common andrological diseases such as erectile dysfunction， male infertility， and prostate cancer by regulating the activity of the nitric oxide/cyclic guanosine monophosphate （NO/cGMP） pathway， participating in oxidative stress response， regulating the secretion of hypothalamic-pituitary-gonadal axis hormones， improving spermatogenic dysfunction， and inhibiting the proliferation of cancer cells. However， the systematic action network and molecular mechanisms of the active components of Epimedii Folium have not been fully elucidated， thereby limiting its potential for clinical translation and application. In the future， it is necessary to combine cutting-edge technologies such as metabolomics， single-cell sequencing， and targeted nanoscale drug delivery systems， strengthening the research on the compatibility rules of active components and organ-specific delivery， providing a scientific basis for the development of innovative andrology traditional Chinese medicine formulas with international competitiveness， and promoting the innovation and breakthrough of andrology disease treatment modes.

ObjectiveTo observe the clinical effectiveness and safety of Xiaozhong Zhitong Mixture （消肿止痛合剂） combined with antibiotic bone cement in the treatment of diabetic foot ulcer （DFU） with damp-heat obstructing syndrome. MethodsA total of 72 DFU patients with damp-heat obstructing syndrome were randomly assigned to treatment group （36 cases） and the control group （36 cases）. Both groups received standard treatment and topical antibiotic bone cement for ulcer wounds， while the treatment group received oral Xiaozhong Zhitong Mixture （50 ml per time， three times daily） in additionally. Both groups underwent daily wound dressing changes for 21 consecutive days. Ulcer healing rate， serum levels of tumor necrosis factor-alpha （TNF-α）， interleukin-1 beta （IL-1β）， malondialdehyde （MDA）， superoxide dismutase （SOD）， C-reactive protein （CRP）， and white blood cell （WBC） count were observed before and after treatment， and visual analog scale （VAS） scores for wound pain， traditional Chinese medicine （TCM） syndrome scores， and the DFU Healing Scale （DMIST scale） were also compared. Liver and kidney function were evaluated before and after treatment， and adverse events such as allergic reactions， worsening ulcer pain were recorded. ResultsTotally 35 patients in the treatment group and 33 in the control group were included in the final analysis. The ulcer healing rate in the treatment group was （87.93±9.34）%， significantly higher than （81.82±12.02）% in the control group （P = 0.035）. Compared to pre-treatment levels， both groups showed significant reductions in serum CRP， WBC， MDA， IL-1β， and TNF-α levels， with an increase in SOD level （P＜0.05）. TCM syndrome scores， VAS， and DMIST scores also significantly decreased in both groups （P＜0.05）， with greater improvements in the treatment group （P＜0.05）. No significant adverse reactions were observed in either group during treatment. ConclusionXiaozhong Zhitong Mixture combined with antibiotic bone cement has significant advantages in promoting DFU healing， reducing inflammatory response， and alleviating oxidative stress in DFU patients with damp-heat obstructing syndrome， with good safety for DFU patients with damp-heat obstructing syndrome.

ObjectiveTo explore the distribution pattern of tongue image characteristics in patients with glucolipid metabolic disorders and its main syndromes. MethodsA total of 841 patients with glucolipid metabolic disorders （disease group）， and 380 healthy subjects （control group） were included. The disease group was classified into three syndrome types： 283 cases of liver depression and spleen deficiency syndrome， 311 cases of phlegm-dampness obstruction syndrome， and 247 cases of qi stagnation and blood stasis syndrome. Tongue image data were collected using the TFDA-1 Tongue Diagnosis Instrument， and the TDAS V3.0 software was used to analyze the color， texture， and morphological features of the tongue body （TB） and tongue coating （TC） in patents with different syndromes of disease group （including lightness （L）， red-green axis （a）， yellow-blue axis （b）， luminance （Y）， difference between red signal and brightness （Cr）， difference between blue signal and brightness （Cb）， contrast （CON）， angular second moment （ASM）， entropy （ENT）， mean value （MEAN）， tongue coating area/tongue surface area （perAll）， and tongue coating area/non-coated area （perPart））. Logistic regression analysis was conducted to identify influencing factors for different syndrome types of glucolipid metabolic disorders. ResultsThe tongue body indicators TB-L， TB-Y， and TB-Cb in the disease group were significantly higher than those in the control group， while TB-a， TB-b， and TB-Cr were significantly lower. The tongue coating indicators TC-L， TC-Y， TC-Cb， perAll， and perPart in the disease group were significantly higher than those in the control group， while TC-a， TC-b， and TC-Cr were significantly lower （P＜0.05）. Comparing with the different syndromes in disease group， the TB-L and TB-Y of the liver depression and spleen deficiency syndrome， and the phlegm-damp obstruction syndrome were higher than those of the qi stagnation and blood stasis syndrome； the TB-a and TB-Cr of the phlegm-damp obstruction syndrome were lower than those of the qi stagnation and blood stasis syndrome； the perAll of the phlegm-damp obstruction syndrome was higher than that of the qi stagnation and blood stasis syndrome （P＜0.05）. In the analysis of the morphological characteristics of tongue signs， more spotted tongue in disease group compared with control group， more teeth-marked tongue in liver depression and spleen deficiency syndrome than the other two syndromes， more greasy coating in phlegm-damp obstruction syndrome， and more stasis spots of tongue in qi stagnation and blood stasis syndrome （P＜0.05）. Logistic regression analysis identified that greasy coating， spotted tongue， stasis spots of tongue， tooth-marked tongue， perAll， and TB-Cb are the influencing factors of liver depression and spleen deficiency syndrome； greasy coating， tooth-marked tongue， TC-Cb， and TC-Cr are the influencing factors of phlegm-damp obstruction syndrome； cracked tongue， stasis spots of tongue， tooth-marked tongue， and TB-Y are the influencing factors of qi stagnation and blood stasis syndrome （P＜0.05）. ConclusionCompared to healthy individuals， patients with glycolipid metabolic disorder have darker tongue color and thicker， greasy tongue coating. Glycolipid metabolic disorder patients of liver depression and spleen deficiency syndrome exhibit a reddish tongue with finer textures and more tooth marks； patients of phlegm-damp obstruction syndrome have lighter tongue coating with a coarser texture and a higher prevalence of greasy coating； patients of qi stagnation and blood stasis syndrome display lower tongue brightness with a higher prevalence of blood stasis spots.

Objective: To investigate the trends in disease burden due to childhood asthma in China from 1990 to 2021 and to project the disease burden from 2022 to 2035, so as to provide insights into formulation of the control interventions for childhood asthma in China. Methods: The prevalent case, agestandard prevalence, disability-adjusted life years (DALYs) and agestandard DALYs rate of children with asthma at ages of 0 to 14 years and their 95% uncertainty interval (UI) in China from 1990 to 2021 were extracted from the Global Burden of Disease (GBD) database. The temporal trends in the disease burden of childhood asthma were evaluated with estimated annual percentage change (EAPC) and its 95% confidence interval (CI), and the disease burden due to asthma was projected among children at ages of 0 to 14 years in China using a Bayesian age-period-cohort (BAPC) model from 2022 to 2035. Results: There were 9.368 3 million (95%UI=6.410 7 million to 14.026 1 million) prevalent cases of asthma among children at ages of 0 to 14 years in China in 2021, contributing to 0.387 9 million (95%UI=0.216 1 million to 0.668 8 million) DALYs loss. The prevalent cases and DALYs of asthma decreased by 37.28% and 52.55% among children at ages of 0 to 14 years in China in 2021 compared with 1990, and the agestandardized prevalence [EAPC=-0.70%, 95%CI=-1.26% to -0.13%)] and DALY rates [EAPC=-1.71%, 95%CI=-2.32% to -1.10%)] also appeared a tendency towards a decline. From 1990 to 2021, the prevalent cases, prevalence, DALYs and DALYs rate of asthma were all higher among male children than among female children, and the disease burden of asthma was higher among children at ages of 5 to 9 years than at other age groups. BAPC model predicted a decline in both prevalent cases and DALYs of asthma among children at ages of 0 to 14 years in China from 2022 to 2035, with 6.759 6 million prevalent cases and DALYs of 0.228 4 million personyears in 2035, while the prevalence and DALYs rates were projected to rise to 5 143.35/105 and 173.75/105 in 2035. Conclusions Despite a reduction in the disease burden of asthma among children at ages of 0 to 14 years in China from 1990 to 2021, the prevalence remained high. The disease burden due to asthma is projected to appear a decline among children at ages of 0 to 14 years in China from 2022 to 2035; however, the prevalence and DALYs rates still rise. Intensified control measures and targeted interventions are required to reduce the disease burden of childhood asthma.

ObjectiveTo investigate the effect of Danggui Shaoyaosan on ferroptosis in the rat model of non-alcoholic fatty liver disease （NAFLD） and explore the underlying mechanism based on the nuclear factor E₂-related factor 2 （Nrf2）/solute carrier family 7 member 11 （SLC7A11）/glutathione peroxidase 4 （GPX4） signaling pathway. MethodsThe sixty SD rats were randomly grouped as follows： control， model， Yishanfu （0.144 g·kg^-1）， and low-， medium-， and high-dose （2.44， 4.88， and 9.76 g·kg^-1， respectively） Danggui Shaoyaosan. A high-fat diet was used to establish the rat model of NAFLD. After 12 weeks of modeling， rats were treated with corresponding agents for 4 weeks. Then， the body weight and liver weight were measured， and the liver index was calculated. At the same time， serum and liver samples were collected. The levels or activities of total cholesterol （TC）， triglycerides （TG）， alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， and Fe²⁺ in the serum and TC， TG， free fatty acids （FFA）， malondialdehyde （MDA）， superoxide dismutase （SOD）， glutathione peroxidase （GPX）， and Fe²⁺ in the liver were measured. Hematoxylin-eosin staining and oil red O staining were employed to observe the pathological changes in the liver. Immunofluorescence was used to assess the reactive oxygen species （ROS） content in the liver. Mitochondrial morphology was observed by transmission electron microscopy. The protein levels of Nrf2， SLC7A11， GPX4， transferrin receptor 1 （TFR1）， and divalent metal transporter 1 （DMT1） in the liver were determined by Western blot. ResultsCompared with the control group， the model group showed increases in the body weight， liver weight， liver index， levels or activities of TC， TG， ALT， AST， and Fe²⁺ in the serum， levels of TC， TG， FFA， MDA， Fe²⁺， and ROS in the liver， and protein levels of TFR1 and DMT1 in the liver （P<0.01）， and decreases in the activities of SOD， GPX and the protein levels of Nrf2， SLC7A11， and GPX4 in the liver （P<0.05， P<0.01）. Meanwhile， the liver tissue in the model group presented steatosis， iron deposition， mitochondrial shrinkage， and blurred or swollen mitochondrial cristae. Compared with the model group， all doses of Danggui Shaoyaosan reduced the body weight， liver weight， liver index， levels or activities of TC， TG， ALT， AST， and Fe²⁺ in the serum， levels of TC， TG， FFA， MDA， Fe²⁺， and ROS in the liver， and protein levels of TFR1 and DMT1 in the liver （P<0.01）， while increasing the activities of SOD and GPX and the protein levels of Nrf2， SLC7A11， and GPX4 in the liver （P<0.01）. Furthermore， Danggui Shaoyaosan alleviated steatosis， iron deposition， and mitochondrial damage in the liver. ConclusionDanggui Shaoyaosan may inhibit lipid peroxidation and ferroptosis by activating the Nrf2/SLC7A11/GPX4 signaling pathway to treat NAFLD.

Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive decline and memory impairment in clinical. Currently, there are no effective treatments for AD. In recent years, a variety of therapeutic approaches from different perspectives have been explored to treat AD. Although the drug therapies targeted at the clearance of amyloid β-protein (Aβ) had made a breakthrough in clinical trials, there were associated with adverse events. Neuroinflammation plays a crucial role in the onset and progression of AD. Continuous neuroinflammatory was considered to be the third major pathological feature of AD, which could promote the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. At the same time, these toxic substances could accelerate the development of neuroinflammation, form a vicious cycle, and exacerbate disease progression. Reducing neuroinflammation could break the feedback loop pattern between neuroinflammation, Aβ plaque deposition and Tau tangles, which might be an effective therapeutic strategy for treating AD. Traditional Chinese herbs such as Polygonum multiflorum and Curcuma were utilized in the treatment of AD due to their ability to mitigate neuroinflammation. Non-steroidal anti-inflammatory drugs such as ibuprofen and indomethacin had been shown to reduce the level of inflammasomes in the body, and taking these drugs was associated with a low incidence of AD. Biosynthetic nanomaterials loaded with oxytocin were demonstrated to have the capability to anti-inflammatory and penetrate the blood-brain barrier effectively, and they played an anti-inflammatory role via sustained-releasing oxytocin in the brain. Transplantation of mesenchymal stem cells could reduce neuroinflammation and inhibit the activation of microglia. The secretion of mesenchymal stem cells could not only improve neuroinflammation, but also exert a multi-target comprehensive therapeutic effect, making it potentially more suitable for the treatment of AD. Enhancing the level of TREM2 in microglial cells using gene editing technologies, or application of TREM2 antibodies such as Ab-T1, hT2AB could improve microglial cell function and reduce the level of neuroinflammation, which might be a potential treatment for AD. Probiotic therapy, fecal flora transplantation, antibiotic therapy, and dietary intervention could reshape the composition of the gut microbiota and alleviate neuroinflammation through the gut-brain axis. However, the drugs of sodium oligomannose remain controversial. Both exercise intervention and electromagnetic intervention had the potential to attenuate neuroinflammation, thereby delaying AD process. This article focuses on the role of drug therapy, gene therapy, stem cell therapy, gut microbiota therapy, exercise intervention, and brain stimulation in improving neuroinflammation in recent years, aiming to provide a novel insight for the treatment of AD by intervening neuroinflammation in the future.

BACKGROUND:In recent years,epidemiological studies have shown that obesity is a risk factor for knee osteoarthritis,and fatty acid intake,metabolism and biosynthesis are closely related to the development of obesity.However,the causal relationship between fatty acids and osteoarthritis is still unknown.OBJECTIVE:Using the Mendelian randomization analysis to investigate the causal relationship between five fatty acid phenotypes and knee osteoarthritis.METHODS:The genome-wide association study data on fatty acid ratios from the UK Biobank(met-D)and genome-wide association study data on knee osteoarthritis from the EBI-A database were pooled together.Single nucleotide polymorphisms were used as instrumental variables and sensitive single nucleotide polymorphisms were selected for analysis.Two-sample Mendelian randomization analysis was conducted to evaluate the causal relationship between fatty acids and knee osteoarthritis outcome risk.We used inverse variance weighting method,MR-Egger regression method,weighted median method,weighted model method,and simple model method to study the causal relationship between fatty acids and knee osteoarthritis.Further inverse Mendelian randomization analysis was performed in the same way to ensure the validity of the results.RESULTS AND CONCLUSION:The forward analysis and inverse variance weighting method showed a causal relationship between three types of fatty acid phenotypes and knee osteoarthritis.Among them,the proportion of saturated fatty acids to total fatty acids was positively correlated with the risk of knee osteoarthritis(odds ratio[OR]=1.825,95%confidence interval(CI):1.230,2.706,P=0.003),the proportion of omega 3 polyunsaturated fatty acids to total fatty acids was negatively correlated with the risk of knee osteoarthritis(OR=0.822,95%CI:0.688 8,0.981,P=0.03),and the proportion of omega 6 polyunsaturated fatty acids to total fatty acids was positively correlated with the risk of knee osteoarthritis(OR=1.268,95%CI:1.079,1.491,P=0.004).There were two types of fatty acid phenotypes that do not have a causal relationship with knee osteoarthritis,including total fatty acids(OR=0.925,95%CI:0.804-1.066,P=0.283)and the proportion of monounsaturated fatty acids to total fatty acids(OR=0.877,95%CI:0.756-1.018,P=0.084).The reverse analysis results indicated that when knee osteoarthritis was used as exposure data,there was no significant causal relationship with the phenotype of fatty acids.The sensitivity analysis results showed that the P-values of the bidirectional Mendelian randomization Cochran's Q-test and MR Egger regression were both greater than 0.05,indicating that there was no significant heterogeneity or pleiotropy in the causal effect analysis between fatty acid phenotype and knee osteoarthritis.To conclude,reducing the content of saturated fatty acids and omega 6 polyunsaturated fatty acids and increasing the content of omega 3 polyunsaturated fatty acids can reduce the risk of knee osteoarthritis.This provides valuable clues for studying the biological mechanisms of knee osteoarthritis and exploring the early prevention and treatment of knee osteoarthritis,as well as providing new directions for the development of interventional drugs.

Objective:To evaluate the efficacy and safety of nebulized inhalation of recombinant human interferon (IFN) α1b injection in the treatment of respiratory syncytial virus (RSV) associated lower respiratory tract infections (pneumonia and bronchiolitis) in children.Methods:A randomized, double-blind, parallel, placebo-controlled add-on design was used.Children with pneumonia or bronchiolitis aged 2 months to 5 years who tested positive for RSV antigen within 72 hours of onset from 30 clinical trial sites including Beijing Children′s Hospital, Capital Medical University between February 2021 and December 2022 were included in this study and randomly divided into 2 groups at a ratio of 1∶1 based on a stratified-block method.Both groups received basic treatments such as cough control, asthma relieving, expectorant treatment, fever reduction, oxygen therapy, etc.The experimental group received additional nebulized inhalation of IFN α1b injection at a dose of 2.0 μg/(kg·time), twice a day.The control group received nebulized inhalation of placebo twice a day.Clinical efficacy was evaluated based on indicators such as the duration of clinical symptoms and signs, and the Kaplan-Meier method was used to calculate the median and 95% CI of the duration of clinical symptoms and signs.The Log-rank test was used to compared data between groups.Safety was assessed through the incidence of adverse reactions and laboratory tests, and the Chi-square test was used to analyze the difference between groups. Results:There were 123 children in the experimental group and 122 children in the control group.The median durations of all the 5 clinical symptoms and signs [including shortness of breath, wheezing, dyspnea (visible retractions), decreased transcutaneous oxygen saturation, and abnormal mental state] in the experimental group after treatment were slightly shortened than those in the control group [2.7 d(95% CI: 1.9-3.0 d)] vs.[2.9 d(95% CI: 2.6-3.6 d), P=0.027].The improvement in dyspnea (retractions) was especially pronounced in the experimental group, with a relief rate of 50.0% (0, 100%) on the first day of administration[compared with 0 (0, 50.0%) in the control group ( Z=2.002, P=0.025)].The median duration of dyspnea in the experimental group was nearly 1 day shorter than that in the control group [1.0 d(95% CI: 0.7-1.7 d) vs.1.8 d(95% CI: 1.0-2.5 d), P=0.046].There were no significant difference in hospital stay [6.0(5.0, 8.0) d vs.6.5(5.0, 8.0) d, Z=0.675, P=0.500], oxygen therapy duration [32.0(14.0, 96.3) h vs.39.0 (24.0, 83.2) h, Z=0.094, P=0.925], the recovery rate from clinical symptoms during treatment [(105/106, 99.1%) vs.(96/101, 95.0%)], and recurrence rate [(0/106, 0) vs.(2/101, 2.0%)] between the 2 groups (all P>0.05).However, the above-mentioned four indicators in the experimental group showed a trend of clinical benefits.The quantitative virus detection results showed that the RSV viral load in both groups decreased after treatment compared to before treatment.After 2 days of treatment, the decline rate of RSV viral load from the baseline was 0.90 lg copies/(mL·d) in the experimental group and 0.25 lg copies/(mL·d)in the control group, with a statistically significant difference ( P<0.05).Furthermore, there was no statistically significant difference in the incidence of adverse reactions between the 2 groups ( P>0.05).Importantly, no drug-related serious adverse reactions occurred in both groups. Conclusions:The nebulized inhalation therapy of IFN α1b demonstrates efficacy and safety in treating pediatric RSV associated lower respiratory tract infections.It particularly offers outstanding clinical therapeutic value for severe children.

Objective:To evaluate the association between heatwaves and fall-related mortality.Methods:A total of 61 421 fall-related mortality from 2013 to 2022 in 7 provinces of China were included in a time-stratified case-crossover design, with daily meteorological data derived from the fifth generation European Reanalysis dataset produced by the European Centre for Medium-Range Weather Forecasts. Conditional logistic regression chimeric distributed lag nonlinear model was used to analyze the association between heatwaves and fall-related mortality and stratified analysis was conducted according to gender and age.Results:Heatwaves were associated with an increased risk of fall-related morality. The risk of fall-related mortality during heatwaves was higher than during non-heatwave periods ( OR=1.11, 95% CI: 1.05-1.18). The attributable fraction of fall-related motality due to heatwaves was 10.25% (95% CI: 4.49%-15.36%). For each 1 ℃ increase above the heatwave threshold, the risk of fall-related mortality increased by 34% ( OR=1.34, 95% CI: 1.02-1.76). The effect of heatwave duration on fall-related mortality was not statistically significant. Stratified analyses indicated that women experienced a higher risk of fall-related mortality during heatwaves ( OR=1.13, 95% CI: 1.04-1.22) compared to man ( OR=1.10, 95% CI: 1.04-1.17). Conclusions:Heatwave increases the risk of fall-related mortality, and the intensity of heatwaves modify this risk. Women are vulnerable populations.