AIM: To investigate the correlation of the expression of stromal cell-derived factor-1(SDF-1)and angiopoietin like protein 4(ANGPTL4)in serum with the severity of disease in patients with diabetic macular edema(DME).METHODS: From April 2020 to August 2023, 193 patients with diabetic retinopathy who were admitted to our hospital were prospectively separated into DME group(128 cases)(56 cases in mild group, 44 cases in moderate group, 28 cases in severe group)and non DME group(65 cases)according to whether the patients had macular edema and the severity of disease. Enzyme-linked immunosorbent assay(ELISA)was applied to determine the levels of ANGPTL4 and SDF-1 in serum. Multivariate Logistic regression was applied to analyze the factors that affected the severity of DME; receiver operating characteristic(ROC)curve was applied to analyze the diagnostic value of ANGPTL4 and SDF-1 levels in serum of DME patients for the severity of DME.RESULTS: The levels of ANGPTL4 and SDF-1 in serum of the DME group were obviously higher than those of the non DME group(P<0.01); the expression levels of ANGPTL4 and SDF-1 in serum of the mild, moderate, and severe groups increased obviously in sequence(P<0.05); multivariate Logistic regression analysis showed that the levels of ANGPTL4 and SDF-1 in serum were risk factors affecting the severity of DME(P<0.01); The area under the curve(AUC)of serum SDF-1 in the diagnosis of DME severity was 0.772(95%CI: 0.690-0.842), and the AUC of ANGPTL4 in the diagnosis of DME severity was 0.801(95%CI: 0.722-0.867). The AUC of ANGPTL4 combined with SDF-1 in the diagnosis of DME was 0.884(95%CI: 0.816-0.934), the sensitivity was 87.50%, and the specificity was 85.71%, which were significantly higher than ANGPTL4 or SDF-1 alone(Z=2.658, 2.469, all P<0.05).CONCLUSION: The levels of ANGPTL4 and SDF-1 in serum of DME patients are significantly increased, and their levels increase with the severity of the disease. They can be used as auxiliary indicators for diagnosing the severity of DME disease, and the combined diagnosis has a better effect.

AIM: To investigate the correlation of the expression of stromal cell-derived factor-1(SDF-1)and angiopoietin like protein 4(ANGPTL4)in serum with the severity of disease in patients with diabetic macular edema(DME).METHODS: From April 2020 to August 2023, 193 patients with diabetic retinopathy who were admitted to our hospital were prospectively separated into DME group(128 cases)(56 cases in mild group, 44 cases in moderate group, 28 cases in severe group)and non DME group(65 cases)according to whether the patients had macular edema and the severity of disease. Enzyme-linked immunosorbent assay(ELISA)was applied to determine the levels of ANGPTL4 and SDF-1 in serum. Multivariate Logistic regression was applied to analyze the factors that affected the severity of DME; receiver operating characteristic(ROC)curve was applied to analyze the diagnostic value of ANGPTL4 and SDF-1 levels in serum of DME patients for the severity of DME.RESULTS: The levels of ANGPTL4 and SDF-1 in serum of the DME group were obviously higher than those of the non DME group(P<0.01); the expression levels of ANGPTL4 and SDF-1 in serum of the mild, moderate, and severe groups increased obviously in sequence(P<0.05); multivariate Logistic regression analysis showed that the levels of ANGPTL4 and SDF-1 in serum were risk factors affecting the severity of DME(P<0.01); The area under the curve(AUC)of serum SDF-1 in the diagnosis of DME severity was 0.772(95%CI: 0.690-0.842), and the AUC of ANGPTL4 in the diagnosis of DME severity was 0.801(95%CI: 0.722-0.867). The AUC of ANGPTL4 combined with SDF-1 in the diagnosis of DME was 0.884(95%CI: 0.816-0.934), the sensitivity was 87.50%, and the specificity was 85.71%, which were significantly higher than ANGPTL4 or SDF-1 alone(Z=2.658, 2.469, all P<0.05).CONCLUSION: The levels of ANGPTL4 and SDF-1 in serum of DME patients are significantly increased, and their levels increase with the severity of the disease. They can be used as auxiliary indicators for diagnosing the severity of DME disease, and the combined diagnosis has a better effect.

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.

To investigate the correlation between vitamin D nutritional status and insulin resistance in pubertal adolescents.

AIM To investigate the effects of Zhuangyao Shuanglu Tongnao Formula on neuronal apoptosis in rats with cerebral ischemia-reperfusion injury based on the study of oxidative stress and inflammatory response.METHODS The rats were randomly divided into the sham operation group,the model group,the edaravone group(3.0 mg/kg),the low,medium and high dose groups(9.0,18.0,36.0 g/kg)of Zhuangyao Shuanglu Tongnao Formula,with 18 rats in each group.The middle cerebral artery occlusion/reperfusion was conducted by thread embolism method to simulate cerebral ischemia reperfusion injury in rats followed by 6 days corresponding drugs administration.Subsequently,the rats had their neurological function deficit scored by Zeal Longa scoring method;their sizes of cerebral infarction areas measured by TTC staining;their pathological damage and apoptosis of neurons in hippocampal CA1 area of ischemic penumbra of the brain tissue detected by HE staining and TUNEL staining;their SOD activity and levels of GSH,MDA,IL-6,IL-1β,TNF-α in brain tissue detected by kits;and their protein expressions of Bax,Bcl-2,caspase-3,cleaved-capase-3,TLR4,NF-κB p65,Nrf2,HO-1 in rat brain tissue determined by Western blot.RESULTS Compared with the model group,the groups intervened with edaravone,medium and high dose of Zhuangyao Shuanglu Tongnao Formula displayed improvements in the scores of nerve function defects,the rate of cerebral infarction,the rate of neuronal apoptosis,the levels of IL-6,IL-1β,TNF-α and MDA in the ischemic penumbra of brain tissues,the protein expressions of Bax and TLR4,the ratio of cleaved-capase-3/caspase-3 and p-NF-κB p65/NF-κB p65(P＜0.05),the levels of GSH,the activity of SOD and the protein expressions of Bcl-2,Nrf2 and HO-1(P＜0.05).CONCLUSION Being an inhibitor of oxidative stress and inflammatory response,Zhuangyao Shuanglu Tongnao Formula can alleviate brain injury in rats with cerebral ischemia reperfusion injury through the inhibition of neuronal apoptosis and improvement of neural function mediated by the inhibition of TLR4/NF-κB signal pathway and activation of Nrf2/HO-1 signal pathway.

Traumatic fractures and stress fractures are common orthopedic diseases,and there is great potential in researching bone turnover,repair,and promotion of fracture healing.Basic medical experiments often use animal models of long bone fractures in limbs to study the mechanisms of various interventions on fracture healing.Fracture healing is a complex process influenced by multiple factors and involves multiple molecules and pathways.Therefore,to explore the mechanisms more deeply,accelerate the translation of results,and improve the clinical efficacy,it is particularly important to choose the appropriate animal fracture modeling methods in experimental research.Based on this,this paper conducts a literature review of animal species and modeling methods commonly used for long bone fracture models in experimental research.It summarizes five methods:bone defect method,physical impact method,mechanical bending method,open osteotomy method,and drilling method.A side-by-side comparison of their advantages,disadvantages,and scope of application is made,aiming to provide suitable fracture models for studyingthe mechanisms of fracture healing interventions.

Objective To explore the differential expression and mechanisms of bone formation-related genes in osteoporosis(OP)leveraging bioinformatics and machine learning methodologies,and to predict the active ingredients of targeted traditional Chinese medicine(TCM)herbs. Methods The Gene Expression Omnibus(GEO)and GeneCards databases were employed to conduct a comprehensive screening of genes and disease-associated loci pertinent to the pathogenesis of OP.The R package was utilized as the analytical tool for the identification of differentially expressed genes.Least absolute shrinkage and selection operator(LASSO)logis-tic regression analysis and support vector machine-recursive feature elimination(SVM-RFE)algorithm were employed in defining the genetic signature specific to OP.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses for the selected pivotal genes were conducted.The cell-type identification by estimating rela-tive subsets of RNA transcripts(CIBERSORT)algorithm was leveraged to examine the infiltra-tion patterns of immune cells,with Spearman's rank correlation analysis utilized to assess the relationship between the expression levels of the genes and the presence of immune cells.Coremine Medical Database was used to screen out potential TCM herbs for the treatment of OP.Comparative Toxicogenomics Database(CTD)was employed for forecasting the TCM ac-tive ingredients targeting the key genes.AutoDock Vina 1.2.2 and GROMACS 2020 softwares were employed to conclude analysis results,facilitating the exploration of binding affinity and conformational dynamics between the TCM active ingredients and their biological targets. Results Ten genes were identified by intersecting the results from the GEO and GeneCards databases.Through the application of LASSO regression and SVM-RFE algorithm,four piv-otal genes were selected:coat protein(CP),kallikrein 3(KLK3),polymerase γ(POLG),and transient receptor potential vanilloid 4(TRPV4).GO and KEGG pathway enrichment analy-ses revealed that these trait genes were predominantly engaged in the regulation of defense response activation,maintenance of cellular metal ion balance,and the production of chemokine ligand 5.These genes were notably associated with signaling pathways such as ferroptosis,porphyrin metabolism,and base excision repair.Immune infiltration analysis showed that key genes were highly correlated with immune cells.Macrophage M0,M1,M2,and resting dendritic cell were significantly different between groups,and there were signifi-cant differences between different groups(P<0.05).The interaction counts of resveratrol,curcumin,and quercetin with KLK3 were 7,3,and 2,respectively.It shows that the interac-tions of resveratrol,curcumin,and quercetin with KLK3 were substantial.Molecular docking and molecular dynamics simulations further confirmed the robust binding affinity of these bioactive compounds to the target genes. Conclusion Pivotal genes including CP,KLK3,POLG,and TRPV4,exhibited commendable significant prognostic value,and played a crucial role in the diagnostic assessment of OP.Resveratrol,curcumin,and quercetin,natural compounds found in TCM,showed promise in their potential to effectively modulate the bone-forming gene KLK3.This study provides a sci-entific basis for the interpretation of the pathogenesis of OP and the development of clinical drugs.

Thrombotic disease remains a leading cause of morbidity and mortality worldwide.Despite breakthroughs in anticoagulant therapy over the past decade,traditional vitamin K antagonists have been replaced by direct oral anticoagulants(DOACs)that selectively target coagulation factor Ⅹa or Ⅱa.However,for the growing population with concomitant diseases,there is still a lack of satisfactory treatment options.Coagulation-targeted therapy is a challenging task because it interferes with the delicate balance between procoagulant and anticoagulant activities.Epidemiological and animal studies have identified factor Ⅺ as a potential target for anticoagulation,because factor Ⅺ deficiency or inhibition can prevent thrombosis and is associated with little or no bleeding.Based on the concept of contact hemostasis,this review describes the basic principles of the development of coagulation factor Ⅺ inhibitors,elaborates on the pharmacological characteristics of existing factor Ⅺ inhibitors,and summarizes the current situation of clinical trial research,to provide some insight for the development of new anticoagulant drugs and clinical anticoagulant treatment.

PI3Kγ and PI3Kδ have important regulatory roles in the immune system, and targeting these two subtypes helps to reshape the tumor microenvironment. PI3Kγ and PI3Kδ are potential targets for tumor immunotherapy. In this study, a series of new pyrazolopyrimidine derivatives were designed and synthesized on the basis of our previously reported PI3K inhibitors, resulting in the discovery of compound 16l as a potent and selective PI3Kγ/δ dual inhibitor. Compound 16l demonstrated strong biochemical potencies against PI3Kγ and PI3Kδ with IC₅₀ values of 0.11 and 0.79 nmol·L^-1. In cell-based assays, it potently inhibited the PI3Kγ and PI3Kδ mediated Akt S473 phosphorylation with EC₅₀ values of 3 and 7 nmol·L^-1. In vivo, compound 16l exhibited acceptable pharmacokinetic properties in Sprague-Dawley (SD) rats and suppressed the tumor growth in a MC38 syngeneic mouse model. The animal experiments were approved by the Animal Ethics Committee of Hefei Institutes of Physical Science, Chinese Academy of Sciences (approval number: DWLL-2000-06). In addition, no appreciable human ether-a-go-go-related gene (hERG) inhibition was observed for compound 16l even at 30 μmol·L^-1. These results suggested that compound 16l might be a potential research tool for studying the PI3Kγ/δ mediated signaling pathways.

Background::Although overnight fasting is recommended prior to endoscopic retrograde cholangiopancreatography (ERCP), the benefits and safety of high-carbohydrate fluid diet (CFD) intake 2 h before ERCP remain unclear. This study aimed to analyze whether high-CFD intake 2 h before ERCP can be safe and accelerate patients’ recovery.Methods::This prospective, multicenter, randomized controlled trial involved 15 tertiary ERCP centers. A total of 1330 patients were randomized into CFD group ( n = 665) and fasting group ( n = 665). The CFD group received 400 mL of maltodextrin orally 2 h before ERCP, while the control group abstained from food/water overnight (>6 h) before ERCP. All ERCP procedures were performed using deep sedation with intravenous propofol. The investigators were blinded but not the patients. The primary outcomes included postoperative fatigue and abdominal pain score, and the secondary outcomes included complications and changes in metabolic indicators. The outcomes were analyzed according to a modified intention-to-treat principle. Results::The post-ERCP fatigue scores were significantly lower at 4 h (4.1 ± 2.6 vs. 4.8 ± 2.8, t = 4.23, P <0.001) and 20 h (2.4 ± 2.1 vs. 3.4 ± 2.4, t= 7.94, P <0.001) in the CFD group, with least-squares mean differences of 0.48 (95% confidence interval [CI]: 0.26–0.71, P <0.001) and 0.76 (95% CI: 0.57–0.95, P <0.001), respectively. The 4-h pain scores (2.1 ± 1.7 vs. 2.2 ± 1.7, t = 2.60, P = 0.009, with a least-squares mean difference of 0.21 [95% CI: 0.05–0.37]) and positive urine ketone levels (7.7% [39/509] vs. 15.4% [82/533], χ2 = 15.13, P <0.001) were lower in the CFD group. The CFD group had significantly less cholangitis (2.1% [13/634] vs. 4.0% [26/658], χ2 = 3.99, P = 0.046) but not pancreatitis (5.5% [35/634] vs. 6.5% [43/658], χ2 = 0.59, P = 0.444). Subgroup analysis revealed that CFD reduced the incidence of complications in patients with native papilla (odds ratio [OR]: 0.61, 95% CI: 0.39–0.95, P = 0.028) in the multivariable models. Conclusion::Ingesting 400 mL of CFD 2 h before ERCP is safe, with a reduction in post-ERCP fatigue, abdominal pain, and cholangitis during recovery.Trail Registration::ClinicalTrials.gov, No. NCT03075280.