BACKGROUND:Luteolin has a variety of pharmacological activities such as antibacterial,anti-inflammatory,antioxidant,etc.,which can inhibit the release of cellular inflammatory factors,promote cell proliferation,and improve the cellular microenvironment.OBJECTIVE:To explore the potential roles and mechanisms of luteolin in promoting diabetic chronic wound healing using network pharmacology and in vivo experiments.METHODS:Potential targets of luteolin were screened using multiple databases,systemic pharmacology of Chinese medicines database,PubChem and UniProt databases.Genes related to wound healing were identified through the GeneCards database.A protein-protein interaction network was constructed to screen core targets,and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to explore the biological pathways that luteolin may affect.In vivo experiments in mice were conducted to observe the effects of luteolin on wound healing.Eighteen C57BL/6 mice were randomly divided into three groups.A 1 cm diameter full skin defect wound was made on the back of the control group(n=6),and a 1 cm diameter full skin defect wound was made on the back of the model group(n=6)and the treatment group(n=6)after the establishment of the diabetes model.The treatment group was given 200 mg/kg luteolin by gavage once a day for 9 consecutive days after the operation,and the wound healing was observed.At the end of drug administration,the samples were taken for hematoxylin-eosin and Masson staining.qRT-PCR was used to detect the mRNA expression of interleukin 6 and tumor necrosis factor α,and western blot was used to detect the protein expression of phosphatidylinositol 3-kinase/protein kinase B(PI3K/AKT)signaling pathway.RESULTS AND CONCLUSION:(1)Network pharmacological analysis identified 56 potential target genes associated with luteolin for the treatment of chronic wounds,of which the AKT gene was most closely linked to other target genes.Gene Ontology analysis indicated that luteolin could have antioxidant and anti-stress effects and have the potential to act as a multi-targeted drug.Kyoto Encyclopedia of Genes and Genomes analysis indicated that the target genes of luteolin were mainly enriched in the PI3K/AKT signaling pathway.(2)On the 9th day of drug administration,the remaining wound area of mice in the control and treatment groups was smaller than that of the model group(P＜0.05).Hematoxylin-eosin and Masson staining results showed that compared with the model group,the number of trabecular granulation tissues and collagen deposition were increased in the treatment group,and the degree of epithelialization was higher and close to that of the control group.The mRNA expression of interleukin 6 and tumor necrosis factor α on the wound surface was lower in the treatment group than the model group(P＜0.05),while the protein expression of p-PI3K and p-AKT was higher in the treatment group than the model group(P＜0.05).To conclude,luteolin inhibits wound inflammatory response and promotes healing of diabetic wounds by modulating the PI3K/AKT signaling pathway.

ObjectiveTo develop a community-family management model for older adults with mild cognitive impairment (MCI) and to formulate detailed application specifications, and to fully leverage the initiative of communities and families under limited resource conditions, for achieving community-based early detection and early intervention for older adults with MCI. MethodsA systematic literature review was conducted to identify pertinent publications. Corpus-based research methodologies were employed to extract, refine, integrate and synthesize management elements, thereby establishing the specific content and service processes for each stage of the management model. Utilizing the 5W2H analytical framework, essential elements such as management stakeholders, target populations, content and methods for each stage were delineated. The model and its application guidelines were finalized through expert consultation and demonstration. ResultsAn expert evaluation of the management model yielded mean scores of 4.84, 4.32 and 4.84 for acceptability, feasibility and systematicity, respectively. By integrating the identified core elements with expert ratings and feedback, the final iteration of the community-family management model for older adults with MCI was formulated. This model comprised of five stages: screening and identification, comprehensive assessment, intervention planning, monitoring and referral pathways to ensure implementation, and enhanced support for communities, family members and caregivers. Additionally, it included 18 specific application guidelines. ConclusionThe proposed management model may theoretically help delay cognitive decline, improve cognitive function and potentially promote reversal from MCI to normal cognition. It may also enhance the awareness and coping capacity of older adults and their families, strengthen community healthcare professionals' ability to early identify and manage MCI.

ObjectiveTo explore the relationship between negative life events and depression severity in adolescent patients with depressive disorder， as well as the chain mediating role of insomnia symptoms and quality of life. Methods374 outpatient patients and hospitalized patients with adolescent depressive disorders were enrolled. The Adolescent Life Event Scale （ASLEC）， the Insomnia Severity Index （ISI）， the World Health Organization Quality of Life Questionnaire Short Form （WHOQOL-BREF）， and the Center for Epidemiology Depression Scale （CES-D） were used to evaluate the negative life event situation， insomnia symptoms， quality of life level and depression severity of the subjects， respectively. In addition， the PROCESS 4.0 macroprogram was used to analyze the chain mediating effect of insomnia symptoms and quality of life between negative life events and depression severity in patients with adolescent depressive disorder. ResultsThe results of correlation analysis showed that there was a significant correlation between negative life events and insomnia symptoms， quality of life， and depression severity （all P<0.05）. In addition， the results of chain mediation showed that negative life events had a significant direct effect on depression severity， with an effect size of 0.12 （P<0.001）. Insomnia symptoms and quality of life played a mediating role in the relationship between negative life events and depression severity in patients with adolescent depressive disorders， with indirect effect sizes of 0.062 （95%CI： 0.040-0.087） and 0.091 （95%CI： 0.059-0.123）， respectively. It could also play a chain mediation role， and the effect size was 0.039 （95%CI： 0.024-0.057）. ConclusionNegative life events experienced by patients with adolescent depressive disorder not only directly affect the severity of depressive symptoms， but may also indirectly exacerbate depression through insomnia symptoms and quality of life.

BACKGROUND:Luteolin has a variety of pharmacological activities such as antibacterial,anti-inflammatory,antioxidant,etc.,which can inhibit the release of cellular inflammatory factors,promote cell proliferation,and improve the cellular microenvironment.OBJECTIVE:To explore the potential roles and mechanisms of luteolin in promoting diabetic chronic wound healing using network pharmacology and in vivo experiments.METHODS:Potential targets of luteolin were screened using multiple databases,systemic pharmacology of Chinese medicines database,PubChem and UniProt databases.Genes related to wound healing were identified through the GeneCards database.A protein-protein interaction network was constructed to screen core targets,and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to explore the biological pathways that luteolin may affect.In vivo experiments in mice were conducted to observe the effects of luteolin on wound healing.Eighteen C57BL/6 mice were randomly divided into three groups.A 1 cm diameter full skin defect wound was made on the back of the control group(n=6),and a 1 cm diameter full skin defect wound was made on the back of the model group(n=6)and the treatment group(n=6)after the establishment of the diabetes model.The treatment group was given 200 mg/kg luteolin by gavage once a day for 9 consecutive days after the operation,and the wound healing was observed.At the end of drug administration,the samples were taken for hematoxylin-eosin and Masson staining.qRT-PCR was used to detect the mRNA expression of interleukin 6 and tumor necrosis factor α,and western blot was used to detect the protein expression of phosphatidylinositol 3-kinase/protein kinase B(PI3K/AKT)signaling pathway.RESULTS AND CONCLUSION:(1)Network pharmacological analysis identified 56 potential target genes associated with luteolin for the treatment of chronic wounds,of which the AKT gene was most closely linked to other target genes.Gene Ontology analysis indicated that luteolin could have antioxidant and anti-stress effects and have the potential to act as a multi-targeted drug.Kyoto Encyclopedia of Genes and Genomes analysis indicated that the target genes of luteolin were mainly enriched in the PI3K/AKT signaling pathway.(2)On the 9th day of drug administration,the remaining wound area of mice in the control and treatment groups was smaller than that of the model group(P＜0.05).Hematoxylin-eosin and Masson staining results showed that compared with the model group,the number of trabecular granulation tissues and collagen deposition were increased in the treatment group,and the degree of epithelialization was higher and close to that of the control group.The mRNA expression of interleukin 6 and tumor necrosis factor α on the wound surface was lower in the treatment group than the model group(P＜0.05),while the protein expression of p-PI3K and p-AKT was higher in the treatment group than the model group(P＜0.05).To conclude,luteolin inhibits wound inflammatory response and promotes healing of diabetic wounds by modulating the PI3K/AKT signaling pathway.

When inflammation is continuously activated or dysregulated， it can induce chronic tissue injury and organ dysfunction， and participate in the occurrence and development of various inflammatory diseases such as atherosclerosis and inflammatory bowel disease. Owing to high targeting， long-acting efficacy and programmability， nucleic acid drugs provide a new direction for the treatment of inflammatory diseases. This article reviews the classification， mechanism of action and application progress of nucleic acid drugs in inflammatory diseases. It is found that small interfering RNA （siRNA） can specifically cut target mRNA through RNA interference to achieve inhibiting the expression of the target protein； antisense oligonucleotide （ASO） can inhibit target protein expression by inducing microRNA （miRNA） degradation or regulating splicing processes； miRNA can achieve network intervention by regulating multiple inflammatory target genes. At present， important breakthroughs have been made in the field of inflammatory diseases with siRNA drugs including Lumasiran， Nedosiran （for primary hyperoxaluria 1） and Inclisiran （for atherosclerosis）， ASO drugs including Donidalorsen （for hereditary angioedema）， Volanesorsen and Olezarsen （for familial chylomicronemia syndrome） and Lademirsen （for Alport syndrome）， as well as miRNA drugs including Obefazimod （for inflammatory bowel disease） and Remlarsen （for pathological fibrosis）. These drugs are expected to become a new generation of anti-inflammatory therapeutic strategies and bring more precise and efficient treatment options for patients with chronic inflammation and fibrotic diseases.

Background/Aims: The pathophysiology of refractory gastroesophageal reflux disease (RGERD), which differs from proton pump inhibitor dependent gastroesophageal reflux disease (DGERD), remains incompletely elucidated. This study aims to compare esophageal motility patterns, transdiaphragmatic pressure gradients (TPG), and reflux profiles between RGERD and DGERD patients, and to delineate dynamic pressure gradient-esophagogastric junction (EGJ) interactions in these patients. Methods: In this retrospective study, 274 patients who underwent 24-hour impedance-pH monitoring and high-resolution manometry, along with an assessment of proton pump inhibitor responsiveness, were classified as RGERD (32.5%), DGERD (54.4%), or non-GERD (13.1%). Clinical characteristics, TPG, esophageal motility, and reflux metrics were compared between RGERD and DGERD patients. Subgroup analysis excluding hiatal hernia (HH) was conducted to investigate the pathophysiology of RGERD. Results: The RGERD group exhibited a significantly higher proportion of chest pain compared to the DGERD group. Regarding reflux profiles, RGERD patients without HH (RGERDHH- group) experienced increased weakly acidic reflux (P < 0.001) and prolonged bolus exposure (P = 0.006) compared to their counterparts (DGERDHH- group). Mechanistically, the RGERDHH- group showed reduced lower esophageal sphincter basal pressure (P = 0.010) and EGJ contractile integral (P = 0.005). Notably, following a wet-swallow, the RGERDHH- group experienced the significant elevation in gastric pressure and TPG. Correlation analyses revealed weakly acidic reflux and bolus exposure were positively correlated with gastric pressure variation, and inversely correlated with lower esophageal sphincter basal pressure. Conclusions Transient gastric pressure elevation and compromised EGJ barrier function drive weakly acidic reflux and esophageal bolus exposure. This pressure gradient-barrier mismatch underpins the refractoriness of RGERD.

Background/Aims: Cholangiocarcinoma (CCA) is a primary malignant neoplasm with an extremely poor prognosis. While combined chemoradiotherapy has been demonstrated to delay CCA progression to a certain extent, the absence of specific molecular biomarkers or targets significantly hinders the diagnosis and treatment of CCA. Methods: Through cross-analysis of proteomics and ADMA modificationomics, we identified DDX1 overexpressed in CCA with elevated R602-ADMA modifications. HPLC-MS/MS identified PRMT1 as the methyltransferase and USP10 as the deubiquitinating enzyme for DDX1. Immunofluorescence and nuclear-cytoplasmic partitioning experiments confirmed DDX1’s nuclear localization. GO and KEGG analyses clarify the biological functions of DDX1 in response to hypoxia. RNA-seq transcriptomics analyzed key pathways influenced by DDX1. A hydrodynamic in situ CCA mouse model was established to validate the chemopreventive effects of the PRMT1-specific inhibitor GSK715 on CCA development. Results: DDX1 promotes CCA progression both in vivo and in vitro and can be inhibited by GSK715. Mechanistically, PRMT1 mediates ADMA modification at position R602 of DDX1. This modification promotes DDX1 nuclear localization by recruiting USP10 to deubiquitinate DDX1, while simultaneously inhibiting PRMT1 degradation. DDX1 promotes the transcription of PRMT1 and USP10 by binding to the mRNA 3’UTR region, establishing a positive feedback regulatory pathway. This mechanism promotes the occurrence and development of CCA and can serve as a target for the inhibitor GSK715 to suppress CCA progression. Conclusions Our study identified DDX1-R602-ADMA modification as a novel ADMA modification in CCA. It further confirmed its pivotal role in CCA progression. Targeting the USP10-PRMT1-DDX1 axis may represent a significant therapeutic approach for CCA.

BACKGROUND:Many recent studies have shown a close relationship between inflammatory cytokines and osteoporosis and bone mineral density(BMD).However,the causal relationship between inflammatory cytokines and BMD has not been fully revealed. OBJECTIVE:To explore the potential causal relationship between inflammatory cytokines and BMD using a two-sample Mendelian randomization analysis. METHODS:The single nucleotide polymorphisms associated with 41 circulating inflammatory cytokines were selected from the open database of genome-wide association studies(GWAS)as instrumental variables.The GWAS data about BMD were from the Genetic Factors for Osteoporosis Consortium,involving a total of 32 735 individuals of European ancestry.Inverse variance weighting was used as the primary analysis to evaluate the causal effect.Weighted median,MR Egger regression,simple mode,and weighted mode methods were used to supplement the explanation.We used the MR-Egger intercept and MR-PRESSO method to conduct a pleiotropy test,the Cochran's Q test was used to determine whether there was heterogeneity in the results,and the leave-one-out method was used to evaluate the stability of the results.In addition,to more accurately assess the causality,the Bonferroni-corrected test was used to identify inflammatory cytokines that have a strong causal relationship with BMD. RESULTS AND CONCLUSION:(1)According to the results of the inverse variance weighting method,we found a positive causal relationship between interleukin-8 and lumbar spine BMD[β=0.075,95%confidence interval(CI):0.033-0.117,P=0.000 5),while a negative causal relationship between interleukin-17 and lumbar spine BMD(β=-0.083,95%CI:-0.152 to-0.014,P=0.018).There might be a negative causal relationship between tumor necrosis factor b and femoral neck BMD(β=-0.053,95%CI:-0.088 to-0.018,P=0.003),while a positive causal relationship between basic fibroblast growth factor and femoral neck BMD(β=0.085,95%CI:0.016-0.154,P=0.015).There might be a negative causal relationship between macrophage inflammatory protein-1a and total body BMD(β=-0.056,95%CI:-0.105 to-0.007,P=0.025).There was a negative causal relationship between interleukin-5(β=-0.019,95%CI:-0.031 to-0.006,P=0.004),stromal cell-derived factor-1a(β=-0.022,95%CI:-0.038 to-0.005,P=0.010),hepatocyte growth factor(β=-0.021,95%CI:-0.041 to-0.002,P=0.030),interleukin-4(β=-0.016,95%CI:-0.032 to-0.001,P=0.034)and heel BMD,while a positive causal relationship between nerve growth factor(β=0.019,95%CI:0.002-0.036,P=0.033),granulocyte colony-stimulating factor(β=0.011,95%CI:0.000-0.022,P=0.050),and heel BMD.Meanwhile,after the Bonferroni-corrected test,there was a strong positive causal effect between interleukin-8 and lumbar spine BMD(P=0.000 5).And consistent directional effects for all analyses were observed in MR Egger,weighted median,simple mode,and weighted mode methods.(2)Sensitivity analyses revealed no heterogeneity,pleiotropy,or outliers for the causal effect of circulating inflammatory cytokines on BMD.

Purpose To quantitatively compare the diffusion parameters of mono-and biexponential diffusion-weighted imaging models,and to obtain optimal sets of b-values in diffusion-weighted MRI for obtaining monoexponential apparent diffusion coefficient(ADC)close to perfusion-insensitive intravoxel incoherent motion(IVIM)model ADC(ADCIVIM)in identifying of pulmonary solid benign and malignant lesions.Materials and Methods IVIM was performed in 40 patients with solid nodule and masse in Xi'an Gaoxin Hospital from July 2021 to August 2022 using a 3.0T MR imager.Two experienced diagnostic radiologists subjectively evaluated the IVIM images.A single index model was used to calculate ADC values(ADC0-1 000,ADC20-1 000,ADC50-1 000,ADC80-1 000,ADC150-1 000,ADC300-1 000,ADC500-1 000,ADC300,500,1 000,ADC300,800,1 000,ADC300,500,ADC300,800 and ADC300,1 000).The reference standard ADCIVIM value were calculated using a double-exponential model.The physician's measurements between two physicians were measured.The malignant and benign groups were compared and receiver operator characteristic curve for all parameters were analyzed.Results The measurement consistency of ADC values under b value sets and ADCIVIM was very good,and the intraclass correlation coefficient was more significant than 0.75.The differences between ADCIVIM and ADC values in each b group were statistically significant(t=-6.016--2.500,all P<0.05).The area under the curve(AUC)of ADCIVIM was the largest(0.906),with an optimal threshold of 1.271×10-3 mm2/s,a sensitivity of 80.0%and a specificity of 93.0%.The diagnostic efficacy close to ADCIVIM were ADC300,800(AUC=0.891),ADC50-1 000(AUC=0.827)and ADC300,800,1 000(AUC=0.795),respectively.The optimal threshold of ADC300,800 was 1.140×10-3 mm2/s,the sensitivity and specificity were 80.0%and 93.7%,respectively.Conclusion Combining b-values 300 s/mm2 and 800 s/mm2 is recommended as routine scanning parameters for identifying the insensitive monoexponential ADC between benign and malignant solid pulmonary lesions.

Objective:It aims to examine the effects of the employee medical insurance outpatient mutual assistance on medical insurance costs for patients with diabetes mellitus,offering insights for optimizing outpatient insurance policies and chronic disease management strategies.Methods:Outpatient cost settlement data of urban employees with diabetes mellitus in Lanzhou from 2022 to 2023 was collected.Univariate analysis and interrupted time-series models were used to compare relevant medical insurance cost indicators before and after the reform.Results:The inpatient data of 765 730 diabetes mellitus patients were included in the study,and male patients account for 62.67％.After the reform,average per-visit pooling fund expenditure,average per-visit individual payment expenditures,average per-visit personal account expenditure,average per-visit eligible expense amount,average per-visit total fund payment,and the average per-visit proportion of basic medical pooling payments were decreased(P＜0.05).Moreover,average per-visit pooling fund expenditure,average per-visit individual account expenditure,average per-visit cash payment,average per-visit eligible expense amount,average per-visit total fund payment,and the average per-visit proportion of basic medical pooling payments showed a notable declining trend post-reform(P＜0.05).In contrast,the per-visit fully out-of-pocket expenditure exhibited no significant change before and after the reform(P＞0.05).Conclusion:The reform of the employee medical insurance outpatient mutual assistance system has alleviated the economic burden of disease for diabetic patients and improved the efficiency of medical insurance fund utilization,but it reduced the proportion of basic medical pooling payments.It is recommended to continuously refine the outpatient medical insurance payment system,strengthen supervision of medical expenses and service quality,and balance patient benefits with fund pressure to enhance chronic disease outpatient benefits.