OBJECTIVE To study the ameliorative effect and mechanism of Forsythia suspensa-Lonicera japonica herb pair on acute lung injury （ALI） based on serum exosomal microRNA （miRNA）. METHODS The rats were randomly divided into a blank group （normal saline）， model group （nomal saline）， and F. suspensa-L. japonica herb pair group （2.55 g/kg）， with 10 rats in each group. Except for the blank group， the other groups were used to establish an ALI model by intratracheal dripping of 5 mg/ mL lipopolysaccharides. After modeling， each group was given relevant medicine/normal saline intragastrically， once a day， for 3 consecutive days. After the last medication， the pathological status of lung tissue was observed； lung wet-to-dry weight ratio and leukocyte counts in bronchoalveolar lavage fluid （BALF） were determined. The levels of inflammatory factors [tumor necrosis factor-α（TNF-α）， interleukin-1β （IL-1β）， IL-10] in BALF were determined. Exosomes were isolated from rat serum， and high- throughput sequencing technology was employed to screen differentially expressed miRNA within the exosomes， followed by Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analysis. Based on the screened differentially expressed miRNA and the enriched KEGG pathways， in vitro cellular experiments were conducted for validation. RESULTS The animal experimental results demonstrated that after intervention with the F. suspensa-L. japonica herb pair， the wet-to-dry weight ratio， the number of leukocytes in BALF， as well as the levels of TNF-α and IL-1β in BALF of ALI rats were all significantly reduced （P＜0.01）， while the level of IL-10 was significantly increased （P＜0.01）. The results of high-throughput sequencing experiments revealed that the F. suspensa-L. japonica herb pair could significantly up-regulate the expressions of miR-345-3p， miR-194-5p， miR-653-5p， and others in exosomes. Among them， the KEGG pathways involved in the target genes of differentially expressed miRNA included the hypoxia-inducible factor-1（HIF-1） signaling pathway， among others. The results of cellular E-mail：huang.haiying@126.com validation experiments showed that overexpressed miR-345-3p could significantly elevate the level of IL-10 in the cell supernatant （P＜0.01）， while significantly reducing the levels of TNF-α and IL-1β in the cell supernatant， as well as the mRNA and protein expression levels of protein kinase B1， phosphatidylinositol 3- kinase， and HIF-1α （P＜0.01）. CONCLUSIONS F. suspensa-L. japonica herb pair can alleviate inflammatory responses and thereby exert a therapeutic effect in improving ALI by up-regulating the expression of miR-345-3p in serum exosomes and inhibiting the activity of the HIF-1 signaling pathway.

ObjectiveTo investigate the mechanism of Forsythiae Fructus-Lonicerae Japonicae Flos（FF） in the treatment of acute lung injury（ALI） by investigating the effects of FF on serum metabolomics of rats with ALI. MethodsThirty male SD rats were acclimated for 1 week， and 6 rats were randomly selected as the blank group. The other 24 rats were injected with lipopolysaccharide（LPS） solution by tracheal drip to establish an ALI model. After successful model establishment， the rats were randomly divided into the model group， the FF low-dose group（3.0 g·kg^-1）， the FF high-dose group（6.0 g·kg^-1）， and the dexamethasone group（5 mg·kg^-1）， with six rats in each group. The FF low- and high-dose groups and the dexamethasone group were received daily oral administration of the corresponding drug solution， and the blank group and the model group were gavaged with an equal amount of saline， treatment was administered continuously for 3 d. The pathological conditions of rat lung tissues were evaluated by hematoxylin-eosin（HE） staining， wet/dry mass ratio（W/D） of the lung tissues， and protein concentration in rat bronchoalveolar lavage fluid（BALF）. Metabolomic analysis of rat serum was performed by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry（UPLC-Q-TOF-MS）， combined with multivariate statistical analysis， the potential biomarkers of FF in treating ALI were screened by variable importance in the projection（VIP） value>1， P<0.05 from t-test， and log₂fold change（FC）>1 or log₂FC<-1. Kyoto Encyclopedia of Genes and Genomes（KEGG） database combined with MetaboAnalyst were used for pathway analysis of the screened differential metabolites. The protein expression levels of sphingosine-1-phosphate（S1P）， phosphatidylinositol 3-kinase（PI3K）， protein kinase B1（Akt1）， and phosphorylated Akt1（p-Akt1） were examined by Western bolt. The expression levels of interleukin（IL）-6， IL-1β， and tumor necrosis factor（TNF）-α in BALF were detected by enzyme-linked immunosorbent assay（ELISA）. ResultsCompared with the blank group， rats in the model group showed ALI pathological features such as alveolar lumen dilatation， interstitial hemorrhage and massive inflammatory cell infiltration， and the protein concentration in BALF and W/D of the lung tissues were significantly elevated（P<0.01）. Compared with the model group， the low- and high-dose groups of FF as well as the dexamethasone group exhibited reduced pulmonary bronchial hemorrhage in rats， and the protein concentration in BALF and W/D were significantly decreased（P<0.05）， and the lung injury was significantly alleviated. Analysis of rat serum metabolomics revealed that FF downregulated 38 biomarkers. Pathway enrichment analysis showed that FF primarily exerted therapeutic effects through 7 key metabolic pathways， including arginine biosynthesis， sphingomyelin metabolism， alanine， aspartate and glutamate metabolism， taurine and hypotaurine metabolism， α-linolenic acid metabolism， niacin and nicotinamide metabolism， and retinol metabolism. The results of Western bolt and ELISA showed that， compared with the blank group， the model group exhibited significantly elevated expression levels of S1P， PI3K， Akt1 and p-Akt1 proteins in the lung tissues， as well as increased expression levels of IL-6， IL-1β and TNF-α in BALF（P<0.01）. Compared with the model group， the expression levels of the aforementioned indicators were significantly downregulated in the low- and high-dose FF groups as well as the dexamethasone group（P<0.05， P<0.01）. ConclusionFF may play a role in ALI by regulating amino acid metabolism and lipid metabolism， and its mechanism may be related to the inhibition of S1P/PI3K/Akt1 signaling pathway to attenuate the inflammatory response caused by ALI.

The pharmaceutical industry faces challenges in quality digitization for complex multi-stage processes, especially in small-sample systems. Here, an intelligent quality prediction and diagnostic (IQPD) framework was developed and applied to Tong Ren Tang's Niuhuang Qingxin Pills, utilizing four years of data collected from four production units, covering the entire process from raw materials to finished products. In this framework, a novel path-enhanced double ensemble quality prediction model (PeDGAT) is proposed, which combines a graph attention network and path information to encode inter-unit long-range and sequential dependencies. Additionally, the double ensemble strategy enhances model stability in small samples. Compared to global traditional models, PeDGAT achieves state-of-the-art results, with an average improvement of 13.18% and 87.67% in prediction accuracy and stability on three indicators. Additionally, a more in-depth diagnostic model leveraging grey correlation analysis and expert knowledge reduces reliance on large samples, offering a panoramic view of attribute relationships across units and improving process transparency. Finally, the IQPD framework integrates into a Human-Cyber-Physical system, enabling faster decision-making and real-time quality adjustments for Tong Ren Tang's Niuhuang Qingxin Pills, a product with annual sales exceeding 100 million CNY. This facilitates the transition from experience-driven to data-driven manufacturing.

Schizophrenia,a severe mental illness characterized by high disability and chronicity,imposes a heavy disease burden on society and patients in China.Community-based management plays a crucial role in the long-term and comprehensive management of patients with schizophrenia.Through years of exploration,community-based management models—primarily focused on case management,assertive community treatment(ACT),and crisis intervention—have proven beneficial to the overall recovery of patients.However,notable differences exist in the implementation of these models between domestic and international practices.Given this context,we systematically analyze domestic and international research to examine the characteristics of different management models and the causes of the differences.Based on this analysis,we propose targeted recommendations for improving community-based management of schizophrenia in China.Regarding case management,a tiered approach should be adopted according to regional economic conditions and resource availability to optimize the efficiency of resource allocation.For ACT,we suggest developing a family-centered integrated intervention framework adapted to China's specific context.Finally,regarding crisis intervention,a collaborative family-community-police response mechanism should be established,complemented by enhanced professional training and streamlined referral procedures.We advocate enhancing resource allocation and theoretical research,along with broader involvement of all sectors of society,to jointly optimize the community-based management model for schizophrenia in China.

ObjectiveSerum metabolomics of acute lung injury（ALI） in rats was conducted using ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry（UPLC-Q-TOF-MS） to explore the similarities and differences in the mechanism of Qingqiao（harvested when the fruits of Forsythiae Fructus were initially ripe and still green in color） and Laoqiao（harvested when the fruits of Forsythiae Fructus were ripe） in the treatment of ALI. MethodA total of 24 SD male rats were acclimatized and fed for 1 week， 6 of them were randomly selected for the blank group and 18 for the experimental group. The ALI model was induced in the experimental group by tracheal intubation with lipopolysaccharide（LPS）. After successfully constructing the ALI model， these rats was randomly divided into model group， Qingqiao group and Laoqiao group， with 6 rats in each group. The Qingqiao and Laoqiao groups were administered orally once a day at a dose of 1.5 g·kg^-1， while the blank and model groups received an equivalent volume of saline for 3 consecutive days. The pathological conditions of rat lung tissues were comprehensively assessed by hematoxylin-eosin（HE） staining， wet-to-dry mass ratio（W/D） of lung tissues， and protein concentration in rat bronchoalveolar lavage fluid（BALF）. The levels of interleukin（IL）-6， IL-1β and tumor necrosis factor（TNF）-α in BALF were quantified using enzyme-linked immunosorbent assay（ELISA）. UPLC-Q-TOF-MS was used to identify and analyze the chemical compositions of Qingqiao and Laoqiao， and serum metabolomics of rats in each group was analyzed， combined with multivariate statistical analysis with variable importance in the projection（VIP） value>1， P<0.05 from t-test， and fold change（FC）≥1.5 or FC≤0.5 to screen the differential metabolites Qingqiao and Laoqiao for the treatment of ALI. The Kyoto Encyclopedia of Genes and Genomes（KEGG） database was used in combination with MetaboAnalyst for the metabolic pathway analysis of the screened differential metabolites. ResultCompared with the blank group， rats in the model group exhibited enlarged alveolar lumen， ruptured alveoli， interstitial hemorrhage， bronchial exudation of a large number of neutrophils and erythrocytes， and a significant increase in the protein concentration in the BALF and the W/D value of the lung tissues（P<0.01）. In contrast， compared with the model group， rats in the Qingqiao group and the Laoqiao group showed reduced bronchial hemorrhage in the lungs， and the protein concentration in the BALF and the W/D value of the lung tissues were significantly decreased（P<0.01）， the lung injury was significantly alleviated， but more obvious in the Qingqiao group. Compared with the blank group， the expression levels of IL-6， IL-1β and TNF-α in the BALF of the model group were significantly higher（P<0.01）. Additionally， compared with the model group， the expression levels of IL-6， IL-1β and TNF-α in the Qingqiao and Laoqiao groups were significantly lower（P<0.01）. The chemical composition analysis of Qingqiao and Laoqiao revealed that 63 components were detected in Qingqiao and 55 components were detected in Laoqiao， with 47 common components， 16 components unique to Qingqiao and 8 components unique to Laoqiao. Characterizing the differences in serum metabolomics in rats， 19 and 12 metabolites were called back by Qingqiao and Laoqiao， respectively. The metabolic pathway enrichment analysis showed that Qingqiao exerted its therapeutic effects by affecting 6 key metabolic pathways， including linoleic acid metabolism， phenylalanine metabolism， phenylalanine， tyrosine and tryptophan biosynthesis， glycerophospholipid metabolism， α-linolenic acid metabolism， and arachidonic acid metabolism， and Laoqiao exerted therapeutic effects by affecting 6 key metabolic pathways， including linoleic acid metabolism， arachidonic acid metabolism， sphingolipid metabolism， phenylalanine metabolism， ascorbate and aldarate metabolism， and glycerophospholipid metabolism. ConclusionQingqiao and Laoqiao have therapeutic effects on ALI， and Qingqiao is more effective. Both of them can play a therapeutic role in ALI by regulating amino acid metabolism and lipid metabolism， but the metabolic pathways affected by them are different.

Wubeizi(Galla Chinensis)is a commonly used traditional Chinese medicine in modern clinical practice,which is widely used to treat hemorrhoids,bleeding,mouth ulcers and other diseases.Based on the incopat patent database,the global Galla Chinensis sub-patent search in the past 20 years was conducted,and a total of 8123 related patents were retrieved;Using the basic chart analysis method,the pattern analysis of Galla Chinensis sub-patents was carried out from the aspects of application trend,patent value,technical field,legal status,etc.The analysis results show that the development of Galla Chinensis is in the rapid development stage,Galla Chinensis has in-depth research in the treatment of hemorrhoids,oral ulcers,bleeding,Chinese herbal medicine,Chinese patent medicine and cosmetics are the hot spot of research and development at present,China and South Korea are the main distribution countries of Galla Chinensis patents.The number of Chinese Galla Chinensis patents is large,but the patent quality,value and patent level of the world have a certain gap.In view of the current development trend of Galla Chinensis,there is still a large amount of patent application space in this field.Chinese Galla Chinensis patent applicants can combine their own advantages,development trend and short board to formulate scientific development strategy,thus improving the core competitiveness of Galla Chinensis industry fundamentally.

Objective This study aimed to establish a pre-metastatic niche mouse model utilizing luciferase-labeled Lewis (Luc-Lewis) lung cancer cells and to assess the efficacy of this model employing both qualitative and quantitative methods. Methods C57BL/6 mice were categorized into two groups: a normal control group and a model group, each containing 15 individual mice. The pre-metastatic niche model was established via tail vein injection of Luc-Lewis lung cancer cells. Body mass were measured daily for all groups. Tumor fluorescence signals within the mice were detected using a high-throughput enzyme marker instrument. Lung tissue specimens were harvested to evaluate metastatic progression. HE staining was used to assess histopathological changes. Real-time quantitative PCR and Western blot analysis were used to detect the mRNA and protein expression of lysyl oxidase (LOX), matrix metalloproteinase 9 (MMP9), versican (VCAN), and fibronectin (FN), which are the specific markers for the formation of the microenvironment of lung tissues before metastasis. Results Significant declines in body mass and observable lethargy were noted in the model group when compared to the control group. Distinct fluorescence signals were observed in the lung tissue of the model group, demonstrating a positive correlation with the duration of model establishment. By day 14, elevated mRNA and protein expression levels of LOX, MMP9, VCAN, and FN were significantly evident. In addition, histopathological evaluations revealed augmented interstitial thickness, alveolar atrophy and significant inflammatory cell infiltration within the lung tissues of the model group. By the 21st day, metastatic lesions manifested in the lung tissues of the model group, suggesting an approximate pre-metastatic niche maturation timeline of 14 days. Conclusion A pre-metastatic niche mouse model for Lewis lung cancer is successfully established.
Mice ; Animals ; Lung Neoplasms/pathology* ; Matrix Metalloproteinase 9 ; Mice, Inbred C57BL ; Carcinoma, Lewis Lung ; Disease Models, Animal ; RNA, Messenger ; Tumor Microenvironment

Objective To construct oligomeric hyaluronic acid(5 KDa)-modified ellagic acid-loaded liposomes(EA-HA-L)to improve the aqueous solubility,in vitro transdermal effect and whitening activity of ellagic acid.Methods Oligomeric hyaluronic acid-modified cholesterol(HA-Chol)was prepared by esterification reaction and structurally characterized by FTIR and 1H NMR;Oligomeric hyaluronic acid-modified ellagic acid-loaded liposomes were prepared by film dispersion-ultrasound method,and the prescribing process was optimized by Box-Behnken design-response surface method,and the particle sizes,the polydispersity index(PDI),zeta potential and encapsulation rate of liposomes under the optimal prescribing process were determined;the difference in solubility between EA-HA-L and free EA was evaluated;in vitro transdermal effect of liposomes were investigated using rat abdominal skin;inhibitory effect on tyrosinase and intracellular tyrosinase in mouse melanoma cells(B16-F10)was surveyed via dopa oxidation method.Results HA-Chol was synthesized and characterized;the optimized prescription process was mass ratio of 10:1 for soy phospholipids to HA-Chol,lipid-drug ratio of 40:1,hydration temperature of 30℃,hydration time of 60 min,ultrasound intensity of 35％,ultrasound time of 21 min,and the particle size of EA-HA-L produced under the optimized prescription process was(140.30±1.30)nm,PDI was(0.29±0.01),the encapsulation rate of ellagic acid was 91.16％±3.06％,and the zeta potential was(-5.67±0.09)mV;after EA was encapsulated by liposomes,the solubility of EA in water increased by about 40-fold;the cumulative transdermal amount of EA-HA-L was 46.98±2.17 μg·cm-2 in 24 h,and the intradermal retention was 66.15±0.61 μg·cm-2,which was 1.72 times higher than that of free EA(P<0.0001)and 1.23 times higher than plain liposome(EA-L)(P<0.01);and the tyrosinase inhibitory activity of EA-HA-L was higher than that of both free EA and EA-L in the EA concentration range of 50-400 μg·mL-1.Conclusion Oligomeric hyaluronic acid-modified ellagic acid-loaded liposomes with small particle size and high encapsulation rate were successfully prepared.EA-HA-L significantly improved the water solubility of EA and possessed better transdermal effect and stronger whitening activity than free EA and EA-L.

Objective:To explore the value of the logistic regression model with three-dimensional CT quantitative parameters in combination with qualitative parameters in predicting the invasiveness of pure ground glass nodules (pGGN).Methods:The clinical data and image features of 191 patients (196 lesions) with pGGN on CT confirmed as lung adenocarcinoma by pathology from April 2019 to December 2019 in Anhui Chest Hospital were retrospectively analyzed. Totally, 196 lesions were divided into atypical adenomatous hyperplasia (AAH)+adenocarcinoma in situ (AIS)+minimally invasive adenocarcinoma (MIA) group ( n=128) and invasive adenocarcinoma (IAC) group ( n=68). CT quantitative parameters included the maximum diameter, volume, average CT value and quality of pGGN, and the qualitative parameters included the intrinsic vascular changes, abnormal air-bronchogram, lobulated signs, bubble-like sign, pleura-traction sign, and fuzzy tumor-lung interface sign. The Mann-Whitney U test was used to compare the quantitative parameters and the Pearson χ 2 test was used to compare the qualitative parameters between two groups. The independent predictors of IAC and predictive probability value were screened by univariate analysis in combination with multivariate logistic regression analysis. The ROC curves were drawn to compare the diagnostic probability of logistic regression prediction probability and each single parameter. Results:There were statistically significant differences in maximum diameter [0.92(0.77,1.14) cm vs. 1.41(1.12, 1.93) cm, Z=-7.366, P<0.001], volume[0.31(0.20, 0.53) cm 3 vs. 0.88(0.41, 2.00) cm 3, Z=-6.254, P<0.001], average CT value[-571.5(-637.2, -477.0) HU vs. -418.1(-532.4, -338.5) HU, Z=-5.882, P<0.001], quality[0.14(0.09, 0.25) g vs. 0.42(0.26, 1.21) g, Z=-7.438, P<0.001], intrinsic vascular changes(23 vs. 49, χ2=55.906, P<0.001), abnormal air-bronchogram(13 vs. 30, χ2=29.908, P<0.001) and pleura-traction sign(39 vs. 32, χ2=5.291, P=0.021) between the two groups. The logistic regression analysis showed that the maximum diameter, average CT value, intrinsic vascular changes and abnormal air-bronchogram were the independent risk factors of IAC, and the odds ratio value(95%CI) were 10.624(1.275-88.522), 1.004(1.000-1.008), 3.424(1.458-8.043) and 2.993(1.114-8.043), respectively. The ROC curve demonstrated that the area under the curve, sensitivity and specificity of the logistic regression model were 0.899, 0.912, and 0.711 respectively, which were better than separate analysis results from each single parameter. Conclusion:The logistic regression model with a combination of three-dimensional CT quantitative and qualitative parameters can predict the invasiveness of pGGN better.

Objective:To investigate the influence of different characteristics of implant-supported fixed dental prostheses on the incidence of peri-implant disease.Methods:Prospective cohort was established for patients who received implant-supported fixed dental prostheses at the Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University between June 2014 and September 2015. Several patient-related factors, implant prostheses factors, and oral hygiene maintenance factors were collected. The Log-rank test was used to compare the peri-implant disease rates of various factors, and the Cox proportional hazards model was used to conduct multivariate study on single factor significant factors to analyze the impact on the incidence of peri-implant disease.Results:A total of 214 subjects and 351 implants were included in the cohort, the follow-up period was (11.0±3.5) months. Finally, 43.0% (92/214) of patients and 37.3% (131/351) of implants developed peri-implant diseases. The incidence of peri-implant mucositis and peri-implantitis was 41.1% (88/214) and 4.2% (9/214) at the subject level,and 34.2% (120/351) and 3.1% (11/351) at the implant level. Among the factors associated with the implant prosthesis, single factor Log-rank analysis showed that prostheses retention methods, proximal contact of the prostheses, occlusion situation were statistical significance ( P<0.05). Multivariate analysis using Cox proportional hazards model showed that screw retention (hazard ratio=2.38, 95% CI: 1.42-3.99), proximal contact loss of the prostheses (hazard ratio=2.36, 95% CI: 1.31-4.27) were independent risk factors for peri-implant disease ( P<0.05). Conclusions:Factors such as prostheses retention mode and proximal contact characteristics have important influence on the health status of the implant.