ObjectiveTo explore the clinical efficacy and safety of Da Chaihutang （DCH） for the treatment of sepsis with Yang syndrome. MethodsA total of 70 patients suffering from sepsis with Yang syndrome were randomly divided into an observation group and a control group， with 35 cases in each group. They both received standard Western medicine treatment. The observation group was additionally given a dose of DCH， which was boiled into 100 mL and taken twice. The control group was additionally given an equal volume and dosage of warm water. The intervention lasted for three days. The 28-day all-cause mortality and the changes in the following indicators before and after intervention were compared between the two groups， including sequential organ failure assessment （SOFA）， acute physiology and chronic health evaluation Ⅱ （APACHE Ⅱ） score，white blood cell （WBC），the percentage of neutrophils （NEU%），C-reactive protein （CRP），procalcitonin （PCT），alanine transaminase （ALT），aspartate transaminase （AST），total bilirubin （TBil），creatinine （Cr），blood urea nitrogen （BUN），acute gastrointestinal injury （AGI） grade，gastrointestinal dysfunction score （GDS），serum intestinal fatty acid-binding protein （iFABP）， citrulline （CR），platelet （PLT），prothrombin time（PT），activated partial thromboplastin time （APTT），fibrinogen （Fib），international normalized ratio （INR），and D-dimer （D-D）. ResultsThere was no significant difference between the two groups regarding 28-day all-cause mortality. After the intervention，SOFA，WBC，PCT，and Cr were significantly decreased， and PLT was significantly increased in the control group （P<0.05）. SOFA，APACHE Ⅱ，NEU%，CRP，PCT，ALT，AST，Cr，BUN，AGI grade，GDS，and serum iFABP and CR were significantly improved in the observation group （P<0.05）. After the intervention，APACHE Ⅱ，PCT，AGI grade，GDS，and serum iFABP in the observation group were significantly lower than those in the control group ，while CR and PLT were higher （P<0.05，P<0.01）. There were significant differences regarding the gap of SOFA，APACHE Ⅱ，AST，TBil，AGI grade，GDS，iFABP，CR， and PLT between the two groups （P<0.05，P<0.01）. There were slight differences regarding PT，APTT，Fib，INR，and D-D between the two groups，which were in the clinical normal range. ConclusionOn the basis of Western medicine， DCH helped to reduce sepsis severity and improved multiple organ dysfunction with high clinical efficacy and safety， but further research on its impact on the prognosis of patients with sepsis is still required.

Objective To analyze the proportion and clinicopathological characteristics of HER2-positive breast cancer patients with BRCA1/2 pathogenic variants, and their response to neoadjuvant anti-HER2 targeted therapy. Methods The clinicopathological data of 531 breast cancer patients with germline BRCA1/2 pathogenic variants (201 with BRCA1 variants and 330 with BRCA2 variants) were analyzed. Results Among the 201 BRCA1 and 330 BRCA2 variants, 17 (8.5%) and 42 (12.7%) HER2-positive breast cancer cases were identified, respectively, accounting for 11.1% of all BRCA1/2-mutated breast cancers. Compared with BRCA1/2-mutated HR-positive/HER2-negative patients, HER2-positive patients did not present any significant differences in clinicopathological features; however, compared with triple-negative breast cancer patients, HER2-positive patients had a later onset age and lower tumor grade. Among the 17 patients who received neoadjuvant anti-HER2 targeted therapy, 10 cases achieved pCR (58.8%), whereas 7 cases did not (41.2%). Conclusion HER2-positive breast cancer accounts for more than 10% of BRCA1/2-mutated patients. Approximately 40% of these patients fail to achieve pCR after neoadjuvant targeted therapy. This phenomenon highlights the possibility of combining anti-HER2 targeted agents with poly (adenosine diphosphate-ribose) polymerase inhibitors.

BACKGROUND: Senescent human skin primary fibroblast (FB) models have been established for studying aging-related, proliferative, and inflammatory skin diseases. The aim of this study was to compare the transcriptome characteristics of human primary dermal FBs from children and the elderly with four senescence models. METHODS: Human skin primary FBs were obtained from healthy children (FB-C) and elderly donors (FB-E). Senescence models were generated by ultraviolet B irradiation (FB-UVB), D-galactose stimulation (FB-D-gal), atazanavir treatment (FB-ATV), and replication exhaustion induction (FB-P30). Flow cytometry, immunofluorescence staining, real-time quantitative polymerase chain reaction, co-culturing with immune cells, and bulk RNA sequencing were used for systematic comparisons of the models. RESULTS: In comparison with FB-C, FB-E showed elevated expression of senescence-related genes related to the skin barrier and extracellular matrix, proinflammatory factors, chemokines, oxidative stress, and complement factors. In comparison with FB-E, FB-UVB and FB-ATV showed higher levels of senescence and expression of the genes related to the senescence-associated secretory phenotype (SASP), and their shaped immune microenvironment highly facilitated the activation of downstream immune cells, including T cells, macrophages, and natural killer cells. FB-P30 was most similar to FB-E in terms of general transcriptome features, such as FB migration and proliferation, and aging-related characteristics. FB-D-gal showed the lowest expression levels of senescence-related genes. In comparisons with the single-cell RNA sequencing results, FB-E showed almost complete simulation of the transcriptional spectrum of FBs in elderly patients with atopic dermatitis, followed by FB-P30 and FB-UVB. FB-E and FB-P30 showed higher similarity with the FBs in keloids. CONCLUSIONS Each senescent FB model exhibited different characteristics. In addition to showing upregulated expression of natural senescence features, FB-UVB and FB-ATV showed high expression levels of senescence-related genes, including those involved in the SASP, and FB-P30 showed the greatest similarity with FB-E. However, D-galactose-stimulated FBs did not clearly present aging characteristics.
Humans ; Fibroblasts/drug effects* ; Cellular Senescence/physiology* ; Skin/metabolism* ; Child ; Transcriptome/genetics* ; Aged ; Ultraviolet Rays ; Cells, Cultured ; Galactose/pharmacology*

Due to its synergistic effects and reduced side effects, combination therapy has become an important strategy for treating complex diseases. In traditional Chinese medicine (TCM), the "monarch, minister, assistant, envoy" compatibilities theory provides a systematic framework for drug compatibility and has guided the formation of a large number of classic formulas. However, due to the complex compositions and diverse mechanisms of action of TCM, it is difficult to comprehensively reveal its potential synergistic patterns using traditional methods. Synergistic prediction based on molecular compatibility theory provides new ideas for identifying combinations of active compounds in TCM. Compared to resource-intensive traditional experimental methods, artificial intelligence possesses the ability to mine synergistic patterns from multi-omics and structural data, providing an efficient means for modeling and optimizing TCM combinations. This paper systematically reviews the application progress of AI in the synergistic prediction of TCM active compounds and explores the challenges and prospects of its application in modeling combination relationships, thereby contributing to the modernization of TCM theory and methodological innovation.
Artificial Intelligence ; Medicine, Chinese Traditional/methods* ; Drugs, Chinese Herbal/pharmacology* ; Humans ; Drug Synergism

The construction of experimental animal models plays an important supporting role in research into the mechanisms of action of Chinese medicines.There have been increasing reports of the construction and evaluation of animal models of spleen deficiency;however,the construction method have involved different standards and there has been insufficient objectification of the evaluation indexes.In this review,we summarize the construction and evaluation method of animal models of spleen deficiency from the aspects of animal selection,model establishment,macroscopic characterization,behavioral experiments,and objective indexes of spleen deficiency,with a view to providing theoretical guidance for the construction of experimental animal models of spleen deficiency and references for the selection of animal model platforms for spleen deficiency.

Objective To observe the value of 18F-FDG PET/CT semi-quantitative parameters for predicting spread through air spaces(STAS)of clinical stage Ⅰa—Ⅲa lung adenocarcinoma.Methods Data of 85 patients with clinical stage Ⅰa—Ⅲ a lung adenocarcinoma who underwent preoperative 18F-FDG PET/CT were retrospectively analyzed.The patients were divided into positive group(n=23)or negative group(n=62)according to whether pathology showed STAS or not.Clinical and PET/CT data were compared between groups,and logistic analysis was performed to explore the efficacy of each parameter for predicting STAS.Results Significant differences of gender,carcinoma embryonic antigen,clinical stage,pathological grade,micropapillary growth and proportion were found between groups(all P＜0.05).The maximum,the mean,the peak standard uptake value(SUVmax,SUVmean,SUVpeak),as well as the maximum,the mean and the peak standard uptake value normalized by lean body mass(SULmax,SULmean,SULpeak),also the total lesion glycolysis(TLG)in positive group were all significantly higher than those in negative group(all P＜0.05).Patients'gender,proportion of micropapillary growth,SUVmax and SULmax were all independent risk factors of STAS of clinical stage Ⅰa—Ⅲa lung adenocarcinoma.The area under the curve(AUC)of the above parameters for predicting STAS was 0.666,0.912,0.839 and 0.842,respectively,and of the combination was 0.957.Conclusion 18 F-FDG PET/CT semi-quantitative parameters SUVmax and SULmax were helpful for predicting STAS of clinical stage Ⅰa—Ⅲ a lung adenocarcinoma,and further combination of gender and proportion of micropapillary growth could improve diagnostic efficacy.

Metabolic syndrome is a complex group of metabolic disorders with an increasing global incidence rate,posing a serious threat to human health.Sodium-glucose linked transporter 2(SGLT2)inhibitors are a new type of oral hypoglycemic drug.SGLT2 inhibitors not only lower blood glucose level in a non-insulin-dependent manner by inhibiting glucose reabsorption by renal proximal convoluted tubular epithelial cell to promote urinary glucose excretion,but also by improving islet β cell function,reducing inflammatory responses,and inhibiting oxidative stress.In addition,SGLT2 inhibitors can reduce body weight through osmotic diuresis and increase fat metabolism;reduce blood pressure by inhibiting excessive activation of sympathetic nervous system and by improving vascular function.They can also improve blood lipids by increasing degradation of triacylglycerol;reduce blood uric acid by promoting uric acid excretion in kidney and intestine,and by reducing uric acid synthesis.This article reviews the effects and mechanisms of SGLT2 inhibitors on multiple metabolic disorders in metabolic syndrome and explores their potential application in metabolic syndrome treatment.

Objective RNA sequencing(RNA-seq)and bioinformatic analysis were combined and used to explore the anti-inflammatory effects and mechanisms of naringenin(Nar)in lipopolysaccharide(LPS)-stimulated human peri-odontal ligament stem cells(hPDLSCs).Methods Cell counting kit-8,quantitative real-time reverse transcription poly-merase chain reaction(qRT-PCR),and enzyme-linked immunosorbent assay(ELISA)were adopted to detect the effects of Nar on the proliferation and expression of inflammatory factors in LPS-stimulated hPDLSCs,screening for the opti-mal anti-inflammatory concentration of Nar.Differentially expressed genes(DEGs)were screened using|log2FC|≥1 and P≤0.05 as criteria.Volcano plot analysis,Kyoto En-cyclopedia of Genes and Genomes(KEGG)pathway en-richment analysis,the String database,and the MCODE module of Cytoscape were utilized to select core genes and enriched pathways.The effects on the nuclear factor κB(NF-κB)signaling pathway were verified using ELISA,qRT-PCR,and Western blot.Results Appropriate concentrations of Nar could alleviate the expression of inflammatory fac-tors and promote the proliferation of hPDLSCs stimulated by LPS.The best anti-inflammatory effect was achieved with 20 μmol/L Nar.RNA-seq showed significant enrichment of inflammation-related signaling pathways.The anti-inflamma-tory effect of Nar was mediated by inhibiting the NF-κB signaling pathway,similar to the effect of the NF-κB inhibitor BAY 11-7802.Conclusion Nar could exert its anti-inflammatory effects by inhibiting the NF-κB signaling pathway,making it a potential therapeutic option for the adjuvant treatment of periodontitis.

Objective:To investigate the role of group 3 innate lymphoid cells (ILC3) in skin wound healing, and to explore the underlying mechanisms.Methods:Twenty-four 5-week-old male C57BL/6 mice were randomly and equally allocated into 3 groups: the skin wound + ILC3 inhibitor group (referred to as ILC3 inhibitor group), the skin wound group, and the control group, with 8 mice in each group. Four days before the establishment of the wound model, mice in the ILC3 inhibitor group were intraperitoneally injected with 1 μg of ILC3 inhibitor every 2 days for a total of 2 doses, mice in the skin wound group were injected with an equal volume of physiological saline solution, and mice in the control group were fed normally. To establish a mouse skin wound model, a full-thickness circular incision with a diameter of 0.6 cm was made around the midpoint of the dorsal midline using a biopsy punch after the intraperitoneal injection of anesthetics, which was histologically confirmed to be a full-thickness injury. The size of the wounds was observed and recorded, photographs of the wounds were taken on days 0, 1, 3, 5, 7, and 9 after wounding, and corresponding wound healing rates were calculated. On day 9 after wounding, tissue samples were collected from the wound edges, and subjected to flow cytometry analysis to quantify ILC3 infiltrating around the skin wound, and hematoxylin and eosin (HE) staining was performed to assess the healing status of the skin wounds. Real-time quantitative polymerase chain reaction (qRT-PCR) was conducted to determine the mRNA expression of vitamin D receptor (VDR), Notch1, tumor necrosis factor-alpha (TNF-α), interleukin (IL) -17A, IL-17F, and IL-22 in the wound-edge tissues, and Western blot analysis to determine their protein expression. Statistical analysis was carried out by using one-way analysis of variance and t test. Results:On day 9 after wounding, the skin wound group showed an increased number of ILC3 in the wound-edge tissues (5.31% ± 1.47% vs. 3.10% ± 0.54%, P < 0.01), increased mRNA and protein expression of TNF-α, IL-22, IL-17A, and IL-17F (all P < 0.05), but decreased mRNA and protein expression of VDR (both P < 0.05) compared with the control group; the protein expression of Notch1 was significantly higher in the skin wound group than in the control group ( P < 0.05), but there was no significant difference in its mRNA expression between the two groups ( P > 0.05). On days 1, 3 and 5, the wound healing rates were significantly higher in the ILC3 inhibitor group (45.17% ± 9.90%, 61.58% ± 11.61%, 75.61% ± 9.12%, respectively) than in the skin wound group (25.87% ± 10.96%, 47.78% ± 13.81%, 64.55% ± 10.29%, respectively, all P < 0.05). On day 9, the ILC3 inhibitor group showed a decreased number of ILC3 around the wound (2.69% ± 0.95%, P < 0.01), decreased mRNA and protein expression of TNF-α, IL-22, IL-17A, and IL-17F in the wound-edge tissues (all P < 0.05), but increased mRNA and protein expression of Notch1 and VDR in the wound-edge tissues (all P < 0.05) compared with the skin wound group. On day 9 after wounding, histopathological examination with HE staining revealed continuous and intact epithelial structure, as well as dense and neatly arranged collagen fibers in the ILC3 inhibitor group, and the structures of hair follicles, blood vessels, and sebaceous glands were similar to those in the control group. Conclusions:Skin ILC3 infiltrated local wounds and were involved in the skin wound healing process through inflammatory factors such as TNF-α, IL-17A, IL-17F, and IL-22. Downregulating the number of ILC3 may promote skin wound healing by activating VDR and Notch1, as well as inhibiting the TNF-α signaling pathway and the expression of downstream inflammatory factors.

AIM:To investigate the effect of vaccarin(VAC)on endothelial dysfunction in type 2 diabetes mellitus(T2DM),and to uncover the underlying mechanisms.METHODS:(1)C57BL/6 mice received intraperitoneal injection of streptozotocin and were fed with a high-fat diet(21.8 kJ/kg,60%of the energy source was fat)to construct a T2DM mouse model.Thirty mice were randomly divided into control,T2DM and T2DM+VAC groups,with 10 mice in each group.The mice in T2DM+VAC group were given 1 mg/kg VAC via oral gavage for 6 weeks,while those in control and T2DM groups were given the same volume of PBS.The mRNA and protein expression levels of BCL2-interacting pro-tein 3(BNIP3),PTEN-induced kinase 1(PINK1)and parkin in the thoracic aorta were detected by RT-qPCR and West-ern blot.(2)Human umbilical vein endothelial cells(HUVECs)were stimulated by high glucose(HG;35 mmol/L glu-cose).Mitochondrial membrane potential,autophagy and mitochondrial superoxide levels were detected using JC-1,acri-dine orange(AO)and MitoSOX staining,respectively.RESULTS:Compared with control group,the mRNA and protein levels of BNIP3,PINK1 and parkin were significantly increased in the thoracic aorta of T2DM mice(P<0.05).Compared with T2DM group,the mRNA and protein levels of BNIP3,PINK1 and parkin in the thoracic aorta were significantly re-duced in T2DM+VAC group(P<0.05).The results of JC-1,AO and MitoSOX staining showed that VAC attenuated the decrease in mitochondrial membrane potential and the increase in autophagy and mitochondrial superoxide levels in HG-in-duced HUVECs.Treatment with VAC also inhibited HG-mediated mitochondrial damage in HUVECs after BNIP3 overex-pression.The effect of miR-570-3p mimic on mitochondrial damage was similar to VAC.RT-qPCR and Western blot showed that both miR-570-3p mimic and VAC significantly reduced the mRNA and protein levels of BNIP3,PINK1 and parkin.In contrast,inhibition of miR-570-3p exhibited the opposite effects.CONCLUSION:Treatment with VAC alle-viated endothelial dysfunction in T2DM by inhibiting HG-induced mitochondrial dysfunction through miR-570-3p/BNIP3.