Pulmonary fibrosis（PF） is a progressive and life-threatening disease with limited therapeutic options， highlighting the urgent need for innovative drug discovery strategies. To address this challenge， the authors propose the formula-originated rational intelligent screening&translation（FIRST）， a systematic framework for developing anti-fibrotic monomers derived from classical traditional Chinese medicine（TCM）. The strategy integrates three key dimensions， including tissue-oriented intelligent screening of active compounds， structural optimization based on drug-target spatial interactions and plant biosynthetic pathways， and cross-scale validation of drug. We further highlight its applications in discovering tissue-oriented novel drugs from clinically validated TCM， the development and mechanistic elucidation of anti-fibrotic therapeutics， as well as the clinical translation and secondary development of candidate drugs. This strategy paves the way for first-in-class， formula-derived monomeric drugs with defined structures， clarified mechanisms， and proven safety， offering a transformative avenue to meet the urgent therapeutic needs of PF and setting a new paradigm for TCM-based drug innovation.

Objective To improve the analysis method of the blood components of Yinchenhao decoction （YCHD） in vivo and explore its anti-hepatocellular carcinoma mechanism. Methods Ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry （UPLC-Q-TOF/MS） was used to collect and analyze blood samples from mice. The mice were given a single dose of YCHD with a concentration of 0.1 g/ml and a dose of 25 ml/kg, and then the samples were collected 2 h post–administration, which was to systematically study the chemical components of YCHD in vivo. Network pharmacological methods were used to screen the components and targets of YCHD, and the targets of hepatocellular carcinoma; The common targets of YCHD and hepatocellular carcinoma were identified for GO enrichment and KEGG enrichment. Molecular docking was performed on the main targets to verify the binding ability between the active ingredients and the core targets. The relative mRNA expression levels of serine/threonine-protein kinase（AKT1） and tumor protein p53（TP53） in liver tissues were analyzed via qPCR, including the following mouse groups: mice with concanavalin A（Con-A）-induced acute liver injury without preventive administration, mice with Con-A-induced acute liver injury that received 14 d preventive oral administration of YCHD, and untreated control mice. Results ①The active ingredients of YCHD in the blood were identified by retrieving the data from the in vitro component analysis. They were chrysophanol, herniarin, aloe-emodin, and monotropein. ②The mechanism of action of the blood components against hepatocellular carcinoma （HCC） was further analyzed using network pharmacological methods, and a total of 30 components of YCHD were screened for 213 targets and 215 HCC targets. ③There were 17 intersection targets between YCHD and hepatocellular carcinoma, including AKT1, TP53, receptor tyrosine-protein kinase erbB-2 （ERBB2）, myelocytomatosis oncogene （MYC）, interleukin-1β （IL-1β）, etc. The GO enrichment results indicated that these components were primarily involved in DNA replication，chromosome segregation，leukocyte mediated immunity，leukocyte cell-cell adhesion. The KEGG enrichment results demonstrated that these components were predominantly associated with diverse cancer pathways. Additionally, the results indicated involvement in the citrate cycle （TCA cycle）, pyruvate metabolism, and p53 signaling pathway, ect. ④The results of molecular docking showed that chrysophanol, herniarin, and aloe - emodin had strong binding abilities with AKT1, TP53, ERBB2, MYC, and IL-1β. ⑤The relative expression of AKT1 and TP53 mRNA was significantly higher in the modelling group than in the control group. The relative expression of AKT1 and TP53 mRNA was significantly lower in the drug administration group than in the modelling group. Conclusion There were 4 blood components in YCHD, among which chrysophanol, herniarin, and aloe-emodin may act on AKT1, TP53, ERBB2, MYC, IL-1β and then participated in the regulation of cancer signaling pathways and p53 signaling pathway to play a role in the treatment of HCC.

Pulmonary fibrosis（PF） is a progressive and life-threatening disease with limited therapeutic options， highlighting the urgent need for innovative drug discovery strategies. To address this challenge， the authors propose the formula-originated rational intelligent screening&translation（FIRST）， a systematic framework for developing anti-fibrotic monomers derived from classical traditional Chinese medicine（TCM）. The strategy integrates three key dimensions， including tissue-oriented intelligent screening of active compounds， structural optimization based on drug-target spatial interactions and plant biosynthetic pathways， and cross-scale validation of drug. We further highlight its applications in discovering tissue-oriented novel drugs from clinically validated TCM， the development and mechanistic elucidation of anti-fibrotic therapeutics， as well as the clinical translation and secondary development of candidate drugs. This strategy paves the way for first-in-class， formula-derived monomeric drugs with defined structures， clarified mechanisms， and proven safety， offering a transformative avenue to meet the urgent therapeutic needs of PF and setting a new paradigm for TCM-based drug innovation.

ObjectiveTo investigate whether Huanglian Jiedutang can inhibit neutrophil infiltration in the brains of middle cerebral artery occlusion （MCAO） mice by regulating the expression of neutrophil-related chemokines in exosomes， thereby achieving therapeutic effects. MethodsA total of 130 male specific pathogen-free （SPF） C57BL/6J mice were randomly divided into four groups： Sham-operated group， MCAO model group， Huanglian Jiedutang group （6 g·kg^-1）， and Ginaton group （21.6 mg·kg^-1）， with 10 mice in the Ginaton group and 40 mice in each of the remaining three groups. Mice in the Huanglian Jiedutang group and the Ginaton group were administered the corresponding drugs by oral gavage once daily at a volume of 0.15 mL·（10 g）^-1 for 7 consecutive days， while the sham-operated and model groups received an equal volume of saline via the same route. After 7 days， MCAO surgery was performed. The distal and proximal ends of the right common carotid artery （CCA） were ligated， a small incision was made between the two ligatures， and a silicone rubber-coated monofilament with a rounded tip was inserted into the lumen to occlude the CCA. The filament was left in place for 1 h to establish a focal cerebral ischemia model. At 24 h after modeling， mice were evaluated. Neurological function was assessed using the Longa score. Cerebral infarct volume was measured by 2，3，5-triphenyltetrazolium chloride （TTC） staining. Cerebral blood flow was observed by laser speckle imaging. Hematoxylin and eosin （HE） staining and Nissl staining were used to observe pathological changes in brain tissues. Exosomes were isolated from mouse plasma and brain tissues by ultracentrifugation and molecular size exclusion and identified by electron microscopy， particle size analysis， and protein blotting. Long-chain RNA libraries of exosomes were constructed and sequenced. Real-time quantitative reverse transcription polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of inflammatory factors and neutrophil-related chemokines in exosomes from plasma and brain tissues of each group. Enzyme-linked immunosorbent assay （ELISA） was used to detect the protein expression of inflammatory factors and neutrophil-related chemokines in exosomes from brain tissues of each group. Immunohistochemistry was used to detect the expression of the neutrophil-specific protein myeloperoxidase （MPO） in the brains of mice in each group. ResultsCompared with the sham-operated group， the model group showed decreased neurological function scores （P<0.01）， obvious cerebral infarction （P<0.01）， reduced cerebral blood flow （P<0.01）， neuronal necrosis in the brain， and decreased numbers of Nissl bodies （P<0.01）. The mRNA expression levels of IL-1β， MPO， CXCL1， CXCL2， CXCL3， CXCL10， CCL2， and CCL3 in exosomes from plasma and brain tissues were significantly increased （P<0.05， P<0.01）. The protein expression levels of IL-1β， MPO， CXCL2， and CXCL10 in exosomes from brain tissues were increased （P<0.05， P<0.01）， and MPO-positive rates and mean optical density values in brain tissues were elevated （P<0.01）. Compared with the model group， the Huanglian Jiedutang group and the Ginaton group showed increased neurological function scores （P<0.05）， reduced cerebral infarct volume （P<0.01）， restored cerebral blood flow （P<0.01）， reduced necrotic cells in the brain， and increased numbers of Nissl bodies （P<0.01）. In the Huanglian Jiedutang group， the mRNA expression levels of IL-1β， MPO， CXCL1， CXCL2， CXCL3， CXCL10， CCL2， and CCL3 in exosomes from plasma and brain tissues were decreased （P<0.05， P<0.01）. The protein expression levels of IL-1β， MPO， CXCL2， and CXCL10 in exosomes from brain tissues were reduced （P<0.05， P<0.01）， and MPO-positive rates and mean optical density values in brain tissues were decreased （P<0.01）. ConclusionHuanglian Jiedutang can effectively regulate the expression of neutrophil-related chemokines in exosomes from plasma and brain tissues of MCAO mice， thereby reducing neutrophil infiltration in the brain and achieving therapeutic effects.

ObjectiveTo investigate whether Huanglian Jiedutang can inhibit neutrophil infiltration in the brains of middle cerebral artery occlusion （MCAO） mice by regulating the expression of neutrophil-related chemokines in exosomes， thereby achieving therapeutic effects. MethodsA total of 130 male specific pathogen-free （SPF） C57BL/6J mice were randomly divided into four groups： Sham-operated group， MCAO model group， Huanglian Jiedutang group （6 g·kg^-1）， and Ginaton group （21.6 mg·kg^-1）， with 10 mice in the Ginaton group and 40 mice in each of the remaining three groups. Mice in the Huanglian Jiedutang group and the Ginaton group were administered the corresponding drugs by oral gavage once daily at a volume of 0.15 mL·（10 g）^-1 for 7 consecutive days， while the sham-operated and model groups received an equal volume of saline via the same route. After 7 days， MCAO surgery was performed. The distal and proximal ends of the right common carotid artery （CCA） were ligated， a small incision was made between the two ligatures， and a silicone rubber-coated monofilament with a rounded tip was inserted into the lumen to occlude the CCA. The filament was left in place for 1 h to establish a focal cerebral ischemia model. At 24 h after modeling， mice were evaluated. Neurological function was assessed using the Longa score. Cerebral infarct volume was measured by 2，3，5-triphenyltetrazolium chloride （TTC） staining. Cerebral blood flow was observed by laser speckle imaging. Hematoxylin and eosin （HE） staining and Nissl staining were used to observe pathological changes in brain tissues. Exosomes were isolated from mouse plasma and brain tissues by ultracentrifugation and molecular size exclusion and identified by electron microscopy， particle size analysis， and protein blotting. Long-chain RNA libraries of exosomes were constructed and sequenced. Real-time quantitative reverse transcription polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of inflammatory factors and neutrophil-related chemokines in exosomes from plasma and brain tissues of each group. Enzyme-linked immunosorbent assay （ELISA） was used to detect the protein expression of inflammatory factors and neutrophil-related chemokines in exosomes from brain tissues of each group. Immunohistochemistry was used to detect the expression of the neutrophil-specific protein myeloperoxidase （MPO） in the brains of mice in each group. ResultsCompared with the sham-operated group， the model group showed decreased neurological function scores （P<0.01）， obvious cerebral infarction （P<0.01）， reduced cerebral blood flow （P<0.01）， neuronal necrosis in the brain， and decreased numbers of Nissl bodies （P<0.01）. The mRNA expression levels of IL-1β， MPO， CXCL1， CXCL2， CXCL3， CXCL10， CCL2， and CCL3 in exosomes from plasma and brain tissues were significantly increased （P<0.05， P<0.01）. The protein expression levels of IL-1β， MPO， CXCL2， and CXCL10 in exosomes from brain tissues were increased （P<0.05， P<0.01）， and MPO-positive rates and mean optical density values in brain tissues were elevated （P<0.01）. Compared with the model group， the Huanglian Jiedutang group and the Ginaton group showed increased neurological function scores （P<0.05）， reduced cerebral infarct volume （P<0.01）， restored cerebral blood flow （P<0.01）， reduced necrotic cells in the brain， and increased numbers of Nissl bodies （P<0.01）. In the Huanglian Jiedutang group， the mRNA expression levels of IL-1β， MPO， CXCL1， CXCL2， CXCL3， CXCL10， CCL2， and CCL3 in exosomes from plasma and brain tissues were decreased （P<0.05， P<0.01）. The protein expression levels of IL-1β， MPO， CXCL2， and CXCL10 in exosomes from brain tissues were reduced （P<0.05， P<0.01）， and MPO-positive rates and mean optical density values in brain tissues were decreased （P<0.01）. ConclusionHuanglian Jiedutang can effectively regulate the expression of neutrophil-related chemokines in exosomes from plasma and brain tissues of MCAO mice， thereby reducing neutrophil infiltration in the brain and achieving therapeutic effects.

BACKGROUND:Repetitive trans-spinal magnetic stimulation(rTSMS)can inhibit inflammatory responses following spinal cord injury.rTSMS applies magnetic field stimulation to the spinal cord region to modulate neuronal excitability and synaptic transmission,thereby promoting plasticity and repair of the nervous system. OBJECTIVE:To observe the effects of rTSMS on the Toll-like receptor 4(TLR4)/nuclear factor(NF)-κB/NLRP3 signaling pathway after spinal cord injury and explore its mechanism in promoting motor function recovery. METHODS:Male C57BL/6J mice,SPF grade,were randomly divided into sham surgery group,spinal cord injury group,and rTSMS group.The latter two groups of mice were anesthetized and the T9 vertebral plate was removed using rongeur forceps to expose the spinal cord,and the spinal cord was clamped using a small aneurysm clip for 20 seconds to establish the spinal cord injury model.Mice in the rTSMS group underwent a 21-day rTSMS intervention starting on day 1 after spinal cord injury.The stimulation lasted 10 minutes per day,5 days per week with an interval of 2 days.Basso Mouse Scale scores were used to assess motor function recovery in mice after spinal cord injury at 1,3,7,14,and 21 days after spinal cord injury.Western blot was employed to detect the expression of AQP4,apoptotic factors Bax,Bcl-2,CL-Caspase-3,inflammatory factors tumor necrosis factor-α,interferon-γ,interleukin-6,interleukin-4,and the TLR4/NF-κB/NLRP3 signaling pathway related proteins in the injured spinal cord.Oxidative stress assay kit was used to measure the activity of superoxide dismutase,glutathione peroxidase,and malondialdehyde content at the site of spinal cord injury.Immunofluorescence staining was performed to detect the expression of neuronal nuclei(NeuN). RESULTS AND CONCLUSION:The Basso Mouse Scale score in the rTSMS group was significantly higher than that in the spinal cord injury group(P<0.05).Compared with the spinal cord injury group,the rTSMS group showed a reduction in spinal cord water content.The expression of AQP4 protein,malondialdehyde content,and expression of Bax,Bcl-2,CL-Caspase-3,tumor necrosis factor-α,interferon-γ,interleukin-6,and TLR4/NF-κB/NLRP3 signaling pathway related proteins were all decreased in the rTSMS group,while the activities of superoxide dismutase and glutathione peroxidase,as well as the expression of Bcl-2,interleukin-4,and NeuN,were all increased(P<0.05).These results suggest that rTSMS downregulates the expression of proteins related to the TLR4/NF-κB/NLRP3 signaling pathway,alleviating symptoms after spinal cord injury such as spinal cord edema,oxidative stress,apoptosis,and inflammation,exerting neuroprotective effects,and thereby promoting the recovery of hindlimb motor function after spinal cord injury.

Objective:This study aims to investigate the alterations in m 6A methylation associated with age-related idiopathic pulmonary fibrosis(IPF). Methods:By collecting peripheral blood samples from IPF patients, we investigated the changes in m6A modification levels of total RNA and key regulatory factors in elderly IPF patients.Then, the pulmonary fibrosis models of young and old mice were constructed for verification.A total of 10 IPF patients and 10 healthy controls were selected for this study.The m 6A methylation quantitative kit was employed to assess the m 6A modification levels of total RNA.The expression levels of key m 6A methylation regulators, METTL3, METTL14, and FTO, were quantified using qRT-PCR.Additionally, thirty-two healthy male C57BL/6 mice, comprising 16 mice aged 10-12 weeks and 16 mice aged 6-7 months, were divided into four groups: young control(A), young pulmonary fibrosis(B), aged control(C), and aged pulmonary fibrosis(D), with 8 mice in each group.Mice in groups B and D were intratracheally administered bleomycin to establish a pulmonary fibrosis model, while those in groups A and C received normal saline.Twenty-eight days post-model establishment, the mice were euthanized, and lung tissues were collected for analysis.Histological evaluations were performed using hematoxylin and eosin(HE)staining, Masson staining, hydroxyproline content determination, and immunohistochemistry to assess the extent of pulmonary fibrosis.The m 6A methylation quantification kit was also utilized to measure the m 6A modification levels of total RNA in lung tissue.Furthermore, the mRNA and protein expression levels of the methyltransferase METTL3 were assessed by qRT-PCR and Western blot experiments. Results:The level of m 6A modification was significantly elevated in the aged IPF patient group(0.36±0.03)compared to the control group t=4.882( P<0.05).Furthermore, the expression of METTL3 was markedly higher in the aged IPF patients( t=6.082), while the expression of METTL14 was significantly lower t=17.58( P<0.05).In contrast, the expression level of FTO did not exhibit a significant difference.It is hypothesized that the increased m 6A modification of total RNA in aged IPF patients is closely associated with METTL3.Furthermore, the degree of lung fibrosis in aged mice was more severe than that in young mice.Immunohistochemistry results indicated that TGF-β1 expression was elevated in the lung fibrosis group, with higher levels observed in group D compared to group B( t=5.891, P<0.05), and in group C compared to group A t=4.135( P<0.05).The percentage of positive area for α-SMA was significantly greater in the lung fibrosis mouse model than in the control group t=20.08( P<0.05).The level of m 6A modification was increased in both lung fibrosis groups relative to the normal control group( P<0.05), although no significant difference was found between group D and group B. Overall, METTL3 mRNA and protein expression were upregulated in the lung fibrosis group, with expression in group D being lower than in group B( P<0.05). Conclusions:The level of m 6A modification is elevated in pulmonary fibrosis, and the expression of METTL3 is upregulated in this condition.The downregulation of METTL3 may be associated with the extent of aging, which subsequently exacerbates the progression of pulmonary fibrosis.

Objective:To assess the core competencies of internal medicine residents undergoing standardized residency training and to explore the effectiveness of core competency evaluation on mobile devices.Methods:The mobile formative evaluation module was developed based on the "Xueyiku" teaching management platform. From January to December 2023, clinical teachers were asked to evaluate 150 internal medicine residents based on the "Resident Core Competency Milestone Evaluation System in China Consortium of Elite Teaching Hospitals", and the results were analyzed using non-parametric tests.Results:Among the six core competencies of internal medicine residents, professionalism received the highest score, whereas teaching skill received a lower score (97.50 vs. 90.00; H=167.31, P<0.001). Second-year residents had significantly higher scores than first-year residents (93.00 vs. 90.00; P<0.001), but similar scores to third-year residents (93.00 vs. 93.00; P>0.05). In addition, there was no significant difference in score among residents with different medical education backgrounds ( P>0.05). Conclusions:More emphasis should be placed on improving the teaching skills of internal medicine residents, along with the implementation of tiered progressive training. The mobile core competency evaluation is an effective means for assessing the comprehensive skills of residents in a timely manner.

Chirality is not only a natural phenomenon but also a bridge between chemistry and life sciences.An effective way to obtain a single enantiomer is through racemates resolution.Recent literature shows that chiral metal-organic frameworks(CMOFs)have many applications in various fields because of their diverse topologies and functionalities.This review outlines the design idea and summarizes the latest synthesis strategies and applications of CMOFs.It highlights key advances and issues in the separation domain.In conclusion,the review provides perspectives on the challenges and prospective advance-ments of CMOFs materials and CMOFs-based separation technologies.

Objective:This study aims to investigate the alterations in m 6A methylation associated with age-related idiopathic pulmonary fibrosis(IPF). Methods:By collecting peripheral blood samples from IPF patients, we investigated the changes in m6A modification levels of total RNA and key regulatory factors in elderly IPF patients.Then, the pulmonary fibrosis models of young and old mice were constructed for verification.A total of 10 IPF patients and 10 healthy controls were selected for this study.The m 6A methylation quantitative kit was employed to assess the m 6A modification levels of total RNA.The expression levels of key m 6A methylation regulators, METTL3, METTL14, and FTO, were quantified using qRT-PCR.Additionally, thirty-two healthy male C57BL/6 mice, comprising 16 mice aged 10-12 weeks and 16 mice aged 6-7 months, were divided into four groups: young control(A), young pulmonary fibrosis(B), aged control(C), and aged pulmonary fibrosis(D), with 8 mice in each group.Mice in groups B and D were intratracheally administered bleomycin to establish a pulmonary fibrosis model, while those in groups A and C received normal saline.Twenty-eight days post-model establishment, the mice were euthanized, and lung tissues were collected for analysis.Histological evaluations were performed using hematoxylin and eosin(HE)staining, Masson staining, hydroxyproline content determination, and immunohistochemistry to assess the extent of pulmonary fibrosis.The m 6A methylation quantification kit was also utilized to measure the m 6A modification levels of total RNA in lung tissue.Furthermore, the mRNA and protein expression levels of the methyltransferase METTL3 were assessed by qRT-PCR and Western blot experiments. Results:The level of m 6A modification was significantly elevated in the aged IPF patient group(0.36±0.03)compared to the control group t=4.882( P<0.05).Furthermore, the expression of METTL3 was markedly higher in the aged IPF patients( t=6.082), while the expression of METTL14 was significantly lower t=17.58( P<0.05).In contrast, the expression level of FTO did not exhibit a significant difference.It is hypothesized that the increased m 6A modification of total RNA in aged IPF patients is closely associated with METTL3.Furthermore, the degree of lung fibrosis in aged mice was more severe than that in young mice.Immunohistochemistry results indicated that TGF-β1 expression was elevated in the lung fibrosis group, with higher levels observed in group D compared to group B( t=5.891, P<0.05), and in group C compared to group A t=4.135( P<0.05).The percentage of positive area for α-SMA was significantly greater in the lung fibrosis mouse model than in the control group t=20.08( P<0.05).The level of m 6A modification was increased in both lung fibrosis groups relative to the normal control group( P<0.05), although no significant difference was found between group D and group B. Overall, METTL3 mRNA and protein expression were upregulated in the lung fibrosis group, with expression in group D being lower than in group B( P<0.05). Conclusions:The level of m 6A modification is elevated in pulmonary fibrosis, and the expression of METTL3 is upregulated in this condition.The downregulation of METTL3 may be associated with the extent of aging, which subsequently exacerbates the progression of pulmonary fibrosis.