Diabetic nephropathy （DKD）， as a common microvascular complication of diabetes mellitus （DM）， is a major cause of end-stage renal disease （ESRD）. Its clinical manifestations include increased urinary protein excretion， thickening of the glomerular basement membrane， and renal tubulointerstitial fibrosis. The pathogenesis of DKD is complex and involves multiple factors， including disordered glucose metabolism， hemodynamic alterations， and oxidative stress. Although modern medical approaches can alleviate certain symptoms， they still have limitations such as insufficient therapeutic targeting and prominent adverse effects. The transforming growth factor-β/Smad （TGF-β/Smad） signaling pathway is not only a tissue fibrosis pathway that has attracted considerable attention in recent years， but also regulates multiple protein molecules， including the glomerular podocyte slit diaphragm protein Podocin， interleukin-1β （IL-1β）， and superoxide dismutase （SOD）， thereby participating in various pathological processes and ultimately mediating renal injury. Flavonoid compounds， owing to their sustained pharmacological effects， broad spectrum of action， and high safety profile， have become ideal candidates for targeted therapy research in DKD. Existing studies have shown that these compounds can exert inhibitory effects on renal fibrosis， alleviate inflammatory responses， protect podocytes， and reduce oxidative stress by regulating the interactions between the TGF-β/Smad signaling pathway and the aforementioned protein molecules， thereby maintaining renal structure and function， reducing proteinuria， and significantly improving DKD lesions. This review briefly outlines the composition and functions of the TGF-β/Smad signaling pathway， elucidates the mechanisms by which this pathway regulates DKD， and focuses on summarizing major studies from the past decade on flavonoid-based interventions in DKD through targeted inhibition of the TGF-β/Smad signaling pathway. Furthermore， it discusses the considerable therapeutic potential of flavonoids in the treatment of this disease， aiming to provide a scientific basis for future clinical prevention and treatment of DKD and to promote the development of targeted drugs.

OBJECTIVE To investigate the effects and mechanism of modified Xiaoqinglong decoction combined with bone marrow mesenchymal stem cells （BMSCs） on nasal-pulmonary-intestinal mucosal immunity in rats with cold asthma. METHODS SD rats were randomly divided into blank group， model group， BMSCs group， BMSCs+modified Xiaoqinglong decoction （6.39 g/kg） group， and BMSCs+dexamethasone （0.125 mg/kg） group， with 10 rats in each group. The cold asthma rat model was established by sensitization and atomization challenge with ovalbumin combined with aluminum hydroxide， together with cold air stimulation from air conditioners. One hour before the initial atomization challenge， rats in all groups except the blank group and model group were injected with BMSCs suspension via the tail vein. Starting from the 15th day of the experiment， rats in each group were intragastrically administered corresponding liquid medicine or normal saline once a day for 7 consecutive days. After the last administration， the asthmatic behavioral changes and pathological morphological changes of lung tissues in rats were evaluated. The levels of interleukin-6 （IL-6） and IL-10 in nasopharyngeal lavage fluid， bronchoalveolar lavage fluid （BALF） and intestinal mucus were detected. The expression levels of proteins related to the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway in nasal， lung and intestinal tissues were determined. RESULTS Compared with the blank group， the asthmatic behavioral score， lung tissue injury score， IL-6 levels in nasopharyngeal lavage fluid， BALF and intestinal mucus， PI3K protein expression and Akt phosphorylation levels in nasal， lung and intestinal tissues of rats in the model group were significantly increased （ P ＜0.05）； the IL-10 levels in nasopharyngeal lavage fluid， BALF and intestinal mucus were significantly decreased （ P ＜0.05）. Alveolar atrophy， collapse and even fusion， abnormal hyperplasia and hypertrophy of bronchial smooth muscle， and massive inflammatory cell infiltration were observed. Compared with the model group， most of the above quantitative indicators in the BMSCs group， BMSCs+modified Xiaoqinglong decoction group and BMSCs+dexamethasone group were significantly reversed （ P ＜0.05）， and pathological injuries of lung tissues were markedly alleviated. Compared with the BMSCs group， most of the above quantitative indicators were further improved in the BMSCs+modified Xiaoqinglong decoction group （ P ＜0.05）. CONCLUSIONS Modified Xiaoqinglong decoction combined with BMSCs can effectively improve nasal-pulmonary-intestinal mucosal immunity and relieve asthmatic symptoms in cold asthma rats， and its mechanism may be related to inhibiting the activation of the PI3K/Akt signaling pathway.

OBJECTIVE To investigate the effects and mechanism of modified Xiaoqinglong decoction combined with bone marrow mesenchymal stem cells （BMSCs） on nasal-pulmonary-intestinal mucosal immunity in rats with cold asthma. METHODS SD rats were randomly divided into blank group， model group， BMSCs group， BMSCs+modified Xiaoqinglong decoction （6.39 g/kg） group， and BMSCs+dexamethasone （0.125 mg/kg） group， with 10 rats in each group. The cold asthma rat model was established by sensitization and atomization challenge with ovalbumin combined with aluminum hydroxide， together with cold air stimulation from air conditioners. One hour before the initial atomization challenge， rats in all groups except the blank group and model group were injected with BMSCs suspension via the tail vein. Starting from the 15th day of the experiment， rats in each group were intragastrically administered corresponding liquid medicine or normal saline once a day for 7 consecutive days. After the last administration， the asthmatic behavioral changes and pathological morphological changes of lung tissues in rats were evaluated. The levels of interleukin-6 （IL-6） and IL-10 in nasopharyngeal lavage fluid， bronchoalveolar lavage fluid （BALF） and intestinal mucus were detected. The expression levels of proteins related to the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway in nasal， lung and intestinal tissues were determined. RESULTS Compared with the blank group， the asthmatic behavioral score， lung tissue injury score， IL-6 levels in nasopharyngeal lavage fluid， BALF and intestinal mucus， PI3K protein expression and Akt phosphorylation levels in nasal， lung and intestinal tissues of rats in the model group were significantly increased （ P ＜0.05）； the IL-10 levels in nasopharyngeal lavage fluid， BALF and intestinal mucus were significantly decreased （ P ＜0.05）. Alveolar atrophy， collapse and even fusion， abnormal hyperplasia and hypertrophy of bronchial smooth muscle， and massive inflammatory cell infiltration were observed. Compared with the model group， most of the above quantitative indicators in the BMSCs group， BMSCs+modified Xiaoqinglong decoction group and BMSCs+dexamethasone group were significantly reversed （ P ＜0.05）， and pathological injuries of lung tissues were markedly alleviated. Compared with the BMSCs group， most of the above quantitative indicators were further improved in the BMSCs+modified Xiaoqinglong decoction group （ P ＜0.05）. CONCLUSIONS Modified Xiaoqinglong decoction combined with BMSCs can effectively improve nasal-pulmonary-intestinal mucosal immunity and relieve asthmatic symptoms in cold asthma rats， and its mechanism may be related to inhibiting the activation of the PI3K/Akt signaling pathway.

Objective To investigate the changes and diagnostic value of serum hypoxia inducible factor 1 subunit alpha(HIF-1α)and Toll-like receptor 4(TLR4)levels in patients with chronic obstructive pulmonary disease(COPD)complicated with pulmonary Aspergillosis infection.Methods A total of 240 COPD patients who visited Xi'an Qinhuang Hospital(hereinafter referred to as the hospital)from December 2020 to Decem-ber 2023 were selected as the study subjects in the study,and another 218 volunteers who underwent physical examinations at the hospital were selected as the control group.The COPD patients were separated into an in-fected group(124 cases)and an uninfected group(116 cases)based on whether they had pulmonary Aspergil-losis infection.Enzyme-linked immunosorbent assay was applied to detect the levels of HIF-1α and TLR4 in patients.Fully automated biochemical analyzer was applied to detect lactate dehydrogenase(LDH)and albu-min(ALB)levels.Multivariate Logistic regression was applied to analyze the influencing factors of infection in COPD patients.Pearson correlation was applied to analyze the correlation between HIF-1α and TLR4 levels in the infected group.Receiver operating characteristic(ROC)curve was applied to analyze the diagnostic val-ue of HIF-1α and TLR4 levels for the occurrence of infection in COPD patients.Results Compared with the control group,the COPD group showed an increase in HIF-1α and TLR4 levels(P＜0.05).Compared with the uninfected group,the proportion of dyspnea,antibiotics＞3 types,the duration of antibiotic use ≥ 14 days,mechanical ventilation procedures,the longer glucocorticosteroid(GC)use time,and levels of LDH,HIF-1α,TLR4 in the infected group were higher(P＜0.05),while the level of ALB was lower(P＜0.05).The types of antibiotics＞3 types,the duration of antibiotic use ≥ 14 days,the duration of GC use,and elevat-ed levels of LDH,HIF-1α,and TLR4 were independent risk factors for infection in COPD patients(P＜0.05),while elevated level of ALB was an independent protective factor for infection in COPD patients(P＜0.05).The levels of HIF-1α and TLR4 in the infected group were positively correlated(r=0.453,P＜0.001).The area under the curve(AUC)of HIF-1α and TLR4 in diagnosing infection in COPD patients alone was 0.816 and 0.813,and the AUC of their combined diagnosis was 0.930,which was better than their indi-vidual diagnoses(Zcombination-HIF-1α=4.923,Z combination-TLR4=5.192,P＜0.001,P＜0.001).Conclusion The levels of HIF-1α and TLR4 increase in COPD patients,and further increase after infection with pulmonary Aspergil-lus.They are independent risk factors for infection in patients,and the two are positively correlated.The combined di-agnosis of pulmonary aspergillosis has certain value and provides a theoretical basis for clinical diagnosis.

Ulcerative colitis (UC) is a chronic inflammatory disorder with a complex etiology, characterized by intestinal inflammation and barrier dysfunction. Platycodon grandiflorus polysaccharides (PGP), the primary component of Platycodon grandiflorus, and hesperidin (Hesp), a prominent active component in Citrus aurantium L. (CAL), have both demonstrated anti-inflammatory properties. This study aims to elucidate the underlying mechanism of the synergistic effect of PGP combined with Hesp on UC, focusing on the coordinated interaction between the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathways. A mouse model of UC induced by dextran sulfate sodium (DSS) and a cell model using lipopolysaccharide (LPS)-induced RAW264.7/IEC6 cells were employed to investigate the in vitro and in vivo anti-inflammatory effects of PGP combined with Hesp on UC and its potential mechanism of action. The results indicated that compared to the effects of either drug alone, the combination of PGP and Hesp significantly modulated inflammatory factor levels, inhibited oxidative stress, regulated colonic mucosal immunity, suppressed apoptosis, and restored intestinal barrier function in vitro and in vivo. Further in vitro studies revealed that PGP significantly inhibited the PI3K/AKT signaling pathway, while Hesp significantly inhibited the JAK2/STAT3 signaling pathway. The use of inhibitors and activators targeting both pathways validated the synergistic effects of PGP combined with Hesp on the PI3K/AKT and JAK2/STAT3 signaling pathways. These findings suggest that PGP combined with Hesp exhibits a synergistic effect on DSS-induced colitis, potentially mediated through the phosphatase and tensin homolog (PTEN)/PI3K/AKT and interleukin-6 (IL-6)/JAK2/STAT3 signaling pathways.
Animals ; STAT3 Transcription Factor/genetics* ; Janus Kinase 2/genetics* ; Polysaccharides/administration & dosage* ; Colitis, Ulcerative/chemically induced* ; Mice ; Signal Transduction/drug effects* ; Proto-Oncogene Proteins c-akt/genetics* ; Drug Synergism ; Male ; Hesperidin/administration & dosage* ; Platycodon/chemistry* ; Phosphatidylinositol 3-Kinases/genetics* ; Disease Models, Animal ; RAW 264.7 Cells ; Mice, Inbred C57BL

Forced normalization (FN) is a rare epileptic psychiatric disorder that usually characterized by the disappearance of seizures and acute psychosis in patients with paradoxical normalization of the electroencephalogram following a change in the dose of antiseizure medication (ASM) or the initiation of a new medication. This article reports a case of a young female patient with Lennox-Gastaut syndrome who developed FN twice after a change in the ASM regimen, which improved after ASM reduction and olanzapine treatment. Further literature review summarizing the clinical features of FN found that there were slightly more females than males in patients with FN, the onset was more common in young adults, and most patients had refractory epilepsy. The psychiatric and behavioral abnormalities included delusions, hallucinations, bizarre behavior, mania, depression, and dissociation. The changes in ASM were the main inducing factor. Most patients improved by adjusting ASM or adding antipsychotic drugs. By reviewing this case, this article aims to increase awareness of the clinical features, characteristics of mental behavioral abnormalities, treatment and prognosis of FN and to improve the clinical management of the disease.

Objective To screen hub genes and signaling pathways associated with acute ischemic stroke(AIS)using bioinformatics methods,identify potential biomarkers,and provide new evidence for the mechanism research of AIS.Methods The gene expression dataset GSE37587 of AIS patients and healthy controls was obtained from the public database gene expression omnibus(GEO).The differentially expressed genes(DEGs,|log2 FC|≥1.2,FDR＜0.05)were screened using the limma package.The enrichment analysis of GO/KEGG was performed with the DAVID database.The weighted correlation network analysis(WGCNA)was used to construct a gene co-expression network for screening key modules.Then,a protein-protein interaction(PPI)network was constructed based on the STRING database and Cytoscape software to identify hub genes.The dataset GSE16561 was used to validate.Meanwhile,the clinical samples from 30 AIS patients and 30 healthy controls visited Zibo First Hospital from January to May 2025 were validated by the real time fluorescence quantitative PCR(qRT-PCR).The diagnostic efficacy was evaluated using the receiver operating characteristics(ROC)curve.Results A total of 653 DEGs were identified,including 252 up-regulated and 401 down-regulated genes.They were mainly enriched in biological processes such as ribosome biogenesis,endoplasmic reticulum protein processing,and oxidative phospho-rylation,as well as signaling pathways such as viral infection-related pathways and PD-L1/PD-1 checkpoint pathways in cancer.The core genes in the light green module identified by the WGCNA analysis were significantly enriched in the pathways such as mitophagy,ribosome,and endocytosis.The hub genes such as RPL34 and DDIT3 were screened from the PPI network,and their expression levels were significantly correlated with AIS.The analysis of the ROC curve showed that the areas under the ROC curve(AUCROC)of the hub genes for the diagnosis of AIS were 0.78-0.82,which had high clinical application value.Conclusion Ribosomal proteins,endoplas-mic reticulum stress-related genes,and viral infection response pathways are key molecular events in the occurrence of AIS.The genes such as RPL34 and DDIT3 are expected to be potential biomarkers for AIS,providing experimental evidence for the development of di-agnostic markers.

ObjectiveTo investigate the anti-Alzheimer's disease （AD） effect of Dipsacus asper（DA） in the Caenorhabditis elegans model， and decipher the underlying mechanism via the peroxisome proliferator-activated receptor α （PPARα）/transcription factor EB （TFEB） pathway. MethodsFirst， transgenic AD C. elegans individuals were assigned into the blank control， model， positive control （WY14643， 20 µmol·L^-1）， and low-， medium-， and high-dose （100， 200， and 400 mg·L^-1， respectively） DA groups. The amyloid β-42 （Aβ₄₂） formation in the muscle cells， the paralysis time， and the deposition of amyloid β-protein （Aβ） in the head were detected. The lysosomal autophagy in the BV2 cell model was examined by Rluc-LC3wt/G120A. The expression levels of lysosomal autophagy-related proteins LC3Ⅱ， LC3I， LAMP2， and TFEB were detected by Western blot. Real-time quantitative polymerase chain reaction （Real-time PCR） was employed to determine the mRNA levels of autophagy-related genes beclin1 and Atg5 and lysosome-related genes LAMP2 and CLN2 downstream of PPARα/TFEB. A reporter gene assay was used to detect the transcriptional activities of PPARα and TFEB. Immunofluorescence was used to detect the fluorescence intensity of PPARα， and the active components of the ethanol extract of DA were identified by UPLC-MS. RCSB PDB， Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， and Autodock were used to analyze the binding between the active components and PPARα-ligand-binding domain （LBD）. ResultsCompared with the model group， the positive control group and 200 and 400 mg·L^-1 DA groups showed prolonged paralysis time （P<0.05）， and all the treatment groups showed decreased Aβ deposition in the head （P<0.01）. DA within the concentration range of 50-500 mg·L^-1 did not affect the viability of BV2 cells. In addition， DA enhanced the autophagy flux （P<0.05）， up-regulated the mRNA levels of beclin1， Atg5， LAMP2， and CLN2 （P<0.05， P<0.01）， promoted the nuclear translocation of TFEB （P<0.05）， increased LAMP2 expression and autophagy flux （P<0.05， P<0.01）， and enhanced the transcriptional activities of PPARα and TFEB （P<0.01）. The positive control group and 200 and 400 mg·L^-1 DA groups showed enhanced fluorescence intensity of PPARα in the BV2 nucleus （P<0.01）. UPLC-MS detected nine known compounds of DA， from which 8 active components of DA were screened out. The docking results suggested that a variety of components in DA could bind to PPARα-LBD and form stable hydrogen bonds. ConclusionDA may reduce the pathological changes in AD by regulating the PPARα-TFEB pathway.

With the change of infectious disease incidence pattern and the development of related technologies, progresses have been made in the research of infectious disease epidemiology. In recent years, due to the change in the requirements of infectious disease prevention and control, the research focus has expanded from common infectious diseases to diseases which have been eliminated or might be eliminated, as well as emerging and re-emerging infectious diseases. Infectious disease data has been characterized by multiple sources and modalities. Along with the rapid development of pathogen detection methods, infectious disease surveillance has shifted from a single disease-targted one to a comprehensive one. Moreover, novel technologies such as multi-omics and artificial intelligence have been applied in infectious disease epidemiology research. The international cooperation in this field has become increasingly crucial, and the revision of the International Health Regulations and the negotiation of pandemic agreement will have a profound impact. In the future, infectious disease epidemiology research will develop with more powerful tools to improve its capabilities.

Objective:To compare the degranulation levels of basophils in peripheral blood mononuclear cell (PBMC) and granulocyte populations between healthy subjects and patients with sepsis, and to explore the underlying mechanisms. Additionally, plasma cytokine levels were measured in these volunteers.Methods:Peripheral blood samples were collected from both healthy individuals and sepsis patients. The degranulation level of basophils in sepsis patients and its potential mechanisms were examined. Plasma levels of IL-1β, IL-9, and IL-10 were detected, and Pearson correlation analysis was performed to assess the relationship between degranulated basophils in the granulocyte population and IL-9 levels.Results:Compared with healthy subjects, sepsis patients showed a reduction in basophil percentages within PBMC and granulocyte populations by 94.8% and 37.9%, respectively ( Z = -6.441, P < 0.05; Z = -2.681, P < 0.05). In contrast, both the proportion and number of degranulated basophils in the granulocyte population were increased (both P < 0.05). Plasma levels of IL-1β, IL-9, and IL-10 were significantly elevated in sepsis patients--by 80.6%, 36.7%, and 11.9-fold, respectively ( Z = -4.258, P < 0.05; Z = -3.606, P < 0.05; Z = -4.814, P < 0.05). Moreover, plasma IL-9 levels were highly correlated with both the percentage and count of degranulated basophils in the granulocyte population (both P < 0.05). GO and KEGG enrichment analyses revealed cytological changes and potential mechanisms involving basophils in the PBMC of sepsis patients. Conclusions:The decreased total count of basophils in sepsis patients may elevate the risk of secondary infection. Degranulated basophils in the granulocyte population may contribute to excessive inflammatory responses through IL-9 secretion.