Increasing evidence shows that the early lesions of Parkinson's disease (PD) originate from gut, and correction of microbiota dysbiosis is a promising therapy for PD. FLZ is a neuroprotective agent on PD, which has been validated capable of alleviating microbiota dysbiosis in PD mice. However, the detailed mechanisms still need elucidated. Through metabolomics and 16S rRNA analysis, we identified glycoursodeoxycholic acid (GUDCA) was the most affected differential microbial metabolite by FLZ treatment, which was specially and negatively regulated by Clostridium innocuum, a differential microbiota with the strongest correlation to GUDCA production, through inhibiting bile salt hydrolase (BSH) enzyme. The protection of GUDCA on colon and brain were also clarified in PD models, showing that it could activate Nrf2 pathway, further validating that FLZ protected dopaminergic neurons through promoting GUDCA production. Our study uncovered that FLZ improved PD through microbiota-gut-brain axis, and also gave insights into modulation of microbial metabolites may serve as an important strategy for treating PD.

Although enteric glial cell (EGC) abnormal activation is reported to be involved in the pathogenesis of Parkinson's disease (PD), and inhibition of EGC gliosis alleviated gut and dopaminergic neuronal dysfunction was verified in our previous study, the potential role of gut microbiota on EGC function in PD still need to be addressed. In the present study, fecal microbiota transplantation revealed that EGC function was regulated by gut microbiota. By employing 16S rRNA and metabolomic analysis, we identified that 3-indolepropionic acid (IPA) was the most affected differential microbial metabolite that regulated EGC gliosis. The protective effects of IPA on PD were validated in rotenone-stimulated EGCs and rotenone (30 mg/kg i.g. for 4 weeks)-induced PD mice, as indicated by decreased inflammation, improved intestinal and brain barrier as well as dopaminergic neuronal function. Mechanistic study showed that IPA targeted pregnane X receptor (PXR) in EGCs, and inhibition of IL-13Rα1 involved cytokine-cytokine receptor interaction pathway, leading to inactivation of downstream JAK1-STAT6 pathway. Our data not only provided evidence that EGC gliosis was critical in spreading intestinal damage to brain, but also highlighted the potential role of microbial metabolite IPA in alleviating PD pathological damages through gut-brain axis.

[This corrects the article DOI: 10.1016/j.apsb.2025.02.029.].

ObjectiveThe lung mesenchymal stem cells （LMSCs） induced by D-galactose （D-gal） were intervened by Wenfei Huaxian decoction-containing serum to explore the mechanism of Wenfei Huaxian decoction in delaying the senescence of LMSCs through the nicotinamide phosphoribosyltransferase/silent information regulator 1 （NAMPT/SIRT1） signaling pathway. MethodWenfei Huaxian decoction-containing serum was prepared. LMSCs were isolated by gradient density centrifugation， and they were cultured and identified in vitro. The senescence model in vitro was established by stimulating cells via D-gal for 24 h. LMSCs cells were modeled after being treated with different volume fractions （5%， 10%， 20%， 40%， and 80%） of Wenfei Huaxian decoction-containing serum for 24 h， and the cell proliferation level was detected by methyl thiazolyl tetrazolium （MTT） method. The cells were randomly divided into blank serum group， model group， and high， medium， and low dose groups of Wenfei Huaxian decoction-containing serum. Senescence-associated β-galactosidase （SA-β-gal） staining was used to detect the senescence of LMSCs in each group. The content of NAD + was detected by colorimetry. The levels of senescence-associated factors （p16 and p53）， interleukin-6 （IL-6）， and tumor necrosis factor-α （TNF-α） in cell culture supernatant were detected by enzyme-linked immunosorbent assay （ELISA）. Western blot was used to detect the relative expression of senescence-associated proteins and NAMPT/SIRT1 signaling pathway-related proteins. ResultCompared with the blank serum group， the proliferation of LMSCs was significantly inhibited after D-gal stimulation for 24 h （P<0.01）. Compared with the model group， the proliferation of LMSCs could be promoted after intervention with the corresponding Wenfei Huaxian decoction-containing serum （P<0.05， P<0.01）. Compared with the blank serum group， the SA-β-gal staining of LMSCs in the model group after D-gal stimulation was enhanced， and the content of NAD⁺ was increased （P<0.01）. The expression levels of senescence factors p16 and p53， as well as SASP pro-inflammatory factors IL-6 and TNF-α in the cell culture supernatant， were significantly increased （P<0.01）. The expression of senescence-associated proteins p16， p21， and p53 increased （P<0.01）， and the protein expression of NAMPT， SIRT1， peroxisome proliferator-activated receptor γ coactivator 1α （PGC-1α）， and forkhead box family transcription factor O1 （FoxO1） decreased （P<0.01）. Compared with the model group， the SA-β-gal staining of LMSCs in each group of Wenfei Huaxian decoction-containing serum was significantly reduced， and the content of NAD⁺ was decreased （P<0.01）. The senescence factors （p16 and p53） and inflammatory factors （IL-6 and TNF-α） in the cell culture supernatant were significantly decreased （P<0.01）. The expression of senescence-associated proteins （P16， P21， and P53） decreased （P<0.05， P<0.01）. The protein expressions of NAMPT， SIRT1， PGC-1α， and FoxO1 were significantly up-regulated （P<0.05， P<0.01）. ConclusionWenfei Huaxian decoction can alleviate senescence and inflammatory response damage of D-gal-induced LMSCs， and its mechanism may be related to the regulation of the NAMPT/SIRT1 signaling pathway.

ObjectiveTo observe the protective effect of Didang Xianxiong decoction on the kidneys of diabetic rats， its regulation on the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway， and its influence on podocyte apoptosis and explore the mechanism of Didang Xianxiong decoction in improving diabetic nephropathy. MethodThe diabetic model was established by a single intraperitoneal injection of streptozotocin （STZ） solution of 55 mg·kg^-1. The successfully replicated model rats were randomly divided into the model group， Didang Xianxiong decoction group （8.10 g·kg^-1）， Xiao Xianxiongtang group （4.05 g·kg^-1）， Didangtang group （4.05 g·kg^-1）， and alagebrium （ALT-711） group （3 mg·kg^-1）， with six rats in each group. In addition， six rats were included in the blank group. After continuous administration for eight weeks， hematoxylin-eosin （HE） staining was used to observe the pathological changes in rats' kidney tissue. Masson staining was used to observe the degree of collagen deposition. Periodic acid-Schiff （PAS） staining was used to observe basement membrane lesions， and immunohistochemistry was used to detect the expression of phosphorylation （p）-PI3K and p-Akt proteins in rats' kidney tissue. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling （TUNEL） method was used to detect podocyte apoptosis. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of PI3K and Akt in rats' kidney tissue. Western blot was used to detect the protein expression of PI3K， p-PI3K， Akt， p-Akt， B-cell lymphoma 2 （Bcl-2）， Bcl-2-associated X protein （Bax）， phosphorylation glycogen synthase kinase-3β （p-GSK-3β）， and Caspase-3 in the kidney tissue. ResultCompared with the normal group， the model group had compensatory expansion of glomeruli， proliferation of mesangial cells， a large amount of collagen deposition in the mesangial stroma， thickening of the basement membrane， decreased mRNA expression of PI3K and Akt， and inhibition of PI3K and Akt protein phosphorylation （P<0.01）. It also underwent enhanced apoptotic signaling， decreased expression of anti-apoptotic protein Bcl-2 （P<0.01）， and increased expression of Bax， p-GSK-3β， and Caspase-3 （P<0.01）. Compared with the model group， Didang Xianxiong decoction significantly improved kidney tissue pathology， increased mRNA expression of PI3K and Akt （P<0.01）， significantly up-regulated phosphorylation levels of PI3K and Akt proteins （P<0.01） and Bcl-2 expression （P<0.01）， downregulated the expression of Bax， p-GSK-3β， and Caspase-3 （P<0.01）， and weakened podocyte apoptotic signaling. ConclusionDidang Xianxiong decoction may promote the activation of the PI3K/Akt signaling pathway， inhibit podocyte apoptosis， and thus slow down the progression of diabetic nephropathy.

Objective:To investigate the epidemiological characteristics of herpangina (HA) and its correlation with the incidence of hand, foot and mouth disease (HFMD) in children aged ≤6 years in Yinzhou District of Ningbo from 2017 to 2022.Methods:Epidemiological characteristics of HA in children aged ≤6 years were analyzed based on the electronic medical record data and public health management data from 2017 to 2022 collected from the Health Information Platform of Yinzhou. The incidence of HFMD was calculated using the infectious disease reporting data from the public health management data. Autoregressive integrated moving average model and cross-correlation function were used to evaluate the correlation between the incidence of HA and HFMD.Results:From 2017 to 2022, a total of 25 385 cases of HA were detected in children aged ≤6 years in Yinzhou, the male-to-female ratio of the cases was 1.12∶1. The average annual incidence of HA was 4 986.67/100 000, with the highest incidence in 2018 (10 477.09/100 000) and the lowest incidence in 2020 (870.88/100 000). The incidence peak of HA was during June to July. The incidence of HA was higher in age group 1 year (7 950.45/100 000) than in other age groups. The incidences of HA in Yunlong, Jiangshan and Xiaying were higher, with the incidence of 8 764.31/100 000, 8 377.58/100 000 and 7 965.31/100 000, respectively. The correlation coefficients between the incidence of HA and HFMD at lag day 0, 7, 12 and 18 were 0.199, 0.139, 0.090 and 0.086, respectively (all P<0.05). Conclusions:From 2017 to 2022, the incidence of HA was high in children aged ≤6 years in Yinzhou with obvious seasonality and area difference. The incidence of HA was correlated with the incidence of HFMD and the incidence of HFMD had certain lags. The comprehensive prevention and control of HA and HFMD should be further strengthened by prioritizing HA surveillance and implementing integrated surveillance and management of HA and HFMD.

Objective:To evaluate the predictive efficacy of sinus CT radiomics for treatment outcomes in nasal polyp patients undergoing endoscopic sinus surgery.Methods:A retrospective cohort study was conducted at the First Affiliated Hospital of Sun Yat-sen University, including 194 patients with nasal polyps treated between January 2015 and December 2019. The cohort comprised 132 males and 62 females, aged 16 to 75 years. Patients were divided into a training set ( n=135) and an internal validation set ( n=59). An external validation set ( n=34), consisting of 22 males and 12 females aged 16 to 59 years, was included from January 2020 to December 2021. Disease control was evaluated using the criteria from the European Position Paper on Rhinosinusitis and Nasal Polyps 2020 (EPOS 2020). Radiomic features were extracted from sinus CT images and analyzed using the least absolute shrinkage and selection operator (LASSO) regression. Models combining radiomic and clinical features were developed to predict treatment efficacy. Results:The radiomics and combined models, based on four selected features, outperformed the clinical feature model in the training set, with AUC values of 0.901 and 0.915, versus 0.874, respectively. In the internal validation set, AUCs were 0.839, 0.832, and 0.716. Despite reduced AUCs in the external set, the radiomics model maintained good generalizability (0.748, 0.764, 0.620). Decision curve analysis showed significant clinical benefits in both radiomics and combined models.Conclusion:The CT-based radiomics model demonstrates significant predictive power in identifying refractory nasal polyps, suggesting its potential for clinical application in treatment outcome prediction.

Objective:To explore the role and relationship between oxidative stress and immune infiltration in idiopathic pul-monary fibrosis(IPF),and to predict the relevant therapeutic herbal medicines and active ingredients.Methods:GSE10667 gene expression profiles were downloaded from GEO database to obtain differential expression genes,differential expression of oxidative stress genes(DEOSGs)were identified in combination with oxidative stress genes.GSEA was used to evaluate the pathways and biologi-cal processes in IPF,and GO,KEGG and PPI network analysis were performed on DEOSGs.Candidate central genes were derived from PPI results and CytoHubba,and GSE110147 was validated as an independent group to identify central genes;in addition,the immune microenvironment of samples was evaluated using CIBERSORTF,and correlation between central gene levels and relative proportion of immune cells was explored;finally,therapeutic herbal medicines and components were predicted by central genes,and mole-cular docking verification was carried out.Results:A total of 51 DEOSGs,four central genes(ICAM-1,APOE,MMP-1,TGF-β2)were obtained;DEOSGs were mainly related to oxidative stress,immune response,etc;four central gene levels were closely correlated with 8 relative proportions of immune cells;therapeutic herbal medicines included 4 flavors such as Huangqi and Chuanxiong,and the active ingredients included 8 kinds of β-carotene,etc,the molecular docking results were stable.Conclusion:Oxidative stress and immune firing are exist in IPF,and oxidative stress may be recognized by immune cells or directly activate immune cells.

Objective:To explore the clinical and genetic characteristics of a child with autosomal recessive primary microcephaly (MCPH).Methods:A case study has been carried out on a boy who had presented at the Inner Mongolia Maternity and Child Health Care Hospital for microcephaly and mental deficiency in September 2022. Prenatal ultrasound images were retrospectively analyzed, and whole exome sequencing and Sanger sequencing were carried out for his family. A literature review was also carried out using keywords such as " ASPM gene", "microcephaly", "prenatal diagnosis", "primary microcephaly", " ASPM", "MCPH5", "MCPH", "autosomal recessive microcephaly", and "prenatal diagnosis on ultrasonography" on the PubMed database, Wanfang Data and China National Knowledge until September 2023. This study was approved by Medical Ethics Committee of the Inner Mongolia Maternity and Child Health Care Hospital (Ethics No. 2021-093-1). Results:The proband had shown progressive reduction in biparietal diameter (BPD) and head circumference (HC) during the fetal period. He was found to harbor compound heterozygous variants of the ASPM gene, which included a paternally derived c. 8044C>T (p.R2682X) and a maternally derived c.8652dup (p.A2885Sfs*35). Both variants were classified as pathogenic (PVS1+ PM2_Supporting+ PP4; PVS1+ PM2_Supporting+ PM3) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). For other fetuses in his family, prenatal ultrasound and genetic testing were all normal. Literature research has identified 11 relevant articles, which included 14 MCPH cases. All of the MCPH5 cases had shown various degrees of reduced BPD/HC on fetal imaging (100%, 15/15). Developmental delay, intellectual disability, and attention deficits were noted in all survived cases, with one case having seizures (12.5%, 1/8). Their genotypes had included homozygotes (46.2%, 6/13) and compound heterozygotes (53.8%, 7/13) for nonsense variants (45%, 9/20) and frameshifting variants (55%, 11/20). Conclusion:The compound heterozygous variants c. 8044C>T (p.R2682X) and c. 8652dup (p.A2885Sfs*35) of the ASPM gene probably underlay the reduced BPD and HC in this proband with MCPH.

Periodontitis is a common chronic inflammatory disease that causes the periodontal bone destruction and may ultimately result in tooth loss.With the progression of periodontitis,the osteoimmunology microenvironment in periodontitis is damaged and leads to the formation of pathological alveolar bone resorption.CD301b+macrophages are specific to the osteoimmunology microenvironment,and are emerging as vital booster for conducting bone regeneration.However,the key upstream targets of CD301b+macrophages and their potential mechanism in periodontitis remain elusive.In this study,we concentrated on the role of Tim4,a latent upstream regulator of CD301b+macrophages.We first demonstrated that the transcription level of Timd4(gene name of Tim4)in CD301b+macrophages was significantly upregulated compared to CD301b-macrophages via high-throughput RNA sequencing.Moreover,several Tim4-related functions such as apoptotic cell clearance,phagocytosis and engulfment were positively regulated by CD301b+macrophages.The single-cell RNA sequencing analysis subsequently discovered that Cd301b and Timd4 were specifically co-expressed in macrophages.The following flow cytometric analysis indicated that Tim4 positive expression rates in total macrophages shared highly synchronized dynamic changes with the proportions of CD301b+macrophages as periodontitis progressed.Furthermore,the deficiency of Tim4 in mice decreased CD301b+macrophages and eventually magnified alveolar bone resorption in periodontitis.Additionally,Tim4 controlled the p38 MAPK signaling pathway to ultimately mediate CD301b+macrophages phenotype.In a word,Tim4 might regulate CD301b+macrophages through p38 MAPK signaling pathway in periodontitis,which provided new insights into periodontitis immunoregulation as well as help to develop innovative therapeutic targets and treatment strategies for periodontitis.