BACKGROUND:Studies have shown that metformin has anti-inflammatory,anti-tumor,anti-aging and vasoprotective effects,and can inhibit the progression of osteoarthritis,but its specific mechanism of action remains unclear. OBJECTIVE:To investigate the mechanism of metformin on cartilage protection in a rat model of osteoarthritis. METHODS:Forty male Sprague-Dawley rats were randomly divided into four groups(n=10 per group):blank,control,sham-operated,and metformin groups.The blank group did not undergo any surgery.In the sham-operated group,the joint cavity was exposed.In the model group and the metformin group,the modified Hulth method was used to establish the osteoarthritis model.At 1 day after modeling,the rats in the metformin group were given 200 mg/kg/d metformin by gavage,and the model,blank,and sham-operated groups were given normal saline by gavage.Administration in each group was given for 4 weeks consecutively.Hematoxylin-eosin staining,toluidine blue staining,and safranin O-fast green staining were used to observe the morphological structure of rat knee joints.Immunohistochemical staining and western blot were used to detect the protein expression of SOX9,type Ⅱ collagen,a disintegrin and metalloproteinase with thrombospondin motifs 5(ADAMTS5),Beclin1,P62,phosphatidylinositol 3-kinase(PI3K),p-PI3K,protein kinase B(AKT),p-AKT,mammalian target of rapamycin(Mtor),and p-Mtor in rat cartilage tissue. RESULTS AND CONCLUSION:The results of hematoxylin-eosin,toluidine blue and safranin O-fast green staining showed smooth cartilage surface of the knee joints and normal histomorphology in the blank group and the sham-operated group,while in the model group,there was irregular cartilage surface of the knee joint and cartilage damage,with a decrease in the number of chondrocytes and the content of proteoglycans in the cartilage matrix.In the metformin group,there was a significant improvement in the damage to the structure of the cartilage in the knee joints of the rats,and the cartilage surface tended to be smooth,with an increase in the number of chondrocytes and the content of proteoglycans in the cartilage matrix.Immunohistochemistry staining and western blot results showed that compared with the control and sham-operated groups,the expression of SOX9,type Ⅱ collagen,and Beclin1 proteins in the cartilage tissue of rats in the model group was significantly decreased(P<0.05).Conversely,the expression of ADAMTS5,P62,as well as p-PI3K,p-AKT,and p-Mtor proteins was significantly increased(P<0.05).Furthermore,compared with the model group,the expression of SOX9,type Ⅱ collagen,and Beclin1 proteins in the cartilage tissue of rats in the metformin group was significantly increased(P<0.05),while the expression of ADAMTS5,P62,as well as p-PI3K,p-AKT,and p-Mtor proteins was significantly decreased(P<0.05).To conclude,Metformin can improve the autophagy activity of chondrocytes and reduce the degradation of cartilage matrix in osteoarthritis rats by inhibiting the activation of PI3K/AKT/Mtor signaling pathway,thus exerting a protective effect on articular cartilage.

Brain metastases are the most common intracranial tumors, and their incidence is increasing with the improvement of systemic treatments and survival rates. Optimal treatment usually requires a multidisciplinary approach, including radiotherapy, surgical resection, chemotherapy, targeted therapy, and immunotherapy. Stereotactic radiotherapy, compared to whole-brain radiotherapy, offers improved local control rates and reduced risk of neurocognitive impairment, and has become a new standard option for the treatment of brain metastases. Additionally, the widespread use of targeted and immune therapies in brain metastases has significantly improved the survival of some patients. This article reviews and integrates recent literature on the treatment of brain metastases and analyzes the role of stereotactic radiotherapy in comprehensive treatment, aiming to provide a reference for the selection of clinical treatment plans.

Ten novel xanthones, garpedunxanthones A-G (1-5, 6a/6b, 7a/7b) and nujiangxanthone Q (8), along with sixteen known analogs (9-24), were isolated from Garcinia pedunculata and G. nujiangensis. Their structures were elucidated through high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) data, comprehensive nuclear magnetic resonance (NMR) spectroscopic analyses, and electronic circular dichroism (ECD) calculations. All compounds without cytotoxicity were assessed for anti-inflammatory properties by measuring the inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW264.7 cells. Structure-activity relationships are also discussed. Compounds 7b, 19, and 21 exhibited significant anti-inflammatory activity with IC₅₀ values of 16.44 ± 0.69, 14.28 ± 0.78, and 10.67 ± 3.28 μmol·L^-1, respectively. Enzyme-linked immunosorbent assay (ELISA) demonstrated that compounds 7b, 19, and 21 inhibited the expression of pro-inflammatory cytokines TNF-α and IL-6 in a dose-dependent manner. The inhibitory effect of compound 21 on IL-6 at 20 μmol·L^-1 was comparable to that of the positive control. In network pharmacology studies, potential targets of compounds and inflammation were identified from PharmMapper and GeneCards databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the overlapped targets were intricately associated with major pathogenic processes linked to inflammation, including positive regulation of mitogen-activated protein kinase (MAPK) cascade, protein kinase activity, NO synthase regulator activity, MAPK signaling pathway, and EGFR tyrosine kinase inhibitor resistance.
Xanthones/therapeutic use* ; Garcinia ; Anti-Inflammatory Agents/therapeutic use* ; Plant Preparations/therapeutic use* ; Structure-Activity Relationship ; Nitric Oxide/metabolism* ; RAW 264.7 Cells ; Animals ; Mice ; Enzyme-Linked Immunosorbent Assay ; Mitogen-Activated Protein Kinase Kinases/metabolism* ; Circular Dichroism

Objective To explore the effect of miR-1-3p on the malignant biological behavior of human esophageal squamous cell carcinoma cells and the potential mechanisms.Methods The Gene Expression Omnibus(GEO)database was analyzed to screen differentially expressed miRNAs in esophageal squamous cell carcinoma(ESCC).qRT-PCR was used to detect the expression of miR-1-3p in human ESCC cell lines(KYSE30,KYSE150,KYSE410,KYSE510,and Eca109)and normal esophageal epithelial cell line HET-1A.CCK-8,wound healing,Transwell assays,and flow cytometry were applied to detect the effect of miR-1-3p on the proliferation,migration,invasion,and apoptosis of ESCC cells.Bioinformatics tool was used to predict the target genes of miR-1-3p.A Kaplan-Meier survival curve was drawn to analyze the correlation between STC2 expression and overall survival of patients in the ESCC cohort of the TCGA database.Fluorescence in situ hybridization was performed to verify the subcellular location of miR-1-3p in ESCC cells,and dual-luciferase reporter gene assay was performed to validate the regulation of miR-1-3p on stanniocalcin 2(STC2).RNA immunoprecipitation assays were used to detect the binding of miR-1-3p and STC2.Western blot assay was performed to determine the effect of miR-1-3p on the expression of STC2 and endoplasmic reticulum stress pathway-related proteins,including p-PERK,p-eIF2α,and ATF4.CCK-8,wound healing,Transwell assays,and flow cytometry were applied to detect the effect of STC2 overexpression and knockdown on the proliferation,migration,invasion,and apoptosis of ESCC cells.Results The expression of miR-1-3p was lower in ESCC cell lines than in HET-1A cells(all P<0.05).The transfection of miR-1-3p mimic decreased the proliferation,invasion,and migration of ESCC cells(all P<0.05)and promoted the apoptosis of ESCC cells(all P<0.001).Bioinformatics tool showed that STC2 was a target gene of miR-1-3p.The expression of STC2 in ESCC tissues was higher than that in normal esophageal epithelial tissues in the ESCC cohort of TCGA database and was negatively correlated with prognosis(all P<0.05).miR-1-3p was located in the cytoplasm and can directly bind to STC2 mRNA.The transfection of miR-1-3p mimic downregulated the expression of STC2,p-PERK,p-eIF2α,and ATF4(all P<0.05).The overexpression of STC2 promoted the proliferation,invasion,and migration(all P<0.05)and inhibited the apoptosis of ESCC cells(all P<0.05).Knockdown of STC2 inhibited the proliferation,invasion,and migration(all P<0.05)and promoted the apoptosis of ESCC cells(all P<0.05).Conclusion miR-1-3p inhibits the malignant biological behavior and promotes the apoptosis of esophageal squamous cell carcinoma cells by regulating STC2 possibly by suppressing the endoplasmic reticulum stress.

Objective:A genome-wide molecular characterization of FJ21351116, a strain of G3P[8]-E2 2021 collected in Fujian, China, was performed.Methods:Whole genome sequencing of FJ21351116 was performed using a high-sensitivity group A rotavirus whole genome sequencing method. Genomic characteriza-tion of the virus was assessed by nucleic acid sequence analysis using MEGA 11.0, Geneious 9.0.2 and DNASTAR software. Neutralization epitopes of VP7 and VP4 (VP8*) were analyzed using BioEdit v. 7.0.9.0 and PyMOL v. 2.5.2.Results:In this study, FJ21351116 was shown to be a G3-P[8]-I2-R2-C2-M2-A2-N2-T2-E2-H2 genotype, and the result of phylogenetic tree showed that the VP7, VP4, VP3, and NSP2-NSP5 genes of the FJ21351116 strain were related to the equine-like DS-1-like G3P[8] genes that have been detected in Japan in recent years. VP6, VP1, VP2, and NSP1 genes are closely related to G2P[4] in most countries, especially in Singapore, suggesting that this strain was formed by genetic reassortment during the evolution of equine-like G3P[8] and G2P[4]. Evolutionary relationships between the VP7/VP4 genes of FJ21351116 and Rotarix and RotaTeq vaccines suggest that the multiple mutations in both VP7 and VP4 (VP8*) neutralizing antigenic epitopes and vaccine amino acid sites. It is hypothesized that the Rotarix and RotaTeq vaccines may be less effective against equine DS-1-like G3P[8] RVA, and the sequence differences with Rotarix are higher than those with RotaTeq.Conclusions:In this study, we found a rare case of DS-1-like G3P [8] RVA strain in China. Currently, horse-like DS-1-like G3P [8] RVA is relatively rare in China and may be poorly protected by vaccine strains, emphasizing the importance of continuous monitoring of RVA strains and the development of efficient and full-coverage RVA vaccines.

Osteosarcoma is a common primary malignant bone tumor in adolescents and children,characterized by a high recurrence rate and metastasis,making its treatment extremely challenging.Traditional treatment modalities,including surgery,radiation therapy,and chemotherapy,can alleviate symptoms to some extent,but improving long-term survival rates remains a pressing issue.With the continuous development of immunotherapy,breakthroughs have been made in the research of tumor immune microenvironment and the application of immunotherapy in recent years,providing new perspectives and strategies for osteosarcoma treatment.Currently,immunotherapy strategies include tumor vaccines,targeted cytokines,immune checkpoint inhibition,adoptive cell therapy,combination therapy,etc.,significantly enhancing patient immune responses from the aspects of boosting immunity,overcoming immune tolerance,and preventing immune evasion,thereby effectively improving the patients'survival rates and prognosis.This review aims to systematically introduce the immune microenvironment of osteosarcoma and discuss the latest advances in immunotherapy in clinical translational research of osteosarcoma.By deeply understanding the immune characteristics of osteosarcoma and corresponding treatment methods,it is hopeful to provide more effective strategies for personalized treatment,contributing to the improvement of the patients' survival rates and prognosis.

Background With urbanization and residential space expansion, ecological environment and human health issues have become hot social topics. Forest health, as a way of seeking health in nature, has begun to receive public attention in the context of the gradually increasing sub-healthy population and various psychological and physical diseases at a young age. Objective To systematically evaluate the effects of forest therapy on selected physical and mental health indicators. Methods Relevant research literature was retrieved from domestic and international databases (China National Knowledge Infrastructure, Wanfang Database, China Biomedical Literature Service System, Web of Science, ScienceDirect, PubMed, Embase, and Cochrane Library), with a time range from database establishment to January 31, 2023. Relevant data were extracted for meta-analysis to explore the relationship between forest therapy and selected psychological and physiological indicators. Results A total of 85 articles were included, and the meta-analysis results showed that better scores of Profile of Mood States, Positive and Negative Affect Scale, Beck Depression Inventory, and State Trait Anxiety Scale were found in the forest group than those in the urban group (P<0.05); the levels of systolic blood pressure, diastolic blood pressure, heart rate, sympathetic nerve indicator [ln (LF/HF)], salivary cortisol, and serum inflammatory factors were lower in the forest group than in the urban group, while parasympathetic nerve indicator [ln (HF)] level was higher in the forest group than in the urban group (P<0.05). The results of subgroup analysis showed that the changes in heart rate (SMD=−1.62, 95%CI: −2.41, −0.82), ln (HF) (SMD=1.29, 95%CI: 0.73, 1.85), ln (LF/HF) (SMD=−1.49, 95%CI: −2.13, −0.86), and salivary cortisol (SMD=−0.53, 95%CI: −0.81, −0.25) were more significant when the duration of forest therapy was ≤ 0.5 h, the recovery effect on emotional state was better in the >0.5~3 h group (such as tension SMD=−2.40, 95%CI: −3.21, 1.59), and the reduction effects on systolic blood pressure (SMD=−0.53, 95%CI: −1.03, −0.03) and diastolic blood pressure (SMD=−0.42, 95%CI: −0.88, 0.04) were better in the >3 h group. Seated meditation showed better recovery effects on multiple indicators of Profile of Mood States (such as fatigue SMD=−2.26, 95%CI: −3.07, −1.45), while walking showed better recovery effects on physiological indicators such as blood pressure (systolic blood pressure SMD=−0.57, 95%CI: −1.07, −0.06; diastolic blood pressure SMD=−0.72, 95%CI: −1.36, −0.07) and heart rate (SMD=−1.51, 95%CI: −2.38, -0.64). Except for blood pressure, the health benefits of forest therapy in the younger age group were generally better than those in the middle-aged and elderly group. Conclusion Relaxed and comfortable psychological feeling is reported when practicing forest therapy; it can lower blood pressure and heart rate, regulate the autonomic nervous system; it can also reduce the release of stress hormones and lower serum levels of inflammatory factors, exerting an auxiliary recovery effect on cardiovascular and immune system disorders. At the same time, the therapy duration, form, and age of the subjects have a certain impact on the effects of forest therapy practice.

Objective:To investigate the efficiency of biochemical screening and hotspot gene screening in the detection of neonatal inherited metabolic diseases.Methods:This was a prospective multi-center study.The study was carried out on 21 442 neonatal samples collected from 12 hospitals in 10 provinces from November 2020 to November 2021.The results of biochemical screening and hotspot gene screening were analyzed jointly.Biochemical screening methods included glucose-6-phosphate dehydrogenase deficiency enzyme activity assay and neonatal tandem mass spectrometry.Genetic screening analysis involved 135 genes associated with 75 neonatal diseases.Results:Of all the 21 442 neonates enrolled in the study, 21 205 were subject to biochemical screening.A total of 813 cases were positive in the initial screening, and 0.45% of them (95 cases) were diagnosed after recall.All the 21 442 neonates underwent gene screening.About 168 positive cases were detected in the initial screening, and 0.73% (156 cases) of them were confirmed finally.Biochemical and genetic screening improved the detection sensitivity of such diseases as primary carnitine deficiency, neonatal intrahepatic cholestasis caused by citrin deficiency, and 2-methylbutyrylglycinemia.Moreover, biochemical and genetic screening enabled the detection of more diseases, including the common single-gene genetic diseases such as thalassemia and Wilson disease.Conclusions:In neonatal screening, the combination of biochemical screening and gene screening expands the number of diseases detected and improve screening efficiency.

Objective:To investigate the effect of tumor deposits on the prognosis and lymph node staging in patients with gastric cancer.Methods:The clinicopathological data of 907 patients with gastric cancer admitted to the Fourth Hospital of Hebei Medical University from Jan to Dec 2016 were retrospectively analyzed. According to the pathological diagnosis, the patients were divided into tumor deposits positive group (121 cases) and tumor deposits negative group (786 cases), and the relationship between tumor deposits and clinicopathological features and prognosis was analyzed.Results:Tumor deposits were found in 121 patients among 907 cases. Univariate analysis showed that tumor deposits were correlated with pT stage, pN stage, pTNM stage, tumor diameter, nerve invasion and vascular invasion (all P<0.05). Multivariate analysis showed that pT stage ( P<0.001), pN stage ( P=0.002), pTNM stage ( P=0.001), tumor diameter ( P=0.033),nerve invasion ( P=0.017), vascular invasion ( P=0.011) were the independent influencing factors of positive tumor deposits. The prognosis of patients with tumor deposits was worse than those without ( χ2=77.869, P<0.001). By univariate analysis, age, tumor location, size, pT stage, pN stage, pTNM stage, tumor thrombus, nerve invasion, tumor deposits and number affected prognosis (all P<0.05). Multivariate analysis showed that age, pT stage, pN stage, pTNM stage, nerve invasion, vascular invasion and the number of tumor deposits were independent prognostic factors (all P<0.05). By stratified analysis tumor deposits were found to have statistical difference in N0~N3a stage (all P<0.05). Conclusion:Tumor deposits is an independent risk factor affecting the prognosis of gastric cancer patients.

Objective:To explore the protective effect and safety of RotaTeq vaccine on children with rotavirus gastroenteritis (RVGE) in high mortality areas in the world and guide the correct use of RotaTeq vaccine.Methods:The literature on RotaTeq vaccine in high mortality areas in the world published from February 2006 to December 2021 was searched, screened and sorted out according to the exclusion and inclusion criteria, and the data were analyzed by RevMan 5.3, Stata 14.0 and SPSS 26.0 softwares.Results:A total of 5 reports were enrolled, including 63 974 subjects, including 32 092 subjects in the vaccine group and 31 882 subjects in the placebo group. In high mortality areas, the protection rates of RotaTeq vaccine against RVGE, severe rotavirus gastroenteritis (SRVGE) and very severe rotavirus gastroenteritis (VSRVGE) were VE RVGE=35% (95% CI: 28%-41%), VE SRVGE=51% (95% CI: 33%-65%) and VE VSRVGE=64% (95% CI: 41%-78%). The protection rates of SRVGE in Asia and Africa are VE SRVGE=43% (95% CI: 28%-55%) and VE SRVGE=57% (95% CI: 17%-77%), respectively. There was no significant difference in the incidences of serious adverse events (SAEs) between RotaTeq vaccine group and placebo group ( χ2=2.05, P=0.152). Conclusions:RotaTeq vaccine has a certain protective effect on severe and above RVGE with good safety in high mortality areas in the world.