Andrographolide sulfonate (AS) is a sulfonated derivative of andrographolide extracted from Andrographis paniculata (Burm.f.) Nees, and has been approved for several decades in China. The present study aimed to investigate the novel therapeutic application and possible mechanisms of AS in the treatment of rheumatoid arthritis. Results indicated that administration of AS by injection or gavage significantly reduced the paw swelling, improved body weights, and attenuated pathological changes in joints of rats with adjuvant-induced arthritis. Additionally, the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β in the serum and ankle joints were reduced. Bioinformatics analysis, along with the spleen index and measurements of IL-17 and IL-10 levels, suggested a potential relationship between AS and Th17 cells under arthritic conditions. In vitro, AS was shown to block Th17 cell differentiation, as evidenced by the reduced percentages of CD4⁺ IL-17A⁺ T cells and decreased expression levels of RORγt, IL-17A, IL-17F, IL-21, and IL-22, without affecting the cell viability and apoptosis. This effect was attributed to the limited glycolysis, as indicated by metabolomics analysis, reduced glucose uptake, and pH measurements. Further investigation revealed that AS might bind to hexokinase2 (HK2) to down-regulate the protein levels of HK2 but not glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or pyruvate kinase M2 (PKM2), and overexpression of HK2 reversed the inhibition of AS on Th17 cell differentiation. Furthermore, AS impaired the activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signals in vivo and in vitro, which was abolished by the addition of lactate. In conclusion, AS significantly improved adjuvant-induced arthritis (AIA) in rats by inhibiting glycolysis-mediated activation of PI3K/AKT to restrain Th17 cell differentiation.
Animals ; Th17 Cells/immunology* ; Diterpenes/pharmacology* ; Arthritis, Rheumatoid/metabolism* ; Proto-Oncogene Proteins c-akt/immunology* ; Glycolysis/drug effects* ; Cell Differentiation/drug effects* ; Phosphatidylinositol 3-Kinases/genetics* ; Rats ; Male ; Rats, Sprague-Dawley ; Humans ; Andrographis paniculata/chemistry* ; Arthritis, Experimental/drug therapy* ; Interleukin-17/immunology* ; Signal Transduction/drug effects*

Objective To investigate the protective effect and mechanism of heat acclimation(HA)on electromagnetic field(EMF)induced hippocampus neuron injury in mice.Methods Forty healthy BALB/c male mice(18～22 g,7 weeks old)were randomly divided into 4 groups(n=10):Control group(Con),HA group(34℃,30 d),EMF group(2 450 MHz,20 min/d,4 weeks)and HA+EMF group(HA preconditioning+EMF).Sucrose preference test was performed to evaluate sucrose preference levels of mice in each group.Tail suspension test and forced swimming test were utilized to observe the immobility time.Morris water maze test was conducted to determine the learning and memory capabilities.Pathological changes in the hippocampus were observed with HE staining.Immunohistochemical assay for Iba1(marker of microglia),CD68(marker of pro-inflammatory phenotype)and CD206(marker of anti-inflammatory phenotype)were used to detect the number and activation phenotype of microglia in the hippocampus.ELISA was applied to measure the levels of TNF-α,IL-1β,TGF-β and IL-10 in the hippocampus of each group.Western blotting was performed to determine the protein levels of HSP70 in the hippocampus.Results As compared with the Con group,the EMF group showed a decreased preference for sucrose(P<0.05),prolonged immobile time in the tail suspension test(P<0.01)as well as in the forced swimming test(P<0.01),extented escape latency on the 7th day(P<0.01),and a decreased time of crossing the platform(P<0.05).EMF exposure resulted in that the hippocampal neurons were in disordered arrangement,loose structure and irregular morphology,with swollen cytoplasm and condensed nuclei,swollen and more microglial cells in the hippocampus(P<0.01),and enhanced relative fluorescence intensity of CD68(P<0.01),but not in CD206 fluorescence intensity(P=0.885).All these findings suggested that activated microglia predominantly exhibited a pro-inflammatory M1 phenotype during this phase.In the hippocampus,the levels of TNF-α and IL-1β were significantly increased,while the levels of IL-10 and TGF-β were significantly decreased(P<0.01).HA treatment reversed the conditions induced by EMF exposure,including better preference for sucrose(P<0.01),shorten immobile time in tail suspension test(P<0.05)and forced swimming test(P<0.01),less escape latency on the 7th day(P<0.01),and improved hippocampal cell injuries.Compared with the Con group,there were more microglial cells in the hippocampus in the HA+EMF group,with increased relative fluorescence intensity of M2 phenotype marker CD206(P<0.01)and decreased CD68 fluorescence intensity(P<0.01).HA treatment also significantly decreased the expression of TNF-α and IL-1β levels(P<0.01),increased the expression of IL-10 and TGF-β(P<0.01),and elevated the protein level of HSP70(P<0.01)when compared with the EMF group.Conclusion HA may ameliorate EMF-induced hippocampus neurons injury in mice by altering the phenotype of activated microglia and inhibiting inflammatory responses.

Objective To explore the research hotspots and development trends of microbiota-gut-brain axis(MGBA)related literature both domestically and internationally.Methods Relevant MGBA literature from 2000 to 2023 was retrieved from the Web of Science Core Collection,and bib-liometric and visualization analyses were conducted using CiteSpace 6.3.R1 software.Results A total of 857 MGBA-related articles were analyzed.China and the United States are representative countries in this field,with CRYAN J F and University College Cork being the most influential author and the most productive institution,respectively.In recent years,high-frequency research had fo-cused on neurodegenerative diseases,intra-and extra-axis interactions with the body,and interventions involving short-chain fatty acids(SCFAs),tryptophan metabolism and serotonin.Conclusion The research in MGBA continues to be hotspot,and the research focus gradually transit from the verifica-tion of the relationship with diseases to the intra-axis interaction mechanism.The research hotspot of nervous system related diseases has been enduring in this field,and the therapeutic measures targeting the metabolites of intestinal flora and metabolomics are expected to become the future research trend in this field.

BACKGROUND:In the co-culture environment of mesenchymal stem cells and macrophages,mesenchymal stem cells can promote the polarization of macrophages into anti-inflammatory macrophages to reduce inflammation,and macrophages can promote the osteogenic differentiation of mesenchymal stem cells.The co-culture of both plays an important role in regulating the immune system and promoting tissue regeneration. OBJECTIVE:To summarize the methods,influencing factors and possible mechanisms of co-culture between mesenchymal stem cells and macrophages,and to provide theoretical basis and experimental methods for the application of co-culture of mesenchymal stem cells and macrophages in tissue engineering. METHODS:The first author searched the relevant articles published from January 1970 to September 2023 in PubMed and CNK by computer from January to September 2023.The Chinese and English key words were"mesenchymal stem cells,macrophages,co-culture".Finally,63 articles were included and analyzed. RESULTS AND CONCLUSION:(1)In vitro co-culture of mesenchymal stem cells and macrophages can be divided into direct contact co-culture and indirect contact co-culture according to the model,and two-dimensional cell co-culture and three-dimensional cell co-culture according to the dimension.(2)The co-culture of mesenchymal stem cells and macrophages can promote the polarization of macrophages towards M2 type and enhance the osteogenic effect of mesenchymal stem cells.(3)In the co-culture model,the methods of co-culture,the proportion and time of co-culture,the phenotype of macrophages,and the cell source and conditions all affected the immune regulation of macrophages and the osteogenesis of mesenchymal stem cells.(4)Cell interaction in co-culture may regulate the immune function of macrophages,proliferation,migration and osteogenesis of mesenchymal stem cells through cell-secreted soluble factors,extracellular vesicles,cell-cell contact,and metabolic pathways.(5)Mesenchymal stem cells and macrophages can enhance cardiac function after acute myocardial infarction,promote epithelial wound healing,reduce lung inflammation,improve renal function,and accelerate bone repair.(6)There are still some problems in co-culture of mesenchymal stem cells and macrophages,such as the selection of co-culture conditions,the maintenance of good cell state and interaction of co-cultured cells.(7)The co-culture of mesenchymal stem cells and macrophages can improve the local inflammatory microenvironment and promote tissue regeneration and repair,so it will have a broad application prospect in tissue engineering.

Objective:To investigate the effect of melatonin (MEL) on learning and memory abilities of fluoride-exposed offspring rats and the role of gut microbiota.Methods:Twelve 8-week-old Sprague-Dawley (SD) rats (8 females and 4 males) with a body weight ranging from 180 to 220 g were selected and divided into control group 1 and fluoride-exposed group 1 using a random number table method, with 6 rats in each group (female ∶ male = 2 ∶ 1). They were free to drink purified water or purified water containing 100 mg/L sodium fluoride, respectively. After 2 months, male and female rats were raised together in cages, and the first postnatal day (PND) of the offspring rats was recorded as PND0. In PND21, the offspring rats of fluoride-exposed group 1 were divided into fluoride-exposed group (Group F, n = 6) and fluoride + MEL group (Group FM, n = 6) using a group design, and continued to be exposed to fluoride through drinking water. The offspring rats of control group 1 were divided into control group (Group C, n = 6) and MEL group ( n = 6). The groups FM and MEL were given 20 mg/kg MEL by gavage, while the groups C and F were given the same dose of normal saline by gavage. In PND60, novel object recognition and Morris water maze tests were used to observe the learning and memory abilities of the offspring rats. Western blotting (WB) was used to detect the expression level of brain derived neurotrophic factor (BDNF) in the hippocampus of the offspring rats. And 16S rDNA sequencing technology was used to detect the changes in the structure and composition of gut microbiota in fecal samples. Results:The results of novel object recognition test showed that there was a statistically significant difference in the discrimination index (DI) among the four groups of offspring rats ( F = 3.95, P = 0.024). The DI in groups C and FM was higher than that of Group F ( P < 0.05). The results of Morris water maze test showed that compared with Group C, the platform-crossing time of the offspring rats of Group F were less and they had a longer time to reach the platform for the first time ( P < 0.05). Compared with Group F, the platform-crossing time of the offspring rats of Group FM were increased and they had a shorter time to reach the platform for the first time ( P < 0.05). The WB results showed that compared with Group C (1.00 ± 0.07), the expression level of BDNF protein in Group F (0.68 ± 0.26) was lower ( P < 0.05). Compared with Group F, the expression level of BDNF protein in Group FM (0.99 ± 0.14) was higher ( P < 0.05). Anosim similarity analysis showed significant differences in the structure and composition of gut microbiota in the four groups of offspring rats ( R = 0.395 062, P = 0.002). The distribution characteristics of gut microbiota species showed that at the phylum level, compared with Group C, the relative abundance of Bacteroidetes in Group F increased from 14.26% to 37.00%, and the relative abundance of Firmicutes decreased from 68.78% to 45.95%. Compared with Group F, the relative abundance of Firmicutes in Group FM increased from 45.95% to 65.26%, and the relative abundance of Bacteroidetes decreased from 37.00% to 23.00%. At the genus level, compared with Group C, the relative abundance of Lactobacillus, Dubosiella, HT002 and UCG-005 in Group F was lower, while the relative abundance of unclassified Muribaculaceae was higher. Compared with Group F, the relative abundance of Lactobacillus, Dubosiella, HT002 and UCG-005 in Group FM was higher, while the relative abundance of unclassified Muribaculaceae was lower. The results of linear discriminant analysis revealed that the Candidatus-Saccharimonas and Incertae-Sedis were significantly enriched in Group C, unclassified Muribaculaceae and Muribaculum were significantly enriched in Group F, and Allorhizobium- Neorhizobium- Pararhizobium- Rhizobium were significantly enriched in Group FM. Conclusion:MEL can improve the learning and memory impairment of offspring rats induced by fluoride exposure by changing the structure and composition of gut microbiota.

Objective:To explore the evaluation value of serum levels of positive pentameric protein 3 (PTX3) and creatine kinase isoenzyme MB (CK-MB) on volume load in patients with chronic decompensated heart failure (CDHF).Methods:A total of 300 CDHF patients who visited the Xingtai Central Hospital from July 2019 to July 2022 were selected and divided into a capacity overload group ( n=182) and a non capacity overload group ( n=118) based on their capacity balance level. Two clinical data sets were compared and analyzed. The receiver operating characteristic (ROC) curve was used to analyze the evaluation value of serum PTX3 and CK-MB levels on the volume load of CDHF patients. The clinical disease characteristics of the two groups of patients were analyzed using univariate analysis, and the influencing factors of volume load of CDHF patients were analyzed using logistic regression. A column chart model was constructed and validated. Results:The body mass index (BMI), waist circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose (FBG), glycosylated hemoglobin (HbA 1c), C-reactive protein (CRP), uric acid (UA), homeostasis model assessment of insulin resistance (HOMA-IR) of patients in the capacity overload group were higher than those in the non-capacity overload group, and the differences were statistically significant (all P<0.05). The PTX3, CK-MB, pulmonary capillary wedge pressure (PCWP), and CVP levels of patients in the capacity overload group were higher than those in the non-capacity overload group, while albumin, hemoglobin, and hematocrit were lower than those in the non-capacity overload group, and the differences were statistically significant (all P<0.05). The ROC curve showed that the area under the curve (AUC) of PTX3 and CK-MB for predicting capacity overload in CDHF patients are 0.795 and 0.718, with sensitivity of 86.2% and 83.7%, specificity of 65.4% and 68.6%, respectively, indicating high predictive accuracy; The AUC of the two joint predictions is 0.817, the sensitivity was 92.5%, and the specificity was 70.6%. The prediction accuracy was higher than PTX3 ( Z=3.812, P<0.05) and CK-MB ( Z=3.365, P<0.05). PTX3, CK-MB, albumin, hemoglobin, hematocrit, PCWP, and central venous pressure (CVP) were all influencing factors of volume load status in CDHF patients (all P<0.05). The column chart risk prediction model established based on these factors had high accuracy and strong applicability in clinical treatment. Conclusions:Serum PTX3 and CK-MB levels are influencing factors for volume overload in CDHF patients. A column chart model constructed in combination with indicators such as albumin, hemoglobin, hematocrit, PCWP, and CVP has high predictive value for the volume overload status of CDHF.

Objective:To explore the differences of gene expression profiles of precursors of exhausted T cells (Tpex) and terminal exhausted T cells (Tex) in the peripheral blood of patients with active pulmonary tuberculosis (ATB).Methods:Twenty-five cases of ATB, 13 cases of latent tuberculosis infection (LTBI) and 10 health controls were enrolled from January 2021 to October 2022 in the Fifth People′s Hospital of Wuxi. The proportions of Tpex and Tex in the peripheral blood mononuclear cells (PBMCs) of the three groups were detected by flowcytometry. PBMCs of ATB were separated into Tpex and Tex by fluorescence-activated cell sorting. RNA-sequencing was performed and up-regulated and down-regulated genes were screended. Differently expressed genes were analyzed by gene set enrichment analysis of gene ontology (GO) to find regulatory pathways affecting cell metabolism and function. Wilcoxon matched-pairs signed rank test, Kruskal-Wallis test and Dunn multiple comparsion test were used for statistical analysis.Results:The proportion of Tpex in ATB group was 2.86%(1.74%), which was lower than 7.93%(6.16%) of Tex, and the difference was statistically significant ( Z=-3.91, P<0.001). The proportions of Tpex and Tex in LTBI group were 9.47%(6.26%) and 7.43%(5.48%), respectively, and the difference was not statistically significant ( Z=-0.93, P=0.345). The proportions of Tpex and Tex in healthy control group were 8.42%(2.69%) and 6.49%(5.14%), respectively, with no statistical significance ( Z=-1.36, P=0.170). There was statistical difference of the proportion of Tpex among the three groups ( H=21.93, P<0.001), and the proportion of Tpex in ATB group was lower than those in LTBI and heathy control groups, and the differences were both statistically significant ( Z=4.16, P<0.001 and Z=3.34, P=0.003, respectively), while the proportions of Tex in these three groups were not statistically different ( H=2.17, P=0.338). Compared with Tex, the gene expressions of memory markers, such as B-cell lymphoma 2 of Tpex were up-regulated, and the gene expressions of exhausted markers, such as lymphocyte activation gene 3 were down-regulated. In terms of cellular metabolism, the gene expressions of mitochondrial protein complex, mitochondrial matrix and oxidative phosphorylation of Tpex were up-regulated, and the gene expressions of glycolysis were down-regulated. The gene expressions of pyruvate metabolism in Tex were up-regulated, and the gene expressions of CD4 + T lymphocyte activation and differentiation and glycolytic process in Tpex were down-regulated. Conclusions:Tpex in ATB express more characteristics of memory cells and less features of exhausted markers compared with Tex, and the function of mitochondria of Tpex preserves well.

Background In the Global Burden of Disease research, it has been found that atmospheric fine particulate matter (PM_2.5) pollution significantly harms human health. Currently, there is limited research on polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) that exhibit high toxicity effects in PM_2.5 . Objective By studying the spatiotemporal distribution and variation characteristics of PCDD/Fs in PM_2.5 in Pudong area of Shanghai, to assess the associated population health risk. Methods This study set up 28 sampling points in Pudong area. One sample of PM_2.5 was collected during winter (February 2022) and summer (July 2022) at each site, with a sampling period lasting 24 h. The concentration of PM_2.5 was measured by membrane filter method, and the content of 17 kinds of 2,3,7,8-substituted chlorinated PCDD/Fs in the samples was analyzed using isotope dilution. Seasonal variations (winter and summer) in the concentrations of PM_2.5 and PCDD/Fs were evaluated, sources of PCDD/Fs pollution were tracing by principal component analysis, and health risks to the population from respiratory exposure to PCDD/Fs were estimated by VLIER-HUMAAN model. Results The PM_2.5 concentrations in the 28 samples ranged from 10 to 126 μg·m⁻³, while the concentrations of PCDD/Fs in PM_2.5 ranged from 58 to 2625 fg·m⁻³. The concentration of PM_2.5 during winter (11-126 μg·m⁻³) was higher than that during summer (10-60 μg·m⁻³). The concentration range of PCDD/Fs in winter was from 58 to 2625 fg·m⁻³, which corresponded to a range of toxic equivalent quantity (WHO-TEQ) concentration from 2.99 to 40.97 fg·m⁻³ when taking World Health Organization's toxic equivalency factor (WHO-TEQ); the concentration range of PCDD/Fs in summer was from 72 to 446 fg·m⁻³, which corresponded to a range of WHO-TEQ concentration from 2.66 to 16.61 fg·m⁻³. This range in summer was significantly lower than that observed in winter. The results of principal component analysis revealed that waste incineration was the primary source of PCDD/Fs in winter PM_2.5 in the area, whereas traffic emissions emerged as the main source in summer. The assessment of Pudong residents' respiratory exposure to PCDD/Fs in PM_2.5 showed significantly higher exposure of children in summer and winter than that of adults, indicating higher susceptibility of children to air pollutants. Both the hazard ratios (HR) for children and adults were below 1, while the cancer risks (CR) ranged from 8.41×10⁻⁸ to 2.35×10⁻⁶. Notably, during winter, the CR at 4 locations slightly exceeds 1×10⁻⁶, indicating a potential carcinogenic risk. Conclusion The overall pollution level of PCDD/Fs in PM_2.5 in Pudong area is relatively low, but it shows clear seasonal patterns. Waste incineration and traffic are the main sources of PCDD/Fs in PM_2.5 in the area. Although the cancer risk of exposure to PCDD/Fs in PM_2.5 for children or adults is relatively low, there is a certain risk at some locations in winter, necessitating additional monitoring and control.

Burkitt lymphoma is a highly aggressive B-cell lymphoma and the fastest proliferating human malignant tumor.If the disease is found in the early stage,the patient could have a high possibility to be cured successfully,whereas the prognosis is poor in the late stage.Burkitt lymphoma can occur in children and adults,and it is categorized as local(Africa),sporadic,and immunodeficiency associated type.Sporadic Burkitt lymphoma mainly affects children and ado-lescents,and the most common initial sites are abdominal organs and lymph nodes.Sporadic Burkitt lymphoma manifested by initial oral and maxillofacial lesions is rela-tively rare.Here,a case of pediatric sporadic Burkitt lym-phoma,with oral and maxillofacial lesions as the first symptoms,was reported.The patient was treated in the Department of Periodontology,Shandong University School and Hospital of Stomatology.After timely checkup was pro-vided,the patient was transferred to another hospital and had good results.In this article,an incidence of Burkitt lympho-ma,with oral and maxillofacial lesions as the first symptom,was reviewed to provide reference for oral clinicians to achieve early diagnosis and treatment of patients with Burkitt lymphoma with oral diseases and improve the success rate of treatment.

Objective To compare the efficacy and safety of endoscopic ligation treatment and endoscopic tissue glue injection for secondary prevention of gastric variceal bleeding.Methods Patients with cirrhosis and esophagogastric variceal bleeding treated with gastric variceal ligation in Zhongshan Hospital,Fudan University,from January 2017 to December 2019 were screened(ligation group).And during the same period,patients underwent endoscopic cyanoacrylate treatment were also screened(tissue glue group).59 patients were included in the two groups after propensity score matching.Univariate and multivariate Cox proportional hazard regression models were used to anslyze risk factors for re-bleeding.Kaplan-Meier curves were plotted to analyze re-bleeding rate and mortality of the two treatment groups.Results There was no statistically significant difference in the eradication rate of esophagogastric varices between the ligation group and the tissue glue group(83.05％vs 79.66％,P=0.778);the ligation group required fewer median endoscopic treatments for variceal eradication(2 vs 3,P=0.017)and a lower average dosage of cyanoacrylate(0.70 mL vs 2.67 mL,P＜0.001).Multivariate Cox regression analysis showed that portal shunt was a risk factor for esophagogastric varices re-bleeding(HR=3.14,95％CI 1.02-9.68,P=0.046),endoscopic variceal ligation was a protective factor against re-bleeding(HR=0.25,95％CI 0.08-0.71,P=0.010).Compared with endoscopic cyanoacrylate injection,endoscopic ligation treatment did not significantly increase the 2-year risk of esophagogastric variceal re-bleeding(18.69％vs 36.29％,P=0.067)or risk of death(1.69％vs 3.39％,P=1.000);patients with GOV1 type had a significantly lower risk of re-bleeding after endoscopic ligation treatment(0 vs 40.27％,P=0.012)and there was a trend towards a lower re-bleeding risk in patients with GOV2 type after endoscopic ligation treatment(13.27％vs 34.16％,P=0.056).Conclusions Endoscopic ligation treatment has higher eradication rate for esophagogastric varices,and does not increase the risk of re-bleeding,death,or other adverse events.Therefore,it can be considered an effective secondary prevention way for patients with gastric varices.