OBJECTIVES: To investigate the therapeutic effects of inulin-type oligosaccharides of Morinda officinalis (IOMO) in a murine model of Streptococcus pneumoniae meningitis (SPM) and explore its possible mechanisms. METHODS: A total of 120 male C57BL/6J mice were randomly assigned into Sham, SPM+Saline, SPM+IOMO (25 mg/kg), and SPM+IOMO (50 mg/kg) groups. After modeling, the mice received daily gavage of saline or IOMO at the indicated doses for 7 consecutive days, and the changes in symptom scores and mortality of the mice were monitored. Brain pathology and neuronal injury of the mice were assessed using HE and Nissl staining, and qRT-PCR was performed to detect mRNA levels of the inflammatory mediators. Brain edema and blood-brain barrier (BBB) permeability of the mice were evaluated by measuring brain water content and Evans blue (EB) staining; Western blotting was used to analyze the expressions of BBB-associated proteins, and flow cytometry was employed to detect IFN‑γ expression level in the infiltrating lymphocytes. Open-field test (OFT) and novel object recognition test (NORT) were conducted to assess learning and memory ability of the mice on day 21 after modeling. RESULTS: IOMO treatment at 50 mg/kg significantly reduced the symptom scores and mortality rate of SPM mice, alleviated brain damage, and downregulated mRNA levels of IL-6, TNF‑α, IL-1β, IL-18, IFN‑γ, iNOS, NLRP3, ASC, caspase-1 and GSDMD in the brain tissue. IOMO treatment also decreased brain water content and EB leakage, upregulated VE-cadherin and occludin expressions, and suppressed AQP4, iNOS, and IFN‑γ levels of the mice. IOMO-treated mice exhibited improved learning and memory compared with the saline-treated mice on day 21 after SPM modeling. CONCLUSIONS IOMO alleviates SPM symptoms, reduces mortality, and mitigates cognitive deficits in mice possibly by suppressing cerebral inflammation and protecting BBB functions.
Animals ; Morinda/chemistry* ; Mice, Inbred C57BL ; Male ; Mice ; Meningitis, Pneumococcal/drug therapy* ; Blood-Brain Barrier/metabolism* ; Inulin/therapeutic use* ; Oligosaccharides/therapeutic use* ; Disease Models, Animal ; Interferon-gamma/metabolism* ; Brain Edema

Objective:To identify predictors of adverse pregnancy outcomes(APOs)in patients with systemic lupus erythematosus(SLE).Methods:A retrospective analysis was conducted on 318 SLE pa-tients who delivered at Peking University People's Hospital from May 2016 to September 2021.These pa-tients were categorized into two groups:The APOs group(n=85)and the non-APOs group(n=233).Various factors,including disease duration,clinical manifestations,laboratory parameters,and systemic lupus erythematosus disease activity index 2000(SLED AI-2000)scores,were analyzed for their associa-tion with APOs.SPSS 26.0 software was used to analyze the data.Results:The mean age of SLE pa-tients in this study was(24.65±5.26)years.Among the 318 pregnancies studied,302(302/318,94.97％)resulted in live births,while 16(16/318,5.03％)cases ended in stillbirths,with no neonatal deaths reported.Among the live births,206(206/302,68.21％)were full-term infants,65(65/302,21.52％)cases were small for gestational age(SGA),and 31(31/302,10.26％)cases were preterm.The SLEDAI-2000 scores were significantly higher in the APOs group compared with the non-APOs group(5.82±4.97 vs.3.74±3.72,t=4.019,P=0.001),suggesting greater disease activity as a risk fac-tor.Similarly,glucocorticoid doses were markedly higher in the APOs group[12.50(7.50,50.00)mg vs.10.00(5.00,15.00)mg,P＜0.001],underscoring the link between disease severity and APOs.Univariate analysis revealed that lupus nephritis(31.76％vs.21.03％,x2=3.946,P=0.047),throm-bocytopenia(24.71％vs.9.01％,x2=13.380,P＜0.001),hypocomplementemia(36.47％vs.26.03％,x2=4.847,P=0.028),antiphospholipid antibody positivity(20.00％vs.11.16％,x2=4.163,P=0.041),and absence of pregnancy treatment(21.18％vs.11.59％,x2=4.713,P=0.030)were associated with increased APOs risk.Multivariate Logistic regression identified thrombocyto-penia(OR=2.671,95％CI:1.309-5.449,P=0.007),hypocomplementemia(OR=1.935,95％CI:1.104-3.393,P=0.021),and antiphospholipid antibody positivity(OR=2.153,95％CI:1.054-4.399,P=0.035)as independent predictors of APOs.Conclusion:These findings highlight that certain clinical and laboratory features,including thrombocytopenia,hypocomplementemia,and antiphospholipid antibody positivity,are critical independent predictors of APOs in SLE patients.The study underscores the importance of close monitoring and proactive management of these risk factors to improve pregnancy outcomes in SLE patients.

Objective Using different concentrations of Coxsackievirus B3(CVB3)to infect young SD rats.To investigate the distribution of coxsackievirus B3(CVB3)in rat tissues and the immune response and inflammatory factors,to clarify the immunopathological mechanism of viral infection and provide an experimental basis for drug screening and efficacy evaluation.Methods Young SD rats(7 days old)were injected intraperitoneally with different doses of CVB3(TCID50=10-3.34/100 μL)and the proportions of lymphocyte subsets(CD4+,CD8+)in whole blood at days 4 and 8 were detected by flow cytometry.The CVB3 loads in the heart,liver,spleen,brain,kidney,and gastrointestinal tissues were detected by real-time fluorescence quantitative polymerase chain reaction,TNF-α and IFN-γ levels were detected by enzyme-linked immunosorbent assay,and histomorphologic changes were observed by hematoxylin and eosin staining.Results Different doses of CVB3 caused different degrees of diarrhea and decreased body mass in young rats.CVB3 was mainly distributed in the stomach,small intestine,large intestine,and stools,with the highest load in the large intestine and stools.The stock solution group(TCID50=10-3.34/100 μL)increased the proportion of CD8+T cells in the whole blood in young rats and decreased the CD4+/CD8+ratio(P＜0.05,P＜0.01).Compared with the nomal group high TNF-α and low IFN-γ expression were observed in the large intestine of young rats in the concentrate group(P＜0.05,P＜0.01),and submucosal edema and inflammatory cell infiltration were observed in the large intestine(cecum and rectum).There were no significant differences in the proportion of lymphocyte subsets,TNF-α and IFN-γ levels,and morphological changes in whole blood of young rats in the group 10-1,10-2,and 10-3(P＞0.05).Conclusions Different doses of CVB3 can induce infections in young SD rats.CVB3(TCID50=10-3.34/100 μL)causes pathological changes in the large intestine(cecum and rectum)in young rats,and high virus replication can increase levels of inflammatory factors and cause an imbalance of immune cells.CVB3 may have a unique pathogenic mechanism in young rats,providing a theoretical basis for developing evaluation strategies for drugs against CVB3 virus infections.

Objective Using different concentrations of Coxsackievirus B3(CVB3)to infect young SD rats.To investigate the distribution of coxsackievirus B3(CVB3)in rat tissues and the immune response and inflammatory factors,to clarify the immunopathological mechanism of viral infection and provide an experimental basis for drug screening and efficacy evaluation.Methods Young SD rats(7 days old)were injected intraperitoneally with different doses of CVB3(TCID50=10-3.34/100 μL)and the proportions of lymphocyte subsets(CD4+,CD8+)in whole blood at days 4 and 8 were detected by flow cytometry.The CVB3 loads in the heart,liver,spleen,brain,kidney,and gastrointestinal tissues were detected by real-time fluorescence quantitative polymerase chain reaction,TNF-α and IFN-γ levels were detected by enzyme-linked immunosorbent assay,and histomorphologic changes were observed by hematoxylin and eosin staining.Results Different doses of CVB3 caused different degrees of diarrhea and decreased body mass in young rats.CVB3 was mainly distributed in the stomach,small intestine,large intestine,and stools,with the highest load in the large intestine and stools.The stock solution group(TCID50=10-3.34/100 μL)increased the proportion of CD8+T cells in the whole blood in young rats and decreased the CD4+/CD8+ratio(P＜0.05,P＜0.01).Compared with the nomal group high TNF-α and low IFN-γ expression were observed in the large intestine of young rats in the concentrate group(P＜0.05,P＜0.01),and submucosal edema and inflammatory cell infiltration were observed in the large intestine(cecum and rectum).There were no significant differences in the proportion of lymphocyte subsets,TNF-α and IFN-γ levels,and morphological changes in whole blood of young rats in the group 10-1,10-2,and 10-3(P＞0.05).Conclusions Different doses of CVB3 can induce infections in young SD rats.CVB3(TCID50=10-3.34/100 μL)causes pathological changes in the large intestine(cecum and rectum)in young rats,and high virus replication can increase levels of inflammatory factors and cause an imbalance of immune cells.CVB3 may have a unique pathogenic mechanism in young rats,providing a theoretical basis for developing evaluation strategies for drugs against CVB3 virus infections.

Objective:To identify predictors of adverse pregnancy outcomes(APOs)in patients with systemic lupus erythematosus(SLE).Methods:A retrospective analysis was conducted on 318 SLE pa-tients who delivered at Peking University People's Hospital from May 2016 to September 2021.These pa-tients were categorized into two groups:The APOs group(n=85)and the non-APOs group(n=233).Various factors,including disease duration,clinical manifestations,laboratory parameters,and systemic lupus erythematosus disease activity index 2000(SLED AI-2000)scores,were analyzed for their associa-tion with APOs.SPSS 26.0 software was used to analyze the data.Results:The mean age of SLE pa-tients in this study was(24.65±5.26)years.Among the 318 pregnancies studied,302(302/318,94.97％)resulted in live births,while 16(16/318,5.03％)cases ended in stillbirths,with no neonatal deaths reported.Among the live births,206(206/302,68.21％)were full-term infants,65(65/302,21.52％)cases were small for gestational age(SGA),and 31(31/302,10.26％)cases were preterm.The SLEDAI-2000 scores were significantly higher in the APOs group compared with the non-APOs group(5.82±4.97 vs.3.74±3.72,t=4.019,P=0.001),suggesting greater disease activity as a risk fac-tor.Similarly,glucocorticoid doses were markedly higher in the APOs group[12.50(7.50,50.00)mg vs.10.00(5.00,15.00)mg,P＜0.001],underscoring the link between disease severity and APOs.Univariate analysis revealed that lupus nephritis(31.76％vs.21.03％,x2=3.946,P=0.047),throm-bocytopenia(24.71％vs.9.01％,x2=13.380,P＜0.001),hypocomplementemia(36.47％vs.26.03％,x2=4.847,P=0.028),antiphospholipid antibody positivity(20.00％vs.11.16％,x2=4.163,P=0.041),and absence of pregnancy treatment(21.18％vs.11.59％,x2=4.713,P=0.030)were associated with increased APOs risk.Multivariate Logistic regression identified thrombocyto-penia(OR=2.671,95％CI:1.309-5.449,P=0.007),hypocomplementemia(OR=1.935,95％CI:1.104-3.393,P=0.021),and antiphospholipid antibody positivity(OR=2.153,95％CI:1.054-4.399,P=0.035)as independent predictors of APOs.Conclusion:These findings highlight that certain clinical and laboratory features,including thrombocytopenia,hypocomplementemia,and antiphospholipid antibody positivity,are critical independent predictors of APOs in SLE patients.The study underscores the importance of close monitoring and proactive management of these risk factors to improve pregnancy outcomes in SLE patients.

Objective A model for studying oral ulcers induced by betel nut-extract was constructed in rats.Changes in the structure and diversity of oral flora were observed to explore the involvement of oral flora and local inflammatory factors in the pathogenesis of oral ulcers induced by betel nut-extract and to provide theoretical support for the prevention and treatment of oral ulcers in the clinic.Methods Thirty SD rats were randomly divided into normal,model and intervention groups(Guilin watermelon cream,8 mg/d for 7 days),with 10 rats/group.The oral mucosa of rats was subcutaneously injected with 10 g/mL of betel nut-extract to generate an oral ulcer model.The histomorphological changes were observed,and ulcer area and ulcer scores were assessed.Local oral tissue tumor necrosis factor-α(TNF-α),interleukin(IL)-2 and IL-8 levels were determined.Oral mucosal tissues were sampled for HE staining and analyzed for the structural distribution of oral flora and the diversity of microbial communities using high-throughput sequencing method.Results Compared with rats in the normal group,those in the model group had an increased ulcer area,significantly increased ulcer scores(P＜0.01),and significantly increased levels of TNF-α,IL-2 and IL-8 in the oral mucosal tissues(P＜0.01).The amount Streptococcus(P＜0.05)and Veillonella(P＜0.001)in the oral saliva of the model group rats was significantly reduced.The model group rats showed oral mucosal epithelial cell hyperplasia or focal necrosis,mucosal lamina propria edema,and hemorrhage accompanied by mass neutrophil and monocyte infiltration.Compared with the model group rats,the intervention group rats had significantly reduced ulcerated area(P＜0.05,P＜0.01)and ulcer scores(P＜0.05).And oral mucosal tissue levels of TNF-α(P＜0.01),IL-2(P＜0.05)and IL-8(P＜0.05),as well as significantly increased Streptococcus(P＜0.001)and Veillonella(P＜0.01)and significantly reduced Staphylococcus(P＜0.01)in the oral saliva.The degree of lesions in the oral mucosal tissues was significantly improved in the intervention group.Conclusions Betel nut-extract can be used to successfully reproduce a rat model of oral ulcer,and it is speculated that the development of oral ulcers after exposure to betel nut-extract may be related to an imbalance in the oral flora and local tissue inflammatory mediators.

Objective:To explore the predictive value of uterine artery blood flow parameters of Doppler ultrasound combined with coagulation related indicators on the pregnancy outcome of recurrent abortion caused by thrombophilia.Methods:A total of 82 patients with recurrent abortion who admitted to the department of gynecology outpatient of Beijing Haidian Hospital from January 2020 to January 2023 were selected.All patients received relevant treatment,and the follow-up results were calculated as statistic method.Before treatment on the day after admission,uterine artery pulse index(PI),resistance index(RI),the ratio of the maximum blood flow velocity of systolic pressure(S)to the maximum blood flow velocity of end-diastolic(D)(S/D),and activated partial thromboplastin time(APTT),prothrombin time(PT),fibrinogen(FIB),thrombin time(TT)and D-dimer(D-D)of all patients were detected.Pearson correlation analysis was adopted to analyze the correlations between PI,RI,S/D and each of APTT,PT,FIB,TT and D-D.Receiver operating characteristic(ROC)curve was used to analyze the values of single PI,RI,S/D,APTT,PT,FIB,TT and D-D,and the value of the combined detection of them in predicting the pregnancy outcome of recurrent abortion caused by thrombophilia.Results:Follow up results showed that 49 cases of 82 patients with recurrent abortion were successful pregnancy and 33 cases of them occurred pregnancy loss,and the PI,RI and S/D of pregnant women with successful pregnancy were significantly lower than those of pregnant women who occurred pregnancy loss,with statistical significance(t=10.598,6.693,3.059,P<0.05).The levels of APTT,PT,FIB,TT and D-D of pregnant women with successful pregnancy were significantly lower than those of pregnant women who occurred pregnancy loss,and the differences were statistically significant(t=9.552,96.462,22.767,5.100,95.805,P<0.05),respectively.PI appeared respectively positive correlation with APTT,PT,FIB,TT and D-D(r=3.178,P<0.05),and RI appeared respectively positive correlation with APTT,PT,FIB and D-D(r=3.246,P<0.05),and S/D also appeared respectively positive correlation with PT,FIB,TT and D-D(r=3.246,P<0.05).The sensitivities of single PI,RI,S/D,APTT,PT,FIB,TT and D-D detection,and the combined detection of them were respectively 42.40%,48.50%,39.40%,48.50%,63.60%,72.70%,42.40%,39.40%and 84.80%in predicting the pregnancy outcome of recurrent abortion caused by thrombophilia.The specificities of them were respectively 98.00%,71.40%,55.10%,75.50%,59.20%,71.40%,77.60%,85.70%and 98.80%,and the AUC values of them were respectively 0.674,0.685,0.409,0.646,0.784,0.788,0.566,0.563 and 0.941.Conclusion:Both single and combination of PI,RI and S/D of uterine artery blood flow parameters,as well as APTT,PT,FIB,TT and D-D of coagulation related indicators,have a certain value in predicting pregnancy outcome of recurrent abortion caused by thrombophilia,and the combined detection has higher predictive value.

OBJECTIVE To investigate the effects of Forsythia suspensa ethanol extract on the proliferation， migration and invasion of lung cancer cells NCI-H226. METHODS As research objects， lung cancer cells NCI-H226 were divided into control group， F. suspensa ethanol extract low-， medium- and high-concentration groups （5， 10， 20 mg/mL）， activator group [10 mg/mL F. suspensa ethanol extract+0.5 μmol/L nuclear factor kappa B （NF-κB） signaling pathway activator PMA]， inhibitor group （10 mg/mL F. suspensa ethanol extract+10 μmol/L NF-κB signaling pathway inhibitor BAY 11-7082） and positive control group （20 μg/mL cisplatin）. Except for the control group of cells without intervention， all other groups of cells were cultured with corresponding drugs for 24 hours； the proliferation， migration and invasion of cells were all detected， and the proliferation rate， migration rate， and the number of invading cells were also calculated； protein expressions of NF-κB p65， NF-κB inhibitory protein α （IκBα）， phosphorylated NF-κB p65 （p-NF-κB p65） and phosphorylated IκBα （p-IκBα） were determined. RESULTS Compared with control group， the proliferation rate， migration rate， and the number of invading cells as well as the protein expressions of p- IκBα and p-NF-κB p65 were decreased significantly in F. suspensa ethanol extract groups and positive control group （P＜0.05）. Compared with F. suspensa ethanol extract medium-concentration group， the proliferation rate， migration rate， and the number of invading cells as well as above protein expressions were all decreased significantly in inhibitor group （P＜0.05）， while those of activator group were increased significantly （P＜0.05）. CONCLUSIONS F. suspensa ethanol extract can inhibit the proliferation， migration and invasion of lung cancer cells NCI-H226， and the mechanism of which may be related to the inhibition of NF-κB signaling pathway.

As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound 59 showed a desirable AXL kinase inhibitory activity (IC₅₀: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound 59 could potently inhibit BaF3/TEL-AXL cell viability (IC₅₀: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

Pregnancy ; Female ; Humans ; Pregnancy Outcome ; Cross-Sectional Studies ; Lupus Erythematosus, Systemic/epidemiology* ; Pregnancy Complications/epidemiology* ; Menstruation Disturbances