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 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.

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

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.

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.

Background::Given that seizures may be triggered by vaccination, this study aimed to evaluate the risk and correlative factors of seizures in patients with epilepsy (PWE) after being vaccinated against coronavirus disease 2019 (COVID-19).Methods::This study retrospectively enrolled PWE who were vaccinated against COVID-19 in the epilepsy centers of 11 hospitals in China. We divided the PWE into two groups as follows: (1) patients who developed seizures within 14 days of vaccination were assigned to the SAV (with seizures after vaccination) group; (2) patients who were seizure-free within 14 days of vaccination were assigned to the SFAV (seizure-free after vaccination) group. To identify potential risk factors for seizure reccurence, the binary logistic regression analysis was performed. Besides, 67 PWE who had not been vaccinated were also included for elucidating the effects of vaccination on seizures recurrence, and binary logistic regression analysis was performed to determine whether vaccination would affect the recurrence rate of PWE who had drug reduction or withdrawal.Results::The study included a total of 407 patients; of which, 48 (11.8%) developed seizures within 14 days after vaccination (SAV group), whereas 359 (88.2%) remained seizure-free (SFAV group). The binary logistic regression analysis revealed that duration of seizure freedom ( P < 0.001) and withdrawal from anti-seizure medications (ASMs) or reduction in their dosage during the peri-vaccination period were significantly associated with the recurrence of seizures (odds ratio= 7.384, 95% confidence interval = 1.732–31.488, P = 0.007). In addition, 32 of 33 patients (97.0%) who were seizure-free for more than three months before vaccination and had a normal electroencephalogram before vaccination did not have any seizures within 14 days of vaccination. A total of 92 (22.6%) patients experienced non-epileptic adverse reactions after vaccination. Binary logistic regression analysis results showed that vaccine did not significantly affect the recurrence rate of PWE who had the behavior of ASMs dose reduction or withdrawal ( P = 0.143). Conclusions::PWE need protection from the COVID-19 vaccine. PWE who are seizure-free for >3 months before vaccination should be vaccinated. Whether the remaining PWE should be vaccinated depends on the local prevalence of COVID-19. Finally, PWE should avoid discontinuing ASMs or reducing their dosage during the peri-vaccination period.

Epilepsy is one of the most common diseases of the central nervous system, affecting tens of millions of people around the world. Most of clinically used antiepileptic drugs are based on ion mechanism to antagonize epileptic seizures, targeted to various ion channels or ion channel receptors. However, with the in-depth research on the pathogenesis of epilepsy, the non-ionic antiepileptic mechanism has increasingly become the key to the control of various intractable epilepsy, and the relevant drugs have gradually achieved clinical transformation. In this paper, non-ionic antiepileptic mechanisms are classified to clinical and preclinical types according to whether clinical transformation has been achieved. The application of non-ionic antiepileptic drugs in refractory epilepsy was mainly introduced, including everolimus, cannabidiol, fenfluramine, padsevonil, medium chain triglyceride modified ketogenic diet, and anakinra. Additionally, some preclinical non-ionic antiepileptic mechanisms such as prostaglandin, adenosine, metabolic glutamate receptor and mitochondrial mechanism are briefly introduced. The authors believe that the current stage of ionic antiepileptic drugs research has reached the bottleneck of transformation and it is difficult to achieve a major breakthrough in the mechanism, but there are broader research prospects in non-ionic antiepileptic mechanisms because a large number of them have not yet been clinically transformed. From a deeper perspective, some non-ionic antiepileptic mechanisms may have been involved in the fundamental mechanism of epileptogenesis, and they may be the prospect for the future treatment of refractory epilepsy.

Objective:To investigate the level and the influencing factors of blood uric acid in monks and nuns in Wutai Mountain area, and to explore the relationship between blood uric acid level and BMI and blood lipids levels.Methods:Physical examinations and laboratory tests were performed on monks and nuns in Wutai Mountain area. There were 207 males and 261 females. Physical examination includes height, weight, blood pressure, blood uric acid, blood lipid, blood glucose and other indicators. The blood uric acid level was measured using the uricase method. Chi-square test for trend, and t test were utilized for statistical analysis. Results:The average blood uric acid level of the monk and the nun was (372±6) μmol/L and (290±4) μmol/L, respectively. Obviously, the average blood uric acid level of the monk was significantly higher than it in the nun ( t=11.636, P<0.01). The total incidence rate of hyperuricemia, which was diagnosed when the blood uric acid level was higher than 420 μmol/L in males and the blood uric acid level was higher than 360 μmol/L in females. In particular, the incidence rate of hyperuricemia was much higher in the monk (24.3%, 50/207) than in the nuns (13.4%, 35/261) ( χ2=8.966, P<0.01) . Analysis by age, the prevalence of hyperuricemia in men was 20.3%(42/207) before the age of 50, which was higher than that after the age of 50 (3.9%, 8/207) ( χ2=26.3, P< 0.01); The prevalence of hyperuricemia in women before the age of 50 was 2.7%(7/261), which was lower than that after the age of 50 (10.7%, 28/261) ( χ2=13.51, P<0.01). The uric acid level of men and women between 50-60 years old, showed the opposite trend. The level of uric acid in men decreased and increased in women. In addition, the prevalence of triglyceride abnormalities and overweight was more significantly in monks and nuns with high uric acid than those with the normal uric acid level [71.8%(61/85) vs 45.2%(173/383), χ2=19.68, P<0.01; 54.1%(46/85) vs 19.8%(76/383), χ2=42.4, P<0.01]; while no significant difference of total cholesterol and blood glucose levels was observed between these two groups. Conclusion:There are differences in blood uric acid levels among Wutai Mountain area monks and nuns of different ages and genders. The level of blood uric acid in male is significantly higher than that in female. Lipid metabolism and over weight are closely related to elevated level of the uric acid, which might be the risk factors of uric acid abnormality in Wutai Mountain population.

Objective:To explore the testicular descent process and temporal morphology and position changes of its neighboring tissues and organs in mice with three dimensional (3D) histological reconstruction technique.Methods:Tissue below the kidney plane of male Kunming mice was harvested on gestation days (GD)15, GD17, GD19, postnatal days (PD)3 and PD7.The tissue was then serially sectioned and stained with hematoxylin and eosin (HE). Slices were scanned and saved by the PerkinElmer automatic section analysis system.Afterward, Photoshop software was used for image registration and alignment, and 3D-doctor software was employed for 3D reconstruction and analysis.Results:(1)The epididymis enveloped the testis, and the tail of the epididymis was connected with the gubernaculum, but no direct connection was found between the lower pole of the testis and the gubernaculum.During pregnancy, each part of the epididymis and the vas deferens of mice were piled up into a mass, making it hard to identify the epididymis.The gubernaculum leads to " swelled" . After birth, the epididymis became large, elongated, and morphologi-cally recognizable, and the gubernaculum degenerated into fibrous cords.During the whole process, the volume of gubernaculum was significantly smaller than that of testicle.(2)Testicles on both sides were similar in shape and asymmetrical in position.The left testicle was lower than the right testicle, and descended before the right one.During pregnancy, testicles on both sides descended from the lower pole of the kidney, the left testical stopped at the lower part of the bladder.and the right one stopped at middle part of the bladder.After birth, the left testicle dropped below the neck of the bladder.Finally, the left testicle was lower than the right testicle.(3) The epididymis descend prior to the testicles.Throughout the process, the tail of the epididymis descended before the testicles, and it pulled the whole epididymis down.Testicles entered the scrotum along the descending path of the epididymis.After the complete descent, the tail of the epididymis remained below the testicles.Conclusions:Through observation, the testicular descend process in mice includes the following steps.First, the tail of the epididymis is pulled down to the inner ring by the gubernaculum, and the tail and body of the epididymis expand the inner ring and the inguinal canal through their morphological changes.The epididymis then continues to go down into the scrotum and expands it.Finally, the testicles and the head of the epididymis follow the epididymis body and enter the scrotum through the enlarged inner ring and inguinal canal.