ObjectiveObesity has been identified as one of the most important risk factors for cognitive dysfunction. Physical exercise can ameliorate learning and memory deficits by reversing synaptic plasticity in the hippocampus and cortex in diseases such as Alzheimer’s disease. In this study, we aimed to determine whether 8 weeks of treadmill exercise could alleviate hippocampus-dependent memory impairment in high-fat diet-induced obese mice and investigate the potential mechanisms involved. MethodsA total of sixty 6-week-old male C57BL/6 mice, weighing between 20-30 g, were randomly assigned to 3 distinct groups, each consisting of 20 mice. The groups were designated as follows: control (CON), high-fat diet (HFD), and high-fat diet with exercise (HFD-Ex). Prior to the initiation of the treadmill exercise protocol, the HFD and HFD-Ex groups were fed a high-fat diet (60% fat by kcal) for 20 weeks. The mice in the HFD-Ex group underwent treadmill exercise at a speed of 8 m/min for the first 10 min, followed by 12 m/min for the subsequent 50 min, totally 60 min of exercise at a 0° slope, 5 d per week, for 8 weeks. We employed Y-maze and novel object recognition tests to assess hippocampus-dependent memory and utilized immunofluorescence, Western blot, Golgi staining, and ELISA to analyze axon length, dendritic complexity, number of spines, the expression of c-fos, doublecortin (DCX), postsynaptic density-95 (PSD95), synaptophysin (Syn), interleukin-1β (IL-1β), and the number of major histocompatibility complex II (MHC-II) positive cells. ResultsMice with HFD-induced obesity exhibit hippocampus-dependent memory impairment, and treadmill exercise can prevent memory decline in these mice. The expression of DCX was significantly decreased in the HFD-induced obese mice compared to the control group (P<0.001). Treadmill exercise increased the expression of c-fos (P<0.001) and DCX (P=0.001) in the hippocampus of the HFD-induced obese mice. The axon length (P<0.001), dendritic complexity (P<0.001), the number of spines (P<0.001) and the expression of PSD95 (P<0.001) in the hippocampus were significantly decreased in the HFD-induced obese mice compared to the control group. Treadmill exercise increased the axon length (P=0.002), dendritic complexity(P<0.001), the number of spines (P<0.001) and the expression of PSD95 (P=0.001) of the hippocampus in the HFD-induced obese mice. Our study found a significant increase in MHC-II positive cells (P<0.001) and the concentration of IL-1β (P<0.001) in the hippocampus of HFD-induced obese mice compared to the control group. Treadmill exercise was found to reduce the number of MHC-II positive cells (P<0.001) and the concentration of IL-1β (P<0.001) in the hippocampus of obese mice induced by a HFD. ConclusionTreadmill exercise led to enhanced neurogenesis and neuroplasticity by increasing the axon length, dendritic complexity, dendritic spine numbers, and the expression of PSD95 and DCX, decreasing the number of MHC-II positive cells and neuroinflammation in HFD-induced obese mice. Therefore, we speculate that exercise may serve as a non-pharmacologic method that protects against HFD-induced hippocampus-dependent memory dysfunction by enhancing neuroplasticity and neurogenesis in the hippocampus of obese mice.

The study was conducted to investigate the mechanism of Xinyang Tablets( XYP) in modulating the fat mass and obesity-associated protein(FTO)/N6-methyladenosine(m6A) signaling pathway to ameliorate ventricular remodeling in heart failure(HF). A mouse model of HF was established by transverse aortic constriction(TAC). Mice were randomized into sham, model, XYP(low, medium, and high doses), and positive control( perindopril) groups(n= 10). From day 3 post-surgery, mice were administrated with corresponding drugs by gavage for 6 consecutive weeks. Following the treatment, echocardiography was employed to evaluate the cardiac function, and RT-qPCR was employed to determine the relative m RNA levels of key markers, including atrial natriuretic peptide( ANP), B-type natriuretic peptide( BNP), β-myosin heavy chain(β-MHC), collagen type I alpha chain(Col1α), collagen type Ⅲ alpha chain(Col3α), alpha smooth muscle actin(α-SMA), and FTO. The cardiac tissue was stained with Masson's trichrome and wheat germ agglutinin(WGA) to reveal the pathological changes. Immunohistochemistry was employed to detect the expression levels of Col1α, Col3α, α-SMA, and FTO in the myocardial tissue. The m6A modification level in the myocardial tissue was measured by the m6A assay kit. An H9c2 cell model of cardiomyocyte injury was induced by angiotensin Ⅱ(AngⅡ), and small interfering RNA(siRNA) was employed to knock down FTO expression. RT-qPCR was conducted to assess the relative m RNA levels of FTO and other genes associated with cardiac remodeling. The m6A modification level was measured by the m6A assay kit, and Western blot was employed to determine the phosphorylated phosphatidylinositol 3-kinase(p-PI3K)/phosphatidylinositol 3-kinase(PI3K) and phosphorylated serine/threonine kinase(p-Akt)/serine/threonine kinase(Akt) ratios in cardiomyocytes. The results of animal experiments showed that the XYP treatment significantly improved the cardiac function, reduced fibrosis, up-regulated the m RNA and protein levels of FTO, and lowered the m6A modification level compared with the model group. The results of cell experiments showed that the XYP-containing serum markedly up-regulated the m RNA level of FTO while decreasing the m6A modification level and the p-PI3K/PI3K and p-Akt/Akt ratios in cardiomyocytes. Furthermore, FTO knockdown reversed the protective effects of XYP-containing serum on Ang Ⅱ-induced cardiomyocyte hypertrophy. In conclusion, XYP may ameliorate ventricular remodeling by regulating the FTO/m6A axis, thereby inhibiting the activation of the PI3K/Akt signaling pathway.
Animals ; Ventricular Remodeling/drug effects* ; Heart Failure/physiopathology* ; Signal Transduction/drug effects* ; Mice ; Male ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Mice, Inbred C57BL ; Humans ; Adenosine/analogs & derivatives* ; Myocytes, Cardiac/metabolism* ; Disease Models, Animal

A scoping review was performed to systematically search and summarize the clinical research in the treatment of dysmenorrhea with oral Chinese patent medicines. The oral Chinese patent medicines for treating dysmenorrhea in three major drug lists, guidelines, and textbooks were screened, and the relevant clinical trials were retrieved from eight Chinese and English databases. The key information of the included trials was extracted and visually analyzed. A total of 50 Chinese patent medicines were included, among which oral Chinese patent medicines for the dysmenorrhea patients with the syndrome of Qi stagnation and blood stasis accounted for the highest proportion, and the average daily cost varied greatly among Chinese patent medicines. A total of 150 articles were included, involving 22 Chinese patent medicines, among which Guizhi Fuling Capsules/Pills, Sanjie Zhentong Capsules, and Dan'e Fukang Soft Extract were the most frequently studied. These articles mainly reported randomized controlled trial(RCT), which mainly focused on the comparison of the intervention effect between Chinese patent medicines combined with western medicine and western medicine alone, and the sample size was generally 51-100 cases. The high-frequency outcome indicators belonged to nine domains such as effective rate, adverse reactions, and laboratory examinations. This study showed that oral Chinese patent medicines had advantages in the treatment of dysmenorrhea, and the annual number of related clinical trials showed an overall growing trend. However, there were still problems such as insufficient safety information and vague description of traditional Chinese medicine(TCM) syndromes types in the instructions of Chinese patent medicines. The available clinical research had shortcomings such as uneven distribution of Chinese patent medicines, limited research scale, poor methodological rigor, and insufficient standardization of outcome indicators. In the future, it is necessary to deepen the development of high-quality clinical research and improve the contents of the instructions to ensure the effectiveness and safety of the clinical application of oral Chinese patent medicines in the treatment of dysmenorrhea.
Dysmenorrhea/drug therapy* ; Humans ; Drugs, Chinese Herbal/administration & dosage* ; Female ; Administration, Oral ; Nonprescription Drugs/administration & dosage*

This study investigates the effect and underlying mechanism of Guizhi Tongluo Tablets(GZTL) in treating atherosclerosis(AS) in a mouse model. Apolipoprotein E-knockout(ApoE~(-/-)) mice were randomly assigned to the following groups: model, high-, medium-, and low-dose GZTL, and atorvastatin(ATV), and age-matched C57BL/6J mice were selected as the control group. ApoE~(-/-) mice in other groups except the control group were fed with a high-fat diet for the modeling of AS and administrated with corresponding drugs via gavage for 8 weeks. General conditions, signs of blood stasis, and body mass of mice were monitored. Aortic plaques and their stability were assessed by hematoxylin-eosin, Masson, and oil red O staining. Serum levels of total cholesterol(TC), triglycerides(TG), and low-density lipoprotein cholesterol(LDL-C) were measured by biochemical assays, and those of interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), and interleukin-6(IL-6) were determined via enzyme-linked immunosorbent assay. Apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL). Single-cell RNA sequencing(scRNA-seq) was employed to analyze the differential expression of CD72hi macrophages(CD72hi-Mφ) in the aortas of AS patients and mice. The immunofluorescence assay was employed to visualize CD72hi-Mφ expression in mouse aortic plaques, and real-time fluorescence quantitative PCR was utilized to determine the mRNA levels of IL-1β, TNF-α, and IL-6 in the aorta. The results demonstrated that compared with the control group, the model group exhibited significant increases in body mass, aortic plaque area proportion, necrotic core area proportion, and lipid deposition, a notable decrease in collagen fiber content, and an increase in apoptosis. Additionally, the model group showcased elevated serum levels of TC, TG, LDL-C, IL-1β, TNF-α, and IL-6, alongside marked upregulations in the mRNA levels of IL-1β, TNF-α, and IL-6 in the aorta. In comparison with the model group, the GZTL groups and the ATV group showed a reduction in body mass, and the medium-and high-dose GZTL groups and the ATV group demonstrated reductions in aortic plaque area proportion, necrotic core area proportion, and lipid deposition, an increase in collagen fiber content, and a decrease in apoptosis. Furthermore, the treatment goups showcased lowered serum levels of TC, TG, LDL-C, IL-1β, TNF-α, and IL-6. The data of scRNA-seq revealed significantly elevated CD72hi-Mφ signaling in carotid plaques of AS patients compared with that in the normal arterial tissue. Animal experiments confirmed that CD72hi-Mφ expression, along with several pro-inflammatory cytokines, was significantly upregulated in the aortas of AS mice, which were downregulated by GZTL treatment. In conclusion, GZTL may alleviate AS by inhibiting CD72hi-Mφ activity.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Atherosclerosis/immunology* ; Mice ; Mice, Inbred C57BL ; Macrophages/immunology* ; Male ; Humans ; Apolipoproteins E/genetics* ; Tablets ; Tumor Necrosis Factor-alpha/genetics* ; Apoptosis/drug effects* ; Interleukin-1beta/genetics* ; Interleukin-6/genetics* ; Disease Models, Animal ; Mice, Knockout

OBJECTIVES: To investigate the genomic characteristics and prognostic factors of juvenile myelomonocytic leukemia (JMML) with RAS mutations. METHODS: A retrospective analysis was conducted on the clinical data of JMML children with RAS mutations treated at the Hematology Hospital of Chinese Academy of Medical Sciences, from January 2008 to November 2022. RESULTS: A total of 34 children were included, with 17 cases (50%) having isolated NRAS mutations, 9 cases (27%) having isolated KRAS mutations, and 8 cases (24%) having compound mutations. Compared to children with isolated NRAS mutations, those with NRAS compound mutations showed statistically significant differences in age at onset, platelet count, and fetal hemoglobin proportion (P<0.05). Cox proportional hazards regression model analysis revealed that hematopoietic stem cell transplantation (HSCT) and hepatomegaly (≥2 cm below the costal margin) were factors affecting the survival rate of JMML children with RAS mutations (P<0.05); hepatomegaly was a factor affecting survival in the non-HSCT group (P<0.05). CONCLUSIONS Children with NRAS compound mutations have a later onset age compared to those with isolated NRAS mutations. At initial diagnosis, children with NRAS compound mutations have poorer peripheral platelet and fetal hemoglobin levels than those with isolated NRAS mutations. Liver size at initial diagnosis is related to the prognosis of JMML children with RAS mutations. HSCT can improve the prognosis of JMML children with RAS mutations.
Humans ; Leukemia, Myelomonocytic, Juvenile/therapy* ; Mutation ; Male ; Female ; Child, Preschool ; Retrospective Studies ; Child ; Infant ; GTP Phosphohydrolases/genetics* ; Membrane Proteins/genetics* ; Adolescent ; Hematopoietic Stem Cell Transplantation ; Proportional Hazards Models ; Proto-Oncogene Proteins p21(ras)/genetics* ; Prognosis

BACKGROUND: Hypertension is associated with an increased risk of calcific aortic valve stenosis (CAVS). However, the directionality of causation between blood pressure traits and aortic stenosis is unclear, as is the benefit of antihypertensive drugs for CAVS. METHODS: Using genome-wide association studies (GWAS) summary statistics, we performed bidirectional two-sample univariable mendelian randomization (UVMR) to assess the causal associations of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) with CAVS. Multivariable mendelian randomization (MVMR) was conducted to evaluate the direct effect of hypertension on CAVS, adjusting for confounders. Drug target mendelian randomization (MR) and summary-level MR (SMR) were used to estimate the effects of 12 classes of antihypertensive drugs and their target genes on CAVS risk. Inverse variance weighting was the primary MR method, with sensitivity analyses to validate results. RESULTS: UVMR showed SBP, DBP, and PP have causal effects on CAVS, with no significant reverse causality. MVMR confirmed the causality between hypertension and CAVS after adjusting for confounders. Drug-target MR analyses indicated that calcium channel blockers (CCBs), loop diuretics, and thiazide diuretics via SBP lowering exerted protective effects on CAVS risk. SMR analysis showed that the CCBs target gene CACNA2D2 and ARBs target gene AGTR1 were positively associated with CAVS risk, while diuretics target genes SLC12A5 and SLC12A1 were negatively associated with aortic stenosis risk. CONCLUSIONS Hypertension has a causal relationship with CAVS. Managing SBP in hypertensive patients with CCBs may prevent CAVS. ARBs might exert protective effects on CAVS independent of blood pressure reduction. The relationship between diuretics and CAVS is complex, with opposite effects through different mechanisms.

Objective To investigate the differences in visual perception between children with autism spectrum disorder(ASD)and typically developing(TD)children when watching different intention videos,and to explore the feasibility of machine learning algorithms in objectively distinguishing between ASD children and TD children.Methods A total of 58 children with ASD and 50 TD children were enrolled and were asked to watch the videos containing joint intention and non-joint intention,and the gaze duration and frequency in different areas of interest were used as original indicators to construct classifier-based models.The models were evaluated in terms of the indicators such as accuracy,sensitivity,and specificity.Results When using eight common classifiers,including support vector machine,linear discriminant analysis,decision tree,random forest,and K-nearest neighbors(with K values of 1,3,5,and 7),based on the original feature indicators,the highest classification accuracy achieved was 81.90% .A feature reconstruction approach with a decision tree classifier was used to further improve the accuracy of classification,and then the model showed the accuracy of 91.43% ,the specificity of 89.80% ,and the sensitivity of 92.86% ,with an area under the receiver operating characteristic curve of 0.909(P<0.001).Conclusions The machine learning model based on eye-tracking data can accurately distinguish ASD children from TD children,which provides a scientific basis for developing rapid and objective ASD screening tools.[Chinese Journal of Contemporary Pediatrics,2024,26(2):151-157]

Objective To investigate the impact and mechanism of efaproxiral (RSR13),a hemoglobin allosteric agent,on lung injury in rats caused by explosion-induced shock waves in plateau areas. Methods Eighty-two healthy male SD rats (8-week-old,transferred from an altitude of 2 880 m to 4700 m within 6 h)were randomly divided into blast injury group and RSR13+blast injury group (intraperitoneal injection of 150 mg/kg RSR132 h before explosion).Sixty rats were positioned at 5 m from the explosion source and divided into 5-m blast injury group (n=30)and 5-m RSR13+blast injury group (n=30). Additionally,16 rats were positioned at 6 m from the explosion source and then assigned into 6-m blast injury group (n=8)and 6-m RSR13+blast injury group (n=8).The left 6 rats served as control (n=6).Survival outcomes of each rat group positioned 5 m from the explosion source were observed over a 24-hour period.HE staining was used to evaluate the pathological score of the surviving rats positioned at 6 m from the explosion source in 24 h after explosion,along with arterial blood gas analysis.The contents of glutathione (GSH),malondialdehyde (MDA ) and superoxide dismutase (SOD ) in the lung tissues were determined by colorimetry.Western blotting was conducted to measure the expression levels of cleaved caspase-3 and occludin in the lung tissue.Results RSR13 pretreatment increased the survival rate immediately after explosion (93.3％ vs 46.7％,P<0.01 )and at 1 h after explosion (86.7％ vs 46.7％,P<0.01 )in plateau areas of 5 m from the explosion source.At high altitude,RSR13 pretreatment reduced the pathological score of lung injury in rats 6 m away from the explosion source (8.27±0.93 vs 13.70±0.78,P<0.01 ),but had no significant effect on the results of arterial blood gas analysis in rats with lung blast injury (P>0.05 ).In addition,RSR13 pretreatment also increased GSH content (40.27±12.47 vs 22.62±10.88 μg/g,P<0.05),but showed no obvious effect on MDA content and SOD activity (P>0.05 ),decreased the protein level of cleaved caspase-3 (P<0.01 )and increased that of occludin (P<0.05 )in the lung tissues.Conclusion RSR13 exerts significant protective effect on lung injury in rats caused by explosion-induced shock waves in high-altitude environment,which may be related to its increasing antioxidant capacity,reducing cell apoptosis and decreasing barrier permeability of lung ventilation.

Objective:To investigate the correlation between pre- and post-treatment changing trends in peripheral blood inflammatory markers and efficacy and their predictive value for prognosis in non-small cell lung cancer (NSCLC) patients treated with the first-line immunotherapy plus chemotherapy.Methods:The clinical data of NSCLC patients admitted to the Department of Radiation and Chemotherapy for Lung Oncology, Zhongnan Hospital of Wuhan University from October 2018 to May 2023 were retrospectively analyzed. The χ2 test was used to analyze the correlation between the changing trend of peripheral blood inflammatory markers and the efficacy of immunotherapy plus chemotherapy. The influencing factors of objective response rate (ORR) were assessed using binary logistic regression analysis. Kaplan-Meier survival curve and Cox proportional hazards model were used to analyze the prognostic value of the changing trend of peripheral blood inflammation markers on patients' prognosis. Results:A total of 102 NSCLC patients treated with first-line immunotherapy plus chemotherapy were included. The proportion of patients with bone metastases was higher in the lymphocyte to monocyte ratio (LMR) decreased group ( n=50) than that in the increased group ( n=52) ( χ2=4.28, P=0.039), whereas the pathological type of patients in the platelet to lymphocyte ratio (PLR) decreased group ( n=51) was more common in squamous carcinoma compared to patients in the increased group ( n=51) ( χ2=18.99, P<0.001), and a higher proportion of patients in the prognostic nutritional index (PNI) decreased group ( n=46) was female than that in the increased group ( n=56) ( χ2=4.29, P=0.038), with statistically significant differences. The 2-cycle objective response rate (ORR) of patients in the LMR increased and decreased groups was 63.5% (33/52) and 44.0% (22/50) ( χ2=3.89, P=0.049), the 2-cycle ORR of patients in the neutrophil to lymphocyte ratio (NLR) increased ( n=24) and decreased ( n=78) groups was 29.2% (7/24) and 61.5% (48/78) ( χ2=7.74, P=0.005), and the 2-cycle ORR for patients in the systemic immune inflammatory index (SII) increased group ( n=27) and decreased group ( n=75) was 33.3% (9/27) and 61.3% (46/75) ( χ2=6.26, P=0.012), with statistically significant differences. Multivariate analysis showed that the changing trend of inflammatory markers in peripheral blood were not related to ORR. The Kaplan-Meier survival curve indicated that patients in the group with SII decreased had longer median progression-free survival (PFS) (not reached vs. 7.1 months, χ2=9.35, P=0.002) and median overall survival (OS) (not reached vs. 16.6 months, χ2=11.08, P<0.001) than those in the SII increased group, and patients in the NLR decreased group had longer median OS (not reached vs. 22.2 months, χ2=4.56, P=0.033) than that in the NLR increased group. Univariate analysis suggested that both brain and bone metastasis ( HR=4.04, 95% CI: 1.23-13.35, P=0.022), increased SII ( HR=2.83, 95% CI: 1.41-5.66, P=0.003) were found to be significant factors affecting the PFS of NSCLC patients, both brain and bone metastasis ( HR=3.47, 95% CI: 1.05-11.45, P=0.041), increased NLR ( HR=2.17, 95% CI: 1.05-4.51, P=0.037) and increased SII ( HR=3.12, 95% CI: 1.54-6.30, P=0.002) were found to be significant factors affecting the OS of NSCLC patients. Multivariate analysis demonstrated that both brain and bone metastasis ( HR=4.32, 95% CI: 1.30-14.40, P=0.017) and increased SII ( HR=2.89, 95% CI: 1.44-5.81, P=0.003) were independent risk factors for PFS in NSCLC patients, both brain and bone metastasis ( HR=3.76, 95% CI: 1.13-12.50, P=0.031) and increased SII ( HR=3.47, 95% CI: 1.28-9.41, P=0.014) remained independent risk factors for OS in patients with NSCLC. Conclusion:The changing trend of peripheral blood inflammatory markers of NSCLC patients cannot independently predict the efficacy of 2-cycle immunotherapy plus chemotherapy. Both brain and bone metastasis, as well as the changing trend of SII can be used as important indicators to predict PFS and OS in advanced NSCLC patients treated with first-line immunotherapy plus chemotherapy. The simultaneous occurrence of brain and bone metastasis and SII increased suggest poor prognosis of NSCLC patients.

Objective To investigate the effects of methionine restriction(MR)on macrophages in lipopolysaccharide(LPS)-induced acute lung injury(ALI)and to explore the underlying mechanism.Methods According to the random number table method,36 male C57BL/6J mice(6～8 weeks old,23±2 g)were divided into 3 groups with 12 mice in each group:the sham group,the LPS group and the LPS+MR group.HE staining and pathological scoring of lung injury were performed in lung tissues.The expression of LPS-binding protein(LBP)and Toll-like receptor-4(TLR4)was detected by RT-qPCR and Western blotting.Macrophage-colony stimulating factor(M-CSF),granulocyte-macrophage-colony stimulating factor(GM-CSF)and chemokine C-C motif ligand 3(CCL3)which are all macrophage-associated chemokines were analyzed by immunohistochemistry.Results Compared with the sham group,the pathological score of lung injury in the LPS group was significantly increased(P＜0.01);The mRNA and protein expression levels of LBP and TLR4 were significantly increased;The number of positive cells of CD11b,F4/80,M-CSF,GM-CSF and CCL3 were significantly increased(P＜0.01).MR significantly improved LPS-induced ALI,and decreased the pathological score of lung injury(P＜0.01);The mRNA and protein expression levels of LBP and TLR4 were decreased;Compared with the LPS group,the number of positive cells of CD11 b,F4/80,M-CSF,GM-CSF and CCL3 were reduced in the LPS+MR group(P＜0.01).Conclusion MR could attenuate LPS-induced ALI by inhibiting the expression of macrophage chemokines and preventing infiltration and activation of macrophage to lungs.