OBJECTIVE: To explore the functional roles and underlying mechanisms of neferine in the context of angiotensin II (Ang II)-induced hypertension and vascular dysfunction. METHODS: Male mice were infused with Ang II to induce hypertension and randomly divided into treatment groups receiving neferine or a control vehicle based on baseline blood pressure using a random number table method. The hypertensive mouse model was constructed by infusing Ang II via a micro-osmotic pump (500 ng/kg per minute), and neferine (0.1, 1, or 10 mg/kg), valsartan (10 mg/kg), or double distilled water was administered intragastrically once daily for 6 weeks. A non-invasive blood pressure system, ultrasound, and hematoxylin and eosin staining were performed to assess blood pressure and vascular changes. RNA sequencing and network pharmacology were employed to identify differentially expressed transcripts (DETs) and pathways. Vascular ring tension assay was used to test vascular function. A7R5 cells were incubated with neferine for 24 h and then treated with Ang II to record the real-time Ca²⁺ concentration by confocal microscope. Immunohistochemistry (IHC) and Western blot were used to evaluate vasorelaxation, calcium, and the extracellular signal-regulated kinase (ERK)1/2 pathway. RESULTS: Neferine treatment effectively mitigated the elevation in blood pressure, pulse wave velocity, aortic thickening in the abdominal aorta of Ang II-infused mice (P<0.05). RNA sequencing and network pharmacology analysis identified 355 DETs that were significantly reversed by neferine treatment, along with 25 potential target genes, which were further enriched in multiple pathways and biological processes, such as ERK1 and ERK2 cascade regulation, calcium pathway, and vascular smooth muscle contraction. Further investigation revealed that neferine treatment enhanced vasorelaxation and reduced Ca²⁺-dependent contraction of abdominal aortic rings, independent of endothelium function (P<0.05). The underlying mechanisms were mediated, at least in part, via suppression of receptor-operated channels, store-operated channels, or voltage-operated calcium channels. Neferine pre-treatment demonstrated a reduction in intracellular Ca²⁺ release in Ang II stimulated A7R5 cells. IHC staining and Western blot confirmed that neferine treatment effectively attenuated the upregulation of p-ERK1/2 both in vivo and in vitro, which was similar with treatment of ERK1/2 inhibitor PD98059 (P<0.05). CONCLUSIONS Neferine remarkably alleviates Ang II-induced elevation of blood pressure, vascular dysfunction, and pathological changes in the abdominal aorta. This beneficial effect is mediated by the modulation of multiple pathways, including calcium and ERK1/2 pathways.
Animals ; Angiotensin II ; Male ; Benzylisoquinolines/therapeutic use* ; Network Pharmacology ; Blood Pressure/drug effects* ; Sequence Analysis, RNA ; Mice ; Hypertension/chemically induced* ; Mice, Inbred C57BL ; Calcium/metabolism*

Objective To investigate the inhibitory effects of Wumeiwan on oxidative stress injury of ulcerative colitis mice induced by dextran sulfate sodium(DSS)by regulating Kelch-like ECH related protein 1(Keap-1)-nuclear factor E2 related factor 2(Nrf2)/heme oxygenase-1(HO-1)signaling pathwayand.Methods Forty C57BL/6 mice were randomly divided into five groups:normal group,model group,positive control group,experimental-L,-H groups.UC mice model were induced by free access to 2％DSS water.Mice in normal and model group were orally administered with 0.9％NaCl,mice in positive control group were orally treated with Mesalazine solution(0.005 g·10 g-1·d-1),while mice in experimental groups were orally administered with Wumeiwan decoction at the dose of 0.13 and 0.26 g·10 g-1·d-1,respectively.All the drugs were administered for consecutive 7 days,1 times a day.The levels of disease activity index(DAI)and the colon length were scored.The levels of superoxide dismutase(SOD),catalase(CAT),cyclooxygenase-2(COX-2)and inducible nitric oxide synthase(iNOS)in colon tissue of mice were determined by real-time fluorescence quantitative polymerase chain reaction(qRT-PCR)method.The level of Keap-1,Nrf2,HO-1 proteins in colon tissue were determined by Western blot method.Results The levels of DAI of seventh day in normal group,positive control group,experimental-L,-H groups were 0、(2.62±0.33),(1.87±0.35),(1.87±0.35)and(1.58±0.35);the colon lengths were(8.16±0.47)、(5.98±0.24),(7.58±0.38),(7.33±0.24)and(7.48±0.51)cm;the SOD mRNA were 1.01±0.16、0.40±0.01,1.43±0.45,0.65±0.01 and 0.83±0.02;the CAT mRNA were 1.01±0.20、0.45±0.01,0.84±0.02,0.68±0.07 and 0.87±0.05;the COX-2 mRNA were 1.03±0.33、16.65±0.60,4.78±0.25,14.07±0.60 and 7.39±0.15;the iNOS mRNA were 1.04±0.40、20.71±0.66,8.09±0.93,15.44±0.68 and 11.66±0.06;the levels of Keap-1 were 1.22±0.16、1.10±0.05,1.18±0.05,1.94±0.08 and 1.17±0.08;the levels of Nrf2 were 1.12±0.16、0.76±0.15,0.65±0.13,0.70±0.16 and 0.82±0.18;the levels of HO-1 were 1.34±0.15、1.00±0.12,0.89±0.10,1.50±0.18 and 1.40±0.13,respectively.Significant difference was found between normal group and model group(P＜0.01,P＜0.05);significant difference was also found between the experimental-L,-H groups and model group(P＜0.01,P＜0.05).Conclusion Wumeiwan can inhibit oxidative stress in mice with UC,the mechanisms may be related to adjusted the expression of Keap-1-Nrf2/HO-1 signaling pathway protein in colon.

Objective To establish an evaluation system of pathogen detection rate of hospitalized patients before antimicrobial treatment based on process and outcome indicators,and study its application effect.Methods Hospi-talized patients with therapeutic antimicrobial treatment in a tertiary first-class hospital from July 2022 to June 2023 were selected as the study objects.Difference in process and outcome indicators were compared between before(Ju-ly-December 2022,control group)and after(January-June 2023,intervention group)the implementation of inter-vention in the evaluation system for pathogen detection rate of hospitalized patients before antimicrobial treatment.Results 41 577 and 27 052 hospitalized patients received therapeutic antimicrobial agents were included in the inter-vention group and control group,respectively.Pathogen detection rate and the accurate pathogen detection rate in the intervention group were both higher than those in the control group(74.2％vs 62.8％and 90.3％vs 82.5％,respectively),both with statistically significant differences(both P＜0.001).The goal achievement rate and im-provement rate for pathogen detection rate were 237.5％and 18.2％respectively,the goal achievement rate and im-provement rate for accurate pathogen detection rate were 104.0％and 9.5％respectively.For the process indica-tors,the conformity rate of detection and diagnosis,accurate collection rate,timely transfer rate,acceptance rate of pathogen specimens in the intervention group were all higher than those in the control group,differences were all statistically significant(all P＜0.001).For the outcome indicators,detection rates of targeted indicators and blood culture specimens,pathogen detection rate before treatment of restricted and special grade antimicrobial agent,as well as detection rate of sterile body fluid specimens in the intervention group were all higher than those in the con-trol group,with statistical significance(all P＜0.05).In addition,the positive rate of blood culture specimens in-creased from 18.5％before intervention to 21.7％after intervention,with statistically significant difference(P＜0.05).Conclusion The establishment of indicator evaluation system can improve the detection rate and accurate detection rate of pathogens before antimicrobial treatment,as well as the management quality and connotation of indicators.

OBJECTIVE: To investigate the value of pretreatment inflammatory-nutritional biomarkers in predicting the pathological response of locally advanced rectal cancer (LARC) after neoadjuvant chemotherapy (nCT). METHODS: This retrospective study included eligible participants who underwent nCT followed by radical surgery. Pretreatment inflammatory nutritional biomarkers were calculated within one week prior to nCT. Correlations between biomarkers and pathological responses were analyzed. The cut-off values of the pretreatment biomarkers for predicting non-response were determined using receiver operating characteristic (ROC) curve analysis. The inflammation-nutrition score was calculated using the lymphocyte level, neutrophil-to-lymphocyte ratio (NLR), and prognostic nutritional index (PNI). RESULTS: A total of 235 patients were retrospectively recruited between January 2017 and September 2022. Lower lymphocyte levels, lymphocyte monocyte ratio (LMR), and PNI, and higher NLR and platelet-to-lymphocyte ratio (PLR) were observed in patients without response. Multivariate logistic regression analysis revealed that NLR could independently predict non-response to nCT in patients with LARC. The sensitivity and specificity of the inflammation-nutrition score for predicting nonresponse were 71.2% and 61.7%, respectively. CONCLUSION The pretreatment inflammation-nutrition score is a practical parameter for predicting non-response to nCT in patients with LARC. Patients with high scores were more likely to respond poorly to nCT.
Humans ; Retrospective Studies ; Neoadjuvant Therapy ; Lymphocytes ; Biomarkers ; Rectal Neoplasms/pathology*

BACKGROUND: The benefits of healthy lifestyles are well recognized. However, the extent to which improving unhealthy lifestyles reduces cardiovascular disease (CVD) risk needs to be discussed. We evaluated the impact of lifestyle improvement on CVD incidence using data from the China-PAR project (Prediction for Atherosclerotic Cardiovascular Disease Risk in China). METHODS: A total of 12,588 participants free of CVD were followed up for three visits after the baseline examination. Changes in four lifestyle factors (LFs) (smoking, diet, physical activity, and alcohol consumption) were assessed through questionnaires from the baseline to the first follow-up visit. Cox proportional hazard models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). The risk advancement periods (RAPs: the age difference between exposed and unexposed participants reaching the same incident CVD risk) and population-attributable risk percentage (PAR%) were also calculated. RESULTS: A total of 909 incident CVD cases occurred over a median follow-up of 11.14 years. Compared with maintaining 0-1 healthy LFs, maintaining 3-4 healthy LFs was associated with a 40% risk reduction of incident CVD (HR = 0.60, 95% CI: 0.45-0.79) and delayed CVD risk by 6.31 years (RAP: -6.31 [-9.92, -2.70] years). The PAR% of maintaining 3-4 unhealthy LFs was 22.0% compared to maintaining 0-1 unhealthy LFs. Besides, compared with maintaining two healthy LFs, improving healthy LFs from 2 to 3-4 was associated with a 23% lower risk of CVD (HR = 0.77, 95% CI: 0.60-0.98). CONCLUSIONS Long-term sustenance of healthy lifestyles or improving unhealthy lifestyles can reduce and delay CVD risk.

Humans ; Siblings ; Forensic Medicine ; Forensic Genetics

Humans ; Stroke, Lacunar ; Mendelian Randomization Analysis ; Leukocytes ; Telomere/genetics* ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide

Objective:To analyze the risk factors of bronchopulmonary dysplasia(BPD)in very preterm infants(VPI), and to provide scientific basis for the prevention and treatment of BPD in VPI.Methods:A prospective multicenter study was designed to collect the clinical data of VPI in department of neonatology of 28 hospitals in 7 regions from September 2019 to December 2020.According to the continuous oxygen dependence at 28 days after birth, VPI were divided into non BPD group and BPD group, and the risk factors of BPD in VPI were analyzed.Results:A total of 2 514 cases of VPI including 1 364 cases without BPD and 1 150 cases with BPD were enrolled.The incidence of BPD was 45.7%.The smaller the gestational age and weight, the higher the incidence of BPD( P<0.001). Compared with non BPD group, the average birth age, weight and cesarean section rate in BPD group were lower, and the incidence of male infants, small for gestational age and 5-minute apgar score≤7 were higher( P<0.01). In BPD group, the incidences of neonatal respiratory distress syndrome(NRDS), hemodynamically significant patent ductus arteriosus, retinopathy of prematurity, feeding intolerance, extrauterine growth restriction, grade Ⅲ~Ⅳ intracranial hemorrhage, anemia, early-onset and late-onset sepsis, nosocomial infection, parenteral nutrition-associated cholestasis were higher( P<0.05), the use of pulmonary surfactant(PS), postnatal hormone exposure, anemia and blood transfusion were also higher, and the time of invasive and non-invasive mechanical ventilation, oxygen use and total hospital stay were longer( P<0.001). The time of starting enteral nutrition, cumulative fasting days, days of reaching total enteral nutrition, days of continuous parenteral nutrition, days of reaching 110 kcal/(kg·d) total calorie, days of reaching 110 kcal/(kg·d) oral calorie were longer and the breastfeeding rate was lower in BPD group than those in non BPD group( P<0.001). The cumulative doses of amino acid and fat emulsion during the first week of hospitalization were higher in BPD group( P<0.001). Multivariate Logistic regression analysis showed that NRDS, invasive mechanical ventilation, age of reaching total enteral nutrition, anemia and blood transfusion were the independent risk factors for BPD in VPI, and older gestational age was the protective factor for BPD. Conclusion:Strengthening perinatal management, avoiding premature delivery and severe NRDS, shortening the time of invasive mechanical ventilation, paying attention to enteral nutrition management, reaching whole intestinal feeding as soon as possible, and strictly mastering the indications of blood transfusion are very important to reduce the incidence of BPD in VPI.

The vagina contains at least a billion microbial cells,dominated by lactobacilli.Here we perform metagenomic shotgun sequencing on cervical and fecal samples from a cohort of 516 Chinese women of reproductive age,as well as cervical,fecal,and salivary samples from a second cohort of 632 women.Factors such as pregnancy history,delivery history,cesarean section,and breastfeeding were all more important than menstrual cycle in shaping the microbiome,and such information would be necessary before trying to interpret differences between vagino-cervical micro-biome data.Greater proportion of Bifidobacterium breve was seen with older age at sexual debut.The relative abundance of lactobacilli especially Lactobacillus crispatus was negatively associated with pregnancy history.Potential markers for lack of menstrual regularity,heavy flow,dysmenor-rhea,and contraceptives were also identified.Lactobacilli were rare during breastfeeding or post-menopause.Other features such as mood fluctuations and facial speckles could potentially be predicted from the vagino-cervical microbiome.Gut and salivary microbiomes,plasma vitamins,metals,amino acids,and hormones showed associations with the vagino-cervical microbiome.Our results offer an unprecedented glimpse into the microbiota of the female reproductive tract and call for international collaborations to better understand its long-term health impact other than in the settings of infection or pre-term birth.

Objective: To analyze the clinical epidemiological characteristics including composition of pathogens , clinical characteristics, and disease prognosis acute bacterial meningitis (ABM) in Chinese children. Methods: A retrospective analysis was performed on the clinical and laboratory data of 1 610 children <15 years of age with ABM in 33 tertiary hospitals in China from January 2019 to December 2020. Patients were divided into different groups according to age,<28 days group, 28 days to <3 months group, 3 months to <1 year group, 1-<5 years of age group, 5-<15 years of age group; etiology confirmed group and clinically diagnosed group according to etiology diagnosis. Non-numeric variables were analyzed with the Chi-square test or Fisher's exact test, while non-normal distrituction numeric variables were compared with nonparametric test. Results: Among 1 610 children with ABM, 955 were male and 650 were female (5 cases were not provided with gender information), and the age of onset was 1.5 (0.5, 5.5) months. There were 588 cases age from <28 days, 462 cases age from 28 days to <3 months, 302 cases age from 3 months to <1 year of age group, 156 cases in the 1-<5 years of age and 101 cases in the 5-<15 years of age. The detection rates were 38.8% (95/245) and 31.5% (70/222) of Escherichia coli and 27.8% (68/245) and 35.1% (78/222) of Streptococcus agalactiae in infants younger than 28 days of age and 28 days to 3 months of age; the detection rates of Streptococcus pneumonia, Escherichia coli, and Streptococcus agalactiae were 34.3% (61/178), 14.0% (25/178) and 13.5% (24/178) in the 3 months of age to <1 year of age group; the dominant pathogens were Streptococcus pneumoniae and the detection rate were 67.9% (74/109) and 44.4% (16/36) in the 1-<5 years of age and 5-<15 years of age . There were 9.7% (19/195) strains of Escherichia coli producing ultra-broad-spectrum β-lactamases. The positive rates of cerebrospinal fluid (CSF) culture and blood culture were 32.2% (515/1 598) and 25.0% (400/1 598), while 38.2% (126/330)and 25.3% (21/83) in CSF metagenomics next generation sequencing and Streptococcus pneumoniae antigen detection. There were 4.3% (32/790) cases of which CSF white blood cell counts were normal in etiology confirmed group. Among 1 610 children with ABM, main intracranial imaging complications were subdural effusion and (or) empyema in 349 cases (21.7%), hydrocephalus in 233 cases (14.5%), brain abscess in 178 cases (11.1%), and other cerebrovascular diseases, including encephalomalacia, cerebral infarction, and encephalatrophy, in 174 cases (10.8%). Among the 166 cases (10.3%) with unfavorable outcome, 32 cases (2.0%) died among whom 24 cases died before 1 year of age, and 37 cases (2.3%) had recurrence among whom 25 cases had recurrence within 3 weeks. The incidences of subdural effusion and (or) empyema, brain abscess and ependymitis in the etiology confirmed group were significantly higher than those in the clinically diagnosed group (26.2% (207/790) vs. 17.3% (142/820), 13.0% (103/790) vs. 9.1% (75/820), 4.6% (36/790) vs. 2.7% (22/820), χ²=18.71, 6.20, 4.07, all P<0.05), but there was no significant difference in the unfavorable outcomes, mortility, and recurrence between these 2 groups (all P>0.05). Conclusions: The onset age of ABM in children is usually within 1 year of age, especially <3 months. The common pathogens in infants <3 months of age are Escherichia coli and Streptococcus agalactiae, and the dominant pathogen in infant ≥3 months is Streptococcus pneumoniae. Subdural effusion and (or) empyema and hydrocephalus are common complications. ABM should not be excluded even if CSF white blood cell counts is within normal range. Standardized bacteriological examination should be paid more attention to increase the pathogenic detection rate. Non-culture CSF detection methods may facilitate the pathogenic diagnosis.
Adolescent ; Brain Abscess ; Child ; Child, Preschool ; Escherichia coli ; Female ; Humans ; Hydrocephalus ; Infant ; Infant, Newborn ; Male ; Meningitis, Bacterial/epidemiology* ; Retrospective Studies ; Streptococcus agalactiae ; Streptococcus pneumoniae ; Subdural Effusion ; beta-Lactamases