Objective:To explore the effects of Liuwei Dihuang Wan on the behaviors and Toll-like receptor 4/nuclear factor kappa-B(TLR4/NF-κB) signal transduction pathway of amyloid β-precursor protein/presenilin-1(APP/PS1) double transgenic mice.Methods:Forty 3-month-old female APP/PS1 mice were randomly divided into model group, low-dose group(0.59 g/kg), medium-dose group(1.18 g/kg), high-dose group(2.36 g/kg)of Liuwei Dihuang Wan(gavaged according to grouped doses), and ibuprofen group(0.04 g/kg, gavage) using a random number table method, with 8 mice in each group.Eight 3-month-old wild-type female C57BL/6 mice with matched body weight were used as the control group.The mice in control group and model group were given an equal volume of 0.9% sodium chloride solution by gavage.The gavage administration was twice a day for a continuous period of 3 months.Morris water maze test was used to detect the learning and memory abilities of mice. ELISA was used to detect the serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β(IL-1β) and immunohistochemistry was used to detect the levels of amyloid β-protein (Aβ), glial fibrillary acidic protein(GFAP) and NF-κB in hippocampal tissue.Western blot was used to detect the expression levels of TLR4, myeloid differentiation primary response gene 88(MyD88), and phosphorylated NF-κB(p-NF-κB) proteins in hippocampal tissue.The SPSS 20.0 software was used for data analysis. Multiple group comparisons were conducted by repeated measure ANOVA or one-way ANOVA.Results:The results of repeated measure ANOVA showed that as for the escape latency of the 6 groups of mice, the interaction effect between time and group was significant ( Finteraction=117.219, P<0.001). The escape latencies of mice in the 6 groups on the 5th day were all lower than those on the 1st day (all P<0.05). The escape latencies of mice in the ibuprofen group and the medium-dose and high-dose groups of Liuwei Dihuang Wan were lower than that in the model group from 1st day to 5th day(all P<0.05). On the 3rd to 5th day, the escape latencies of mice in the medium-dose and high-dose groups of Liuwei Dihuang Wan were lower than those in the low-dose group of Liuwei Dihuang Wan (all P<0.05). There were statistically significant differences in the percentage of residence time in the platform quadrant and the numbers of crossing platform among the 6 groups of mice ( F=5.451, 4.824, both P<0.05). The percentage of residence time in the platform quadrant (50.77±5.49)%, (54.39±5.71)%, (51.98±6.12)%), and the numbers of crossing platform((5.9±1.1) times, (6.0±1.3) times, (5.1±0.8) times) in the high-dose and medium-dose groups of Liuwei Dihuang Wan and the ibuprofen group were all higher than those in the model group ((27.32±3.22)%, (2.2±1.0) times )(all P<0.05). The immunohistochemical results showed that there were statistically significant differences in the integrated optical density values of Aβ, GFAP and NF-κB in the hippocampal tissues of 6 groups of mice ( F=57.52, 45.37, 79.10, all P<0.05). The integrated optical density values of Aβ, GFAP and NF-κB in the high-dose and medium-dose groups of Liuwei Dihuang Wan and the ibuprofen group were all lower than those in the model group (all P<0.05). And the integrated optical density values of Aβ, GFAP, and NF-κB in the high-dose and medium-dose groups of Liuwei Dihuang Wan were all lower than those in the low-dose group of Liuwei Dihuang Wan (all P<0.05). There were statistically significant differences in the levels of serum TNF-α and IL-1β detected by ELISA ( F=3.996, 6.395, both P<0.05) and the proteins levels of TLR4, MyD88, and p-NF-κB in hippocampal tissue detected by Western blot among the 6 groups( F=15.710, 3.522, 4.119, all P<0.05). The serum TNF-α and IL-1β levels in the high-dose and medium-dose groups of Liuwei Dihuang Wan and ibuprofen group were all lower than those in the model group (all P<0.05). The serum TNF-α ((18.90±2.33) ng/L, (21.56±2.49) ng/L) and IL-1β ((5.88±0.80) ng/L, (6.75±0.83) ng/L) levels in the high-dose and medium-dose groups of Liuwei Dihuang Wan were lower than those in the low-dose group ((30.77±2.89) ng/L, (9.11±1.27) ng/L) (all P<0.05). The protein expression levels of TLR4, MyD88, and p-NF-κB in the hippocampus of the high-dose and medium-dose groups of Liuwei Dihuang Wan and ibuprofen group were lower than those of the model group (all P<0.05). The protein expression levels of TLR4 ((0.254±0.091), (0.318±0.122)), MyD88 ((0.229±0.077), (0.386±0.119)), and p-NF-κB ((0.412±0.188), (0.358±0.119)) in the hippocampus of the high-dose and medium-dose groups of Liuwei Dihuang Wan were lower than those of the low-dose group ((0.617±0.172), (0.672±0.166), (0.799±0.227)) (all P<0.05). Conclusion:Liuwei Dihuang Wan can significantly alleviate learning and memory impairment in Alzheimer's disease model mice, possibly by inhibiting TLR4/NF-κB signal pathway, reducing TNF-α and IL-1β expression, thereby alleviate central immune inflammatory response and exert anti Alzheimer's disease effects.

Objective In this study,we analyzed the transcriptome sequences of Kupffer cells exposed to simulated microgravity for 3 d and conducted biological experiments to determine how microgravity initiates apoptosis in Kupffer cells. Methods Rotary cell culture system was used to construct a simulated microgravity model.GO and KEGG analyses were conducted using the DAVID database.GSEA was performed using the R language.The STRING database was used to conduct PPI analysis.qPCR was used to measure the IL1B,TNFA,CASP3,CASP9,and BCL2L11 mRNA expressions.Western Blotting was performed to detect the level of proteins CASP3 and CASP 9.Flow cytometry was used to detect apoptosis and mitochondrial membrane cells.Transmission electron microscopy was used to detect changes in the ultrastructure of Kupffer cells. Results Transcriptome Sequencing indicated that simulated microgravity affected apoptosis and the inflammatory state of Kupffer cells.Simulated microgravity improved the CASP3,CASP9,and BCL2L11 expressions in Kupffer cells.Annexin-V/PI and JC-1 assays showed that simulated microgravity promoted apoptosis in Kupffer cells.Simulated microgravity causes M1 polarization in Kupffer cells. Conclusion Our study found that simulated microgravity facilitated the apoptosis of Kupffer cells through the mitochondrial pathway and activated Kupffer cells into M1 polarization,which can secrete TNFA to promote apoptosis.

This article seeks to delve into the correlation between pituitary neuroendocrine tumors(PitNET)and neuropsychiatric disorders while summarizing the most recent advancements in related research.Some patients with PitNET,benign tumors arising from pituitary gland cells,may develop specific clinical symptoms due to either tumor compression or abnormal hormone secretion.In recent years,investigators have identified a significant association between PitNET and neurological as well as psychiatric disorders.Patients with PitNET frequently manifest neurological and psychiatric symptoms,including depression,anxiety,and cognitive impairment,significantly impacting their quality of life and prognosis.These symptoms may be associated with distorted body image,hormonal imbalances,and inadequate treatment.The holistic approach to PitNET encompasses surgical intervention,radiation therapy,and drug therapy,each with its distinct set of advantages and drawbacks.Presently,transsphenoidal resection stands out as the most frequently employed method in treating PitNET to ameliorate the patient's neurological and psychiatric disorders.However,the use of dopamine agonists(DAs)in the treatment of prolactin(PRL)tumors and growth hormone(GH)adenomas may potentially induce or exacerbate neurological and psychiatric symptoms.The impact of radiation therapy on PitNET patients varies depending on the radiation dose and treatment area.Given that both the PitNET disease itself and its treatment may lead to neurological and psychiatric disorders,it is essential to assess and address the neurological and psychiatric status of all PitNET patients.Careful consideration should be given to PitNET patients with neurological and psychiatric disorders to determine whether these issues stem from dopamine agonist(DAs)treatment.The primary consideration should be given to patients with PRL microadenomas with normal PRL levels to minimize the dose of bromocriptine or cabergoline to the most effective level or even discontinue the medication with subsequent follow-up.Caution is advised when considering the discontinuation or reduction of medication for PRL large adenomas.A gradual reduction approach may be undertaken based on related factors such as PRL levels and tumor size.Close follow-up through monitoring patient PRL levels and enhanced pituitary MRI is crucial to prevent tumor enlargement following the reduction of medication.While some PitNET patients have experienced improvement or recovery from neurological and psychiatric disorders through personalized comprehensive treatment,it is important to note that certain patients may exhibit irreversible symptoms.Currently,research on the combination of PitNET and neuropsychiatric disorders remains relatively limited.Moving forward,it is imperative to delve deeper into its pathogenesis,aiming to enhance diagnostic methods for neuropsychiatric disorders in PitNET patients.This includes refining and updating diagnostic criteria and expanding intervention methods.These efforts are crucial in mitigating the incidence of PitNET in conjunction with neuropsychiatric disorders,ultimately improving the overall quality of life for patients.

A method based on ultra-high performance liquid chromatography coupled with triple quadrupole linear ion trap-tandem mass spectrometry(UHPLC-QTRAP-MS/MS) was developed for the simultaneous determination of 41 bioactive constituents of flavonoids, organic acids, nucleosides, and amino acids in Lysimachiae Herba. The content of multiple bioactive constituents was compared among the samples from different habitats. The chromatographic separation was performed in a Waters XBridge®C_(18) column(4.6 mm×100 mm, 3.5 μm) at 30 ℃. The gradient elution was performed with 0.4% methanol(A)-formic acid water(B) as the mobile phase at a flow rate of 0.8 mL·min~(-1), and the multiple-reaction monitoring(MRM) mode was adopted. According to the content of 41 constituents, hierarchical cluster analysis(HCA), orthogonal partial least squares discriminant analysis(OPLS-DA), and gray relational analysis(GRA) were perfomed to comprehensively evaluate the samples from different habitats. The results showed that the 41 constituents exhibited good linear relationship within the tested concentration ranges, with the correlation coefficients(r) greater than 0.999 4. The method featured good precision, repeatability, and stability with the relative standard deviations(RSDs) less than 5.0%. The average recoveries of the 41 constituents ranged from 98.06% to 101.9%, with the RSDs of 0.62%-4.6%. HCA and OPLS-DA separated 48 batches of Lysimachiae Herba samples from different habitats into three categories: the producing areas in Sichuan and Chongqing, the producing areas in Jiangsu, Zhejiang, and Jiangxi, and the producing areas in Guizhou. The content of 41 constituents varied among the Lysimachiae Herba samples from different habitats. The GRA results revealed that the Lysimachiae Herba sample from Nanchong City, Sichuan Province had the best comprehensive quality. The method developed in this study was accurate and reliable and thus can be used for comprehensive evaluation of Lysimachiae Herba quality and provide basic information for the selection of habitats.
Tandem Mass Spectrometry/methods* ; Multivariate Analysis ; Chromatography, High Pressure Liquid/methods* ; Drugs, Chinese Herbal/chemistry* ; Amino Acids/analysis*

A quantitative analysis of multi-components by single marker method (QAMS) was established for simultaneous determination of gallic acid, protocatechuic acid, catechin, epicatechin, p-coumaric acid, ferulic acid and phloridzin in Cynomorium songaricum Rupr. The analysis was performed on a ChromCore Polae C₁₈ column (250 mm×4.6 mm, 5 μm) , with a mobile phase consisting of acetonitrile-0.3% phosphoric acid aqueous solution for gradient elution. The volume flow rate, column temperature and sample injection volume were set at 1.0 mL·min^-1, 25 ℃, and 40 µL, respectively. The relative correction factors of gallic acid and protocatechuic acid, catechin, epicatechin, p-coumaric acid, ferulic acid and phloridzin were calculated and the durability was also investigated. The contents of these seven compounds in fourteen batches of Cynomorium songaricum Rupr. from different producing areas or batches were determined by external standard method (ESM) and quantitative analysis of multi-components with a single-marker method (QAMS), respectively. SPSS and Origin Pro software were employed for principal components assay, similarity evaluation and cluster analysis. The specificity, precision, repeatability, stability and linear range (R² > 0.999 0) of the seven components were all good. The average recovery was 96.89%-103.16% and RSD was 0.55%-2.76%. Then gallic acid was chosen as internal reference for calculation the correction factors for the other six components, the average relative correction factors of protocatechuic acid, catechin, epicatechin, p-coumaric acid, ferulic acid and phloridzin were 1.141 5, 0.200 5, 0.208 0, 2.361 9, 1.867 7, 0.204 6, respectively. Student's test results showed that there was no significant difference between the data analyzed by ESM and the data obtained from QAMS method. Through data visualization analysis, the contents of gallic acid, protocatechuic acid, catechin and epicatechin in different samples were significantly different, indicating that these four components might be the main quality markers of Cynomorium songaricum Rupr. for gaving more contributes to the principal components. The cluster analysis showed that samples from Xinjiang and samples from Inner Mongolia were clustered in significantly different categories, meaning that the quality of Cynomorium songaricum Rupr. had great relation with producing areas. The method of QAMS established in this study is a simple, economical and practical method with scientific and applicable charactistics for evaluating the quality of Cynomorium songaricum Rupr. efficiently and scientifically.

Objective: To examine the association of greenness exposure with waist circumference (WC) and central obesity in older adults in China. Methods: Based on the cross-sectional data from the Chinese Longitudinal Healthy Longevity Survey in 2017-2018, 14 056 participants aged 65 years and over were included. Demographic characteristics, lifestyle, WC, and other information were collected through a questionnaire and physical examination. Based on the satellite monitoring data of moderate-resolution imaging spectroradiometer (MODIS) provided by NASA, the annual mean of normalized difference vegetation index (NDVI) within a radius of 1 000 meters was obtained as the measurement value of greenness exposure. Multivariate linear regression model, multivariate logistic regression model, and restricted cubic splines (RCS) model were used to analyze the association and dose-response relationship between greenness exposure and WC and central obesity in older adults in China. Results: A total of 14 056 participants were enrolled with a median age of 84.0 years [IQR: 75.0-94.0 years]. About 45.0% (6 330) of them were male and 48.6% (5 853) were illiterate. There were 10 964 (78.0%) participants from rural. The mean of WC was (84.4±10.8) cm. Central obesity accounted for 60.2% (8 465), and the NDVI range was (-0.06, 0.78). After adjusting for confounding factors, the multivariate linear regression model showed that the change value of WC in the urban group [β (95%CI):-0.49 (-0.93, -0.06)] was smaller than that in the rural [-0.78 (-0.98, -0.58)] for every 0.1 unit increase in NDVI (P_interaction=0.022). Compared with the Q₁ group in NDVI, WC of Q₂ and Q₃ groups in rural decreased, and the β (95%CI) values were-1.74 (-2.5, -0.98) and-2.78 (-3.55, -2.00), respectively. The multivariate logistic regression model showed that after adjusting for confounding factors, the risk of central obesity decreased for urban and rural older adults with an increase of 0.1 unit in NDVI, and the OR (95%CI) values were 0.87 (0.80, 0.95) and 0.86 (0.82, 0.89), respectively (P_interaction=0.284). Compared with the Q₁ group in NDVI, the risk of central obesity in the Q₂ and Q₃ groups in rural was lower, and the OR (95%CI) values were 0.68 (0.58, 0.80) and 0.57 (0.49, 0.68), respectively. The results of the multivariate regression model with RCS showed that there was a non-linear association of NDVI with WC (P_nonlinear=0.006) and central obesity (P_nonlinear=0.025). Conclusion: Greenness exposure is negatively associated with WC and central obesity in older adults in China.

Objective: To analyze the prevalence and the risk factors of fungal sepsis in 25 neonatal intensive care units (NICU) among preterm infants in China, and to provide a basis for preventive strategies of fungal sepsis. Methods: This was a second-analysis of the data from the "reduction of infection in neonatal intensive care units using the evidence-based practice for improving quality" study. The current status of fungal sepsis of the 24 731 preterm infants with the gestational age of <34⁺⁰ weeks, who were admitted to 25 participating NICU within 7 days of birth between May 2015 and April 2018 were retrospectively analyzed. These preterm infants were divided into the fungal sepsis group and the without fungal sepsis group according to whether they developed fungal sepsis to analyze the incidences and the microbiology of fungal sepsis. Chi-square test was used to compare the incidences of fungal sepsis in preterm infants with different gestational ages and birth weights and in different NICU. Multivariate Logistic regression analysis was used to study the outcomes of preterm infants with fungal sepsis, which were further compared with those of preterm infants without fungal sepsis. The 144 preterm infants in the fungal sepsis group were matched with 288 preterm infants in the non-fungal sepsis group by propensity score-matched method. Univariate and multivariate Logistic regression analysis were used to analyze the risk factors of fungal sepsis. Results: In all, 166 (0.7%) of the 24 731 preterm infants developed fungal sepsis, with the gestational age of (29.7±2.0) weeks and the birth weight of (1 300±293) g. The incidence of fungal sepsis increased with decreasing gestational age and birth weight (both P<0.001). The preterm infants with gestational age of <32 weeks accounted for 87.3% (145/166). The incidence of fungal sepsis was 1.0% (117/11 438) in very preterm infants and 2.0% (28/1 401) in extremely preterm infants, and was 1.3% (103/8 060) in very low birth weight infants and 1.7% (21/1 211) in extremely low birth weight infants, respectively. There was no fungal sepsis in 3 NICU, and the incidences in the other 22 NICU ranged from 0.7% (10/1 397) to 2.9% (21/724), with significant statistical difference (P<0.001). The pathogens were mainly Candida (150/166, 90.4%), including 59 cases of Candida albicans and 91 cases of non-Candida albicans, of which Candida parapsilosis was the most common (41 cases). Fungal sepsis was independently associated with increased risk of moderate to severe bronchopulmonary dysplasia (BPD) (adjusted OR 1.52, 95%CI 1.04-2.22, P=0.030) and severe retinopathy of prematurity (ROP) (adjusted OR 2.55, 95%CI 1.12-5.80, P=0.025). Previous broad spectrum antibiotics exposure (adjusted OR=2.50, 95%CI 1.50-4.17, P<0.001), prolonged use of central line (adjusted OR=1.05, 95%CI 1.03-1.08, P<0.001) and previous total parenteral nutrition (TPN) duration (adjusted OR=1.04, 95%CI 1.02-1.06, P<0.001) were all independently associated with increasing risk of fungal sepsis. Conclusions: Candida albicans and Candida parapsilosis are the main pathogens of fungal sepsis among preterm infants in Chinese NICU. Preterm infants with fungal sepsis are at increased risk of moderate to severe BPD and severe ROP. Previous broad spectrum antibiotics exposure, prolonged use of central line and prolonged duration of TPN will increase the risk of fungal sepsis. Ongoing initiatives are needed to reduce fungal sepsis based on these risk factors.
Infant ; Infant, Newborn ; Humans ; Birth Weight ; Intensive Care Units, Neonatal ; Retrospective Studies ; Tertiary Care Centers ; Infant, Extremely Low Birth Weight ; Gestational Age ; Infant, Extremely Premature ; Sepsis/epidemiology* ; Retinopathy of Prematurity/epidemiology* ; Bronchopulmonary Dysplasia/epidemiology*

A comprehensive analytical method based on ultra-fast liquid chromatography coupled with triple quadrupole/linear ion trap tandem mass spectrometry(UFLC-QTRAP-MS/MS) was established for simultaneous determination of the content of 45 bioactive constituents including flavonoids, alkaloids, amino acids, phenolic acids, and nucleosides in Epimedium brevicornum. The multiple bioactive constituents in leaves, petioles, stems and rhizomes of E. brevicornum were analyzed. The gradient elution was performed at 30 ℃ in an XBridge~® C_(18) column(4.6 mm×100 mm, 3.5 μm) with 0.4% formic acid aqueous solution-acetonitrile as the mobile phase at a flow rate of 0.8 mL·min~(-1). Single factor experiment and response surface methodology were employed to optimize the extraction conditions. Multivariate statistical analyses including systematic cluster analysis(SCA), principal component analysis(PCA), partial least squares discriminant analysis(PLS-DA), and one-way analysis of variance(One-way ANOVA) were carried out to classify the samples from different parts and identify different constituents. Grey relation analysis(GRA) and entropy weight-TOPSIS analysis were performed to build a multi-index comprehensive evaluation model for different parts of E. brevicornum. The results showed that there was a good relationship between the mass concentrations of 45 constituents and the corresponding peak areas, with the correlation coefficients(r) not less than 0.999 0. The precision, repeatability, and stability of the established method were good for all the target constituents in this study, with the relative standard deviations(RSDs) less than 5.0%(0.62%-4.9%) and the average recovery of 94.51%-105.7%. The above results indicated that the bioactive constituents varied in different parts of E. brevicornum, and the overall quality followed the trend of leaves > petioles > rhizomes > stems. This study verified the rationality of the Chinese Pharmacopoeia(2020 edition) stipulating that the medicinal part of E. brevicornum is the leaf. Moreover, our study indicated that the rhizome had the potential for medicinal development. The established method was accurate and reliable, which can be used to comprehensive evaluate and control the quality of E. brevicornum. This study provides data reference for clarifying the medicinal parts and rationally utilizing the resources of E. brevicornum.
Chromatography, High Pressure Liquid ; Epimedium ; Tandem Mass Spectrometry ; Chromatography, Liquid ; Multivariate Analysis

BACKGROUND: Butylphthalide (NBP) and edaravone (EDV) injection are common acute ischemic stroke medications in China, but there is a lack of large real-world safety studies on them. This study aimed to determine the incidence of adverse events, detect relevant safety signals, and assess the risk factors associated with these medications in real-world populations. METHODS: In this study, data of acute ischemic stroke patients were extracted from the electronic medical record database of six tertiary hospitals between January 2019 and August 2021. Baseline confounders were eliminated using propensity score matching. The drugs' safety was estimated by comparing the results of 24 laboratory tests standards on liver function, kidney function, lipid level, and coagulation function. The drugs' relative risk was estimated by logistic regression. A third group with patients who did not receive NBP or EDV was constructed as a reference. Prescription sequence symmetry analysis was used to evaluate the associations between adverse events and NBP and EDV, respectively. RESULTS: 81,292 patients were included in this study. After propensity score matching, the NBP, EDV, and third groups with 727 patients in each group. Among the 15 test items, the incidence of adverse events was lower in the NBP group than in the EDV group, and the differences were statistically significant. The multivariate logistic regression equation revealed that NBP injection was not a promoting factor for abnormal laboratory test results, whereas EDV had statistically significant effects on aspartate transaminase, low-density lipoprotein cholesterol and total cholesterol. Prescription sequence symmetry analysis showed that NBP had a weak correlation with abnormal platelet count. EDV had a positive signal associated with abnormal results in gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, prothrombin time, and platelet count. CONCLUSIONS In a large real-world population, NBP has a lower incidence of adverse events and a better safety profile than EDV or other usual medications.

OBJECTIVES: To investigate the incidence of extrauterine growth retardation (EUGR) and its risk factors in very preterm infants (VPIs) during hospitalization in China. METHODS: A prospective multicenter study was performed on the medical data of 2 514 VPIs who were hospitalized in the department of neonatology in 28 hospitals from 7 areas of China between September 2019 and December 2020. According to the presence or absence of EUGR based on the evaluation of body weight at the corrected gestational age of 36 weeks or at discharge, the VPIs were classified to two groups: EUGR group (n=1 189) and non-EUGR (n=1 325). The clinical features were compared between the two groups, and the incidence of EUGR and risk factors for EUGR were examined. RESULTS: The incidence of EUGR was 47.30% (1 189/2 514) evaluated by weight. The multivariate logistic regression analysis showed that higher weight growth velocity after regaining birth weight and higher cumulative calorie intake during the first week of hospitalization were protective factors against EUGR (P<0.05), while small-for-gestational-age birth, prolonged time to the initiation of total enteral feeding, prolonged cumulative fasting time, lower breast milk intake before starting human milk fortifiers, prolonged time to the initiation of full fortified feeding, and moderate-to-severe bronchopulmonary dysplasia were risk factors for EUGR (P<0.05). CONCLUSIONS It is crucial to reduce the incidence of EUGR by achieving total enteral feeding as early as possible, strengthening breastfeeding, increasing calorie intake in the first week after birth, improving the velocity of weight gain, and preventing moderate-severe bronchopulmonary dysplasia in VPIs.
Female ; Fetal Growth Retardation ; Gestational Age ; Hospitalization ; Humans ; Incidence ; Infant ; Infant, Newborn ; Infant, Premature ; Infant, Very Low Birth Weight ; Prospective Studies ; Risk Factors