This study used the natural flavonoid compound silybin as the parent compound and synthesized 16 silybin derivatives through oxidative dehydrogenation, alkylation, selective demethylation, and acylation. The structures of these derivatives were confirmed by 1H NMR, 13C NMR, and MS. All derivatives were found to be new compounds never reported in previous literature. Using gastric cancer cell line SGC-7901 and human glioblastoma cell line LN-229, the in vitro anti-tumor activity of the novel silybin derivative was determined through MTT assay with lapatinib as the positive control. The experimental results indicate that the synthesized novel silybin derivatives have a certain degree of anti-proliferative effect on two types of cancer cells, with compounds I2 and I14 showing strong anti-proliferative activity against LN-229 and SGC-7901 cells.

ObjectiveTo explore the effect of Qingre Huayu Jianpi prescription （QHJ） on colitis-associated colorectal cancer （CAC） in mice， and its related mechanism. MethodC57BL/6 mice were randomly divided into four groups including the normal， model， QHJ low-dose （QHJ-L， 10 g·kg^-1）， and QHJ high-dose （QHJ-H， 40 g·kg^-1） groups. Azoxymethane （AOM） and dextran sodium sulfate （DSS） were combined to chemically build a CAC mouse model for 14 weeks. Each drug group was given intragastrically from the 5^th week to the 14^th week， once per day. An equal volume of water was fed to the normal and model groups. The mouse survival rate， colon length， weight， and pathological alterations were assessed. The protein expressions of Wnt-3a protein signaling （Wnt3a）， β-catenin， Non-phosphor-β-catenin （Non-p-β-catenin）， and cholesterol-binding glycoproteins 133 （CD133） were detected by Western blot. The localization and expression of the cluster of differentiation （CD） 80 and CD11 antigen-like family member B （CD11b） were detected by immunohistochemistry （IHC）. The colon organoids derived from CAC mice were isolated and cultured to detect the expression of Wnt signaling pathway-related proteins. ResultThe survival rate of the CAC mice was improved by QHJ treatment and the number of colon tumors was inhibited significantly. Compared with those in the normal group， the expression levels of Wnt3a， β-catenin， Non-p-β-catenin， and CD133 in colon tissues in the model group were significantly increased （P<0.05， P<0.01）. Compared with those in the model group， the levels of Wnt3a and β-catenin in the QHJ-L group were significantly decreased （P<0.01）， and the protein levels of Wnt3a， β-catenin， Non-p-β-catenin， and CD133 in the QHJ-H group were significantly decreased （P<0.05， P<0.01）. Meanwhile， the expression level of CD11b in the model group was significantly increased compared with that in the normal group while the CD80 level was significantly decreased （P<0.05， P<0.01）. Compared with those in the model group， CD11b in QHJ-L and QHJ-H groups was significantly decreased， and CD80 was significantly increased（P<0.05， P<0.01）. The expressions of Non-p-β-catenin and CD133 in colonic organoids of CAC model mice were significantly increased， while QHJ treatment could inhibit the expressions of Non-p-β-catenin and CD133 in colonic organoids （P<0.01）. ConclusionQHJ could inhibit the inflammation-cancer development in CAC mice， the mechanism of which might be related to regulating the microenvironment and inhibiting the over-activation of Wnt signaling.

Background Polycyclic aromatic hydrocarbons (PAHs), one of the main components of fine particulate matter (PM_2.5), have a certain impact on ambient air quality, and long-term exposure to PAHs may pose potential health risks to human beings. Objective To identify the distribution characteristics and sources of PAHs in atmospheric PM_2.5 in a district of Taizhou City from 2019 to 2021, and to evaluate the health risks of PAHs to the population in the area through the inhalation pathway. Methods From 2019 to 2021, air PM_2.5 sampling was carried out at a state-controlled surveillance point in a district of Taizhou City for 7 consecutive days on the 10th-16th of each month, the sampling time was 24 h·d⁻¹, and the sampling flow rate was 100 L·min⁻¹. PM_2.5 mass concentration was calculated by gravimetric method. A total of 16 PAHs were determined by ultrasonic extraction-liquid chromatography. Kruskal-Wallis H test was used to compare the distribution charac teristics of PAHs concentrations by years and seasons, characteristic ratio and principal component analysis (PCA) was used to analyze their sources, and a lifetime carcinogenic risk (ILCR) model was used to assess the health risk of PAHs. Results From 2019 to 2021, the annual average concentrations [M (P₂₅, P₇₅)] of ∑PAHs in atmospheric PM_2.5 in the selected district of Taizhou City were 6.52 (2.46, 10.59), 8.52 (4.56, 12.29), and 3.72 (1.51, 7.11) ng·m⁻³, respectively, and the annual benzo[a]pyrene (BaP) excess rates (national limit: 1 ng·m⁻³) were 27.38% (23/84), 47.62% (40/84), and 19.04% (16/84), respectively, both presenting 2020> 2019 > 2021 (P<0.001, P<0.05). The ∑PAHs concentration distribution showed a seasonal variation, with the highest value in winter and the lowest value in summer (P<0.05). Among the atmospheric PM_2.5 samples, the proportion of 5-ring PAHs was the highest, the proportion of 2-3-ring PAHs was the lowest; the proportion of 2-4-ring PAHs showed a yearly upward trend, and the proportion of 5-6-ring PAHs showed yearly downward trend (P<0.05). The characteristic ratio and PCA results suggested that the sources of sampled PAHs were mainly mixed sources such as dust, fossil fuel (natural gas), coal combustion, industrial emissions, and motor vehicle exhaust emissions. The ILCR (R_ILCR) of PAHs by inhalation for men, women, and children were 1.83×10⁻⁶, 2.35×10⁻⁶, and 2.04×10⁻⁶, respectively, and the annual average R_ILCR was 2.07×10⁻⁶, all greater than 1×10⁻⁶. Conclusion For the sampled time period, the main sources of PAHs pollution in atmospheric PM_2.5 in the target district of Taizhou City are dust, fossil fuel (natural gas), coal combustion, industrial emissions, motor vehicle emissions, etc., and PAHs may have a potential carcinogenic risk to local residents.

Objective To investigate the predictive value of lactate/albumin ratio(LAR),interleukin-6(IL-6)and CD4+T lymphocyte count in 28-day mortality in patients with severe pneumonia and sepsis.Methods A total of 73 patients with severe pneumonia and sepsis admitted to the Respiratory Intensive Care Unit(RICU)of Zhengzhou Central Hospital Affiliated to Zhengzhou University from January 2022 to June 2023 were enrolled and divided into the survival group(n=43)and the death group(n=30)according to their 28-day outcomes.The clinical data of the patients were collected from their electronic medical records,including age,gender,comorbidities with hypertension,diabetes,and coronary artery heart disease(CHD),as well as sequential organ failure assessment(SOFA)score,acute physiology and chronic health evaluation Ⅱ(APACHE Ⅱ)score,mean arterial pressure(MAP),confusion,uremia,respiratory rate,blood pressure,age ≥65 years(CURB-65)score,total bilirubin(Tbil),serum creatinine(Scr),platelet count(PLT),white blood cell(WBC)count,procalcitonin(PCT),and C-reactive protein(CRP)at admission to RICU.On the 1st,3rd,and 7th day after admission to RICU,the patients'arterial blood was drawn,and the lactate level was detected by a fully automated blood gas analyzer.The peripheral venous blood was drawn,and the serum albumin and IL-6 levels were detected by enzyme-linked immunosorbent assay,and the CD4+T lymphocyte subset count was measured by flow cytometry.The LAR of patients on the 1st,3rd and 7th day was calculated.The clinical data of the patients and the LAR,IL-6 level and CD4+T lymphocyte count on the 1st,3rd,and 7th day were compared between the two groups.The influencing factors of 28-day mortality in patients with severe pneumonia and sepsis were analyzed by logistic regression,and the predictive value of each influencing factor on the 28-day mortality in patients with severe pneumonia and sepsis was evaluated by the receiver operating characteristic(ROC)curve.Results There was no significant difference in gender,age,proportions of comorbidities with hypertension,diabetes and CHD,length of stay in RICU,and Tbil,MAP,PLT,Scr,WBC,PCT and CRP at admission to RICU(P＞0.05).The APACHE Ⅱ and CURB-65 scores of the patients in the death group were significantly higher than those in the survival group(P＜0.05).On the 1st,3rd and 7th day,the CD4+T lymphocyte count in the death group was significantly lower than that in the survival group,while the SOFA score was significantly higher than that in the survival group(P＜0.05).On the first day,there was no significant difference in the LAR and IL-6 level be-tween the death group and the survival group(P＞0.05).However,on the 3rd and 7th day,the LAR and IL-6 level in the death group were significantly higher than those in the survival group(P＜0.05).The LAR,IL-6 level and SOFA score on the 3rd and 7th day in the survival group were significantly lower than those on the 1st day,and these indicators on the 7th day were sig-nificantly lower than those on the 3rd day(P＜0.05);the CD4+T lymphocyte count on the 3rd and 7th day was significantly higher than that on the 1st day(P＜0.05),while it showed no significant difference on the 7th and 3r day(P＞0.05).The IL-6 level on the 7th day in the death group was significantly lower than that on the 1st and 3rd day(P＜0.05),while there was no significant difference in IL-6 level on the 1st day compared with the 3r day(P＞0.05);moreover,there was no significant difference in LAR,CD4+T lymphocyte count and SOFA score between each time point(P＞0.05).Pearson correlation analy-sis showed that on the 3rd day,the LAR and IL-6 level were significantly positively correlated with the SOFA score in patients with severe pneumonia and sepsis(r=0.385,0.394;P＜0.05).On the 7th day,the LAR and IL-6 level were also significantly positively correlated with the SOFA score(r=0.418,0.402;P＜0.05).On the 3 rd and 7 th day,CD4+T lymphocyte count was significantly negatively correlated with the SOFA score(r=-0.451,-0.454;P＜0.05).Logistic regression analysis showed that the APACHE Ⅱ score,LAR,IL-6 level and CD4+T lymphocyte count on the 3rd day,and the IL-6 level and CD4+T lym-phocyte count on the 7th day were the influencing factors for 28-day mortality in patients with severe pneumonia and sepsis(P＜0.05).The ROC curve showed that the APACHE Ⅱ score,LAR,IL-6 level and CD4+T lymphocyte count on the 3rd day and the combination of the three,IL-6 level and CD4+T lymphocyte count on the 7th day and the combination of the two had certain predictive value for the 28-day mortality in patients with severe pneumonia and sepsis(P＜0.05).The area under the ROC curve(AUC)of LAR,IL-6 level and CD4+T lymphocyte count on the 3rd day combined to predict 28-day mortality in patients with severe pneumonia and sepsis was 0.891,and the AUC of APACHE Ⅱ score for predicting 28-day mortality in pa-tients with severe pneumonia and sepsis was 0.769.The AUC values of LAR,IL-6 level and CD4+T lymphocyte count on the 3rd day for predicting 28-day mortality in patients with severe pneumonia and sepsis were 0.795,0.757 and 0.770,respective-ly,and the AUC values of IL-6 level and CD4+T lymphocyte count on the 7th day and their combination for predicting 28-day mortality in patients with severe pneumonia and sepsis were 0.743,0.802 and 0.888,respectively.Conclusion The 3-day LAR,IL-6 level and CD4+T lymphocyte count,and the 7-day IL-6 level and CD4+T lymphocyte count after admission are re-lated to the 28-day mortality in patients with severe pneumonia and sepsis.The combined LAR,IL-6 level and CD4+T lympho-cyte count on the 3rd day can better assess the severity and prognosis of patients.

[Objective]To evaluate the changes in cardiac structure and ventricular function in patients with Ander-son-Fabry Disease(AFD)by two-dimensional speckle tracking echocardiography(2D-STE)and to explore the character-istics of their early cardiac involvement.[Methods]All 45 patients diagnosed with AFD in this observational study under-went routine ultrasonic cardiogram(UCG)examination and 2D-STE.The patients were divided into 2 groups based on UCG measurements:with left ventricular hypertrophy(interventricular septum or posterior left ventricular wall thickness≥12 mm)and without left ventricular hypertrophy.TomTec software was used to analyze the echocardiographic images,then the baseline data,UCG routine parameters and myocardial strain of the two groups were compared.[Results]The study in-cluded 27 males(60.0%)and 18 females(40.0%),with an average age of(32.33±16.11),17 cases(37.78%)with left ventricular hypertrophy and 28 cases(62.22%)without left ventricular hypertrophy.All patients had normal left ventricu-lar ejection fraction(LVEF)(>50%).Compared with those without left ventricular hypertrophy,patients with left ventric-ular hypertrophy had significantly more target organ involvement,significantly higher E/A and average E/E' ratios(P<0.05).No statistical difference was found in global and segmental longitudinal strain(LS),circumferential strain(CS)and radial strain(RS)of the endocardium and myocardium between the two groups(all P>0.05).There were lower abso-lute values of global and segmental LS and CS in the myocardium than in the endocardium(all P<0.05),and higher abso-lute values of LS and RS in the mid segment than in the basal and apical segments(all P<0.05).[Conclusions]There is no significant association between early systolic dysfunction and left ventricular wall thickness.2D-STE strain can be used to detect AFD in the early stage.Ventricular wall myocardium exhibits more serious involvement than endocardium and mid segment was less involved than the apical and basal segments.

Diabetic peripheral neuropathy is a common diabetic complication.Presently,our understanding of its pathogenesis is incomplete,and there are no effective treatment options.In-depth research requires the use of animal experiments.The criteria for modeling success and the evaluation method for peripheral nerve function recovery are critical for carrying out animal experiments into type 2 diabetic peripheral neuropathy.However,but there has been a lack of systematic interrogation and analysis of the evaluation method used with type 2 diabetic peripheral neuropathy models.Therefore,the author reviewed the recent data,summarized and analyzed the evaluation method used for animal models of type 2 diabetic peripheral neuropathy of small and large nerve fibers,and proposed future directions for development,providing a reference for related research.

Objective To observe the analgesic effects of mild moxibustion on primary dysmenorrhea(PD)rats with cold and dampness stagnation syndrome and its effect on BDNF/TrkB signaling pathway in hypothalamus;To explore its mechanism for the treatment of PD.Methods A total of 32 Wistar non-pregnant female rats were randomly divided into blank group,model group,Western medicine group and mild moxibustion group,with 8 rats in each group.Except for the blank group,the other groups received estradiol benzoate intraperitoneal injection combined with ice bath treatment + oxytocin intraperitoneal injection to establish PD with cold and dampness stagnation syndrome model.The mild moxibustion group received treatment at"Shenque"and"Guanyuan"from the eighth day of modeling for 10 min,and the Western medicine group was given ibuprofen solution intragastically for 4 days.The latency period of rats twisting was observed and the twisting score was calculated,Western blot and PCR were used to detect the expressions of c-fos,BDNF,TrkB protein and mRNA in hypothalamic tissue.Results Compared with the blank group,the model group showed a shortened latency period and an increased twisting score(P<0.01),the expressions of c-fos,BDNF,TrkB protein and mRNA in hypothalamic tissue increased(P<0.01,P<0.05).Compared with the model group,the mild moxibustion group had a longer latency period and lower twisting score(P<0.01),while the expressions of c-fos,BDNF,TrkB protein and mRNA in hypothalamic tissue increased(P<0.01,P<0.05).Conclusion Mild moxibustion may effectively improve the pain state of PD rats with cold and dampness stagnation syndrome.This mechanism may be related to downregulating c-fos expression,inhibiting BDNF/TrkB signaling pathway activation,thereby inhibiting pain signal transmission,regulating pain occurrence and maintenance.

More than 80% of the world’s populations are at risk of vector-borne diseases, with mosquito-borne diseases as a significant global public health problem. Mosquito populations control is critical to interrupting the transmission of mosquito-borne diseases. This review summarizes the physical attributes, smell, vision, touch, and hearing of mosquitoes to unravel the preferences of female mosquitoes, and describes the mechanisms underlying the best male mating by female mosquitoes, so as to provide new insights into management of mosquito-borne diseases.

Objective To propose strategies for developing clinical predictive models,aiming to assist researchers in conducting standardized clinical prediction model studies.Methods Literature review was conducted to summarize the operational steps and content for developing clinical predictive models.Then,a methodological framework was summarized and refined through expert consultation.Results The 11-step methodological framework for developing clinical predictive models was obtained by synthesizing the experience of 456 clinical predictive modeling studies and expert consultation,and the details were analyzed and elaborated.Conclusions This study presents methodological strategies and recommendations for the development of clinical predictive models,intended to serve as a guide for researchers.

Objective:To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China.Methods:Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed.Results:6 893 patients in CP ( n=6 453, 93.6%) or AP ( n=440, 6.4%) receiving initial imatinib ( n=4 906, 71.2%), nilotinib ( n=1 157, 16.8%), dasatinib ( n=298, 4.3%) or flumatinib ( n=532, 7.2%) -therapy. With the median follow-up of 43 ( IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance ( n=1 055, 15.3%), intolerance ( n=248, 3.6%), pursuit of better efficacy ( n=168, 2.4%), economic or other reasons ( n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph + ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph + ACA, poorer TFS; Ph + ACA, poorer OS. Conclusion:At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.