Background The active metabolite of benzo[a]pyrene (BaP), 7,8-dihydroxy-9,10-epoxybenzo[a]pyrene (BPDE), can form adducts with DNA, but the spectrum of BPDE-DNA adducts is unclear. Objective To identify the distribution of BPDE adduct sites and associated genes at the whole-genome level by chromatin immunoprecipitation followed by sequencing (ChIP-Seq), and serve as a basis for further exploring the toxicological mechanisms of BaP. Methods Human bronchial epithelial-like cells (16HBE) were cultured to the fourth generation inthe logarithmic growth phase. Cells were harvested and added to chromatin immunoprecipitation lysis buffer. The lysate was divided into experimental and control groups. The experimental group received a final concentration of 20 μmol·L⁻¹ BPDE solution, while the control group received an equivalent volume of dimethyl sulfoxide solution. The cells were then incubated at 37 °C for 24 h. Chromatin fragments of 100-500 bp were obtained through sonication. BPDE-specific antibody (anti-BPDE 8E11) was used to enrich DNA fragments with BPDE adducts. High-throughput sequencing was conducted to detect BPDE adduct sites. The top 1000 peak sequences were subjected to motif analysis using MEME and DREME software. BPDE adduct target genes at the whole-genome level were annotated, and Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of BPDE adduct target genes were conducted using bioinformatics techniques. Results The high-throughput sequencing detected a total of 842 BPDE binding sites, distributed across various chromosomes. BPDE covalently bound to both coding and non-coding regions of genes, with 73.9% binding sites located in intergenic regions, 19.6% in intronic regions, and smaller proportions in upstream 2 kilobase, exonic, downstream 2 kilobase, and 5' untranslated regions. Regarding the top 1000 peak sequences, four reliable motifs were identified, revealing that sites rich in adenine (A) and guanine (G) were prone to binding. Through the enrichment analysis of binding sites, a total of 199 BPDE-adduct target genes were identified, with the majority located on chromosomes 1, 5, 7, 12, 17, and X. The GO analysis indicated that these target genes were mainly enriched in nucleic acid and protein binding, participating in the regulation of catalytic activity, transport activity, translation elongation factor activity, and playing important roles in cell division, differentiation, motility, substance transport, and information transfer. The KEGG analysis revealed that these target genes were primarily enriched in pathways related to cardiovascular diseases, cancer, and immune-inflammatory responses. Conclusion Using ChIP-Seq, 199 BPDE adduct target genes at genome-wide level are identified, impacting biological functions such as cell division, differentiation, motility, substance transport, and information transfer. These genes are closely associated with cardiovascular diseases, tumors, and immune-inflammatory responses.

Background There is a lack of research evidence on the association between sugar-sweetened beverage (SSB) consumption and gestational diabetes mellitus (GDM) in China. Objective To explore the association between frequency of SSB consumption before pregnancy and risk of GDM in pregnant women in Shaanxi Province, and to provide a scientific basis for targeted interventions to control maternal blood glucose. Methods The recruitment to the China Birth Cohort study started in October 2020. Pregnant women at 6-16 weeks who had their first prenatal examination at five hospitals in Shaanxi Province were recruited. A maternal health questionnaire was used to collect basic information about pregnant women. A semi-quantitative food frequency questionnaire was used to collect the consumption of carbonated beverages, fruit and vegetable juice beverages, coffee beverages, and milk tea beverages in one year before pregnancy, which were summed to obtain the SSB consumption. Pregnant women were divided into three groups according to SSB consumption, namely <1 serving·week⁻¹, 1-4 servings·week⁻¹, and ≥5 servings·week⁻¹. GDM was confirmed by oral glucose tolerance test (OGTT) between 24-28 weeks of gestation. A binary logistic regression model was applied to explore the association between SSB consumption and risk of GDM. Multiple linear regression was applied to investigate the associations between SSB consumption (per 1-serving·d⁻¹ increase) and OGTT fasting plasma glucose, 1-hour glucose, and 2-hour glucose. Results A total of 3811 pregnant women were finally enrolled in this study, of which 752 developed GDM, with an incidence rate of 19.7%. The incidence rates of GDM in pregnant women with SSB consumption frequency of <1 serving·week⁻¹, 1-4 servings·week⁻¹, and ≥5 servings·week⁻¹ were 18.0%, 21.1%, and 26.8%, respectively. After adjusting for maternal age, pre-pregnancy body mass index (BMI), education, number of children born, family history of diabetes, smoking, alcohol consumption, physical activity level, and total energy intake, the risk of GDM increased by 26% (OR=1.26, 95%CI: 1.05, 1.50) in the 1-4 servings·week⁻¹ group and by 76% (OR=1.76, 95%CI: 1.31, 2.38) in the ≥5 servings·week⁻¹ group compared to the <1 serving·week⁻¹ SSB consumption group, respectively. Further stratified analysis revealed no interaction effect (P_interaction>0.05) between SSB consumption and maternal age, pre-pregnancy BMI, or first labor or not. For each additional SSB consumption per day, the risk of GDM increased by 94% (OR=1.94, 95%CI: 1.37, 2.75); and the maternal OGTT 1-hour glucose and 2-hour glucose increased by 0.33 mmol·L⁻¹ and 0.18 mmol·L⁻¹, respectively (P<0.05), and no significant increase in fasting plasma glucose was found (P>0.05). Conclusion Higher SSB consumption before pregnancy increases the risk of GDM in pregnant women.

Background Benzo[a]pyrene (BaP) has neurotoxicity, which can induce the loss of hippocampal neurons in humans and animals and lead to spatial learning and memory dysfunction, but its mechanism is still unclear. Objective To observe the ferroptosis of mouse hippocampal neuron HT22 cells induced by 7,8-dihydroxy-9,10-epoxybenzo[a]pyrene (BPDE), an active metabolite of BaP, and to explore its potential mechanism, so as to provide a basis for the study of BaP neurotoxicity mechanism. Method Mouse hippocampal neuron HT22 cells were selected and divided into four groups: solvent control group and low, medium, and high concentration BPDE exposure groups (0.25, 0.50, and 0.75 μmol·L⁻¹). Cell survival was detected by CCK8 method. Cell morphology and ultrastructure were observed under light and electron microscopes. The levels of reactive oxygen species (ROS) and Fe²⁺ were detected by fluorescence probe method. Iron, 4-hydroxynonenoic acid (4-HNE), malondialdehyde (MDA), glutathione (GSH), and glutathione peroxidase (GSH-PX) levels were detected with commercial kits. The expression levels of acyl-CoA synthase long chain family member 4 (ACSL4), cyclooxygenase 2 (COX2), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) were detected by Western blotting. After interventions with ferroptosis inhibitors 20 μmol·L⁻¹ deferoxamine (DFO) and 10 μmol·L⁻¹ ethyl 3-amino-4-cyclohexylaminobenzoate (Fer-1), the cell survival rate of each BPDE exposure group and the changes of the ferroptosis characteristic indicators and protein expression levels were observed. Results With the increase of BPDE concentration, the survival rate of HT22 cells decreased gradually, and the survival rate of each BPDE group was significantly lower than that of the solvent control group (P<0.01). Under light microscope, the number of cells in the high concentration BPDE group was significantly reduced, and atrophic cells and reduced synapses were recorded. Under electron microscope, the HT22 cells in the high concentration BPDE group showed mitochondrial shrinkage, decreased crista, and increased mitochondrial membrane density. Compared with the solvent control group, the levels of intracellular lipid ROS, Fe²⁺, 4-HNE, and MDA significantly increased in the high concentration group (P<0.01), the GSH and GSH-PX levels were significantly decreased (P<0.01), the protein expression levels of ASCL4 and COX2 were significantly increased (P<0.01), and the protein expression levels of SCL7A11 and GPX4 were significantly decreased (P<0.01). The ferroptosis inhibitors DFO and Fer-1 significantly reversed the cell survival rate (P<0.01), the ferroptosis characteristic indicators (ROS, Fe²⁺, 4-HNE, MDA, GSH, and GSH-PX levels) (P<0.01), and the expression levels of ferroptosis-related proteins (ACSL4, COX2, SLC7A11, and GPX4) (P<0.01) in the high concentration BPDE group. Conclusion BPDE can induce ferroptosis in mouse hippocampal neuron HT22 cells, which may be related to the inhibition of SLC7A11/GSH/GPX4 axis and the induction of iron metabolism disorder.

Defining and visualizing the three-dimensional (3D) structures of pharmaceuticals provides a new and important tool to elucidate the phenomenal behavior and underlying mechanisms of drug delivery systems. The mechanism of drug release from complex structured dosage forms, such as bilayer osmotic pump tablets, has not been investigated widely for most solid 3D structures. In this study, bilayer osmotic pump tablets undergoing dissolution, as well as after dissolution in a desiccated solid state were examined, and visualized by synchrotron radiation micro-computed tomography (SR-μCT). In situ formed 3D structures at different in vitro drug release states were characterized comprehensively. A distinct movement pattern of NaCl crystals from the push layer to the drug layer was observed, beneath the semi-permeable coating in the desiccated tablet samples. The 3D structures at different dissolution time revealed that the pushing upsurge in the bilayer osmotic pump tablet was directed via peripheral "roadways". Typically, different regions of the osmotic front, infiltration region, and dormant region were classified in the push layer during the dissolution of drug from tablet samples. According to the observed 3D microstructures, a "subterranean river model" for the drug release mechanism has been defined to explain the drug release mechanism.

Objective:To evaluate clinical efficacy and safety of topical compound oleum lithospermi in the treatment of mild to moderate diaper dermatitis.Methods:A multicenter, randomized, positive-drug parallel-controlled clinical trial was conducted in 19 hospitals from July 2019 to August 2020. Children aged 0 - 12 months with mild to moderate diaper dermatitis were enrolled and randomly divided into 2 groups using a random number table: test group topically treated with compound oleum lithospermi, and control group topically treated with zinc oxide cream. The treatment was carried out 6 - 8 times a day for 7 days. Visits were scheduled on days 0 and 7, and total response rate and clinical healing time were evaluated. Changes in the dermatitis family impact (DFI) score were compared between the test group and control group, and adverse events were recorded. Statistical analysis was carried out by using independent-sample t test for normally distributed continuous data, Wilcoxon rank sum test for non-normally distributed continuous data, and chi-square test or Fisher′s exact test for unordered categorical data; survival curves were drawn, and log-rank test was used for comparisons between two groups. Results:A total of 343 children with diaper dermatitis were enrolled in this study. Among them, 31 children violated the protocol, so 312 were included in the per protocol set, including 157 in the test group and 155 in the control group, and all completed the visits on days 0 and 7. The total response rate was significantly higher in the test group (87.26%, 137/157) than in the control group (78.71%, 122/155; χ2 = 4.04, P = 0.044) . The clinical healing time was significantly shorter in the test group (5.33 days) than in the control group (6.13 days; χ2 = 4.67, P = 0.025) . After 7-day treatment, the DFI score significantly decreased in both the 2 groups compared with that before the treatment, but there was no significant difference in the DFI score between the 2 groups (test group: 4.02 ± 6.96, control group: 3.58 ± 5.90, Z = -0.39, P = 0.686) . The incidence of adverse events was 2.92% (5/171) and 5.45% (9/165) in the test group and control group respectively, and there was no significant difference between the 2 groups ( χ2 = 0.03, P = 0.865) . Conclusion:Compound oleum lithospermi can markedly reduce the clinical severity of diaper dermatitis, improve the total response rate, shorten the clinical treatment period, and improve the quality of life of children′s families with a favorable safety profile.

Psoriasis is characterized by abnormal proliferation of keratinocytes, as well as infiltration of immune cells into the dermis and epidermis, causing itchy, scaly and erythematous plaques of skin. The understanding of this chronic inflammatory skin disease remains unclear and all available treatments have their limitations currently. Here, we showed that IMMH002, a novel orally active S1P modulator, desensitized peripheral pathogenic lymphocytes to egress signal from secondary lymphoid organs and thymus. Using different psoriasis animal models, we demonstrated that IMMH002 could significantly relieve skin damage as revealed by PASI score and pathological injure evaluation. Mechanistically, IMMH002 regulated CD3 T lymphocytes re-distribution by inducing lymphocytes' homing, thus decreased T lymphocytes allocation in the peripheral blood and skin but increased in the thymus. Our results suggest that the novel S1P agonist, IMMH002, exert extraordinary capacity to rapidly modulate T lymphocytes distribution, representing a promising drug candidate for psoriasis treatment.

Objective To compare the efficacy and safety of the long-term intermittent maintenance treatment with tacrolimus 0.03％ ointment versus traditional treatment in reducing relapses and prolonging the recurrence interval in children with moderate to severe atopic dermatitis (AD).Methods A two-phase randomized,open-labelled,controlled clinical trial was conducted from September 2012 to November 2013.In the first phase,a total of 171 children aged 2-15 years with moderate to severe AD were enrolled from 7 hospitals in China,and received conventional treatment with tacrolimus 0.03％ ointment twice a day for 2-6 weeks.At the end of the treatment,the patients who achieved an investigator's global assessment (IGA) score ≤ 2 (n =125) were randomly classified into 2 groups to receive the second-phase treatment:test group (n =62) receiving intermittent maintenance treatment with tacrolimus 0.03％ ointment twice a week (Monday and Thursday),and control group (n =63) receiving no treatment.If the patients in the 2 groups experienced relapse,they received conventional treatment with tacrolimus 0.03％ ointment twice a day.The overall observation period was 6 months.The primary endpoint was the time to the first relapse,which was defined as the number of days from the end of the first-phase treatment to the first relapse.The secondary endpoints included the number of relapses at the second-phase trial,the disease severity at the time of relapse,the duration of relapse,the pruritus score at the time of relapse,the total amount of tacrolimus ointment used,the total response rate at the second-phase trial,and the incidence of adverse events.Results A total of 125 children with AD were enrolled into the second-phase trial,and 121 of them completed the follow-up.Among the 121 patients,the recurrence rate was significantly lower in the test group (25/60,41.7％) than in the control group (46/61,75.4％;x2 =14.20,P ＜ 0.001).The time to the first relapse was significantly longer in the test group (46.9 ± 37.7 d) than in the control group (28.8 ± 32.3 d;Z =1 093.50,P =0.020).The total number of recurrence was 31 and 86 in the test group and control group respectively,and the mean number of recurrence in each patient was significantly lower in the test group (0.52 ± 0.68) than in the control group (1.41 ± 1.23,t =4.96,P ＜ 0.001).There were no significant differences between the two groups regarding disease severity during relapse (eczema area and severity index:Z =971.50,P =0.39),duration of relapse (Z =747.00,P =0.07),and pruritus score during relapse (Z =894.00,P =0.95).The therapeutic drug was tolerated well in all the children,and no tacrolimus-related serious adverse events occurred.Conclusion The intermittent maintenance treatment with tacrolimus 0.03％ ointment twice a week for 6 months can effectively and safely prevent and reduce relapses,and prolong the recurrence interval in children with moderate to severe AD.

Objective To investigate the risk factors of perioperative complications of laparoscopic radical distal gastrectomy and influence of body shape on the short-term therapeutic effects.Methods The retrospective case-control study was conducted.The clinicopathological data of 506 patients (328 males and 178 females,average age 60 years with the range of 24-85 years) who underwent laparoscopic radical distal gastrectomy+D2 lymph nodes dissection in the 8 clinical centers between March 2016 and November 2018 were collected,including 143 in the First Affiliated Hospital of Xiamen University,66 in the Affiliated Hospital of Qinghai University,66 in the Second Affiliated Hospital of Wenzhou Medical University,64 in the Zhongshan Hospital of Xiamen University,54 in the Affiliated Hangzhou First people's Hospital of Zhejiang University School of Medicine,48 in the Zhangzhou Affiliated Hospital of Fujian Medical University,35 in the Affiliated Quanzhou First Hospital of Fujian Medical University,30 in the Second Affiliated Hospital of Xiamen Medical College.The maximum thickness of subcutaneous fat at the level of umbilicus (USCF),the maximum vertical distance between the anterior abdominal skin and the back skin at the level of the umbilicus (UAPD),the maximum horizontal distance between the anterior abdominal skin and the back skin at the level of the umbilicus (UTD),the maximum verticaldistance between the anterior abdominal skin and the back skin at the level of the xiphoid bone (XAPD),the maximum horizontal distance between the.anterior abdominal skin and the back skin at the level of the xiphoid bone (XTD),the distance between the anterior abdominal skin and the root of celiac artery (CAD) and the maximum horizontal distance at a right angle to CAD (CATD) were measured using preoperative imaging examinations.Observation indicators:(1) intraoperative and postoperative situations;(2) follow-up situations;(3) risk factors analysis of perioperative complications;(4) influence of body shape related indexes on intraoperative situations and postoperative recovery:① Pearson univariate correlation analysis,② liner regression model analysis.Followup using outpatient examination and telephone interview was performed to detect the postoperative survival and tumor recurrence or metastasis up to December 2018.Measurement data with normal distribution were represented as Mean±SD.Measurement data with skewed distribution were described as M (range).Comparisons of count data were analyzed using the chi-square test.Comparisons of ordinal data were analyzed by Mann-Whitney U nonparametric test.Risk factors of perioperative complications of laparoscopic distal gastrectomy were analyzed by Logistic regression model.Influence of body shape related indexes on intraoperative situations and postoperative recovery was analyzed by Pearson univariate correlation analysis and liner regression model.Results (1) Intraoperative and postoperative situations:all the 506 patients underwent successful laparoscopic distal gastrectomy,including 103 with Billroth Ⅰ anastomosis,140 with Billroth Ⅱ anastomosis,201 with Billroth Ⅱ + Braun anastomosis,62 with Roux-en-Y anastomosis.The operation time,volume of intraoperative blood loss,number of lymph nodes dissected,time to postoperative anal exsufflation,time for initial fluid diet intake,time for initial semi-fluid diet intake and duration of postoperative hospital stay were (233±44)minutes,(102±86)mL,34±13,(3.6±1.5)days,(5.8±3.3)days,(8.3±3.8)days,(12.2±5.7)days respectively in the 506 patients.Of 506 patients,196 were defined as pathological stage Ⅰ,122 were defined as pathological stage Ⅱ and 188 were defined as pathological stage Ⅲ postoperatively.Of 506 patients,93 had 106 times of perioperative complications,including 33 times of pulmonary and upper respiratory infection,12 times of incisional infection,11 times of anastomotic leakage,11 times of abdominal infection,8 times of intestinal obstruction,8 times of gastroplegia,6 times of abdominal hemorrhage,5 times of bacteremia,3 times of anastomotic hemorrhage,3 times of lymph fluid leakage,2 times of pancreatic leakage,1 time of urinary infection,1 time of anatomotic stenosis,1 time of deep venous thrombosis and 1 time of pulmonary embolism;the same patient can merge multiple complications.Eleven patients were in the Clavien-Dindo classification ≥ Ⅲ.(2) Follow-up situations:465 of 506 patients were followed up for 1-32 months with a median time of 12 months.During the follow-up,451 had postoperative survival and 38 had tumor recurrence or metastasis.(3) Risk factors analysis of perioperative complications.① Results of univariate analysis showed that age,body mass index (BMI),preoperative hemoglobin,preoperative serum albumin and XAPD were related factors affecting perioperative complications of laparoscopic distal gastrectomy (x2 =10.289,7.427,5.269,5.481,4.285,P＜ 0.05).② Results of multivariate analysis showed that age,BMI,preoperative serum albumin were independent related factors affecting perioperative complications of laparoscopic distal gastrectomy (odds ratio =1.033,1.118,0.937,95％ interval confidence:1.011-1.057,1.025-1.219,0.887-0.990,P＜0.05).(4) Influence of body shape related indexes on intraoperative situations and postoperative recovery.① Results of Pearson univariate correlation analysis showed correlations between UAPD,XAPD,CAD,CATD and volume of intraoperative blood loss (r=0.107,0.169,0.179,0.106,P＜0.05),between UAPD,XAPD,CAD and the number of lymph nodes dissected (r=-0.137,-0.143,-0.173,P＜0.05),between USCF,XAPD and time to postoperative anal exsufflation (r =0.122,0.109,P＜0.05),between USCF,XAPD,CAD and time for initial fluid diet intake (r=0.132,0.108,0.132,P＜0.05),between USCF,XAPD and duration of postoperative hospital stay (r=0.116,0.100,P＜0.05).② Results of liner regression model analysis showed a positive correlation between CAD and volume of intraoperative blood loss (r =6.776),a negative correlation between CAD and the number of lymph nodes dissected (r =-0.841),with statistically significant differences (t =2.410,-1.992,P＜ 0.05);a positive correlation between USCF and time to postoperative anal exsufflation (r=0.170),between USCF and time for initial fluid diet intake (r=0.365),between USCF and duration of postoperative hospital stay (r=0.636) respectively,with statisticallysignificant differences (t =2.188,1.981,2.107,P＜ 0.05).Conclusions Abdominal shape can influence intraoperative situations and postoperative recovery of laparoscopic distal gastrectomy,but cannot increase risks ofperioperative complications.Age,BMI and preoperative serum albumin are independent related factors affecting perioperative complications of laparoscopic distal gastrectomy.

Objective: To analyze the relationship between inflammatory factors and relevant risk factors in patients of essential hypertension (EH) combining acute coronary syndrome (ACS) with its clinical significance. Methods: Our research included 3 groups: EH group, n=79 patients with standard criteria, EH+ACS group, n=85 and Control group, n=48 normal subjects. Blood levels of lipoprotein-associated phospholipase A2 (Lp-PLA2), tryptase (TPS) and relevant clinical, biochemical parameters were measured; risk factors for cardiovascular disease were examined and the relationship between above parameters, risk factors and ACS occurrence in EH patients was studied by Logistic regression analysis. Results: The OR values were all greater than 1 in fibrinogen (Fbg), high-sensitivity C-reactive protein (hs-CRP), TPS, atherosclerotic plaque, Lp-PLA2 and EH grading. Fbg was the most significant independent risk factor (OR=22.242, 95% CI 6.458-76.609, P<0.0001), the standardized partial regression coefficient b'as absolute value (b') was 1.079 which was the highestone in above 6 variables with the strongest impact for ACS occurrence in EH patients. Conclusion: Fbg, hs-CRP, TPS, atherosclerotic plaque and EH grading were the independent risk factors for ACS occurrence in EH patients; Fbg was the highest risk factor for ACS occurrence with the strongest impact, which provided a new direction for ACS prevention and treatment.

Objective To evaluate the protective value of cardioplegia solution plus metformin in different cardiac arrest time and concentration of metformin in isolated rat hearts .Methods There were 36 male Sprague–Dawley rats divided into six groups randomly, according to the duration of cardioplegic arrest(30 min or 60min) and the concentrations of metformin(50μmol/L or 100 μmol/L) .Langendorff-perfused Sprague-Dawley rat hearts were perfused for 20 minutes with Krebs-Henseleit buffer followed by 30 or 60 minutes of crystalloid cardioplegia or plus metformin (50 or 100 μmol/L) and 60 minutes of reperfu-sion.The left ventricular performance was recorded at 5 time points.The expressions of AMPKαand phosphorylation of AMPKαwere detected by western Blot.The changes of myocardial mitochondria were observed under transmission electron mi-croscope.Results There were no significant differences in Con(A), 50(A) and 100(A) groups in LVDP, ±dp/dtmax and HR.Compared with Con(B) group subjected to 60 minutes of ischemia followed by 60 minutes of reperfusion, the 100(B) group significantly improved myocardial performance , and the ratio of p-AMPKα/AMPKαwas the highest in all 6 groups.The structure of myocardial mitochondria in 100(B) group was better protected than that of Con(B) group.Conclusion These findings suggested that the left ventricular performance was protected in rat heart perfused by cardioplegia plus 100 μmol/L after 60 minutes cardioplegic arrest .The mechanism may be the activation of AMPK and the protection of structures of myocardial mitochondria.