Objective To simulate modern social stress using a pre-pregnancy chronic mild stress(CMS)model and to explore the mechanisms of emotional,behavioral,and neurodevelopmental changes in male offspring of pre-pregnancy liver qi stagnation female mice through corticosterone(CORT)-brain-derived neurotrophic factor(BDNF)extracellular signal-regulated kinase(ERK)1/2 signaling cascade-mediated hippocampal injury.This study aimed to elucidate the impact of negative life events on offspring and the interventional mechanism of Shuyu Capsules.Methods CMS stress was used to induce pre-pregnancy depression in female rats(liver qi stagnation state),followed by intervention with Shuyu and fluoxetine capsules.After screening,male rats were mated and 12 male offspring from each group were selected for behavioral testing and detection of serum CORT levels by enzyme-linked immunosorbent assay.BDNF,ERK1/2,phospho(p)-ERK1/2,cAMP-response element binding protein(CREB),and p-CREB protein levels in the hippocampus were detected by Western Blot,and BDNF,ERK1,ERK2,and CREB mRNA levels in the hippocampus were detected by reverse transcription-polymerase chain reaction(RT-PCR),to verify the effects of pre-pregnancy CMS on the BDNF-ERK1/2-CREB signaling pathway and to investigate the key micro-mechanisms of Shuyu Capsules on emotional and learning memory-related behaviors of male offspring of females with pre-pregnancy liver qi stagnation syndrome.Results The distance,number of entries,and duration of stay in the central area in open-field experiments were significantly reduced in offspring in the model group(all P＜0.05).The escape latency during the exploration period of the water-maze experiment was significantly prolonged(P＜0.05)and the swimming distance,duration of the target quadrant,and number of platform crossings were significantly reduced(P＜0.05,P＜0.05,P＜0.01),the suspension time and frequency in the forced-swimming experiment were increased(P＜0.05,P＜0.01),and the incubation period was shortened(P＜0.05)in offspring in the model group.Prophylactic treatment with Shuyu Capsules and fluoxetine improved the depression-like behavior and cognitive impairment in the offspring in the model group.Biochemical tests showed that CORT levels were increased in the CMS model group(P＜0.05),BDNF,p-ERK1/2,and p-CREB protein levels in the hippocampus were decreased(all P＜0.05),and BDNF,ERK1,ERK2,and CREB mRNA levels were significantly reduced(P＜0.01,P＜0.05,P＜0.01,P＜0.05).Treatment with Shuyu Capsules and fluoxetine increased the CORT content and BDNF,ERK1/2,and CREB protein and mRNA levels in male offspring to varying degrees.Conclusions High levels of CORT in offspring act selectively on the hippocampus,exerting adverse effects on the emotional and learning memory functions of rats by downregulating the BDNF-ERK1/2 signaling cascade.The Chinese medicine Shuyu Capsules can reduce the impact of an adverse intrauterine environment on offspring development by correcting abnormal levels and pathways of glucocorticoids.

Objective To simulate modern social stress using a pre-pregnancy chronic mild stress(CMS)model and to explore the mechanisms of emotional,behavioral,and neurodevelopmental changes in male offspring of pre-pregnancy liver qi stagnation female mice through corticosterone(CORT)-brain-derived neurotrophic factor(BDNF)extracellular signal-regulated kinase(ERK)1/2 signaling cascade-mediated hippocampal injury.This study aimed to elucidate the impact of negative life events on offspring and the interventional mechanism of Shuyu Capsules.Methods CMS stress was used to induce pre-pregnancy depression in female rats(liver qi stagnation state),followed by intervention with Shuyu and fluoxetine capsules.After screening,male rats were mated and 12 male offspring from each group were selected for behavioral testing and detection of serum CORT levels by enzyme-linked immunosorbent assay.BDNF,ERK1/2,phospho(p)-ERK1/2,cAMP-response element binding protein(CREB),and p-CREB protein levels in the hippocampus were detected by Western Blot,and BDNF,ERK1,ERK2,and CREB mRNA levels in the hippocampus were detected by reverse transcription-polymerase chain reaction(RT-PCR),to verify the effects of pre-pregnancy CMS on the BDNF-ERK1/2-CREB signaling pathway and to investigate the key micro-mechanisms of Shuyu Capsules on emotional and learning memory-related behaviors of male offspring of females with pre-pregnancy liver qi stagnation syndrome.Results The distance,number of entries,and duration of stay in the central area in open-field experiments were significantly reduced in offspring in the model group(all P＜0.05).The escape latency during the exploration period of the water-maze experiment was significantly prolonged(P＜0.05)and the swimming distance,duration of the target quadrant,and number of platform crossings were significantly reduced(P＜0.05,P＜0.05,P＜0.01),the suspension time and frequency in the forced-swimming experiment were increased(P＜0.05,P＜0.01),and the incubation period was shortened(P＜0.05)in offspring in the model group.Prophylactic treatment with Shuyu Capsules and fluoxetine improved the depression-like behavior and cognitive impairment in the offspring in the model group.Biochemical tests showed that CORT levels were increased in the CMS model group(P＜0.05),BDNF,p-ERK1/2,and p-CREB protein levels in the hippocampus were decreased(all P＜0.05),and BDNF,ERK1,ERK2,and CREB mRNA levels were significantly reduced(P＜0.01,P＜0.05,P＜0.01,P＜0.05).Treatment with Shuyu Capsules and fluoxetine increased the CORT content and BDNF,ERK1/2,and CREB protein and mRNA levels in male offspring to varying degrees.Conclusions High levels of CORT in offspring act selectively on the hippocampus,exerting adverse effects on the emotional and learning memory functions of rats by downregulating the BDNF-ERK1/2 signaling cascade.The Chinese medicine Shuyu Capsules can reduce the impact of an adverse intrauterine environment on offspring development by correcting abnormal levels and pathways of glucocorticoids.

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

Objective:To explore the clinical efficacy and adverse reactions of albumin-bound paclitaxel (Nab-P) and conventional paclitaxel combined with cisplatin and concurrent radiotherapy for the treatment of patients with locally advanced esophageal squamous cell carcinoma.Methods:Forty-nine patients with locally advanced esophageal squamous cell carcinoma admitted to the First People's Hospital of Suqian from November 2016 to May 2020 were included. Of the 49 patients, 23 cases were treated with Nab-P combined with cisplatin and concurrent radiotherapy (NP group), 26 cases were treated with conventional paclitaxel combined with cisplatin and concurrent radiotherapy (TP group). All patients received 2 cycles of chemotherapy. The curative efficacy was evaluated one month after the end of radiotherapy, and the curative effect and adverse reactions of the two treatment regimens were compared.Results:The objective remission rate in NP group was 78.3% (18/23), and the disease control rate was 100.0% (23/23). The objective response rate in TP group was 61.5% (16/26), and the disease control rate was 92.3% (24/26). The objective response rate and disease control rate in NP group were higher than those in TP group, but the differences were not statistically significant (both P > 0.05). The common adverse reactions were mainly hair loss, loss of appetite, bone marrow suppression, radiation esophagitis, radiation pneumonia, malaise and myalgia. The incidence rate of grade 3-4 acute bone marrow suppression in NP group (8.7%, 2/23) was lower than that in TP group (38.5%, 10/26), and the difference was statistically significant ( χ2 = 4.35, P = 0.037). The incidence rate of myalgia in NP group (26.1%, 6/23) was lower than that in TP group (61.5%, 16/26), and the difference was statistically significant ( χ2 = 4.85, P = 0.028). Conclusions:Nab-P combined with cisplatin and concurrent radiotherapy has good efficacy in the treatment of patients with locally advanced esophageal squamous cell carcinoma, and the incidence rate of adverse reactions is lower than that of conventional paclitaxel combined with cisplatin and concurrent radiotherapy, so that the regimen is safe.

OBJECTIVE: To explore the relationship between occupational aluminum exposure and fasting blood glucose level in workers. METHODS: A cluster sampling method was used to select 178 occupational aluminum-exposed workers as the exposure group, and 178 workers without occupational aluminum exposure as the control group in a large aluminum factory in Shanxi Province. Glucose oxidase method was used to measure the fasting blood glucose level, and inductively coupled plasma mass spectrometry was used to measure the plasma aluminum level in these workers. A generalized linear model was used to analyze the correlation between plasma aluminum exposure level and fasting blood glucose in these workers. RESULTS: The blood aluminum level of workers in the exposure group was higher than that of the control group [median: 39.58 vs 16.67 μg/L, P<0.01]. The fasting blood glucose level of workers in the exposure group was higher than that of the control group [(5.33±0.79) vs(5.15±0.41) mmol/L, P<0.01]. The results of the generalized linear model analysis showed that the blood aluminum level of workers was positively correlated with their fasting blood glucose level after adjusting for age, body mass index, smoking, drinking, exercise, family history of diabetes, and incidence of diabetes(P<0.05). There was a dose-response relationship between the blood aluminum level and fasting blood glucose level of workers in the groups of junior high school and below and high school(all P_(trend)<0.01). There was no correlation found between blood aluminum level and fasting blood glucose level in the group of college and above(P_(trend)>0.05). There was a dose-response relationship between the blood aluminum level and the fasting blood glucose level in the workers in the non-exercise group(P_(trend)<0.01). There was no correlation found between the blood aluminum level and the fasting blood glucose level in the exercise group(P_(trend)>0.05). CONCLUSION: The blood aluminum level of workers exposed to occupational aluminum is positively correlated with their fasting blood glucose level. Higher education level or exercise can moderately reduce the effect of blood aluminum level on fasting blood glucose.

OBJECTIVE：To preliminarily optimize the preparation technology of Ligustrazine pellicle ，and to study its in vitro percutaneous permeation characteristics. METHODS ：With the amounts of PVA- 124，ethyl alcohol ，glycerin，tween-80 and azone as factors ，single factor experiment was used to optimize the Ligustrazine pellicle matrix formulation ；modified scoring standard was used to evaluate the film formation time ，film formation ability ，ductility，uniformity and the presence of bubble. On the basis of the optimal matrix formulation ，the pellicle with different loading amount of ligustrazine （300，250，200，150，100，50 mg/mL） was prepared and its maximum loading amount was investigated. HPLC method was adopted to determine the content of ligustrazine，and methodology investigation was conducted. Isolated back skin of rats were collected ，the percutaneous permeation test was conducted for high ，medium and low loading amount （100，75，50 mg/mL）of Ligustrazine pellicle. At 15，30，45，60， 75，90，120，150，180 min，the sample was taken and the permeation rate of ligustrazine was calculated. RESULTS ：When the amounts of PVA- 124，ethyl alcohol，glycerin，tween-80 and azone were 2.5 g，7.0 mL，1.97 mL，0.07 mL，0.28 mL（in terms of 50 mL formulation amount ），the optimal matrix formulation of Ligustrazine pellicle was obtained. The maximum drug loading amount of ligustrazine was 100 mg/mL. The linear ranges of ligustrazine was 3.125-100 μg/mL. The specificity，precision， reproducibility，recovery and stability investigation of content determination method of ligustrazine were all in line with the requirements（RSD＜2％）. The permeation rate of high ，medium and low loading amount of Ligustrazine pellicle were 608.42， 384.19，158.20 μg（/ cm2·h）. CONCLUSIONS ：According to the optimized formulation ，the prepared Ligustrazine pellicle had a short film forming time ，stable and re liable quality ； the drug-loading amount was up to 100 mg/mL. The pellicle with drug-loading amount of 75 mg/mL had reached the penetration rate range of effective plasma concentration of ligustrazine treatment.

Objective To determine the levels of total antioxidative capacity(TAOC) and malondialdehyde(MDA) in liver exposed to hyperoxia,and to explore whether oxygen inhalation could cause liver injury in newborn rats.Methods Sixty-four newborn rats which were less than 12-hour-old were enrolled in this study.The rats were randomly divided into hyperoxia group(FiO2=0.85,n=32) and control group(air,n=32).Eight rats in each group were randomly sacrificed to obtain liver tissues at 1d,3d,7d and 14d.The TAOC of liver homogenates was detected by chemical colorimetry,and the MDA level of liver homogenates was measured by thiobarbituric acid test.Results In the hyperoxia group,TAOC in liver increased on the 1st day[(3.60±0.28)U/mg prot vs(3.39±0.19)U/mg prot,P<0.05];TAOC began to decreased on the 3rd day,and significantly lower than that of control group on the 14th day [(3.10±0.15)U/mg prot vs (3.56±0.14)U/mg prot,P<0.01].In the hyperoxia group,the MDA level increased on the 3rd day[(3.58±0.11)nmol/mg prot vs(2.82±0.14)nmol/mg prot,P<0.01],and reached a peak on the 7th day[(3.58 ±0.11)nmol/mg prot vs(2.82±0.14)nmol/mg prot,P<0.01],then decreased but still remained higher than control group on the 14th day [(2.92±0.18)nmol/mg prot vs(2.77 ±0.09)nmol/mg prot,P<0.01].Conclusion Too more MDA in liver and TAOC decrease may cause liver injury in newborn rats exposed to hyperoxia.With the oxygen inhalation time prolonging,the liver injury aggravation.