OBJECTIVE To investigate the antidepressant mechanism of Shugan hewei tang （SGHWT） based on the metabolomics of prefrontal cortex （PFC）-nucleus accumbens （NAc）-ventral tegmental area （VTA） neural circuit. METHODS Male SD rats were randomly divided into blank group， model group， SGHWT low-， medium- and high-dose groups [3.67， 7.34， 14.68 g/（kg·d）， by raw material]， and fluoxetine group [1.58 mg/（kg·d）， positive control]， with 12 rats in each group. Except for the blank group， the depression model was established by chronic unpredictable mild stress combined with individual cage housing in the remaining groups， and the corresponding drug solution or normal saline was administered via gavage during modeling， once a day， for 6 consecutive weeks. After the last administration， the body weight， sucrose preference rate， total moving distance， frequency into the center and immobility time of rats in each group were detected. Samples of PFC， NAc and VTA areas of rats in the blank group， model group， SGHWT medium-dose group and fluoxetine positive control groups were collected，and their histomorphological features were observed， and non-targeted metabolomics analysis （except for fluoxetine group）were performed and validated. RESULTS Compared with model group， the cytolysis， structural damage and other pathological damages in three brain regions of rats were significantly alleviated in each drug group， while their body weight， sucrose preference rate， total moving distance and frequency into the center were all significantly higher or longer （P＜0.05）， and immobility time was significantly shorter （P＜0.05）. The results of non-targeted metabolomics showed that a total of 78 endogenous differential metabolites were identified， with 40， 35 and 24 in the PFC， NAc and VTA regions respectively， mainly involved in amino acid， lipid and sphingolipid metabolism. The results of metabolic pathway enrichment analysis showed that SGHWT affected the neural circuits of depressed rats by regulating sphingolipid metabolism， alanine， aspartic acid and glutamic acid metabolism， saturated fatty acid biosynthesis， among which alanine， aspartic acid and glutamic acid metabolism was predominantly involved. Validation experiments showed that SGHWT significantly increased the phosphorylation levels of protein kinase B （Akt） and mammalian target of rapamycin （mTOR）， and decreased the protein expression of N-methyl-D-aspartic acid receptor 1 （NMDAR1） in the NAc region of rats. CONCLUSIONS SGHWT significantly improves the depression-like behavior and attenuates pathological damage of PFC-NAc-VTA neural circuit of model rats， the mechanism of which is associated with inhibiting NMDAR1 expression and activating the Akt/mTOR signaling pathway.

Objective:To investigate the effects of ceftriaxone(CTX) on nuclear factor erythroid 2-related factor 2(Nrf2)/glutathione peroxidase 4(GPX4) pathway and ferroptosis in early brain injury in rats with subarachnoid hemorrhage(SAH).Methods:Forty-eight clean grade male SD rats were randomly divided into sham operation group (Sham group), SAH group, SAH+ CTX group and SAH+ CTX+ Nrf2 inhibitor group (SAH+ CTX+ ML385 group) according to the random number table with 12 rats in each group.Seven days before modeling, rats in SAH+ CTX+ ML385 group were injected intraperitoneally with ML385 (30 mg · kg -1) once a day for consecutive 7 days.And 5 days before modeling, rats in SAH+ CTX group and SAH+ CTX+ ML385 group were treated with CTX(200 mg · kg -1) by intraperitoneal injection once a day for five consecutive days.Rats in Sham group and SAH group were intraperitoneally injected with the same amount of 0.9% sodium chloride solution.After 24 hours of modeling, the neurological function score and brain tissue water content of rats in each group were measured.HE staining was used to observe the morphology of neurons in CA1 and CA3 regions of hippocampus.Prussian blue staining was used to observe the iron deposition in cerebral cortex.Spectrophotometer was used to determine the iron content, malonic dialdehyde(MDA) content, glutathione(GSH) content and GPX4 activity in cerebral cortex.Western blot was used to detect the expression levels of Nrf2 and GPX4 proteins in cerebral cortex.SPSS 23.0 was used for statistical analysis.One-way ANOVA was used to compare the mean of multiple groups of samples, and Dunnett- t test was used for further pairwise comparison between groups. Results:There was a statistically significant difference in the neurological function scores of rats in the four groups 24 hours after SAH ( F=48.40, P<0.001). The neurological function score of rats in the SAH group 24 hours after SAH was significantly lower than those in Sham group and SAH+ CTX group (both P<0.05). The brain water content of rats in the four groups 24 h after SAH was statistically significant ( F=49.61, P<0.001). The brain water content of rats in the SAH group 24 h after SAH was significantly higher than that in Sham group and SAH+ CTX group(both P<0.05). There was statistically significant differences in the number of neuronal necrosis in CA1 and CA3 regions of hippocampus in the four groups 24 hours after SAH ( F=17.44, 246.50, both P<0.001). The numbers of neuronal necrosis in CA1 and CA3 regions of hippocampus in SAH group were significantly higher than those in Sham group and SAH+ CTX group, and the numbers of neuronal necrosis in CA1 and CA3 regions of hippocampus in SAH+ CTX+ ML385 group were significantly higher than those in SAH+ CTX group (all P<0.05). Twenty-four hours after SAH, the amount of iron deposited in the cerebral cortex of rats in the four groups was statistically significant ( F=2 363.0, P<0.001). The iron deposition in the cerebral cortex of rats in the SAH group was significantly higher than those in Sham group and SAH+ CTX group (both P<0.05). There were significant differences in iron content, MDA content, GSH content and GPX4 activity in the cerebral cortex of the four groups 24 h after SAH( F=2 380.0, 1 322.0, 789.1, 815.5, all P<0.001). The content of iron and MDA in the cerebral cortex of rats in SAH group were significantly higher than those in Sham group, while the content of GSH and the activity of GPX4 were significantly lower than those in Sham group (all P<0.05). The content of iron and MDA in the cerebral cortex of rats in SAH+ CTX group were lower than those in SAH group, and the content of GSH and the activity of GPX4 were higher than those in SAH group (all P<0.05). At 24 h after SAH, the expression levels of Nrf2 and GPX4 protein in the cerebral cortex of the four groups were statistically significant ( F=888.7, 1 556.0, both P<0.001). The protein expression levels of Nrf2 (0.382±0.014) and GPX4 (0.329±0.019) in the cerebral cortex in SAH group were lower than those in Sham group ((0.746±0.009), (0.953±0.009)) (both P<0.05). The expression levels of Nrf2 (0.631±0.006) and GPX4 (0.833±0.008) protein in the cerebral cortex in the SAH+ CTX group were significantly higher than those in the SAH group (both P<0.05). The expression levels of Nrf2 (0.427±0.009) and GPX4 (0.525±0.011) protein in the cerebral cortex in SAH+ CTX+ ML385 group were significantly lower than those in SAH+ CTX group (both P<0.05). Conclusion:Ceftriaxone may inhibit ferroptosis during EBI in SAH rats by regulating Nrf2/GPX4 signal axis.

ObjectiveTo compare the therapeutic effects of oral Chinese medicines （including Chinese patent medicines） on coronary artery disease （CAD） by the Bayesian network Meta-analysis. MethodThe randomized controlled trials of treating CAD with oral Chinese medicines were retrieved from the China National Knowledge Infrastructure （CNKI）， Wanfang Data， VIP， PubMed， Web of Science， Embase， and Cochrane Library from the inception to December 1， 2022. The Cochrane risk of bias assessment tool was used to evaluate the quality of the included articles. The direct meta-analysis was performed to compare the performance of oral Chinese medicines alone and in combination with Western medicine in the treatment of CAD in terms of intima-media thickness （IMT）， vascular endothelial function， plaque score， hypersensitive C-reactive protein （hs-CRP）， total cholesterol （TC）， triglyceride （TG）， high-density lipoprotein cholesterol （HDL-C）， low-density lipoprotein cholesterol （LDL-C）， and total response rate. Furthermore， the Bayesian network Meta-analysis was performed to compare the therapeutic effects of different Chinese medicines. ResultA total of 41 articles were included. The direct meta-analysis results showed that Chinese medicines combined with Western medicine outperformed Western medicine alone in recovering all the indicators of CAD. The Bayesian network meta-analysis yielded the following results. In terms of the total response rate， modified Huangqi Guizhi Wuwutang and Sanqi Huayu pills had obvious advantages over other Chinese medicines. In terms of IMT and plaque score， Xiaoban Huazhuo decoction， Yiqi Tongluo formula， Ruangan Jiangzhi capsules， and Guanxin Shutong capsules had obvious advantages over other Chinese medicines. In terms of blood lipid indicators， Shenqi Roumai mixture， Ruangan Jiangzhi capsules， Xiaoban Huazhuo decoction， Qiwei Sanxiong decoction， and Sanqi Huayu pills were superior to other Chinese medicines. The Chinese medicines above mainly had the functions of activating blood， resolving stasis， resolving phlegm， and dredging vessels. ConclusionThe combination of oral Chinese medicines and Western medicine is effective in treating CAD. Clinicians can use the drugs targeting abnormal indicators according to the results of this Bayesian network meta-analysis combined with the actual situation of patients to achieve better therapeutic effects.

BACKGROUND: Extreme temperature events, including extreme cold, are becoming more frequent worldwide, which might be harmful to pregnant women and cause adverse birth outcomes. We aimed to investigate the association between exposure to low ambient temperature in pregnant women and adverse birth outcomes, such as preterm birth, low birth weight, and stillbirth, and to summarize the evidence herein. METHODS: Relevant studies were searched in PubMed, Cochrane, and Embase electronic databases until November 2021. Studies involving low ambient temperature, preterm birth, birth weight, and stillbirth were included. The guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses were followed to conduct this study risk of bias and methods for data synthesis. RESULTS: A total of 34 studies were included. First, pregnant women exposed to low ambient temperature had an increased risk of preterm birth (risk ratio [RR] 1.08; 95% confidence interval [CI] 1.04-1.13). Subgroup analyses revealed that exposure during late pregnancy was more likely to induce preterm birth. In addition, only pregnant women exposed to <1st percentile of the mean temperature suffered increased risk of preterm birth. Moreover, pregnant women living in medium or hot areas were more prone to have preterm births than those in cold areas when exposed to low ambient temperatures. Asians and Blacks were more susceptible to low ambient temperatures than Caucasians. Second, pregnant women exposed to low ambient temperature had an increased risk of low birth weight (RR 1.07; 95% CI 1.03-1.12). Third, pregnant women had an increased risk of stillbirth while exposed to low ambient temperature during the entire pregnancy (RR 4.63; 95% CI 3.99-5.38). CONCLUSIONS: Exposure to low ambient temperature during pregnancy increases the risk of adverse birth outcomes. Pregnant women should avoid exposure to extremely low ambient temperature (<1st percentile of the mean temperature), especially in their late pregnancy. This study could provide clues for preventing adverse outcomes from meteorological factors. REGISTRATION No. CRD42021259776 at PROSPERO ( https://www.crd.york.ac.uk/PROSPERO/ ).
Pregnancy ; Infant, Newborn ; Female ; Humans ; Pregnancy Outcome ; Premature Birth/epidemiology* ; Stillbirth/epidemiology* ; Temperature ; Pregnancy Complications

Objective:To explore the effects of enriched environment combined with melatonin on learning and memory function and DNA oxidative damage in senescence accelerated mouse prone 8 (SAMP8) mice.Methods:Twenty-four 6-month-old SPF healthy male SAMP8 mice were randomly divided into model group, enriched environment group, melatonin group and enriched environment+ melatonin group, with 6 mice in each group. Six homologous SAMR1 mice of the same age were used as the control group. The mice in the enriched environment group and the enriched environment+ melatonin group were fed in the enriched environment. At the same time, the mice in the melatonin group and the enriched environment+ melatonin group were subcutaneously injected with melatonin (8 mg /(kg·d)) once a day for 28 d. The mice in the model group, the control group and the enriched environment group were subcutaneously injected with an equal volume of 0.9% sodium chloride solution once a day for 28 days. Aging score was used to evaluate the aging of mice. Morris water maze and Y maze tests were used to evaluate the learning and memory ability of mice. The cell morphology of hippocampus in mice was observed by hematoxylin-eosin staining, and the level of Aβ 1-42 protein in hippocampus of mice was detected by immunohistochemical staining. The levels of γ-H2A histone family member X(γ-H2AX) and 8-hydroxy-2 deoxyguanosine(8-OHdG) proteins in hippocampus of mice were detected by Western blot and Enzyme-linked immunosorbent assay. SPSS 25.0 statistical software was used to process the data. One-way analysis of variance was used for comparison among multiple groups, and LSD- t test was used for further pairwise comparison. Results:(1)There was a statistical difference in aging scores among the 5 groups of mice after intervention ( F=126.4, P<0.01). After intervention, the aging scores of mice in the enriched environment group, melatonin group, and enriched environment+ melatonin group were lower than that in the model group (all P<0.05), and the score of the enriched environment+ melatonin group was significantly lower than that in the enriched environment group ( P<0.05). (2)The time and group interaction, group main effect and time main effect of the escape latency among the 5 groups of mice were statistically significant ( F=11.2, 799.9, 121.8, all P<0.01). From day 2 to day 4, the escape latencies of mice in the enriched environment group, melatonin group and enriched environment+ melatonin group were significantly lower than that in the model group (all P<0.05). There was a statistically significant difference in the target quadrant residence time and cross-platform times among the 5 groups ( F=70.38, 48.83, both P<0.01). The target quadrant residence time and cross-platform times of mice in the enriched environment group, melatonin group, and enriched environment+ melatonin group were significantly higher than that in the model group (all P<0.05). (3) There were significant differences in the total number of alternations and correct rates among the 5 groups ( F=291.328, 113.482, both P<0.01). The total numbers of alternations and correct rates in melatonin group ((29.46±3.75)times, (53.16±3.47)%) and the enriched environment+ melatonin group((32.57±3.52)times, (58.60±4.13)%)were significantly higher than those in the model group ((18.62±3.96)times, (43.61±3.92) %)(all P<0.05). (4)The results of hematoxylin-eosin staining and immunohistochemistry staining showed that compared with the model group, the cell structure and morphology of the hippocampus of mice in enriched environment group, melatonin group, and enriched environment+ melatonin group were significantly improved, and the expression of Aβ 1-42 was significantly reduced (all P<0.05). (5) There were statistically significant differences in the levels of γ-H2AX and 8-OHdG proteins in the hippocampus of the 5 groups of mice ( F=78.09, 117.20, both P<0.01). The levels of γ-H2AX and 8-OHdG of mice in the enriched environment+ melatonin group ((1.37±0.26), (4.79±0.35)pg/μg) were significantly lower than those in the enriched environment group ((2.83±0.25), (7.23±0.41)pg/μg) and the melatonin group ((2.43±0.22), (6.69±0.28)pg/μg) (all P<0.05). Conclusion:Both enriched environment and melatonin can significantly improve the learning and memory function of SAMP8 mice, and the combined treatment effect is more significant.The mechanism may be related to the reduction of DNA oxidative damage in hippocampus.

Background::Sepsis, a serious condition with high mortality, usually causes sepsis associated encephalopathy (SAE) that involves neuronal cell death. However, the cell death programs involved and their underlying mechanisms are not clear. This study aimed to explore the regulatory mechanisms of different cell death programs in SAE.Methods::A neonatal rat model of SAE was established by cecal ligation and perforation. Survival rate and vital signs (mean arterial pressure and heart rate) were monitored, nerve reflexes were evaluated, and cortical pathological changes were observed by hematoxylin and eosin staining. The expression of pyroptosis, apoptosis, and necroptosis (PANoptosis)-related proteins, mitogen-activated protein kinase (MAPK), and its upstream regulator toll-like receptor 9 (TLR9) were detected. The expression of TLR9 in neurons was observed by immunofluorescence staining. The ultrastructure of neurons was observed by transmission electron microscope.Results::First, PANoptosis was found in cortical nerve cells of the SAE rats. Meanwhile, the subunits of MAPKs, p38 MAPK, Jun N-terminal kinase, and extracellular signal-regulated kinase (ERK) were activated. After pharmacologically inhibiting each of the subunits, only p38 MAPK was found to be associated with PANoptosis. Furthermore, blocking the p38 MAPK signaling pathway activated necroptosis but inhibited apoptosis and pyroptosis. When necroptosis was pharmacologically inhibited, apoptosis and pyroptosis were reactivated. Finally, we found that the expression of TLR9, a regulator of MAPKs, was significantly increased in this model. After down-regulation of TLR9, p38 MAPK, and ERK signaling pathways were inhibited, which led to the inhibition of PANoptosis. Further analysis found that down-regulation of TLR9 improved the survival rate and reduced the pathological changes in SAE rats.Conclusions::Our study showed that the programs comprising PANoptosis are activated simultaneously in SAE rats. TLR9 activated PANoptosis through the p38 MAPK signaling pathway. TLR9 may work as a potential target for SAE treatment.

Objective:To investigate the accuracy and feasibility of 3D-printing individualized template-guided and CT-guided 192Ir interstitial brachytherapy in the central recurrent gynecologic tumors by comparing pre-plan and intraoperative physical dosimetric parameters. Methods:This study involved 38 patients with central recurrent gynecologic tumors who underwent 3D printing individual template (3D-PIT)-assisted and CT-guided 192Ir interstitial brachytherapy in the Department of Radiation Oncology of the Peking University Third Hospital from Jan 2018 to Dec 2019.The prescription doses for the target tumor areas were 10-36 Gy to be delivered at 5-6 Gy/fraction for 2-6 fractions.The pre-plan and intraoperative dosimetric parameters were compared, including the minimum prescription doses delivered to 90% and 100% of target volume( D90, D100)and the mean percentage of volume receiving 100% of the prescription doses ( V100). Meanwhile, the doses delivered to 2 cm 3 ( D2 cm 3) of organs at risk (bladders, rectums, and colons) were analyzed.The quality parameters of the brachytherapy were studied, including conformity index (CI), homogeneity index (HI), and external index (EI) of the target volume.Perioperative complications were also observed. Results:A total of 194 treatments were included.During the treatment, 5-13 (median 6) needles were inserted, with a prescription dose of 5-6 Gy per fraction.There were no statistical differences between pre-plan and intraoperative D90, D100, V100, CI, HI, and EI as well as the D2 cm 3 of bladders and colons at risk ( P>0.05). In contrast, for the D2 cm 3 of rectums, the intraoperative dose was slightly higher than the pre-plan dose, showing a statistical difference ( t=-0.335, P=0.027). Conclusions:The 3D-PIT-assisted and CT-guided 192Ir interstitial brachytherapy at a high dose rate is accurate and feasible in the treatment of recurrent gynecologic tumors, meeting the pre-plan dose requirement.

The main treatment options for cervical cancer include surgery and/or radiotherapy combined with chemotherapy. Radiotherapy consists of external beam radiotherapy and brachytherapy (BT). BT contains high-dose-rate (HDR-BT) and low-dose-rate brachytherapy (LDR-BT). The prognosis of cervical cancer is relatively good. However, some patients experience substantial treatment failures, such as intra-pelvic and/or extra-pelvic recurrences. Recurrent cervical cancer (RCC) has poor prognosis due to lack of effective and safe approach. In 2002, Professor Wang Junjie introduced CT-guidance into the field of LDR-BT, and fully applied 3D printing technology in BT in 2015, which met the requirement of preoperative LDR-BT planning, and significantly improving the precision, quality and efficiency of BT. In 2018, Professor Wang Junjie proposed the concept of stereotactic ablation brachytherapy (SABT). Chinese experts have attempted to treat RCC with BT for nearly two decades and accumulated certain clinical experience. Based on the 3D-printing template (3D-PT) assisted CT-guidance, the standard and consensus of BT for RCC were established, including the indications, dosimetric requirements, technological procedures and radiation protection, etc. At present, there is still a lack of phage Ⅲ clinical and evidence-based medicine for the treatment of RCC with 3D-PT guidance, which requires prospective multi-center, randomized studies to improve the evidence-based level of BT.

Objective:To investigate the effect of jugular tubercle thickness on pathogenesis of hemifacial spasm (HFS) and its curative efficacy by microvascular decompression (MVD).Methods:One hundred and thirty-five HFS patients accepted MVD in our hospital from June 2017 to May 2018 were enrolled in this study. The thickness of the jugular tubercle was measured on preoperative magnetic resonance imaging (MRI) with steady state acquisition (FIESTA) sequence. The differences of jugular tubercle thickness and arterial flow rate from the jugular tubercle to the brainstem between the healthy side and symptomatic side in these patients were compared. These patients were divided into immediate symptom-relief group ( n=112) and symptom residual group ( n=23) according to the symptom relief one d after MVD; the difference of jugular tubercle thickness between the two groups were compared. Results:No significant difference in the jugular tubercle thickness was noted between the healthy side and the symptomatic side in all 135 patients ( t=0.787, P=0.432). The arterial flow rate from the jugular tubercle to the brainstem in the symptomatic side (95.6%) was significantly higher than that in the healthy side (57.0%, P<0.05). The jugular tubercle thickness in the symptomatic residual group ([5.13±2.19] mm) was significantly higher than that in the immediate symptom-relief group ([4.03±1.16] mm, t=2.114, P=0.0396). Conclusion:The thickness of jugular tubercle is not associated with HFS onset, but may affect the immediate outcome of MVD.

OBJECTIVE: To investigate the efficacy of image-guided radioactive 125I seed (IGRIS) implantation for pelvic recurrent cervical cancer (PRCC) after external beam radiotherapy (EBRT), and analyze the influence of clinical and dosimetric factors on efficacy. METHODS: From July 2005 to October 2015, 36 patients with PRCC received IGRIS. We evaluated local progression-free survival (LPFS) and overall survival (OS). RESULTS: The median follow up was 11.5 months. The 1- and 2-year LPFS rate was 34.9% and 20%, respectively. The multivariate analysis indicated recurrence site (central or pelvic wall) (hazard ratio [HR]=0.294; 95% confidence interval [CI]=0.121–0.718), lesion volume (HR=2.898; 95% CI=1.139–7.372), D 90 (HR=0.332; 95% CI=0.130–0.850) were the independent factors affecting LPFS. The 1- and 2-year OS rate was 52.0% and 19.6%, respectively. The multivariate analysis suggested pathological type (HR=9.713; 95% CI=2.136–44.176) and recurrence site (HR=0.358; 95% CI=0.136–0.940) were the independent factors affecting OS. The dosimetric parameters of 33 patients mainly included D 90 (128.5±47.4 Gy), D 100 (50.4±23.7 Gy) and V 100 (86.7%±12.9%). When D 90 ≥105 Gy or D 100 ≥55 Gy or V 100 ≥91%, LPFS was extended significantly, but no significant difference for OS. The 79.2% of 24 patients with local pain were suffering from pain downgraded after radioactive 125I seed implantation. CONCLUSION: IGRIS implantation could be a safe and effective salvage treatment for PRCC after EBRT, which could markedly release the pain. Recurrence site, tumor volume and dose were the main factors affected efficacy. Compared with central recurrence, it was more suitable for patients with pelvic wall recurrent cervical cancer after EBRT.
Brachytherapy ; Disease-Free Survival ; Follow-Up Studies ; Humans ; Multivariate Analysis ; Radiometry ; Radiotherapy* ; Radiotherapy, Image-Guided ; Recurrence ; Salvage Therapy* ; Tumor Burden ; Uterine Cervical Neoplasms*