ObjectiveTo explore the mechanism by which Xiaoyaosan regulates HPT axis dysfunction in the rat model with the syndrome of liver depression and spleen deficiency by observing its effect on the glycoprotein hormone α-subunit （CGA）/glutathione peroxidase 2 （GPX2）/thyroid-stimulating hormone β-subunit （TSHβ） pathway for thyroid hormone synthesis. MethodsSeventy-two male SD rats were randomized into six groups： normal， model， high-dose （16.7 g·kg^-1）， medium-dose （8.35 g·kg^-1）， and low-dose （4.175 g·kg^-1） Xiaoyaosan， and fluoxetine （0.001 8 g·kg^-1） groups， with 12 rats in each group. The rat model of liver depression and spleen deficiency was induced by chronic restraint stress for 21 days. The intervention groups were treated with Xiaoyaosan decoctions or fluoxetine suspension， respectively. After modeling， hematoxylin-eosin staining was employed to observe morphological changes in the thyroid and pituitary tissue of the rats. Serum levels of triiodothyronine （T3）， tetraiodothyronine （T4）， and thyroid-stimulating hormone （TSH） were measured by enzyme-linked immunosorbent assay （ELISA）. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot were employed to determine the mRNA and protein levels， respectively， of TSH receptor （TSHR） in the thyroid tissue， thyrotropin-releasing hormone receptor （TRHR） and TSHβ in the pituitary tissue， and thyrotropin-releasing hormone （TRH）， CGA， GPX2， and TSHβ in the hypothalamic tissue. ResultsCompared with the normal group， the model group showed significant atrophy and irregularity of thyroid follicles， a marked reduction in colloid secretion， extensive vacuolar degeneration of adenocytes in the anterior pituitary， lowered serum levels of T3， T4， and TSH （P<0.01）， and down-regulated mRNA and protein levels of TSHR in the thyroid tissue， TRHR and TSHβ in the pituitary tissue， and TRH， CGA， GPX2， and TSHβ in the hypothalamic tissue （P<0.01）. Compared with the model group， high- and medium-dose Xiaoyaosan and fluoxetine alleviated the pathological changes in the thyroid and pituitary tissue， outperforming the low-dose Xiaoyaosan group. Moreover， they elevated the serum levels of T3， T4， and TSH （P<0.05， P<0.01）. The serum TSH level was also elevated in the low-dose Xiaoyaosan group （P<0.05）. The mRNA and protein levels of TSHR in the thyroid， TRHR and TSHβ in the pituitary， and TRH， CGA， GPX2， and TSHβ in the hypothalamus were up-regulated in the high- and medium-dose Xiaoyaosan groups （P<0.05， P<0.01）. Additionally， the mRNA and protein levels of TSHβ in the hypothalamus were up-regulated in the low-dose Xiaoyaosan group （P<0.01）. In the fluoxetine group， the mRNA and protein levels of TSHR in the thyroid， TRHR in the pituitary， and TRH， CGA， and GPX2 in the hypothalamus were up-regulated （P<0.05， P<0.01）. ConclusionThe downregulation of CGA/GPX2/TSHβ pathway may be one of the biological mechanisms underlying HPT axis dysfunction in the rat model with the syndrome of liver depression and spleen deficiency. Xiaoyaosan may regulate the HPT axis dysfunction by up-regulating the CGA/GPX2/TSHβ pathway.

ObjectiveTo observe the effects of modified Chaihu Shugansan on the calmodulin-dependent protein kinase Ⅱ（CaMKⅡ）/cAMP-response element binding protein （CREB） signaling pathway in the hippocampus and heart tissue of a rat model with myocardial ischemia and depression and explore the mechanism by which this formula prevents and treats coronary heart disease combined with depression. MethodsThe model of myocardial ischemia combined with depression was established by high-fat diet， intraperitoneal injection of isoproterenol （ISO）， and chronic unpredictable mild stress （CUMS）. A total of 108 SD male rats were randomly divided into normal group， model group， high （23.4 g·kg^-1）， medium （11.7 g·kg^-1）， and low （5.85 g·kg^-1） dose groups of modified Chaihu Shugansan， CaMKⅡ inhibitor （KN93） group， and KN93 + high， medium， and low dose groups of modified Chaihu Shugansan， with 12 rats in each group. From the first day of modeling to the end of modeling， drugs were administered once a day. In the seventh and eighth weeks， the KN93 group and the KN93 + high， medium， and low dose groups of modified Chaihu Shugansan were intraperitoneally injected with KN93 three times weekly. At the end of the eighth week， behavioral tests including sucrose preference， open field， and elevated plus maze were conducted. Electrocardiogram （ECG） lead Ⅱ changes were observed in each group of rats， and hematoxylin-eosin （HE） staining was performed to observe changes in heart tissue. Serum levels of triglycerides （TG）， total cholesterol （TC）， high-density lipoprotein （HDL）， low-density lipoprotein （LDL）， and lactate dehydrogenase （LDH） were measured by using an enzyme-labeled instrument. Creatine kinase （CK） and creatine kinase-MB （CK-MB） were detected by ultraviolet spectrophotometry， while serum monocyte chemoattractant protein-1 （MCP-1） was measured by enzyme-linked immunosorbent assay （ELISA）. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect mRNA expression of CaMKⅡ and CREB in hippocampal and heart tissue， and Western blot was performed to assess protein expression of CaMKⅡ， phosphorylated （p）-CaMKⅡ， CREB， and p-CREB. ResultsCompared to the normal group， the model group showed significant reductions in sucrose preference rate， total activity distance in the open field， number of entries into the center area of the open field， and percentage of entries into the open arms of the elevated plus maze （P<0.01）. The ECG showed ST-segment elevation， and HE staining showed serious degeneration of myocardial fibers， disordered arrangement， and infiltration of a large number of inflammatory cells. In addition， serum TC and LDL levels increased （P<0.01）， and HDL level decreased （P<0.01）. CK， CK-MB， LDH， and MCP-1 levels significantly increased （P<0.05， P<0.01）. The mRNA expression of CaMKⅡ and CREB and the protein expression of p-CaMKⅡ and p-CREB decreased in the hippocampal tissue （P<0.05， P<0.01）， but those increased in the heart tissue （P<0.01）. Compared to the model group， the high， medium， and low dose groups of modified Chaihu Shugansan showed improvements in these abnormalities. The KN93 group had reduced sucrose preference， total activity distance in the open field， number of entries into the center area of the open field， and percentage of entries into the open arms of the elevated plus maze （P<0.01）， as well as decreased serum CK， CK-MB， LDH， and MCP-1 levels （P<0.05， P<0.01）. KN93 also reduced ST-segment elevation， alleviated the degeneration degree of myocardial fibrosis， and lowered inflammatory cell infiltration. The mRNA expression of CaMKⅡ and CREB and the protein expression of p-CaMKⅡ and p-CREB in both the hippocampal and heart tissue were reduced （P<0.05， P<0.01）. The KN93 + high， medium， and low dose groups of modified Chaihu Shugansan showed further improvements in these abnormalities compared to the KN93 group. ConclusionThe modified Chaihu Shugansan exerts antidepressant and myocardial protective effects in rats with myocardial ischemia and depression， possibly related to bidirectional regulation of the CaMKⅡ/CREB signaling pathway， with the high-dose modified Chaihu Shugansan showing the best effects.

Aldehyde oxidase (AOX) is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics. AOX-mediated metabolism can result in unexpected outcomes, such as the production of toxic metabolites and high metabolic clearance, which can lead to the clinical failure of novel therapeutic agents. Computational models can assist medicinal chemists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability. In this study, we developed a novel graph neural network called AOMP for predicting AOX-mediated metabolism. AOMP integrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction, while utilizing transfer learning from ¹³C nuclear magnetic resonance data to enhance its performance on both tasks. AOMP significantly outperformed the benchmark methods in both cross-validation and external testing. Using AOMP, we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability, which were validated through in vitro experiments. Furthermore, for the convenience of the community, we established the first online service for AOX metabolism prediction based on AOMP, which is freely available at https://aomp.alphama.com.cn.

Hemodynamics plays a vital role in the development and progression of cardiovascular diseases, and is closely associated with changes in morphology and function. Reliable detection of hemodynamic changes is essential to improve treatment strategies and enhance patient prognosis. The combination of computational fluid dynamics with cardiovascular imaging technology has extended the accessibility of hemodynamics. This review provides a comprehensive summary of recent developments in the application of computational fluid dynamics for cardiovascular hemodynamic assessment and a succinct discussion for potential future development.

Objective To observe the value of the ratio of cerebral hyperdensities(PCHD)/venous sinus maximum density for predicting hemorrhagic transformation(HT)after endovascular treatment(EVT)in patients with acute ischemic stroke(AIS).Methods Data of 79 AIS patients with PCHD immediately after EVT were retrospectively analyzed.The patients were divided into HT group(n=41)or non-HT group(n=38)based on the presence of HT or not.Clinical data and CT parameters were compared between groups.The value of the ratio of PCHD/venous sinus maximum density for predicting HT was evaluated.Results The maximum density of PCHD and the ratio of PCHD/venous sinus maximum density in HT group were both higher than those in non-HT group(both P＜0.001).Taken 87 HU as the best cut-off value of the maximum density of PCHD,the sensitivity,specificity and area under the curve(AUC)for predicting HT after EVT in AIS patients was 90.24%,71.05%and 0.79,respectively.Taken 0.94 as the best cut-off value of the ratio of PCHD/venous sinus maximum density,the sensitivity,specificity and AUC was 97.56%,71.05%and 0.81,respectively.No significant difference of AUC was found between the former and the latter(P＞0.05).Conclusion The ratio of PCHD/venous sinus maximum density immediately after EVT could be used to predict HT in AIS patients.

BACKGROUND:Resistance exercise increases muscle mass and improves muscle strength,but there is a lack of conclusive evidence on its effects on body composition.Controversial results from randomized controlled trials and multiple Meta-analyses pose a problem for clinical decisions on exercise interventions. OBJECTIVE:Based on the methodological paradigm of umbrella review,to explore the efficacy and safety of resistance exercise in improving the body composition of overweight and obese people. METHODS:We searched PubMed,Cochrane Library,Web of Science,and CNKI for systematic reviews on the effect of resistance exercise in overweight and obese people published from database inception to August 31,2022.Chinese search terms included"anti-resistance,resistance,self-weight,Meta,Meta-analysis,body composition,body fat percentage,fat mass,lean body mass,body mass."English search terms included"resistance training,strength training,weight-lifting strengthening program,body composition,body fat distribution,Meta-analysis,data pooling,overviews,clinical trial,clinical trial overviews."PRISMA was used to evaluate the methodological quality of the included studies,and a GRADE evaluation system was used to grade the quality of evidence. RESULTS AND CONCLUSION:A total of 14 Meta-analyses were included,and GRADE evidence quality evaluation showed that 2 outcome indicators were intermediate,12 were low,and 14 were extremely low.Compared with the control group,23 of the 32 outcome measures showed significant improvement.The intervention effect of resistance exercise on body fat percentage has reached a consensus,but the intervention effects on lean body mass,body mass index and visceral fat still need further confirmation.Resistance exercise is an effective and safe method to improve the body composition of overweight and obese people.The overall quality of the research and the evidence quality of the outcome indicators included in the systematic evaluation are generally low.In the future,the initial state,exercise goal and willingness of the subjects should be fully combined on the basis of clarifying the sample characteristics and refining the scheme design.Through multiple,scientific and personalized exercise prescription designs of water,air and elastic resistance,the safety and compliance of resistance exercise can be improved,providing clear evidence-based support and decision-making basis for resistance exercise intervention.

OBJECTIVE:Masks are one of the most important defenses against the virus.However,the impact of wearing masks during daily activities or sports on respiratory and circulatory function remains controversial.A comprehensive quantitative evaluation of the effects of mask-wearing on human heart rate,oxygen saturation and end-expiratory carbon dioxide by Meta-analysis was conducted.The effects of wearing different types of masks at different exercise intensities and time of exercise on the human respiratory and circulatory system were explored. METHODS:By February 2023,with"mask,face mask,N95,training,sports,running,walking,cycling"as the Chinese search terms and"masks,respiratory protective devices,N95 respirators,surgical face masks,exercise,resistance training,explosive training,muscle exercises"as English search terms,the experimental studies addressing the influence of exercise with a mask on hemodynamic indexes were retrieved from CNKI,Web of Science,PubMed,Cochrane Library and WanFang databases.The outcome indicators included three continuous variables-exercise center rate,blood oxygen saturation and end-expiratory carbon dioxide.Stata16.0 software was used to analyze the outcome indicators of the included literature.The PEDro scale was used as a quality assessment tool,and the funnel plot was used to analyze the impact of publication bias. RESULTS:Totally 25 articles involving 857 healthy children and adults were included in this Meta-analysis.The overall methodological quality was high,with 22 studies scoring 6 points on the PEDro scale,2 studies scoring 7 points and 1 study scoring 8 points.The meta-analysis results showed that compared with the control group,exercise with masks had no significant effect on heart rate(SMD=0.02,95%CI:-0.11 to 0.15,P=0.81),but increased end-expiratory carbon dioxide(SMD=0.60,95%CI:0.37 to 0.83,P=0.00),decreased oxygen saturation(SMD=-0.28,95%CI:-0.47 to-0.09,P=0.03).Intensity and duration were the factors that affected the heterogeneity between studies.Wearing a mask during high-intensity exercise significantly increased heart rate(SMD=-0.20,95%CI:-0.36 to-0.04,P=0.02).The effect of high-intensity and short-time exercise on blood oxygen saturation was significantly higher than that of other exercises(SMD=-0.40,95%CI:-0.70 to-0.10;SMD=-0.25,95%CI:-0.45 to-0.04).For end-expiratory carbon dioxide,maintaining a certain intensity and increasing the exercise time or increasing the intensity further increased the index significantly,reaching a moderate effect size(SMD=0.61,95%CI:0.06 to 1.15;SMD=0.58,95%CI:0.04 to 1.13). CONCLUSION:Existing evidence suggests that exercise with masks may have the adverse effect of increasing end-expiratory carbon dioxide and decreasing blood oxygen saturation.The influence of different exercise test time and intensities on the three outcome indexes was different.Wearing a mask during high-intensity exercise can significantly increase heart rate and decrease blood oxygen saturation.Maintaining moderate intensity for a long period or further increasing the intensity of exercise will lead to increased end-expiratory carbon dioxide levels.

Objective:To study the current status of longitudinal extrauterine growth restriction (EUGR) in extremely preterm infants (EPIs) and to develop a prediction model based on clinical data from multiple NICUs.Methods:From January 2017 to December 2018, EPIs admitted to 32 NICUs in North China were retrospectively studied. Their general conditions, nutritional support, complications during hospitalization and weight changes were reviewed. Weight loss between birth and discharge > 1SD was defined as longitudinal EUGR. The EPIs were assigned into longitudinal EUGR group and non-EUGR group and their nutritional support and weight changes were compared. The EPIs were randomly assigned into the training dataset and the validation dataset with a ratio of 7∶3. Univariate Cox regression analysis and multiple regression analysis were used in the training dataset to select the independent predictive factors. The best-fitting Nomogram model predicting longitudinal EUGR was established based on Akaike Information Criterion. The model was evaluated for discrimination efficacy, calibration and clinical decision curve analysis.Results:A total of 436 EPIs were included in this study, with a mean gestational age of (26.9±0.9) weeks and a birth weight of (989±171) g. The incidence of longitudinal EUGR was 82.3%(359/436). Seven variables (birth weight Z-score, weight loss, weight growth velocity, the proportion of breast milk ≥75% within 3 d before discharge, invasive mechanical ventilation ≥7 d, maternal antenatal corticosteroids use and bronchopulmonary dysplasia) were selected to establish the prediction model. The area under the receiver operating characteristic curve of the training dataset and the validation dataset were 0.870 (95% CI 0.820-0.920) and 0.879 (95% CI 0.815-0.942), suggesting good discrimination efficacy. The calibration curve indicated a good fit of the model ( P>0.05). The decision curve analysis showed positive net benefits at all thresholds. Conclusions:Currently, EPIs have a high incidence of longitudinal EUGR. The prediction model is helpful for early identification and intervention for EPIs with higher risks of longitudinal EUGR. It is necessary to expand the sample size and conduct prospective studies to optimize and validate the prediction model in the future.

AIM:The objective of this study is to examine the expression of profilin 1(PFN1)in mice with di-abetic nephropathy and determine its association with immune cell infiltration.METHODS:This study presents an analy-sis of PFN1 expression and immune cell infiltration in patients with diabetic nephropathy,utilizing transcriptome expres-sion data from kidney tissue microarray.Additionally,the findings were validated in a diabetic nephropathy mouse model.Sixteen C57BL/6 mice were randomly assigned into two groups,namely the normal group and the model group,in an equal manner.The model group underwent the establishment of the diabetic nephropathy model through intraperitoneal injection of streptozotocin.Subsequently,the expression levels of CD11b,F4/80,CC chemokine receptor 4(CCR4),interleukin-1 receptor type I(IL-1R1),B-cell lymphoma-2(Bcl-2),Bcl-2-associated X protein(Bax)and caspase-3 in kidney tissue were assessed upon successful establishment of the diabetic nephropathy model.Furthermore,the overexpression of PFN1 was observed in a cellular model of diabetic nephropathy,and the protein expression levels of monocyte chemotactic pro-tein-1(MCP-1)and caspase-3 were assessed.RESULTS:The expression of PFN1 was found to be significantly in-creased in the GSE30122 dataset of transcriptome expression in kidney tissues affected by diabetic nephropathy(P＜0.01).This increase in PFN1 expression was found to be correlated with the presence of macrophages and T cells.Fur-thermore,the renal tissue of the diabetic nephropathy model group exhibited significant pathological changes.In this mod-el group,the expression levels of PFN1,CD11b,F4/80,CCR4,IL-1R1,Bax,Bcl-2,and caspase-3 were all significant-ly increased(P＜0.01).Overexpression of PFN1 could enhance the expression of MCP-1 and caspase-3 proteins.CON-CLUSION:Macrophages and Th17 cells were identified within the renal tissue of mice with diabetic nephropathy,con-comitant with an up-regulation in the expression of PFN1.This up-regulation was observed to facilitate the induction of apoptosis in the context of diabetic nephropathy.

Objective:To investigate the effects of carbon black and cadmium (Cd) combined exposure on autophagy and inflammatory response mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) pathway in human bronchial epithelial (16HBE) cells.Methods:In January 2022, human bronchial epithelial (16HBE) cells were resuscitated and cultured. Carbon black nanoparticles (CBNPs) were oxidized to adsorb Cd ions to construct "CBNPs-Cd" complexes. CCK-8 assay was used to detect the effects of different concentrations and time combinations of CBNPs and Cd on the viability of 16HBE cells. The subsequent dose groups were exposed to 2 μg/ml Cd, 100 μg/ml CBNPs, 100 μg/ml CBNPs+2 μg/ml Cd for 24 h. The number of autophagosomes and autolysosomes was detected by transmission electron microscopy. Western blotting was used to detect the protein expressions of PERK, eukaryotic initiation factor 2α (eIf2α), activating transcription factor 4 (ATF4), sequestosome 1 (SQSTM1/P62), and microtubule-associated protein 1 light chain 3 (LC3). After PERK gene was silenced by siRNA technology, the changes of autophagy marker proteins P62 and LC3 were detected, and the expressions of inflammatory factors interleukin-6 (IL6) and interleukin-8 (IL8) were detected by fluorescence quantitative PCR technique. One-way ANOVA analysis was used to compare three groups or more. LSD test was used for comparison between two groups. Factorial analysis was used for multivariate component analysis. Results:There was no significant change in cell viability of 16HBE after 24 h exposure to CBNPs and Cd alone or combined ( P>0.05). Compared with the control group, the expressions of P62 and LC3 in 16HBE cells were significantly increased in the CBNPs and Cd alone/combined exposure group ( P<0.05), and the number of autophagosomes and autophagolysosomes in the combined exposure group was increased compared with other groups. Compared with the control group, CBNPs and Cd alone exposure group had no significant effects on p-PERK/PERK and p-eIf2α/eIf2α protein expression ( P>0.05). However, the protein expressions of p-PERK/PERK and p-eIf2α/eIf2α and ATF4 were all increased in the combined exposure group ( P<0.05), and the levels of IL6 and IL8 in 16HBE cells in the combined exposure group of CBNPs and Cd were significantly higher than those in the control group ( P<0.05). The levels of LC3 protein, IL6 and IL8 were decreased in the CBNPs-Cd combined exposure group after knockdown of PERK gene ( P<0.05). The results of factorial analysis showed that exposure to CBNPs and Cd had significant effects on the expression of P62, LC3 and IL6 ( P<0.05), but the interaction between the two chemicals had no statistical significance ( P>0.05) . Conclusion:CBNPs-Cd combined exposure may inhibit autophagy and increase inflammation in human bronchial epithelial cells through activation of PERK-eIf2α-ATF4 pathway.