Objective:To investigate whether short chain fatty acid(SCFAs) intervention has an antidepressant effect by improving gut microbiota dysregulation and regulating the TLR4/MyD88/NF-κB inflammatory pathway in depression model mice.Methods:Totally 60 SPF grade male C57BL/6 J mice aged 6-8 weeks were randomly divided into three groups: control group, depression model group, and SCFAs group, with 20 mice in each group.The mice in depression model group and SCFAs group were given the chronic unpredictable mild stress (CUMS) stimulations for 8 weeks to establish the depression model.From the 6th week, SCFAs group mice were given a mixed solution of short chain fatty acid salts for drinking, until modeling was completed, meanwhile mice in the model group were given 0.78% NaCl solution for drinking.The depression-like behavior was assessed using the sucrose preference test (SPT) and forced swimming test (FST) following modeling, and the open field test (OFT) was employed to evaluate the anxiety-like behavior of mice.16S rRNA gene sequence was used to analyze the gut microbiota of mice.The activation of astrocytes and TLR4/MyD88/NF-κB inflammatory pathway in hippocampus was determined by immunofluorescence staining and Western blot.SPSS 26.0 was used for statistical analysis, one-way ANOVA was used for comparison among the three groups, and LSD- t test was used for further pairwise comparisons. Results:There were statistically significant differences in the sugar water preference rate, the immobility time in FST, and the percentage of activity time in OFT among the three groups ( F=10.554, 10.912, 12.599, all P<0.05).The the sugar water preference rate and the percentage of activity time in OFT of the depression model group were both lower than those of the control group (both P<0.05), and the immobility time in FST was higher than that of the control group ( P<0.05).The sugar water preference rate in SCFAs group((84.7±3.5)%, (75.3±6.0)%)and the percentage of activity time in OFT((7.4±1.4)%, (3.2±0.9)%) were both higher than those in the depression model group(both P<0.05 ), while the immobility time in FST was shorter than that in the depression model group((110.5±21.5) s, (148.0±20.1) s, P<0.05).There was a statistical difference in the β diversity of gut microbiota among three groups ( P=0.001).At the family level, compared with the depression model group, the relative abundance of Rikenellaceaee and Bacteroidaceae increased in the SCFAs group, while the relative abundance of Clostridia_UCG-014 decreased.At the genus level, the relative abundance of Clostridia_UCG-014 and Prevotella decreased, while the relative abundance of Alistipes increased (all P<0.05).The immunofluorescence results showed that there was a statistically significant difference in GFAP expression levels among the three groups of mice ( F=16.565, P=0.004).The GFAP expression in the depression model group was higher than that in the control group and SCFAs group (both P<0.05).The Western blot results showed that there were statistically significant differences in the expression levels of TLR4, MYD88, and NF-κB ptoteins in the hippocampal tissue of the three groups ( F=70.59, 174.39, 14.40, all P<0.05).The protein levels of TLR4, MyD88, and NF-κB in the depression model group were all higher than those in the control group and SCFAs group (all P<0.05). Conclusion:SCFAs can ameliorate the depressive-like behavior in depression model mice and reduce the activation of astrocytes in the hippocampus, which may be associated with the improvement of dysregulated gut microbiota and down-regulation of the TLR4/MyD88/NF-κB pathway protein.

BACKGROUND:Tyrosine kinase inhibitors,as well as other types of small-molecule cancer drugs,can cause severe cardiotoxicity. OBJECTIVE:To perform a heart safety re-evaluation by observing the effects of antitumor drugs on isolated heart electrocardiograph,cardiac action potential and associated ion channels and cytotoxicity. METHODS:Extracorporeal cardiac perfusion was given to the isolated rabbit heart using Langendorff perfusion:Sunitinib(0.3,3,10 μmol/L),Crizotinib(0.3,1,3 μmol/L),and Doxorubicin(1,30 μmol/L)were perfused sequentially for 120 minutes to record electrocardiograph and left ventricular pressure.A blank control group was set for comparison.Manual patch clamp was used to record the effects of Crizotinib,Sunitinib,Doxorubicin on hERG,Cav1.2,Nav1.5 channel currents and action potential in human induced pluripotent stem cell derived cardiomyocytes.Adenosine triphosphate level in human induced pluripotent stem cell derived cardiomyocytes was detected by CellTiter-Glo luminescent cell viability assay. RESULTS AND CONCLUSION:Isolated rabbit heart using Langendorff perfusion:Compared with the blank ontrol group,Sunitinib and Crizotinib at≥3 μmol/L decreased heart rate(P<0.01)and prolonged QT/QTc interval(P<0.01),and reduced left ventricular pressure to different extents.Manual patch clamp recording:Compared with the blank control group,Sunitinib and Crizotinib at 3 μmol/L inhibited the activities of hERG,Nav1.5 and Cav1.2 channels and significantly prolonged the duration of action potential(P<0.01).According to the analysis of the test article,the difference between the labeled concentration and the measured concentration of the recovered solution was not significant.Cell viability assays:Compared with the blank control group,adenosine triphosphate content in human induced pluripotent stem cell derived cardiomyocytes significantly decreased after treatment with Sunitinib(IC50=4.64 μmol/L),Doxorubicin(IC50=4.21 μmol/L)and Crizotinib(IC50=2.87 μmol/L),indicating that cell viability significantly decreased(P<0.01).To conclude,this study successfully established an early cardiac safety evaluation method for antitumor drugs,which provides good support and help for the subsequent development of antitumor drugs.

Rotator cuff injury often leads to shoulder pain and dysfunction. For the injured rotator cuff tendon without continuous interruption, conservative treatment is often used. However, the shoulder is used frequent in daily life, which makes that the rotator cuff injury generally shows gradual aggravation and eventually progresses to complete tear due to poor blood supply of the rotator cuff tendon tissue and weak repair ability. In order to reverse the pathophysiological changes after rotator cuff injury and promote the repair of injured rotator cuff tendon, a series of conservative treatments for rotator cuff injury have been explored. Extracorporeal shock wave therapy (ESWT) is one of the representative treatments, but its molecular biological mechanism in promoting rotator cuff repair is still unclear. Therefore, the authors review the progress of ESWT for rotator cuff injury from aspects of the molecular biological mechanism and clinical application status, so as to provide a reference for future researches and clinical application of ESWT.

This article summarizes the pregnant women's readiness for discharge from five aspects, including the concept, research status at home and abroad, evaluation tools, influencing factors, and interventions of readiness for discharge, so as to provide reference for future research on pregnant women's readiness for discharge.

Objective:To explore the relationship between marital status and mild cognitive impairment in older adults.Methods:This study is a cluster random sampling.From January to December 2020, a questionnaire survey was conducted among older adults aged 60 years and over in four cities of Hebei Province.Finally, 2690 older adults with mild cognitive impairment and normal cognitive function were enrolled.The older adults were divided into 2 groups according to their marital status: married and living with their spouses(group E1), divorced or living alone(group E2). The mini-mental state examination(MMSE)scores of older adults in the two groups were compared.Moreover, the cognitive differences of older adults between the two groups and the interaction of marital status, social activities and life events on cognitive outcomes were analyzed.Results:The married older adults with partners had better cognitive preservation( P<0.01). The more life events were more likely to cause cognitive impairment( P<0.01), and the interaction of marital status, social activities and life events had a significant impact on cognition( P<0.01). Older men who were married and lived with spouse had better cognition than older women who were married and lived with spouse( P<0.05 in Model 3). The cognition of widowed elderly women was better than those of widowed elderly men( P<0.1 in Model 1; P<0.1 in Model 2). Among elderly men, the cognition of those married and living with spouse was better than that those of widowed( P<0.01 in models 1 and 2, P<0.1 in model 3). Among elderly women, those married and living with spouse had better cognitive outcomes than those widowed( P<0.01 in Model 1, P<0.01 in Model 2). Conclusions:Marital companionship is a protective factor for the cognition of older adults, and there are gender differences in the impact of marital status on cognition in late life.

BackgroundThe comorbidity rate of bipolar disorder and borderline personality disorder （BPD） is high， and the cognitive impairment of comorbidity patients is more serious. ObjectiveTo explore the difference of cognitive function between bipolar disorder patients with BPD or not， so as to provide references for clinical diagnosis and treatment. MethodsUsing simple random sampling， 60 patients with bipolar disorder comorbidity BPD treated in the First Hospital of Hebei Medical University from April 2021 to April 2022 were selected as the research group， including 33 patients with bipolar depression and 27 patients with bipolar mania. At the same time， 60 patients with bipolar disorder were randomly selected as the control group， including 35 patients with bipolar depression and 25 patients with bipolar mania. The cognitive function of patients was evaluated by the Chinese version of Repeatable Battery for the Assessment of Neuropsychological Status （RBANS） and the Stroop Color Word Test. ResultsThe immediate memory， visual span， speech function and total score of RBANS in the comorbid group were lower than those in the non-comorbid group， and the differences were statistically significant （t=-2.356， -2.138， -3.306， -2.729， P<0.05 or 0.01）. The single word time， single color time， double word time and double color time in Stroop Color Word Test in comorbid group were longer than those in non-comorbid group， and the differences were statistically significant （t=4.808， 3.341， 5.249， 5.167， P<0.01）. The immediate memory， visual span， speech function and total score in RBANS of bipolar depression patients with comorbid BPD were lower than those of bipolar depression patients without comorbid BPD （t=-2.446， -2.407， -2.231， -2.078， P<0.05）， and the time of single word， single color， double word and double color in Stroop Color Word Test were longer than those of non-comorbid BPD patients （t=-3.652， 3.035， 4.406， 5.016， P<0.01）. The speech function and total score of RBANS in bipolar manic patients in comorbid group were higher than those in non-comorbid group （t=-2.777， -2.347， P<0.05 or 0.01）， and the time of single word， single color， double word and double color in Stroop Color Word Test were longer than those in non-comorbid group （t=3.600， 2.658， 2.943， 4.337， P<0.05 or 0.01）. ConclusionThe cognitive impairment of bipolar disorder patients comorbid with BPD is more severe than that of patients without comorbid with BPD. ［Funded by Medical Science Research Project of Hebei Province in 2022 （number， 20221407）］

Activating humoral and cellular immunity in lymph nodes (LNs) of nanoparticle-based vaccines is critical to controlling tumors. However, how the physical properties of nanovaccine carriers orchestrate antigen capture, lymphatic delivery, antigen presentation and immune response in LNs is largely unclear. Here, we manufactured gold nanoparticles (AuNPs) with the same size but different shapes (cages, rods, and stars), and loaded tumor antigen as nanovaccines to explore their disparate characters on above four areas. Results revealed that star-shaped AuNPs captured and retained more repetitive antigen epitopes. On lymphatic delivery, both rods and star-shaped nanovaccines mainly drain into the LN follicles region while cage-shaped showed stronger paracortex retention. A surprising finding is that the star-shaped nanovaccines elicited potent humoral immunity, which is mediated by CD4⁺ T helper cell and follicle B cell cooperation significantly preventing tumor growth in the prophylactic study. Interestingly, cage-shaped nanovaccines preferentially presented peptide-MHC I complexes to evoke robust CD8⁺ T cell immunity and showed the strongest therapeutic efficacy when combined with the PD-1 checkpoint inhibitor in established tumor study. These results highlight the importance of nanoparticle shape on antigen delivery and presentation for immune response in LNs, and our findings support the notion that different design strategies are required for prophylactic and therapeutic vaccines.

Objective To explore the correlation between childhood trauma and plasma adiponectin levels in patients with depression.Methods A total of 121 patients with depression and 39 healthy controls(control group)were enrolled.Childhood trauma questionnaire(CTQ-SF)was used to assess the experience of childhood abuse and neglect,and the patients with depression were divided into trauma group(n=53)and non-trauma group(n=68)according to the CTQ-SF score.The 17-item Hamilton depression scale-17(HAMD17)and the Hamilton anxiety scale(HAMA)were used to evaluate the severity of depression and anxiety symptoms,respectively.Plasma adiponectin levels of subjects were measured by enzyme-linked immunosorbent assay.Results The plasma adiponectin level of trauma group[3.82(2.44,4.92)μg/mL]was significantly lower than that of non-trauma group[4.64(2.98,6.43)μg/mL,P=0.01]and the control group[6.29(4.54,7.51)μg/mL,P＜0.01].The plasma adiponectin level of non-trauma group was lower than that of the control group(P＜0.01).Correlation analysis showed that plasma adiponectin level in patients with depression was negatively correlated with childhood trauma(r=-0.34,P＜0.01).Multivariate linear regression analysis showed that plasma adiponectin level was negatively correlated with childhood trauma scores in patients with depression(β=-0.05,P＜0.01).Conclusions Patients with depression who have experienced childhood trauma have lower plasma levels of adiponectin,and childhood trauma may be associated with decreased plasma adiponectin levels in patients with depression.

The continuing challenges that limit effectiveness of tumor therapeutic vaccines were high heterogeneity of tumor immunogenicity, low bioactivity of antigens, as well as insufficient lymph nodes (LNs) drainage of antigens and adjuvants. Transportation of in situ neoantigens and adjuvants to LNs may be an effective approach to solve the abovementioned problems. Therefore, an FA-TSL/AuNCs/SV nanoplatform was constructed by integrating simvastatin (SV) adjuvant loaded Au nanocages (AuNCs) as cores (AuNCs/SV) and folic acid modified thermal-sensitive liposomes (FA-TSL) as shells to enhance de novo antitumor immunity. After accumulation in tumor guided by FA, AuNCs mediated photothermal therapy (PTT) induced the release of tumor-derived protein antigens (TDPAs) and the shedding of FA-TSL. Exposed AuNCs/SV soon captured TDPAs to form in situ recombinant vaccine (AuNCs/SV/TDPAs). Subsequently, AuNCs/SV/TDPAs could efficiently transport to draining LNs owing to the hyperthermia induced vasodilation effect and small particle size, achieving co-delivery of antigens and adjuvant for initiation of specific T cell response. In melanoma bearing mice, FA-TSL/AuNCs/SV and laser irradiation effectively ablated primary tumor, against metastatic tumors and induced immunological memory. This approach served a hyperthermia enhanced platform drainage to enable robust personalized cancer vaccination.

Objective:To investigate the effect of salvianolic acid on depressive behavior in depression model rats induced by chronic mild stress (CMS) and its mechanism.Methods:Fifty healthy male clean grade Sprague-Dawley(SD) rats were divided into five groups according to a random number table with 10 in each group: control group (nCMS+ Nal group), CMS+ normal saline group (CMS+ Nal group), CMS+ fluoxetine group (CMS+ Flu group), CMS+ salvia acid group (CMS+ Sal group), CMS+ fluoxetine+ Salvia acid group (CMS+ Flu+ Sal group). Except the control group, the rats in the other four groups were all received CMS modeling for 21 days. Twenty-one days after CMS modeling, rats were intraperitoneally injected with 0.9% normal saline (10 mg·kg -1·d -1), fluoxetine (20 mg·kg -1·d -1), salvia acid(40 mg·kg -1·d -1), fluoxetine(20 mg·kg -1·d -1)+ salvia acid(40 mg·kg -1·d -1)for 21 days. During the administration period, rats in the other four groups continued to receive CMS intervention for 21 days. Forced swimming test and sucrose preference test were conducted at baseline (day 0), after modeling (day 21) and after intervention (day 42) so as to evaluate depression like behavior. Then the rats were sacrificed and the hippocampus and prefrontal cortex were taken. The mRNA levels of Toll like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) were detected by RT-qPCR. The cytokines including interleukin-1β(IL-1β), interleukin-2(IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were detected by Luminex technique.SPSS 21.0 was used for statistical analysis.Repeated measurement ANOVA was used for behavioral data analysis, one-way ANOVA was used for molecular index data analysis, and Spearman was used for correlation analysis. Results:The results of repeated measurement ANOVA showed that the interaction effects between group and time of body mass, sucrose preference, forced swimming immobility time were significant at baseline, after modeling and after intervention ( F=18.238, 6.921, 7.591, all P<0.05). After modeling, compared with nCMS+ Nal group, the rats in CMS+ Flu group, CMS+ Sal group, CMS+ Flu+ Sal group and CMS+ Nal group had lower body weight, lower sucrose preference rate and longer forced swimming immobility time (all P<0.05). After intervention, compared with CMS+ Nal group(body weight (350.15±41.65)g, sucrose preference(52.95±11.13)%, static time(91.40±15.22)s), the body weight((378.21±30.78)g, (385.12±43.19)g, (391.41±31.21)g, (402.33±18.67)g, all P<0.05) and sucrose preference((69.30±15.56)%, (68.12±10.99)%, (71.18±9.51)%, (75.47±11.55)%, all P<0.05) of CMS+ Flu group, CMS+ Sal group, CMS+ Flu+ Sal group and nCMS+ Nal group were all increased, while the forced swimming immobility time ((68.81±21.74)s, (66.10±25.51)s, (63.53±22.32)s, (71.21±21.41)s, all P<0.05) were shorter (all P<0.05). After intervention, among the body weight, sucrose preference and the immobility time of CMS+ Flu group、CMS+ Sal group and CMS+ Flu+ Sal group, there were no differences between each two groups(all P>0.05). After intervention, the levels of TLR4 mRNA and MyD88 mRNA in prefrontal cortex and hippocampus of CMS+ Flu group, CMS+ Sal group, CMS+ Flu+ Sal group and nCMS+ Nal group were all lower than those in CMS+ Nal group (all P<0.05). In prefrontal cortex, the levels of TLR4 mRNA (0.715±0.358) and MyD88 mRNA (0.739±0.233) in CMS+ Flu+ Sal group were lower than those in CMS+ Sal group (1.943±0.606, 1.815±0.897) (both P<0.05). The level of TLR4 mRNA in prefrontal cortex and hippocampus of rats were positively correlated with the level of MyD88 mRNA and TNF-α level and forced swimming immobility time and negatively correlated with sucrose preference rate (prefrontal cortex r=0.915, 0.041, 0.027, -0.178, all P<0.05; hippocampus r=0.810, 0.070, 0.011, -0.153, all P<0.05). Conclusion:The antidepressant effect of salvianolic acid is presumedly achieved by inhibiting the immunoinflammatory response mediated by the TLR4/Myd88 signaling pathway in CMS rats.