The relationship between serum resolvin D1, NLRP3, cytokine levels, and adolescents with first-episode medication-naïve major depressive disorder.

BACKGROUND: Inflammation has become a critical pathological mechanism of Major Depressive Disorder (MDD). NLRP3 is a critical inflammatory pathway to maintain the immune balance. Recently, preclinical evidence showed that Resolvin D1 might potentially offer a new option for antidepressant treatment due to its protective effects through the inhibition of neuroinflammation. However, whether they have clinical value in the diagnosis and treatment evaluation of adolescent depression was unclear. METHODS: Forty-eight untreated first-episode adolescent patients with moderate to severe major depressive disorder, as well as 30 healthy adolescents (HCs, age and gender-matched), were enrolled for this study. Their ages ranged from 13 to 18 (15.75 ± 1.36) years. The patients were treated with fluoxetine for 6-8 weeks. HDRS-17 was used to evaluate the severity of depressive symptoms. Venous blood samples were collected at baseline for the two groups and at the time-point of post-antidepressant treatment for the patients. Serum concentrations of RvD1, NLRP3, IL-1ß, IL-18, and IL-4 were measured by enzyme-linked immunosorbent assays (ELISA) pre- and post-fluoxetine treatment. RESULTS: Serum levels of RvD1 and anti-inflammatory cytokine IL-4 were significantly elevated in adolescents with MDD compared to healthy adolescents, but no significant difference in NLRP3, IL-1ß, and IL-18 between the two groups. Meanwhile, RvD1 (positively) and IL-4 (negatively) were correlated with the severity of symptoms (HDRS-17 scores) after adjusting age, gender, and BMI. Interestingly, fluoxetine treatment significantly reduced the serum levels of RvD1, NLRP3, IL-1ß, and IL-18 in MDD adolescents but increased the levels of IL-4 relative to baseline. Furthermore, we observed that serum levels of RvD1 might be an excellent distinguishing indicator for depression and healthy adolescents. CONCLUSIONS: Our study is the first to compare RvD1 and NLRP3 between adolescent MDD and HCs. Our findings of reactive increase of RvD1 in adolescent MDD comprised a novel and critical contribution. Our results showed the presence of inflammation resolution unbalanced in adolescents with MDD and indicated that RvD1 might be an ideal biomarker for diagnosing and treating adolescent MDD.

ACAT2 suppresses the ubiquitination of YAP1 to enhance the proliferation and metastasis ability of gastric cancer via the upregulation of SETD7.

The contributions of aberrantly expressed metabolic enzymes to gastric cancer (GC) initiation and progression have been widely appreciated in recent years. Acetyl-CoA acetyltransferase 2 (ACAT2) is one member of the acetyl- CoA thiolase family. Previous studies demonstrated that ACAT2 either promotes or suppresses tumor progression in different conditions. However, the function and mechanisms of ACAT2 in GC remain unknown. We found that the expression of this enzyme was significantly increased in GC tissues compared with normal counterparts, which prompted us to further investigate the roles of this protein in GC biology. In vitro functional studies showed that ACAT2 knockdown markedly halted the proliferation and the motility of GC cells; these functions favoring malignant phenotypes of GC cells were further validated in animal experiments. Mechanistically, ACAT2 depletion significantly reduced the transcription of SETD7, which is a histone methyltransferase and plays critical roles in GC cells. We found that the pro-tumoral functions of ACAT2 were largely dependent on SETD7. Moreover, SETD7 decreased the ubiquitination level of Yes-associated protein 1 (YAP1), thereby protecting YAP1 from proteasome degradation. Increased YAP1 protein expression remarkably activated the YAP1/TAZ-TEAD1 signaling pathway, which further boosted the malignant phenotypes in GC cells. In conclusion, these findings highlight the pro-tumoral functions and molecular underpinnings of ACAT2 in GC cells, and suggest that ACAT2 could be a promising target in GC treatment.

Association between adult attachment and mental health states among health care workers: the mediating role of social support.

Background: To determine the relationships between attachment style, social support, and mental health states, as well as the mediation mechanism within this relationship, we conducted a survey among healthcare workers during the coronavirus disease 2019 (COVID-19) epidemic quarantine. Methods: The survey assessed their mental health states, adult attachment style, social support, and some other relevant information. Mental health states were represented by the overall state of sleep, physical and emotional assessment. A multiple mediator model was used to explain how social support could mediate the relationship between attachment and mental health states during COVID-19 quarantine. Results: Our findings revealed that 33.3% of the participants experienced emotional issues, 8.5% had sleep problems, and 24.9% reported physical discomfort. The direct effect of adult attachment styles on mental health states during COVID-19 quarantine was significant (c' = -0.3172; p < 0.01). The total indirect effect also showed statistical significance (ab = -0.1857; p < 0.01). Moreover, the total effect of adult attachment styles on mental health states was -0.5029 (c = -0.5029; p < 0.01). Subjective social support and utilization of social support play mediating roles in the relationship between attachment style and mental health states, respectively (ab1 = -0.1287, 95% CI: -0.9120 to -0.3341, ab2 = 0.0570, 95% CI: -0.4635 to -0.1132). Conclusion: These findings highlight social support played a mediation role between attachment style and mental health states. Thus, offering social support during a crisis might be useful for those individuals with an insecure attachment.

Mapping of the influenza A virus genome RNA structure and interactions reveals essential elements of viral replication.

Influenza A virus (IAV) represents a constant public health threat. The single-stranded, segmented RNA genome of IAV is replicated in host cell nuclei as a series of 8 ribonucleoprotein complexes (vRNPs) with RNA structures known to exert essential function to support viral replication. Here, we investigate RNA secondary structures and RNA interactions networks of the IAV genome and construct an in vivo structure model for each of the 8 IAV genome segments. Our analyses reveal an overall in vivo and in virio resemblance of the IAV genome conformation but also wide disparities among long-range and intersegment interactions. Moreover, we identify a long-range RNA interaction that exerts an essential role in genome packaging. Disrupting this structure displays reduced infectivity, attenuating virus pathogenicity in mice. Our findings characterize the in vivo RNA structural landscape of the IAV genome and reveal viral RNA structures that can be targeted to develop antiviral interventions.

Twenty natural amino acid substitution screening at the last residue 121 of influenza A virus NS2 protein reveals the critical role of NS2 in promoting virus genome replication by coordinating with viral polymerase.

Both influenza A virus genome transcription (vRNA→mRNA) and replication (vRNA→cRNA→vRNA), catalyzed by the influenza RNA polymerase (FluPol), are dynamically regulated across the virus life cycle. It has been reported that the last amino acid I121 of the viral NS2 protein plays a critical role in promoting viral genome replication in influenza mini-replicon systems. Here, we performed a 20 natural amino acid substitution screening at residue NS2-I121 in the context of virus infection. We found that the hydrophobicity of the residue 121 is essential for virus survival. Interestingly, through serial passage of the rescued mutant viruses, we further identified adaptive mutations PA-K19E and PB1-S713N on FluPol which could effectively compensate for the replication-promoting defect caused by NS2-I121 mutation in the both mini-replicon and virus infection systems. Structural analysis of different functional states of FluPol indicates that PA-K19E and PB1-S713N could stabilize the replicase conformation of FluPol. By using a cell-based NanoBiT complementary reporter assay, we further demonstrate that both wild-type NS2 and PA-K19E/PB1-S713N could enhance FluPol dimerization, which is necessary for genome replication. These results reveal the critical role NS2 plays in promoting viral genome replication by coordinating with FluPol.IMPORTANCEThe intrinsic mechanisms of influenza RNA polymerase (FluPol) in catalyzing viral genome transcription and replication have been largely resolved. However, the mechanisms of how transcription and replication are dynamically regulated remain elusive. We recently reported that the last amino acid of the viral NS2 protein plays a critical role in promoting viral genome replication in an influenza mini-replicon system. Here, we conducted a 20 amino acid substitution screening at the last residue 121 in virus rescue and serial passage. Our results demonstrate that the replication-promoting function of NS2 is important for virus survival and efficient multiplication. We further show evidence that NS2 and NS2-I121 adaptive mutations PA-K19E/PB1-S713N regulate virus genome replication by promoting FluPol dimerization. This work highlights the coordination between NS2 and FluPol in fulfilling efficient genome replication. It further advances our understanding of the regulation of viral RNA synthesis for influenza A virus.

Progranulin inhibits fibrosis by interacting with and up-regulating DNAJC3 during mouse skin wound healing.

Scars place a heavy burden on both individuals and society. Our previous study found that reduction of progranulin (PGRN) promotes fibrogenesis in mouse skin wound healing. However, the underlying mechanisms have not been elucidated. Here, we report that PGRN overexpression decreases the expression of profibrotic genes alpha-smooth muscle actin (αSMA), serum response factor (SRF), and connective tissue growth factor (CTGF), thereby inhibiting skin fibrosis during wound repair. Bioinformatics analysis suggested that the heat shock protein (Hsp) 40 superfamily C3 (DNAJC3) is a potential downstream molecule of PGRN. Further experiments showed that PGRN interacts with and upregulates DNAJC3. Moreover, this antifibrotic effect was rescued by DNAJC3 knockdown. In summary, our study suggests that PGRN inhibits fibrosis by interacting with and upregulating DNAJC3 during wound healing in mouse skin. Our study provides a mechanistic explanation of the effect of PGRN on fibrogenesis in skin wound healing.

Fine Regulation of Influenza Virus RNA Transcription and Replication by Stoichiometric Changes in Viral NS1 and NS2 Proteins.

In the influenza virus life cycle, viral RNA (vRNA) transcription (vRNA→mRNA) and replication (vRNA→cRNA→vRNA), catalyzed by the viral RNA-dependent RNA polymerase in the host cell nucleus, are delicately controlled, and the levels of the three viral RNA species display very distinct synthesis dynamics. However, the underlying mechanisms remain elusive. Here, we demonstrate that in the context of virus infection with cycloheximide treatment, the expression of viral nonstructural protein 1 (NS1) can stimulate primary transcription, while the expression of viral NS2 inhibits primary transcription. It is known that the NS1 and NS2 proteins are expressed with different timings from unspliced and spliced mRNAs of the viral NS segment. We then simulated the synthesis dynamics of NS1 and NS2 proteins during infection by dose-dependent transfection experiments in ribonucleoprotein (RNP) reconstitution systems. We found that the early-expressed NS1 protein can stimulate viral mRNA synthesis, while the late-expressed NS2 protein can inhibit mRNA synthesis but can promote vRNA synthesis in a manner highly consistent with the dynamic changes in mRNA/vRNA in the virus life cycle. Furthermore, we observed that the coexistence of sufficient NS1 and NS2, close to the status of the NS1 and NS2 levels in the late stage of infection, could boost vRNA synthesis to the highest efficiency. We also identified key functional amino acids of NS1 and NS2 involved in these regulations. Together, we propose that the stoichiometric changes in the viral NS1 and NS2 proteins during infection are responsible for the fine regulation of viral RNA transcription and replication. IMPORTANCE In order to ensure efficient multiplication, influenza virus transcribes and replicates its segmented, negative-sense viral RNA genome in highly ordered dynamics across the virus life cycle. How the virus achieves such regulation remains poorly understood. Here, we demonstrate that the stoichiometric changes in the viral NS1 and NS2 proteins during infection could be responsible for the fine regulation of the distinct dynamics of viral RNA transcription and replication. We thus propose a fundamental mechanism exploited by influenza virus to dynamically regulate the synthesis of its viral RNA through the delicate control of viral NS1 and NS2 protein expression.

Predicting Responses to Electroconvulsive Therapy in Adolescents with Treatment-Refractory Depression Based on Resting-State fMRI.

OBJECTS: The efficacy of electroconvulsive therapy (ECT) in the treatment of adolescents with treatment-refractory depression is still unsatisfactory, and the individual differences are large. It is not clear which factors are related to the treatment effect. Resting-state fMRI may be a good tool to predict the clinical efficacy of this treatment, and it is helpful to identify the most suitable population for this treatment. METHODS: Forty treatment-refractory depression adolescents were treated by ECT and evaluated using HAMD and BSSI scores before and after treatment, and were then divided into a treatment response group and a non-treatment group according to the reduction rate of the HAMD scale. We extracted the ALFF, fALFF, ReHo, and functional connectivity of patients as predicted features after a two-sample t-test and LASSO to establish and evaluate a prediction model of ECT in adolescents with treatment-refractory depression. RESULTS: Twenty-seven patients achieved a clinical response; symptoms of depression and suicidal ideation were significantly improved after treatment with ECT, which was reflected in a significant decrease in the scores of HAMD and BSSI (p < 0.001). The efficacy was predicted by ALFF, fALFF, ReHo, and whole-brain-based functional connectivity. We found that models built on a subset of features of ALFF in the left insula, fALFF in the left superior parietal gyrus, right superior parietal gyrus, and right angular, and functional connectivity between the left superior frontal gyrus, dorsolateral-right paracentral lobule, right middle frontal gyrus, orbital part-left cuneus, right olfactory cortex-left hippocampus, left insula-left thalamus, and left anterior cingulate gyrus-right hippocampus to have the best predictive performance (AUC > 0.8). CONCLUSIONS: The local brain function in the insula, superior parietal gyrus, and angular gyrus as well as characteristic changes in the functional connectivity of cortical-limbic circuits may serve as potential markers for efficacy judgment of ECT and help to provide optimized individual treatment strategies for adolescents with depression and suicidal ideation in the early stages of treatment.

A propensity score matching study: The prevalence of mental health problems among pregnant women at first antenatal care increased in Chongqing during the first wave of the COVID-19 pandemic.

Background: The 2019 coronavirus disease (COVID-19) pandemic increased the risks of mental health challenges, especially anxiety and depression. However, the impact of COVID-19 on mental health during pregnancy has not been fully established. Therefore, we investigated the impact of the COVID-19 pandemic on maternal mental health. Methods: Two cohorts of pregnant women at their first antenatal care in the First Affiliated Hospital of Chongqing Medical University were enrolled in this study. One cohort was enrolled before the COVID-19 outbreak, from 1 June to 31 December 2019 (n = 5,728, pre-COVID-19 group), while the other was enrolled during the COVID-19 pandemic, from 24 January to 23 March 2020 (n = 739, COVID-19 pandemic group). Symptoms of depression, anxiety, and somatization disorders were assessed by the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-15 (PHQ-15), with a cutoff point of 10 for moderate-to-severe depression, anxiety, and somatoform symptoms. The propensity score matching method (1:1) was used to balance differences in demographic characteristics between groups. A chi-square analysis was performed to compare differences in demographic characteristics between the groups. Results: Prevalence of moderate-to-severe depression, anxiety, and somatoform symptoms among pregnant women at their first antenatal care visit during the COVID-19 pandemic (9.5, 2.2, and 20.8%, respectively) was significantly lower than those before the pandemic (16.3, 4.4, and 25.7%, respectively) (p < 0.05). Compared with the same period before the pandemic, during the pandemic, the number of women newly registered for antenatal care decreased by nearly 50%. There were significant differences in the distributions of demographic characteristics between the groups (p < 0.05). After matching the demographic characteristics, differences in the prevalence of maternal mental health disorders between the groups reversed dramatically. Prevalence of moderate-to-severe depression, anxiety, and somatoform symptoms during the COVID-19 pandemic in this population (2.3, 9.6, and 20.8%, respectively) was significantly higher than those before the pandemic (0.3, 3.9, and 10%, respectively) (p < 0.05). Conclusion: The COVID-19 pandemic increased mental health risks among pregnant women. As a large proportion of pregnant women with mental health challenges delay their prenatal care or change healthcare facilities after the outbreak of public health emergencies, there is a need to establish a balanced healthcare system in medical institutions at all levels.

Prospective study on Maresin-1 and cytokine levels in medication-naïve adolescents with first-episode major depressive disorder.

Background: Inflammation and immune activation may play a role in the pathological mechanism of Major Depressive Disorder (MDD). Evidence from cross-sectional and longitudinal studies of adolescents and adults has shown that MDD is associated with increased plasma pro-inflammatory cytokines (e.g., IL-1ß, IL-6). It has been reported that Specialized Pro-resolving Mediators (SPMs) mediate inflammation resolution, and Maresin-1 can activate the process of inflammation and promote inflammation resolution by promoting macrophage phagocytosis. However, no clinical studies have been conducted to evaluate the relationship between the levels of Maresin-1 and cytokine and the severity of MDD symptomatology in adolescents. Methods: 40 untreated adolescent patients with primary and moderate to severe MDD and 30 healthy participants as the healthy control (HC) group aged between 13 and 18 years old were enrolled. They received clinical and Hamilton Depression Rating Scale (HDRS-17) evaluation and then, blood samples were collected. Patients in the MDD group were re-evaluated for HDRS-17, and blood samples were taken after a six to eight-week fluoxetine treatment. Results: The adolescent patients with MDD had lower serum levels of Maresin-1 and higher serum levels of interleukin 6 (IL-6) compared with the HC group. Fluoxetine treatment alleviated depressive symptoms in MDD adolescent patients, which was reflected by higher serum levels of Maresin-1 and IL-4 and lower HDRS-17 scores, serum levels of IL-6, and IL-1ß. Moreover, the serum level of Maresin-1 was negatively correlated with the depression severity scores on the HDRS-17. Conclusion: Adolescent patients with primary MDD had lower levels of Maresin-1 and higher levels of IL-6 compared with the HC group, implying that the peripheral level of pro-inflammatory cytokines may be elevated in MDD, resulting in the insufficiency of inflammation resolution. The Maresin-1 and IL-4 levels increased after anti-depressant treatment, whereas IL-6 and IL-1ß levels decreased significantly. Moreover, Maresin-1 level negatively correlated with depression severity, suggesting that reduced levels of Maresin-1 promoted the progression of MDD.

Degree of obesity and gastrointestinal adverse reactions influence the weight loss effect of liraglutide in overweight or obese patients with type 2 diabetes.

Background: Liraglutide can effectively reduce the weight of patients with type 2 diabetes. Nonetheless, its weight loss effect was highly heterogeneous in different patients in the clinical practice. Objective: To identify the factors most associated with the weight loss effect of liraglutide in obese or overweight patients with type 2 diabetes with poorly controlled oral medication in northeast China. Design: A prospective study. Methods: A prospective study was performed in subjects with type 2 diabetes who were taking oral medication and had a body mass index (BMI) of ⩾24 kg/m2. Liraglutide was administered for at least 12 weeks, while the original hypoglycemic regimen was kept unchanged (Phase I). Later, liraglutide treatment was continued or stopped as necessary or as subjects thought fit in the 13-52 weeks that followed (Phase II), and the potential factors affecting the effect of weight loss of liraglutide were analyzed. Results: Of the 127 recruited subjects, 90 had comprehensive follow-up data at week 12. In Phase I, the subjects' blood sugar levels and weight decreased significantly(P < 0.001). Among all the significant factors, the gastrointestinal adverse reactions score (GARS) was more correlated with BMI change (ΔBMI; r = 0.43) and waist circumference change (ΔWC; r = 0.32) than the baseline BMI (BMI0) and WC (WC0). At week 12, linear regression showed that BMI0 independently affected ΔBMI and ΔWC, whereas WC0 only affected ΔWC. The GARS was significantly associated with ΔBMI and ΔWC, and this association continued until week 52, even after most subjects had discontinued liraglutide treatment. Conclusion: The degree of obesity and gastrointestinal adverse reactions were the most promising predictors of weight loss in liraglutide treatment.

Maresin-1 improves LPS-induced depressive-like behavior by inhibiting hippocampal microglial activation.

Maresin-1 is an antiphlogistic agonist synthesized by macrophages from docosahexaenoic acid (DHA). It has both anti-inflammatory and pro-inflammatory properties and has been found to enhance neuroprotection and cognitive function. However, there is limited knowledge of its effects on depression and the potential mechanism remains unclear. In this study, the effects of Maresin-1 on lipopolysaccharide (LPS)-induced depressive symptoms and neuroinflammation were investigated in mice and the possible cellular and molecular mechanisms were further clarified. Maresin-1 treatment (5 µg/kg, i.p.) led to improved tail suspension times, as well as distances moved in an open-field test but it did not improve reductions in sugar-water consumption in mice with depressive-like behaviors induced by LPS (1 mg/kg, i.p.); TSPO PETCT scanning showed that Maresin-1 reduced the standardized uptake value (SUV) of [18 F] DPA-714 in brain regions associated with depression (e.g., hippocampus and pre-frontal cortex), while immunofluorescence of hippocampal and indicated that Maresin-1 inhibited microglial activation reducing the expression of the pro-inflammatory cytokine IL-1ß and NLRP3. The RNA sequencing of mouse hippocampi showed that genes expressed differentially between Maresin-1-treated and LPS-treated tissue were associated with tight connections between cells and the stress-activated MAPK cascade negative regulatory pathways. Overall, this study demonstrates that peripheral application of Maresin-1 could partially relieve LPS-induced depressive-like behaviors and showed for the first time that this effect was related to its anti-inflammatory action on microglia, thus providing new clues for the pharmacological mechanism underlying the anti-depression properties of Maresin-1.

Initial clinical and experimental analyses of ALDOA in gastric cancer, as a novel prognostic biomarker and potential therapeutic target.

The effect of ALDOA, an important regulator of tumor metabolism and immune cell function, on gastric cancer (GC) immune infiltration has not been elucidated. Hence, we explored the feasibility of using ALDOA combined with immune molecular markers as novel prognostic or therapeutic targets for GC patients. Bioinformatic analyses were initially performed in multiple databases to assess the prognostic prediction values of ALDOA expression in GC. Subsequently, both ALDOA expression and the clinicopathological characteristics of a total of 114 GC patients who underwent curative gastrectomy were collected to demonstrate the potential association between ALDOA expression and the biological behaviors of GC. Next, the expression of ALDOA and its effect on prognosis were determined at the mRNA and protein levels, respectively, using tissue microarrays and cellular experiments. Subsequently, several molecular mechanisms were revealed based on elaborate analyses, indicating that ALDOA expression was potentially involved in the progression of GC and could be considered a promising biomarker for evaluating the prognosis of GC. High ALDOA expression was frequently found in GC cells and GC tissues at the mRNA and protein levels. Based on survival analysis, the expression of ALDOA indicated comparatively poor overall survival (OS) in GC and was identified as an independent prognostic predictor of GC. Correlation analysis showed that ALDOA expression had a positive association with lymph node metastasis in GC patients. Additionally, microRNA-1179 was found to play a key role in inhibiting the expression of ALDOA in the metabolic pathways of GC cells, which might disrupt the expression of various immune molecules and be detrimental to the prognosis of GC. ALDOA should be considered a promising molecular target for evaluating the prognosis of GC, owing to its potential role in immune regulation.

Anti-inflammatory effects of Chaishi Tuire Granules on influenza A treatment by mediating TRAF6/MAPK14 axis.

Objectives: Influenza is an infectious respiratory disease that can cause severe inflammatory reactions and threaten human life. Chaishi Tuire Granules (CSTRG), a Chinese patent medicine widely used clinically in the treatment of respiratory diseases in China, has a definite anti-inflammatory effect. However, the mechanism of CSTRG in the treatment of influenza is still unclear. This study aimed to demonstrate the anti-inflammatory effect of CSTRG on influenza A treatment and potential mechanisms. Methods: Influenza-associated mice pneumonia model was used to explore the antiviral and anti-inflammatory effects of CSTRG in vivo. Bioinformatics analysis methods such as network pharmacology and molecular docking were carried out to predict the main active components and potential anti-inflammatory targets of CSTRG. The anti-inflammatory activity of CSTRG was determined using the lipopolysaccharide (LPS)-induced macrophages RAW264.7 cells in vitro. Results: In vivo results showed that CSTRG can reduce the viral load in the lung tissue of infected mice, reduce the expression of TNF-α and IL-6 in lung tissue and serum, and regulate the host inflammatory response. Additionally, CSTRG treatment markedly improves the sick signs, weight loss, lung index, and lung pathological changes. Bioinformatics analysis predicted that six active compounds of CSTRG including quercetin, kaempferol, luteolin, beta-sitosterol, sitosterol, and stigmasterol could contribute to the anti-influenza activity through regulating the TRAF6/MAPK14 axis. The following research confirmed that CSTRG significantly inhibited pro-inflammatory cytokines (TNF-α and IL-6) by suppressing the expression of TRAF6 and MAPK14 in LPS-stimulated macrophages RAW264.7 cells. Conclusion: CSTRG might inhibit the inflammatory response by mediating the TRAF6/MAPK14 axis. In the future, in-depth research is still needed to verify the mechanism of CSTRG in the treatment of influenza.

Changes in gray matter volume following electroconvulsive therapy in adolescent depression with suicidal ideation: A longitudinal structural magnetic resonance imaging study.

Objective: We aimed to investigate changes in whole-brain gray matter volumes (GMVs) before and after electroconvulsive therapy (ECT) in adolescents with major depressive disorder (MDD) and suicidal ideation (SI). Methods: Thirty adolescents with MDD and SI were observed, and structural magnetic resonance imaging (sMRI) was performed at baseline and after ECT for each patient. But Twenty-five healthy controls (HCs) were scanned only at baseline. The voxel-based morphometry (VBM) techniques were used to examine GMVs. Results: Compared with HCs, MDDs at baseline showed decreased GMVs in the left middle temporal gyrus, right superior temporal gyrus, right middle temporal gyrus, left precuneus, right precuneus, and left superior frontal gyrus. After ECT, MDDs showed increased GMVs in the right superior frontal gyrus and right superior temporal gyrus. Pearson's correlation found that Beck Scale for Suicide Ideation (BSSI) scores at baseline were negatively correlated with GMVs in the left superior frontal gyrus and HAMD and BSSI scores after ECT were negatively correlated with GMVs in the right superior temporal gyrus. Conclusion: Frontal-temporal-precuneus structure changes may be a potential cause of depressive and suicidal symptoms in adolescents. ECT may improve depressive and suicidal symptoms in adolescents by regulating brain structures to compensate original defects.

MiR-574-5p promotes cell proliferation by negatively regulating small C-terminal domain phosphatase 1 in esophageal squamous cell carcinoma.

Objectives: Esophageal cancer is one of the most common cancers with high incidence and mortality rates, especially in China. MicroRNA (miRNA) can be used as a prognostic marker for various human cancers. This study aims to detect suitable miRNA markers for esophageal squamous cell carcinoma (ESCC). Materials and Methods: Our previous gene expression data of ESCC cells and the data from GSE43732 and GSE112840 were analyzed. The expression of miR-574-5p in ESCC patients and controls was analyzed by real-time quantitative PCR. The effect of miR-574-5p on proliferation was detected by real-time cell analysis (RTCA) and EdU proliferation assay after cell transfections. The target gene small C-terminal domain phosphatase 1 (CTDSP1) of miR-574-5p was validated by luciferase reporter assay and western blotting. Results: In the current study, the bioinformatics analysis found miR-574-5p up-regulated in ESCC. The qPCR assay of 26 ESCC and 13 adjacent/ normal tissues confirmed these results. We further demonstrated that miR-574-5p overexpression promoted cell proliferation. Then the dual-luciferase reporter assay and the rescue experiment suggested that CTDSP1 was a direct target of miR-574-5p. Conclusion: MiR-574-5p played an oncological role in ESCC by interacting and negatively regulating CTDSP1. These results provided a deeper understanding of the effect of miR-574-5p on ESCC.

miR-351 promotes atherosclerosis in diabetes by inhibiting the ITGB3/PIK3R1/Akt pathway and induces endothelial cell injury and lipid accumulation.

BACKGROUND: The miR-351 gene is significantly upregulated in diabetic mice with atherosclerosis. However, the mechanism by which its presence is important for the overall disease has not been elucidated. Therefore, this study will investigate the mechanism of miR-351 in the process of diabetes mellitus with atherosclerosis through miR-351 gene knockout mice. METHODS: In this study, miR-351-/- C57BL/6 mice were first induced to form a type 2 diabetes mellitus model with atherosclerosis by STZ injection and a high-fat diet. Pathological tests (oil red O, HE, and Masson staining) combined with biochemical indices (TC, TG, LDL-C, HDL-C, TNF-α, hs-CRP, NO, SOD, MDA, CAT, and GSH-Px) were performed to evaluate the pathological degree of atherosclerosis in each group. Mouse aortic endothelial cells were treated with oxidized low-density lipoprotein (ox-LDL) and 30 mM glucose to establish a diabetic atherosclerosis cell model. Combined with cell oil red O staining and flow cytometry, the effects of silencing miR-351 on lipid accumulation and cell apoptosis in the diabetic atherosclerosis cell model were determined. Fluorescence in situ hybridization was used to detect the localization and transcription levels of miR-351 in cells. The target genes of miR-351 were predicted by bioinformatics and verified by dual-luciferase activity reporting. Western blotting was used to detect the expression levels of phosphorylated inosine 3-kinase regulatory subunit 1 (PIK3R1)/serine/threonine kinase 1 (Akt) and apoptosis-related proteins after transfection with integrin subunit ß3 (ITGB3) small interfering ribonucleic acid (siRNA). RESULTS: The expression of the miR-351 gene was significantly increased in the high-fat wild-type (HWT) group, and its expression was significantly decreased in the knockout mice. Silencing miR-351 effectively alleviated atherosclerosis in mice. The levels of miR-351 expression, apoptosis, lipid accumulation, and oxidative stress in ox-LDL + high glucose-induced endothelial cells were significantly increased. These phenomena were effectively inhibited in lentivirus-infected miR-351-silenced cell lines. Bioinformatics predicted that miR-351-5p could directly target the ITGB3 gene. Transfection of ITGB3 siRNA reversed the downregulation of apoptosis, decreased oil accumulation, and decreased oxidative stress levels induced by miR-351 silencing. In addition, it inhibited the activation of the PIK3R1/Akt pathway. CONCLUSION: Silencing miR-351 upregulates ITGB3 and activates the PIK3R1/Akt pathway, thereby exerting anti-apoptosis and protective effects on endothelial cells.

The Influence of Self-Esteem and Psychological Flexibility on Medical College Students' Mental Health: A Cross-Sectional Study.

Background: Mental health problems has become a major public health issue among medical students. Self-esteem and psychological flexibility were important associated factors for mental health, but their relations have not been discussed in medical students. The present study aimed to assess the status of mental health problems among medical students and identified whether psychological flexibility had a mediating role in the effects of self-esteem on the top three most common psychological symptoms. Methods: A total of 810 undergraduate students from 18 classes comprised in the sample. Nine dimensions of psychological symptoms was assessed by the Symptom Checklist-90-revised (SCL-90-R). Self-esteem was measured by the Self-esteem Scale (SES) and psychological flexibility was evaluated by the Acceptance and Action Questionnaire 2nd Edition (AAQ-II) and Cognitive Fusion Questionnaire (CFQ-F). Univariate analysis and logistic regression analysis were used to determine the relationship among the top three common psychological symptoms, self-esteem, psychological flexibility, and participants' characteristics. The mediating effect of psychological flexibility between self-esteem and psychological symptoms was detected by bootstrap method. Results: 57.8% of the medical undergraduate students reported positive at least one of the nine psychological symptom dimensions assessed by the SCL-90-R and 13.8% of students had moderate or more severe symptoms. The symptoms of obsessive-compulsiveness, interpersonal sensitivity, and depression were the three most common psychological symptoms among the medical students. Meanwhile, self-esteem and psychological flexibility were negatively associated to the symptoms of obsessive-compulsiveness, interpersonal sensitivity, and depression. And, almost 50% effects of self-esteem on these three symptoms in medical students exert indirect effects through psychological flexibility. Conclusions: Psychological distress was quite common in the Chinese medical students. The three most common psychological symptoms were successively obsessive-compulsiveness, interpersonal sensitivity, and depression. Low self-esteem and psychological inflexibility might be the risk factors for these top three symptoms, and psychological flexibility might play a mediating role in the effects of self-esteem on these psychological symptoms.

Microglia Loss and Astrocyte Activation Cause Dynamic Changes in Hippocampal [18F]DPA-714 Uptake in Mouse Models of Depression.

Major depression is a serious and chronic mental illness. However, its etiology is poorly understood. Although glial cells have been increasingly implicated in the pathogenesis of depression, the specific role of microglia and astrocytes in stress-induced depression remains unclear. Translocator protein (TSPO) has long been considered a marker of neuroinflammation and microglial activation. However, this protein is also present on astrocytes. Thus, it is necessary to explore the relationships between TSPO, microglia, and astrocytes in the context of depression. In this study, C57BL/6J male mice were subjected to chronic unpredictable stress (CUS) for 5 weeks. Subsequently, sucrose preference and tail suspension tests (TSTs) were performed to assess anhedonia and despair in these mice. [18F]DPA-714 positron emission tomography (PET) was adopted to dynamically assess the changes in glial cells before and 2, 4, or 5 weeks after CUS exposure. The numbers of TSPO+ cells, ionized calcium-binding adaptor molecule (Iba)-1+ microglial cells, TSPO+/Iba-1+ cells, glial fibrillary acidic protein (GFAP)+ astrocytes, TSPO+/GFAP+ cells, and TUNEL-stained microglia were quantified using immunofluorescence staining. Real-time PCR was used to evaluate interleukin (IL)-1ß, IL-4, and IL-18 expression in the hippocampus. We observed that hippocampal [18F]DPA-714 uptake significantly increased after 2 weeks of CUS. However, the signal significantly decreased after 5 weeks of CUS. CUS significantly reduced the number of Iba-1+, TSPO+, and TSPO+/Iba-1+ cells in the hippocampus, especially in the CA1 and dentate gyrus (DG) subregions. However, this intervention increased the number of GFAP+ astrocytes in the CA2/CA3 subregions of the hippocampus. In addition, microglial apoptosis in the early stage of CUS appeared to be involved in microglia loss. Further, the expression of pro-inflammatory cytokines (IL-1ß and IL-18) was significantly decreased after CUS. In contrast, the expression of the anti-inflammatory cytokine IL-4 was significantly increased after 2 weeks of CUS. These results suggested that the CUS-induced dynamic changes in hippocampal [18F]DPA-714 uptake and several cytokines may be due to combined microglial and astrocyte action. These findings provide a theoretical reference for the future clinical applications of TSPO PET.

Dynamic microglial activation is associated with LPS-induced depressive-like behavior in mice: An [18F] DPA-714 PET imaging study.

Major depressive disorder (MDD) is a highly pervasive, severe psychological condition for which the precise underlying pathophysiology is incompletely understood, although microglial activation is known to play a role in this context. In this study we analyzed the association between neuroinflammation and depressive-like behaviors in a lipopolysaccharide (LPS)-induced mouse model system using 10-12-week-old male C57BL/6 mice. Microglial activation and associated neuroinflammatory activity were monitored via positron emission tomography (PET) imaging. Animals were assessed at three time points, including 24 h prior to LPS injection, 24 h post-LPS injection, and 72 h post-LPS injection. Analyses of microglial activation and hippocampal neuroinflammation were conducted through [18]F DPA-714 PET imaging and immunohistochemical staining for ionized calcium-binding adapter molecule 1 (Iba-1) and translocator protein (TSPO). Moreover, NOD-like receptor protein 3 (NLRP3) inflammasome activity and interleukin-1ß (IL-1ß) levels were assessed at 24 h post-LPS injection. We found that LPS treatment was associated with a marked increase in depressive-like behavior at 24 h post-injection time point, and that it was less pronounced at the 72 h post-injection time point. These changes coincided with enhanced [18F] DPA-714 PET uptake in the whole brain, hippocampus, cortex and amygdala together with increased hippocampal microglial activation as evidenced by immunofluorescent staining. By 72 h post-injection, however, these PET and immunofluorescence phenotypes had returned to baseline levels. Furthermore, increased NLRP3 inflammasome activation and IL-1ß expression were evident at 24 h post-LPS injection. These data demonstrate that dynamic microglial activation is associated with LPS-induced depressive-like behaviors and hippocampal neuroinflammation in a mouse model system.