Zhi-zi-chi decoction mitigates depression by enhancing lncRNA Six3os1 expression and promoting histone H3K4 methylation at the BDNF promoter.

Traditional Chinese medicine, particularly Zhi-zi-chi decoction (ZZCD), is gaining recognition as a potential treatment for depression. This study aimed to uncover the molecular mechanisms behind ZZCD's antidepressant effects, focusing on lncRNA Six3os1 and histone H3K4 methylation at the BDNF promoter. Network pharmacology and in vivo experiments were conducted to identify ZZCD targets and evaluate its impact on depression-related behaviours and neuron injury. The role of Six3os1 in recruiting KMT2A to the BDNF promoter and its effects on oxidative stress and neuron injury were investigated. ZZCD reduced depression-like behaviours and neuron injury in mice subjected to chronic stress. It upregulated Six3os1, which facilitated KMT2A recruitment to the BDNF promoter, leading to increased histone H3K4 methylation and enhanced BDNF expression. ZZCD also inhibited CORT-induced neuron injury, inflammatory response and oxidative stress in vitro. ZZCD's antidepressant properties involve Six3os1 upregulation, which exerts neuroprotective effects by inhibiting oxidative stress and neuron injury, thereby alleviating depressive symptoms. Targeting Six3os1 upregulation may offer a potential therapeutic intervention for depression.

Electrolyte Optimization Strategy: Enabling Stable and Eco-Friendly Zinc Adaptive Interfacial Layer in Zinc Ion Batteries.

Aqueous zinc ion batteries (AZIBs) have emerged as a promising battery technology due to their excellent safety, high capacity, low cost, and eco-friendliness. However, the cycle life of AZIBs is limited by severe side reactions and zinc dendrite growth on the zinc electrode surface, hindering large-scale application. Here, an electrolyte optimization strategy utilizing the simplest dipeptide glycylglycine (Gly-Gly) additive is first proposed. Theoretical calculations and spectral analysis revealed that, due to the strong interaction between the amino group and Zn atoms, Gly-Gly preferentially adsorbs on zinc's surface, constructing a stable and adaptive interfacial layer that inhibits zinc side reactions and dendrite growth. Furthermore, Gly-Gly can regulate zinc ion solvation, leading to a deposition mode shift from dendritic to lamellar and limiting two-dimensional dendrite diffusion. The symmetric cell with the addition of a 20 g/L Gly-Gly additive exhibits a cycle life of up to 1100 h. Under a high current density of 10 mA cm-2, a cycle life of 750 cycles further demonstrates the reliable adaptability of the interfacial layer. This work highlights the potential of Gly-Gly as a promising solution for improving the performance of AZIBs.

Antidepressant-like effects of geniposide in chronic unpredictable mild stress-induced mice by regulating the circ_0008405/miR-25-3p/Gata2 and Oip5os1/miR-25-3p/Gata2 networks.

Evidence exists suggesting the anti-depressive activities of geniposide (GP), a major compound in Gardenia jasminoides Ellis. Accordingly, the present study attempts to explore the anti-depressive mechanism of GP in chronic unpredictable mild stress (CUMS)-induced depression-like behaviors of mice. CUMS-induced mice were given GP daily and subjected to behavioral tests to observe the effect of GP on the depression-like behaviors. It was noted that GP administration reduced depression-like behaviors in CUMS mice. Transcriptome sequencing was conducted in three control and three CUMS mice. Differentially expressed circRNAs, lncRNAs and mRNAs were then screened by bioinformatics analyses. Intersection analysis of the transcriptome sequencing results with the bioinformatics analysis results was followed to identify the candidate targets. We found that Gata2 alleviated depression-like behaviors via the metabolism- and synapse-related pathways. Gata2 was a target of miR-25-3p, which had binding sites to circ_0008405 and Oip5os1. circ_0008405 and Oip5os1 competitively bound to miR-25-3p to release the expression of Gata2. GP administration ameliorated depression-like behaviors in CUMS mice through regulation of the circ_0008405/miR-25-3p/Gata2 and Oip5os1/miR-25-3p/Gata2 crosstalk networks. Taken together, GP may exert a potential antidepressant-like effect on CUMS mice, which is ascribed to regulation of the circ_0008405/miR-25-3p/Gata2 and Oip5os1/miR-25-3p/Gata2 crosstalk networks.

Can amide proton transfer-weighted imaging differentiate tumor grade and predict Ki-67 proliferation status of meningioma?

OBJECTIVES: To determine the utility of the amide proton transfer-weighted MR imaging in differentiating the WHO grade and predict proliferative activity of meningioma. METHODS: Fifty-three patients with WHO grade I meningiomas and 26 patients with WHO grade II meningiomas underwent conventional and APT-weighted sequences on a 3.0 Tesla MR before clinical intervention. The APT-weighted (APTw) parameters in the solid tumor region were obtained and compared between two grades using the t test; the receiver operating characteristic (ROC) curve was used to assess the best parameter for predicting the grade of meningiomas. Pearson's correlation coefficient was calculated between the APTwmax and Ki-67 labeling index in meningiomas. RESULTS: The APTwmax and APTwmean values were not significantly different between WHO grade I and grade II meningiomas (p = 0.103 and p = 0.318). The APTwmin value was higher and the APTwmax-min value was lower in WHO grade II meningiomas than in WHO grade I tumors (p = 0.027 and p = 0.019). But the APTwmin was higher and the APTwmax-min was lower in microcystic meningiomas than in WHO grade II meningiomas (p = 0.001 and p = 0.006). The APTwmin combined with APTwmax-min showed the best diagnostic performance in predicting the grade of meningiomas with an AUC of 0.772. The APTwmax value was positively correlated with Ki-67 labeling index (r = 0.817, p < 0.001) in meningiomas; the regression equation for the Ki-67 labeling index (%) (Y) and APTwmax (%) (X) was Y = 4.9 × X - 12.4 (R2 = 0.667, p < 0.001). CONCLUSION: As a noninvasive imaging method, the ability of APTw-MR imaging in differentiating the grade of meningiomas is limited, but the technology can be used to predict the proliferative activity of meningioma. KEY POINTS: • The APTw min value was higher and the APTw max-min value was lower in WHO grade II meningioma than in grade I tumors. • The APTw min value was higher and the APTw max-min value was lower in microcystic meningiomas than in WHO grade II meningiomas. • The APTw max value was positively correlated with meningioma proliferation index.

Differentiating the histologic grades of gliomas preoperatively using amide proton transfer-weighted (APTW) and intravoxel incoherent motion MRI.

The purpose of this work was to investigate the diagnostic performance of amide proton transfer-weighted (APTW) and intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) in the preoperative grading of gliomas. Fifty-one patients with suspected gliomas were recruited and underwent a preoperative MRI examination that included APTW and IVIM sequences. All cases were confirmed by postsurgical histopathology. APTW signal intensity, true diffusion coefficient (D), perfusion fraction (f) and pseudo-diffusion coefficient (D*) were applied to assess the solid tumor component and contralateral normal-appearing white matter. The relative APTW signal intensity (rAPTW) was also used. Independent-sample and paired-sample t-tests were used to compare differences in MRI parameters between low-grade glioma (LGG) and high-grade glioma (HGG) groups. The diagnostic performance was assessed with the receiver operating characteristic curve. Twenty-six patients were pathologically diagnosed with LGG and 25 were diagnosed with HGG. APTW, rAPTW and f values were significantly higher (all p < 0.001), whereas D values were significantly lower (p < 0.001) in the HGG group than in the LGG group. There was no significant difference between D* values for the two groups. rAPTW had an area under the curve (AUC) of 0.957, with a sensitivity of 100% and a specificity of 84.6%, followed by APTW, f, D and D*. The combined use of APTW and IVIM showed the best diagnostic performance, with an AUC of 0.986. In conclusion, APTW and IVIM, as two promising supplementary sequences for routine MRI, could be valuable in differentiating LGGs from HGGs.

Discriminating MGMT promoter methylation status in patients with glioblastoma employing amide proton transfer-weighted MRI metrics.

OBJECTIVES: To explore the feasibility of using amide proton transfer-weighted (APTw) MRI metrics as surrogate biomarkers to identify the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in glioblastoma (GBM). METHODS: Eighteen newly diagnosed GBM patients, who were previously scanned at 3T and had a confirmed MGMT methylation status, were retrospectively analysed. For each case, a histogram analysis in the tumour mass was performed to evaluate several quantitative APTw MRI metrics. The Mann-Whitney test was used to evaluate the difference in APTw parameters between MGMT methylated and unmethylated GBMs, and the receiver-operator-characteristic analysis was further used to assess diagnostic performance. RESULTS: Ten GBMs were found to harbour a methylated MGMT promoter, and eight GBMs were unmethylated. The mean, variance, 50th percentile, 90th percentile and Width10-90 APTw values were significantly higher in the MGMT unmethylated GBMs than in the MGMT methylated GBMs, with areas under the receiver-operator-characteristic curves of 0.825, 0.837, 0.850, 0856 and 0.763, respectively, for the discrimination of MGMT promoter methylation status. CONCLUSIONS: APTw signal metrics have the potential to serve as valuable imaging biomarkers for identifying MGMT methylation status in the GBM population. KEY POINTS: • APTw-MRI is applied to predict MGMT promoter methylation status in GBMs. • GBMs with unmethylated MGMT promoter present higher APTw-MRI than methylated GBMs. • Multiple APTw histogram metrics can identify MGMT methylation status. • Mean APTw values showed the highest diagnostic accuracy (AUC = 0.825).

Predicting IDH mutation status in grade II gliomas using amide proton transfer-weighted (APTw) MRI.

PURPOSE: To assess the amide proton transfer-weighted (APTw) MRI features of isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant grade II gliomas and to test the hypothesis that the APTw signal is a surrogate imaging marker for identifying IDH mutation status preoperatively. METHODS: Twenty-seven patients with pathologically confirmed low-grade glioma, who were previously scanned at 3T, were retrospectively analyzed. The Mann-Whitney test was used to evaluate relationships between APTw intensities for IDH-mutant and IDH-wildtype groups, and receiver operator characteristic (ROC) analysis was used to assess the diagnostic performance of APTw. RESULTS: Based on histopathology and molecular analysis, seven cases were diagnosed as IDH-wildtype grade II gliomas and 20 cases as IDH-mutant grade II gliomas. The maximum and minimum APTw values, based on multiple regions of interest, as well as the whole-tumor histogram-based mean and 50th percentile APTw values, were significantly higher in the IDH-wildtype gliomas than in the IDH-mutant groups. This corresponded to the areas under the ROC curves of 0.89, 0.76, 0.75, and 0.75, respectively, for the prediction of the IDH mutation status. CONCLUSION: IDH-wildtype lesions typically were associated with relatively high APTw signal intensities as compared with IDH-mutant lesions. The APTw signal could be a valuable imaging biomarker by which to identify IDH1 mutation status in grade II gliomas. Magn Reson Med 78:1100-1109, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Applying protein-based amide proton transfer MR imaging to distinguish solitary brain metastases from glioblastoma.

OBJECTIVES: To determine the utility of amide proton transfer-weighted (APTw) MR imaging in distinguishing solitary brain metastases (SBMs) from glioblastomas (GBMs). METHODS: Forty-five patients with SBMs and 43 patients with GBMs underwent conventional and APT-weighted sequences before clinical intervention. The APTw parameters and relative APTw (rAPTw) parameters in the tumour core and the peritumoral brain zone (PBZ) were obtained and compared between SBMs and GBMs. The receiver-operating characteristic (ROC) curve was used to assess the best parameter for distinguishing between the two groups. RESULTS: The APTwmax, APTwmin, APTwmean, rAPTwmax, rAPTwmin or rAPTwmean values in the tumour core were not significantly different between the SBM and GBM groups (P = 0.141, 0.361, 0.221, 0.305, 0.578 and 0.448, respectively). However, the APTwmax, APTwmin, APTwmean, rAPTwmax, rAPTwmin or rAPTwmean values in the PBZ were significantly lower in the SBM group than in the GBM group (P < 0.001). The APTwmin values had the highest area under the ROC curve 0.905 and accuracy 85.2% in discriminating between the two neoplasms. CONCLUSION: As a noninvasive imaging method, APT-weighted MR imaging can be used to distinguish SBMs from GBMs. KEY POINTS: • APTw values in the tumour core were not different between SBMs and GBMs. • APTw values in peritumoral brain zone were lower in SBMs than in GBMs. • The APTw min was the best parameter to distinguish SBMs from GBMs.

Early extremity MRI findings and pathological synovial changes in antigen-induced arthritis rabbit model.

PURPOSE: To investigate the association between early extremity MRI (E-MRI) findings and synovial pathological changes in antigen-induced arthritis (AIA) rabbit model. MATERIALS AND METHODS: AIA was successfully induced in the right knee of 32 sensitized Japanese white rabbits, which were then divided into four groups according to the time of killing after AIA induction: 1-week (Group A), 2-weeks (Group B), 3-weeks (Group C), and 4-weeks (Group D); the left knee served as control in each rabbit. RESULTS: There were varying degrees of joint effusion in all AIA groups. E-MRI scan showed low signal in T1-weighted images (T1Wi) and high signal in T2-weighted images (T2Wi). Enhanced E-MRI revealed elevated synovial signal at the right knee in the three-dimensional spoiled gradient T1WI, showing linear and band-shaped, diffuse hyperintensity. Histological examination of right knees found scattered inflammatory cell infiltration, swelling, and proliferation of the synovial cells at 7 days after AIA induction and dispersed and disordered proliferation of synovial cells up to 3 layers at 28 days postinduction. The synovial enhancement of right knee E-MRI was consistent with a synovial pathology score for all rabbits (Kappa = 0.965, P < 0.01). CONCLUSION: E-MRI can reveal the degree of changes in the joints and synovium at different periods of the AIA model.

M1 linear ubiquitination of LKB1 inhibits vascular endothelial cell injury in atherosclerosis through activation of AMPK.

Endothelial cell injury is confirmed to be the initial step in the atherosclerosis (AS) process. Here, we tried to elucidate the role of liver kinase B1 (LKB1) and adenosine phosphate protein kinase (AMPK) in modulating vascular endothelial cells (VECs) in AS. High-fat feed (HFD)-induced AS rat models were prepared and treated with AMPK activator A-769662 alone or combined with chloroquine. An analysis of VEC injury, inflammation response, and autophagy followed it. The M1 linear ubiquitination of LKB1 was assessed by co-immunoprecipitation. The interaction between LKB1 and AMPK was analyzed. Primary aortic VECs were isolated and induced by LPS to verify the effects of LKB1 and AMPK on VEC injury in AS. Activation of AMPK reduced the VEC injury and inflammatory response of VECs and promoted autophagy caused by AS. LKB1 could regulate the activation of AMPK in AS. M1 linear ubiquitination enhanced LKB1 activity and increased AMPK activation to protect against VEC injury in AS, which was validated by in vitro experiments. Our current study highlighted that M1 linear ubiquitination of LKB1 may induce the activation of LKB1 to activate AMPK, which inhibited VEC injury in AS.

Geniposide improves depression by promoting the expression of synapse-related proteins through the Creb1/Six3os1 axis.

The present study aims to investigate the mechanism of Geniposide in the treatment of depression. By screening the effective components and targets of Zhi-zi-chi decoction, 140 candidate targets related to depression were identified. Further transcriptome sequencing was conducted to screen differentially expressed mRNAs and lncRNAs; 7 candidate Geniposide treatment targets for depression were obtained. KEGG/GO enrichment analysis and molecular docking were performed to select the optimal drug target, revealing that Creb1 is an important target. Additionally, Six3os1 is the lncRNA with the smallest P-value among the differentially expressed lncRNAs, and the JASPAR database revealed a binding site between Creb1 and the Six3os1 promoter. The intersection of Synapse-related genes obtained from the GeneCards database and differentially expressed mRNAs produced 6 synaptic-related genes. RNA-protein interaction prediction revealed that Six3os1 interacts with the protein encoded by these genes. Geniposide upregulates the expression of Creb1 and Six3os1. Creb1 can transcriptionally activate Six3os1, thereby upregulating the expression of the synaptic-related proteins Htr3a and Htr2a, improving depression.

Genome-Wide Analysis of Dental Caries Variability Reveals Genotype-by-Environment Interactions.

Genotype-by-environment interactions (GEI) may influence dental caries, although their effects are difficult to detect. Variance quantitative trait loci (vQTL) may serve as an indicator of underlying GEI effects. The aim of this study was to investigate GEI effects on dental caries by prioritizing variants from genome-wide vQTL analysis. First, we identified vQTLs from ~4.3 M genome-wide variants in three cohorts of white children aged 3-5 (n = 396, n = 328, n = 773) using Levene's test. A total of 39 independent vQTLs with p < 1 × 10-6 were identified, some of which were located in or near genes with plausible biological roles in dental caries (IGFBP7, SLC5A8, and SHH involved in tooth development and enamel mineralization). Next, we used linear regression to test GEI effects on dental caries with the 39 prioritized variants and self-reported environmental factors (demographic, socioeconomic, behavioral, and dietary factors) in the three cohorts separately. We identified eight significant GEIs indicating that children with vQTL risk genotypes had higher caries experience if they had less educated parents, lower household/parental income, brushed their teeth less frequently, consumed sugar-sweetened beverages more frequently, were not breastfed, and were female. We reported the first genome-wide vQTL analysis of dental caries in children nominating several novel genes and GEI for further investigations.

Potential risk factors and genetic variants associated with dental caries incidence in Appalachia using genome-wide survival analysis.

OBJECTIVE: The aim of this study was to identify the potential risk factors and genetic variants associated with dental caries incidence using survival analysis. METHODS: The Center for Oral Health Research in Appalachia recruited and prospectively followed pregnant women and their children. A total of 909 children followed from birth for up to 7 years were included in this study. Annual intra-oral examinations were performed to assess dental caries experience including the approximate time to first caries incidence in the primary dentition. Cox proportional hazards models were used to assess the associations of time to first caries incidence with self-reported risk factors and 4.9 million genetic variants ascertained using a genome-wide genotyping array. RESULTS: A total of 196 of 909 children (21.56%) had their first primary tooth caries event during follow-up. Household income, home water source, and mother's educational attainment were significantly associated with time to first caries incidence in the stepwise Cox model. The heritability (i.e., proportion of variance explained by genetics) of time to first caries was 0.54. Though no specific genetic variants were associated at the genome-wide significance level (P < 5E-8), we identified 14 loci at the suggestive significance level (5E-8 < P < 1E-5), some of which were located within or near genes with plausible biological functions in dental caries. CONCLUSION: Our findings indicate that household income, home water source, and mother's educational attainment are independent risk factors for dental caries incidence. We nominate several suggestive loci for further investigation.

Bacterial community modifies host genetics effect on early childhood caries.

Background: By age five approximately one-fifth of children have early childhood caries (ECC). Both the oral microbiome and host genetics are thought to influence susceptibility. Whether the oral microbiome modifies genetic susceptibility to ECC has not been tested. We test whether the salivary bacteriome modifies the association of a polygenic score (PGS, a score derived from genomic data that summarizes genetic susceptibility to disease) for primary tooth decay on ECC in the Center for Oral Health Research in Appalachia 2 longitudinal birth cohort. Methods: Children were genotyped using the Illumina Multi-Ethnic Genotyping Array and underwent annual dental examinations. We constructed a PGS for primary tooth decay using weights from an independent, genome-wide association meta-analysis. Using Poisson regression, we tested for associations between the PGS (high versus low) and ECC incidence, adjusting for demographic characteristics (n=783). An incidence-density sampled subset of the cohort (n=138) had salivary bacteriome data at 24- months of age. We tested for effect modification of the PGS on ECC case status by salivary bacterial community state type (CST). Results: By 60-months, 20.69% of children had ECC. High PGS was not associated with an increased rate of ECC (incidence-rate ratio:1.09 (95% confidence interval (CI): 0.83, 1.42)). However, having a cariogenic salivary bacterial CST at 24-months was associated with ECC (odds ratio (OR): 7.48 (95%CI: 3.06, 18.26)), which was robust to PGS adjustment. An interaction existed between the salivary bacterial CST and the PGS on the multiplicative scale (P= 0.04). The PGS was associated with ECC (OR: 4.83 (95% CI: 1.29, 18.17)) only among individuals with a noncariogenic salivary bacterial CST (n=70). Conclusions: Genetic causes of caries may be harder to detect when not accounting for cariogenic oral microbiomes. As certain salivary bacterial CSTs increased ECC-risk across genetic-risk strata, preventing colonization of cariogenic microbiomes would be universally beneficial.

Biomedical Teleacupuncture between China and Austria Using Heart Rate Variability-Part 2: Patients with Depression.

It has been shown in previous studies that the autonomic nervous system can be affected by acupuncture. Within this study, teleacupuncture between China and Austria is used for quantifying the effects of heart rate (HR) and heart rate variability (HRV) in 33 Chinese patients (27 females, 6 males; mean age ± SD 49.5 ± 13.1 years; range 22-72 years) suffering from depression. Electrocardiographic signals before, during, and after acupuncture at the acupoint Baihui (GV20) were recorded in Harbin and analyzed in Graz using teleacupuncture. HRV data were analyzed in the time and frequency domain. Mean HR decreased significantly (P < 0.05) during and after acupuncture, whereas total HRV increased significantly after the third acupuncture stimulation period (P < 0.05) and also 5-10 minutes after (P < 0.05) acupuncture. The study shows that HRV could be a useful parameter for quantifying clinical effects of acupuncture on the autonomic nervous system.

Improving the diagnosis of acute ischemic stroke on non-contrast CT using deep learning: a multicenter study.

OBJECTIVE: This study aimed to develop a deep learning (DL) model to improve the diagnostic performance of EIC and ASPECTS in acute ischemic stroke (AIS). METHODS: Acute ischemic stroke patients were retrospectively enrolled from 5 hospitals. We proposed a deep learning model to simultaneously segment the infarct and estimate ASPECTS automatically using baseline CT. The model performance of segmentation and ASPECTS scoring was evaluated using dice similarity coefficient (DSC) and ROC, respectively. Four raters participated in the multi-reader and multicenter (MRMC) experiment to fulfill the region-based ASPECTS reading under the assistance of the model or not. At last, sensitivity, specificity, interpretation time and interrater agreement were used to evaluate the raters' reading performance. RESULTS: In total, 1391 patients were enrolled for model development and 85 patients for external validation with onset to CT scanning time of 176.4 ± 93.6 min and NIHSS of 5 (IQR 2-10). The model achieved a DSC of 0.600 and 0.762 and an AUC of 0.876 (CI 0.846-0.907) and 0.729 (CI 0.679-0.779), in the internal and external validation set, respectively. The assistance of the DL model improved the raters' average sensitivities and specificities from 0.254 (CI 0.22-0.26) and 0.896 (CI 0.884-0.907), to 0.333 (CI 0.301-0.345) and 0.915 (CI 0.904-0.926), respectively. The average interpretation time of the raters was reduced from 219.0 to 175.7 s (p = 0.035). Meanwhile, the interrater agreement increased from 0.741 to 0.980. CONCLUSIONS: With the assistance of our proposed DL model, radiologists got better performance in the detection of AIS lesions on NCCT.

HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2.

We intended to characterize functional relevance of microRNA (miR)-224-3p in endothelial cell (EC) apoptosis and reactive oxygen species (ROS) accumulation in atherosclerosis, considering also the integral involvement of histone deacetylase 1 (HDAC1)-mediated hypoxia-inducible factor-1α (HIF1α) deacetylation. The binding affinity between miR-224-3p and Fos-like antigen 2 (FOSL2) was predicted and validated. Furthermore, we manipulated miR-224-3p, FOSL2, HDAC1, and HIF1α expression in oxidized low-density lipoprotein (ox-LDL)-induced ECs, aiming to clarify their effects on cell activities, inflammation, and ROS level. Additionally, we examined the impact of miR-224-3p on aortic atherosclerotic plaque and lesions in a high-fat-diet-induced atherosclerosis model in ApoE-/- mice. Clinical atherosclerotic samples and ox-LDL-induced human aortic ECs (HAECs) exhibited low HDAC1/miR-224-3p expression and high HIF1α/FOSL2 expression. miR-224-3p repressed EC cell apoptosis, inflammatory responses, and intracellular ROS levels through targeting FOSL2. HIF1α reduced miR-224-3p expression to accelerate EC apoptosis and ROS accumulation. Moreover, HDAC1 inhibited HIF1α expression by deacetylation, which in turn enhanced miR-224-3p expression to attenuate EC apoptosis and ROS accumulation. miR-224-3p overexpression reduced atherosclerotic lesions in vivo. In summary, HDAC1 overexpression may enhance the anti-atherosclerotic and endothelial-protective effects of miR-224-3p-mediated inhibition of FOSL2 by deacetylating HIF1α, underscoring a novel therapeutic insight against experimental atherosclerosis.

Antidepressant-Like Effect of Geniposide in Mice Exposed to a Chronic Mild Stress Involves the microRNA-298-5p-Mediated Nox1.

Depression is a common mental disorder that presents a considerable challenge for public health. The natural product geniposide has neuroprotective effects on depression, but the underlying mechanism behind these effects had remained undefined. The present study was designed to investigate the role of microRNAs (miRs) in this mechanism. It studied mice with depression-like behavior established by exposure to chronic unpredictable mild stress (CUMS) for 2 months. The CUMS mice were intragastrically fed with geniposide at a dose of 10 ml/kg daily for two consecutive weeks. We monitored the depression-like behaviors of the CUMS mice by the forced swimming test (FST) and tail suspension test (TST). Then, we measured the cerebral expression of miR-298-5p and NADPH oxidase 1 (Nox1) mRNA in the CUMS mice by the RT-qPCR. The targeting relationship between miR-298-5p and Nox1 was evaluated by dual-luciferase reporter gene assay. The concentrations of adenosine triphosphate (ATP) and reactive oxygen species (ROS) were determined by the CellTiter-Glo® and flow cytometry, respectively. The mitochondrial membrane potential (MMP) was detected using JC-1 staining. Moreover, the expression of inflammatory cytokines (TNF-α, IL-1ß, IL-6, and TGF-ß) was determined by ELISA, RT-qPCR, and western blot analysis. We found that miR-298-5p was poorly-expressed while Nox1 was highly-expressed in the brain tissues of the CUMS-induced mice. Intriguingly, Geniposide treatment reversed the behavioral abnormalities of CUMS mice, including shortened immobility time. Geniposide inhibited the Nox1 expression by increasing miR-298-5p levels. There were increased ATP content and MMP and reduced contents of ROS and inflammatory cytokines in the CUMS mice receiving geniposide treatment. Hence, this study revealed an antidepressant effect of geniposide on CUMS-induced depression-like behavior in mice by down-regulating the miR-298-5p-targeted Nox1. This highlights a novel candidate target for the treatment of depression.

Electroacupuncture alleviates Parkinson disease and regulates the expression of brain-gut peptides.

The non-motor symptoms (NMS) of Parkinson's disease (PD) are found in more than 90% of patients with PD. Here, we explored the effects of electroacupuncture (EA) stimulation at Zhong wan (CV-12), Qihai (RN-7), Zusanli (ST-36) and Taichong (LR-3) on NMS and brain-gut peptides of PD. We found that EA intervention alleviated the motor deficit induced by 6-OHDA in rats indicated by the decreased abnormal involuntary movements (AIMs) scores and the net number of rotations and increased cylinder test grade. It also improved the spatial memory and attenuated anxiety-like and depression of PD model rats. EA treatment significantly inhibited neuronal apoptosis in PD model animals, as demonstrated by the increased number of TH positive cells and reduced number of apoptotic cells in the substantia nigra. The expression of cleaved caspase-3 and cleaved PARP in PD model rats was markedly suppressed by EA stimulation. Moreover, EA remarkably inhibited the inflammatory response in PD model rats, as revealed by the decreased levels of TNF-α, IL-1ß, and COX-2 mRNA expression. It also attenuated the oxidative stress in rats, as indicated by the increased levels of SOD and GSH and the decreased level of MDA. EA treatment contributed to alleviating PD by regulating brain-gut peptides in rats, such as NPY, CCK, SST, GAS, and PYY. In conclusion, EA stimulation at CV-12, RN-7, ST-36, and LR-3 effectively alleviates the NMS of PD partly through regulating the levels of brain-gut peptides.

Geniposide Alleviates Oxidative Stress of Mice With Depression-Like Behaviors by Upregulating Six3os1.

Depression is a major cause of disease burden and severely impairs well-being of patients around the globe. Geniposide (GP) has been revealed to play a significant role in depression treatment. Of note, RNA sequencing of this study identified highly expressed long non-coding RNA Six3os1 in response to GP treatment. Thus, we aim to explore how GP affected chronic unpredictable mild stress (CUMS)-induced depression-like behaviors in mice in vivo and in vitro and the downstream molecular mechanism related to Six3os1. The relationship of Six3os1, miR-511-3p and Fezf1 was evaluated by dual-luciferase reporter gene assay, RIP assay, and RNA pulling down assay. Ectopic expression and knockdown experiments were developed in CUMS-induced mice and neurons with or without GP treatment. In vitro experiments and behavioral tests were conducted to examine alteration of CUMS-triggered oxidative stress following different interferences. The experimental data validated that GP treatment resulted in high expression of Six3os1 and Fezf1 and poor expression of miR-511-3p in CUMS-induced neurons. Six3os1 activated the AKT signaling pathway by upregulating miR-511-3p-targeted Fezf1. Either GP treatment or overexpression of Six3os1 or Fezf1 alleviated depression-like behaviors of CUMS-induced mice. GP treatment, miR-511-3p inhibition or overexpression of Six3os1 or Fezf1 not only reduced oxidative stress in CUMS-induced mice and neurons, but also reduced CUMS-induced neuronal apoptosis. Collectively, GP treatment-mediated Six3os1 upregulation ameliorated oxidative stress of mice with depression-like behaviors via the miR-511-3p/Fezf1/AKT axis.