Network Pharmacology and Molecular Docking Identify the Potential Mechanism and Therapeutic Role of Scutellaria baicalensis in Alzheimer's Disease.

Aim: Scutellaria baicalensis, a traditional Chinese medicinal herb renowned for its anti-inflammatory, antioxidant, and anti-tumor properties, has shown promise in alleviating cognitive impairment associated with Alzheimer's disease. Nonetheless, the exact neuroprotective mechanism of Scutellaria baicalensis against Alzheimer's disease remains unclear. In this study, network pharmacology was employed to explore the possible mechanisms by which Scutellaria baicalensis protects against Alzheimer's disease. Methods: The active compounds of Scutellaria baicalensis were retrieved from the TCMSP database, and their corresponding targets were identified. Alzheimer's disease-related targets were obtained through searches in the GeneCards and OMIM databases. Cytoscape 3.6.0 software was utilized to construct a regulatory network illustrating the "active ingredient-target" relationships. Subsequently, the target genes affected by Scutellaria baicalensis in the context of Alzheimer's disease were input into the String database to establish a PPI network. GO analysis and KEGG analysis were conducted using the DAVID database to predict the potential pathways associated with these key targets. Following this, the capacity of these active ingredients to bind to core targets was confirmed through molecular docking. In vitro experiments were then carried out for further validation. Results: A total of 36 active ingredients from Scutellaria baicalensis were screened out, which corresponded to 365 targets. Molecular docking results demonstrated the robust binding abilities of Baicalein, Wogonin, and 5,2'-Dihydroxy-6,7,8-trimethoxyflavone to key target proteins (SRC, PIK3R1, and STAT3). In vitro experiments showed that the active components of Scutellaria baicalensis can inhibit STAT3 expression by downregulating the PIK3R1/SRC pathway in Neuro 2A cells. Conclusion: In summary, these findings collectively suggest that Scutellaria baicalensis holds promise as a viable treatment option for Alzheimer's disease.

Comparison of Mycoplasma pneumoniae infection in children admitted with community acquired pneumonia before and during the COVID-19 pandemic: a retrospective study at a tertiary hospital of southwest China.

PURPOSE: The COVID-19 pandemic has notably altered the infection dynamics of various pathogens. This study aimed to evaluate the pandemic's impact on the infection spectrum of Mycoplasma pneumoniae (M. pneumoniae) among children with community acquired pneumonia (CAP). METHODS: We enrolled pediatric CAP patients admitted to a tertiary hospital in southwest China to compare the prevalence and characteristics of M. pneumoniae infections before (2018-2019) and during (2020-2022) the COVID-19 pandemic. Detection of M. pneumoniae IgM antibodies in serum were conducted using either indirect immunofluorescence or passive agglutination methods. RESULTS: The study included 1505 M. pneumoniae-positive and 3160 M. pneumoniae-negative CAP patients. Notable findings were the higher age and frequency of pneumonia-associated symptoms in M. pneumoniae-positive patients, alongside a lower male proportion and fewer respiratory co-infections. The year 2019 saw a notable increase in M. pneumoniae infections compared to 2018, followed by a decline from 2020 to 2022. The COVID-19 pandemic period witnessed significant alterations in age distribution, male proportion, and co-infections with specific pathogens in both M. pneumoniae-positive and negative patients. The M. pneumoniae infections were predominantly seasonal, peaking in autumn and winter during 2018 and 2019. Although there was a sharp drop in February 2020, the infection still peaked in cold months of 2020 and 2021. However, the typical seasonal pattern was nearly absent in 2022. CONCLUSIONS: The COVID-19 pandemic has markedly changed the infection landscape of M. pneumoniae in pediatric CAP patients, with shifts observed in infection rates, demographic profiles, co-infections, and seasonal patterns.

Identification of Plasma Inflammatory Markers of Adolescent Depression Using the Olink Proteomics Platform.

Purpose: The quality of life of worldwide adolescents has been seriously affected by depression. Notably, the inflammatory response is closely associated with the pathophysiology of depression. The present study applied a novel targeted proteomics technology, Olink proximity extension assay (PEA), to profile circulating immune-related proteins in adolescents with depression. Methods: In the present study, the expression levels of 92 inflammation-related proteins were compared between adolescents with depression (ADs) (n=15) and healthy controls (HCs) (n=15), using the OLINK PEA inflammation panel. We further validated 5 top proteins that were identified through KEGG and GO analyses between 40 HCs and 50 ADs, including CCL4, CXCL5, CXCL6, CXCL11, and IL-18 using enzyme linked immunosorbent assay (ELISA). Results: We identified 13 differentially expressed proteins between the two cohorts, including 5 up-regulated and 8 down-regulated proteins. Among them, the TRAIL protein levels were significantly negatively correlated with the HAMA-14 score (r=-0.538, p= 0.038), and the levels of transforming growth factor α (TGF-α) were significantly associated with a change in appetite (r = -0.658, p = 0.008). After validation by ELISA, CCL4, CXCL5, CXCL11, and IL-18 showed significant changes between ADs and HCs (p < 0.05), while CXCL6 showed an up-regulated tendency in ADs (p=0.0673). The pooled diagnostic efficacy (area under the curve [AUC]) of these five inflammation markers in clinical diagnosis for adolescent depression was 0.819 (95% CI: 0.735-0.904). Conclusion: We report a number of inflammation-related plasma biomarkers, which uncover a potential involvement of chemokines, cytokines, and cytokine receptors in adolescent depression. Their roles in the pathophysiology of depression need to be further elucidated.

Enhanced Biohomogeneous Composite Membrane-Encapsulated Nanoplatform with Podocyte Targeting for Precise and Safe Treatment of Diabetic Nephropathy.

Diabetic nephropathy (DN), associated with high mobility and disability, is the leading cause of end-stage kidney disease worldwide. Dysfunction of the mammalian target of the rapamycin (mTOR) pathway and reactive oxygen species (ROS) activation in the glomeruli is the main hypnosis for DN progression. However, the use of mTOR inhibitors for DN treatment remains controversial. In this study, we built a multifunctional selective mechanistic target of rapamycin complex 1 (mTORC1) inhibiting nanoplatform (naming as ESC-HCM-B) that targets the release of mTOR and ROS inhibitors near podocytes, aiming to confirm whether combination therapy is an alternative method for DN treatment. The results showed that ESC-HCM-B achieved high drug loading because of the core mesoporous silica nanoparticles (MSNPs), and the enhanced biohomogeneous composite membrane endowed ESC-HCM-B with the characteristics of avoiding immune phagocytosis, automatic valve-type slow-release drug, and high stability. In vitro, the nanoplatform showed high efficiency in podocyte targeting but no significant cytotoxicity or apoptotic promotion. In particular, the quantum dots carried by ESC-HCM-B further amplified the effect of "nanoenzyme"; this mechanism reduced the ROS level in podocytes induced by high glucose, protected mitochondrial damage, and restored mitochondrial energy metabolism. In vivo, the nanoplatform specifically targeted the glomerular and podocyte regions of the kidney. After treatment, the nanoplatform significantly reduced urinary protein levels and delayed glomerulosclerosis in DN rats. This nanoplatform provides a safe and effective strategy for DN treatment.

A retrospective analysis of factors associated with the length of hospital stay in COVID-19 patients treated with Nirmatrelvir / Ritonavir.

Objectives: This study reviewed factors influencing the length of hospital stay in adult inpatients with confirmed Coronavirus disease (COVID-19) who were treated with Nirmatrelvir/Ritonavir. Methods: We did a retrospective analysis of data from a cohort of inpatients with confirmed diagnosis of Omicron variant of SARS-CoV-2 infection who were treated with Nirmatrelvir/Ritonavir. We included patients who were treated from 13th March 2022 to 6th May 2022 in various in-patient treatment units in Quanzhou, Fujian Province, China. The primary study outcome was the length of hospital stay. Secondary study outcome was viral elimination defined as negative for ORF1ab and N genes [cycle threshold (Ct) value ≥35 in real-time PCR], according to local guidelines. Hazard ratios (HR) of event outcomes were analyzed using Multivariate Cox regression models. Results: We studied 31 inpatients with high risk for severe COVID-19 who were treated with Nirmatrelvir/Ritonavir. We found that inpatients with shorter length of hospital stay (≤17 days) were mostly females with lower body mass index (BMI) and Charlson Comorbidity Index (CCI) index. Their treatment regimen with Nirmatrelvir/Ritonavir was started within 5 days of diagnosis (p < 0.05). Multivariate Cox regression indicated that inpatients starting treatment of Nirmatrelvir/Ritonavir within 5 days had a shorter length of hospital stay (HR 3.573, p = 0.004) and had a faster clearance of viral load (HR 2.755, p = 0.043). Conclusion: This study assumes relevance during the Omicron BA.2 epidemic as our findings suggest that early treatment with Nirmatrelvir/Ritonavir within 5 days of diagnosis (≤5 days) was highly effective in shortening the length of hospital stay and faster viral load clearance.

Polymorphism in genes encoding two fatty acid binding proteins increases risk of ischemic stroke in a Chinese Han population.

Background: Dyslipidemia is an independent predictor of ischemic stroke (IS). Genetic variations in lipid-metabolism related genes may increase the risk of IS. Fatty acid-binding protein 1 (FABP1) and fatty acid-binding protein 2 (FABP2) are lipid chaperones responsible for lipid transport and metabolism. The present study aimed to determine the association between FABP1 or FABP2 and ischemic stroke. Methods: A total of 251 participants were recruited composed of 138 patients with ischemic stroke and 113 healthy subjects. DNA was extracted from peripheral blood samples. The rs2241883 polymorphism in FABP1 and rs1799883 polymorphism in FABP2 were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Generalized multifactor dimensionality reduction (GMDR) was used to find out the interaction combinations between two SNPs and environmental factors. Results: The GA genotype of FABP2 rs1799883 increased susceptibility to ischemic stroke under overdominant inheritance model (p = 0.042). After adjusting for the risk factors of IS, it was associated with a significantly higher risk of IS in the codominant inheritance model (adjust OR = 3.431, 95%CI = 1.060-11.103, p = 0.04). The interactions of FABP1 rs2241883 and FABP2 rs1799883 were not associated with IS risk (p = 0.172). Moreover, interaction analysis of two genes (rs1799883 and rs2241883) and two environmental factors (smoking and alcohol consumption) was associated with an increased risk of IS (p = 0.011). Conclusion: The GA genotype of FABP2 rs1799883, interactions between rs1799883, rs2241883 and smoking and alcohol consumption were associated with IS risk in Chinese Han populations.

Lipid Alteration Signature in the Blood Plasma of Individuals With Schizophrenia, Depression, and Bipolar Disorder.

Importance: No clinically applicable diagnostic test exists for severe mental disorders. Lipids harbor potential as disease markers. Objective: To define a reproducible profile of lipid alterations in the blood plasma of patients with schizophrenia (SCZ) independent of demographic and environmental variables and to investigate its specificity in association with other psychiatric disorders, ie, major depressive disorder (MDD) and bipolar disorder (BPD). Design, Setting, and Participants: This was a multicohort case-control diagnostic analysis involving plasma samples from psychiatric patients and control individuals collected between July 17, 2009, and May 18, 2018. Study participants were recruited as consecutive and volunteer samples at multiple inpatient and outpatient mental health hospitals in Western Europe (Germany and Austria [DE-AT]), China (CN), and Russia (RU). Individuals with DSM-IV or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses of SCZ, MDD, BPD, or a first psychotic episode, as well as age- and sex-matched healthy controls without a mental health-related diagnosis were included in the study. Samples and data were analyzed from January 2018 to September 2020. Main Outcomes and Measures: Plasma lipidome composition was assessed using liquid chromatography coupled with untargeted mass spectrometry. Results: Blood lipid levels were assessed in 980 individuals (mean [SD] age, 36 [13] years; 510 male individuals [52%]) diagnosed with SCZ, BPD, MDD, or those with a first psychotic episode and in 572 controls (mean [SD] age, 34 [13] years; 323 male individuals [56%]). A total of 77 lipids were found to be significantly altered between those with SCZ (n = 436) and controls (n = 478) in all 3 sample cohorts. Alterations were consistent between cohorts (CN and RU: [Pearson correlation] r = 0.75; DE-AT and CN: r = 0.78; DE-AT and RU: r = 0.82; P < 10-38). A lipid-based predictive model separated patients with SCZ from controls with high diagnostic ability (area under the receiver operating characteristic curve = 0.86-0.95). Lipidome alterations in BPD and MDD, assessed in 184 and 256 individuals, respectively, were found to be similar to those of SCZ (BPD: r = 0.89; MDD: r = 0.92; P < 10-79). Assessment of detected alterations in individuals with a first psychotic episode, as well as patients with SCZ not receiving medication, demonstrated only limited association with medication restricted to particular lipids. Conclusions and Relevance: In this study, SCZ was accompanied by a reproducible profile of plasma lipidome alterations, not associated with symptom severity, medication, and demographic and environmental variables, and largely shared with BPD and MDD. This lipid alteration signature may represent a trait marker of severe psychiatric disorders, indicating its potential to be transformed into a clinically applicable testing procedure.

Elevated plasma intestinal fatty acid binding protein and aberrant lipid metabolism predict post-stroke depression.

Post-stroke depression (PSD) is the most common mood disorder caused by stroke. Stroke might bring about increased intestinal permeability accompanied by gut microbiota changes. According to the "gut-brain" axis hypothesis, increased intestinal permeability may contribute to PSD. Therefore, we investigated the association between increased intestinal permeability and the occurrence of PSD. Intestinal fatty acid binding protein (iFABP) is responsible for intestinal fatty acid absorption and transport and is often considered a biomarker of gut hyperpermeability, also known as leaky gut. We enrolled 48 healthy controls (HCs), 48 stroke patients without depression, and 48 PSD patients in this study. Plasma iFABP was measured in the three groups. CRP, LBP, and sCD14 were quantified for bacterial infection assessment. In addition, clinical laboratory indicators of lipid metabolism were assessed. The PSD patients exhibited higher iFABP levels compared with HCs and non-depressed stroke patients. Using OPLS discriminant analysis, four proteins (ApoA1, HDL-C, iFABP, and Lp(a)) were identified as potential biomarkers for distinguishing PSD patients from non-depression stroke patients. Our study discovered that elevated plasma iFABP levels in PSD patients correlated with the degree of depression, along with disturbed lipid metabolism. These findings also suggested the need to consider the role of a leaky gut in depression after stroke.

Reduced plasma levels of RGM-A predict stroke-associated pneumonia in patients with acute ischemic stroke: A prospective clinical study.

Background: Stroke-induced immunodepression syndrome is considered the major etiology of stroke-associated pneumonia (SAP). Repulsive guidance molecule A (RGM-A) is an immunomodulatory protein that is closely related to inflammation and immune responses. To explore the relationship between RGM-A and SAP and facilitate the early identification of patients at high risk of developing SAP, we investigated the predictive value of RGM-A in SAP. Methods: We enrolled 178 patients with acute ischemic stroke (AIS) and finally analyzed 150 patients, among whom 69 had SAP and 81 had non-SAP. During the same period, 40 patients with community-acquired pneumonia and 40 healthy participants were included as controls. SAP was defined according to the modified US Centers for Disease Control and Prevention criteria. Blood samples were collected at 24 h, 48 h, 3 days, 4 to 7 days, and 8 to 14 days after stroke onset. An enzyme-linked immunosorbent assay was used to detect the plasma levels of RGM-A and interleukin-6. Results: The plasma RGM-A levels were significantly decreased in both patients with community-acquired pneumonia and those with AIS, and the decline was most pronounced in patients with SAP (P < 0.001). RGM-A started to decline within 24 h after stroke in the SAP group, and the lowest levels were detected on day 3 and days 4 to 7 (P < 0.001). The RGM-A levels in the SAP group were lower than those in the non-SAP group at all blood collection time points (P < 0.05). In the logistic regression analyses, RGM-A was a protective factor for SAP after adjusting for confounders (adjusted odds ratio = 0.22, 95% confidence interval = 0.091-0.538, P = 0.001). Receiver operating characteristic curve analysis showed that the area under the curve for RGM-A was 0.766 (0.091-0.538; P = 0.001), the cutoff value was 4.881 ng/mL, and the sensitivity and specificity were 80.00 and 76.36%, respectively. Conclusions: We demonstrated that reduced plasma levels of RGM-A might help in the early identification of high-risk patients with SAP and predict the occurrence of SAP in patients with AIS. RGM-A might provide new clues to a potential alternative therapy for SAP.

The GR-FKBP51 interaction modulates fear memory but not spatial or recognition memory.

The glucocorticoid receptor (GR) forms a protein complex with FKBP51 that is increased in post-traumatic stress disorder (PTSD) and by fear conditioned learning. Disrupting the GR-FKBP51 complex with a synthetic peptide can block the storage or retrieval of fear conditioned memories, which could be a novel approach to the alleviate fear associated memory in PTSD. However, a potential unacceptable side effect could be the impairment of other types of memory. Thus, we investigated the effect of disrupting the GR-FKBP51 complex on recognition memory using the novel object and displaced object recognition tasks, spatial memory in the Morris water maze, and on social interaction in Crawley's three-chamber social interaction test. We did not observe adverse effects on these other types of memory and conclude that the GR-FKBP51 interaction remains a promising target for treating psychiatric disorders characterized by unwanted aversive memories such as in PTSD.

Differential Gut Microbiota Compositions Related With the Severity of Major Depressive Disorder.

Objective: Increasing evidence shows a close relationship between gut microbiota and major depressive disorder (MDD), but the specific mechanisms remain unknown. This study was conducted to explore differential gut microbiota compositions related to the severity of MDD. Methods: Healthy controls (HC) (n = 131) and MDD patients (n = 130) were included. MDD patients with Hamilton Depression Rating Scale (HDRS) score <25 and ≥25 were assigned into moderate (n = 72) and severe (n = 58) MDD groups, respectively. Univariate and multivariate analyses were used to analyze the gut microbiota compositions at the genus level. Results: Thirty-six and 27 differential genera were identified in moderate and severe MDD patients, respectively. The differential genera in moderate and severe MDD patients mainly belonged to three (Firmicutes, Actinobacteriota, and Bacteroidota) and two phyla (Firmicutes and Bacteroidota), respectively. One specific covarying network from phylum Actinobacteriota was identified in moderate MDD patients. In addition, five genera (Collinsella, Eggerthella, Alistipes, Faecalibacterium, and Flavonifractor) from the shared differential genera by two MDD groups had a fair efficacy in diagnosing MDD from HC (AUC = 0.786). Conclusions: Our results were helpful for further exploring the role of gut microbiota in the pathogenesis of depression and developing objective diagnostic methods for MDD.

Associations Between Disordered Microbial Metabolites and Changes of Neurotransmitters in Depressed Mice.

Backgrounds: Many pieces of evidence demonstrated that there were close relationships between gut microbiota and depression. However, the specific molecular mechanisms were still unknown. Here, using targeted metabolomics, this study was conducted to explore the relationships between microbial metabolites in feces and neurotransmitters in prefrontal cortex of depressed mice. Methods: Chronic unpredictable mild stress (CUMS) model of depression was built in this study. Targeted liquid chromatography-mass spectrometry analysis was used to detect the microbial metabolites in feces and neurotransmitters in prefrontal cortex of mice. Both univariate and multivariate statistical analyses were applied to identify the differential microbial metabolites and neurotransmitters and explore relationships between them. Results: Ninety-eight differential microbial metabolites (mainly belonged to amino acids, fatty acids, and bile acids) and 11 differential neurotransmitters (belonged to tryptophan pathway, GABAergic pathway, and catecholaminergic pathway) were identified. Five affected amino acid-related metabolic pathways were found in depressed mice. The 19 differential microbial metabolites and 10 differential neurotransmitters were found to be significantly correlated with depressive-like behaviors. The two differential neurotransmitters (tyrosine and glutamate) and differential microbial metabolites belonged to amino acids had greater contributions to the overall correlations between microbial metabolites and neurotransmitters. In addition, the significantly decreased L-tyrosine as microbial metabolites and tyrosine as neurotransmitter had the significantly positive correlation (r = 0.681, p = 0.0009). Conclusions: These results indicated that CUMS-induced disturbances of microbial metabolites (especially amino acids) might affect the levels of neurotransmitters in prefrontal cortex and then caused the onset of depression. Our findings could broaden the understanding of how gut microbiota was involved in the onset of depression.

Altered Metabolism of the Microbiota-Gut-Brain Axis Is Linked With Comorbid Anxiety in Fecal Recipient Mice of Myasthenia Gravis.

Myasthenia gravis (MG) comorbid anxiety seriously affects the progress of MG. However, the exact relationship remains poorly understood. Recently, our preliminary study has revealed that intestinal microbe disturbance is closely related to MG. Therefore, further exploration of whether the microbiome is involved in MG comorbid anxiety is warranted. In this study, gas chromatography-mass spectrometry metabolomics analysis was used to characterize the metabotype of feces, serum, and three brain regions involved in emotion (i.e., the prefrontal cortex, hippocampus, and striatum), which were obtained from mice that were colonized with fecal microbiota from patients with MG (MMb), healthy individuals (HMb), or co-colonization of both patients and healthy individuals (CMb). Functional enrichment analysis was used to explore the correlation between the "microbiota-gut-brain" (MGB) axis and anxiety-like behavior. The behavioral test showed that female MMb exhibited anxiety-like behavior, which could be reversed by co-colonization. Moreover, metabolic characterization analysis of the MGB axis showed that the metabotype of gut-brain communication was significantly different between MMb and HMb, and 146 differential metabolites were jointly identified. Among these, 44 metabolites in feces; 12 metabolites in serum; 7 metabolites in hippocampus; 2 metabolites in prefrontal cortex; and 6 metabolites in striatum were reversed by co-colonization. Furthermore, the reversed gut microbiota mainly belonged to bacteroides and firmicutes, which were highly correlated with the reversed metabolites within the MGB axis. Among three emotional brain regions, hippocampus was more affected. Therefore, disturbances in gut microbiota may be involved in the progress of anxiety-like behavior in MG due to the MGB axis.

MicroRNA-Messenger RNA Regulatory Network Mediates Disrupted TH17 Cell Differentiation in Depression.

Accumulating evidence indicates an important role for microRNA (miRNA)-messenger RNA (mRNA) regulatory networks in human depression. However, the mechanisms by which these networks act are complex and remain poorly understood. We used data mining to identify differentially expressed miRNAs from GSE81152 and GSE152267 datasets, and differentially expressed mRNAs were identified from the Netherlands Study of Depression and Anxiety, the GlaxoSmithKline-High-Throughput Disease-specific target Identification Program, and the Janssen-Brain Resource Company study. We constructed a miRNA-mRNA regulatory network based on differentially expressed mRNAs that intersected with target genes of differentially expressed miRNAs, and then performed bioinformatics analysis of the network. The key candidate genes were assessed in the prefrontal cortex of chronic social defeat stress (CSDS) depression mice by quantitative real-time polymerase chain reaction (qRT-PCR). Three differentially expressed miRNAs were commonly identified across the two datasets, and 119 intersecting differentially expressed mRNAs were identified. A miRNA-mRNA regulatory network including these three key differentially expressed miRNAs and 119 intersecting differentially expressed mRNAs was constructed. Functional analysis of the intersecting differentially expressed mRNAs revealed that an abnormal inflammatory response characterized by disturbed T-helper cell 17 (Th17) differentiation was the primary altered biological function. qRT-PCR validated the decreased expression of Th17 cell differentiation-related genes, including interleukin (IL)17A, IL21, IL22, and IL1ß, and the increased expression of retinoic acid receptor-related orphan receptor gamma-t (RORγt) in CSDS mice, which showed significant depressive- and anxiety-like behaviors. This study indicates that an abnormal inflammatory response characterized by disturbed Th17 cell differentiation is the primary altered biological process in major depressive disorder. Our findings indicate possible biomarkers and treatment targets and provide novel clues to understand the pathogenesis of major depressive disorder.

Proteomics analysis of the gut-brain axis in a gut microbiota-dysbiosis model of depression.

Major depressive disorder (MDD) is a serious mental illness. Increasing evidence from both animal and human studies suggested that the gut microbiota might be involved in the onset of depression via the gut-brain axis. However, the mechanism in depression remains unclear. To explore the protein changes of the gut-brain axis modulated by gut microbiota, germ-free mice were transplanted with gut microbiota from MDD patients to induce depression-like behaviors. Behavioral tests were performed following fecal microbiota transplantation. A quantitative proteomics approach was used to examine changes in protein expression in the prefrontal cortex (PFC), liver, cecum, and serum. Then differential protein analysis and weighted gene coexpression network analysis were used to identify microbiota-related protein modules. Our results suggested that gut microbiota induced the alteration of protein expression levels in multiple tissues of the gut-brain axis in mice with depression-like phenotype, and these changes of the PFC and liver were model specific compared to chronic stress models. Gene ontology enrichment analysis revealed that the protein changes of the gut-brain axis were involved in a variety of biological functions, including metabolic process and inflammatory response, in which energy metabolism is the core change of the protein network. Our data provide clues for future studies in the gut-brain axis on protein level and deepen the understanding of how gut microbiota cause depression-like behaviors.

Association of bone mineral density and depression in different bone sites and ages: A meta-analysis.

Major depressive disorder (MDD) is considered as a risk factor for osteoporosis. Bone mineral density (BMD), as the main tool for diagnosing osteoporosis, has been reported to have correlation with MDD in different cohorts. However, the information in causative link and etiology determinants of osteoporosis in MDD is still under investigation. The results are unclear. Thus, we perform a meta-analysis to evaluate the association between altered BMD and MDD. We searched the electronic databases to find studies examining BMD in patients with MDD. Finally, 26 published studies were included in our meta-analysis up from January 1990 to January 2019. All the data were pooled analysis using RevMan software. The association between altered BMD and MDD was assessed by std. mean difference (STD) and their 95% confidence intervals (CIs) for each study. Twenty-six studies were included in this meta-analysis. Pooled results showed a significant lower BMD in spine (STD=0.51, 95% CI=0.30-0.71, p < .00001), total hip (STD=0.41, 95% CI=0.16 to 0.66, p = .001), and femoral neck (STD=0.93, 95% CI=0.32 to 1.55, p = .003) in MDD compared with controls. After stratification by mean age, gender, recruitment, diagnostic criteria, and measuring methods, no significant difference of BMD was found in bone mineral density of male total hip between MDD and controls(p > .05). Moreover, adults appear to have lower BMD than old cohorts. This is an updated meta-analysis to reveal the association of bone mineral density and depression, suggesting that BMD appears to be more susceptible to occur in spine, total hip, femoral neck in MDD, especially for adults and women. Our meta-analysis may provide clinicians and public health administrators with an important screening tool for assessing depression and avoiding osteoporosis in adult subjects and female.

Comprehensive analysis of the lysine acetylome and succinylome in the hippocampus of gut microbiota-dysbiosis mice.

Introduction: Major depressive disorder is caused by gene-environment interactions, and the host microbiome has been recognized as an important environmental factor. However, the underlying mechanisms of the host-microbiota interactions that lead to depression are complex and remain poorly understood. Objectives: The present study aimed to explore the possible mechanisms underlying gut microbiota dysbiosis-induced depressive-like behaviors. Methods: We used high-performance liquid chromatography-tandem mass spectrometry to analyze alterations in the hippocampal lysine acetylome and succinylome in male mice that had received gut microbiota from fecal samples of either patients with major depressive disorder or healthy controls. This was followed by bioinformatic analyses. Results: A total of 315 acetylation sites on 223 proteins and 624 succinylation sites on 494 proteins were differentially expressed in the gut microbiota-dysbiosis mice. The significantly acetylated proteins were primarily associated with carbon metabolism disruption and gene transcription suppression, while the synaptic vesicle cycle and protein translation were the most significantly altered functions for succinylated proteins. Additionally, our findings suggest that gut microbiota dysbiosis disturbs mitochondria-mediated biological processes and the MAPK signaling pathway through crosstalk between acetylation and succinylation on relevant proteins. Conclusions: This is the first study to demonstrate modifications in acetylation and succinylation in gut microbiota-dysbiosis mice. Our findings provide new avenues for exploring the pathogenesis of gut microbiota dysbiosis-related depression, and highlight potential targets for depression treatment.

Phototropin2-mediated hypocotyl phototropism is negatively regulated by JAC1 and RPT2 in Arabidopsis.

Hypocotyl phototropism is redundantly mediated by phot1 and phot2, two blue light receptor phototropins, under the intensity of blue light>1 µmol m-2 s-1. As light intensity increases, phot1 inhibits the phot2-mediated response. To date, only Arabidopsis Root Phototropism2 (RPT2) has been shown to participate in phot1-mediated inhibition of phototropism. To dissect the signaling network that underlies phot1-mediated inhibition, we carried out a yeast two-hybrid (Y2H) screening assay for RPT2 interacting proteins and identified J-domain protein required for chloroplast accumulation response 1 (JAC1). The interaction between JAC1 and RPT2 was verified by bimolecular fluorescence complementation and Co-IP assays. JAC1 is expressed mainly in cotyledons and hypocotyls. Like RPT2, JAC1 can be induced by blue light, suggesting that it may function similarly to RPT2 in the inhibition of phototropism. Genetic analysis showed that jac1 mutation significantly enhanced the hypocotyl bending of phot1 mutants towards intermediate-intensity blue light, and this effect was inhibited by the constitutive expression of JAC1 in the phot1 jac1 mutant. The phot1 rpt2 double mutant also exhibited enhanced phototropism compared with the phot1 mutant. Taken together, our data clearly demonstrate that JAC1 cooperates with RPT2 to negatively regulate hypocotyl phototropism in plants and may act either downstream of or in parallel with phot1.

Integrated phosphoproteomic and metabolomic profiling reveals perturbed pathways in the hippocampus of gut microbiota dysbiosis mice.

The dysbiosis of gut microbiota is an important environmental factor that can induce mental disorders, such as depression, through the microbiota-gut-brain axis. However, the underlying pathogenic mechanisms are complex and not completely understood. Here we utilized mass spectrometry to identify the global phosphorylation dynamics in hippocampus tissue in germ-free mice and specific pathogen-free mice (GF vs SPF), fecal microbiota transplantation (FMT) model ("depression microbiota" and the "healthy microbiota" recipient mice). As a result, 327 phosphosites of 237 proteins in GF vs SPF, and 478 phosphosites of 334 proteins in "depression microbiota" vs "healthy microbiota" recipient mice were identified as significant. These phosphorylation dysregulations were consistently associated with glutamatergic neurotransmitter system disturbances. The FMT mice exhibited disturbances in lipid metabolism and amino acid metabolism in both the periphery and brain through integrating phosphoproteomic and metabolomic analysis. Moreover, CAMKII-CREB signaling pathway, in response to these disturbances, was the primary common perturbed cellular process. In addition, we demonstrated that the spliceosome, never directly implicated in mental disorders previously, was a substantially neuronal function disrupted by gut microbiota dysbiosis, and the NCBP1 phosphorylation was identified as a novel pathogenic target. These results present a new perspective to study the pathologic mechanisms of gut microbiota dysbiosis related depression and highlight potential gut-mediated therapies for depression.

Associations between disordered gut microbiota and changes of neurotransmitters and short-chain fatty acids in depressed mice.

Mounting evidence suggests that gut microbiota can play an important role in pathophysiology of depression, but its specific molecular mechanisms are still unclear. This study was conducted to explore the associations between changes in neurotransmitters and short-chain fatty acids (SCFAs) and altered gut microbiota in depressed mice. Here, the chronic restraint stress (CRS) model of depression was built. The classical behavioral tests were conducted to assess the depressive-like behaviors of mice. The 16S rRNA gene sequence extracted from fecal samples was used to assess the gut microbial composition. Liquid and gas chromatography mass spectroscopy were used to identify neurotransmitters in hypothalamus and SCFAs in fecal samples, respectively. Finally, 29 differential bacteria taxa between depressed mice and control mice were identified, and the most differentially abundant bacteria taxa were genus Allobaculum and family Ruminococcaceae between the two groups. The acetic acid, propionic acid, pentanoic acid, norepinephrine, 5-HIAA and 5-HT were significantly decreased in depressed mice compared to control mice. Genus Allobaculum was found to be significantly positively correlated with acetic acid and 5-HT. Taken together, these results provided novel microbial and metabolic frameworks for understanding the role of microbiota-gut-brain axis in depression, and suggested new insights to pave the way for novel therapeutic methods.