Post-stroke cognitive impairment: exploring molecular mechanisms and omics biomarkers for early identification and intervention.

Post-stroke cognitive impairment (PSCI) is a major stroke consequence that has a severe impact on patients' quality of life and survival rate. For this reason, it is especially crucial to identify and intervene early in high-risk groups during the acute phase of stroke. Currently, there are no reliable and efficient techniques for the early diagnosis, appropriate evaluation, or prognostication of PSCI. Instead, plenty of biomarkers in stroke patients have progressively been linked to cognitive impairment in recent years. High-throughput omics techniques that generate large amounts of data and process it to a high quality have been used to screen and identify biomarkers of PSCI in order to investigate the molecular mechanisms of the disease. These techniques include metabolomics, which explores dynamic changes in the organism, gut microbiomics, which studies host-microbe interactions, genomics, which elucidates deeper disease mechanisms, transcriptomics and proteomics, which describe gene expression and regulation. We looked through electronic databases like PubMed, the Cochrane Library, Embase, Web of Science, and common databases for each omics to find biomarkers that might be connected to the pathophysiology of PSCI. As all, we found 34 studies: 14 in the field of metabolomics, 5 in the field of gut microbiomics, 5 in the field of genomics, 4 in the field of transcriptomics, and 7 in the field of proteomics. We discovered that neuroinflammation, oxidative stress, and atherosclerosis may be the primary causes of PSCI development, and that metabolomics may play a role in the molecular mechanisms of PSCI. In this study, we summarized the existing issues across omics technologies and discuss the latest discoveries of PSCI biomarkers in the context of omics, with the goal of investigating the molecular causes of post-stroke cognitive impairment. We also discuss the potential therapeutic utility of omics platforms for PSCI mechanisms, diagnosis, and intervention in order to promote the area's advancement towards precision PSCI treatment.

Identification of Potential Biomarkers for Major Depressive Disorder: Based on Integrated Bioinformatics and Clinical Validation.

Major depressive disorder (MDD) is a severe mental illness characterized by a lack of objective biomarkers. Mounting evidence suggests there are extensive transcriptional molecular changes in the prefrontal cortex (PFC) of individuals with MDD. However, it remains unclear whether there are specific genes that are consistently altered and possess diagnostic power. In this study, we conducted a systematic search of PFC datasets of MDD patients from the Gene Expression Omnibus database. We calculated the differential expression of genes (DEGs) and identified robust DEGs using the RRA and MetaDE methods. Furthermore, we validated the consistently altered genes and assessed their diagnostic power through enzyme-linked immunosorbent assay experiments in our clinical blood cohort. Additionally, we evaluated the diagnostic power of hub DEGs in independent public blood datasets. We obtained eight PFC datasets, comprising 158 MDD patients and 263 healthy controls, and identified a total of 1468 unique DEGs. Through integrated analysis, we identified 290 robustly altered DEGs. Among these, seven hub DEGs (SLC1A3, PON2, AQP1, EFEMP1, GJA1, CENPD, HSD11B1) were significantly down-regulated at the protein level in our clinical blood cohort. Moreover, these hub DEGs exhibited a negative correlation with the Hamilton Depression Scale score (P < 0.05). Furthermore, these hub DEGs formed a panel with promising diagnostic power in three independent public blood datasets (average AUCs of 0.85) and our clinical blood cohort (AUC of 0.92). The biomarker panel composed of these genes demonstrated promising diagnostic efficacy for MDD and serves as a useful tool for its diagnosis.

Oral microbiota dysbiosis alters chronic restraint stress-induced depression-like behaviors by modulating host metabolism.

Studies have shown that the microbiota-gut-brain axis is highly correlated with the pathogenesis of depression in humans. However, whether independent oral microbiome that do not depend on gut microbes could affect the progression of depression in human beings remains unclear, neither does the presence and underlying mechanisms of the microbiota-oral-brain axis in the development of the condition. Hence this study that encompasses clinical and animal experiments aims at investigating the correlation between oral microbiota and the onset of depression via mediating the microbiota-oral-brain axis. We compared the oral microbial compositions and metabolomes of 87 patients with depressive symptoms versus 70 healthy controls. We found that the oral microbial and metabolic signatures were significantly different between the two groups. Significantly, germ-free (GF) mice transplanted with saliva from mice exposing to chronic restraint stress (CRS) displayed depression-like behavior and oral microbial dysbiosis. This was characterized by a significant differential abundance of bacterial species, including the enrichment of Pseudomonas, Pasteurellaceae, and Muribacter, as well as the depletion of Streptococcus. Metabolomic analysis showed the alternation of metabolites in the plasma of CRS-exposed GF mice, especially Eicosapentaenoic Acid. Furthermore, oral and gut barrier dysfunction caused by CRS-induced oral microbiota dysbiosis may be associated with increased blood-brain barrier permeability. Pseudomonas aeruginosa supplementation exacerbated depression-like behavior, while Eicosapentaenoic Acid treatment conferred protection against depression-like states in mice. These results suggest that oral microbiome and metabolic function dysbiosis may be relevant to the pathogenesis and pathophysiology of depression. The proposed microbiota-oral-brain axis provides a new way and targets for us to study the pathogenesis of depression.

ProMENDA: an updated resource for proteomic and metabolomic characterization in depression.

Depression is a prevalent mental disorder with a complex biological mechanism. Following the rapid development of systems biology technology, a growing number of studies have applied proteomics and metabolomics to explore the molecular profiles of depression. However, a standardized resource facilitating the identification and annotation of the available knowledge from these scattered studies associated with depression is currently lacking. This study presents ProMENDA, an upgraded resource that provides a platform for manual annotation of candidate proteins and metabolites linked to depression. Following the establishment of the protein dataset and the update of the metabolite dataset, the ProMENDA database was developed as a major extension of its initial release. A multi-faceted annotation scheme was employed to provide comprehensive knowledge of the molecules and studies. A new web interface was also developed to improve the user experience. The ProMENDA database now contains 43,366 molecular entries, comprising 20,847 protein entries and 22,519 metabolite entries, which were manually curated from 1370 human, rat, mouse, and non-human primate studies. This represents a significant increase (more than 7-fold) in molecular entries compared to the initial release. To demonstrate the usage of ProMENDA, a case study identifying consistently reported proteins and metabolites in the brains of animal models of depression was presented. Overall, ProMENDA is a comprehensive resource that offers a panoramic view of proteomic and metabolomic knowledge in depression. ProMENDA is freely available at https://menda.cqmu.edu.cn .

Alterations of the gut microbiota in patients with schizophrenia.

Introduction: Schizophrenia is a complex psychiatric disorder, of which molecular pathogenesis remains largely unknown. Accumulating evidence suggest that gut microbiota may affect brain function via the complex gut-brain axis, which may be a potential contributor to schizophrenia. However, the alteration of gut microbiota showed high heterogeneity across different studies. Therefore, this study aims to identify the consistently altered gut microbial taxa associated with schizophrenia. Methods: We conducted a systematic search and synthesis of the up-to-date human gut microbiome studies on schizophrenia, and performed vote counting analyses to identify consistently changed microbiota. Further, we investigated the effects of potential confounders on the alteration of gut microbiota. Results: We obtained 30 available clinical studies, and found that there was no strong evidence to support significant differences in α-diversity and ß-diversity between schizophrenic patients and healthy controls. Among 428 differential gut microbial taxa collected from original studies, we found that 8 gut microbial taxa were consistently up-regulated in schizophrenic patients, including Proteobacteria, Gammaproteobacteria, Lactobacillaceae, Enterobacteriaceae, Lactobacillus, Succinivibrio, Prevotella and Acidaminococcus. While 5 taxa were consistently down-regulated in schizophrenia, including Fusicatenibacter, Faecalibacterium, Roseburia, Coprococcus and Anaerostipes. Discussion: These findings suggested that gut microbial changes in patients with schizophrenia were characterized by the depletion of anti-inflammatory butyrate-producing genera, and the enrichment of certain opportunistic bacteria genera and probiotics. This study contributes to further understanding the role of gut microbiota in schizophrenia, and developing microbiota-based diagnosis and therapy for schizophrenia.

Integrated analysis of transcriptional changes in major depressive disorder: Insights from blood and anterior cingulate cortex.

Background: Major depressive disorder (MDD) was involved in widely transcriptional changes in central and peripheral tissues. While, previous studies focused on single tissues, making it difficult to represent systemic molecular changes throughout the body. Thus, there is an urgent need to explore the central and peripheral biomarkers with intrinsic correlation. Methods: We systematically retrieved gene expression profiles of blood and anterior cingulate cortex (ACC). 3 blood datatsets (84 MDD and 88 controls) and 6 ACC datasets (100 MDD and 100 controls) were obtained. Differential expression analysis, RobustRankAggreg (RRA) analysis, functional enrichment analysis, immune associated analysis and protein-protein interaction networks (PPI) were integrated. Furthermore, the key genes were validated in an independent ACC dataset (12 MDD and 15 controls) and a cohort with 120 MDD and 117 controls. Results: Differential expression analysis identified 2211 and 2021 differential expressed genes (DEGs) in blood and ACC, respectively. RRA identified 45 and 25 robust DEGs in blood and ACC based on DEGs, and all of them were closely associated with immune cells. Functional enrichment results showed both the robust DEGs in blood and ACC were enriched in humoral immune response. Furthermore, PPI identified 8 hub DEGs (CD79A, CD79B, CD19, MS4A1, PLP1, CLDN11, MOG, MAG) in blood and ACC. Independent ACC dataset showed the area under the curve (AUC) based on these hub DEGs was 0.77. Meanwhile, these hub DEGs were validated in the serum of MDD patients, and also showed a promising diagnostic power. Conclusions: The biomarker panel based on hub DEGs yield a promising diagnostic efficacy, and all of these hub DEGs were strongly correlated with immunity. Humoral immune response may be the key link between the brain and blood in MDD, and our results may provide further understanding for MDD.

Measuring job stress of dental workers in China during the COVID-19 pandemic: reliability and validity of the hospital consultants' job stress questionnaire.

BACKGROUND: The Hospital Consultants' Job Stress Questionnaire (HCJSQ) has been widely used to assess sources and levels of job stress. However, its reliability and validity among Chinese dental workers have not been extensively studied. The objective of this study was to assess the reliability and validity of the HCJSQ specifically in Chinese dental workers. METHODS: The HCJSQ was used to explore the sources and the global ratings of job stress among Chinese dental workers. To assess the reliability and validity of the HCJSQ, various statistical measures were employed, including Cronbach's alpha coefficient, Spearman-Brown coefficient, Spearman correlation coefficient, exploratory factor analysis, confirmatory factor analysis, convergent validity, and discriminant validity. RESULTS: Of the participants, 526 (17.4%) reported high levels of stress, while 1,246 (41.3%) and 1,248 (41.3%) reported moderate and low levels of stress, respectively. The Cronbach's alpha coefficient for the modified HCJSQ was 0.903, and the Spearman-Brown coefficient was 0.904. Spearman correlation coefficient between individuals' items and the total score ranged from 0.438 to 0.785 (p < 0.05). Exploratory factor analysis revealed that three factors accounted for 60.243% of the total variance. Confirmatory factor analysis demonstrated factor loadings between 0.624 and 0.834 on the specified items. The fit indices of the confirmatory factor analysis indicated good model fit, with a Root Mean Square Error of Approximation of 0.064, Normative Fit Index of 0.937, Comparative Fit Index of 0.952, Incremental Fit Index of 0.952, Tucker-Lewis index of 0.941, and Goodness of Fit Index of 0.944. Additionally, the convergent validity and discriminant validity showed a good fit for the three-factor model. CONCLUSION: The results of this study confirm that Chinese dental workers experience high levels of stress, and the three-factor model of the HCJSQ proves to be a suitable instrument for evaluating the sources and levels of job stress among Chinese dental workers. Therefore, it is imperative that relevant entities such as hospitals, medical associations, and government take appropriate measures to address the existing situation.

Chronic restraint stress promotes oral squamous cell carcinoma development by inhibiting ALDH3A1 via stress response hormone.

BACKGROUND: Chronic restraint stress (CRS) has iteratively been reported to be possibly implicated in the development of numerous cancer types. However, its role in oral squamous cell carcinoma (OSCC) has not been well elucidated. Here we intended to evaluate the role and mechanism. METHODS: The effects of CRS were investigated in xenograft models of OSCC by using transcriptome sequencing, LC-MS, ELISA and RT-PCR. Moreover, the role of CRS and ALDH3A1 on OSCC cells was researched by using Trans-well, flow cytometry, western blotting, immunofluorescence, ATP activity and OCR assay. Furthermore, immunohistochemical staining was employed to observe the cell proliferation and invasion of OSCC in xenotransplantation models. RESULTS: CRS promoted the progression of OSCC in xenograft models, stimulated the secretion of norepinephrine and the expression of ADRB2, but decreased the expression of ALDH3A1. Moreover, CRS changed energy metabolism and increased mitochondrial metabolism markers. However, ALDH3A1 overexpression suppressed proliferation, EMT and mitochondrial metabolism of OSCC cells. CONCLUSION: Inhibition of ALDH3A1 expression plays a pivotal role in CRS promoting tumorigenic potential of OSCC cells, and the regulatory of ALDH3A1 on mitochondrial metabolism may be involved in this process.

Salivary microbiota and metabolic phenotype of patients with recurrent aphthous ulcers.

OBJECTIVES: Recurrent aphthous ulcer (RAU) is a prevalent oral mucosal disease, affecting around 20% of the global population. It can greatly impair the quality of life for affected individuals. However, the exact etiology of RAU remains unknown. SUBJECTS AND METHODS: 16S rRNA sequencing (16S rRNA-seq) and non-targeted liquid chromatography-mass spectrometry (LC-MS) were employed to investigate the salivary microbiota and metabolic phenotype between RAU patients (N = 61) and healthy controls (HCs) (N = 105). RESULTS: Findings from 16S rRNA -seq indicated reduced oral microbial diversity in RAU patients compared to HCs, but increased interactions. Clinical variables did not show any significant association with the overall diversity of oral microbiota in RAU patients. However, significant correlations were observed between specific microorganisms and clinical variables. LC-MS results revealed dysregulation of amino acid, lipid, nucleotide, and caffeine metabolism in RAU patients. Furthermore, correlation analysis of 16S rRNA-seq and LC-MS data revealed a significant association between salivary microbiota and metabolites in RAU patients. CONCLUSIONS: Our study revealed notable differences in salivary microbiota and metabolic profiles between RAU patients and HCs, indicating a strong link between oral microbiota dysbiosis, metabolic disturbances, and the onset and progression of RAU.

Multi-Omics Analysis Reveals Age-Related Microbial and Metabolite Alterations in Non-Human Primates.

Aging is a systemic physiological degenerative process, with alterations in gut microbiota and host metabolism. However, due to the interference of multiple confounding factors, aging-associated molecular characteristics have not been elucidated completely. Therefore, based on 16S ribosomal RNA (rRNA) gene sequencing and non-targeted metabolomic detection, our study systematically analyzed the composition and function of the gut microbiome, serum, and fecal metabolome of 36 male rhesus monkeys spanning from 3 to 26 years old, which completely covers juvenile, adult, and old stages. We observed significant correlations between 41 gut genera and age. Moreover, 86 fecal and 49 serum metabolites exhibited significant age-related correlations, primarily categorized into lipids and lipid-like molecules, organic oxygen compounds, organic acids and derivatives, and organoheterocyclic compounds. Further results suggested that aging is associated with significant downregulation of various amino acids constituting proteins, elevation of lipids, particularly saturated fatty acids, and steroids. Additionally, age-dependent changes were observed in multiple immune-regulatory molecules, antioxidant stress metabolites, and neurotransmitters. Notably, multiple age-dependent genera showed strong correlations in these changes. Together, our results provided new evidence for changing characteristics of gut microbes and host metabolism during aging. However, more research is needed in the future to verify our findings.

C-Reactive Protein Levels and Cognitive Decline following Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

Cognitive decline (CD) is devastating with a high incidence in patients after stroke. Although some studies have explored underlying associations between C-reactive protein (CRP) levels and cognitive decline after stroke, consistent results have not been obtained. Therefore, this meta-analysis aimed to explore whether or not higher levels of C-reactive proteins were associated with an increased risk of cognitive decline after stroke. To this end, PubMed, Embase, the Cochrane Library, and Web of Science were searched for eligible studies, and pooled effect sizes from eligible studies were calculated using random effect models. Furthermore, subgroups were established and meta-regression analyses were performed to explain the causes of heterogeneity. Eventually, nine studies with 3893 participants were included. Our statistical results suggested that the concentrations of peripheral CRP may be significantly increased for CD patients after stroke, compared to those of non-CD patients. Subgroup analyses showed that CRP was higher in CD than that in non-CD patients when the mini-mental state examination was used. A higher level of CRP in the acute phase of ischemic stroke may suggest an increased risk of CD after stroke. However, these results should be cautiously interpreted because of the limited sample sizes and the diversity of potential confounders in the studies included in this meta-analysis.

Integrating spatial and single-nucleus transcriptomic data elucidates microglial-specific responses in female cynomolgus macaques with depressive-like behaviors.

Major depressive disorder represents a serious public health challenge worldwide; however, the underlying cellular and molecular mechanisms are mostly unknown. Here, we profile the dorsolateral prefrontal cortex of female cynomolgus macaques with social stress-associated depressive-like behaviors using single-nucleus RNA-sequencing and spatial transcriptomics. We find gene expression changes associated with depressive-like behaviors mostly in microglia, and we report a pro-inflammatory microglia subpopulation enriched in the depressive-like condition. Single-nucleus RNA-sequencing data result in the identification of six enriched gene modules associated with depressive-like behaviors, and these modules are further resolved by spatial transcriptomics. Gene modules associated with huddle and sit alone behaviors are expressed in neurons and oligodendrocytes of the superficial cortical layer, while gene modules associated with locomotion and amicable behaviors are enriched in microglia and astrocytes in mid-to-deep cortical layers. The depressive-like behavior associated microglia subpopulation is enriched in deep cortical layers. In summary, our findings show cell-type and cortical layer-specific gene expression changes and identify one microglia subpopulation associated with depressive-like behaviors in female non-human primates.

Integrated pathway and network analyses of metabolomic alterations in peripheral blood of patients with depression.

Depression is a serious mental illness, but the molecular mechanisms of depression remain unclear. Previous research has reported metabolomic changes in the blood of patients with depression, while integrated analysis based on these altered metabolites was still lacking. The objective of this study was to integrate metabolomic changes to reveal the underlying molecular alternations of depression. We retrieved altered metabolites in the blood of patients with depression from the MENDA database. Pathway analysis was conducted to explore enriched pathways based on candidate metabolites. Pathway crosstalk analysis was performed to explore potential correlations of these enriched pathways, based on their shared candidate metabolites. Moreover, potential interactions of candidate metabolites with other biomolecules such as proteins were assessed by network analysis. A total of 854 differential metabolite entries were retrieved in peripheral blood of patients with depression, including 555 unique candidate metabolites. Pathway analysis identified 215 significantly enriched pathways, then pathway crosstalk analysis revealed that these pathways were clustered into four modules, including amino acid metabolism, nucleotide metabolism, energy metabolism and others. Additionally, eight molecular networks were identified in the molecular network analysis. The main functions of these networks involved amino acid metabolism, molecular transport, inflammatory responses and others. Based on integrated analysis, our study revealed pathway-based modules and molecular networks associated with depression. These results will contribute to the underlying knowledge of the molecular mechanisms in depression.

The prevalence of professional burnout among dentists: a systematic review and meta-analysis.

Professional burnout refers to mental weariness caused by occupational stress. However, there is a lack of systematic studies on the prevalence of professional burnout among dentists. The purpose of this study was to investigate the prevalence of professional burnout among dentists. Databases including PubMed, PsycINFO, Embase, Cochrane, and Web of Science were systematically searched from inception to 28 October 2021. The random-effects model and forest plots were used to assess the pooled prevalence of professional burnout among dentists. A total of 15 studies with a total of 6038 study subjects were included in the meta-analysis, and the overall professional burnout among dentists was 13% (95%CI: 6-23). Subgroup analysis suggested a high prevalence of burnout in Europe, and the least in the Americas. The pooled burnout prevalence in cross-sectional surveys was significantly lower than that in longitudinal studies. In addition, the overall burnout prevalence in the last decade was significantly lower than that of a decade ago. This meta-analysis demonstrated that the prevalence of burnout was relatively low among dentists, and there was a downward trend. Therefore, it is important to continue to pay close attention to the mental health of dentists and effectively prevent and treat professional burnout to better maintain the provision of health care services.

The overall prevalence of professional burnout among dentists was 13%.Subgroup analysis revealed that the prevalence of burnout differed in geographical regions, with the highest in Europe, followed by Asia, and the lowest in America.The pooled burnout prevalence in cross-sectional surveys was significantly lower than that in longitudinal studies. In addition, the overall burnout prevalence in the last decade was significantly lower than that of a decade ago.More attention should be paid to professional burnout among dentists to improve the provision of health care services.

Altered MANF and RYR2 concentrations associated with hypolipidemia in the serum of patients with schizophrenia.

Schizophrenia (SCZ) is associated with abnormal serum lipid profiles, but their relationship is poorly understood. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an important regulator of lipid metabolism. Previous studies have shown its involvement in the pathogenesis of numerous neuropsychiatric disorders, while its role in SCZ is still unknown. Therefore, this study was conducted to examine serum MANF levels in patients with SCZ, and to investigate the potential relationship between MANF, serum lipid levels and SCZ. The results showed that total cholesterol (TC) levels were significantly lower in 225 patients with SCZ than in 233 healthy controls (HCs). According to Ingenuity Pathway Analysis, hypolipidemia is associated with SCZ via MANF/ryanodine receptor 2 (RYR2) pathway. This theory was supported by another sample set, which showed significantly lower MANF levels and higher RYR2 levels in the serum of 170 SCZ patients compared to 80 HCs. Moreover, MANF and RYR2 levels both were significantly correlated with the severity of psychotic symptoms and TC levels. In addition, a model consisting of MANF and RYR2 was found to be effective in distinguishing SCZ patients from HCs. These findings suggested that the MANF/RYR2 pathway might serve as a bridge between hypolipidemia and SCZ, and MANF and RYR2 held promise as biomarkers for SCZ.

Proteomics reveals mitochondrial dysfunction and energy metabolism disturbance of intestine in a nonhuman primate model of depression.

BACKGROUND: The gut-brain axis has been shown to play an important role in depression. However, few studies have examined proteomic changes in the intestine of the nonhuman primate model of depression. METHODS: We investigated the intestinal proteome of macaques (Macaca fascicularis) with depression-like (DL) behaviors by data-independent acquisition techniques. We also performed integration analyses of proteomic changes, previous metabolomic and microbiotic data. Moreover, we confirmed the gene expressions of key proteins. RESULTS: Sixty-five differentially expressed proteins (DEPs) were identified, of which fifty-four DEPs were down-regulated and the others were altered conversely in DL macaques compared with the control group. Pathway analysis indicated that mitochondrial function and energy metabolism were representative functions of DEPs. The key DEPs were significantly associated with glycerophospholipid metabolism and imbalances of gut microbe. We confirmed that key molecules (NDUFB4, UQCR10, PISD) were significantly inhibited, which may disturb the energy transformation of the electron respiratory chain and the homeostasis of the mitochondrial membrane. LIMITATIONS: Further research is warranted to determine the effects of depression on other peripheral organs. CONCLUSIONS: These findings suggest the functional disorder of intestinal mitochondria in DL macaques. The disturbances of glycerophospholipid metabolism and gut microbiota may exacerbate disruptions of energy metabolism. Taking together, our study provides new clues to the relationship between depression and intestinal proteome.

The gut microbiome modulates the transformation of microglial subtypes.

Clinical and animal studies have shown that gut microbiome disturbances can affect neural function and behaviors via the microbiota-gut-brain axis, and may be implicated in the pathogenesis of several brain diseases. However, exactly how the gut microbiome modulates nervous system activity remains obscure. Here, using a single-cell nucleus sequencing approach, we sought to characterize the cell type-specific transcriptomic changes in the prefrontal cortex and hippocampus derived from germ-free (GF), specific pathogen free, and colonized-GF mice. We found that the absence of gut microbiota resulted in cell-specific transcriptomic changes. Furthermore, microglia transcriptomes were preferentially influenced, which could be effectively reversed by microbial colonization. Significantly, the gut microbiome modulated the mutual transformation of microglial subpopulations in the two regions. Cross-species analysis showed that the transcriptome changes of these microglial subpopulations were mainly associated with Alzheimer's disease (AD) and major depressive disorder (MDD), which were further supported by animal behavioral tests. Our findings demonstrate that gut microbiota mainly modulate the mutual transformation of microglial subtypes, which may lead to new insights into the pathogenesis of AD and MDD.

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.

Altered neurometabolite levels in the brains of patients with depression: A systematic analysis of magnetic resonance spectroscopy studies.

BACKGROUND: Numerous magnetic resonance spectroscopy (MRS) studies have reported metabolic abnormalities in the brains of patients with depression, although inconsistent results have been reported. The aim of this study was to explore changes in neurometabolite levels in patients with depression across large-scale MRS studies. METHOD: A total of 307 differential metabolite entries associated with depression were retrieved from 180 MRS studies retrieved from the Metabolite Network of Depression Database. The vote-counting method was used to identify consistently altered metabolites in the whole brain and specific brain regions of patients with depression. RESULTS: Only few differential neurometabolites showed a stable change trend. The levels of total choline (tCho) and the tCho/N-acetyl aspartate (NAA) ratio were consistently higher in the brains of patients with depression, and that the levels of NAA, glutamate and glutamine (Glx), and gamma-aminobutyric acid (GABA) were lower. For specific brain regions, we found lower Glx levels in the prefrontal cortex and lower GABA concentrations in the occipital cortex. We also found lower concentrations of NAA in the anterior cingulate cortex and prefrontal cortex. The levels of tCho were higher in the prefrontal cortex and putamen. CONCLUSION: Our results revealed that most altered neurometabolites in previous studies lack of adequate reproducibility. Through vote-counting method with large-scale studies, downregulation of glutamatergic neurometabolites, impaired neuronal integrity, and disturbed membrane metabolism were found in the pathobiology of depression, which contribute to existing knowledge of neurometabolic changes in depression. Further studies based on a larger dataset are needed to confirm our findings.

Chronic restraint stress promotes the tumorigenic potential of oral squamous cell carcinoma cells by reprogramming fatty acid metabolism via CXCL3 mediated Wnt/ß-catenin pathway.

Chronic stress promotes tumor progression and may harm homeostasis of energy metabolism by disrupting key metabolic processes. Recently, emerging evidence that chemokines CXCL3 as a novel adipokine plays a new role in lipid metabolism and various human malignancies. However, the role and mechanism of the CXCL3 in oral squamous cell carcinoma (OSCC) progression and reprogramming lipid metabolism induced by chronic restraint stress is unclear. The analysis of transcriptome sequencing, LC-MS, GC-MS, CCK8, cell apoptosis assays, cell cycle analysis, qRT-PCR, ELISA, western blotting, immunofluorescence, immunohistochemistry, RNA interference and lentivirus transfection and a xenograft tumor growth and chronic restraint stress model were used to investigate the role of CXCL3 in the regulation of lipid metabolism and OSCC and explore the underlying molecular mechanisms. We showed that CXCL3 plays a critical role in in fatty acid de novo synthesis and tumor growth induced by chronic restraint stress. We demonstrated that chronic restraint stress promoted lipid accumulation, OSCC growth and metastasis in a mouse xenograft model. CXCL3 knockdown and FH535, an inhibitor of Wnt/ß-catenin pathway, could attenuate fatty acid de novo synthesis, cell proliferation and epithelial-mesenchymal transition induced by chronic restraint stress in OSCC cells. Our findings demonstrate that chronic restraint stress promotes the proliferation and metastasis of OSCC by reprogramming fatty acid metabolism via CXCL3 mediated Wnt/ß-catenin pathway. Our study provides novel insights to help understand the underlying mechanisms of CXCL3 in OSCC progression induced by chronic restraint stress.