Multi-omics data reveals the disturbance of glycerophospholipid metabolism caused by disordered gut microbiota in depressed mice.

INTRODUCTION: Although researchers have done intensive research on depression, its pathogenesis is still not fully explained. More and more evidence suggests that gut microbiota is closely related to the onset of depression; but its specific functional ways are not clearly identified. OBJECTIVES: The purpose of our work was to find out how the gut microbiota was involved in the onset of depression, and to identify the potential ways to link the gut and brain in mice with depressive-like behaviors (DLB). METHODS: We used the chronic restraint stress (CRS)-induced depression model here. Gut microbiota compositions in fecal samples, lipid metabolism (in fecal, serum and hippocampus samples) and neurotransmitters in hippocampus samples were detected. RESULTS: We found that the 7 of 13 differential genera that significantly correlated with DLB belonged to phylum Firmicutes. The differential lipid metabolites in fecal samples mainly belonged to glycerophospholipids (GP) and fatty acids (FA) metabolism, and three important "metabolite type-bacterial taxa" correlated pairs were identified: "FA/GP-Firmicutes", "FA/GP-Akkermansia", and "FA/GP-Bifidobacterium". The key differential lipid metabolites significantly correlated with DLB mainly belonged to FA and GP, and the DLB-related metagenomic genes were consistently enriched in GP metabolism and FA metabolism. Three significantly changed short-chain fatty acids (SCFAs) were significantly correlated with the majority of differential genera. Meanwhile, we found that the differential lipid metabolites in serum and hippocampus samples were mainly mapped into the GP metabolism, and there were four differential neurotransmitters from the tryptophan pathway in hippocampus samples. CONCLUSION: Together, our findings could provide novel insights into the role of "microbiota-gut-brain" (MGB) axis in depression, and indicate that the gut microbiota might have a vital role in the onset of DLB by affecting the peripheral/central GP metabolism and tryptophan pathway. The "Firmicutes-SCFAs-GP metabolism-Tryptophan pathway" might be a possible way to link the gut and brain in depressed mice.

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.

Sequential Whole Exome Sequencing Reveals Somatic Mutations Associated with Platinum Response in NSCLC.

PURPOSE: Resistance is one of the main limitations of successful platinum treatment in non-small-cell lung cancer (NSCLC) patients. In this study, we aimed to identify somatic mutations associated with platinum response. PATIENTS AND METHODS: A total of 57 patients who received platinum-based chemotherapy only and 13 patients who received neoadjuvant chemotherapy (NAC) were enrolled. Somatic mutations were obtained from targeted and whole exome sequencing (WES). RESULTS: Somatic mutations in a total of 225 genes were observed. Nonsynonymous variants in EGFR, TTN, TP53 and KRAS, and copy number variations (SCNVs) in chromosome 8q24.3 and 22q11.21 were identified to be associated with platinum response. Based on these mutations, the mutational signature associated with the failure of DNA double-strand break and calcium signaling pathways were identified to be associated with platinum response. Besides, we observed a decrease in tumor mutational burden after chemotherapy. We also evaluated the mutation spectrum consistency between cell-free DNA (cfDNA) and tissue DNA. Somatic mutations detected in cfDNA were consistent with that in tDNA, which indicated that plasma might be used for somatic mutation detection. CONCLUSION: These results support that somatic mutations can affect platinum drug response and provide potential clinical biomarkers for NSCLC treatment.

[Effect of resveratrol on body composition in adult catch-up growth rats and its mechanism].

OBJECTIVE: To observe the effects of resveratrol on body composition in adult catch-up growth rats and to explore the possible mechanism. METHODS: Eight-week-old male SD rats were randomly divided into 6 groups: normal controls for 4 weeks (NC4) group, caloric restriction for 4 weeks (R4) group, calorie restriction meanwhile resveratrol treatment for 4 weeks (R4E) group, normal controls for 12 weeks (NC12) group, catch-up growth (CUG) group and catch-up growth meanwhile resveratrol treatment for 8 weeks (CUGE) group. At the end of the four-week and twelve-week experimental period, the body weight, muscle and fat content of trunk and whole body, the ratio of trunk to whole body fat were detected, and at the end of twelve-week experimental period, the expression of SIRT1 in skeletal muscle and epididymal adipose tissue, and the expression of PPARγ in epididymal adipose tissue were detected. RESULTS: Compared with NC12 group, the fat content of trunk and whole body and trunk to whole body fat ratio in CUG group were increased significantly, along with the expression of PPARγ in epididymal adipose tissue was increased significantly (P＜0.05), while the muscle content of trunk and whole body, the expression of SIRT1 in skeletal muscle and epididymal adipose tissue in CUG group were decreased significantly compared with NC12 group (P＜0.05 or P＜0.01); compared with CUG group, oral administration of resveratrol distinctly reduced the body fat content and trunk to whole body fat ratio in the CUGE groups, and the expression of PPARγ in epididymal adipose tissue of CUGE group was also significantly decreased (P＜0.05). Meanwhile, the muscle content and the expression of SIRT1 in skeletal muscle and epididymal adipose tissue in CUGE group were significantly increased compared with the CUG group (P＜0.05). CONCLUSION: Resveratrol can decrease body fat content, increase muscle content and improve abdominal fat accumulation in adult catch-up growth rats, and its mechanism may be associated with increasing SIRT1 expression in skeletal muscle and visceral adipose tissue, decreasing PPARγ expression in visceral adipose tissue.

A Hereditable Mutation of MSH2 Gene Associated with Lynch Syndrome in a Five Generation Chinese Family.

PURPOSE: In order to clarify which variants of the MMR gene could provide current "healthy" members in affected families a more accurate risk assessment or predictive testing. PATIENTS AND METHODS: One family, which meets the criteria according to both Amsterdam I/II and Bethesda guidelines, is reported in this study. The proband and some relatives of the patient have been investigated for whole genome sequencing, microsatellite instability, immunohistochemical MMR protein staining and verified by Sanger sequencing. RESULTS: A heterozygous insertion of uncertain significance (c.420dup, p.Met141Tyrfs) in MSH2 gene was found in proband (III-16) and part of His relatives. The variant was associated with a lack of expression of MSH2 protein (MMR deficient) and high microsatellite instability analysis (MSI) status in tumor tissues of LS patients. In addition, we found that the variant could affect the expression of MSH2 and the response to chemotherapy drugs in vitro. CONCLUSION: We identified an insertion mutation (rs1114167810, c.420dup, p.Met141Tyrfs) in MSH2 in LS using whole genome-wide sequencing (WGS). We further confirmed that this mutation plays an important role in LS patients of this pedigree based on in vivo and vitro study.

Biomarkers identified for prostate cancer patients through genome-scale screening.

Prostate cancer is a threat to men and usually occurs in aged males. Though prostate specific antigen level and Gleason score are utilized for evaluation of the prostate cancer in clinic, the biomarkers for this malignancy have not been widely recognized. Furthermore, the outcome varies across individuals receiving comparable treatment regimens and the underlying mechanism is still unclear. We supposed that genetic feature may be responsible for, at least in part, this process and conducted a two-cohort study to compare the genetic difference in tumorous and normal tissues of prostate cancer patients. The Gene Expression Omnibus dataset were used and a total of 41 genes were found significantly differently expressed in tumor tissues as compared with normal prostate tissues. Four genes (SPOCK3, SPON1, PTN and TGFB3) were selected for further evaluation after Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis and clinical association analysis. MIR1908 was also found decreased expression level in prostate cancer whose target genes were found expressing in both prostate tumor and normal tissues. These results indicated that these potential biomarkers deserve attention in prostate cancer patients and the underlying mechanism should be further investigated.

Combined Metabolomics and Proteomics Analysis of Major Depression in an Animal Model: Perturbed Energy Metabolism in the Chronic Mild Stressed Rat Cerebellum.

Major depressive disorder (MDD) is a highly prevalent, debilitating mental illness of importance for global health. However, its molecular pathophysiology remains poorly understood. Combined proteomics and metabolomics approaches should provide a comprehensive understanding of MDD's etiology. The present study reports novel "-omics" insights from a rodent model of MDD. Cerebellar samples from chronic mild stressed (CMS)-treated depressed rats and controls were compared with a focus on the differentially expressed proteins and metabolites using isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics and gas chromotography/mass spectrometry (GC-MS) metabolomics techniques, respectively. The combined analyses found significant alterations associated with cerebellar energy metabolism, as indicated by (1) abnormal amino acid metabolism accompanied by corresponding metabolic enzymatic alterations and disturbed protein turnover, (2) increased glycolytic and tricarboxylic acid (TCA) cycle enzyme levels paralleled by changes in the concentrations of associated metabolites, and (3) perturbation of ATP biosynthesis through adenosine accompanied by perturbation of the mitochondrial respiratory chain. To the best of our knowledge, this study is the first to integrate proteomics and metabolomics analyses to examine the pathophysiological mechanism(s) underlying MDD in a CMS rodent model of depression. These results can offer important insights into the pathogenesis of MDD.

Severe disturbance of glucose metabolism in peripheral blood mononuclear cells of schizophrenia patients: a targeted metabolomic study.

BACKGROUND: Schizophrenia is a widespread and debilitating mental disorder. However, the underlying molecular mechanism of schizophrenia remains largely unknown and no objective laboratory tests are available to diagnose this disorder. The aim of the present study was to characterize the alternations of glucose metabolites and identify potential diagnostic biomarkers for schizophrenia. METHODS: Gas chromatography/mass spectrometry based targeted metabolomic method was used to quantify the levels of 13 glucose metabolites in peripheral blood mononuclear cells (PBMCs) derived from healthy controls, schizophrenia and major depression subjects (n = 55 for each group). RESULTS: The majority (84.6%) of glucose metabolites were significantly disturbed in schizophrenia subjects, while only two (15.4%) glucose metabolites were differently expressed in depression subjects relative to healthy controls in both training set (n = 35/group) and test set (n = 20/group). Antipsychotics had only a subtle effect on glucose metabolism pathway. Moreover, ribose 5-phosphate in PBMCs showed a high diagnostic performance for first-episode drug-naïve schizophrenia subjects. CONCLUSION: These findings suggested disturbance of glucose metabolism may be implicated in onset of schizophrenia and could aid in development of diagnostic tool for this disorder.

Combined application of NMR- and GC-MS-based metabonomics yields a superior urinary biomarker panel for bipolar disorder.

Bipolar disorder (BD) is a debilitating mental disorder that cannot be diagnosed by objective laboratory-based modalities. Our previous studies have independently used nuclear magnetic resonance (NMR)-based and gas chromatography-mass spectrometry (GC-MS)-based metabonomic methods to characterize the urinary metabolic profiles of BD subjects and healthy controls (HC). However, the combined application of NMR spectroscopy and GC-MS may identify a more comprehensive metabolite panel than any single metabonomic platform alone. Therefore, here we applied a dual platform (NMR spectroscopy and GC-MS) that generated a panel of five metabolite biomarkers for BD-four GC-MS-derived metabolites and one NMR-derived metabolite. This composite biomarker panel could effectively discriminate BD subjects from HC, achieving an area under receiver operating characteristic curve (AUC) values of 0.974 in a training set and 0.964 in a test set. Moreover, the diagnostic performance of this panel was significantly superior to the previous single platform-derived metabolite panels. Thus, the urinary biomarker panel identified here shows promise as an effective diagnostic tool for BD. These findings also demonstrate the complementary nature of NMR spectroscopy and GC-MS for metabonomic analysis, suggesting that the combination of NMR spectroscopy and GC-MS can identify a more comprehensive metabolite panel than applying each platform in isolation.

Stereological investigation of age-related changes of the capillaries in white matter.

We, for the first time, investigated the age-related changes of the capillaries in white matter using immunohistochemistry and stereological techniques. Ten young female (7 months) and 10 aged female (27 months) rats were used. The total length, total volume, and total surface area of the capillaries in white matter of aged rats were all significantly lower than those of young rats. The age-related changes of the capillaries in white matter may have important implications for age-related white matter atrophy and age-related cognitive impairments.