Deyu Yang

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.

Amino acid metabolic dysfunction revealed in the prefrontal cortex of a rat model of depression

Major depressive disorder (MDD) is a debilitating mood disorder. However, the molecular mechanism(s) underlying depression remain largely unknown. Here, we applied a GC-MS-based metabonomic approach in the chronic unpredictable mild stress (CUMS) model, a well-established rodent model of depression, to investigate significant metabolic changes in the rat prefrontal cortex (PFC). Multivariate statistical analysis - including principal component analysis, partial least squares-discriminate analysis, and pair-wise orthogonal projections to latent structures discriminant - was applied to identify differential PFC metabolites between CUMS rats and healthy controls. As compared to healthy control rats, CUMS rats were characterized by lower levels of isoleucine and glycerol in combination with higher levels of N-acetylaspartate and β-alanine. These findings should provide insight into the pathophysiological mechanism(s) underlying MDD and preliminary leads relevant to diagnostic biomarker discovery for depression.

Bilateral vs. unilateral repetitive transcranial magnetic stimulation in treating major depression: A meta-analysis of randomized controlled trials

Previous studies have demonstrated inconsistent findings regarding the efficacy of bilateral vs. unilateral repetitive transcranial magnetic stimulation (rTMS) in treating major depressive disorder (MDD). Therefore, this meta-analysis was conducted to compare the efficacy of these two rTMS modalities. Data were obtained from seven randomized controlled trials (RCTs) consisting of 509 subjects. Bilateral and unilateral rTMS displayed comparable efficacy in treating MDD with a pooled odds ratios of 1.06 (95% confidence interval (CI)=0.58-1.91) for response rates and 1.05 (95% CI=0.52-2.11) for remission rates. Subgroup analysis found that bilateral rTMS was equally effective in comparison with both left and right unilateral rTMS. No significant differences in drop-out rates were found. No publication bias was detected. In conclusion, the pooled examination demonstrated that bilateral rTMS displays comparable anti-depressant efficacy and acceptability to unilateral rTMS in treating MDD. These findings suggest that simultaneous rTMS of the right and left dorsolateral prefrontal cortices in MDD patients does not provide marginal benefits in terms of efficacy or acceptability. As the number of RCTs included here was limited, further large-scale multi-center RCTs are required to validate our conclusions.

Divergent Urinary Metabolic Phenotypes between Major Depressive Disorder and Bipolar Disorder Identified by a Combined GC-MS and NMR Spectroscopic Metabonomic Approach.

Bipolar disorder (BD) is a complex debilitating mental disorder that is often misdiagnosed as major depressive disorder (MDD). Therefore, a large percentage of BD subjects are incorrectly treated with antidepressants in clinical practice. To address this challenge, objective laboratory-based tests are needed to discriminate BD from MDD patients. Here, a combined gas chromatography-mass spectrometry (GC-MS)-based and nuclear magnetic resonance (NMR) spectroscopic-based metabonomic approach was performed to profile urine samples from 76 MDD and 43 BD subjects (training set) to identify the differential metabolites. Samples from 126 healthy controls were included as metabolic controls. A candidate biomarker panel was identified by further analyzing these differential metabolites. A testing set of, 50 MDD and 28 BD subjects was then used to independently validate the diagnostic efficacy of the identified panel using an area under the receiver operating characteristic curve (AUC). A total of 20 differential metabolites responsible for the discrimination between MDD and BD subjects were identified. A panel consisting of six candidate urinary metabolite biomarkers (propionate, formate, (R*,S*)2,3-dihydroxybutanoic acid, 2,4-dihydroxypyrimidine, phenylalanine, and β-alanine) was identified. This panel could distinguish BD from MDD subjects with an AUC of 0.913 and 0.896 in the training and testing sets, respectively. These results reveal divergent urinary metabolic phenotypes between MDD and BD. The identified urinary biomarkers can aid in the future development of an objective laboratory-based diagnostic test for distinguishing BD from MDD patients.

Sex-Specific Urinary Biomarkers for Diagnosing Bipolar Disorder

Sex-based differences are prominent in affective disorders, but there are no biomarkers available to support sex-specific, laboratory-based diagnostics for male and female bipolar disorder (BD) patients. Here, a NMR-based metabonomic approach was used to preliminarily identify sex-specific urinary metabolite biomarkers for diagnosing male and female BD patients. A male-specific biomarker panel consisting of four metabolites (α-hydroxybutyrate, choline, formate, and N-methylnicotinamide) effectively discriminated between male BD and healthy controls (HC) subjects, achieving an area under the receiver operating characteristic curve (AUC) of 0.942. A female-specific biomarkers panel consisting of four metabolites (α-hydroxybutyrate, oxalacetate, acetone, and N-methylnicotinamide) effectively discriminated between female BD and HC subjects, achieving an AUC of 0.909. The male-specific biomarker panel displayed low discriminatory power in the female group, and the female-specific biomarker panel displayed low discriminatory power in the male group. Moreover, several other metabolites showed different trends between male and female BD subjects. These findings suggest that male and female BD patients have distinct biomarker fingerprints and that these two sex-specific biomarker panels may serve as effective diagnostic tools in distinguishing male and female BD patients from their healthy counterparts. Our work may provide a window into the mechanisms underlying the pathoetiology of BD in both men and women.

Macaques Exhibit a Naturally-Occurring Depression Similar to Humans

Rodent models have dominated preclinical investigations into the mechanisms of depression. However, these models-which rely on subjecting individual rodents to physical stressors - do not realistically resemble the etiopathological development of depression, which occurs naturally in a social context. A non-human primate model that better reflects the social ethological aspects of depression would be more advantageous to investigating pathophysiological mechanisms and developing antidepressant therapeutics. Here, we describe and model a naturally-occurring depressive state in a non-human primate species, the cynomolgus monkey (Macaca fascicularis), in a realistic social ethological context and associate the depressed behavioral phenotype with significant serum metabolic perturbations. One to two subjects per stable social colony (17–22 subjects) manifested a depressive phenotype that may be attributed to psychosocial stress. In accordance with rodent and human studies, the serum metabolic phenotype of depressed and healthy subjects significantly differed, supporting the models face validity. However, application of the fast-acting antidepressant ketamine failed to demonstrate predictive validity. This study proposes a non-human primate depression model in a realistic social ethological context that can better approximate the psychosocial stressors underlying depression.

Behavioral characterization of CD36 knockout mice with SHIRPA primary screen.

CD36 is a member of the class B scavenger receptor family of cell surface proteins, which plays a major role in fatty acid, glucose and lipid metabolism. Besides, CD36 functions as a microglial surface receptor for amyloid beta peptide. Regarding this, we suggest CD36 might also contribute to neuropsychiatric disease. The aim of this study was to achieve a behavioral phenotype of CD36 knockout (CD36(-/-)) mice. We characterized the behavior of CD36(-/-) mice and C57BL/6J mice by subjecting them to a series of tests, which include SHIRPA primary behavioral screen test, 1% sucrose preference test, elevated plus-maze test, open-field test and forced swimming test. The results showed that CD36(-/-) mice traversed more squares, emitted more defecation, exhibited higher tail elevation and had more aggressive behaviors than C57BL/6J mice. The CD36(-/-) mice spent more time and traveled longer distance in periphery zone in the open-field test. Meanwhile, the numbers that CD36(-/-) mice entered in the open arms of elevated plus-maze were reduced. These findings suggest that CD36(-/-) mice present an anxious phenotype and might be involved in neuropsychiatric disorders.

Differential co-expression and regulation analyses reveal different mechanisms underlying major depressive disorder and subsyndromal symptomatic depression.

BackgroundRecent depression research has revealed a growing awareness of how to best classify depression into depressive subtypes. Appropriately subtyping depression can lead to identification of subtypes that are more responsive to current pharmacological treatment and aid in separating out depressed patients in which current antidepressants are not particularly effective.Differential co-expression analysis (DCEA) and differential regulation analysis (DRA) were applied to compare the transcriptomic profiles of peripheral blood lymphocytes from patients with two depressive subtypes: major depressive disorder (MDD) and subsyndromal symptomatic depression (SSD).ResultsSix differentially regulated genes (DRGs) (FOSL1, SRF, JUN, TFAP4, SOX9, and HLF) and 16 transcription factor-to-target differentially co-expressed gene links or pairs (TF2target DCLs) appear to be the key differential factors in MDD; in contrast, one DRG (PATZ1) and eight TF2target DCLs appear to be the key differential factors in SSD. There was no overlap between the MDD target genes and SSD target genes. Venlafaxine (Efexor™, Effexor™) appears to have a significant effect on the gene expression profile of MDD patients but no significant effect on the gene expression profile of SSD patients.ConclusionDCEA and DRA revealed no apparent similarities between the differential regulatory processes underlying MDD and SSD. This bioinformatic analysis may provide novel insights that can support future antidepressant R&D efforts.

Pioglitazone attenuates lipopolysaccharide-induced depression-like behaviors, modulates NF-κB/IL-6/STAT3, CREB/BDNF pathways and central serotonergic neurotransmission in mice

&NA; Immune activation and inflammation are closely associated with the development of depression. Pioglitazone (PIO), a peroxisome proliferator‐activated receptor gamma (PPAR‐&ggr;) agonist, has exhibited antidepressant‐like effects in a couple of studies. However, the underlying mechanisms are far from being fully elucidated. The study aimed to investigate the effects of PIO on depression‐like behaviors induced by lipopolysaccharide (LPS) and to explore the possible underlying mechanisms. The results showed that PIO pretreatment attenuated the depression‐like behaviors in mice challenged with intracerebroventricular (i.c.v.) LPS administration. Moreover, Western blot analysis revealed the effects of PIO on inhibiting activation of the nuclear factor kappa B/interleukin 6/signal transducer and activator of transcription 3 (NF‐&kgr;B/IL‐6/STAT3) pathway, improving down‐regulation of the cAMP response‐element‐binding protein/brain derived neurotrophic factor (CREB/BDNF) pathway, as well as regulating disturbed expression of proteins involved in central serotonergic neurotransmission following LPS administration. The beneficial effects of PIO, at both the behavioral and molecular level, were significantly inhibited by the PPAR‐&ggr; specific antagonist GW9662. In summary, our data reveals for the first time that the modulation of the NF‐&kgr;B/IL‐6/STAT3 and CREB/BDNF pathways, as well as the potential impact on central serotonergic neurotransmission, may be involved in the PPAR‐&ggr;‐dependent effects of PIO on depression‐like behaviors induced by LPS. Additionally, our findings may provide a novel therapeutic target for the treatment of depression‐like behaviors in patients with inflammatory status. Graphical abstract Figure. No caption available. HighlightsPIO attenuated depression‐like behaviors induced by LPS.PIO inhibited LPS‐induced activation of the NF‐&kgr;B/IL‐6/STAT3 pathway.PIO improved LPS‐induced down‐regulation of the CREB/BDNF pathway.PIO potentially impacted on serotonergic neurotransmission in LPS‐treated mice.

Up-regulation of SIRT6 in the hippocampus induced rats with depression-like behavior via the block Akt/GSK3β signaling pathway

HIGHLIGHTSIngenuity Pathway Analysis assessed networks in a rat model of depression (CUMS).Up‐regulation of SIRT6 in the hippocampus of CUMS rat is associated with depression‐like behavior.SIRT6 effects the survival and synaptic plasticity of hippocampal neuron via inhibitory activation of Akt‐GSK3&bgr; signaling pathway. ABSTRACT Major depression is the leading cause of disability worldwide, which is associated with diverse alterations in brain such as neuro‐inflammation, synaptic dysfunction, and cognitive deficit. Accumulating evidences suggest sirtuins (SIRTs) are involved in brain developmental disorders, metabolic diseases and play a key role in cognition and synaptic plasticity, yet the role in mood regulation remains controversial. Hence, Western blotting and RT‐qPCR were used to investigate whether SIRTs (SIRT1–7) expression levels were altered in the hippocampus of rats, which followed 5 weeks of chronic unpredictable mild stress (CUMS) treatment, the results showed depressive‐like behaviors: like body weight, forced swim test and sucrose preference test and SIRT6 was a significant increase in the hippocampal of CUMS rats. Furthermore, via a lentivirus‐mediated transfection in hippocampal neurons, we aimed to detect how SIRT6 influence the function of hippocampus. The SIRT6 overexpression significantly inhibited expressions of proteins and/or phosphoproteins (e.g AKT, p‐AKT, P‐GSK3&bgr;), decreased the ratios of p‐GSK3&bgr;/GSK3&bgr; and p‐Akt/Akt in the primary hippocampus neurons. Thus, our data indicates that SIRT6 is involved in the modulation of depressive‐like behaviors and affects the survival and synaptic plasticity of hippocampal neuron via inhibitory activation of Akt‐GSK3&bgr; signaling.