Libo Zhao

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.

Metabolomic analysis reveals metabolic disturbances in the prefrontal cortex of the lipopolysaccharide-induced mouse model of depression.

Major depressive disorder (MDD) is a debilitating illness. However, the underlying molecular mechanisms of depression remain largely unknown. Increasing evidence supports that inflammatory cytokine disturbances may be associated with the pathophysiology of depression in humans. Systemic administration of lipopolysaccharide (LPS) has been used to study inflammation-associated neurobehavioral changes in rodents, but no metabonomic study has been conducted to assess differential metabolites in the prefrontal cortex (PFC) of a LPS-induced mouse model of depression. Here, we employed a gas chromatography-mass spectrometry-based metabonomic approach in the LPS-induced mouse model of depression to investigate any significant metabolic changes in the PFC. Multivariate statistical analysis, including principal component analysis (PCA), partial least squares-discriminate analysis (PLS-DA), and pair-wise orthogonal projections to latent structures discriminant analysis (OPLS-DA), was implemented to identify differential PFC metabolites between LPS-induced depressed mice and healthy controls. A total of 20 differential metabolites were identified. Compared with control mice, LPS-treated mice were characterized by six lower level metabolites and 14 higher level metabolites. These molecular changes were closely related to perturbations in neurotransmitter metabolism, energy metabolism, oxidative stress, and lipid metabolism, which might be evolved in the pathogenesis of MDD. These findings provide insight into the pathophysiological mechanisms underlying MDD and could be of valuable assistance in the clinical diagnosis of MDD.

Comparative efficacy and acceptability of electroconvulsive therapy versus repetitive transcranial magnetic stimulation for major depression: A systematic review and multiple-treatments meta-analysis.

HighlightsECT was the most efficacious, but least tolerated.R‐rTMS was the best tolerated treatment for MDD.B‐rTMS appears to have the most favorable balance between efficacy and acceptability. Backgrounds: The effects of electroconvulsive therapy (ECT) and bilateral, left prefrontal, and right prefrontal repetitive transcranial magnetic stimulation (rTMS) on major depressive disorder (MDD) have not been adequately addressed by previous studies. Here, a multiple‐treatments meta‐analysis, which incorporates evidence from direct and indirect comparisons from a network of trials, was performed to assess the efficacy and acceptability of these four treatment modalities on MDD. Method: The literature was searched for randomized controlled trials (RCTs) on ECT, bilateral rTMS, and unilateral rTMS for treating MDD up to May 2016. The main outcome measures were response and drop‐out rates. Results: Data were obtained from 25 studies consisting of 1288 individuals with MDD. ECT was non‐significantly more efficacious than B‐rTMS, R‐rTMS, and L‐rTMS. Left prefrontal rTMS was non −significantly less efficacious than all other treatment modalities. In terms of acceptability, R‐rTMS was non‐significantly better tolerated than ECT, B‐rTMS, and L‐rTMS. ECT was the most efficacious treatment with the cumulative probabilities of being the most efficacious treatment being: ECT (65%), B‐rTMS (25%), R‐rTMS (8%), and L‐rTMS (2%). R‐rTMS was the best‐tolerated treatment with the cumulative probabilities of being the best‐tolerated treatment being: R‐rTMS (52%), B‐rTMS (17%), L‐rTMS (16%), and ECT (14%). Coherence analysis detected no statistically significant incoherence in any comparisons of direct with indirect evidence for the response rate and drop‐out rate. Conclusions: ECT was the most efficacious, but least tolerated, treatment, while R‐rTMS was the best tolerated treatment for MDD. B‐rTMS appears to have the most favorable balance between efficacy and acceptability.

Recombinant Tissue Plasminogen Activator Induces Neurological Side Effects Independent on Thrombolysis in Mechanical Animal Models of Focal Cerebral Infarction: A Systematic Review and Meta-Analysis

Background and Purpose Recombinant tissue plasminogen activator (rtPA) is the only effective drug approved by US FDA to treat ischemic stroke, and it contains pleiotropic effects besides thrombolysis. We performed a meta-analysis to clarify effect of tissue plasminogen activator (tPA) on cerebral infarction besides its thrombolysis property in mechanical animal stroke. Methods Relevant studies were identified by two reviewers after searching online databases, including Pubmed, Embase, and ScienceDirect, from 1979 to 2016. We identified 6, 65, 17, 12, 16, 12 and 13 comparisons reporting effect of endogenous tPA on infarction volume and effects of rtPA on infarction volume, blood-brain barrier, brain edema, intracerebral hemorrhage, neurological function and mortality rate in all 47 included studies. Standardized mean differences for continuous measures and risk ratio for dichotomous measures were calculated to assess the effects of endogenous tPA and rtPA on cerebral infarction in animals. The quality of included studies was assessed using the Stroke Therapy Academic Industry Roundtable score. Subgroup analysis, meta-regression and sensitivity analysis were performed to explore sources of heterogeneity. Funnel plot, Trim and Fill method and Egger’s test were obtained to detect publication bias. Results We found that both endogenous tPA and rtPA had not enlarged infarction volume, or deteriorated neurological function. However, rtPA would disrupt blood-brain barrier, aggravate brain edema, induce intracerebral hemorrhage and increase mortality rate. Conclusions This meta-analysis reveals rtPA can lead to neurological side effects besides thrombolysis in mechanical animal stroke, which may account for clinical exacerbation for stroke patients that do not achieve vascular recanalization with rtPA.

Island Sign: An Imaging Predictor for Early Hematoma Expansion and Poor Outcome in Patients With Intracerebral Hemorrhage

Background and Purpose— The aim of the study was to investigate the usefulness of the computed tomography (CT) island sign for predicting early hematoma growth and poor functional outcome. Methods— We included patients with spontaneous intracerebral hemorrhage (ICH) who had undergone baseline CT within 6 hours after ICH symptom onset in our hospital between July 2011 and September 2016. Two readers independently assessed the presence of the island sign on the admission noncontrast CT scan. Multivariable logistic regression analysis was used to analyze the association between the presence of the island sign on noncontrast admission CT and early hematoma growth and functional outcome. Results— A total of 252 patients who met the inclusion criteria were analyzed. Among them, 41 (16.3%) patients had the island sign on baseline noncontrast CT scans. In addition, the island sign was observed in 38 of 85 patients (44.7%) with hematoma growth. Multivariate logistic regression analysis demonstrated that the time to baseline CT scan, initial hematoma volume, and the presence of the island sign on baseline CT scan independently predicted early hematoma growth. The sensitivity of the island sign for predicting hematoma expansion was 44.7%, specificity 98.2%, positive predictive value 92.7%, and negative predictive value 77.7%. After adjusting for the patients’ age, baseline Glasgow Coma Scale score, presence of intraventricular hemorrhage, presence of subarachnoid hemorrhage, admission systolic blood pressure, baseline ICH volume, and infratentorial location, the presence of the island sign (odds ratio, 3.51; 95% confidence interval, 1.26–9.81; P=0.017) remained an independent predictor of poor outcome in patients with ICH. Conclusions— The island sign is a reliable CT imaging marker that independently predicts hematoma expansion and poor outcome in patients with ICH. The noncontrast CT island sign may serve as a potential marker for therapeutic intervention.

Quantitative proteomics analysis of the liver reveals immune regulation and lipid metabolism dysregulation in a mouse model of depression.

Major depressive disorder (MDD) is a highly prevalent and debilitating mental illness with substantial impairments in quality of life and functioning. However, the pathophysiology of major depression remains poorly understood. Combining the brain and body should provide a comprehensive understanding of the etiology of MDD. As the largest internal organ of the human body, the liver has an important function, yet no proteomic study has assessed liver protein expression in a preclinical model of depression. Using the chronic unpredictable mild stress (CUMS) mouse model of depression, differential protein expression between CUMS and control (CON) mice was examined in the liver proteome using isobaric tag for relative and absolute quantitation (iTRAQ) coupled with tandem mass spectrometry. More than 4000 proteins were identified and 66 most significantly differentiated proteins were used for further bioinformatic analysis. According to the ingenuity pathway analysis (IPA), we found that proteins related to the inflammation response, immune regulation, lipid metabolism and NFκB signaling network were altered by CUMS. Moreover, four proteins closely associated with these processes, hemopexin, haptoglobin, cytochrome P450 2A4 (CYP2A4) and bile salt sulfotransferase 1 (SULT2A1), were validated by western blotting. In conclusion, we report, for the first time, the liver protein expression profile in the CUMS mouse model of depression. Our findings provide novel insight (liver-brain axis) into the multifaceted mechanisms of major depressive disorder.

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.

Potential antidepressant and resilience mechanism revealed by metabolomic study on peripheral blood mononuclear cells of stress resilient rats.

ABSTRACT Resilience is an active coping response to stress, which plays a very important role in major depressive disorder study. The molecular mechanisms underlying such resilience are poorly understood. Peripheral blood mononuclear cells (PBMCs) were promising objects in unveiling the underlying pathogenesis of resilience. Hereby we carried out successive study on PBMCs metabolomics in resilient rats of chronic unpredictable mild stress (CUMS) model. A gas chromatography–mass spectrometry (GC–MS) metabolomic approach coupled with principal component analysis (PCA) and orthogonal partial least‐squares discriminant analysis (OPLS‐DA) was used to detect differential metabolites in PBMCs of resilient rats. Ingenuity Pathways Analysis (IPA) was applied for pathway analysis. A set of differential metabolites including Malic acid, Ornithine, l‐Lysine, Stigmasterol, Oleic acid, &ggr;‐Tocopherol, Adenosine and N‐acetyl‐d‐glucosamine were significantly altered in resilient rats, meanwhile promoting antidepressant research. As revealed by IPA that aberrant energy metabolism, HIF&agr; signaling, neurotransmitter, O‐GlcNAcylation and cAMP signaling cascade in peripheral might be evolved in the pathogenesis of coping mechanism. The GC–MS based metabolomics may contribute to better understanding of resilience, as well as shedding light on antidepressant discovery.

Quantitative proteomic study of the plasma reveals acute phase response and LXR/RXR and FXR/RXR activation in the chronic unpredictable mild stress mouse model of depression

Major depressive disorder is a severe neuropsychiatric disease that negatively impacts the quality of life of a large portion of the population. However, the molecular mechanisms underlying depression are still unclear. The pathogenesis of depression involves several brain regions. However, most previous studies have focused only on one specific brain region. Plasma and brain tissues exchange numerous components through the blood-brain barrier. Therefore, in the present study, plasma samples from control (CON) mice and mice subjected to chronic unpredictable mild stress (CUMS) were used to investigate the molecular pathogenesis of depression, and the association between the peripheral circulation and the central nervous system. A total of 47 significant differentially expressed proteins were identified between the CUMS and CON group by an isobaric tag for relative and absolute quantitation (iTRAQ) coupled with tandem mass spectrometry approach. These 47 differentially expressed proteins were analyzed with ingenuity pathway analysis (IPA) software. This revealed that the acute phase response, LXR/RXR and FXR/RXR activation, the complement system and the intrinsic prothrombin activation pathway were significantly changed. Four of the significant differentially expressed proteins (lipopolysaccharide binding protein, fibrinogen β chain, α-1 antitrypsin, and complement factor H) were validated by western blotting. the present findings provide a novel insight into the molecular pathogenesis of depression.