The efficacy and safety of fingolimod plus standardized treatment versus standardized treatment alone for acute ischemic stroke: A systematic review and meta-analysis.

Acute ischemic stroke (AIS) is the most common type of stroke. Fingolimod is a sphingosine analog that acts on sphingosine-1-phosphate receptors (S1PR). Recently, the safety and efficacy of fingolimod in both patients with intracerebral hemorrhage and patients with AIS have been investigated in proof-of-concept trials. In this review, we performed a meta-analysis to evaluate the efficacy and safety of fingolimod for AIS. This study was conducted according to the PRISMA (Preferred Reporting Items for Systemic review and Meta-Analysis) statement. We searched for publications on the PubMed, Embase, Cochrane Central Register of Controlled Trials, Clinical trials, CNKI, Wanfang Data, VIP, CBM up to August 2021. We compiled five studies; a main meta-analysis forest plots were conducted for the values of the proportion of patients whose modified Rankin scale (MRS) score was 0-1 at day 90. There were heterogeneities in each study; the method of sensitivity analysis was performed. A sensitivity analysis was performed with a mean difference (MD) of the efficacy of fingolimod plus standardized treatment versus standardized treatment alone. Random effect model is used for meta-analysis regardless of the I2 index. The analysis was carried out for categorical variables using the risk ratio (RR), LogRR, and its 95% CI. The methodological quality of each randomized controlled trial (RCTs) was assessed according to the Cochrane Collaboration tool to assess the risk of bias (ROB). A meta-analysis of five studies with 228 participants was conducted. The risk ratio of patients whose MRS score was 0-1 at day 90 between fingolimod plus standardized treatment and standardized treatment alone was 2.59 (95%CI, 1.48-4.56). The Fingolimod plus standard treatment group decreased infarct growth and improved clinical function than the standard treatment.

Agomelatine might be more appropriate for elderly, depressed, type 2 diabetes mellitus patients than paroxetine/fluoxetine.

Agomelatine was a novel and melatonergic antidepressant. The present study was conducted to find out whether age was an important factor for agomelatine in treating depressed type 2 diabetes mellitus (T2DM) patients. In total, 193 depressed T2DM patients were included. There were 84 patients ranged from 27 years old to 49 years old (age phase I) (n = 44 receiving agomelatine, n = 40 receiving paroxetine or fluoxetine), and 109 patients ranged from 50 years old to 70 years old (age phase II) (n = 56 receiving agomelatine, n = 53 receiving paroxetine or fluoxetine). The Hamilton Depression Rating Scale (HDRS) score, Hamilton Anxiety Rating Scale (HARS) score, fasting plasma glucose (FPG), hemoglobin A1c (HbA1c) level and body mass index (BMI) were assessed after 12 weeks treatment. After treatment, we found that among patients in age phase I, there were no significant differences in final average HDRS score, HARS score, FPG, HbA1c level, BMI, response rate and remission rate between the two groups. However, among patients in age phase II, compared to patients receiving paroxetine or fluoxetine, patients receiving agomelatine had the significantly lower average HDRS score, HARS score, HbA1c level and BMI, and significantly higher response rate and remission rate. The incidence of treatment-related adverse events was similar between the two groups in both age phases. These results suggested that age was an important factor for agomelatine in treating depressed T2DM patients. Compared to paroxetine/fluoxetine, agomelatine might be more appropriate for elderly depressed T2DM patients.

Diterpene Ginkgolides Exert an Antidepressant Effect Through the NT3-TrkA and Ras-MAPK Pathways.

BACKGROUND: Depression is a highly prevalent mental illness that severely impacts the quality of life of affected individuals. Our recent studies demonstrated that diterpene ginkgolides (DG) have antidepressant effects in mice. However, the underlying molecular mechanisms remained much unclear. METHODS: In this study, we assessed the antidepressant effects of chronic DG therapy in rats by evaluating depression-related behaviors, we also examined potential side effects using biochemical indicators. Furthermore, we performed an in-depth molecular network analysis of gene-protein-metabolite interactions on the basis of metabolomics. RESULTS: Chronic DG treatment significantly ameliorated the depressive-like behavioral phenotype. Furthermore, the neurotrophin signaling-related NT3-TrkA and Ras-MAPK pathways may play an important role in the antidepressant effect of DG in the hippocampus. CONCLUSION: These findings provide novel insight into the mechanisms underlying the antidepressant action of DG, and should help advance the development of new therapeutic strategies for depression.

Efficacy of ginkgo biloba extract as augmentation of venlafaxine in treating post-stroke depression.

BACKGROUND: Post-stroke depression (PSD) is one of the most common psychiatric diseases afflicting stroke survivors. This study was conducted to assess the efficacy of ginkgo biloba extract as augmentation of venlafaxine in treating PSD. METHODS: The included PSD patients were randomly assigned into the experiment group (receiving ginkgo biloba extract plus venlafaxine) and control group (receiving venlafaxine alone). The treatment was continued for eight weeks. The Hamilton Depression Rating Scale (HDRS) and the Self-rating Depression Scale (SDS) were used to assess the depressive symptoms. The National Institutes of Health Stroke Scale (NIHSS) was used to assess the neurological defect, and the Activities of Daily Living (ADL) was used to assess recovery of abilities of patients after stroke. Meanwhile, the levels of serum 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) were measured before and after treatment. The dose of venlafaxine used and adverse events were also recorded. RESULTS: Each group had 40 PSD patients. After treatment, the depressive symptoms, neurological defect and living function were significantly improved in both groups. But the patients receiving ginkgo biloba extract plus venlafaxine had the significantly lower average HDRS score (p=0.0008), SDS score (p<0.00001), NIHSS score (p=0.00001), and higher average ADL score (p=0.0005). Meanwhile, compared to the control group, patients in the experiment group had the significantly higher 5-HT (p<0.00001) level and BDNF level (p<0.00001), needed lower dose of venlafaxine (p=0.007), and experienced fewer adverse events. CONCLUSION: These results demonstrated that the ginkgo biloba extract was a good augmentation of venlafaxine in treating PSD and should be further investigated.

Urinary biomarkers for diagnosing poststroke depression in patients with type 2 diabetes mellitus.

BACKGROUND: Depression can seriously affect the quality of life of type 2 diabetes mellitus (T2DM) patients after stroke. However, there were still no objective methods to diagnose T2DM patients with poststroke depression (PSD). Therefore, we conducted this study to deal with this problem. METHODS: Gas chromatography-mass spectroscopy (GC-MS)-based metabolomics profiling method was used to profile the urinary metabolites from 83 nondepressed T2DM patients after stroke and 101 T2DM patients with PSD. The orthogonal partial least-squares discriminant analysis was conducted to explore the metabolic differences in T2DM patients with PSD. The logistic regression analysis was performed to identify the optimal and simplified biomarker panel for diagnosing T2DM patients with PSD. The receiver operating characteristic curve analysis was used to assess the diagnostic performance of this biomarker panel. RESULTS: In total, 23 differential metabolites (7 decreased and 16 increased in T2DM patients with PSD) were found. A panel consisting of pseudouridine, malic acid, hypoxanthine, 3,4-dihydroxybutyric acid, fructose and inositol was identified. This panel could effectively separate T2DM patients with PSD from nondepressed T2DM patients after stroke. The area under the curve was 0.965 in the training set and 0.909 in the validation set. Meanwhile, we found that the galactose metabolism was significantly affected in T2DM patients with PSD. CONCLUSION: Our results could be helpful for future development of an objective method to diagnose T2DM patients with PSD and provide novel ideas to study the pathogenesis of depression.

A Pattern-Based Method for Medical Entity Recognition From Chinese Diagnostic Imaging Text.

Background: The identification of medical entities and relations from electronic medical records is a fundamental research issue for medical informatics. However, the task of extracting valuable knowledge from these records is challenging due to its high complexity. The accurate identification of entity and relation is still an open research problem in medical information extraction. Methods: A pattern-based method for extracting certain tumor-related entities and attributes from Chinese unstructured diagnostic imaging text is proposed. This method is a composition of three steps. Firstly, an algorithm based on keyword matching is designed to obtain the primary sites of tumors. Then a set of regular expressions is applied to identify primary tumor size information. Finally, a set of rules is defined to acquire metastatic sites of tumors. Results: Our method achieves a recall of 0.697, a precision of 0.825 and an F1 score of 0.755 using an overall weighted metric. For each of the extraction tasks, the F1 scores are 0.784, 0.822 and 0.740. Conclusions: The method proves to be stable and robust with different amounts of testing data. It achieves a comparatively high performance in the CHIP 2018 open challenge, demonstrating its effectiveness in extracting tumor-related entities from Chinese diagnostic imaging text.

Ginkgo biloba extract and its diterpene ginkgolide constituents ameliorate the metabolic disturbances caused by recombinant tissue plasminogen activator in rat prefrontal cortex.

INTRODUCTION: Although recombinant tissue plasminogen activator (rtPA) is a widely used therapy in patients with acute ischemic stroke, rtPA-induced toxicity or its adverse effects have been reported in our previous studies. However, Ginkgo biloba extract (GBE) may provide neuroprotective effects against rtPA-induced toxicity. Thus, in the present study, we investigated whether a single administration of rtPA caused neurotoxicity in the prefrontal cortex (PFC) of rats and determined whether GBE or its diterpene ginkgolide (DG) constituents were neuroprotective against any rtPA-induced toxicity. MATERIALS AND METHODS: We randomly divided adult Sprague-Dawley rats into four groups that were intravenously administered saline, rtPA, rtPA+DG, or rtPA+GBE. The rats were sacrificed 24 hours later and the whole brain removed. A gas chromatography-mass spectrometry metabolomic approach was used to detect molecular changes in the PFC among the groups. Multivariate statistical and pathway analyses were used to determine the relevant metabolites as well as their functions and pathways. RESULTS: We found 32 metabolites differentially altered in the four groups that were primarily involved in neurotransmitter, amino acid, energy, lipid, and nucleotide metabolism. Our results indicated that a single rtPA administration caused metabolic disturbances in the PFC. Both GBE and DG effectively ameliorated these rtPA-induced disturbances, although DG better controlled the rtPA-induced glutamate and aspartate excitotoxicity and the activation of NMDA receptor. CONCLUSION: Our results provide important novel mechanistic insights into the adverse effects of rtPA and offer directions for future exploration on the thrombolytic effects of rtPA combined with the administration of DG or GBE for the treatment of acute ischemic stroke in humans.

Metabolite-related antidepressant action of diterpene ginkgolides in the prefrontal cortex.

PURPOSE: Ginkgo biloba extract (GBE) contains diterpene ginkgolides (DGs), which have been shown to have neuroprotective effects by a number of previous studies. We previously demonstrated part of the action of DG. However, the impact of DG on the prefrontal cortex (PFC) remains unclear. Here, we evaluated the effects of DG and venlafaxine (for comparison) on behavioral and metabolite changes in the PFC using mice models and gas chromatography-mass spectrometry-based metabolomics. MATERIALS AND METHODS: Mice were randomly divided into control (saline), DG (12.18 mg/kg) and venlafaxine (16 mg/kg) groups. After 2 weeks of treatment, depression and anxiety-related behavioral tests were performed. Metabolic profiles of the PFC were detected by gas chromatography-mass spectrometry. RESULTS: The DG group exhibited positive effects in the sucrose preference test. The differential metabolites were mainly related to amino acid metabolism, energy metabolism and lipid metabolism. The results indicated that the DG group exhibited perturbed lipid metabolism, molecular transport and small-molecule biochemistry in the PFC. Compared with the control group, pathway analysis indicated that venlafaxine and DG had similar effects on alanine, aspartate and glutamate metabolism. CONCLUSION: These findings demonstrate that DG has antidepressant-like, but not anxiolytic-like, effects in mice, suggesting that it might have therapeutic potential for the treatment of major depressive disorder.

Venlafaxine exerts antidepressant effects possibly by activating MAPK-ERK1/2 and P13K-AKT pathways in the hippocampus.

Serotonin noradrenaline reuptake inhibitors are effective antidepressant drugs, which include venlafaxine and duloxetine. Venlafaxine is commonly used in a clinical context, but the molecular biological mechanisms behind its effects have not been fully determined. Here, we explored the potential biological effects of venlafaxine on mouse hippocampus. Mice were randomly divided into two groups and injected daily with 0.9% NaCl solution or venlafaxine. A GC-MS-based metabolomic approach was used to identify possible metabolic differences between these groups, and the key proteins involved in the relevant pathways were validated by western blotting. In our experiments, 27 hippocampal metabolites that distinguished the venlafaxine group from the control group were identified. These differential metabolites were subjected to Ingenuity Pathway Analysis, which revealed that they were strongly related to two metabolic pathways (MAPK-ERK1/2 and P13K-AKT signaling pathways). Six key proteins, BDNF, p-c-Raf, p-MAPK, p-MEK, p-AKT, and CREB, were verified by western blotting and the results were consistent with the differential metabolites identified by GC-MS. This study sheds light on the biological mechanisms underlying the effects of venlafaxine.

Insight into the metabolic mechanism of Diterpene Ginkgolides on antidepressant effects for attenuating behavioural deficits compared with venlafaxine.

Depression is a severe and chronic mental disorder, affecting about 322 million individuals worldwide. A recent study showed that diterpene ginkgolides (DG) have antidepressant-like effects on baseline behaviours in mice. Here, we examined the effects of DG and venlafaxine (VLX) in a chronic social defeat stress model of depression. Both DG and VLX attenuated stress-induced social deficits, despair behaviour and exploratory behaviour. To elucidate the metabolic changes underlying the antidepressive effects of DG and VLX, we investigated candidate functional pathways in the prefrontal cortex using a GC-MS-based metabolomics approach. Metabolic functions and pathways analysis revealed that DG and VLX affect protein biosynthesis and nucleotide metabolism to enhance cell proliferation, with DG having a weaker impact than VLX. Glutamate and aspartate metabolism played important roles in the antidepressant effects of DG and VLX. Tyrosine degradation and cell-to-cell signaling and interaction helped discriminate the two antidepressants. L-glutamic acid was negatively correlated, while hypoxanthine was positively correlated, with the social interaction ratio. Understanding the metabolic changes produced by DG and VLX should provide insight into the mechanisms of action of these drugs and aid in the development of novel therapies for depression.

Inhibitory effects of vitamin E on osteocyte apoptosis and DNA oxidative damage in bone marrow hemopoietic cells at early stage of steroid-induced femoral head necrosis.

Apoptosis and DNA oxidative damage serve significant roles in the pathogenesis of steroid­induced femoral head necrosis. Vitamin E demonstrates anti­apoptotic and anti­oxidant properties. Therefore, the present study investigated the effects of vitamin E on osteocyte apoptosis and DNA oxidative damage in bone marrow hemopoietic cells at an early stage of steroid­induced femoral head osteonecrosis. Japanese white rabbits were randomly divided into three groups (steroid, vitamin E­treated, and control groups), each comprising 12 rabbits. Those in the steroid group (group S) were initially injected twice with an intravenous dose of 100 µg/kg Escherichia coli endotoxin, with a 24 h interval between the two injections, and then with an intramuscular dose of 20 mg/kg methylprednisolone, three times at intervals of 24 h in order to establish a rabbit model of osteonecrosis. The vitamin E treated group (group E) received the same treatment as group S, and were administered 0.6 g/kg/d vitamin E daily from the beginning of modeling. The control group (group C) was injected with normal saline at the equivalent dosage and times as the aforementioned two groups. Two time points, weeks 4 and 6 following the completion of modeling, were selected. Osteonecrosis was verified by histopathology with hematoxylin-eosin staining. The apoptosis rate of osteonecrosis was analyzed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The apoptosis expression levels of caspase­3 and B­cell lymphoma 2 (Bcl­2), and DNA oxidative damage of bone marrow hematopoietic cells were analyzed by immunohistochemistry. At weeks 4 and 6 following the completion of modeling, the vacant bone lacunae rates of group E were 15.87±1.97 and 25.09±2.67%, respectively, lower than the results of 20.02±2.21 and 27.79±1.39% for group S; and the osteocyte apoptosis indexes of group E were 20.99±2.95 and 33.93±1.62%, respectively, lower than the results of 26.46±3.37 and 39.90±3.74% from group S. In addition, the Bcl-2 expression at week 4 in the femoral head tissues of group E was higher compared with group S; and the proportion of Bcl­2­positive cells of group E was 9.81±1.01%, higher compared with group S at 8.26±1.13%. The caspase­3 staining data at week 4 in femoral head tissues demonstrated that in the 12 femoral heads of group S, four were negative (32%) and eight were positive (68%); in group E, five were negative (45%) and seven were positive (55%); and in group C, 11 were negative (95%) and one was positive (5%). In addition, the DNA oxidative damage rate at week 4 in the bone marrow hemopoietic cells of group E was (7.24±1.44%), lower compared with group S (11.80±1.26%), and higher compared with group C (5.75±1.47%). Vitamin E is effective in intervening in apoptosis through decreasing caspase­3 expression and upregulating Bcl­2 expression, and by alleviating DNA oxidative damage in bone marrow hemopoietic cells at the early stage of steroid­induced femoral head necrosis in rabbit models.

Biochemical effects of venlafaxine on astrocytes as revealed by 1H NMR-based metabolic profiling.

As a serotonin-norepinephrine reuptake inhibitor [SNRI], venlafaxine is one of the most commonly prescribed clinical antidepressants, with a broad range of antidepressant effects. Accumulating evidence shows that venlafaxine may target astrocytes to exert its antidepressant activity, although the underlying pharmacological mechanisms remained largely unknown. Here, we used a 1H nuclear magnetic resonance (NMR)-based metabonomics method coupled with multivariate statistical analysis to characterize the metabolic profiling of astrocytes treated with venlafaxine to explore the potential mechanism of its antidepressant effect. In total, 31 differential metabolites involved in energy, amino acid and lipid metabolism were identified. Ingenuity pathway analysis was used to identify the predicted pathways and biological functions with venlafaxine and fluoxetine. The most significantly altered network was "amino acid metabolism, cellular growth and proliferation", with a score above 20. Certain metabolites (lysine, tyrosine, glutamate, methionine, ethanolamine, fructose-6-phosphate, and phosphorylethanolamine) are involved in and play a central role in this network. Collectively, the biological effects of venlafaxine on astrocytes provide us with the further understanding of the mechanisms by which venlafaxine treats major depressive disorder.

Targeted Metabolomic Pathway Analysis and Validation Revealed Glutamatergic Disorder in the Prefrontal Cortex among the Chronic Social Defeat Stress Mice Model of Depression.

Major depressive disorder (MDD) is a severe psychiatric disease that has critically affected life quality for millions of people. Chronic stress is gradually recognized as a primary pathogenesis risk factor of MDD. Despite the remarkable progress in mechanism research, the pathogenesis mechanism of MDD is still not well understood. Therefore, we conducted a liquid chromatography-tandem mass spectrometry (LC-MS/MS) detection of 25 major metabolites of tryptophanic, GABAergic, and catecholaminergic pathways in the prefontal cortex (PFC) of mice in chronic social defeat stress (CSDS). The depressed mice exhibit significant reduction of glutamate in the GABAergic pathway and an increase of L-DOPA and vanillylmandelic acid in catecholaminergic pathways. The data of real-time-quantitative polymerase chain reaction (RT-qPCR) and Western blotting analysis revealed an altered level of glutamatergic circuitry. The metabolomic and molecular data reveal that the glutamatergic disorder in mice shed lights to reveal a mechanism on depression-like and stress resilient phenotype.

GC-MS-based metabolomic study on the antidepressant-like effects of diterpene ginkgolides in mouse hippocampus.

Ginkgo biloba extract (GBE), including EGb-761, have been suggested to have antidepressant activity based on previous behavioral and biochemical analyses. However, because GBE contain many constituents, the mechanisms underlying this suggested antidepressant activity are unclear. Here, we investigated the antidepressant-like effects of diterpene ginkgolides (DG), an important class of constituents in GBE, and studied their effects in the mouse hippocampus using a GC-MS-based metabolomics approach. Mice were randomly divided into five groups and injected daily until testing with 0.9% NaCl solution, one of three doses of DG (4.06, 12.18, and 36.54mg/kg), or venlafaxine. Sucrose preference (SPT) and tail suspension (TST) tests were then performed to evaluate depressive-like behaviors in mice. DG (12.18 and 36.54mg/kg) and venlafaxine (VLX) administration significantly increased hedonic behavior in mice in the SPT. DG (12.18mg/kg) treatment also shortened immobility time in the TST, suggestive of antidepressant-like effects. Significant differences in the metabolic profile in the DG (12.18mg/kg) compared with the control or VLX group indicative of an antidepressant-like effect were observed using multivariate analysis. Eighteen differential hippocampal metabolites were identified that discriminated the DG (12.18mg/kg) and control groups. These biochemical changes involved neurotransmitter metabolism, oxidative stress, glutathione metabolism, lipid metabolism, energy metabolism, and kynurenic acid, providing clues to the therapeutic mechanisms of DG. Thus, this study showed that DG has antidepressant-like activities in mice and shed light on the biological mechanisms underlying the effects of diterpene ginkgolides on behavior, providing an important drug candidate for the treatment of depression.

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.

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.

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.

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.

Identification and validation of argininosuccinate synthase as a candidate urinary biomarker for major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a debilitating psychiatric mood disorder. However, no objective laboratory-based test is yet available to aid in the diagnosis of this disorder. METHODS: In order to identify urinary protein biomarker candidates for MDD, the differential proteomic analysis of urine samples from first-episode drug-naïve MDD subjects and healthy controls (HC) was carried out by using two-dimensional gel electrophoresis separation followed by MALDI-TOF/TOF-MS/MS identification. Then, the differential expression levels of some candidate proteins were further validated by immunoblot analysis. RESULTS: Through mass spectrometry and database searching, a total of 27 differential proteins were identified, primarily including enzymes, plasma proteins, serpins, and adhesion molecules. Five proteins were selected for subsequent validation by Western blotting. One arginine recycling enzyme - argininosuccinate synthase (ASS1) - was further confirmed to be significantly downregulated in the urine of 30 depressed subjects while remaining unchanged in the plasma. Importantly, receiver-operator curve analyses revealed that ASS1 displayed strong efficacy in distinguishing MDD subjects from HC. CONCLUSION: The present study provides a range of urinary protein biomarker candidates for MDD, and further demonstrates that ASS1 has a potential for clinical diagnosis of this disorder.