Aberrant Histone Modification of TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 in Major Depressive Disorder.

Activated toll-like receptor (TLR) signaling has been well investigated in major depressive disorder (MDD). We previously reported that TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 play important roles in regulating the toll-like receptor 4 (TLR4) signaling pathway and may serve as novel targets in the pathogenesis of MDD. Recently, aberrant histone modification has been implicated in several psychiatric disorders, including schizophrenia and mood disorder; the most thoroughly studied modification is histone 3 lysine 4 tri-methylation (H3K4me3). In this work, we aimed to explore H3K4me3 differences in the promotors of genes encoding the abovementioned factors in patients with MDD, and whether they were altered after antidepressant treatment. A total of 30 MDD patients and 28 healthy controls were recruited. Peripheral blood mononuclear cells (PBMCs) were collected. The levels of H3K4me3 in the promoters of TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 were measured through chromatin immunoprecipitation (ChIP) followed by DNA methylation assay. Analysis of covariance was used to evaluate between-group differences after adjusting for age, sex, BMI, and smoking. In comparison with healthy controls, patients with MDD showed significantly lower H3K4me3 levels in the promoters of TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 in PBMCs. These levels were not significantly altered after completion of a 4-week antidepressant treatment. To explore the association between depression severity and H3K4me3 levels, a multiple linear regression model was generated. The results revealed that levels of H3K4me3 in the TNIP2 promoters a negative correlation with the 17-item Hamilton Depression Rating Scale (HAND-17) score, whereas that of TLR4 had a positive correlation with this score. The present results suggest that decreased H3K4me3 levels in the promoters of the genes encoding TNFAIP3, TLR4, miR-146a, miR-155, and TNIP2 are involved in psychopathology of major depressive disorder.

Clinical Impact of Androgen Receptor-Suppressing miR-146b Expression in Papillary Thyroid Cancer Aggressiveness.

CONTEXT: Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy. Dysregulated expression of miR-146b and androgen receptor (AR) has been shown to play critical roles in tumorigenesis in PTC. However, the mechanistic and clinical association between AR and miR-146b is not fully understood. OBJECTIVE: The purpose was to investigate miR-146b as the potential AR target miRNA and its involvement in advanced tumor characteristics of PTC. METHODS: Expression of AR and miR-146b were assessed in frozen and formalin-fixed paraffin-embedded tissue samples from PTC and adjacent normal thyroid specimens by quantitative real-time polymerase chain reaction, and their correlation was examined. Human thyroid cancer cell lines BCPAP and TPC-1 were used to evaluate the effect of AR on miR-146b signaling. Chromatin immunoprecipitation (ChIP) assays were performed to determine whether AR binds to the miR-146b promoter region. RESULTS: Pearson correlation analysis confirmed significant inverse correlation between miR-146b and AR expression. Overexpressing AR BCPAP and TPC-1 cells showed relatively lower miR-146b expression. ChIP assay revealed that AR might bind to the androgen receptor element located on the promoter region of miRNA-146b gene, and overexpression of AR suppresses miR-146b-mediated tumor aggressiveness. The low AR/high miR-146b PTC patient group was associated with advanced tumor characteristics, including higher tumor stage, lymph node metastasis, and worse treatment response. CONCLUSION: To sum up, miR-146b is a molecular target of AR transcriptional repression; therefore, AR suppresses miR-146b expression to reduce PTC tumor aggressiveness.

Decreased Expression of Estrogen Receptors Is Associated with Tumorigenesis in Papillary Thyroid Carcinoma.

Papillary thyroid carcinomas (PTC), which is derived from thyroid follicular cells, is the most commonly differentiated thyroid cancer with sex disparity. However, the role of estrogen receptors (ERs) in the pathogenesis of PTC remains unclear. The present study aimed to determine the association of ER mRNA expression levels with clinicopathologic features in PTC. To that aim, the mRNA levels of ESR1 (ERα66), ESR1 (ERα36), ESR2, and G-protein-coupled estrogen receptor 1 (GPER1) in snap-frozen tissue samples from PTCs and adjacent normal thyroid tissues were determined using quantitative reverse transcription polymerase chain reaction (RT-qPCR), and the correlation between ER mRNA expression levels and clinicopathologic features was analyzed. The expression of ERα66, ERα36, ERß, and GPER1 was lower in PTC specimens than in adjacent normal thyroid tissues. Moreover, low GPER1 expression was associated with extrathyroidal extension. There was no obvious difference in expression of ERs between PTC specimens from male and female patients. In conclusion, our findings highlight the importance of ERs in PTC tumorigenesis.

Exosomal let-7e, miR-21-5p, miR-145, miR-146a and miR-155 in Predicting Antidepressants Response in Patients with Major Depressive Disorder.

The intracellular microRNAs that negatively regulate Toll-like receptor 4 signaling pathways in peripheral blood mononuclear cells are associated with major depressive disorder (MDD). However, that the distribution of these microRNAs in exosomes could be a biomarker of central nervous system diseases is just beginning to be explored. In the present study, we isolated serum exosomes from patients with MDD and healthy controls to explore the levels of exosomal microRNAs, including let-7e, miR-21-5p, miR-223, miR-145, miR-146a, and miR-155. We also investigated the changes of these exosomal microRNAs after antidepressant treatment and their association with clinical changes in scores on the Hamilton Depression Rating Scale. An ANCOVA adjusted by age, sex, BMI, and smoking showed higher expression levels of miR-146a (p = 0.006) in patients with MDD compared to controls. Patients who achieved remission showed significantly lower let-7e, miR-21-5p, miR-145, miR-146a, and miR-155 levels before treatment and increased levels after antidepressant treatment compared with the non-remission group. Through receiver operating characteristic (ROC) analysis, let-7e, miR-145, and miR-146a showed acceptable discrimination between the remission and non-remission groups, whereas miR-21-5p and miR-155 showed poor discrimination. These findings demonstrate that exosomal microRNAs may play essential roles in predicting antidepressants response.

TNIP2 mediates GRß-promoted inflammation and is associated with severity of major depressive disorder.

In depression, continual activation of the hypothalamic-pituitaryadrenal (HPA) axis with excess cortisol release leads to impair sensitivity of the glucocorticoid receptor (GR) and increase activity of the pro-inflammatory immune responses. Aberrant expression of GR has been associated with inflammation in patients with major depressive disorder (MDD). Our previous studies showed that the aberrant expression of TNFAIP3 gene, which encodes the NF-κB regulatory protein A20, TNFAIP3-associated proteins and Toll-like receptors (TLRs) are involved in inflammation-associated depression. However, the link between desensitization of GR actions and negative regulation of the TLRs-mediated inflammatory pathway in MDD is yet to be established. Here, we examined the association of depression severity, measured via the 17-item Hamilton Depression Rating Scale (HAMD-17), with the mRNA expression profiling of GRα, GRß, TNFAIP3-interacting proteins (TNIP), including TNIP1, TNIP2, and TNIP3, and TNFAIP3-like proteins, such as cezanne1, cezanne2, trabid, and valosin-containing protein p97/p47 complex-interacting protein p135 (VCIP135), in monocytes from 69 patients with MDD and 42 healthy controls. Herein we found the mRNA expressions of GRß and TNIP2 were significantly higher in monocytes from patients with MDD. Notably, TNIP2 level was positively correlated with the GRß expression and severity of depression, as determined via Pearson's correlation analysis. Mechanistically, we demonstrated that overexpression of GRß promotes the mRNA levels of TNIP2 and tumor necrosis factor alpha (TNF-α) in human monocytes. The promoting effect of GRß on TNF-α expression was partially attenuated upon depletion of TNIP2, suggesting that TNIP2 was required for GRß-mediated enhancement of TNF-α levels. Together, these results suggest that activation of GRß/TNIP2/TNF-α axis may induce inflammation in MDD patients and targeting this newly identified pathway may help in the development of better therapeutic approaches to reduce the development of MDD.

MicroRNA-29a Exhibited Pro-Angiogenic and Anti-Fibrotic Features to Intensify Human Umbilical Cord Mesenchymal Stem Cells-Renovated Perfusion Recovery and Preventing against Fibrosis from Skeletal Muscle Ischemic Injury.

This study was conducted to elucidate whether microRNA-29a (miR-29a) and/or together with transplantation of mesenchymal stem cells isolated from umbilical cord Wharton's jelly (uMSCs) could aid in skeletal muscle healing and putative molecular mechanisms. We established a skeletal muscle ischemic injury model by injection of a myotoxin bupivacaine (BPVC) into gastrocnemius muscle of C57BL/6 mice. Throughout the angiogenic and fibrotic phases of muscle healing, miR-29a was considerably downregulated in BPVC-injured gastrocnemius muscle. Overexpressed miR-29a efficaciously promoted human umbilical vein endothelial cells proliferation and capillary-like tube formation in vitro, crucial steps for neoangiogenesis, whereas knockdown of miR-29a notably suppressed those endothelial functions. Remarkably, overexpressed miR-29a profitably elicited limbic flow perfusion and estimated by Laser Dopple. MicroRNA-29a motivated perfusion recovery through abolishing the tissue inhibitor of metalloproteinase (TIMP)-2, led great numbers of pro-angiogenic matrix metalloproteinases (MMPs) to be liberated from bondage of TIMP, thus reinforced vascular development. Furthermore, engrafted uMSCs also illustrated comparable effect to restore the flow perfusion and augmented vascular endothelial growth factors-A, -B, and -C expression. Notably, the combination of miR29a and the uMSCs treatments revealed the utmost renovation of limbic flow perfusion. Amplified miR-29a also adequately diminished the collagen deposition and suppressed broad-wide miR-29a targeted extracellular matrix components expression. Consistently, miR-29a administration intensified the relevance of uMSCs to abridge BPVC-aggravated fibrosis. Our data support that miR-29a is a promising pro-angiogenic and anti-fibrotic microRNA which delivers numerous advantages to endorse angiogenesis, perfusion recovery, and protect against fibrosis post injury. Amalgamation of nucleic acid-based strategy (miR-29a) together with the stem cell-based strategy (uMSCs) may be an innovative and eminent strategy to accelerate the healing process post skeletal muscle injury.

Deficiency in Androgen Receptor Aggravates the Depressive-Like Behaviors in Chronic Mild Stress Model of Depression.

While androgen receptor (AR) and stress may influence the development of the major depressive disorder (MDD), the detailed relationship, however, remains unclear. Here we found loss of AR accelerated development of depressive-like behaviors in mice under chronic mild stress (CMS). Mechanism dissection indicated that AR might function via altering the expression of miR-204-5p to modulate the brain-derived neurotrophic factor (BDNF) expression to influence the depressive-like behaviors in the mice under the CMS. Adding the antiandrogen flutamide with the stress hormone corticosterone can additively decrease BDNF mRNA in mouse hippocampus mHippoE-14 cells, which can then be reversed via down-regulating the miR-204-5p expression. Importantly, targeting this newly identified AR-mediated miR-204-5p/BDNF/AKT/MAPK signaling with small molecules including 7,8-DHF and fluoxetine, all led to alter the depressive-like behavior in AR knockout mice under CMS exposure. Together, results from these preclinical studies conclude that decreased AR may accelerate the stress-induced MDD via altering miR-204-5p/BDNF/AKT/MAPK signaling, and targeting this newly identified signaling may help in the development of better therapeutic approaches to reduce the development of MDD.

Elevated TNIP3 mRNA Expression in TNF-α-Secreting Cells from Patients with Major Depressive Disorder.

OBJECTIVE: Elevated levels of pro-inflammatory cytokines, in particular tumor necrotic factor alpha (TNF-α), and abnormalities in negative regulation in Toll-like receptor (TLR) signaling pathways are associated with major depressive disorder (MDD). Previous research by our group disclosed lower expression of TNF-α-induced protein 3 (TNFAIP3), one of the negative regulators of the TLR4 signaling pathway, in depressive patients than in healthy controls. METHODS: In this study, we assessed the mRNA levels of TNFAIP3, TNFAIP3-interacting proteins (TNIP), including TNIP1, TNIP2, and TNIP3, and TNFAIP3-like proteins, such as cezanne1, cezanne2, trabid, and VCIP135, in TNF-α-secreting cells and examined their association with severity of depression using the 17-item Hamilton Depression Rating Scale (HAMD-17) scores from 30 MDD patients and 30 healthy controls. Twenty-six patients received a second assessment after treatment with antidepressants for 4 weeks. RESULTS: TNF-α-secreting cells displayed higher TNIP3 mRNA expression in MDD patients than in healthy controls before treatment, which was marginally decreased after antidepressant treatment. In addition, the TNIP2 level could be effectively applied to predict changes in HAMD scores after linear regression analysis. CONCLUSION: Our collective findings suggest that molecules associated with negative regulation of innate immunity are aberrantly expressed in patients with MDD and present potential therapeutic targets.

Aberrant Expression of Intracellular let-7e, miR-146a, and miR-155 Correlates with Severity of Depression in Patients with Major Depressive Disorder and Is Ameliorated after Antidepressant Treatment.

Chronic inflammation and abnormalities in Toll-like receptor (TLR) signaling pathways are associated with major depressive disorder (MDD). Our previous work reported that impaired negative regulators for the TLR pathways are associated with MDD. This study aimed to assess the association between the severity of depression and the intracellular microRNAs that regulate TLR4 signaling in both peripheral blood mononuclear cells (PBMCs) and monocytes from MDD patients. The severity of MDD before and after antidepressant treatment was determined by the 17-item Hamilton Depression Rating Scale, and quantitative RT-PCR was used to measure the levels of intracellular regulatory microRNAs, including let-7e, miR-21-5p miR-145, miR-223, miR-146a, and miR-155, in PBMCs and monocytes isolated from 43 healthy controls and 84 patients with MDD before and after treatment with antidepressants. Assays of PBMCs showed that the levels of let-7e, miR-146a, and miR-155 were lower in MDD patients than in healthy controls and were significantly higher after than before treatment in the 69 patients who completed treatment with antidepressants for four weeks. Levels of miR-146a and miR-155 in monocytes were lower in MDD patients than in controls and were increased in the former after antidepressant treatment. Multiple linear regression analyses found that let-7e and miR-146a expression before treatment was inversely correlated with severity of depression, whereas miR-155 before treatment was directly correlated with severity of depression. These findings suggest that intracellular regulatory microRNAs which regulate TLR4 signaling are aberrantly expressed in patients with MDD and that these levels are ameliorated by antidepressant treatment.

Antidepressants Improve Negative Regulation of Toll-Like Receptor Signaling in Monocytes from Patients with Major Depression.

OBJECTIVE: Changes in the brain's inflammatory status can lead to psychopathological responses, especially depression. Using animal models, recent studies have revealed that this pathology is due, in part, to innate immune responses of monocytes. METHODS: We focus on the involvement of Toll-like receptors (TLRs) and expression of genes encoding their negative regulators, SOCS1, TOLLIP, SIGIRR, MyD88s, NOD2, and TNFAIP3, in CD14+ monocytes from 34 patients with major depressive disorder (MDD) and 33 healthy controls before and after treatment with antidepressants. We also seek to investigate their association with depression severity, measured by the 17-item Hamilton Depression Rating Scale (HAMD-17). RESULTS: mRNA expression of all TLRs, except TLR3 and -5, was significantly higher in monocytes from patients with MDD than in those from controls. Conversely, the "brakes" in TLR signaling, including TOLLIP, MyD88s, NOD2, and TNFAIP3, were downregulated. In clinical findings, the remission group showed higher baseline TLR4 and lower baseline IRAK3 mRNA levels but only baseline elevated SOCS1 mRNA levels, which were inversely correlated with HAMD-17 scores, predicting worsened outcome in MDD patients. In addition, TNFAIP3 mRNA levels were increased by antidepressant treatment. CONCLUSION: Collectively, our findings suggest a role for dysregulation of TLR signaling in monocytes in MDD and identify a balancing effect of antidepressants on this dysregulation.

Increased serum anti-N-methyl-D-aspartate receptor antibody immunofluorescence in psychiatric patients with past catatonia.

OBJECTIVE: Anti-N-methyl-D-aspartate receptor (NMDAR) antibody was thought to be the cause of anti-NMDAR encephalitis, with manifestations similar to catatonia and schizophrenia. Anti-NMDAR antibody in neuropsychiatric patients who had catatonia before were investigated in a follow-up evaluation. The intensity of antibody immunofluorescence was quantified and compared with healthy controls. METHOD: Nineteen patients (eight males and eleven females) agreed to be followed-up. Thirteen had the diagnosis of schizophrenia, two had the diagnosis of major depressive disorder, two had bipolar disorder, one had postpartum depression, and one had herpes simplex encephalitis. No patient had catatonia during the follow-up. Nineteen sex-matched healthy controls were recruited. RESULTS: Using Mann-Whitney U test, patients had greater intensity of anti-NMDAR antibody immunofluorescence than the healthy controls (121,979 ± 86,526 vs. 47,692 ± 26,102, p = 0.003). No correlation was found between immunofluorescence intensity and catatonia scales or symptom severity scores. Neuropsychiatric patients with past catatonia showed greater anti-NMDAR antibody response than the healthy controls. CONCLUSION: NMDAR dysfunction might play a role in the mechanism underlying catatonia. Further studies are needed to confirm this finding.

Increased serum brain-derived neurotrophic factor in male schizophrenic patients with metabolic syndrome.

Increased prevalence of metabolic syndrome was found in patients with schizophrenia. Brain-derived neurotrophic factor (BDNF) was involved in energy metabolism and the pathophysiology of schizophrenia, but differently in males and females. We aimed to investigate the serum BDNF levels in patients with schizophrenia with and without metabolic syndrome.Patients with schizophrenia were recruited. Their demographic data were collected. Metabolic profiles and serum BDNF levels were measured. Clinical symptoms were evaluated with Positive and Negative Syndrome Scale. Metabolic syndrome was determined with the criteria provided by Ministry of Health and Welfare of Taiwan. Framingham Risk Score (FRS) for estimate of 10-year risk for coronary heart disease was provided by National Institutes of Health.Of the 81 participants, 40.7% had metabolic syndrome. Those with metabolic syndrome had higher FRS. Using analysis of covariance adjusted for age and body mass index, male patients with schizophrenia with metabolic syndrome had higher serum BDNF levels than those without (4.6 ±â€Š4.7 vs 3.3 ±â€Š3.8 ng/mL, P = .022). No statistical difference was found between female patients with and without metabolic syndrome.Significant differences of serum BDNF levels were found between male patients with schizophrenia with and without metabolic syndrome, but not in females. This finding suggested the gender difference behind the mechanism of BDNF in metabolic syndrome in schizophrenia.

The Lorazepam and Diazepam Protocol for Catatonia Due to General Medical Condition and Substance in Liaison Psychiatry.

OBJECTIVE: The lorazepam-diazepam protocol had been proved to rapidly and effectively relieve catatonia in patients with schizophrenia or mood disorder. This study aims to investigate the efficacy of lorazepam-diazepam protocol in catatonia due to general medical conditions (GMC) and substance. METHOD: Patients with catatonia that required psychiatric intervention in various settings of a medical center were included. The lorazepam-diazepam protocol had been used to treat the catatonia due to GMC or substance according to DSM-IV criteria. The treatment response had been assessed by two psychiatrists. RESULTS: Eighteen (85.7%) of 21 catatonic patients due to GMC or substance became free of catatonia after the lorazepam-diazepam protocol. Five (23.8%) of the 21 patients had passed away with various causes of death and wide range of time periods after catatonia. CONCLUSION: Our results showed that the lorazepam-diazepam protocol could rapidly and effectively relieve catatonia due to GMC and substance.

TNFAIP3, a negative regulator of the TLR signaling pathway, is a potential predictive biomarker of response to antidepressant treatment in major depressive disorder.

Inflammation and abnormalities in Toll-like receptor (TLR) expression and activation have been linked to major depressive disorder (MDD). However, negative regulators of TLR pathways have not been previously investigated in this context. Here, we sought to investigate the association of depression severity, measured by the 17-item Hamilton Depression Rating Scale (HAMD-17), with mRNA expression levels of negative regulators of the TLR pathway, including SOCS1, TOLLIP, SIGIRR, MyD88s, NOD2 and TNFAIP3, in peripheral blood mononuclear cells (PBMCs) from 100 patients with MDD and 53 healthy controls, before and after treatment with antidepressants. Positive regulators of the TLR4 pathway, including Pellino 1, TRAF6 and IRAK1, were also investigated. Among all patients, MyD88s, and TNFAIP3 mRNAs were expressed at lower levels in PBMCs from patients with MDD. Multiple linear regression analyses revealed that TNFAIP3 mRNA expression before treatment was inversely correlated with severity of depression and effectively predicted improvement in HAMD-17 scores. Among 79 treatment-completers, only TNFAIP3 mRNA was significantly increased by treatment with antidepressants for 4 weeks. Treatment of human monocytes (THP-1) and mouse microglia (SIM-A9) cell lines with fluoxetine significantly increased TNFAIP3 mRNA expression and suppressed IL-6 levels. The suppressive effect of fluoxetine on IL-6 was attenuated by knockdown of TNFAIP3 expression. These findings suggest that both dysfunction of the negative regulatory system in patients with MDD and antidepressant treatment exert anti-inflammatory effects, at least in part through increased expression of the TNFAIP3 gene. They also indicate that modulating expression of the TNFAIP3 gene to rebalance TLR-mediated inflammatory signaling may be potential therapeutic strategy for treating MDD.

TNFAIP3 mRNA Level Is Associated with Psychological Anxiety in Major Depressive Disorder.

BACKGROUND: Major depressive disorder has been shown to be associated with inflammation and the dysregulation of innate immune responses. Previously, we showed an inverse correlation between the severity of depression and level of TNFAIP3 mRNA expression. The present study further evaluated the association between TNFAIP3 mRNA expression level and symptoms of major depressive disorder (MDD) in 91 patients (20 men and 71 women). METHODS: The relationships between subscores on the 17-item Hamilton Depression Rating Scale (HAMD-17) and TNFAIP3 mRNA levels were assessed by multiple linear regression. RESULTS: Only psychological anxiety on the HAMD-17 correlated significantly with TNFAIP3 mRNA expression. Other symptoms, such as depressed mood, insomnia, work and activities, and suicide, were not associated with TNFAIP3 mRNA expression. CONCLUSION: These findings suggest a significant association between anxiety and TNFAIP3 mRNA levels in patients with MDD.

Relapses and recurrences of catatonia: 30-case analysis and literature review.

OBJECTIVE: Relieving catatonia helps identify the underlying etiology and its treatment. However, catatonia may reemerge after some time, but there are few data on the relapses and recurrences of catatonia. We aimed to investigate the characteristics of patients with relapses or recurrences of catatonia as well as the efficacy of the lorazepam-diazepam protocol on them. METHODS: Patients with catatonia who had more than one episode of catatonia and were treated with the lorazepam-diazepam protocol were identified. Their medical charts were reviewed, and interview was conducted. RESULTS: Thirty patients were identified. Nineteen (63.3%) were diagnosed with schizophrenia, five (16.7%) with major depressive disorder, two (6.7%) with bipolar disorder, and four (13.3%) with general medical conditions. In the 68 relapses and relapses the lorazepam-diazepam protocol was used, full response was reported in 54 (79.4%) of them. Twelve of 19 (63.2%) patients with schizophrenia were treated with clozapine. Twenty (66.7%) out of 30 patients were maintained on oral lorazepam by the time of discharge. Literature review showed similar prevalence of schizophrenia in patients with more than one episode of catatonia, and a wide variety of treatment options. CONCLUSION: The lorazepam-diazepam protocol was mostly effective in managing relapses and recurrences of catatonia. Maintenance clozapine and oral lorazepam were beneficial in a significant number of patients.

Antidepressants normalize elevated Toll-like receptor profile in major depressive disorder.

RATIONALE: Abnormalities in Toll-like receptor (TLR) expression in depression have been inferred in part from observed increases in TLR4 levels in peripheral blood mononuclear cells (PBMCs) and postmortem brains of depressed and suicidal patients. Our previous study found differences in the TLR expression in PBMCs between healthy controls and patients with major depressive disorder. Normalization of increased TLR4 in PBMCs by cognitive behavior psychotherapy has been reported. However, the effects of antidepressants remain unknown. OBJECTIVES: Changes in TLR1-9 expression levels of PBMCs were examined in 56 patients with MDD. The 17-item Hamilton Depression Rating Scale (HAMD-17) and mRNA expression levels of TLRs were assessed in parallel with a housekeeping gene using qRT-PCR before and after treatment with antidepressants. RESULTS: TLR3, TLR4, TLR5, TLR7, TLR8, and TLR9 were expressed at elevated levels in patients with MDD and were significantly decreased by treatment with antidepressants for 4 weeks. Antidepressant treatment completely normalized TLR3, TLR5, TLR7, TLR8, and TLR9 levels, whereas TLR1, TLR2, TLR4, and TLR6 were decreased to below normal levels. A subgroup analysis found that only TLR3 was significantly higher at baseline in the nonremission group. In addition, a multiple linear regression analysis revealed that only low TLR3 before treatment predicted improvement in HAMD-17 scores. CONCLUSIONS: These findings suggest that antidepressant treatment exerts anti-inflammatory effects in patients with MDD and identify TLR profiles as a predictor of response to antidepressant therapy. Further studies investigating the effects of manipulating individual TLRs on depression are needed to fully elucidate the underlying mechanism.

Association between toll-like receptor 4 expression and symptoms of major depressive disorder.

BACKGROUND: In our previous study, toll-like receptor 4 (TLR4) mRNA expression level was associated with severity of major depressive disorder (MDD) evaluated with the 17-item Hamilton Depression Rating Scale (HAMD-17). However, there are few studies that have investigated the relationship between symptoms of MDD and changes in TLR4 expression. Therefore, the aim of the present study was to further analyze the association between subscales of HAMD-17 and TLR4. METHODS: Fifty-one patients with MDD (15 male and 36 female) participated in this study. HAMD-17 was used to assess the symptoms of major depression. The mRNA expression levels of TLR4 were examined in parallel with a housekeeping gene, using real-time polymerase chain reaction. A stepwise linear regression forward model was used to evaluate the relationships between items of HAMD-17 and TLR4 expression. RESULTS: Some sickness behavior-associated symptoms, including suicide, somatic symptoms of anxiety, or performance of work and activities, were not associated with TLR4 expression. However, psychological signs of anxiety and loss of weight in HAMD-17 can predict the expression level of TLR4. CONCLUSION: Our results suggest a significant association between anxiety, body weight loss, and TLR4 mRNA levels in patients with MDD. Larger longitudinal studies combining both subjective and objective measures of depression are needed to clarify the link between TLR4 and symptoms of depression.

Association between toll-like receptors expression and major depressive disorder.

Accumulating evidences suggest that Toll-like receptors (TLRs) were involved in the pathophysiology of major depressive disorder. TLR4 was thought to be associated with major depressive disorder in animal model, but the others were still unknown. In order to examine TLR1-9 mRNA expression levels in peripheral blood and their relationships with the psychopathology of major depressive disorder, 30 patients with major depressive disorder were compared with 29 healthy controls. The 17-item Hamilton Depression Rating Scale (HAMD-17) was used to assess the severity of major depression. The mRNA expression levels of TLRs were examined in parallel with a housekeeping gene using real-time polymerase chain reaction (RT-PCR). Analysis of covariance with age and body mass index adjustment revealed a significantly higher expression of TLR3, 4, 5 and 7 mRNA but lower expression of TLR1 and 6 in patients with major depressive disorder as compared with healthy controls. Multiple linear regression analysis revealed that TLR4 was an independent risk factor relating to severity of major depression. These findings suggest that TLRs, especially TLR4, may be involved in the psychopathology of major depression.

Lower serum tropomyosin receptor kinase B levels in patients with schizophrenia.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) have previously been found to be reduced in the prefrontal cortex of patients with schizophrenia. In this study, we tried to investigate the protein levels of BDNF and TrkB from peripheral blood in the veins of individuals with schizophrenia and health controls. METHODS: From January 2008 to November 2010, we recruited 40 schizophrenic patients and 56 healthy controls. Serum BDNF and total TrkB protein levels were detected with enzyme-linked immunosorbent assay (ELISA) kits. Outliners of BDNF and TrkB were excluded initially. Analysis of covariance (ANCOVA) with age adjustment was used for group mean differences of different groups. RESULTS: After using the ANCOVA with age adjustment, the results of this work showed that BDNF presented no significant difference (F = 0.065, p = 0.800), but the serum TrkB protein level was significantly lower in schizophrenic patients than in healthy controls (F = 8.34, p = 0.005). CONCLUSION: Our findings showed a lower TrkB protein level in serum from schizophrenia patients compared with healthy controls, indicating that the signaling transmission of BDNF/TrkB may be affected in peripheral blood from individuals with schizophrenia.