Cytokine profile in first-episode drug-naïve major depressive disorder patients with or without anxiety.

OBJECTIVE: It is known that cytokines play a role in both depression and anxiety. This study aimed to compare the levels of multiple cytokines in patients with first-episode drug-naive major depressive disorder (MDD) with or without anxiety and analyze the correlation between the level of depression or anxiety and the serum cytokine levels. METHODS: The study involved 55 patients with first-episode drug-naive MDD. To assess anxiety symptoms, the 14-item HAMA was used. MDD patients were divided into two groups: 23 MDD patients without anxiety and 32 MDD patients with anxiety. The measurement of 37 cytokines was conducted. Serum cytokine levels between patients with MDD without anxiety and anxiety were compared. In multiple linear regression models, the relationship between the group and abnormal cytokines was explored. The receiver operating characteristic (ROC) curve analysis was performed to estimate diagnostic performance of serum cytokines in discriminating MDD patients with anxiety from MDD patients without anxiety. A correlation was evaluated between the scores of HAMD or HAMA and the serum cytokine levels. RESULTS: In MDD patients with anxiety, IL-17 C and CCL17 levels were significantly lower than in MDD patients without anxiety (all P < 0.05). Multiple measurements were corrected with Benjamini-Hochberger corrections, but none of these differences persisted (all P > 0.05). The results of multiple linear regression models revealed that after controlling for other independent variables, group was not a significant independent predictor of serum IL-17 C or CCL17 (all P > 0.05). The AUC values of IL-17 C and CCL17 were 0.643 and 0.637, respectively, in discriminating MDD patients with anxiety from MDD patients without anxiety. The results of partial correlation analyses showed the scores of HAMD were negatively correlated with the IL-17 C (r = -0.314, P = 0.021) levels with sex as a covariate. CONCLUSIONS: The findings suggest that there is a potential absence of disparity in the levels of circulating cytokines among individuals diagnosed with first-episode drug-naïve MDD, regardless of the presence or absence of comorbid anxiety.

Effect of duloxetine on changes in serum proinflammatory cytokine levels in patients with major depressive disorder.

OBJECTIVE: Accumulating evidence supports the idea that inflammation may contribute to the pathophysiology of major depressive disorder (MDD). Duloxetine, a serotonin-norepinephrine reuptake inhibitor, exhibits anti-inflammatory effects both in vitro and in vivo. In this study, we investigated the impact of duloxetine on changes in serum proinflammatory cytokine levels among individuals diagnosed with MDD. METHODS: A cohort of 23 drug-naïve individuals diagnosed with MDD and 23 healthy controls were included in this study. The severity of depressive symptoms was evaluated using the 24-item Hamilton Depression Scale (HAMD-24). A panel of 7 proinflammatory cytokines, including interleukin-1ß (IL-1ß), IL-2, IL-6, IL-8, IL-12, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), were quantified using multiplex Luminex assays. The levels of serum cytokines in healthy controls and patients with MDD were compared at baseline. All patients received duloxetine at a dosage range of 40-60 mg/day for a duration of 4 weeks. The HAMD-24 scores and serum cytokine levels were compared before and after duloxetine treatment. RESULTS: Compared with healthy controls, patients with MDD had significantly greater levels of IL-2, IL-6, IL-8, IL-12, TNF-α, and IFN-γ (P < 0.05). Moreover, there was a significant decrease in HAMD-24 scores observed pre- and post-treatment (t = 13.161, P < 0.001). Furthermore, after 4 weeks of treatment, the serum levels of IL-8 (t = 3.605, P = 0.002), IL-12 (t = 2.559, P = 0.018), and IFN-γ (t = 3.567, P = 0.002) decreased significantly. However, there were no significant differences in other cytokines, including IL-1ß, IL-2, IL-6, and TNF-α, before and after treatment (P > 0.05). CONCLUSIONS: These findings present compelling evidence, potentially for the first time, indicating that duloxetine treatment may effectively reduce the serum concentrations of IL-8, IL-12, and IFN-γ in individuals diagnosed with MDD. However, the precise mechanisms underlying this effect remain unclear and warrant further investigation.

Intricate role of intestinal microbe and metabolite in schizophrenia.

BACKGROUND: The brain-gut axis has gained increasing attention due to its contribution to the etiology of various central nervous system disorders. This study aims to elucidate the hypothesis that schizophrenia is associated with disturbances in intestinal microflora and imbalance in intestinal metabolites. By exploring the intricate relationship between the gut and the brain, with the goal of offering fresh perspectives and valuable insights into the potential contribution of intestinal microbial and metabolites dysbiosis to the etiology of schizophrenia. METHODS: In this study, we used a 16S ribosomal RNA (16S rRNA) gene sequence-based approach and an untargeted liquid chromatography-mass spectrometry-based metabolic profiling approach to measure the gut microbiome and microbial metabolites from 44 healthy controls, 41 acute patients, and 39 remission patients, to evaluate whether microbial dysbiosis and microbial metabolite biomarkers were linked with the severity of schizophrenic symptoms. RESULTS: Here, we identified 20 dominant disturbances in the gut microbial composition of patients compared with healthy controls, with 3 orders, 4 families, 9 genera, and 4 species. Several unique bacterial taxa associated with schizophrenia severity. Compared with healthy controls, 145 unusual microflora metabolites were detected in the acute and remission groups, which were mainly involved in environmental information processing, metabolism, organismal systems, and human diseases in the Kyoto encyclopedia of genes and genomes pathway. The Sankey diagram showed that 4 abnormal intestinal and 4 anomalous intestinal microbial metabolites were associated with psychiatric clinical symptoms. CONCLUSIONS: These findings suggest a possible interactive influence of the gut microbiota and their metabolites on the pathophysiology of schizophrenia.

Exosomes derived from bone-marrow mesenchymal stem cells alleviate cognitive decline in AD-like mice by improving BDNF-related neuropathology.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive decline in cognitive ability. Exosomes derived from bone-marrow mesenchymal stem cells (BMSC-exos) are extracellular vesicles that can execute the function of bone-marrow mesenchymal stem cells (BMSCs). Given the versatile therapeutic potential of BMSC and BMSC-exos, especially their neuroprotective effect, the aim of this study was to investigate the potential effect of BMSC-exos on AD-like behavioral dysfunction in mice and explore the possible molecular mechanism. METHODS: BMSC-exos were extracted from the supernatant of cultured mouse BMSCs, which were isolated from the femur and tibia of adult C57BL/6 mice, purified and sorted via flow cytometry, and cultured in vitro. BMSC-exos were identified via transmission electron microscopy, and typical marker proteins of exosomes were also detected via Western blot. A sporadic AD mouse model was established by intracerebroventricular injection of streptozotocin (STZ). Six weeks later, BMSC-exos were administered via lateral ventricle injection or caudal vein injection lasting five consecutive days, and the control mice were intracerebroventricularly administered an equal volume of solvent. Behavioral performance was observed via the open field test (OFT), elevated plus maze test (EPM), novel object recognition test (NOR), Y maze test (Y-maze), and tail suspension test (TST). The mRNA and protein expression levels of IL-1ß, IL-6, and TNF-α in the hippocampus were measured via quantitative polymerase chain reaction (qPCR) and Western blot, respectively. Moreover, the protein expression of Aß1-42, BACE, IL-1ß, IL-6, TNF-α, GFAP, p-Tau (Ser396), Tau5, synaptotagmin-1 (Syt-1), synapsin-1, and brain-derived neurotrophic factor (BDNF) in the hippocampus was detected using Western blot, and the expression of GFAP, IBA1, Aß1-42 and DCX in the hippocampus was measured via immunofluorescence staining. RESULTS: Lateral ventricle administration, but not caudal vein injection of BMSC-exos improved AD-like behaviors in the STZ-injected mouse model, as indicated by the increased number of rearing, increased frequency to the central area, and increased duration and distance traveled in the central area in the OFT, and improved preference index of the novel object in the NOR. Moreover, the hyperactivation of microglia and astrocytes in the hippocampus of the model mice was inhibited after treatment with BMSC-exos via lateral ventricle administration, accompanied by the reduced expression of IL-1ß, IL-6, TNF-α, Aß1-42, and p-Tau and upregulated protein expression of synapse-related proteins and BDNF. Furthermore, the results of the Pearson test showed that the preference index of the novel object in the NOR was positively correlated with the hippocampal expression of BDNF, but negatively correlated with the expression of GFAP, IBA1, and IL-1ß. Apart from a positive correlation between the hippocampal expression of BDNF and Syt-1, BDNF abundance was found to be negatively correlated with markers of glial activation and the expression of the inflammatory cytokines, Aß1-42, and p-Tau, which are characteristic neuropathological features of AD. CONCLUSIONS: Lateral ventricle administration, but not caudal vein injection of BMSC-exos, can improve AD-like behavioral performance in STZ-injected mice, the mechanism of which might be involved in the regulation of glial activation and its associated neuroinflammation and BDNF-related neuropathological changes in the hippocampus.

A UPLC-MS/MS method for determination of endogenous l-carnitine and acetyl-l-carnitine in serum of patients with depression.

A simple, rapid, and selective ultra-performance liquid chromatography-tandem mass spectrometry method for determination of l-carnitine (LC) and acetyl-l-carnitine (ALC) in human serum was developed. Acetyl-l-carnitine-d3 (ALC-d3 ) was selected as internal standard (IS). After protein precipitation with acetonitrile-water (1 mL, 2:1, v/v), the analytes and IS were separated on a 2.5-µm XSelect HSS T3 C18 column by gradient elution with methanol-water (containing 0.01% ammonia water) as the mobile phase at a flow rate of 0.2 mL/min. Analytes were detected with multiple reaction monitoring using a positive scan mode with electrospray ionization. Good linearity (R2 > 0.999) was observed in the concentration range for LC and ALC. The inter- and intra-day values of relative error were -10.4% to 10.0% with CVs less than 9.84%. The average recoveries of the two analytes were 91.29%-98.23%. Blood samples containing LC and ALC were stable under various storage conditions. Normal, haemolytic, and hyperlipidaemic serum had no significant effect on the quantification of LC and ALC. This method was successfully applied to study the concentrations of endogenous LC and ALC in the serum of patients with first-episode depression.

Low KISS1 expression predicts poor prognosis for patients with colorectal cancer: A meta-analysis.

KISS1 and KISS1R, a novel pair of metastasis suppressors, are likely to be associated with the prognosis of colorectal cancer (CRC). Here, a meta-analysis was performed to study the role of KISS1 and KISS1R in CRC. Heterogeneity, stability and publication bias were all estimated. Six publications describing a total of 559 CRC patients were included in the present study. Low KISS1 expression predicted 70% higher risk of poor prognosis for general patients (HR, 1.71; 95% CI, 1.28-2.29) and 99% higher risk for East Asian patients (HR, 1.99; 95% CI, 1.46-2.72). Limited evidence indicated that decreased KISS1R expression might predict poor outcome (HR, 2.96; 95% CI, 1.51-5.82). Neither heterogeneity nor publication bias was identified. The current analyses suggest that low KISS1 expression predicts poor overall survival among East Asian patients with CRC. Evidence on other races and KISS1R are still insufficient, and additional studies are required to clarify the risk of CRC associated with KISS1R by race.

The association of functional polymorphism of matrix metalloproteinase-9 gene (rs3918242) with schizophrenia: a meta-analysis.

Introduction: Schizophrenia has a strong genetic basis. It is reported that the matrix metalloproteinase-9 (MMP-9) -1562C/T polymorphism (rs3918242) may be associated with schizophrenia; however, current evidences are conflicting. Methods: A systematic literature search was conducted on PubMed and Web of Science to identify all the available evidences of the association of schizophrenia with rs3918242 polymorphism. Baseline information and genotype distribution were extracted from eligible study for quantitative data synthesis. Odds ratio (OR) and 95% confidence interval (95% CI) were used to estimate the effect size. Quality assessment was performed for each study using Newcastle-Ottawa Scale (NOS). Results: Four eligible studies were included in this study. Data synthesis indicated that rs3918242 polymorphism was not associated with schizophrenia (OR = 1.04, 95% CI = 0.69-1.58), with high heterogeneity (I2 = 75%, p = .007). No publication bias was visually observed according to funnel plot. Sensitivity analysis showed a significant association (OR = 1.29, 95% CI = 1.03-1.63) when a specific study was removed. Conclusions: MMP-9 rs3918242 polymorphism may not be associated with schizophrenia. Given a crucial role of MMP-9 molecule on the pathogenesis of schizophrenia, this result should be verified by more studies with scientifically rigorous design and large population.

Effect of Common Cold on Serum Clozapine Concentrations in Hospitalized Patients with Schizophrenia.

Objective: The present study aims to investigate the effect of common cold on the serum clozapine concentrations in hospitalized patients with schizophrenia. Methods: A total of 65 schizophrenic patients with common cold receiving clozapine treatment were retrospectively enrolled. The demographic data, medication situation, clozapine concentration, and parameters of routine haematological and biochemical laboratory tests were obtained from the medical record system. The serum clozapine concentration and clozapine concentration/dose (C/D) ratios between the baseline period and cold period were compared by paired-sample t tests. Association between the changes in serum concentration and C/D ratios of clozapine and changes in white blood cell (WBC) and neutrophil (NE) counts was evaluated using Pearson correlation analysis. Results: The serum clozapine concentration (t = -9.856, P < 0.001) and clozapine C/D ratios (t = -10.071, P < 0.001) were found to be significantly elevated in the cold period compared to the baseline period. Moreover, the changes in the serum clozapine concentration were found to be significantly elevated in female patients compared to male patients (t = -2.483, P = 0.017). Furthermore, changes in the serum clozapine concentration were positively correlated to the changes in WBC (r = 0.303, P = 0.014) and NE (r = 0.315, P = 0.011) counts. Similarly, changes in clozapine C/D ratios were positively correlated to the changes in WBC (r = 0.275, P = 0.027) and NE (r = 0.328, P = 0.008) counts. Conclusion: The serum clozapine concentrations in patients with schizophrenia during the common cold period were increased, which might by related to the elevated WBC and NE counts.

Neuropathological implication of high blood bilirubin in patients and model rats with depression.

PURPOSE: Elevated bilirubin levels have been associated with major depressive disorder (MDD); however, the exact impact of bilirubin on MDD and the underlying molecular mechanisms remain unclear. Here, we explored the influence of bilirubin on MDD and sought to identify the mechanisms via which bilirubin induces depressive-like behavior. PATIENTS AND METHODS: Forty patients who were diagnosed with MDD and received treatment with selective serotonin reuptake inhibitors (SSRIs) were included, with 43 healthy volunteers serving as controls. Clinical symptoms were evaluated using Hamilton depression rating scale-24 (HAMD-24) and the Hamilton anxiety rating scale. Serum concentrations of total bilirubin (TBIL) and indirect bilirubin (IBIL) were measured at baseline and after treatment using an automated biochemical analyzer. The connection between clinical symptoms and TBIL or IBIL was examined using Pearson correlation. Chronic restraint stress (CRS) was employed to generate a rat model of depression. TBIL, IBIL in rat serum were measured by ELISA. Reactive oxygen species (ROS) contents in rat hippocampal tissues were quantified by flow cytometry. The levels of microglial markers and the extent of neuronal damage in the rat hippocampus were assessed by immunofluorescence and transmission electron microscopy, respectively. RESULTS: Serum TBIL and IBIL levels were higher in patients with MDD than in the healthy controls. After treatment with SSRIs, the serum levels of TBIL and IBIL in MDD patients were significantly reduced. The levels of TBIL and IBIL were associated with HAMD-24 in MDD patients. Compared with the controls, the serum levels of TBIL, IBIL and the hippocampal ROS contents were elevated in CRS-exposed rats. Fluoxetine lowered inflammatory factor levels, mitigated oxidative stress. CONCLUSION: Our findings indicate a possible correlation between elevated serum bilirubin and depressive symptoms. Increases in ROS levels, along with neuronal damage, may represent pathological mechanisms underlying MDD.

Serum indoleamine 2, 3-dioxygenase and tryptophan-2, 3-dioxygenase: potential biomarkers for the diagnosis of major depressive disorder.

OBJECTIVE: The objective of this study was to observe the changes in the levels of indoleamine 2, 3-dioxygenase (IDO) and tryptophan-2, 3-dioxygenase (TDO) in patients with major depressive disorder (MDD) and investigate their potential role as novel biomarkers for diagnosing MDD. METHODS: A total of 55 MDD patients and 55 healthy controls (HC) were enrolled in the study. The severity of MDD was assessed using the 24-item Hamilton Depression Rating Scale (HAMD-24) before and after treatment. The serum concentrations of IDO and TDO were measured at baseline and after treatment. The correlations between the serum levels of IDO and TDO and HAMD-24 scores were evaluated using Pearson's correlation test. Receiver operating characteristic (ROC) curve analysis was used to evaluate the area under the curve (AUC) of serum levels of IDO and TDO for discriminating MDD patients from HC. RESULTS: The serum IDO and TDO concentrations were significantly higher in patients with MDD at baseline than in healthy controls, and decreased significantly after 2 weeks or 1 month of treatment. The levels of IDO and TDO were significantly positively correlated with HAMD-24 scores. Furthermore, the AUC values for IDO and TDO were 0.999 and 0.966, respectively. CONCLUSION: The study suggests that serum IDO and TDO may serve as novel biomarkers for diagnosing MDD. These findings may lead to a better understanding of the pathogenesis of MDD and the development of new therapeutic targets.

Evaluation of plasma-derived extracellular vesicles miRNAs and their connection with hippocampal mRNAs in alcohol use disorder.

Alcohol use disorder (AUD) is a common mental illness with high morbidity and disability. The discovery of laboratory biomarkers has progressed slowly, resulting in suboptimal diagnosis and treatment of AUD. This study aimed to identify promising biomarkers, as well as the potential miRNA-mRNA networks associated with AUD pathogenesis. RNA sequencing was performed on plasma-derived small extracellular vesicles (sEVs) from AUD patients and healthy controls (HCs) to harvest miRNAs expression profiles. Machine learning (ML) models were built to screen characteristic miRNAs, whose target mRNAs were analyzed using TargetScan, miRanda and miRDB databases. Gene Expression Omnibus (GEO) datasets (GSE181804 and GSE180722) providing postmortem hippocampal gene expression profiles of AUD subjects were mined. A total of 247 differentially expressed (DE) plasma-derived sEVs miRNAs and 122 DE hippocampal mRNAs were obtained. Then, 22 overlapping sEVs miRNAs with high importance scores were gained by intersecting 5 ML models. As a result, we established a putative sEVs miRNA-hippocampal mRNA network that can effectively distinguish AUD patients from HCs. In conclusion, we proposed 5 AUD-representative sEVs miRNAs (hsa-miR-144-5p, hsa-miR-182-5p, hsa-miR-142-5p, hsa-miR-7-5p, and hsa-miR-15b-5p) that may participate in the pathogenesis of AUD by modulating downstream target hippocampal genes. These findings may provide novel insights into the diagnosis and treatment of AUD.

Non-invasive evaluation of endometrial microvessels via in vivo intrauterine photoacoustic endoscopy.

The endometrium microvessel system, responsible for supplying oxygen and nutrients to the embryo, holds significant importance in evaluating endometrial receptivity (ER). Visualizing this system directly can significantly enhance ER evaluation. Currently, clinical methods like Narrow-band hysteroscopy and Color Doppler ultrasound are commonly used for uterine blood vessel examination, but they have limitations in depth or resolution. Endoscopic Photoacoustic Imaging (PAE) has proven effective in visualizing microvessels in the digestive tract, while its adaptation to uterine imaging faces challenges due to the uterus's unique physiological characteristics. This paper for the first time that uses high-resolution PAE in vivo to capture a comprehensive network of endometrial microvessels non-invasively. Followed by continuous observation and quantitative analysis in the endometrial injury model, we further corroborated that PAE detection of endometrial microvessels stands as a valuable indicator for evaluating ER. The PAE system showcases its promising potential for integration into reproductive health assessments.

A stronger association of mental disorders with smaller particulate matter and a modifying effect of air temperature.

Mental disorders (MDs) can be triggered by adverse weather conditions and particulate matter (PM) such as PM2.5 and PM10 (aerodynamic diameter ≤2.5 µm and ≤10 µm). However, there is a dearth of evidence on the role of smaller PM (e.g. PM1, aerodynamic diameter ≤1 µm) and the potential modifying effects of weather conditions. We aimed to collect daily data on emergency department visits and hospitalisations for schizophrenia-, mood-, and stress-related disorders in a densely populated Chinese city (Hefei) between 2016 and 2019. A time-stratified case-crossover analysis was used to examine the short-term association of MDs with PM1, PM2.5, and PM10. The potential modifying effects of air temperature conditions (cold and warm days) were also explored. The three size-fractioned PMs were all associated with an increased risk of MDs; however, the association differed between emergency department visit and hospitalisation. Specifically, PM1 was primarily associated with an increased risk of emergency department visit, whereas PM2.5 was primarily associated with an increased risk of hospitalisation, and PM10 was associated with an increased risk of both emergency department visit and hospitalisation. The PM-MD association appeared to be greatest (although not significant) for PM1 (odds ratio range: 1.014-1.055), followed by PM2.5 (odds ratio range: 1.001-1.009) and PM10 (odds ratio range: 1.001-1.006). Furthermore, the PM-MD association was observed on cold days; notably, the association between PM and schizophrenia-related disorders was significant on both cold and warm days. Our results suggest that the smaller the PM, the greater the risk of MDs, and that the PM-MD association could be determined by air temperature conditions.

In vivo endoscopic optical coherence elastography based on a miniature probe.

Optical coherence elastography (OCE) is a functional extension of optical coherence tomography (OCT). It offers high-resolution elasticity assessment with nanoscale tissue displacement sensitivity and high quantification accuracy, promising to enhance diagnostic precision. However, in vivo endoscopic OCE imaging has not been demonstrated yet, which needs to overcome key challenges related to probe miniaturization, high excitation efficiency and speed. This study presents a novel endoscopic OCE system, achieving the first endoscopic OCE imaging in vivo. The system features the smallest integrated OCE probe with an outer diameter of only 0.9 mm (with a 1.2-mm protective tube during imaging). Utilizing a single 38-MHz high-frequency ultrasound transducer, the system induced rapid deformation in tissues with enhanced excitation efficiency. In phantom studies, the OCE quantification results match well with compression testing results, showing the system's high accuracy. The in vivo imaging of the rat vagina demonstrated the system's capability to detect changes in tissue elasticity continually and distinguish between normal tissue, hematomas, and tissue with increased collagen fibers precisely. This research narrows the gap for the clinical implementation of the endoscopic OCE system, offering the potential for the early diagnosis of intraluminal diseases.

Dysregulation of interleukin-8 is involved in the onset and relapse of schizophrenia: An independent validation and meta-analysis.

As a major mental health disorder, symptoms of schizophrenia (SCZ) include delusions, reduced motivation, hallucinations, reduced motivation and a variety of cognitive disabilities. Many of these symptoms are now known to be associated with abnormal regulation of the immune system. Low blood levels of cytokines and chemokines have been suggested to be one of the underlying causes of SCZ. However, their biological roles at different stages of SCZ remain unclear. Our objective was to investigate expression patterns of cytokines and chemokines at different stages of onset and relapse in SCZ patients and to conduct an analysis of their relationship to disease progression. We also aimed to identify immune features associated with different disease trajectories in patients with SCZ. Gene set enrichment analysis (GSEA) was used to interrogate the GSE27383 dataset and identify key genes associated with inflammation. These results led us to recruit 36 healthy controls, 40 patients with first-episode psychosis (FEP), and 39 patients with SCZ relapse. Meso Scale Discovery technology was used to independently validate serum levels of 35 cytokines and chemokines. This was followed by a meta-analysis to gain a more comprehensive understanding of the role of interleukin-8 (IL-8/CXCL8) in SCZ. Analysis of the GSE27383 database revealed 3596 genes with distinct expression patterns. A significant portion of these genes were identified as inflammation-related and showed remarkable enrichment in three key pathways: IL-17, cytokine-cytokine receptor, and AGE-RAGE signaling in diabetic complications. We observed co-expression of CXCL8 and IL-16 within these three pathways. In a subsequent analysis of independently validated samples, a notable discrepancy was detected in the inflammatory status between individuals experiencing FEP and those in relapse. In particular, expression of CXCL8 demonstrated superior predictive capability in FEP and relapsed patients. Notably, results of the meta-analysis confirmed that Chinese and European populations were consistent with the overall results (Z = 4.60, P < 0.001; Z = 3.70, P < 0.001). However, in the American subgroup, there was no significant difference in CXCL8 levels between patients with SCZ compared to healthy controls (Z = 1.09, P = 0.277). Our findings suggest that the inflammatory response in patients with SCZ differs across the different stages, with CXCL8 emerging as a potential predictive factor. Collectively, our data suggest that CXCL8 has the potential to serve as a significant immunological signature of SCZ subtypes. Trial registration: The clinical registration number for this trial is ChiCTR2100045240 (Registration Date: 2021/04/09).

Potential Role of Bmal1 in Lipopolysaccharide-Induced Depression-Like Behavior and its Associated "Inflammatory Storm".

Inflammation plays an important role in the pathogenesis of depression; however, the underlying mechanisms remain unclear. Apart from the disordered circadian rhythm in animal models and patients with depression, dysfunction of clock genes has been reported to be involved with the progress of inflammation. This study aimed to investigate the role of circadian clock genes, especially brain and muscle ARNT-like 1 (Bmal1), in the linkage between inflammation and depression. Lipopolysaccharide (LPS)-challenged rats and BV2 cells were used in the present study. Four intraperitoneal LPS injections of 0.5 mg/kg were administered once every other day to the rats, and BV2 cells were challenged with LPS for 24 h at the working concentration of 1 mg/L, with or without the suppression of Bmal1 via small interfering RNA. The results showed that LPS could successfully induce depression-like behaviors and an "inflammatory storm" in rats, as indicated by the increased immobility time in the forced swimming test and the decreased saccharin preference index in the saccharin preference test, together with hyperactivity of the hypothalamic-pituitary-adrenal axis, hyperactivation of astrocyte and microglia, and increased peripheral and central abundance of tumor necrosis factor-α, interleukin 6, and C-reactive protein. Moreover, the protein expression levels of brain-derived neurotrophic factor, triggering receptor expressed on myeloid cells 1, Copine6, and Synaptotagmin1 (Syt-1) decreased in the hippocampus and hypothalamus, whereas the expression of triggering receptor expressed on myeloid cells 2 increased. Interestingly, the fluctuation of temperature and serum concentration of melatonin and corticosterone was significantly different between the groups. Furthermore, protein expression levels of the circadian locomotor output cycles kaput, cryptochrome 2, and period 2 was significantly reduced in the hippocampus of LPS-challenged rats, whereas Bmal1 expression was significantly increased in the hippocampus but decreased in the hypothalamus, where it was co-located with neurons, microglia, and astrocytes. Consistently, apart from the reduced cell viability and increased phagocytic ability, LPS-challenged BV2 cells presented a similar trend with the changed protein expression in the hippocampus of the LPS model rats. However, the pathological changes in BV2 cells induced by LPS were reversed after the suppression of Bmal1. These results indicated that LPS could induce depression-like pathological changes, and the underlying mechanism might be partly associated with the imbalanced expression of Bmal1 and its regulated dysfunction of the circadian rhythm.

Peripheral Complement Factor-Based Biomarkers for Patients with First-Episode Schizophrenia.

Objective: Schizophrenia (SCZ) is a severe, protracted neurological disorder that causes disruptive conduct in millions of individuals globally. Discovery of potential biomarkers in clinical settings would lead to the development of efficient diagnostic techniques and an awareness of the disease's pathogenesis and prognosis. The aim of the present study was to discover and identify serum complement factor-based biomarkers in discriminating patients with first-episode SCZ from healthy controls. Methods: Eighty-nine patients with first-episode SCZ and 89 healthy controls were included in this study. Psychiatric symptom severity of patients with SCZ was measured with the Brief Psychiatric Rating Scale-18 Item Version (BPRS) and the Scales for the Assessment of Negative/Positive Symptoms (SANS/SAPS). A total of 5 complement factors including complement component 1 (C1), C2, C3, C4, and 50% hemolytic complement (CH50) were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits. The levels of serum complement factors in the SCZ and control groups were compared, and the receiver operating characteristic (ROC) curve method was used to assess the diagnostic values of various complement factors for separating SCZ patients from healthy controls. Pearson's correlation test was used to assess the relationships between serum complement factor concentrations and the psychiatric symptom severity. Results: There was an increase in serum levels of C1, C2, C3, C4, and CH50 among patients with SCZ. Moreover, based on ROC curve analysis, the AUC value of a combined panel of C1, C2, C3, C4, and CH50 was 0.857 when used to discriminate patients with SCZ from healthy controls. Furthermore, serum C2, C3, and CH50 levels were positively correlated to the scores of SANS, SAPS, and BPRS in patients with SCZ, respectively. Conclusion: These results suggested that circulating complement factors including C1, C2, C3, C4, and CH50 may have potential in discovering biomarkers for diagnosing first-episode SCZ.

Serum cytokines-based biomarkers in the diagnosis and monitoring of therapeutic response in patients with major depressive disorder.

BACKGROUND: Several lines of evidence have suggested that cytokines are implicated in the pathophysiology of depression and antidepressant treatment outcome. However, the results are not always congruent and partly contradictory. We therefore examined the serum levels of multiple cytokines in patients with major depressive disorder (MDD), with the aim to identify serum cytokines-based biomarkers for MDD diagnosis and antidepressant response. METHODS: Fifty-nine patients with MDD and 61 healthy controls were included. The baseline levels of serum cytokines between MDD group and control group were compared, and the discriminative ability of different cytokines in predicting MDD patients from healthy controls was investigated using the receiver operating characteristic (ROC) curve method. The baseline levels of serum cytokines between antidepressant nonresponders and responders were compared, and the discriminative ability of different cytokines in predicting nonresponders from responders was evaluated using the ROC curve method. RESULTS: Compared to controls, 15 of the 37 serum cytokines were increased, while 8 cytokines were decreased in MDD patients (all P < 0.05). The results of ROC curve showed that the Area Under Curve (AUC) values of 15 cytokines including IL-2, IL-5, IL-6, IL-8, IL-12, IL-13, IL-16, CCL3, CCL4, CCL17, CXCL10, TNF-α, TNF-ß, VEGF-C, and FGF basic were greater than 0.7 in discriminating MDD patients from healthy control. Moreover, after 4-week treatment, levels of the 2 cytokines (IL-12 and TSLP) elevated at baseline significantly down-regulated, and levels of the 6 cytokines (IL-5, IL-16, CCL17, CXCL10, TNF-ß, and PIGF) decreased at baseline significantly up-regulated (all P < 0.05). Furthermore, a positive relationship was found between TNF-α levels and Hamilton Depression Rating Scale-24 (HAMD-24) scores in patients with MDD at baseline (r = 0.302, P = 0.019). Additionally, compared to responders, nonresponders exhibited decreased levels of IL-1α, IL-5, IL-13, IL-15, VEGF, and ICAM-1 (all P < 0.05). The ROC curve analysis demonstrated that a combined panel of IL-1α, IL-5, and ICAM-1 achieved a high accuracy in discriminating antidepressant nonresponders from responders (AUC = 0.850, sensitivity = 83.3%, specificity = 81.8%). CONCLUSIONS: These results suggested that alterations in peripheral cytokines levels hold significant promise as biomarkers for MDD diagnosis and antidepressant response.

Functional roles, regulatory mechanisms and theranostics applications of ncRNAs in alcohol use disorder.

Alcohol use disorder (AUD) is one of the most prevalent neuropsychological disorders worldwide, and its pathogenesis is convoluted and poorly understood. There is considerable evidence demonstrating significant associations between multiple heritable factors and the onset and progression of AUD. In recent years, a substantial body of research conducted by emerging biotechnologies has increasingly highlighted the crucial roles of noncoding RNAs (ncRNAs) in the pathophysiology of mental diseases. As in-depth understanding of ncRNAs and their mechanisms of action, they have emerged as prospective diagnostic indicators and preclinical therapeutic targets for a variety of psychiatric illness, including AUD. Of note, dysregulated expression of ncRNAs such as circRNAs, lncRNAs and miRNAs was routinely found in AUD individuals, and besides, exogenous regulation of partial ncRNAs has also been shown to be effective in ameliorating alcohol preference and excessive alcohol consumption. However, the exact molecular mechanism still remains elusive. Herein, we systematically summarized current knowledge regarding alterations in the expression of certain ncRNAs as well as their-mediated regulatory mechanisms in individuals with AUD. And finally, we detailedly reviewed the potential theranostics applications of gene therapy agents targeting ncRNAs in AUD mice. Overall, a deeper comprehension of functional roles and biological mechanisms of ncRNAs may make significant contributions to the accurate diagnosis and effective treatment of AUD.

Potential value of Interleukin-6 as a diagnostic biomarker in human MDD and the antidepressant effect of its receptor antagonist tocilizumab in lipopolysaccharide-challenged rats.

Depression is a common mental disease with disastrous effect on the health and wealth globally. Focusing on the role for inflammation and immune activation in the pathogenesis of depression, many tries have been taken into effect targeting at the blockage of inflammatory cytokines, among which interleukin- 6 (IL-6) and its receptor antagonist tocilizumab attracts more attention, with inconsistent findings. Moderate to severe depressive disorder (MSDD) patients were enrolled and the serum concentrations of IL-6 and tumor necrosis factor-α (TNF-α) measured, their correlation with the Hamilton Depression Rating Scale-24 (HAMD-24) scores was analyzed, and their role in discriminating MSDD patients from the health controls were evaluated. Meanwhile, a depression rat model was established by intraperitoneal injection of LPS, and tocilizumab was administrated doing 50 mg/kg via intravenous injection. The behavioral performance was observed, the serum concentration of IL-6, TNF-α, and C-reactive protein (CRP) was measured, and the protein expression of IL-6 and TNF-α in the hippocampus were also detected. The activity of the Hypothalamic-pituitary-adrenal (HPA) axis was observed, and the protein expression levels in the hippocampus were detected via western blot. Moreover, the immunofluorescence staining (IF) technique was used to investigate the co-location of IL-6 and neuron (MAP2), astrocyte (GFAP), or microglial (IBA-1). The results showed that the serum IL-6 level was significantly increased in the MSDD patients and lipopolysaccharide (LPS)-challenged rats, with a significant correlation with the HAMD-24 scores or struggling time in the FST and corticosterone (CORT) abundance. Results of ROC analysis showed a significant diagnosis value of IL-6 in discriminating MSDD patients or depression rats from the controls in the present study. Tocilizumab could relieve the depression-like behaviors induced by LPS, together with a normal abundance of serum CORT and hypothalamic CRH expression. Moreover, tocilizumab could alleviate the "inflammatory storm" and impaired hippocampal synaptic plasticity in LPS-challenged depression rats, inhibiting the hyperactivation of astrocyte and microglia, decreasing the peripheral and central abundance of IL-6, CRP, and TNF-α, and balancing the hippocampal expression levels of synaptic plasticity-associated proteins and key molecular in Wnt/ß-catenin signaling pathway. These results indicated a predictive role of IL-6 in discriminating depression from controls, and demonstrated an antidepressant effect of tocilizumab in LPS-challenged rats, targeting at the inflammatory storm and the subsequent impairments of hippocampal synaptic plasticity.