RETN gene polymorphisms interact with alcohol dependence in association with depression.

BACKGROUND: Previous studies suggest that alcohol dependence is associated with increased risk of depression. The occurrence of depressive symptoms is related to polymorphisms in various genetic regions. This study aimed to investigate the interaction of RETN gene polymorphisms (rs1477341, rs3745368) with alcohol dependence on depressive symptoms in adult male during acute alcohol withdrawal. METHODS: A total of 429 male adults were recruited in this study. Alcohol dependence was assessed using the Michigan alcoholism screening test (MAST). Depression was assessed using the 20-item self-rating depression scale (SDS). Hierarchical regression analysis was used to evaluate the interaction between genes and alcohol dependence on depression. Region of significance (ROS) test was used to explain the interaction effect. The strong and weak forms of the differential susceptibility and diathesis models were used to determine which fits the data better. RESULTS: Our results showed that MAST scores were significantly positively associated with SDS scores (r = 0.23, p < 0.01) in alcohol-dependent patients during alcohol withdrawal. The interaction between genotype and alcohol dependence was significant (ß = -0.14, p < 0.05) in a strong diathesis-stress model. Susceptibility for depression symptoms was associated with alcohol dependence in RETN rs1477341 A carriers. Specifically, those that showed more alcohol dependence and the A allele of RETN rs1477341 exhibited more depression symptoms. However, RETN rs3745368 had no significant interaction with alcohol dependence. CONCLUSIONS: The A allele of RETN rs1477341 may correlate with susceptibility to depression symptoms in alcohol-dependent individuals during acute alcohol withdrawal.

Fibroblast growth factor 21 associating with serotonin and dopamine in the cerebrospinal fluid predicts impulsivity in healthy subjects.

BACKGROUND: Impulsivity is more commonly reported in subjects with mental disorders compared to healthy subjects, suggesting a potential application of impulsivity in predicting impulsivity-related mental disorders. However, no biomarker of impulsivity available so far. This study explored the association between cerebrospinal fluid (CSF) fibroblast growth factor 21 (FGF21), a key hormonal mediator of the stress response, and impulsivity in healthy subjects. METHODS: A total of 126 healthy persons subjected to surgery of anterior cruciate ligament were recruited in the present study. The impulsiveness of the subjects was evaluated by the Chinese version of the Barratt Impulsiveness Scale (BIS)-11 before surgery. CSF and blood samples of the subjects were collected before spinal anesthesia for surgery. The levels of FGF21, serotonin and dopamine in CSF and the level of FGF21 in blood of the subjects were measured by ELISA using commercial kits. RESULTS: Negative correlations were found between BIS-11 total score and either FGF21, serotonin or dopamine in CSF. However, BIS-11 total score was not correlated with FGF21 in blood. In addition, FGF21 was positively correlated with serotonin and dopamine in CSF, respectively. Multivariable linear regression models indicated that the decrease of FGF21 level associating with the decrease of serotonin and dopamine level in CSF contributed to the higher impulsivity. Furthermore, receiver operating characteristic curve (ROC) analysis indicated an important role of CSF FGF21 predicting high impulsivity. CONCLUSIONS: FGF21, serotonin and dopamine in CSF associate with impulsivity in opposite directions. The decrease of CSF FGF21 is related to higher impulsivity, and indicate that CSF FGF21 may predict impulsivity in healthy subjects.

Lower serum nicotinamide N-methyltransferase levels in patients with bipolar disorder during acute episodes compared to healthy controls: a cross-sectional study.

BACKGROUND: Nicotinamide N-methyltransferase (NNMT) has been implicated in the pathogenesis of neuropsychiatric diseases. Bipolar disorder (BD) is associated with metabolic abnormalities and NNMT regulates energy metabolism and may also exert a causal role in metabolic disorders. The present study aimed to determine serum NNMT levels in patients with BD and compared the results with that of healthy controls, to explore the correlation between NNMT and clinical and metabolic characteristics. METHODS: The NNMT levels of 80 patients having a manic episode of BD and 65 non-psychiatric control individuals were measured using enzyme-linked immunosorbent assay. Metabolic parameters were evaluated using standard laboratory methods. RESULTS: The serum NNMT levels of bipolar mania patients were significantly lower than that of non-psychiatric controls. Furthermore, the serum levels of NNMT were found to be negatively correlated with Young Mania Rating Scale (YMRS) scores and the duration of the illness. Moreover, lower NNMT serum levels were found in patients with a history of antipsychotic medication and dyslipidemia. Our results also demonstrated the different patterns of correlation that exist between the study groups. Serum NNMT levels were found to be negatively correlated with triglyceride, cholesterol, and apolipoprotein B levels in the BD group, while the same was found to be negatively associated only with high-density lipoprotein cholesterol in the control group. CONCLUSIONS: These findings support the suggestion that lower NNMT serum levels are significantly associated with BD and that serum NNMT has the potential to regulate lipid metabolism in BD patients.

Partial splenic embolization of patients with hypersplenism by transradial or transfemoral approach: a prospective randomized controlled trial.

BACKGROUND: Partial splenic artery embolization (PSE) is an effective treatment modality for patients with hypersplenism. It is less invasive and has a quicker recovery compared with surgical procedures. PSE is usually performed using a femoral artery approach that requires bedrest for a few hours, which is rarely the case for transradial PSE. PURPOSE: To compare the transradial and transfemoral approaches for embolization of spleen in patients with hypersplenism. MATERIAL AND METHODS: In all, 84 patients with hypersplenism who required PSE were recruited. They were randomly divided into two groups on the basis of the procedure followed: the transradial approach (R-PSE, n = 39) or transfemoral approach (F-PSE, n = 45). Technical success, puncture rate, total procedure time, X-ray exposure time, length of stay in hospital (LOS), and complications of the two groups were recorded. RESULTS: The procedure time, X-ray exposure time, and LOS were found to be lower in the R-PSE group than in the F-PSE. However, this difference was not statistically significant. CONCLUSION: The transradial artery approach for PSE in patients with hypersplenism is feasible with no major complications as compared to the femoral approach.

The Therapeutic Effect of Stellate Ganglion Block on Facial Nerve Palsy in Patients with Type 2 Diabetes Mellitus.

BACKGROUND/AIMS: The conventional systemic corticosteroid treatment for acute peripheral facial nerve palsy in patients with type 2 diabetes mellitus can induce hyperglycemia, and an alternative local therapy may be necessary. Our purpose in this study is to evaluate therapeutic effects of stellate ganglion block (SGB) on facial nerve palsy in patients with type 2 diabetes mellitus. METHODS: A total of 361 cases of acute peripheral, chronic peripheral, acute central and chronic central facial nerve palsy treated with SGB or conventional therapy were included in this retrospective study. The facial nerve function score (Sunnybrook Facial Grading System) obtained at before and after treatment in non-SGB and SGB groups was used to assess the outcome. Furthermore, the blood glucose level in acute peripheral facial nerve palsy was measured. RESULTS: The facial nerve function score in the SGB group was higher than that in the non-SGB group after treatment in peripheral facial nerve palsy, while the blood glucose level in the non-SGB group increased and was higher than that in the SGB group during the treatment in acute peripheral facial nerve palsy. CONCLUSIONS: Our findings suggest that SGB has better therapeutic effect than conventional treatment on acute and chronic peripheral facial nerve palsy in patients with type 2 diabetes mellitus.

Astrocyte-dependent protective effect of quetiapine on GABAergic neuron is associated with the prevention of anxiety-like behaviors in aging mice after long-term treatment.

Previous studies have demonstrated that quetiapine (QTP) may have neuroprotective properties; however, the underlying mechanisms have not been fully elucidated. In this study, we identified a novel mechanism by which QTP increased the synthesis of ATP in astrocytes and protected GABAergic neurons from aging-induced death. In 12-month-old mice, QTP significantly improved cell number of GABAegic neurons in the cortex and ameliorated anxiety-like behaviors compared to control group. Complimentary in vitro studies showed that QTP had no direct effect on the survival of aging GABAergic neurons in culture. Astrocyte-conditioned medium (ACM) pretreated with QTP (ACMQTP) for 24 h effectively protected GABAergic neurons against aging-induced spontaneous cell death. It was also found that QTP boosted the synthesis of ATP from cultured astrocytes after 24 h of treatment, which might be responsible for the protective effects on neurons. Consistent with the above findings, a Rhodamine 123 test showed that ACMQTP, not QTP itself, was able to prevent the decrease in mitochondrial membrane potential in the aging neurons. For the first time, our study has provided evidence that astrocytes may be the conduit through which QTP is able to exert its neuroprotective effects on GABAergic neurons. The neuroprotective properties of quetiapine (QTP) have not been fully understood. Here, we identify a novel mechanism by which QTP increases the synthesis of ATP in astrocytes and protects GABAergic neurons from aging-induced death in a primary cell culture model. In 12-month-old mice, QTP significantly improves cell number of GABAegic neurons and ameliorates anxiety-like behaviors. Our study indicates that astrocytes may be the conduit through which QTP exerts its neuroprotective effects on GABAergic neurons.

Desvenlafaxine prevents white matter injury and improves the decreased phosphorylation of the rate-limiting enzyme of cholesterol synthesis in a chronic mouse model of depression.

Serotonin/norepinephrine reuptake inhibitors antidepressants exert their effects by increasing serotonin and norepinephrine in the synaptic cleft. Studies show it takes 2-3 weeks for the mood-enhancing effects, which indicate other mechanisms may underlie their treatment effects. Here, we investigated the role of white matter in treatment and pathogenesis of depression using an unpredictable chronic mild stress (UCMS) mouse model. Desvenlafaxine (DVS) was orally administrated to UCMS mice at the dose of 10 mg/kg/day 1 week before they went through a 7-week stress procedure and lasted for over 8 weeks before the mice were killed. No significant changes were found for protein markers of neurons and astrocytes in UCMS mice. However, myelin and oligodendrocyte-related proteins were significantly reduced in UCMS mice. DVS prevented the stress-induced injury to white matter and the decrease of phosphorylated 5'-AMP-activated protein kinase and 3-hydroxy-3-methyl-glutaryl-CoA reductase protein expression. DVS increased open arm entries in an elevated plus-maze test, sucrose consumption in the sucrose preference test and decreased immobility in tail suspension and forced swimming tests. These findings suggest that stress induces depression-like behaviors and white matter deficits in UCMS mice. DVS may ameliorate the oligodendrocyte dysfunction by affecting cholesterol synthesis, alleviating the depression-like phenotypes in these mice. We examined the possible role of oligodendrocyte and myelin in the pathological changes of depression with an unpredictable chronic mild stress (UCMS) mouse model. Oligodendrocyte-related proteins in the mouse brain were specifically changed during the stress period. The depressive-like behaviors and oligodendrocyte deficits could be prevented by the administration of desvenlafaxine. Oligodendrocyte and myelin may be an essential target of desvenlafaxine for the treatment of depression.

Quetiapine attenuates glial activation and proinflammatory cytokines in APP/PS1 transgenic mice via inhibition of nuclear factor-κB pathway.

BACKGROUND: In Alzheimer's disease, growing evidence has shown that uncontrolled glial activation and neuroinflammation may contribute independently to neurodegeneration. Antiinflammatory strategies might provide benefits for this devastating disease. The aims of the present study are to address the issue of whether glial activation and proinflammatory cytokine increases could be modulated by quetiapine in vivo and in vitro and to explore the underlying mechanism. METHODS: Four-month-old amyloid precursor protein (APP) and presenilin 1 (PS1) transgenic and nontransgenic mice were treated with quetiapine (5mg/kg/d) in drinking water for 8 months. Animal behaviors, total Aß levels, and glial activation were evaluated by behavioral tests, enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot accordingly. Inflammatory cytokines and the nuclear factor kappa B pathway were analyzed in vivo and in vitro. RESULTS: Quetiapine improves behavioral performance, marginally affects total Aß40 and Aß42 levels, attenuates glial activation, and reduces proinflammatory cytokines in APP/PS1 mice. Quetiapine suppresses Aß1-42-induced activation of primary microglia by decresing proinflammatory cytokines. Quetiapine inhibits the activation of nuclear factor kappa B p65 pathway in both transgenic mice and primary microglia stimulated by Aß1-42. CONCLUSIONS: The antiinflammatory effects of quetiapine in Alzheimer's disease may be involved in the nuclear factor kappa B pathway. Quetiapine may be an efficacious and promising treatment for Alzheimer's disease targeting on neuroinflammation.

Chronic phencyclidine induces inflammatory responses and activates GSK3ß in mice.

Use of phencyclidine (PCP) in rodents can mimic some aspects of schizophrenia. However, the underlying mechanism is still unclear. Growing evidence indicates that neuroinflammation plays a significant role in the pathophysiology of schizophrenia. In this study, we focused on inflammatory responses as target of PCP for inducing schizophrenia-like symptoms. 3-month-old C57BL/6J mice received daily injections of PCP (20 mg/kg, i.p.) or saline for one week. PCP-injected mice produced schizophrenia-like behaviours including impaired spatial short-term memory assessed by the Y-maze task and sensorimotor gating deficits in a prepulse inhibition task. Simultaneously, chronic PCP administration induced astrocyte and microglial activation in both the cortex and hippocampus. Additionally, the proinflammatory cytokine interleukin-1ß was significantly up-regulated in PCP administrated mice. Furthermore, PCP treatment decreased ratio of the phospho-Ser9 epitope of glycogen synthase kinase-3ß (GSK3ß) over total GSK3ß, which is indicative of increased GSK3ß activity. These data demonstrate that chronic PCP in mouse produces inflammatory responses and GSK3ß activation.

A Mendelian randomization study of the entire phenome to explore the causal links between epilepsy.

OBJECTIVE: The causes and triggering factors of epilepsy are still unknown. The results of genome-wide association studies can be utilized for a phenome-wide association study using Mendelian randomization (MR) to identify potential risk factors for epilepsy. METHODS: This study utilizes two-sample MR analysis to investigate whether 316 phenotypes, including lifestyle, environmental factors, blood biomarker, and more, are causally associated with the occurrence of epilepsy. The primary analysis employed the inverse variance weighted (IVW) model, while complementary MR analysis methods (MR Egger, Wald ratio) were also employed. Sensitivity analyses were also conducted to evaluate heterogeneity and pleiotropy. RESULTS: There was no evidence of a statistically significant causal association between the examined phenotypes and epilepsy following Bonferroni correction (p < 1.58 × 10-4) or false discovery rate correction. The results of the MR analysis indicate that the frequency of tiredness or lethargy in the last 2 weeks (p = 0.042), blood uridine (p = 0.003), blood propionylcarnitine (p = 0.041), and free cholesterol (p = 0.044) are suggestive causal risks for epilepsy. Lifestyle choices, such as sleep duration and alcohol consumption, as well as biomarkers including steroid hormone levels, hippocampal volume, and amygdala volume were not identified as causal factors for developing epilepsy (p > 0.05). CONCLUSIONS: Our study provides additional insights into the underlying causes of epilepsy, which will serve as evidence for the prevention and control of epilepsy. The associations observed in epidemiological studies may be partially attributed to shared biological factors or lifestyle confounders.

Mechanism of cognitive impairment and white matter damage in the MK-801 mice model of schizophrenia treated with quetiapine.

Schizophrenia has been linked to cognitive impairment and white matter damage in a growing number of studies this year. In this study, we used the MK-801-induced schizophrenia-like mice model to investigate the effects of quetiapine on behavioral changes and myelin loss in the model mice. The subjects selected for this study were C57B6/J male mice, MK-801 (1 mg/kg/d intraperitoneal injection) modeling for 1 week and quetiapine (10 mg/kg/d intraperitoneal injection) treatment for 2 weeks. Behavioral tests were then performed using the three-chamber paradigm test and the Y maze test. Moreover, western blot, immunohistochemistry, and immunofluorescence were conducted to investigate the changes in oligodendrocyte spectrum markers. In addition, we performed some mechanism-related proteins by western blot. Quetiapine ameliorated cognitive impairment and cerebral white matter damage in MK-801 model mice, and the mechanism may be related to the PI3K/AKT pathways. The present study suggests that quetiapine has a possible mechanism for treating cognitive impairment and white matter damage caused by schizophrenia.

Repetitive transcranial magnetic stimulation and fluoxetine attenuate astroglial activation and benefit behaviours in a chronic unpredictable mild stress mouse model of depression.

Objectives: Repetitive transcranial magnetic stimulation (rTMS) has been considered as an effective antidepressant treatment; however, the mechanism of its antidepressant effect is still unclear. Fluoxetine, a selective serotonin reuptake inhibitor antidepressant, may be neuroprotective. The objective of the present study was to evaluate the effect and underlying possible neuroprotective mechanism of rTMS and fluoxetine on abnormal behaviours in a depressive mouse model induced by chronic unpredictable mild stress (CUMS).Methods: After 28 days of CUMS exposure, mice were chronically treated with rTMS (10 Hz for 5 s per train, total 20 trains per day) and (or) fluoxetine (5 mg/kg/day, intraperitoneally) for 28 days targeting on the frontal cortex. After the behavioural tests, the protein expressions of glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) were measured by immunohistochemistry and (or) Western Blot.Results: The results showed rTMS and (or) fluoxetine attenuated the locomotion decrease, anxiety and depressive like behaviours in the CUMS-exposed mice.Conclusion: Our results suggest that both rTMS and fluoxetine could benefit the CUMS-induced abnormal behaviours including depressive-like behaviours, and the beneficial effects of rTMS as well as fluoxetine on depression might be partly related to their neuroprotective effect on attenuating astroglial activation and BDNF decrease.

Changes in metabolic hormones and trace elements in CSF in active smokers indicate oxidative damage to brain cells.

Objective: This study aimed to reveal associations between metabolic hormones in cerebral spinal fluid (CSF) and cigarette smoking-induced weight gain and to explore the underlying mechanism. Methods: A total of 156 adult men were included, comprising active smokers and nonsmokers. In addition to demographic information and body mass index (BMI), plasma levels of ApoA1 and ApoB, high-density lipoprotein, low-density lipoprotein, cholesterol, triglyceride, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase in the participants were measured. Moreover, the metabolic hormones adiponectin, fibroblast growth factor 21 (FGF21), ghrelin, leptin, and orexin A, as well as the trace elements iron and zinc in CSF, were assessed. Results: Compared to nonsmokers, active smokers showed higher BMI, and elevated CSF levels of FGF21, Zn, and Fe, but decreased levels of metabolic hormones adiponectin, ghrelin, leptin, and orexin A. Negative correlations existed between CSF FGF21 and ghrelin, between CSF Zn and ghrelin, as well as between CSF Fe and orexin A in active smokers. Furthermore, elevated CSF FGF21 and Zn predicted ghrelin level decrease in the smokers. Conclusion: These data relate smoking-induced weight gain to its neurotoxic effect on the neurons that synthesize metabolic hormones such as adiponectin, ghrelin, leptin, or orexin A in the brain, by disrupting mitochondrial function and causing oxidative stress in the neurons.

[Study on MSO/GO-based determination method for trace amount of aqueous Hg2+].

OBJECTIVE: To establish a highly sensitive fluorometric nanobiosensor for determination of aqueous mercury ions (Hg(2+)) using optimized mercury-specific oligonucleotide (MSO) probes and graphene oxide (GO). METHODS: The nanobiosensor was assembled by attaching the self-designed MSO(1) (5' end labeled with fluorophore carboxyfluorescein (FAM), denoted as FAM-MSO(1)) and MSO(2) to the surface of GO through strong non-covalent bonding forces. Upon the addition of Hg(2+), the formation of the T-Hg(2+)-T configuration desorbed the FAM-MSO(1) and MSO(2) from the surface of GO, resulting in a restoration of the fluorescence of FAM-MSO(1). Using the specific mispairing of T-Hg(2+)-T and the changes in fluorescent signals in solutions, quantitative analysis of Hg(2+) could be performed. RESULTS: The average thickness of the prepared GO sheets was only 1.4 nm. For the Hg(2+) nanobiosensor, the optimum concentrations of FAM-MSO(1) and MSO(2) were both 1 µmol/L, the optimum volume of 0.5 g/L GO was 5 µL, and the limit of detection was 10 pmol/L; it had low cross-reactivity with 10 other kinds of non-specific metal ions; the fluorescence recovery efficiency was up to 65% in the re-determination of Hg(2+) after addition of Na(2)S(2)O(3). CONCLUSION: The MSO/GO-based nanobiosensor is convenient to operate, highly sensitive, highly specific, highly accurate, and reusable. It can be applied to determine trace amount of Hg(2+) in aqueous solutions.

An examination of Alzheimer's disease and white matter from 1981 to 2023: a Bibliometric and visual analysis.

Background: Alzheimer's disease (AD) is characterized by the presence of gray matter lesions and alterations in white matter. This study aims to investigate the research related to white matter in the context of AD from a Bibliometric standpoint. Methods: Regular and review articles focusing on the research pertaining to Alzheimer's disease (AD) and white matter were extracted from the Web of Science Core Collection (WOSCC) database, covering the period from its inception to 10th July 2023. The "Bibliometrix" R package was employed to summarize key findings, to quantify the occurrence of top keywords, and to visualize the collaborative network among countries. Furthermore, VOSviewer software was utilized to conduct co-authorship and co-occurrence analyses. CiteSpace was employed to identify the most influential references and keywords based on their citation bursts. The retrieval of AD- and white matter-related publications was conducted by the Web of Science Core Collection. Bibliometric analysis and visualization, including the examination of annual publication distribution, prominent countries, active institutions and authors, core journals, co-cited references, and keywords, were carried out by using VOSviewer, CiteSpace, the Bibliometrix Package, and the ggplot2 Package. The quality and impact of publications were assessed using the total global citation score and total local citation score. Results: A total of 5,714 publications addressing the intersection of Alzheimer's disease (AD) and white matter were included in the analysis. The majority of publications originated from the United States, China, and the United Kingdom. Prominent journals were heavily featured in the publication output. In addition to "Alzheimer's disease" and "white matter," "mild cognitive impairment," "MRI" and "atrophy" had been frequently utilized as "keywords." Conclusion: This Bibliometric investigation delineated a foundational knowledge framework that encompasses countries, institutions, authors, journals, and articles within the AD and white matter research domain spanning from 1981 to 2023. The outcomes provide a comprehensive perspective on the broader landscape of this research field.

Quetiapine prevents oligodendrocyte and myelin loss and promotes maturation of oligodendrocyte progenitors in the hippocampus of global cerebral ischemia mice.

White matter impairment is a feature of vascular depression. The anti-psychotic quetiapine has been shown to enhance the therapeutic effects of anti-depressants on vascular depression, but the mechanism remains unknown. In this study, we found that 2 weeks of treatment with quetiapine prior to bilateral carotid artery occlusion and reperfusion, in an animal model of vascular depression, resulted in reduced myelin breakdown and oligodendrocyte loss compared to placebo-treated mice on post-operative day (POD) 7. For late stage of recovery (POD40), quetiapine treatment resulted in enhanced oligodendrocyte maturation relative to placebo. The results suggest that quetiapine is a potential intervention for oligodendrocyte damage and this may contribute to its anti-depressant effects through white matter protection in vascular depression.

Hyperforin promotes mitochondrial function and development of oligodendrocytes.

St. John's wort has been found to be an effective and safe herbal treatment for depression in several clinical trials. However, the underlying mechanism of its therapeutic effects is unclear. Recent studies show that the loss and malfunction of oligodendrocytes are closely related to the neuropathological changes in depression, which can be reversed by antidepressant treatment. In this study, we evaluated the effects of hyperforin, a major active component of St. John's wort, on the proliferation, development and mitochondrial function of oligodendrocytes. The study results revealed that hyperforin promotes maturation of oligodendrocytes and increases mitochondrial function without affecting proliferation of an oligodendrocyte progenitor cell line and neural stem/progenitor cells. Hyperforin also prevented mitochondrial toxin-induced cytotoxicity in an oligodendrocyte progenitor cell line. These findings suggest that hyperforin may stimulate the development and function of oligodendrocytes, which could be a mechanism of its effect in depression. Future in vitro and in vivo studies are required to further characterize the mechanisms of hyperforin.

TELO2 induced progression of colorectal cancer by binding with RICTOR through mTORC2.

Colorectal cancer (CRC) is a common cancer worldwide, and its treatment strategies are limited. The underlying mechanism of CRC progression remains to be determined. Telomere maintenance 2 (TELO2) is a mTOR­interacting protein. Both the role and molecular mechanism of TELO2 in cancer progression remain unknown. In this study, the gene expression database of normal and tumor tissue, in addition to western blot analysis, and immunohistochemistry (IHC) were used to determine the expression and location of TELO2 in CRC and normal tissues. Clinical features of a tissue array were collected and analyzed. WST­1, soft agar, flow cytometry, wound healing, and invasion assays were employed to verify the role of TELO2 in the growth, cell cycle, migration, and invasion of CRC cells. The correlation between TELO2 and RICTOR (rapamycin­insensitive companion of mTOR) was analyzed by bioinformatics, IHC, and immunoprecipitation. Normal and serum­deprived cells were collected to detect the protein level of TELO2 and its downstream effectors. The results revealed that TELO2 was significantly upregulated in CRC, and TELO2 inhibition significantly restrained the growth, cell cycle, and metastasis of CRC cells. TELO2 overexpression correlated with age, lymph node metastasis, and TNM stage of CRC patients. In addition, TELO2 was positively correlated with RICTOR in CRC and induced tumor progression mainly via RICTOR with serum in culture. RICTOR induced the degradation of TELO2 upon serum deprivation in an mTOR­independent manner. These findings indicate that TELO2 promotes tumor progression via RICTOR in a serum­dependent manner, which may be a potential therapeutic target for CRC.

The Interaction of Single Nucleotide Polymorphisms on Fibroblast Growth Factor 19 Superfamily Genes Is Associated With Alcohol Dependence-Related Aggression.

Alcohol dependence (AD) is characterized by compulsive alcohol consumption, which involves behavioral impairments such as aggression. Members of fibroblast growth factor (FGF) 19 superfamily, including FGF19, FGF21, and FGF23, are major endocrine mediators that play an important role in alcohol metabolism and alcohol related disorders. The objective of the present study is to explore the possible associations among the interaction of single nucleotide polymorphisms (SNPs) of the FGF 19 superfamily, AD occurrence, and aggression in patients with AD. A total of 956 subjects were enrolled in this study, including 482 AD patients and 474 healthy controls (HCs). Michigan alcoholism screening test (MAST) was used to measure the level of AD, a Chinese version of the Buss-Perry Aggression Questionnaire was used to evaluate the aggressive behavior of subjects, and MassARRAY@ system was used to genotype rs948992 of FGF19, rs11665841 and rs11665896 of FGF21, rs7955866 and rs11063118 of FGF23. The results showed that AD patients presented a significantly higher level of aggression compared to HCs, and MAST scores were significantly positively associated Buss-Perry aggression scores (r = 0.402, p < 0.001) in AD patients. The interaction of FGF19 rs948992 TC × FGF21 rs11665896 GG presented the high-risk genotype combination predicting the high level of AD. In addition, the interaction of FGF19 rs948992 TC × FGF21 rs11665896 TG × FGF23 rs11063118 TT presented the high-risk genotype combination predicting the high level of aggression in AD patients. Our results added evidence linking the combination of rs948992 TC × rs11665896 TG × rs11063118 TT to aggressive behavior in AD patients and pointed out the potential usefulness of the SNPs of FGF19 superfamily as a predictor for the aggression in AD patients.

Chronic effects of venlafaxine on synaptophysin and neuronal cell adhesion molecule in the hippocampus of cerebral ischemic mice.

Venlafaxine, a novel antidepressant, inhibits serontonin and norepinephrine reuptake in the presynaptic cleft. Unlike typical selective serontonin reuptake inhibitors (SSRIs), venlafaxine may have modulatory effects on nerve terminals and neuronal plasticity. Our preliminary data found that 5 mg.kg-1.d-1 of venlafaxine treatment prevented decreased synaptophysin (SYP) in the hippocampus, which results from chronic restrained stress in the rat model. The present study investigates whether venlafaxine regulates alterations of synaptophysin and neuronal cell adhesion molecule (NCAM) in a post-stroke depression mouse model. We compared the expression level of SYP and NCAM in the hippocampus of global cerebral ischemic (GCI) mice treated with different doses of venlafaxine using immunohistological and Western blot analysis. Pre-treatment with intraperitoneal injection of venlafaxine (2.5 and 5.0 mg.kg-1.d-1) for 14 days significantly prevented the decrease of SYP in the hilus area of the hippocampus in vehicle-treated GCI mice. NCAM was significantly higher in the hippocampus of vehicle-treated GCI mice, and pretreatment with venlafaxine prevented alterations of NCAM, with the high-dose venlafaxine group comparable with vehicle-sham mice. The results suggest the alteration of neuronal remodeling proteins in the hippocampus may be an underlying mechanism of venlafaxine in treating post-stroke depression.