Mouse KL2 is a unique MTSE involved in chromosome-based spindle organization and regulated by multiple kinases during female meiosis.

Microtubule-severing enzymes (MTSEs) play important roles in mitosis and meiosis of the primitive organisms. However, no studies have assessed their roles in mammalian meiosis of females, whose abnormality accounts for over 80% of the cases of gamete-originated human reproductive disease. In the current study, we reported that katanin-like 2 (KL2) was the only MTSE concentrating at chromosomes. Furthermore, the knockdown of KL2 significantly reduced chromosome-based increase in the microtubule (MT) polymer, increased aberrant kinetochore-MT (K-MT) attachment, delayed meiosis, and severely affected normal fertility. Importantly, we demonstrated that the inhibition of aurora B, a key kinase for correcting aberrant K-MT attachment, eliminated KL2 from chromosomes completely. KL2 also interacted with phosphorylated eukaryotic elongation factor-2 kinase; they competed for chromosome binding. We also observed that the phosphorylated KL2 was localized at spindle poles, and that KL2 phosphorylation was regulated by extracellular signal-regulated kinase 1/2. In summary, our study reveals a novel function of MTSEs in mammalian female meiosis and demonstrates that multiple kinases coordinate to regulate the levels of KL2 at chromosomes.

NLRP4E regulates actin cap formation through SRC and CDC42 during oocyte meiosis.

BACKGROUND: Members of the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing (NLRP) family regulate various physiological and pathological processes. However, none have been shown to regulate actin cap formation or spindle translocation during the asymmetric division of oocyte meiosis I. NLRP4E has been reported as a candidate protein in female fertility, but its function is unknown. METHODS: Immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), and western blotting were employed to examine the localization and expression levels of NLRP4E and related proteins in mouse oocytes. small interfering RNA (siRNA) and antibody transfection were used to knock down NLRP4E and other proteins. Immunoprecipitation (IP)-mass spectrometry was used to identify the potential proteins interacting with NLRP4E. Coimmunoprecipitation (Co-IP) was used to verify the protein interactions. Wild type (WT) or mutant NLRP4E messenger RNA (mRNA) was injected into oocytes for rescue experiments. In vitro phosphorylation was employed to examine the activation of steroid receptor coactivator (SRC) by NLRP4E. RESULTS: NLRP4E was more predominant within oocytes compared with other NLRP4 members. NLRP4E knockdown significantly inhibited actin cap formation and spindle translocation toward the cap region, resulting in the failure of polar body extrusion at the end of meiosis I. Mechanistically, GRIN1, and GANO1 activated NLRP4E by phosphorylation at Ser429 and Thr430; p-NLRP4E is translocated and is accumulated in the actin cap region during spindle translocation. Next, we found that p-NLRP4E directly phosphorylated SRC at Tyr418, while p-SRC negatively regulated p-CDC42-S71, an inactive form of CDC42 that promotes actin cap formation and spindle translocation in the GTP-bound form. CONCLUSIONS: NLRP4E activated by GRIN1 and GANO1 regulates actin cap formation and spindle translocation toward the cap region through upregulation of p-SRC-Tyr418 and downregulation of p-CDC42-S71 during meiosis I.

Establishment of a prognostic model related to tregs and natural killer cells infiltration in bladder cancer.

BACKGROUND: Regulatory T cells (Tregs) and natural killer (NK) cells play an essential role in the development of bladder urothelial carcinoma (BUC). AIM: To construct a prognosis-related model to judge the prognosis of patients with bladder cancer, meanwhile, predict the sensitivity of patients to chemotherapy and immunotherapy. METHODS: Bladder cancer information data was obtained from The Cancer Genome Atlas and GSE32894. The CIBERSORT was used to calculate the immune score of each sample. Weighted gene co-expression network analysis was used to find genes that will have the same or similar expression patterns. Subsequently, multivariate cox regression and lasso regression was used to further screen prognosis-related genes. The prrophetic package was used to predict phenotype from gene expression data, drug sensitivity of external cell line and predict clinical data. RESULTS: The stage and risk scores are independent prognostic factors in patients with BUC. Mutations in FGFR3 lead to an increase in Tregs percolation and affect the prognosis of the tumor, and additionally, EMP1, TCHH and CNTNAP3B in the model are mainly positively correlated with the expression of immune checkpoints, while CMTM8, SORT1 and IQSEC1 are negatively correlated with immune checkpoints and the high-risk group had higher sensitivity to chemotherapy drugs. CONCLUSION: Prognosis-related models of bladder tumor patients, based on Treg and NK cell percolation in tumor tissue. In addition to judging the prognosis of patients with bladder cancer, it can also predict the sensitivity of patients to chemotherapy and immunotherapy. At the same time, patients were divided into high and low risk groups based on this model, and differences in genetic mutations were found between the high and low risk groups.

Application of dendritic cells in tumor immunotherapy and progress in the mechanism of anti-tumor effect of Astragalus polysaccharide (APS) modulating dendritic cells: a review.

Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that are essential in mediating the body's natural and adaptive immune responses. The body can regulate the function of DCs in various ways to enhance their antitumor effects. In the tumour microenvironment (TME), antigen-specific T cell responses are initiated through DC processing and delivery of tumour-associated antigens (TAAs); conversely, tumour cells inhibit DC recruitment by releasing metabolites, cytokines and other regulatory TME and function. Different subpopulations of DCs exist in tumour tissues, and their functions vary. Insight into DC subgroups in TME allows assessment of the effectiveness of tumour immunotherapy. Astragalus polysaccharide (APS) is the main component of the Chinese herb Astragalus membranaceus. The study found that the antitumor effects of APS are closely related to DCs. APS can promote the expression of surface molecules CD80 and CD86, promote the maturation of DCs, and activate CTL to exert antitumor effects. We reviewed the application of DCs in tumor immunotherapy and the mechanism of modulation of DCs by Astragalus polysaccharide to provide new directions and strategies for tumor therapy and new drug development.

Associations of gut microbiota with dyslipidemia based on sex differences in subjects from Northwestern China.

BACKGROUND: The gut microbiota (GM) has been proven to play a role in the regulation of host lipid metabolism, which provides a new theory about the pathogenesis of dyslipidemia. However, the associations of GM with dyslipidemia based on sex differences remain unclear and warrant elucidation. AIM: To investigate the associations of GM features with serum lipid profiles based on sex differences in a Chinese population. METHODS: This study ultimately recruited 142 participants (73 females and 69 males) at Honghui Hospital, Xi'an Jiaotong University. The anthropometric and blood metabolic parameters of all participants were measured. According to their serum lipid levels, female and male participants were classified into a high triglyceride (H_TG) group, a high total cholesterol (H_CHO) group, a low high-density lipoprotein cholesterol (L_HDL-C) group, and a control (CON) group with normal serum lipid levels. Fresh fecal samples were collected for 16S rRNA gene sequencing. UPARSE software, QIIME software, the RDP classifier and the FAPROTAX database were used for sequencing analyses. RESULTS: The GM composition at the phylum level included Firmicutes and Bacteroidetes as the core GM. Different GM features were identified between females and males, and the associations between GM and serum lipid profiles were different in females and males. The GM features in different dyslipidemia subgroups changed in both female patients and male patients. Proteobacteria, Lactobacillaceae, Lactobacillus and Lactobacillus_salivarius were enriched in H_CHO females compared with CON females, while Coriobacteriia were enriched in L_HDL-C females. In the comparison among the three dyslipidemia subgroups in females, Lactobacillus_salivarius were enriched in H_CHO females, and Prevotellaceae were enriched in L_HDL-C females. Compared with CON or H_TG males, Prevotellaceae, unidentified_Ruminococcaceae, Roseburia and Roseburia_inulinivorans were decreased in L_HDL-C males (P value < 0.05), and linear discriminant analysis effect size analysis indicated an enrichment of the above GM taxa in H_TG males compared with other male subgroups. Additionally, Roseburia_inulinivorans abundance was positively correlated with serum TG and total cholesterol levels, and Roseburia were positively correlated with serum TG level. Furthermore, Proteobacteria (0.724, 95%CI: 0.567-0.849), Lactobacillaceae (0.703, 95%CI: 0.544-0.832), Lactobacillus (0.705, 95%CI: 0.547-0.834) and Lactobacillus_salivarius (0.706, 95%CI: 0.548-0.835) could distinguish H_CHO females from CON females, while Coriobacteriia (0.710, 95%CI: 0.547-0.841), Coriobacteriales (0.710, 95%CI: 0.547-0.841), Prevotellaceae (0.697, 95%CI: 0.534-0.830), Roseburia (0.697, 95%CI: 0.534-0.830) and Roseburia_inulinivorans (0.684, 95%CI: 0.520-0.820) could discriminate H_TG males from CON males. Based on the predictions of GM metabolic capabilities with the FAPROTAX database, a total of 51 functional assignments were obtained in females, while 38 were obtained in males. This functional prediction suggested that cellulolysis increased in L_HDL-C females compared with CON females, but decreased in L_HDL-C males compared with CON males. CONCLUSION: This study indicates associations of GM with serum lipid profiles, supporting the notion that GM dysbiosis may participate in the pathogenesis of dyslipidemia, and sex differences should be considered.

Potential Metabolic Biomarkers for Early Detection of Oral Lichen Planus, a Precancerous Lesion.

Background: Oral lichen planus (OLP) is a T-cell-mediated chronic inflammatory disorder and precancerous oral lesion with high incidence. The current diagnostic method of OLP is very limited and metabolomics may provide a new approach for quantitative evaluation. Methods: The Ultra-Performance Liquid Chromatography-Quadrupole/Orbitrap High Resolution Mass Spectrometry (UHPLC-Q-Orbitrap HRMS) was applied to analyze the change of metabolites in serum of patients with OLP. A total of 115 OLP patients and 124 healthy controls were assigned to either a training set (n = 160) or a test set (n = 79). The potential biomarkers and the change of serum metabolites were profiled and evaluated by multivariate analysis. Results: Totally, 23 differential metabolites were identified in the training set between OLP group and healthy group. Three prominent metabolites in receiver operating characteristic (ROC) were selected as a panel to distinguish OLP or healthy individuals in the test set, and the diagnostic accuracy was 86.1%. Conclusions: This study established a new method for the early detection of OLP by analyzing serum metabolomics using UHPLC-Q-Orbitrap HRMS, which will help in understanding the pathological processes of OLP and identifying precancerous lesions in oral cavity.

Copper/B2pin2-Catalyzed Difluoroalkylation of Methylenecyclopropanes with Bromodifluorinated Acetates and Acetamides: One-Pot Synthesis of CF2-Containing Dihydronaphthalene Derivatives.

Novel copper/B2pin2-catalyzed difluoroalkylation of methylenecyclopropanes with bromodifluorinated acetates and acetamides via a tandem radical process involving ring-opening/intramolecular cyclization has been reported. This protocol is not only tolerated to a diverse range of substrates but also applicable to the synthesis of useful difluoromethylated compounds. Moreover, the reaction could be performed on a gram scale with a high yield, which opens up the possibility for practical applications.

[Development of a quality of life instrument for evaluation of the quality of life scale for Chinese patients with oral cancer].

PURPOSE: To develop a quality of life instrument for Chinese patients with oral cancer and to assess its reliability, validity and sensitivity. METHODS: A 44-item QOL questionnaire was developed with reference to the 36-item medical outcomes study on short-form health status (SF-36) and University of Washington Quality of Life Questionnaire (UW-QOL), combining with China's population and socio-cultural characteristics, named as Zhengzhou university oral cancer quality of life (ZZU-QOL) scale. Based on 271 patients, student's t test, correlation analysis, factor analysis were performed for its reliability and validity using SPSS 19.0 software package. RESULTS: Test-retest reliability: in all areas and for total score between 2 measurements of the correlation coefficient in the range of 0.86-1.00, there was no significant difference. Homogeneity reliability: Cornbrash'a coefficient in all fields was larger than 0.6, indicating the scale had good reliability. Construct validity: ZZU-QOL, SF-36 analysis and UW-QOL scale factor selected by the first seven cumulative contribution factor variance were 69.3%, 63.4% and 66.5%. The criterion validity with SF-36 and UW-QOL was 0.768 and 0.634, respectively. The ZZU-QOL scale can sensitively distinguish differences in preoperative and postoperative quality of life of oral cancer. CONCLUSIONS: The ZZU-QOL scale is practical, reliable and valid, and might be used for measuring the quality of life in Chinese patients with oral cancer.

Sonochemical degradation of methyl orange in the presence of Bi2WO6: Effect of operating parameters and the generated reactive oxygen species.

The Bi2WO6 was prepared by the hydrothermal method and its sonocatalytic activity was studied in the degradation of methyl orange (MO) solutions. The effects of catalytic activity of Bi2WO6 on dye were inspected by the change in absorbance of dye with UV-vis spectrometer. The influences of operational parameters such as the addition amount of Bi2WO6, pH, the initial concentration of dyes, ultrasonic power and irradiation time on the degradation ratio were investigated. In addition, the obtained results indicated that the kinetics of sonochemical reactions of MO were consistent with the pseudo first-order kinetics and Bi2WO6 had excellent reusability and stability during the sonochemical degradation processes. The generation and kinds of reactive oxygen species (ROS) and their influence on the sonochemical degradation of MO were determined by the methods of oxidation-extraction spectrophotometry and ROS scavengers. The results indicate that the degradation of MO in the presence of Bi2WO6 under ultrasonic irradiation is related to the generation of ROS, in which both singlet molecular oxygen ((1)O2) and hydroxyl radical (OH) play important roles in the sonochemical degradation of MO. These experimental results provide a sound foundation for the further development of Bi2WO6 as a sonocatalyst in wastewater treatment.

Studies on the interaction between promethazine and human serum albumin in the presence of flavonoids by spectroscopic and molecular modeling techniques.

Fluorescence, absorption, time-correlated single photon counting (TCSPC), and circular dichroism (CD) spectroscopic techniques as well as molecular modeling methods were used to study the binding characterization of promethazine (PMT) to human serum albumin (HSA) and the influence of flavonoids, rutin and baicalin, on their affinity. The results indicated that the fluorescence quenching mechanism of HSA by PMT is a static quenching due to the formation of complex. The reaction was spontaneous and mainly mediated by hydrogen bonds and hydrophobic interactions. The binding distance between the tryptophan residue of HSA and PMT is less than 8nm, which indicated that the energy transfer from the tryptophan residue of HSA to PMT occurred. The binding site of PMT on HSA was located in sites I and the presence of PMT can cause the conformational changes of HSA. There was the competitive binding to HSA between PMT and flavonoids because of the overlap of binding sites in HSA. The flavonoids could decrease the association constant and increase the binding distance. In addition, their synergistic effect can further change the conformation of HSA. The decrease in the affinities of PMT binding to HSA in the presence of flavonoids may lead to the increase of free drug in blood, which would affect the transportation or disposition of drug and evoke an adverse or toxic effect. Hence, rationalising dosage and diet regimens should be taken into account in clinical application of PMT.

Spectroscopic investigation on the sonodynamic damage to protein in the presence of eosine B.

In this work, bovine serum albumin (BSA) and eosine B (EB) were selected as a model protein and sonosensitizer, respectively. The sonodynamic damage to protein in the presence of EB and its mechanism were studied by means of absorption and fluorescence spectra. The results indicated that the synergistic effects of ultrasound and EB can efficiently damage the BSA molecules, and the damage of protein could be mainly due to the generation of reactive oxygen species (ROS). The damage degree of protein increased with the increase of ultrasonic time and EB concentration because of the increased quantities of ROS. Hydroxyl free radical (OH) was the major mediators of the ultrasound-inducing proteins damage in the presence of EB. In addition, the quantities of ROS from the diphenylcarbazide (DPCI)-EB solutions and the DPCI-fluorescein (FS) solutions with or without ROS scavengers were contrasted, respectively. The results show that FS mainly produce OH, but the quantities of ROS in the presence of FS were lower than those of EB, which indicates that the nitro and bromine substituent groups on the benzene ring of FS increase the quantity of ROS, but do not change the kinds of ROS.

Associations between impulsivity, aggression, and suicide in Chinese college students.

BACKGROUND: Although there are accumulating data regarding the epidemiology of suicide in China, there are meager data on suicidal ideation and attempts among college students. Interestingly, elevated impulsivity is thought to facilitate the transition from suicidal thoughts to suicidal behavior. Therefore, the objective of this research was to identify the associations between suicide and the personality factors of impulsivity and aggression. METHODS: This study's sampling method employed stratified random cluster sampling. A multi-stage stratified sampling procedure was used to select participants (n = 5,245). We conducted structured interviews regarding a range of socio-demographic characteristics and suicidal morbidity. The Patient Health Questionnaire depression module (PHQ-9) was used to acquire the information about thoughts of being better off dead or hurting themselves in some ways during the past two weeks. The impulsivity symptoms in this study were assessed with the BIS-11-CH (i.e., the Chinese version of the BIS-11), and the Aggressive symptoms were assessed with the BAQ. The statistical package for social science (SPSS) v.13.0 program (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Socio-demographic variables such as ethnic and gender were compared between groups, through the use of χ2 tests. The nonparametric test (k Independent Sample test, Kruskal-Wallis H) was performed to determine differences between the personality factors of impulsivity and aggression and suicide. RESULTS: In total, 9.1% (n = 479) of the 5,245 students reported they have ever thought about committing suicide; and 1% (n = 51) reported a history of attempted suicide (attempters). The analyses detected significant differences in scores on cognitive impulsivity (p < 0.01), when comparing individuals who only had suicidal ideation and individuals who had attempted suicide. Moreover, significant differences were found between ideators only and attempters on scores of self-oriented attack (p < .001). CONCLUSIONS: Suicidal ideation is prevalent among Chinese university students. Students with high aggression scores were more susceptible to committing suicide. Scores on self-oriented attack and cognitive impulsivity may be important factors for differentially predicting suicide ideation and suicide attempts.

[DFT/TDDFT study on the structure and absorption spectra of free base, N-/neo-confused porphyrin].

Porphyrin is an important class of photochemical materials, which has been widely used in various fields. Computational investigations into the ground state structures and orbital energy levels of free base porphyrin (FBP), neo-confused porphyrin (NECP) and N-confused porphyrin (NCP) were performed with density functional theory(DFT). Absorption spectra were calculated at TD-B3LYP/6-31+G(d). Degeneracy of HOMO and HOMO-1 is lost, which would account for the shoulder peaks about the most intense transitions of FBP and NECP. Following FBP, NECP and NCP order, the orbital energy level (OEL) of LUMO decreases while the OEL of HOMO increases, which lead to the red shift of adsorption spectra. The energy difference between LUMO and LUMO+1 is almost the same as the difference between HOMO and HOMO-1, which would account for the only most intense transition of NCP. Solvent effect on ground state structures and absorption spectra was also investigated. The data shows that the character peak of Soret band and Q band changes in different solvent (benzene, chloroform, acetonitrile and water). So we further focus on discussing the N atom position and solvent effects on the energy level and Soret/Q bands of FBP, NCP and NECP, as well as clarifying its variation regularity and mechanism.

[Study of tape A behavior in patients with oral lichen planus].

PURPOSE: To study the type of behavior in patients with oral lichen planus (OLP). METHODS: This study included 78 patients who were diagnosed as OLP and 79 healthy people. Using case-control method, subjects in 2 groups completed the questionnaire of type A behavior and SCL-90. Then the results were analyzed with SPSS 19.0 soft ware package. RESULTS: The scores in questionnaire of type A behavior and SCL-90 between the 2 groups had significant difference (P<0.05). CONCLUSIONS: There is a significant correlation between oral lichen planus and type A behavior.

Regulation of feeding behavior, gastrointestinal function and fluid homeostasis by apelin.

Apelin was first identified and characterized from bovine stomach extracts as an endogenous ligand for the APJ receptor. Apelin/APJ system is abundantly present in peripheral tissues and central nervous system. Apelin plays a broad role in regulating physiological and pathological functions. Recently, many reports have showed the effects of apelin on feeding behavior, however the results are inconsistent, due to different administration routes, animal species, forms of apelin, etc. Apelin has been involved in stimulating gastric cell proliferation, cholecystokinin (CCK) secretion, histamine release, gastric acid and bicarbonate secretion, and regulation of gastrointestinal motility. In addition, apelin produced regulatory effects on drinking behavior, diuresis, arginine vasopressin (AVP) release and glucocorticoids secretion. This article reviews the role of apelin on feeding behavior, gastrointestinal function and fluid homeostasis.

Depression among Chinese university students: prevalence and socio-demographic correlates.

The purpose of the present study was to estimate the prevalence of depression in Chinese university students, and to identify the socio-demographic factors associated with depression in this population. A multi-stage stratified sampling procedure was used to select university students (N = 5245) in Harbin (Heilongjiang Province, Northeastern China), who were aged 16-35 years. The Beck Depression Inventory (BDI) was used to determine depressive symptoms of the participants. BDI scores of 14 or higher were categorized as depressive for logistic regression analysis. Depression was diagnosed by the Structured Clinical Interview (SCID) for the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV). 11.7% of the participants had a BDI score 14 or higher. Major Depressive Disorder was seen in 4.0% of Chinese university students. There were no statistical differences in the incidence of depression when gender, ethnicity, and university classification were analyzed. Multivariate analysis showed that age, study year, satisfaction with major, family income situation, parental relationship and mother's education were significantly associated with depression. Moderate depression is prevalent in Chinese university students. The students who were older, dissatisfied with their major, had a lower family income, poor parental relationships, and a lower level of mother's education were susceptible to depression.

cRGD-functionalized polymeric magnetic nanoparticles as a dual-drug delivery system for safe targeted cancer therapy.

In this paper we give a method of integrated treatment for cancer and drug-induced complications in the process of cancer therapy through dual-drug delivery system (DDDS). Two hydrophilic drugs, doxorubicin (an antitumor drug) and verapamil (an antiangiocardiopathy drug) combined preliminarily with chitosan shell coated on magnetic nanoparticles (MNPs), followed by entrapping into the PLGA nanoparticles. Further modification was conducted by conjugating tumor-targeting ligand, cyclo(Arg-Gly-Asp-D-Phe-Lys) (c(RGDfK)) peptide, onto the end carboxyl groups on the PLGA-NPs. The size of the resulting cRGD-DOX/VER-MNP-PLGA NPs was approximately 144nm under simulate physiological environment. Under present experiment condition, the entrapment efficiencies of DOX and VER were approximately 74.8 and 53.2wt% for cRGD-DOX/VER-MNP-PLGA NPs. This paper contains interesting pilot data such as NIR-triggered drug release, in vivo drug distribution studies and whole-mouse optical imaging. Histopathological examinations and electrocardiogram comparison demonstrated that the intelligent DDDS could markedly inhibit the growth of tumor and potentially offer an approach for safe cancer therapy.

Intrathecal apelin-13 produced different actions in formalin test and tail-flick test in mice.

Apelin was identified as natural ligand for APJ, a G protein-coupled receptor. APJ is expressed in spinal cord and dorsal root ganglion. This study was designed to investigate the effects and mechanisms of intrathecally (i.t.) administered apelin-13 on nociceptive response in formalin test and tail-flick test. In formalin test, i.t. injection of apelin-13 (0.3-3 nmol/mouse) had no effect on the nociceptive response in either acute phase (0-10 min) or interphase (10-20 min), but significantly produced hyperalgesic effect in late phase (20-30 min) at the dose of 3 nmol/mouse. The APJ receptor antagonist apelin-13(F13A) and GABAA receptor antagonist bicuculline methiodide, but not opioid receptor antagonist naloxone, significantly blocked the hyperalgesia caused by apelin-13 in late phase, indicating that i.t. apelin-13- induced hyperalgesia was mediated by APJ and GABAA receptor, rather than opioid receptor. However, in tail-flick test, i.t. injected apelin-13 (1 and 3 nmol/mouse) induced a significant antinociceptive effect, which was significantly antagonized by apelin-13(F13A) and naloxone, suggesting APJ and opioid receptor were involved in the antinociception of spinal apelin-13.

Supraspinal antinociceptive effect of apelin-13 in a mouse visceral pain model.

Apelin, as the endogenous ligand of the APJ receptor, is a novel identified neuropeptide whose biological functions are not fully understood. APJ receptor mRNA was found in several brain regions related to descending control system of pain, such as amygdala, hypothalamus and dorsal raphe nucleus (DRN). The present study was designed to determine whether supraspinal apelin-13 may produce antinociceptive effect observed in the acetic acid-induced writhing test, a model of visceral pain. Apelin-13 not only significantly produced preemptive antinociception at the dose of 0.3, 0.5, 1 and 3 µg/mouse when injected intracerebroventricularly (i.c.v.) before acetic acid, but also significantly induced antinociception at a dose of 0.5, 1 and 3 µg/mouse when injected i.c.v. after acetic acid. And i.c.v. apelin-13 did not influence 30-min locomotor activity counts in mice. Intrathecal (i.t.) administration of apelin-13 (1 and 3 µg/mouse) significantly decreased the number of writhes, however, intraperitoneal (i.p.) injection of apelin-13 (10-100 µg/mouse) had no effect on the number of writhes in the writhing test. The specific APJ receptor antagonist apelin-13(F13A), no-specific opioid receptor antagonist naloxone and µ-opioid receptor antagonist ß-funaltrexamine hydrochloride (ß-FNA) could significantly antagonize the antinociceptive effect of i.c.v. apelin-13, suggesting APJ receptor and µ-opioid receptor are involved in this process. Central low dose of apelin-13 (0.3 µg/mouse, i.c.v.) could significantly potentiate the analgesic potencies of modest and even relatively ineffective doses of morphine administrated at supraspinal level. This enhanced antinociceptive effect was reversed by naloxone, suggesting that the potentiated analgesic response is mediated by opioid-responsive neurons.

Centrally administered apelin-13 induces depression-like behavior in mice.

Apelin, a novel bioactive peptide highly concentrated in the brain, is identified as the endogenous ligand for angiotensin-like 1 receptor (APJ). The present study was designed to investigate the effect of apelin-13 on emotion-related behavior using the forced swimming test (FST) and tail suspension test (TST). Intracerebroventricular (i.c.v.) administration of apelin-13 (0.3, 1 and 3µg/mouse) dose-dependently increased the immobility time in the FST and TST, compared with control group. However, the APJ receptor antagonist apelin-13(F13A) (0.3-10µg/mouse, i.c.v.) had no influence on immobility time in the FST. The increase of immobility time induced by apelin-13 was significantly blocked by apelin-13(F13A), non-selective opioid receptor antagonist naloxone and κ-opioid receptor antagonist nor-binaltorphimine dihydrochloride (nor-BNI), respectively, but not the non-selective corticotrophin-releasing factor (CRF) receptor antagonist α-helical CRF(9-41) in the FST. In order to eliminate the possibility of a false-positive result in the FST or TST, spontaneous activity and motor function were checked. The results demonstrate that apelin-13 alone or antagonists co-administered with apelin-13 did influence spontaneous activity counts. And apelin-13 had no effect on the motor behavior in the rotarod test and wire hanging test. These results indicate that centrally administered apelin-13 elicited depression-like behavior in mice, which was mediated via APJ receptor and κ-opioid receptor, but not CRF receptor.