Bioinformatic Analysis on the Prognostic Value of Neurotransmitter Receptor-Related Genes in Kidney Renal Clear Cell Carcinoma.

Context: Kidney renal clear-cell carcinoma (KIRC) is a malignant tumor. At an early stage, KIRC patients may experience only mild fever and fatigue or even no symptoms, and these early nonspecific indications can delay treatment. Neurotransmitters and their receptors may be very useful in determining tumorigenesis and predicting metastasis. Objective: The study intended to investigate the predictive value of neurotransmitter receptor-related genes (NRRGs) using public KIRC data, by determining the biological processes that implicate the prognostic NRRGs and establishing a predictive NR-related risk model, to provide an empirical basis for identifying and treating KIRC patients. Design: The research team performed a genetic case-control study. Setting: The study took place at Research Center of Health, Big Data Mining and Applications, Wannan Medical College, Wuhu, China. Methods: The research team: (1) obtained the transcriptome data related to KIRC from the Cancer Genome Atlas (TCGA) and ArrayExpress databases; (2) developed the differentially expressed NRRGs (DENRRGs) by identifying the NRRGs that intersected with DEGs in KIRC and normal samples; (3) carried out functional enrichment analyses of the DENRRGs; (4) screened the characteristic genes of the DENRRGs using machine learning; (5) created a predictive model using multivariate Cox analyses of the distinctive genes; (6) obtained independent prognostic factors for KIRC patients and established a nomograph model; (7) investigated the sensitivity of KIRC patients to therapeutic agents to examine the variations in immunological features between high-risk and low-risk individuals. Results: Differential analysis found that 115 NRRGs intersected with 5275 DEGs to provide 52 DENRRGs. Functional enrichment showed that DENRRGs were mainly involved in signal transduction in the nervous system. The machine learning on the 52 DENRRGs filtered out nine characteristic genes. Subsequently, the research team found eight prognostic biomarkers-histamine receptor H2 (HRH2), gamma-aminobutyric acid (GABA) receptor subunit epsilon (GABRE), cholinergic receptor nicotinic delta subunit (CHRND), glutamate receptor ionotropic subunit 2D (GRIN2D), glutamate metabotropic receptor 4 (GRM4), glycine receptor alpha 3 (GLRA3), cholinergic receptor nicotinic beta 4 subunit (CHRNB4), and cholinergic receptor muscarinic-1 (CHRM1)-and established a predictive model. Furthermore, the team precisely predicted the KIRC patients' prognoses using a nomogram that combined their ages, risk scores, and M stages. The infiltration levels of 21 immune cells also significantly differed between the high-risk and low-risk groups, with neutrophils having a significant positive correlation with GABRE and HRH2 and a significant negative correlation with CHRNB4 and GRM4. Finally, the 50% inhibitory concentration (IC50) values for various drugs, such as 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR), 8-hydroxy-7-(6-sulfonaphthalen-2-yl)diazenyl-quinoline-5-sulfonic acid (NSC-87877), Sunitinib, c-Jun N-terminal kinase (JNK) inhibitor VIII, and tanespimyci (X17.AAG) were significantly lower for high-risk group. Conclusions: By studying the relevance of biomarkers to the immunological microenvironment of KIRC, the current research team was able to propose a new predictive model for KIRC based on NRRGs, to offer a novel viewpoint for investigating KIRC. The study's results suggest new avenues for research into the pathophysiology and therapy of KIRC. Determining the precise molecular processes by which predictive biomarkers regulate KIRC requires further evidence and analysis.

Electroacupuncture at PC6 (Neiguan) Attenuates Angina Pectoris in Rats with Myocardial Ischemia-Reperfusion Injury Through Regulating the Alternative Splicing of the Major Inhibitory Neurotransmitter Receptor GABRG2.

Angina pectoris is the most common manifestation of coronary heart disease, causing suffering in patients. Electroacupuncture at PC6 can effectively alleviate angina by regulating the expression of genes, whether the alternative splicing (AS) of genes is affected by acupuncture is still unknown. We established a rat model of myocardial ischemia-reperfusion by coronary artery ligation and confirmed electroacupuncture alleviated the abnormal discharge caused by angina pectoris measured in EMG electromyograms. Analysis of the GSE61840 dataset established that AS events were altered after I/R and regulated by electroacupuncture. I/R decreased the expression of splicing factor Nova1 while electroacupuncture rescued it. Further experiments in dorsal root ganglion cells showed Nova1 regulated the AS of the GABRG2, specifically on its exon 9 where an important phosphorylation site is present. In vivo, results also showed that electroacupuncture can restore AS of GABRG2. Our results proved that electroacupuncture alleviates angina results by regulating alternative splicing.

Peripheral receptors and neuromediators involved in the antihyperalgesic effects of acupuncture: a state-of-the-art review.

The present study aims to describe state-of-the-art of preclinical studies that have investigated peripheral receptors and neuromediators involved in the antihyperalgesic effects of acupuncture. The PubMed, Scopus, and Web of Science databases were searched using the integrative review method. Preclinical articles that involved the study of peripheral receptors and neuromediators on the pain control effects of acupuncture in rats or mice were selected using a predefined search strategy. From this search, 456 articles were found, and 29 of them met the inclusion criteria of the study. The selected articles addressed the following peripheral receptors: opioid (n = 9), adenosine (n = 5), cannabinoid (n = 5), transient receptor potential vanilloid (TRPV) (n = 3), histamine (n = 2), adrenergic (n = 1), muscarinic (n = 1), corticotrophin-releasing factor (CRF) (n = 2), IL-1 (n = 1), and endothelin (n = 1) receptors. The peripheral neuromediators correlated with the peripheral pain control effect were as follows: opioid peptides (n = 4), adenosine (n = 3), histamine (n = 1), substance P (n = 1) calcitonin gene-related peptide (CGRP) (n = 1), anandamide (n = 1), nitric oxide (n = 1), and norepinephrine (n = 1). This review summarizes the methods used to investigate the peripheral effects of acupuncture and discusses the main findings on each family of receptors and neuromediators. Ten families of peripheral receptors and 8 types of neuromediators were correlated with the antihyperalgesic effects of acupuncture in preclinical studies. Considering the benefits of a better understanding of the role of peripheral receptors and neuromediators in the context pain management, the findings of the present study highlight the importance of deepening the exploration of the peripheral mechanisms of acupuncture.

The retrotrapezoid nucleus and the neuromodulation of breathing.

Breathing is regulated by a host of arousal and sleep-wake state-dependent neuromodulators to maintain respiratory homeostasis. Modulators such as acetylcholine, norepinephrine, histamine, serotonin (5-HT), adenosine triphosphate (ATP), substance P, somatostatin, bombesin, orexin, and leptin can serve complementary or off-setting functions depending on the target cell type and signaling mechanisms engaged. Abnormalities in any of these modulatory mechanisms can destabilize breathing, suggesting that modulatory mechanisms are not overly redundant but rather work in concert to maintain stable respiratory output. The present review focuses on the modulation of a specific cluster of neurons located in the ventral medullary surface, named retrotrapezoid nucleus, that are activated by changes in tissue CO2/H+ and regulate several aspects of breathing, including inspiration and active expiration.

Chemical Composition of Essential Oil from Flower of 'Shanzhizi' (Gardenia jasminoides Ellis) and Involvement of Serotonergic System in Its Anxiolytic Effect.

Gardenia jasminoides Ellis is a famous fragrant flower in China. Previous pharmacological research mainly focuses on its fruit. In this study, the essential oil of the flower of 'Shanzhizi', which was a major variety for traditional Chinese medicine use, was extracted by hydro distillation and analyzed by GC-MS. Mouse anxiety models included open field, elevated plus maze (EPM), and light and dark box (LDB), which were used to evaluate its anxiolytic effect via inhalation. The involvement of monoamine system was studied by pretreatment with neurotransmitter receptor antagonists WAY100635, flumazenil and sulpiride. The monoamine neurotransmitters contents in the prefrontal cortex (PFC) and hippocampus after aroma inhalation were also analyzed. The results showed that inhalation of G. jasminoides essential oil could significantly elevated the time and entries into open arms in EPM tests and the time explored in the light chamber in LDB tests with no sedative effect. WAY100635 and sulpiride, but not flumazenil, blocked its anxiolytic effect. Inhalation of G. jasminoides essential oil significantly down-regulated the 5-HIAA/5-HT in the PFC and reduced the 5-HIAA content in hippocampus compared to the control treatment. In conclusion, inhalation of gardenia essential oil showed an anxiolytic effect in mice. Monoamine, especially the serotonergic system, was involved in its anxiolytic effect.

Scopoletin ameliorates anxiety-like behaviors in complete Freund's adjuvant-induced mouse model.

Anxiety disorder is highly prevalent worldwide and represents a chronic and functionally disabling condition, with high levels of psychological stress characterized by cognitive and physiological symptoms. Scopoletin (SP), a main active compound in Angelica dahurica, is traditionally used for the treatment of headache, rhinitis, pain, and other conditions. Here, we evaluated the effects of SP in a mouse model of complete Freund's adjuvant (CFA)-induced chronic inflammation anxiety. SP (2.0, 10.0, 50.0 mg/kg) administration for 2 weeks dose-dependently ameliorated CFA-induced anxiety-like behaviors in the open field test and elevated plus maze test. Moreover, we found that SP treatment inhibited microglia activation and decreased both peripheral and central IL-1ß, IL-6, and TNF-α levels in a dose-dependent manner. Additionally, the imbalance in excitatory/inhibitory receptors and neurotransmitters in the basolateral nucleus after CFA injection was also modulated by SP administration. Our findings indicate that the inhibition of the nuclear factor-kappa B and mitogen-activated protein kinase signaling pathways involving anti-inflammatory activities and regulation of the excitatory/inhibitory balance can be attributed to the anxiolytic effects of SP. Moreover, our molecular docking analyses show that SP also has good affinity for gamma-aminobutyric acid (GABA) transaminase and GABAA receptors. Therefore, these results suggest that SP could be a candidate compound for anxiolytic therapy and for use as a structural base for developing new drugs.

The effects of neuromedin S on the hypothalamic-pituitary-testicular axis in male pigs in vitro.

Evidence has shown that neuromedin S (NMS) and its receptor (NMU2R) are expressed in the hypothalamus, pituitary, and testis of pigs. To determine the potential mechanisms of NMS, we systematically investigated the direct effects of NMS on the hypothalamic-pituitary-testicular (HPT) axis of male pigs in vitro. We initially confirmed that NMU2R distributed in isolated hypothalamic cells, anterior pituitary cells and Leydig cells using immunocytochemistry. Subsequently we investigated the direct effects of NMS on hormone secretion from cells (anterior pituitary cells and Leydig cells) treated with different doses of NMS. The results showed that NMS increase the release of LH and FSH from anterior pituitary cells and testosterone from Leydig cells. NMS up-regulated the expression of NMU2R and GnRH mRNAs in hypothalamic cells, NMU2R, LH and FSH mRNAs in anterior pituitary cells, and NMU2R, STAR, P450 and 3ß-HSD mRNAs and the expression of PCNA and Cyclin B1 protein in Leydig cells; moreover, it down-regulated the expression of GnIH mRNA in hypothalamic cells. Using immunofluorescence staining and confocal microscopy, we also demonstrated the colocalization of NMU2R and AR or GnIH in Leydig cells. These data in vitro indicated that NMS may regulate the release and/or synthesis of LH, FSH and testosterone at different levels of the reproductive axis through NMU2R, which provided novel evidence of the potential roles of NMS in regulation of pig reproduction.

The past and future of novel, non-dopamine-2 receptor therapeutics for schizophrenia: A critical and comprehensive review.

Since the discovery of chlorpromazine in the 1950's, antipsychotic drugs have been the cornerstone of treatment of schizophrenia, and all attenuate dopamine transmission at the dopamine-2 receptor. Drug development for schizophrenia since that time has led to improvements in side effects and tolerability, and limited improvements in efficacy, with the exception of clozapine. However, the reasons for clozapine's greater efficacy remain unclear, despite the great efforts and resources invested therewith. We performed a comprehensive review of the literature to determine the fate of previously tested, non-dopamine-2 receptor experimental treatments. Overall we included 250 studies in the review from the period 1970 to 2017 including treatments with glutamatergic, serotonergic, cholinergic, neuropeptidergic, hormone-based, dopaminergic, metabolic, vitamin/naturopathic, histaminergic, infection/inflammation-based, and miscellaneous mechanisms. Despite there being several promising targets, such as allosteric modulation of the NMDA and α7 nicotinic receptors, we cannot confidently state that any of the mechanistically novel experimental treatments covered in this review are definitely effective for the treatment of schizophrenia and ready for clinical use. We discuss potential reasons for the relative lack of progress in developing non-dopamine-2 receptor treatments for schizophrenia and provide recommendations for future efforts pursuing novel drug development for schizophrenia.

Functional Imaging of Neurotransmitters in Hymenolepis diminuta Treated with Senna Plant Through Light and Confocal Microscopy.

Previous studies have shown the anthelmintic efficacy of Senna alata, Senna alexandrina and Senna occidentalis on the zoonotic parasite Hymenolepis diminuta through microscopic studies on morphological structure. The present study is based on the light and confocal microscopic studies to understand if Senna extracts affect neurotransmitter activity of the parasites. A standard concentration (40 mg/mL) of the three leaf extracts and one set of 0.005 mg/mL concentration of the reference drug praziquantel were tested against the parasites, keeping another set of parasites in phosphate buffer saline as a control. Histochemical studies were carried out using acetylthiocholine iodide as the substrate and acetylcholinesterase as the marker enzyme for studying the expression of the neurotransmitter of the parasite and the staining intensity was observed under a light microscope. Immunohistochemical studies were carried out using anti serotonin primary antibody and fluorescence tagged secondary antibody and observed using confocal microscopy. Intensity of the stain decreases in treated parasites compared with the control which implies loss of activity of the neurotransmitters. These observations indicated that Senna have a strong anthelmintic effect on the parasite model and thus pose as a potential anthelmintic therapy.

Nelumbo nucifera Seed Extract Promotes Sleep in Drosophila melanogaster.

The sleep-promoting effects of the water extract of Nelumbo nucifera seeds (NNE) were investigated in an invertebrate model. The effects of NNE on the subjective nighttime activity, sleep episodes, and sleep time were determined using Drosophila melanogaster and locomotor activity monitoring systems in basal and caffeine-induced arousal conditions. The movements of fruit flies were analyzed using the Noldus EthoVision-XT system, and the levels of neuromodulators were analyzed using HPLC. Expression of neuromodulator receptors was analyzed using real-time PCR. NNE was shown to contain neurotransmission-related components; γ-aminobutyric acid (GABA) (2.33±0.22 mg/g), tryptophan (2.00±0.06 mg/g), quinidine (0.55±0.33 mg/g), and neferine (0.16±0.01 mg/g). The total activity of flies during nighttime was decreased by 52% with 1.0% NNE treatment. In the individual and collective conditions, the subjective nighttime activities (45/38%) and sleep bouts (20/14%) of flies was significantly decreased with NNE treatment, while total sleep times (10/27%) were significantly increased. This sleep-promoting effect is more pronounced in caffeine-treated conditions; the nighttime activity of flies was reduced by 53%, but total sleep time was increased by 60%. Our video-tracking analysis showed a significant decrease of the moving distance and velocity of flies by NNE. This NNE-mediated sleep-promoting effect was associated with up-regulation of GABAA/GABAB and serotonin receptors. The NNE-mediated increase of GABA content was identified in flies. These results demonstrate that NNE effectively promotes sleep in flies by regulating the GABAergic/serotonergic neuromodulators, and could be an alternative agent for sleep promotion.

Discovery of a Human Neuromedin U Receptor 1-Selective Hexapeptide Agonist with Enhanced Serum Stability.

Neuromedin U (NMU) activates two NMU receptors (NMUR1 and NMUR2) and is a useful antiobesity drug lead. We report discovery of a hexapeptide agonist, 2-thienylacetyl-Trp1-Phe(4-F)2-Arg3-Pro4-Arg5-Asn6-NH2 (4). However, the NMUR1 selectivity and serum stability of this agonist were unsatisfactory. Through a structure-activity relationship study focused on residue 2 of agonist 4, serum stability, and pharmacokinetic properties, we report here the discovery of a novel NMUR1 selective hexapeptide agonist 7b that suppresses body weight gain in mice.

Sex difference in the contribution of GABAB receptors to tibial neuromodulation of bladder overactivity in cats.

This study investigated the role of γ-aminobutyric acid subtype B (GABAB) receptors in tibial and pudendal neuromodulation of bladder overactivity induced by intravesical administration of dilute (0.5%) acetic acid (AA) in α-chloralose-anesthetized cats. To inhibit bladder overactivity, tibial or pudendal nerve stimulation (TNS or PNS) was applied at 5 Hz and two or four times threshold (T) intensity for inducing toe or anal sphincter twitch. TNS at 2T or 4T intensity significantly (P < 0.05) increased the bladder capacity to 173.8 ± 16.2 or 198.5 ± 24.1%, respectively, of control capacity. Meanwhile, PNS at 2T or 4T intensity significantly (P < 0.05) increased the bladder capacity to 217 ± 18.8 and 221.3 ± 22.3% of control capacity, respectively. CGP52432 (a GABAB receptor antagonist) at intravenous dosages of 0.1-1 mg/kg completely removed the TNS inhibition in female cats but had no effect in male cats. CGP52432 administered intravenously also had no effect on control bladder capacity or the pudendal inhibition of bladder overactivity. These results reveal a sex difference in the role of GABAB receptors in tibial neuromodulation of bladder overactivity in cats and that GABAB receptors are not involved in either pudendal neuromodulation or irritation-induced bladder overactivity.

Mecanismos responsables de la relajación neuromuscular en el tracto gastrointestinal / Mechanisms responsible for neuromuscular relaxation in the gastrointestinal tract

El sistema nervioso entérico (SNE) es responsable de la génesis de los patrones motores que aseguran un correcto tránsito intestinal. Las neuronas entéricas se clasifican en aferentes, interneuronas y motoneuronas, que pueden a su vez ser excitatorias, causando contracción, o inhibitorias, provocando la relajación de la musculatura lisa. Los mecanismos de relajación muscular son claves para entender procesos fisiológicos como la relajación de los esfínteres, la acomodación gástrica o la fase descendente del reflejo peristáltico. El óxido nítrico (NO) y el ATP o una purina relacionada son los principales neurotransmisores inhibitorios. Las neuronas nitrérgicas sintetizan NO a partir del enzima nNOS. El NO difunde a través de la membrana celular uniéndose a su receptor, la guanilil ciclasa, y activando posteriormente una serie de mecanismos intracelulares que provocan finalmente una relajación muscular. El ATP actúa como neurotransmisor inhibitorio junto con el NO y el receptor de membrana purinérgico P2Y1 ha sido identificado como elemento clave para entender cómo el ATP relaja la musculatura intestinal. Aunque probablemente ningún clínico duda de la importancia del NO en la fisiopatología motora digestiva, la relevancia de la neurotransmisión purinérgica es aparentemente mucho menor puesto que el ATP no ha sido todavía asociado a una disfunción motora concreta. El objetivo de esta revisión es mostrar el funcionamiento de ambos mecanismos de relajación para poder establecer las bases fisiológicas de posibles disfunciones motoras asociadas a la alteración de la relajación intestinal (AU)

The enteric nervous system (ENS) is responsible for the genesis of motor patterns ensuring an appropriate intestinal transit. Enteric neurons are classified into afferent, interneuron, and motoneuron types, with the latter two being further categorized as excitatory or inhibitory, which cause smooth muscle contraction or inhibition, respectively. Muscle relaxation mechanisms are key for the understanding of physiological processes such as sphincter relaxation, gastric accommodation, or descending peristaltic reflex. Nitric oxide (NO) and ATP or a related purine represent the primary inhibitory neurotransmitters. Nitrergic neurons synthesize NO through nNOS enzyme activity. NO diffuses across the cell membrane to bind its receptor, namely, guanylyl cyclase, and then activates a number of intracellular mechanisms that ultimately result in muscle relaxation. ATP acts as an inhibitory neurotransmitter together with NO, and the purinergic P2Y1 membrane receptor has been identified as a key item in order to understand how ATP may relax intestinal smooth muscle. Although, probably, no clinician doubts the significance of NO in the pathophysiology of digestive motility, the relevance of purinergic neurotransmission is apparently much lower, as ATP has not been associated with any specific motor dysfunction yet. The goal of this review is to discuss the function of both relaxation mechanisms in order to establish the physiological grounds of potential motor dysfunctions arising from impaired intestinal relaxation (AU)

Receptor and transporter binding and activity profiles of albiflorin extracted from Radix paeoniae Alba.

Albiflorin, a traditional Chinese herb, is a main component of Radix paeoniae Alba, which has been used for the treatment of depressive disorders since ancient times. However, the mechanism of the antidepressant effect of albiflorin is poorly understood. Thus, we explored the binding profile of albiflorin at neurotransmitter receptors and transporters. We also characterised the in vivo effect of albiflorin on monoaminergic systems by using microanalysis to determine the extracellular levels of serotonin (5-HT) and norepinephrine (NE) in the hypothalamus of freely moving rats administered albiflorin. We found that albiflorin inhibited the uptake of 5-HT and NE and displayed robust binding affinities for the transporters of both neurotransmitters. By contrast, albiflorin (10 µM) showed no significant affinity to a wide array of central nervous system receptors. The results of our in vivo microdialysis studies showed that administration of albiflorin (3.5, 7.0, 14.0 mg/kg) significantly increased extracellular concentrations of 5-HT and NE in the hypothalamus of freely moving rats. Overall, the current study showed that albiflorin is a novel 5-HT and NE reuptake inhibitor with high selectivity.

Estrategias terapéuticas para el tratamiento de la prostatitis crónica/síndrome de dolor pélvico crónico / Therapeutic strategies for the treatment of chronic prostatitis / chronic pelvic pain syndrome

La prostatitis crónica/síndrome de dolor pélvico crónico es una enfermedad con una repercusión sobre la calidad de vida que en ocasiones es equiparable a la de los pacientes con infarto de miocardio, diabetes mellitus, etc. Durante años, la terapia médica estándar se ha realizado con antiinflamatorios no esteroideos, alfa-bloqueantes y antibióticos. Con el objetivo de analizar las alternativas terapéuticas existentes en la actualidad se ha llevado a cabo una búsqueda bibliográfica en PubMed de los artículos publicados hasta marzo del 2014, encontrando diversas terapias para el tratamiento de la prostatitis crónica/síndrome de dolor pélvico crónico como modificaciones en los estilos de vida, fitoterapia, extractos bacterianos orales inmunoestimulantes, acupuntura, terapia miofascial y biofeedback, terapias neuromoduladoras, ondas de choque extracorpóreas, fármacos con efecto sobre el sistema nervioso central y periférico, terapias cognitivo-conductuales y terapias térmicas. Aunque muchos de estos estudios muestran a priori unos resultados satisfactorios, son necesarios ensayos clínicos controlados y aleatorizados con el objetivo de determinar la efectividad real así como la durabilidad de estos tratamientos en el tiempo (AU)

The chronic prostatitis/chronic pelvic pain syndrome is a disease with an impact on quality of life which is sometimes comparable to that of patients with myocardial infarction, diabetes mellitus, etc. For years, the standard medical therapy was performed with non steroidal anti-inflammatory, alpha-blockers and antibiotics. In order to analyze existing therapeutic alternatives at the moment, a comprehensive literature search in PubMed database was conducted for articles published up to March 2014 data, founding several therapies for the treatment of chronic prostatitis/chronic pelvic pain syndrome as changes in lifestyle, herbal medicine, oral immunostimulant bacterial extracts, acupuncture, myofascial therapy and biofeedback, neuromodulatory therapies, extracorporeal shockwave, medications known to affect the central and peripheral nervous system, cognitive-behavioral therapies and thermal therapies. Although many of these studies show a priori satisfactory results, controlled randomized clinical trials are necessary to determine the actual effectiveness and durability of these treatments over time (AU)

[Role of brain lipid sensing in nervous regulation of energy balance]. / Rôle de la détection centrale des lipides dans le contrôle nerveux de la balance énergétique.

Fatty acid sensitive neurons located in hypothalamus, hippocampus or striatum are able to detect daily variations of plasma fatty acid levels. Thus, these neurons play a role to regulate energy balance by controling food intake, insulin secretion or hepatic glucose production. Molecular mechanisms that mediate fatty acid effects include receptor FAT (fatty acid transporter)/CD36. Deregulation of this brain lipid sensing may be an early event leading to further dysfunction of energy balance leading to obesity and type 2 diabetes.

The effects of avermectin on amino acid neurotransmitters and their receptors in the pigeon brain.

The objective of this study was to examine the effects of avermectin (AVM) on amino acid neurotransmitters and their receptors in the pigeon brain. Four groups two-month-old American king pigeons (n=20/group) were fed either a commercial diet or an AVM-supplemented diet (20mg/kg·diet, 40 mg/kg·diet, or 60 mg/kg·diet) for 30, 60, or 90 days. The contents of aspartic acid (ASP), glutamate (GLU), glycine (GLY), and γ-aminobutyric acid (GABA) in the brain tissues were determined using ultraviolet high-performance liquid chromatography (HPLC). The expression levels of the GLU and GABA receptor genes were analyzed using real-time quantitative polymerase chain reaction (qPCR). The results indicate that AVM exposure significantly enhances the contents of GABA, GLY, GLU, and ASP in the cerebrum, cerebellum, and optic lobe. In addition, AVM exposure increases the mRNA expression levels of γ-aminobutyric acid type A receptor (GABAAR), γ-aminobutyric acid type B receptor (GABABR), N-methyl-d-aspartate 1 receptor (NR1), N-methyl-d-aspartate 2A receptor (NR2A), and N-methyl-d-aspartate 2B receptor (NR2B) in a dose- and time-dependent manner. Moreover, we found that the most damaged organ was the cerebrum, followed by the cerebellum, and then the optic lobe. These results show that the AVM-induced neurotoxicity may be associated with its effects on amino acid neurotransmitters and their receptors. The information presented in this study will help supplement the available data for future AVM toxicity studies.

Cerebral mechanisms of general anesthesia.

How does general anesthesia (GA) work? Anesthetics are pharmacological agents that target specific central nervous system receptors. Once they bind to their brain receptors, anesthetics modulate remote brain areas and end up interfering with global neuronal networks, leading to a controlled and reversible loss of consciousness. This remarkable manipulation of consciousness allows millions of people every year to undergo surgery safely most of the time. However, despite all the progress that has been made, we still lack a clear and comprehensive insight into the specific neurophysiological mechanisms of GA, from the molecular level to the global brain propagation. During the last decade, the exponential progress in neuroscience and neuro-imaging led to a significant step in the understanding of the neural correlates of consciousness, with direct consequences for clinical anesthesia. Far from shutting down all brain activity, anesthetics lead to a shift in the brain state to a distinct, highly specific and complex state, which is being increasingly characterized by modern neuro-imaging techniques. There are several clinical consequences and challenges that are arising from the current efforts to dissect GA mechanisms: the improvement of anesthetic depth monitoring, the characterization and avoidance of intra-operative awareness and post-anesthesia cognitive disorders, and the development of future generations of anesthetics.

Development of a neuromedin U-human serum albumin conjugate as a long-acting candidate for the treatment of obesity and diabetes. Comparison with the PEGylated peptide.

Neuromedin U (NMU) is an endogenous peptide implicated in the regulation of feeding, energy homeostasis, and glycemic control, which is being considered for the therapy of obesity and diabetes. A key liability of NMU as a therapeutic is its very short half-life in vivo. We show here that conjugation of NMU to human serum albumin (HSA) yields a compound with long circulatory half-life, which maintains full potency at both the peripheral and central NMU receptors. Initial attempts to conjugate NMU via the prevalent strategy of reacting a maleimide derivative of the peptide with the free thiol of Cys34 of HSA met with limited success, because the resulting conjugate was unstable in vivo. Use of a haloacetyl derivative of the peptide led instead to the formation of a metabolically stable conjugate. HSA-NMU displayed long-lasting, potent anorectic, and glucose-normalizing activity. When compared side by side with a previously described PEG conjugate, HSA-NMU proved superior on a molar basis. Collectively, our results reinforce the notion that NMU-based therapeutics are promising candidates for the treatment of obesity and diabetes.