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Hypoxia-inducible factor-1 (HIF-1) is a critical transcription factor that regulates the expression of genes involved in cellular adaptation to low oxygen levels. Aberrant regulation of the HIF-1 signaling pathway is linked to various human diseases. Previous studies have established that HIF-1α is rapidly degraded in a von Hippel-Lindau protein (pVHL)-dependent manner under normoxic conditions. In this study, we find that pVHL binding protein 1 (VBP1) is a negative regulator of HIF-1α but not HIF-2α using zebrafish as an in vivo model and in vitro cell culture models. Deletion of vbp1 in zebrafish caused Hif-1α accumulation and upregulation of Hif target genes. Moreover, vbp1 was involved in the induction of hematopoietic stem cells (HSCs) under hypoxic conditions. However, VBP1 interacted with and promoted the degradation of HIF-1α in a pVHL-independent manner. Mechanistically, we identify the ubiquitin ligase CHIP and HSP70 as new VBP1 binding partners and demonstrate that VBP1 negatively regulated CHIP and facilitated CHIP-mediated degradation of HIF-1α. In patients with clear cell renal cell carcinoma (ccRCC), lower VBP1 expression was associated with worse survival outcomes. In conclusion, our results link VBP1 with CHIP stability and provide insights into underlying molecular mechanisms of HIF-1α-driven pathological processes.
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Carcinoma de Células Renales , Neoplasias Renales , Animales , Humanos , Pez Cebra/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Factores de Transcripción/metabolismo , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Proteínas del Citoesqueleto , Chaperonas MolecularesRESUMEN
Orexin is exclusively produced in neurons localized within the lateral hypothalamic area (LHA) and perifornical area (PFA). Orexin has been identified as a key promotor of arousal. The selective loss of orexinergic neurons results in narcolepsy. It is known that the intrinsic electrophysiological properties are critical for neurons to perform their functions in corresponding brain regions. In addition to hypothalamic orexin, other brain nuclei are involved in the regulation of sleep and wakefulness. Quite a lot of studies focus on elucidating orexin-induced regulation of sleep-wake states and modulation of neuronal electrophysiological properties in several brain regions. Here, we summarize that the orexinergic neurons exhibit spontaneous firing activity which is associated with the states of sleep-wake cycle. Orexin mainly exerts postsynaptic excitatory effects on multiple brain nuclei associated with the process of sleep and wakefulness. This review may provide a background to guide future research about the cellular mechanisms of orexin-induced maintaining of arousal.
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We report a case-series study of 5 patients with Japanese spotted fever from the Three Gorges Area in China, including 1 fatal case. Seroprevalence of Rickettsia japonica was ≈21% among the local population. Our report highlights the emerging potential threat to human health of Japanese spotted fever in the area.
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Infecciones por Rickettsia , Rickettsia , Rickettsiosis Exantemáticas , Humanos , Infecciones por Rickettsia/diagnóstico , Infecciones por Rickettsia/epidemiología , Infecciones por Rickettsia/microbiología , Estudios Seroepidemiológicos , Pueblos del Este de Asia , Rickettsiosis Exantemáticas/diagnóstico , Rickettsiosis Exantemáticas/epidemiología , Rickettsiosis Exantemáticas/microbiología , Rickettsia/genética , China/epidemiologíaRESUMEN
Dopamine (DA) is a catecholamine neurotransmitter widely distributed in the central nervous system. It participates in various physiological functions, such as feeding, anxiety, fear, sleeping and arousal. The regulation of feeding is exceptionally complex, involving energy homeostasis and reward motivation. The reward system comprises the ventral tegmental area (VTA), nucleus accumbens (NAc), hypothalamus, and limbic system. This paper illustrates the detailed mechanisms of eight typical orexigenic and anorexic neuropeptides that regulate food intake through the reward system. According to recent literature, neuropeptides released from the hypothalamus and other brain regions regulate reward feeding predominantly through dopaminergic neurons projecting from the VTA to the NAc. In addition, their effect on the dopaminergic system is mediated by the prefrontal cortex, paraventricular thalamus, laterodorsal tegmental area, amygdala, and complex neural circuits. Research on neuropeptides involved in reward feeding can help identify more targets to treat diseases with metabolic disorders, such as obesity.
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Dopamina , Neuropéptidos , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Área Tegmental Ventral/metabolismo , Neuropéptidos/metabolismo , Neuronas Dopaminérgicas/metabolismo , RecompensaRESUMEN
INTRODUCTION: Calcium-sensitive receptor (CaSR) is expressed in the enteric nervous system of gastrointestinal tract. However, its role in the regulation of gastrointestinal motility has not yet been fully elucidated. We aimed to investigate the effect of the CaSR agonist - R568 on gastric motility and its potential mechanism. METHODS: In vivo, R568 was given by gavage to explore gastric emptying with or without capsaicin which specifically blocks the function of vagal afferents; neurotransmitters synthetized in the myenteric plexus of the gastric corpus and antrum were analysed by ELISA and immunofluorescence staining; gastric muscle strips contraction recording and intracellular single unit firing recording were used to study the effect of R568 on muscle strips and myenteric interstitial cells of Cajal (ICCs) ex vitro. RESULTS: Gastric emptying was inhibited by R568 in Kunming male mice, and capsaicin weakened this effect. The expression of c-fos-positive neurons increased in the nucleus tractus solitarius when R568 was treated. R568 decreased the expression of cholinergic neurons and reduced the synthesis of acetylcholine. Conversely, R568 increased the expression of nitrogenic neurons and enhanced the synthesis of nitric oxide in the myenteric plexus. Ex vitro results showed that R568 inhibited the contraction of the gastric antral muscle strip and suppressed the spontaneous firing activity of pacemaker ICCs. CONCLUSION: Activation of the gastrointestinal CaSR inhibited gastric motility in vivo and ex vitro. Transmitting nutrient signals to the brain through the vagal afferent nerve, modulating the cholinergic and nitrergic system in the enteric nervous system, and inhibiting activity of pacemaker ICCs in the myenteric plexus are involved in the mechanism of CaSR in gastric motility suppression.
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Calcio , Sistema Nervioso Entérico , Ratones , Animales , Masculino , Calcio/metabolismo , Calcio/farmacología , Capsaicina/farmacología , Capsaicina/metabolismo , Sistema Nervioso Entérico/fisiología , Plexo Mientérico/metabolismo , Motilidad Gastrointestinal/fisiologíaRESUMEN
Eugenol, an active ingredient of many medicinal aromatic plants, has been proved to have the hypolipidemic effect, but its potential mechanism of action is still unknown. This study aimed to investigate whether eugenol regulates liver lipid accumulation in high-fat diet (HFD) induced nonalcoholic fatty liver disease (NAFLD) rats via the gut-brain-liver axis involving glucagon-like peptide-1 (GLP-1). Hepatic vagotomy was performed in NAFLD rats to determine the role of eugenol in regulating hepatic lipid accumulation via vagus nerve. The results showed that after eight weeks of eugenol administration in NAFLD rats, serum total cholesterol (TC), triglyceride (TG) and hepatic TG decreased. However, eugenol showed no significant effect on the increased food intakes and weight gain caused by the HFD. Eugenol promoted the secretion of GLP-1 into the blood, increased GLP-1 receptor (GLP-1R) expression in the duodenum, liver, arcuate nucleus (ARC) and paraventricular nucleus (PVN), increased c-fos expression in the nucleus tractus solitarii (NTS), and promoted ZO-1 and occludin expression in duodenum. Furthermore, steatosis and lipid accumulation were significantly alleviated. Hepatic vagotomy partially attenuated the improvement of eugenol in hepatic lipid accumulation in NAFLD rats. In conclusion, eugenol regulates hepatic lipid metabolism via a gut-brain-liver axis involving in GLP-1, providing a new strategy for the treatment of NAFLD.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Encéfalo/metabolismo , Dieta Alta en Grasa/efectos adversos , Eugenol/metabolismo , Eugenol/farmacología , Eugenol/uso terapéutico , Péptido 1 Similar al Glucagón/metabolismo , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ratas , Triglicéridos/metabolismoRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is demonstrated to be closely related to the disorder of gut microbiota and the intestinal mucosal barrier. Luteolin is a natural flavonoid with various activities. We aimed to investigate whether Luteolin can alleviate NAFLD and its possible mechanism involving the gut-liver axis. A rat NAFLD model was established by feeding a high-fat diet (HFD), and Luteolin was administered intragastrically. The effects of Luteolin on liver biochemical parameters, intestinal histopathology and integrity, gut microbiota, lipopolysaccharides (LPS), inflammatory cytokines, and the Toll-like receptor 4 (TLR4) signaling pathway were evaluated. We found that Luteolin restored the expression of the tight junction proteins in the intestine and ameliorated the increase permeability of the intestinal mucosa to Fluorescein isothiocyanate-dextran (FD4) caused by a high-fat diet, thus enhancing the function of the intestinal barrier. In addition, Luteolin inhibited the TLR4 signaling pathway in the liver, thereby reducing the secretion of pro-inflammatory factors and alleviating NAFLD. 16S rRNA gene sequencing revealed that Luteolin intervention significantly altered the composition of the gut microbiota in NAFLD rats and increased the richness of gut microbiota. Luteolin alleviates NAFLD in rats via restoration and repair of the damaged intestinal mucosal barrier and microbiota imbalance.
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Microbioma Gastrointestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Hígado/efectos de los fármacos , Luteolina/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Peso Corporal/efectos de los fármacos , Citocinas/metabolismo , Dieta Alta en Grasa , Disbiosis/tratamiento farmacológico , Resistencia a la Insulina/fisiología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Enfermedad del Hígado Graso no Alcohólico/patología , Permeabilidad , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismoRESUMEN
Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by repetitive motor movements and vocal tics. The clinical manifestations of TS are complex and often overlap with other neuropsychiatric disorders. TS is highly heritable; however, the underlying genetic basis and molecular and neuronal mechanisms of TS remain largely unknown. We performed whole-exome sequencing of a hundred trios (probands and their parents) with detailed records of their clinical presentations and identified a risk gene, ASH1L, that was both de novo mutated and associated with TS based on a transmission disequilibrium test. As a replication, we performed follow-up targeted sequencing of ASH1L in additional 524 unrelated TS samples and replicated the association (P value = 0.001). The point mutations in ASH1L cause defects in its enzymatic activity. Therefore, we established a transgenic mouse line and performed an array of anatomical, behavioral, and functional assays to investigate ASH1L function. The Ash1l+/- mice manifested tic-like behaviors and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol. We also found that Ash1l disruption leads to hyper-activation and elevated dopamine-releasing events in the dorsal striatum, all of which could explain the neural mechanisms for the behavioral abnormalities in mice. Taken together, our results provide compelling evidence that ASH1L is a TS risk gene.
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Proteínas de Unión al ADN/genética , N-Metiltransferasa de Histona-Lisina/genética , Síndrome de Tourette/genética , Adolescente , Adulto , Animales , Niño , Preescolar , China , Proteínas de Unión al ADN/metabolismo , Familia , Femenino , Predisposición Genética a la Enfermedad/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Mutación/genética , Padres , Trastornos de Tic/genética , Síndrome de Tourette/complicaciones , Factores de Transcripción/genética , Secuenciación del Exoma/métodosRESUMEN
Nano Ru-based catalysts, including monometallic Ru and Ru-Zn nanoparticles, were synthesized via a precipitation method. The prepared catalysts were evaluated on partial hydrogenation of benzene towards cyclohexene generation, during which the effect of reaction modifiers, i.e., ZnSO4, MnSO4, and FeSO4, was investigated. The fresh and the spent catalysts were thoroughly characterized by XRD, TEM, SEM, XPS, XRF, and DFT studies. It was found that Zn2+ or Fe2+ could be adsorbed on the surface of a monometallic Ru catalyst, where a stabilized complex could be formed between the cations and the cyclohexene. This led to an enhancement of catalytic selectivity towards cyclohexene. Furthermore, electron transfer was observed from Zn2+ or Fe2+ to Ru, hindering the catalytic activity towards benzene hydrogenation. In comparison, very few Mn2+ cations were adsorbed on the Ru surface, for which no cyclohexene could be detected. On the other hand, for Ru-Zn catalyst, Zn existed as rodlike ZnO. The added ZnSO4 and FeSO4 could react with ZnO to generate (Zn(OH)2)5(ZnSO4)(H2O) and basic Fe sulfate, respectively. This further benefited the adsorption of Zn2+ or Fe2+, leading to the decrease of catalytic activity towards benzene conversion and the increase of selectivity towards cyclohexene synthesis. When 0.57 mol·L-1 of ZnSO4 was applied, the highest cyclohexene yield of 62.6% was achieved. When MnSO4 was used as a reaction modifier, H2SO4 could be generated in the slurry via its hydrolysis, which reacted with ZnO to form ZnSO4. The selectivity towards cyclohexene formation was then improved by the adsorbed Zn2+.
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Benceno/química , Compuestos Ferrosos/química , Compuestos de Manganeso/química , Rutenio/química , Sulfatos/química , Sulfato de Zinc/química , Catálisis , Ciclohexenos/química , Hidrogenación , Hierro/químicaRESUMEN
Understanding the mechanisms regulating feeding is crucial to unraveling the pathogenesis of obesity. The study primary explored the effects of orexin-A and neuropeptide Y (NPY) signaling in the hypothalamic paraventricular nucleus (PVN) on feeding and glucose-sensitive (GS) neuron activity in rats. Microinjection of orexin-A into the PVN promoted feeding and modulated the spontaneous firing of GS neurons. Those effects were eliminated by pre-injection of the orexin-A receptor-1 (OX1R) antagonist SB-334867 and weaken by the NPY-1 receptor (NPY-1R) antagonist BMS-193885. After orexin-A administration into the PVN, the number of c-fos cells in the arcuate nucleus (ARC) was significantly higher than that in the group receiving normal saline. Furthermore, most cells exhibited co-expression of NPY and c-fos, indicating activation of NPY neurons in the ARC by PVN-administered orexin-A, which might be involved in feeding regulation. These findings indicate that orexin-A and NPY signaling in the PVN are essential to regulating GS neuronal excitability and feeding in rats.
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Ingestión de Alimentos/efectos de los fármacos , Glucosa/farmacología , Neuronas/efectos de los fármacos , Neuropéptido Y/metabolismo , Orexinas/farmacología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Animales , Benzoxazoles/farmacología , Dihidropiridinas/farmacología , Masculino , Naftiridinas , Neuronas/metabolismo , Neuronas/fisiología , Receptores de Orexina/genética , Receptores de Orexina/metabolismo , Orexinas/administración & dosificación , Núcleo Hipotalámico Paraventricular/metabolismo , Compuestos de Fenilurea/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Sprague-Dawley , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/metabolismo , Transducción de Señal/efectos de los fármacos , Urea/análogos & derivados , Urea/farmacologíaRESUMEN
Obesity has become a global problem due to its sharply increased prevalence and associated complications. Orexin and opioid signaling can regulate feeding behavior and represent potential therapeutic targets for obesity. In the present experiment, we sought to ascertain the effects of orexin-A and µ-opioid signaling regulation in the basomedial amygdala (BMA) on feeding and investigate the physiology of gastric distension (GD)-responsive neurons in a diet-induced obesity (DIO) and diet-induced obesity resistance (DR) rat model. Intra-BMA infusions of orexin-A increased the firing of BMA GD neurons and increased food intake, and that these effects could be abolished by pretreatment with the orexin-1 receptor (OX-1R) antagonist SB334867, these effects could also be somewhat attenuated by co-administration of naloxone. In the DIO and DR rats, mRNA expression of OX-1R and µ-opioid receptors were increased in the BMA. Our results strongly suggest that orexin-A and opioid signaling in the BMA play a major role in regulating GD neuronal excitability and feeding behavior in obesity.
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Amígdala del Cerebelo/fisiopatología , Ingestión de Alimentos , Naloxona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Obesidad/tratamiento farmacológico , Obesidad/fisiopatología , Receptores de Orexina/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Animales , Dieta Alta en Grasa/efectos adversos , Ingestión de Alimentos/efectos de los fármacos , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Obesidad/etiología , Obesidad/metabolismo , Orexinas/metabolismo , Ratas , Ratas Wistar , Receptores Opioides mu/metabolismoRESUMEN
A decontaminating composite, Mg3 Al-LDH-Nb6 , has been successfully prepared by immobilizing Lindqvist [H3 Nb6 O19 ]5- (Nb6 ) into a Mg3 Al-based layered double hydroxide (Mg3 Al-LDH). To our knowledge, this represents the first successful approach to the immobilization of polyoxoniobate. As a versatile catalyst, Mg3 Al-LDH-Nb6 can effectively catalyze the degradation of both vesicant and nerve agent simulants by multiple pathways under mild conditions. Specifically, the sulfur mustard simulant, 2-chloroethyl ethyl sulfide (CEES), is converted into the corresponding nontoxic 2-chloroethyl ethyl sulfoxide (CEESO) by selective oxidation, whereas the Tabun (G-type nerve agent) simulant, diethyl cyanophosphonate (DECP), and the VX (V-type nerve agent) simulant, O,S-diethyl methylphosphonothioate (OSDEMP), are detoxified through hydrolysis and perhydrolysis, respectively. A possible mechanism is proposed on the basis of control experiments and spectroscopic studies. The Mg3 Al-LDH-Nb6 composite exhibits remarkable robustness and can be readily reused for up to ten cycles with negligible loss of its catalytic activity. More importantly, a protective "self-detoxifying" material has easily been constructed by integrating Mg3 Al-LDH-Nb6 into textiles. In this way, the flexible and permeable properties of textiles have been combined with the catalytic activity of polyoxoniobate to remove 94 % of CEES in 1â h by using nearly stoichiometric dilute H2 O2 (3 %) as oxidant with 96 % selectivity.
RESUMEN
It has been well-known that hypothalamic orexigenic neuropeptides, orexin-A, and melanin-concentrating hormone (MCH), play important roles in regulation of gastric function. However, what neural pathway mediated by the two neuropeptides affects the gastric function remains unknown. In this study, by way of nucleic stimulation and extracellular recording of single unit electrophysiological properties, we found that electrically stimulating the lateral hypothalamic area (LH) or microinjection of orexin-A into the arcuate nucleus (ARC) excited most gastric distension-responsive neurons in the nuclei and enhanced the gastric function including motility, emptying, and acid secretion of conscious rats. The results indicated that LH-ARC orexin-A-ergic projections may exist and the orexin-A in the ARC affected afferent and efferent signal transmission between ARC and stomach. As expected, combination of retrograde tracing and immunohistochemistry showed that some orexin-A-ergic neurons projected from the LH to the ARC. In addition, microinjection of MCH and its receptor antagonist PMC-3881-PI into the ARC affected the role of orexin-A in the ARC, indicating a possible involvement of the MCH pathway in the orexin-A role. Our findings suggest that there was an orexin-A-ergic pathway between LH and ARC which participated in transmitting information between the central nuclei and the gastrointestinal tract and in regulating the gastric function of rats.
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Núcleo Arqueado del Hipotálamo/citología , Área Hipotalámica Lateral/citología , Vías Nerviosas/citología , Vías Nerviosas/metabolismo , Estómago/inervación , Animales , Núcleo Arqueado del Hipotálamo/fisiología , Área Hipotalámica Lateral/fisiología , Masculino , Orexinas/metabolismo , Ratas , Ratas Wistar , Estómago/fisiologíaRESUMEN
The current study investigated the effects of nesfatin-1 in the hypothalamic paraventricular nucleus (PVN) on gastric motility and the regulation of the lateral hypothalamic area (LHA). Using single unit recordings in the PVN, we show that nesfatin-1 inhibited the majority of the gastric distention (GD)-excitatory neurons and excited more than half of the GD-inhibitory (GD-I) neurons in the PVN, which were weakened by oxytocin receptor antagonist H4928. Gastric motility experiments showed that administration of nesfatin-1 in the PVN decreased gastric motility, which was also partly prevented by H4928. The nesfatin-1 concentration producing a half-maximal response (EC50) in the PVN was lower than the value in the dorsomedial hypothalamic nucleus, while nesfatin-1 in the reuniens thalamic nucleus had no effect on gastric motility. Retrograde tracing and immunofluorescent staining showed that nucleobindin-2/nesfatin-1 and fluorogold double-labeled neurons were observed in the LHA. Electrical LHA stimulation changed the firing rate of GD-responsive neurons in the PVN. Pre-administration of an anti- nucleobindin-2/nesfatin-1 antibody in the PVN strengthened gastric motility and decreased the discharging of the GD-I neurons induced by electrical stimulation of the LHA. These results demonstrate that nesfatin-1 in the PVN could serve as an inhibitory factor to inhibit gastric motility, which might be regulated by the LHA.
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Proteínas de Unión al Calcio/farmacología , Proteínas de Unión al ADN/farmacología , Motilidad Gastrointestinal/efectos de los fármacos , Área Hipotalámica Lateral/efectos de los fármacos , Proteínas del Tejido Nervioso/farmacología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Estómago/efectos de los fármacos , Animales , Estimulación Eléctrica , Vaciamiento Gástrico/efectos de los fármacos , Masculino , Neuronas/efectos de los fármacos , Nucleobindinas , Ratas , Ratas Wistar , Receptores de Oxitocina/antagonistas & inhibidoresRESUMEN
The present study was aimed to investigate the effects of orexin-A and orexin-1 receptor (OX1R) antagonist injected into the fourth ventricle of rats on food-intake and spontaneous physical activity (SPA). Obese rat model was induced by high fat diet. Different doses of orexin-A or SB334867, an OX1R antagonist, were injected into the fourth ventricle of obese and normal rats respectively. SPA and food intake were monitored for 4 h after injection in both light and dark environment. In the light measurement cycle, different doses of orexin-A significantly stimulated feeding and SPA in all injected rats, and the animals' responses showed a dose-dependent manner (P < 0.05-0.01), and compared with those of normal rats, the orexin-A induced food intake and SPA were more pronounced in obese rats. In the dark measurement cycle, different doses of orexin-A had no obvious effect on food intake and SPA in both normal and obese rats (P > 0.05). In the light cycle, different doses of SB334867 significantly decreased food intake and SPA in all rats during 0-2 h and 2-4 h after injection (P < 0.05), but the food intake and SPA in obese rats were significantly greater than those of normal rats. In the dark cycle, different doses of SB334867 showed no obvious effect on food intake and SPA of normal and obese rats (P > 0.05). These results suggest that fourth cerebral ventricle nuclei may be one target for orexin-A and light condition may play an important role in orexin-A and OX1R physiological functional processes.
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Ingestión de Alimentos/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Antagonistas de los Receptores de Orexina/farmacología , Orexinas/farmacología , Animales , Benzoxazoles/farmacología , Dieta Alta en Grasa , Cuarto Ventrículo , Naftiridinas , Obesidad , Receptores de Orexina , Ratas , Urea/análogos & derivados , Urea/farmacologíaRESUMEN
Ghrelin is an acylated peptide originally identified in the rat stomach as the endogenous ligand for growth hormone secretagogue receptor (GHSR) that promotes gastric motility. Our aims were to explore the effects of ghrelin on gastric-distension-sensitive neurons in the hippocampus and the potential for ghrelin to regulate gastric motility through the arcuate nucleus (Arc). Single-unit discharges in the hippocampus were recorded extracellularly, and gastric motility in conscious rats was monitored. The expression of GHSR-1a in the hippocampus was determined by PCR, Western blot and fluo-immunohistochemistry staining. Retrograde tracing and fluo-immunohistochemistry staining were used to determine ghrelin neuron projection. Ghrelin-Fluoro-Gold double-labelled neurons and GHSR-1a expression were observed in the Arc and hippocampus, respectively. There were gastric-distension-sensitive neurons in the hippocampus that could be excited by ghrelin or by electrical stimulation of the Arc. The excitatory effects could be blocked completely or partly by pretreatment with the ghrelin receptor antagonist [d-Lys-3]-GHRP-6. Gastric motility was significantly promoted by the administration of ghrelin into the hippocampus in a dose-dependent manner that could be completely abolished by [d-Lys-3]-GHRP-6. Electrical stimulation of the Arc could promote gastric motility as well. Nevertheless, these effects could be mitigated by pretreatment with [d-Lys-3]-GHRP-6. Electrical lesioning of the hippocampus diminished the excitatory effects on gastric motility that were induced by electrical stimulation the Arc. Our findings suggest that ghrelin plays an important role in promoting gastric motility via the hippocampus. The Arc may be involved in regulation of the influence of the hippocampus on gastric motility.
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Núcleo Arqueado del Hipotálamo/fisiología , Motilidad Gastrointestinal/fisiología , Ghrelina/metabolismo , Hipocampo/fisiología , Hipotálamo/fisiología , Neuronas/fisiología , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Estimulación Eléctrica/métodos , Hipocampo/metabolismo , Hipotálamo/metabolismo , Masculino , Neuronas/metabolismo , Ratas , Ratas Wistar , Receptores de Ghrelina/antagonistas & inhibidores , Receptores de Ghrelina/metabolismoRESUMEN
BACKGROUND: The Calcium-sensing receptor (CaSR) participates in the regulation of gastrointestinal (GI) motility under normal conditions and might be involved in the regulation of GI dysmotility in patients with Parkinson's disease (PD). METHODS: CaSR antagonist-NPS-2143 was applied in in vivo and ex vivo experiments to study the effect and underlying mechanisms of CaSR inhibition on GI dysmotility in the MPTP-induced PD mouse model. FINDINGS: Oral intake of NPS-2143 promoted GI motility in PD mice as shown by the increased gastric emptying rate and shortened whole gut transit time together with improved weight and water content in the feces of PD mice, and the lack of influence on normal mice. Meanwhile, the number of cholinergic neurons, the proportion of serotonergic neurons, as well as the levels of acetylcholine and serotonin increased, but the numbers of nitrergic and tyrosine hydroxylase immunoreactive neurons, and the levels of nitric oxide synthase and dopamine decreased in the myenteric plexus in the gastric antrum and colon of PD mice in response to NPS-2143 treatment. Furthermore, the numbers of c-fos positive neurons in the nucleus tractus solitarius (NTS) and cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) increased in NPS-2143 treated PD mice, suggesting the involvement of both the enteric (ENS) and central (CNS) nervous systems. However, ex vivo results showed that NPS-2143 directly inhibited the contractility of antral and colonic strips in PD mice via a non-ENS mediated mechanism. Further studies revealed that NPS-2143 directly inhibited the voltage gated Ca2+ channels, which might, at least in part, explain its direct inhibitory effects on the GI muscle strips. INTERPRETATION: CaSR inhibition by its antagonist ameliorated GI dysmotility in PD mice via coordinated neuronal regulation by both ENS and CNS in vivo, although the direct effects of CaSR inhibition on GI muscle strips were suppressive.
Asunto(s)
Motilidad Gastrointestinal , Naftalenos , Enfermedad de Parkinson , Receptores Sensibles al Calcio , Animales , Masculino , Ratones , Modelos Animales de Enfermedad , Vaciamiento Gástrico/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Ratones Endogámicos C57BL , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Receptores Sensibles al Calcio/antagonistas & inhibidores , Receptores Sensibles al Calcio/metabolismoRESUMEN
Although the novel satiety peptide nesfatin-1 has been shown to regulate gastric motility, the underlying mechanisms have yet to be elucidated. The study aimed to explore the effects of nesfatin-1 on ghrelin-responsive gastric distension (GD) neurons in the arcuate nucleus (Arc), and potential regulation mechanisms of gastric motility by the paraventricular nucleus (PVN). Single-unit discharges in the Arc were recorded extracellularly, and gastric motility in conscious rats was monitored during the administration of nesfatin-1 to the Arc or electrical stimulation of the PVN. Retrograde tracing and fluo-immunohistochemistry staining were used to determine NUCB2/nesfatin-1 neuronal projections. Nesfatin-1 inhibited most of the ghrelin-responsive GD-excitatory neurons, but excited ghrelin-responsive GD-inhibitory neurons in the Arc. Gastric motility was significantly reduced by nesfatin-1 administration to the Arc in a dose-dependent manner. The firing activity in the Arc and changes to gastric motility were partly reduced by SHU9119, an antagonist of melanocortin 3/4 receptors. Electrical stimulation of PVN excited most of the ghrelin-responsive GD neurons in the Arc and promoted gastric motility. Nonetheless, pretreatment with an anti-NUCB2/nesfatin-1 antibody in the Arc further increased the firing rate of most of the ghrelin-responsive GD-excitatory neurons and decreased the ghrelin-responsive GD-inhibitory neurons following electrical stimulation of the PVN. Gastric motility was enhanced by pretreatment with an anti-NUCB2/nesfatin-1 antibody in the Arc following PVN stimulation. Furthermore, NUCB2/nesfatin-1/fluorogold double-labeled neurons were detected in the PVN. These results suggest that nesfatin-1 could serve as an inhibitory factor in the Arc to regulate gastric motility via the melanocortin pathway. The PVN could be involved in the regulation of the Arc in gastric activity.
Asunto(s)
Potenciales de Acción , Núcleo Arqueado del Hipotálamo/fisiología , Proteínas de Unión al Calcio/farmacología , Proteínas de Unión al ADN/farmacología , Motilidad Gastrointestinal/efectos de los fármacos , Ghrelina/farmacología , Proteínas del Tejido Nervioso/farmacología , Neuronas/fisiología , Animales , Núcleo Arqueado del Hipotálamo/citología , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Masculino , Hormonas Estimuladoras de los Melanocitos/farmacología , Neuronas/efectos de los fármacos , Nucleobindinas , Ratas , Ratas WistarRESUMEN
The globus pallidus plays a critical role in movement regulation. Glutamate being an important excitatory neurotransmitter modulates the activity of pallidal neurons through both ionotropic and metabotropic glutamate receptors (mGluRs). Morphological studies have shown that group III mGluRs are generally located presynaptically in the globus pallidus. Up to now, little is known about the in vivo electrophysiological effects of group III mGluRs on the pallidal neurons. This study investigated the electrophysiological and behavioral effects of group III mGluRs on pallidal neurons in both normal and 6-hydroxydopamine (6-OHDA) lesioned parkinsonian rats. Micropressure ejection of group III mGluR agonist, L-2-amino-4-phosphonobutyrate (L-AP4), increased or decreased the firing rate of pallidal neurons in both normal and parkinsonian rats. The L-AP4-induced excitatory effects on the lesioned side of parkinsonian rats (117.4 ± 17.2%) were stronger than that in normal rats (64.3 ± 10.1%). While the proportion of neurons that were unresponsive to L-AP4 on the lesioned side of parkinsonian rats (50%) was more than that of normal rats (13%). Unilateral microinjection of L-AP4 into the globus pallidus induced a contralateral dystonic posturing in the presence of systemic haloperidol administration. The selective group III mGluRs antagonist, (RS)-α-cyclopropyl-4-phosphonophenylglycine, had no effect on pallidal neurons when used alone and could block both L-AP4-induced electrophysiological and behavioral effects. Combining electrophysiological and behavioral findings, we concluded that activation of group III mGluRs modulate the activity of pallidal neurons under both normal and parkinsonian state.