共查询到20条相似文献,搜索用时 31 毫秒
1.
Seung‐Ryoung Jung Luz E. Farias Altamirano Martin Kruse Jong Bae Seo Duk‐Su Koh Bertil Hille 《Journal of pineal research》2016,61(1):69-81
Pinealocytes secrete melatonin at night in response to norepinephrine released from sympathetic nerve terminals in the pineal gland. The gland also contains many other neurotransmitters whose cellular disposition, activity, and relevance to pineal function are not understood. Here, we clarify sources and demonstrate cellular actions of the neurotransmitter γ‐aminobutyric acid (GABA) using Western blotting and immunohistochemistry of the gland and electrical recording from pinealocytes. GABAergic cells and nerve fibers, defined as containing GABA and the synthetic GAD67, were identified. The cells represent a subset of interstitial cells while the nerve fibers were distinct from the sympathetic innervation. The GABAA receptor subunit α1 was visualized in close proximity of both GABAergic and sympathetic nerve fibers as well as fine extensions among pinealocytes and blood vessels. The GABAB1 receptor subunit was localized in the interstitial compartment but not in pinealocytes. Electrophysiology of isolated pinealocytes revealed that GABA and muscimol elicit strong inward chloride currents sensitive to bicuculline and picrotoxin, clear evidence for functional GABAA receptors on the surface membrane. Applications of elevated potassium solution or the neurotransmitter acetylcholine depolarized the pinealocyte membrane potential enough to open voltage‐gated Ca2+ channels leading to intracellular calcium elevations. GABA repolarized the membrane and shut off such calcium rises. In 48–72‐h cultured intact glands, GABA application neither triggered melatonin secretion by itself nor affected norepinephrine‐induced secretion. Thus, strong elements of GABA signaling are present in pineal glands that make large electrical responses in pinealocytes, but physiological roles need to be found. 相似文献
2.
Wenmei Fan Bingyi Shi Hongshan Wei Xihui Ma Xiuyun He Kai Feng 《Digestive diseases and sciences》2013,58(7):1909-1915
Background
It was well known that angiotension II can inhibit hepatic stellate cell activation. The GABAB receptor was upregulated when the hepatic stellate cell line was stimulated by angiotension II in our previous study. But the role of the GABAB receptor in liver fibrosis has never been reported.Aim
In the present study, we investigated the effects of this receptor on carbon tetrachloride-induced liver fibrosis in rats.Methods
The rats were divided into four groups including GABAB receptor agonist, antangonist, model and control group. α-smooth muscle actin (α-SMA) and GABAB receptor expression levels were detected by immunohistochemistry and real-time polymerase chain reaction. Liver function tests were performed once blood samples was taken; Western blot analysis was used to detect protein expression level of α-SMA and TGF-β1.Results
We found baclofen ameliorated the CCl4-induced rats’s liver fibrosis. The highest liver enzymes and α-SMA protein levels were found in the CGP35348 group.Conclusion
The GABAB receptor may have a protective role in the liver. 相似文献3.
Fulvia Berton Walter G. Francesconi Samuel G. Madamba Walter Zieglgänsberger George Robert Siggins 《Alcoholism, clinical and experimental research》1998,22(1):183-191
Acamprosate (calcium acetylhomotaurine) is used therapeutically in Europe to reduce relapse in weaned alcoholics. However, the mechanisms of acamprosate action in the central nervous system are still obscure, although early studies suggested an action on GABA receptors. The nucleus accumbens (NAcc) is a brain region thought to underlie ethanol reinforcement. Recent studies from our laboratory have demonstrated that ethanol inhibits both N-methyl-D-aspartate (NMDA) and non-NMDA types of glutamatergic synaptic transmission in the NAcc.1,2 In the present study, we used voltage- and current-clamp intracellular recording of NAcc core neurons in a slice preparation to examine acamprosate actions on resting membrane properties and pharmacologically isolated synaptic responses. We isolated NMDA and non-NMDA receptor-mediated excitatory postsynaptic potentials or currents (EPSP/Cs) with 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphonovaler-ate (d-APV), respectively. Bicuculline was also included to block GABAA receptors. Superfusion of acamprosate (5, 50, and 300 μM) did not alter the resting membrane properties of NAcc neurons. However, 300 μM acamprosate significantly increased the NMDA receptor-mediated components of EPSP/Cs (NMDA-EPSP/Cs) with recovery on washout. In contrast, 300 μM acamprosate had no significant effect on the non-NMDA receptor component of the EPSP/Cs (non-NMDA-EPSP/Cs). To test acamprosate actions on the GABA system, we superfused 60 μM d-APV and 20 μM CNQX to block glutamatergic transmission and evoked monosynaptic GABAA receptor-mediated synaptic responses within the NAcc. Acamprosate (300 μM) did not change these monosynaptic GABAA-IPSCs. We also used a paired-pulse paradigm to test whether acamprosate could act on presynaptic GABAB, autoreceptors, in the presence of d-APV and CNQX to block glutamatergic transmission. Like 0.5 μM CGP 34358 (a GABAB receptor blocker), acamprosate significantly decreased the paired-pulse inhibition (PPI) of GABAA-IPSCs at short interstimulus intervals (ISIs). Thus, acamprosate may concomitantly enhance NMDA-EPSP/Cs while blocking presynaptic GABAB receptor-mediated inhibition of GABA release. These results suggest that acamprosate's clinical efficacy in preventing relapse in weaned alcoholics could derive from its interactions with both the glutamatergic and GABAergic systems in the NAcc. Synaptic Transmission, Alcohol, Ethanol, EPSPs, NMDA Receptors. 相似文献
4.
There is an urgent need for new approaches to limit the severity of coronavirus infections. Many cells of the immune system express receptors for the neurotransmitter γ-aminobutyric acid (GABA), and GABA-receptor (GABA-R) agonists have anti-inflammatory effects. Lung epithelial cells also express GABA-Rs, and GABA-R modulators have been shown to limit acute lung injuries. There is currently, however, no information on whether GABA-R agonists might impact the course of a viral infection. Here, we assessed whether clinically applicable GABA-R agonists could be repurposed for the treatment of a lethal coronavirus (murine hepatitis virus 1, MHV-1) infection in mice. We found that oral GABA administration before, or after the appearance of symptoms, very effectively limited MHV-1-induced pneumonitis, severe illness, and death. GABA treatment also reduced viral load in the lungs, suggesting that GABA-Rs may provide a new druggable target to limit coronavirus replication. Treatment with the GABAA-R-specific agonist homotaurine, but not the GABAB-R-specific agonist baclofen, significantly reduced the severity of pneumonitis and death rates in MHV-1-infected mice, indicating that the therapeutic effects were mediated primarily through GABAA-Rs. Since GABA and homotaurine are safe for human consumption, they are promising candidates to help treat coronavirus infections. 相似文献
5.
Transient lower esophageal sphincter relaxations (TLESRs) are rapid and prolonged relaxations of the lower esophageal sphincter
(LES) that are not associated with swallowing. They are the mechanism by which most gastroesophageal reflux episodes occur
in normal people and in patients with esophagitis. Transient LES relaxations appear to be mediated by a vagovagal reflex initiated
by gastric distention. Baclofen is a γ -aminobutyric acid (GABA) derivative that inhibits the production of TLESRs by acting
as a GABAB receptor agonist at one or more loci along the vagovagal reflex arc. Animal and human studies suggest that baclofen decreases
the number of reflux events and amount of esophageal acid exposure. Baclofen or another GABAB receptor agonist may be clinically useful in treatment of gastroesophageal reflux disease. 相似文献
6.
Azam Almasi Mohammad Zarei Safoura Raoufi Abdolrahman Sarihi Iraj Salehi Alireza Komaki Nasrin Hashemi-Firouzi Siamak Shahidi 《Metabolic brain disease》2018,33(6):1859-1867
The neurotransmitter γ-aminobutyric acid (GABA) is involved in the process of memory. It has been reported that the inhibition of GABAB receptors has beneficial effects on cognition. The aim of this study was to investigate the role of CGP35348 (a GABAB receptor antagonist) on dentate gyrus GABAB receptor inhibition and its effects on learning and memory impairments that had been induced in adult male rats by microinjection of β-amyloid (Aβ). Seventy Wistar male rats were randomly divided into seven groups: control, sham (receiving the Aβ vehicle only), Aβ, Aβ + CGP35348 (1, 10, and 100 μg/μL), and CGP35348 alone (10 μg/μL). Memory impairment was induced by unilateral interventricular microinjection of Aβ (6 μg/6 μL). Rats were cannulated bilaterally in the dentate gyrus, and then, they were treated for 20 consecutive days. Learning and memory were assessed using the novel object recognition and passive avoidance learning tests. The discrimination index and the step-through latency were significantly increased in the Aβ + CGP35348 group in comparison to the Aβ only group (P?<?0.05 and P?<?0.01, respectively). Data showed that the discrimination index was decreased in the Aβ + CGP35348 group in comparison with the control group (P?<?0.05) and sham group (P?<?0.01). Moreover, the step-through latency was significantly decreased in the Aβ + CGP35348 group in comparison to the control and sham groups (P?<?0.01). Data from this study indicated that intra-hippocampal microinjection of the GABAB receptor antagonist counteracts the learning, memory, and cognitive impairments induced by Aβ. It can be concluded that the GABAB receptor antagonist is a possible therapeutic agent against the progression of acute Aβ toxicity-induced memory impairment. 相似文献
7.
Fan Xiao Kangkang Yu Fang Dong Yunlei Liang Cheng Jun Hongshan Wei 《Digestive diseases and sciences》2010,55(2):261-267
Background/Aims Angiotensin II (Ang II) plays an important role in the activation of hepatic stellate cells (HSCs). In this study it was
found that expression of the GABAB receptor was elevated in HSCs treated with Ang II. We attempted to elucidate the mechanism of the GABAB receptor in HSCs activation. Methods First, the target gene (GABAB receptor) was screened by gene chip in HSCs treated with Ang II. Second, the biological function of the GABAB receptor was analyzed by MTT, cell-cycle assay, real-time PCR, and western blot. The methods of MTT and cell-cycle assay
were used to evaluate the effect of the GABAB receptor on proliferation and DNA synthesis of HSCs. Expression of ECM, TGF-β1, and α-SMA was analyzed by real-time PCR and
western blot. Results The GABAB receptor’s specific agonist CGP35348 inhibited the activation of HSCs, which could be partially reversed by the GABAB receptor’s antagonist. Conclusions Our in-vitro results demonstrated that the GABAB receptor could inhibit HSCs activation. 相似文献
8.
Nicole Guetg Said Abdel Aziz Niklaus Holbro Rostislav Turecek Tobias Rose Riad Seddik Martin Gassmann Suzette Moes Paul Jenoe Thomas G. Oertner Emilio Casanova Bernhard Bettler 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(31):13924-13929
GABAB receptors are the G-protein–coupled receptors for GABA, the main inhibitory neurotransmitter in the brain. GABAB receptors are abundant on dendritic spines, where they dampen postsynaptic excitability and inhibit Ca2+ influx through NMDA receptors when activated by spillover of GABA from neighboring GABAergic terminals. Here, we show that an excitatory signaling cascade enables spines to counteract this GABAB-mediated inhibition. We found that NMDA application to cultured hippocampal neurons promotes dynamin-dependent endocytosis of GABAB receptors. NMDA-dependent internalization of GABAB receptors requires activation of Ca2+/Calmodulin-dependent protein kinase II (CaMKII), which associates with GABAB receptors in vivo and phosphorylates serine 867 (S867) in the intracellular C terminus of the GABAB1 subunit. Blockade of either CaMKII or phosphorylation of S867 renders GABAB receptors refractory to NMDA-mediated internalization. Time-lapse two-photon imaging of organotypic hippocampal slices reveals that activation of NMDA receptors removes GABAB receptors within minutes from the surface of dendritic spines and shafts. NMDA-dependent S867 phosphorylation and internalization is predominantly detectable with the GABAB1b subunit isoform, which is the isoform that clusters with inhibitory effector K+ channels in the spines. Consistent with this, NMDA receptor activation in neurons impairs the ability of GABAB receptors to activate K+ channels. Thus, our data support that NMDA receptor activity endocytoses postsynaptic GABAB receptors through CaMKII-mediated phosphorylation of S867. This provides a means to spare NMDA receptors at individual glutamatergic synapses from reciprocal inhibition through GABAB receptors. 相似文献
9.
Taneera J Jin Z Jin Y Muhammed SJ Zhang E Lang S Salehi A Korsgren O Renström E Groop L Birnir B 《Diabetologia》2012,55(7):1985-1994
Aims/hypothesis
γ-Aminobutyric acid (GABA) is a signalling molecule in the interstitial space in pancreatic islets. We examined the expression and function of the GABA signalling system components in human pancreatic islets from normoglycaemic and type 2 diabetic individuals.Methods
Expression of GABA signalling system components was studied by microarray, quantitative PCR analysis, immunohistochemistry and patch-clamp experiments on cells in intact islets. Hormone release was measured from intact islets.Results
The GABA signalling system was compromised in islets from type 2 diabetic individuals, where the expression of the genes encoding the α1, α2, β2 and β3 GABAA channel subunits was downregulated. GABA originating within the islets evoked tonic currents in the cells. The currents were enhanced by pentobarbital and inhibited by the GABAA receptor antagonist, SR95531. The effects of SR95531 on hormone release revealed that activation of GABAA channels (GABAA receptors) decreased both insulin and glucagon secretion. The GABAB receptor antagonist, CPG55845, increased insulin release in islets (16.7?mmol/l glucose) from normoglycaemic and type 2 diabetic individuals.Conclusions/interpretation
Interstitial GABA activates GABAA channels and GABAB receptors and effectively modulates hormone release in islets from type 2 diabetic and normoglycaemic individuals. 相似文献10.
Tamar Dugladze Nino Maziashvili Christoph B?rgers Shalva Gurgenidze Ute H?ussler Aline Winkelmann Carola A. Haas Jochen C. Meier Imre Vida Nancy J. Kopell Tengis Gloveli 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(37):15073-15078
GABAB receptors (GABABRs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABABR agonist baclofen can also promote excitability and seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of γ oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased γ activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 µM), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 µM), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK+ BCs), through enhanced inhibition of GABA release via presynaptic GABABRs. We conclude that cell type–specific up-regulation of GABABR-mediated autoinhibition in CCK+ BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice.Neuronal activity in the hippocampus shows oscillations in behavior-relevant frequency ranges including γ frequencies (30–80 Hz) (1). γ activity is prominent in the aroused brain and has been implicated in higher-level brain functions, such as sensory binding, perception (2), and storage and recall of information (3, 4). At the same time, γ frequency oscillations are also prevalent in epileptic patients and are most often observed at seizure onset during in depth EEG recordings (5). The GABAergic system plays a pivotal role in the generation of γ oscillations (6–8). However, it remains to be resolved how distinct GABAergic receptor subtypes, in particular GABAB receptors (GABABRs), contribute to the generation and modulation of pathological network oscillatory activity.GABABRs mediate slow inhibitory effects and control synaptic transmission and the excitability of neurons in cortical networks. GABABRs are expressed both postsynaptically in somato-dendritic compartments and presynaptically in axon terminals, in excitatory principal cell and inhibitory interneurons (9–11). The effects of GABABR activation on the network are dominated by inhibition leading to an overall dampened population activity. However, if GABAergic interneurons are effected dominantly, as observed for example, during high-frequency stimulation, GABABR activation can produce disinhibition in principal cells (12, 13). Accordingly, the role of GABABRs in epilepsy and seizure generation remains ambiguous. GABABRs are expected to have an overall antiepileptic effect, and indeed, the receptor KO animals show an epileptic phenotype (14). However, there is also evidence that the receptor agonist baclofen can induce seizures in patients after intrathecal application (15, 16). The picture is further complicated by the fact that GABABR expression can be altered in both epileptic patients, e.g., in mesial temporal lobe epilepsy (mTLE) (17), and animal models (18). Thus, cell type–specific alterations in GABABR expression may change network excitability during the progression of mTLE.Using a chronic kainate (KA) model of mTLE, which reproduces major electrophysiological and histopathological characteristics of human mTLE (19, 20), we studied the role of GABABRs in altered hippocampal network activity. Our results suggest that enhanced and persistent GABABR activation in epileptic mice suppresses the inhibitory output from hippocampal interneurons, in particular cholecystokinin (CCK)-expressing basket cells (BCs) onto pyramidal cells (PCs). This reduction in the inhibitory output of interneurons, in turn, leads to disinhibition in hippocampal networks, enhances γ activity, and promotes the transition to pathological hyperexcitability. 相似文献
11.
R. J. Whitten R. Maitra J. N. Reynolds 《Alcoholism, clinical and experimental research》1996,20(7):1313-1319
We sought to test the hypotheses that closely related alcohols would have effects on GABAA receptor function that were not predicted by differences in lipid solubility, and that the subunit structure of the GABAA receptor would significantly affect the actions of different alcohols. Cloned subunits of human GABAA receptors were expressed in Xenopus oocytes, and two-electrode voltage-clamp recording was used to quantify the membrane current response to GABAA in the presence and absence of different alcohols. 1-Butanol and 2-butanol differentially potentiated the response to 20 μM GABA in oocytes expressing the α1β2γ2L and α2β2γ2L, receptor isoforms. In the α1β2γ2L receptor construct, 1-butanol was more potent than 2-butanol to potentiate GABA, receptor function, but 2-butanol had a greater efficacy. In the α2β2 receptor construct, 1-butanol and 2-butanol were equipotent, but 2-butanol again had a greater efficacy. In the a2p2 receptor construct, both 1-butanol and 2-butanol produced large potentiations of the current response to 3 μM GABA. The efficacy for butanol potentiation of GABA responses in the absence of a γ2L subunit was greater, but the potency was greatly reduced. Low concentrations (20 mM) of ethanol potentiated GABA responses in the α1β2γ2L receptor construct. Ethanol potentiation of GABAA receptor function was completely blocked by the benrodiazepine receptor partial inverse agonist R015-4513 at a concentration (0.5 μM) that did not alter the control GABA response. In contrast, R015-4513 did not block potentiation of GABAA receptor activity induced by npropanol, 1-butanol, 2-butanol, 1-heptanol, or propofol (2,0-diisopropylphenol). These results suggest that alcohols have specific interactions with GABAA receptors, and that ethanol may have unique effects not shared by other longer chain alcohols. 相似文献
12.
Aims/hypothesis: The neurotransmitters glutamate and γ-aminobutyric acid (GABA) could participate in the regulation of the endocrine functions of islets of Langerhans. We investigated
the role of the metabotropic glutamate (mGluRs) and GABAB (GABABRs) receptors in this process.
Methods: We studied the expression of mGluRs and GABA
BRs in rat and human islets of Langerhans and in pancreatic α-cell and beta-cell lines using RT-PCR and immunoblot analysis.
Effects of mGluR and GABA
B
R agonists on insulin secretion were determined by radioimmunoassays and enzyme-linked immunoadsorbent assays (ELISAs).
Results: We detected mGluR3 and mGluR5 (but not mGluR1, 6 and 7) mRNAs in all of the samples examined. Trace amount of mGluR2 was found in MIN6 beta cells; mGluR4 was identified in rat islets; and mGluR8 expression was detected in rat islets, RINm5F and MIN6 cells. GABA
BR1 a/b and 2 mRNAs were identified in islets of Langerhans and MIN6 cells. The expression of mGluR3, mGluR5, GABABR1 a/b and GABABR2 proteins was confirmed using specific antibodies. Group I (mGluR1/5) and group II (mGluR2/3) specific mGluR agonists increased
the release of insulin in the presence of 3 to 10 mmol/l or 3 to 25 mmol/l glucose, respectively, whereas a group III (mGluR4/6–8)
specific agonist inhibited insulin release at high (10–25 mmol/l) glucose concentrations. Baclofen, a GABABR agonist, also inhibited the release of insulin but only in the presence of 25 mmol/l glucose.
Conclusion/interpretation: These data suggest that mGluRs and GABABRs play a role in the regulation of the endocrine pancreas with mechanisms probably involving direct activation or inhibition
of voltage dependent Ca2+-channels, cAMP generation and G-protein-mediated modulation of KATP channels. [Diabetologia (2002) 45: 242–252]
Received: 18 September 2001 and in revised form: 5 November 2001 相似文献
13.
14.
Wilson Ranu Ramirez Nunez Michiko Regina Ozaki Adriana Mendes Vinagre Edgard Ferro Collares Eros Antonio de Almeida 《Arquivos brasileiros de cardiologia》2015,104(2):144-151
Background
In pathological situations, such as acute myocardial infarction, disorders of motility of the proximal gut can trigger symptoms like nausea and vomiting. Acute myocardial infarction delays gastric emptying (GE) of liquid in rats.Objective
Investigate the involvement of the vagus nerve, α 1-adrenoceptors, central nervous system GABAB receptors and also participation of paraventricular nucleus (PVN) of the hypothalamus in GE and gastric compliance (GC) in infarcted rats.Methods
Wistar rats, N = 8-15 in each group, were divided as INF group and sham (SH) group and subdivided. The infarction was performed through ligation of the left anterior descending coronary artery. GC was estimated with pressure-volume curves. Vagotomy was performed by sectioning the dorsal and ventral branches. To verify the action of GABAB receptors, baclofen was injected via icv (intracerebroventricular). Intravenous prazosin was used to produce chemical sympathectomy. The lesion in the PVN of the hypothalamus was performed using a 1mA/10s electrical current and GE was determined by measuring the percentage of gastric retention (% GR) of a saline meal.Results
No significant differences were observed regarding GC between groups; vagotomy significantly reduced % GR in INF group; icv treatment with baclofen significantly reduced %GR. GABAB receptors were not conclusively involved in delaying GE; intravenous treatment with prazosin significantly reduced GR% in INF group. PVN lesion abolished the effect of myocardial infarction on GE.Conclusion
Gastric emptying of liquids induced through acute myocardial infarction in rats showed the involvement of the vagus nerve, alpha1- adrenergic receptors and PVN. 相似文献15.
Michael Doengi Daniela Hirnet Philippe Coulon Hans-Christian Pape Joachim W. Deitmer Christian Lohr 《Proceedings of the National Academy of Sciences of the United States of America》2009,106(41):17570-17575
We studied GABAergic signaling in astrocytes of olfactory bulb slices using confocal Ca2+ imaging and two-photon Na+ imaging. GABA evoked Ca2+ transients in astrocytes that persisted in the presence of GABAA and GABAB receptor antagonists, but were suppressed by inhibition of GABA uptake by SNAP 5114. Withdrawal of external Ca2+ blocked GABA-induced Ca2+ transients, and depletion of Ca2+ stores with cyclopiazonic acid reduced Ca2+ transients by approximately 90%. This indicates that the Ca2+ transients depend on external Ca2+, but are mainly mediated by intracellular Ca2+ release, conforming with Ca2+-induced Ca2+ release. Inhibition of ryanodine receptors did not affect GABA-induced Ca2+ transients, whereas the InsP3 receptor blocker 2-APB inhibited the Ca2+ transients. GABA also induced Na+ increases in astrocytes, potentially reducing Na+/Ca2+ exchange. To test whether reduction of Na+/Ca2+ exchange induces Ca2+ signaling, we inhibited Na+/Ca2+ exchange with KB-R7943, which mimicked GABA-induced Ca2+ transients. Endogenous GABA release from neurons, activated by stimulation of afferent axons or NMDA application, also triggered Ca2+ transients in astrocytes. The significance of GABAergic Ca2+ signaling in astrocytes for control of blood flow is demonstrated by SNAP 5114-sensitive constriction of blood vessels accompanying GABA uptake. The results suggest that GABAergic signaling is composed of GABA uptake-mediated Na+ rises that reduce Na+/Ca2+ exchange, thereby leading to a Ca2+ increase sufficient to trigger Ca2+-induced Ca2+ release via InsP3 receptors. Hence, GABA transporters not only remove GABA from the extracellular space, but may also contribute to intracellular signaling and astrocyte function, such as control of blood flow. 相似文献
16.
《Digestive and liver disease》2022,54(4):543-553
AimWe explored whether tumor-derived extracellular vesicles (EVs) could deliver long noncoding RNA (lncRNA) PART1 into macrophage to orchestrate macrophage polarization in the progression of hepatocellular carcinoma (HCC).MethodThe expression patterns of PART1, microRNA (miR)-372-3p and TLR4 were detected by RT-qPCR in the HCC tissues and HCC cells. PART1 was silenced or overexpressed in HCC cells to assess its effects on the HCC cell process. EVs were isolated from PART1-overexpressed HCC cells, and co-cultured with macrophages, and gain- and loss-of-function assays were implemented in macrophages to evaluate their role in macrophage polarization. Relationship among PART1, miR-372-3p, and TLR4 was evaluated. Effect of EV-PART1 on tumorigenicity in vivo was detected by subcutaneous tumorigenicity test in nude mice.ResultPART1 and TLR4 were upregulated while miR-372-3p was downregulated in HCC tissues and cells. PART1 increased HCC cell proliferation, migration, invasion, and EMT. Mechanistically, PART1 bound to miR-372-3p to downregulate its expression, whereas TLR4 was negatively targeted by miR-372-3p in the macrophages. EVs containing PART1, TLR4 overexpression, or miR-372-3p inhibition induced M2 polarization of macrophages. Also, EVs containing PART1 promoted M2 polarization of macrophages and the occurrence of HCC by affecting miR-372-3p/TLR4 axis.ConclusionHCC cell-derived EVs might up-regulate TLR4 by inhibiting miR-372-3p via PART1 delivery to promote macrophage M2 polarization in HCC. 相似文献
17.
《Growth hormone & IGF research》2014,24(2-3):60-66
ObjectiveThe illicit use of anabolic androgenic steroids (AAS), especially among young adults, is of major concern. Among AAS users it is common to combine the AAS nandrolone decanoate (ND), with intake of growth hormone (GH) and a connection between gonadal steroids and the GH system has been suggested. Both AAS and GH affect functions in the brain, for example those associated with the hypothalamus and pituitary, and several GH actions are mediated by growth factors such as insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2). The GABAergic system is implicated in actions induced by AAS and previous studies have provided evidence for a link between GH and GABAB receptors in the brain. Our aim was to examine the impact of AAS administration and a subsequent administration of GH, on the expression of GABAB receptors and important GH mediators in rat brain.DesignThe aim was to investigate the CNS effects of a high-dose ND, and to study if a low, but physiological relevant, dose of GH could reverse the ND-induced effects. In the present study, male rats were administered a high dose of ND every third day during three weeks, and subsequently the rats were given recombinant human GH (rhGH) during ten days. Quantitative PCR (qPCR) was used to analyze gene expression in hypothalamus, anterior pituitary, caudate putamen, nucleus accumbens, and amygdala.ResultsIn the pituitary gland, the expression of GABAB receptor subunits was affected differently by the steroid treatment; the GABAB1 mRNA expression was decreased whereas a distinct elevation of the GABAB2 expression was found. Administration of ND also caused a decrease of GHR, IGF-1, and IGF-2 mRNA expression in the pituitary while the corresponding expression in the hypothalamus, caudate putamen, nucleus accumbens, and amygdala was unaffected. The rhGH administration did not alter the GABAB2 expression but increased the GABAB1 gene expression in the hypothalamus as compared to the AAS treated group.ConclusionsThese results provide new insights on the impact of ND and GH on the brain and highlight the interaction of these hormones with systems influencing GABAB receptor expression. The physiological significance of the observed effects of these hormones is discussed. 相似文献
18.
《Expert Review of Gastroenterology & Hepatology》2013,7(10):997-1006
ABSTRACTIntroduction: Macrophages represent a highly heterogeneous and plastic cell type found in most tissues of the body; the intestine is home to enormous numbers of these cells. Considerable interest surrounds the ‘M2 macrophage,’ as it is able to control and regulate inflammation, while promoting tissue repair.Areas covered: As potent inducers of M2 macrophages, intestinal helminths and helminth-derived products are ideal candidates for small molecule drug design to drive M2 macrophage polarization. Several gastrointestinal helminths have been found to cause M2 macrophage-inducing infections. This review covers current knowledge of helminth products and their impact on macrophage polarization, which may in the future lead to new therapeutic strategies.A literature search was performed using the following search terms in PubMed: M2 macrophage, alternative activation, helminth products, helminth ES, helminth therapy, nanoparticle, intestinal macrophages. Other studies were selected by using references from articles identified through our original literature search.Expert commentary: While the immunomodulatory potential of helminth products is well established, we have yet to fully characterize many components of the intestinal helminth product library. Current work aims to identify the protein motifs responsible for modulation of macrophages and other components of the immune system. 相似文献
19.
Laksmi Wulandari Muhammad Amin Gatot Soegiarto Kenji Ishiwata 《The Indian journal of tuberculosis》2021,68(3):340-349
BackgroundTuberculosis is a chronic infection caused by Mycobacterium tuberculosis (M.tb), which needs proper macrophage activation for control. It has been debated whether the co-infection with helminth will affect the immune response to mycobacterial infection.ObjectiveTo determine the effect of sequential co-infection of Heligmosomoides polygyrus (H.pg) nematodes and M.tb on T cell responses, macrophages polarization and lung histopathological changes.MethodThis study used 49 mice divided into 7 treatment groups, with different sequence of infection of M.tb via inhalation and H.pg via oral ingestion for 8 and 16 weeks. T cells response in the lung, intestine, and peripheral blood were determined by flow cytometry. Cytokines (IL-4, IFN-γ, TGB-β1, and IL-10) were measured in peripheral blood using ELISA. Lung macrophage polarization were determined by the expression of iNOS (M1) or Arginase 1 (M2). Mycobacterial count were done in lung tissue. Lung histopathology were measured using Dorman’s semiquantitative score assessing peribronchiolitis, perivasculitis, alveolitis, and granuloma formation.ResultM.tb infection induced Th1 response and M1 macrophage polarization, while H.pg infection induced Th2 and M2 polarization. In sequential co-infection, the final polarization of macrophage was dictated by the sequence of co-infection. However, all groups with M.tb infection showed the same degree of mycobacterial count in lung tissues and lung tissue histopathological changes.ConclusionSequential co-infection of H.pg and M.tb induces different T cell response which leads to different macrophage polarization in lung tissue. Helminth infection induced M2 lung macrophage polarization, but did not cause different mycobacterial count nor lung histopathological changes. 相似文献
20.
We investigated the effects of gamma-aminobutyric acid (GABA) agonists muscimol and baclofen (GABA(A) and GABA(B) agonists, respectively) and antagonists bicuculline methiodide (BMI, GABA(A) antagonist) or 2-hydroxysaclofen (SAC) and CGP 55845A (GABA(B) antagonists) on prolactin (PRL) secretion in castrated rams. The drugs were applied by microdialysis into either the medial preoptic area (mPOA) or ventromedial hypothalamus (VMH). Dialysis of baclofen into the mPOA significantly increased mean PRL (p < 0.05), whereas SAC caused a small, but significant decrease (p < 0.01). Dialysis of either muscimol or BMI into the mPOA had no effect on prolactin. In the VMH, baclofen significantly increased (p < 0.01) mean PRL but SAC and CGP 55845A were ineffective, whereas dialysis of either muscimol or BMI increased mean prolactin (p < 0.01). These results show that infusion into the mPOA of drugs that affect GABA(B) receptor alter PRL release, whereas infusion of a GABA(A) agonists and antagonist was without effect on PRL release. In contrast, infusion of both GABA(A) and GABA(B) agonists and a GABA(A) antagonist into the VMH altered PRL secretion. This suggest that GABAergic neurons in both regions participate in regulating PRL secretion, but by different receptor systems. 相似文献