RESUMO
The prevailing opinion emphasizes fronto-parietal network (FPN) is key in mediating general fluid intelligence (gF). Meanwhile, recent studies show that human MT complex (hMT+), located at the occipito-temporal border and involved in 3D perception processing, also plays a key role in gF. However, the underlying mechanism is not clear, yet. To investigate this issue, our study targets visuo-spatial intelligence, which is considered to have high loading on gF. We use ultra-high field magnetic resonance spectroscopy (MRS) to measure GABA/Glu concentrations in hMT+ combining resting-state fMRI functional connectivity (FC), behavioral examinations including hMT+ perception suppression test and gF subtest in visuo-spatial component. Our findings show that both GABA in hMT+ and frontal-hMT+ functional connectivity significantly correlate with the performance of visuo-spatial intelligence. Further, serial mediation model demonstrates that the effect of hMT+ GABA on visuo-spatial gF is fully mediated by the hMT+ frontal FC. Together our findings highlight the importance in integrating sensory and frontal cortices in mediating the visuo-spatial component of general fluid intelligence.
Assuntos
Lobo Frontal , Inteligência , Imageamento por Ressonância Magnética , Ácido gama-Aminobutírico , Humanos , Lobo Frontal/fisiologia , Lobo Frontal/diagnóstico por imagem , Masculino , Ácido gama-Aminobutírico/metabolismo , Inteligência/fisiologia , Feminino , Adulto Jovem , Adulto , Espectroscopia de Ressonância Magnética/métodos , Percepção Espacial/fisiologiaRESUMO
Paired-pulse transcranial magnetic stimulation is a valuable tool for investigating inhibitory mechanisms in motor cortex. We recently demonstrated its use in measuring cortical inhibition in visual cortex, using an approach in which participants trace the size of phosphenes elicited by stimulation to occipital cortex. Here, we investigate age-related differences in primary visual cortical inhibition and the relationship between primary visual cortical inhibition and local GABA+ in the same region, estimated using magnetic resonance spectroscopy. GABA+ was estimated in 28 young (18 to 28 years) and 47 older adults (65 to 84 years); a subset (19 young, 18 older) also completed a paired-pulse transcranial magnetic stimulation session, which assessed visual cortical inhibition. The paired-pulse transcranial magnetic stimulation measure of inhibition was significantly lower in older adults. Uncorrected GABA+ in primary visual cortex was also significantly lower in older adults, while measures of GABA+ that were corrected for the tissue composition of the magnetic resonance spectroscopy voxel were unchanged with age. Furthermore, paired-pulse transcranial magnetic stimulation-measured inhibition and magnetic resonance spectroscopy-measured tissue-corrected GABA+ were significantly positively correlated. These findings are consistent with an age-related decline in cortical inhibition in visual cortex and suggest paired-pulse transcranial magnetic stimulation effects in visual cortex are driven by GABAergic mechanisms, as has been demonstrated in motor cortex.
Assuntos
Envelhecimento , Espectroscopia de Ressonância Magnética , Inibição Neural , Estimulação Magnética Transcraniana , Córtex Visual , Ácido gama-Aminobutírico , Humanos , Estimulação Magnética Transcraniana/métodos , Adulto , Idoso , Masculino , Feminino , Adulto Jovem , Espectroscopia de Ressonância Magnética/métodos , Inibição Neural/fisiologia , Ácido gama-Aminobutírico/metabolismo , Idoso de 80 Anos ou mais , Adolescente , Envelhecimento/fisiologia , Córtex Visual/fisiologia , Córtex Visual/diagnóstico por imagemRESUMO
This study hypothesized that SCFA, acetate impacts positively on hypothalamic pyroptosis and its related abnormalities in experimentally induced PCOS rat model, possibly through NrF2/HIF1-α modulation. Eight-week-old female Wister rats were divided into groups (n = 5), namely control, PCOS, acetate and PCOS + acetate groups. Induction of PCOS was performed by administering 1 mg/kg body weight of letrozole for 21 days. After PCOS confirmation, the animals were treated with 200 mg/kg of acetate for 6 weeks. Rats with PCOS were characterized with insulin resistance, leptin resistance, increased plasma testosterone as well as degenerated ovarian follicles. There was also a significant increase in hypothalamic triglyceride level, triglyceride-glucose index, inflammatory biomarkers (SDF-1 and NF-kB) and caspase-6 as well as plasma LH and triglyceride. A decrease was observed in plasma adiponectin, GnRH, FSH, and hypothalamic GABA with severe inflammasome expression in PCOS rats. These were accompanied by decreased level of NrF2/HIF1-α, and the alterations were reversed when treated with acetate. Collectively, the present results suggest the therapeutic impact of acetate on hypothalamic pyroptosis and its related comorbidity in PCOS, a beneficial effect that is accompanied by modulation of NrF2/HIF1-α.
Assuntos
Hipotálamo , Subunidade alfa do Fator 1 Induzível por Hipóxia , Síndrome do Ovário Policístico , Piroptose , Ratos Wistar , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/patologia , Feminino , Animais , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/patologia , Piroptose/efeitos dos fármacos , Ratos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Resistência à Insulina , Fator 2 Relacionado a NF-E2/metabolismo , Modelos Animais de Doenças , Letrozol/farmacologia , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Hormônio Luteinizante/sangue , Hormônio Foliculoestimulante/sangue , Adiponectina/metabolismo , Adiponectina/sangue , Testosterona/sangue , Leptina/sangue , Leptina/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
Bestrophin-1 (Best1) is an anion channel genetically linked to vision-threatening retinal degenerative channelopathies. Here, we identify interactions between Best1 and both isoforms of glutamic acid decarboxylases (GAD65 and GAD67), elucidate the distinctive influences of GAD65 and GAD67 on Best1's permeability to various anions/neurotransmitters, discover the functionality of Best1 as a γ-Aminobutyric acid (GABA) type A receptor, and solve the structure of GABA-bound Best1. GAD65 and GAD67 both promote Best1-mediated Cl- currents, but only GAD65 drastically enhances the permeability of Best1 to glutamate and GABA, for which GAD67 has no effect. GABA binds to Best1 on an extracellular site and stimulates Best1-mediated Cl- currents at the nano-molar concentration level. The physiological role of GAD65 as a cell type-specific binding partner and facilitator of Best1 is demonstrated in retinal pigment epithelial cells. Together, our results reveal critical regulators of Best1 and inform a network of membrane transport metabolons formed between bestrophin channels and glutamate metabolic enzymes.
Assuntos
Bestrofinas , Glutamato Descarboxilase , Ácido Glutâmico , Ácido gama-Aminobutírico , Glutamato Descarboxilase/metabolismo , Glutamato Descarboxilase/genética , Bestrofinas/metabolismo , Bestrofinas/genética , Humanos , Ácido gama-Aminobutírico/metabolismo , Ácido Glutâmico/metabolismo , Células HEK293 , Animais , Epitélio Pigmentado da Retina/metabolismo , Neurotransmissores/metabolismo , Ligação Proteica , Receptores de GABA-A/metabolismo , Receptores de GABA-A/genéticaRESUMO
The role of the gut microbiota in the gut-brain axis has attracted attention in recent years. Some gut microbiota produces γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter in mammals, in vitro, but the correlation between gut microbiota composition and intestinal GABA concentration, as well as the action of intestinal GABA in vivo, are poorly understood. Herein, we found that the intestinal GABA concentration was increased in mice by the intervention of the gut microbiota with neomycin or Bifidobacterium bifidum TMC3115 (TMC3115). Administration of TMC3115 reduced anxiety without affecting serum levels of serotonin, corticosterone, or GABA. We further found that intestinal epithelial cells expressed GABA receptor subunits and mediated mitogen-activated protein kinase signaling upon GABA stimulation. In addition, administration of TMC3115 induced mitogen-activated protein kinase signaling in colonic epithelial cells but not in small intestinal epithelial cells in mice. These results indicate that GABA produced by the gut microbiota, mainly in the colon, may affect host behavioral characteristics via GABA receptors expressed in intestinal epithelial cells without being transferred to the blood. This study suggests a novel mechanism by which intestinal GABA exerts physiological effects, even in the presence of the blood-brain barrier.
Assuntos
Ansiedade , Células Epiteliais , Microbioma Gastrointestinal , Ácido gama-Aminobutírico , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Ácido gama-Aminobutírico/metabolismo , Ansiedade/metabolismo , Células Epiteliais/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Neomicina/farmacologia , Camundongos Endogâmicos C57BL , Receptores de GABA/metabolismo , Bifidobacterium/metabolismo , Probióticos/farmacologia , HumanosRESUMO
In emotion research, anxiety and fear have always been interconnected, sharing overlapping brain structures and neural circuitry. Recent investigations, however, have unveiled parallel long-range projection pathways originating from the ventral hippocampus, shedding light on their distinct roles in anxiety and fear. Yet, the mechanisms governing the emergence of projection-specific activity patterns to mediate different negative emotions remain elusive. Here, we show a division of labor in local GABAergic inhibitory microcircuits of the ventral hippocampus, orchestrating the activity of subpopulations of pyramidal neurons to shape anxiety and fear behaviors in mice. These findings offer a comprehensive insight into how distinct inhibitory microcircuits are dynamically engaged to encode different emotional states.
Assuntos
Ansiedade , Medo , Hipocampo , Células Piramidais , Animais , Medo/fisiologia , Ansiedade/fisiopatologia , Hipocampo/fisiologia , Camundongos , Células Piramidais/fisiologia , Masculino , Neurônios GABAérgicos/fisiologia , Neurônios GABAérgicos/metabolismo , Camundongos Endogâmicos C57BL , Comportamento Animal/fisiologia , Ácido gama-Aminobutírico/metabolismo , Vias Neurais/fisiologiaRESUMO
Background: In the realm of wheat seed germination, abiotic stresses such as salinity and high temperature have been shown to hinder the process. These stresses can lead to the production of reactive oxygen species, which, within a certain concentration range, may actually facilitate seed germination. γ-aminobutyric acid (GABA), a non-protein amino acid, serves as a crucial signaling molecule in the promotion of seed germination. Nevertheless, the potential of GABA to regulate seed germination under the simultaneous stress of heat and salinity remains unexplored in current literature. Methods: This study employed observational methods to assess seed germination rate (GR), physiological methods to measure H2O2 content, and the activities of glutamate decarboxylase (GAD), NADPH oxidase (NOX), superoxide dismutase (SOD), and catalase (CAT). The levels of ABA and GABA were quantified using high-performance liquid chromatography technology. Furthermore, quantitative real-time PCR technology was utilized to analyze the expression levels of two genes encoding antioxidant enzymes, MnSOD and CAT. Results: The findings indicated that combined stress (30 °C + 50 mM NaCl) decreased the GR of wheat seeds to about 21%, while treatment with 2 mM GABA increased the GR to about 48%. However, the stimulatory effect of GABA was mitigated by the presence of ABA, dimethylthiourea, and NOX inhibitor, but was strengthened by H2O2, antioxidant enzyme inhibitor, fluridone, and gibberellin. In comparison to the control group (20 °C + 0 mM NaCl), this combined stress led to elevated levels of ABA, reduced GAD and NOX activity, and a decrease in H2O2 and GABA content. Further investigation revealed that this combined stress significantly suppressed the activity of superoxide dismutase (SOD) and catalase (CAT), as well as downregulated the gene expression levels of MnSOD and CAT. However, the study demonstrates that exogenous GABA effectively reversed the inhibitory effects of combined stress on wheat seed germination. These findings suggest that GABA-induced NOX-mediated H2O2 signalling plays a crucial role in mitigating the adverse impact of combined stress on wheat seed germination. This research holds significant theoretical and practical implications for the regulation of crop seed germination by GABA under conditions of combined stress.
Assuntos
Germinação , Peróxido de Hidrogênio , Sementes , Triticum , Ácido gama-Aminobutírico , Peróxido de Hidrogênio/metabolismo , Triticum/efeitos dos fármacos , Triticum/metabolismo , Triticum/crescimento & desenvolvimento , Triticum/genética , Germinação/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Sementes/efeitos dos fármacos , Sementes/crescimento & desenvolvimento , Transdução de Sinais/efeitos dos fármacos , Catalase/metabolismo , Catalase/genética , Estresse Salino/efeitos dos fármacos , Resposta ao Choque Térmico/efeitos dos fármacos , Resposta ao Choque Térmico/fisiologia , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genéticaRESUMO
Abnormalities in gamma-aminobutyric acid (GABA)ergic neurotransmission play a role in the pathogenesis of autism, although the mechanisms responsible for alterations in specific brain regions remain unclear. Deficits in social motivation and interactions are core symptoms of autism, likely due to defects in dopaminergic neural pathways. Therefore, investigating the morphology and functional roles of GABAergic neurons within dopaminergic projection areas could elucidate the underlying etiology of autism. The aim of this study was to (1) compare the morphology and arborization of glutamate decarboxylase (GAD)-positive neurons from the midbrain tegmentum; (2) evaluate synaptic activity in primary neurons from the striatum; and (3) assess GABAergic postsynaptic puncta in the ventral striatum of wild-type (WT) and Shank3-deficient mice. We found a significant decrease in the number of short neurites in GAD positive primary neurons from the midbrain tegmentum in Shank3-deficient mice. The application of a specific blocker of GABAA receptors (GABAAR) revealed significantly increased frequency of spontaneous postsynaptic currents (sPSCs) in Shank3-deficient striatal neurons compared to their WT counterparts. The mean absolute amplitude of the events was significantly higher in striatal neurons from Shank3-deficient compared to WT mice. We also observed a significant reduction in gephyrin/GABAAR γ2 colocalization in the striatum of adult male Shank3-deficient mice. The gene expression of collybistin was significantly lower in the nucleus accumbens while gephyrin and GABAAR γ2 were lower in the ventral tegmental area (VTA) in male Shank3-deficient compared to WT mice. In conclusion, Shank3 deficiency leads to alterations in GABAergic neurons and impaired GABAergic function in dopaminergic brain areas. These changes may underlie autistic symptoms, and potential interventions modulating GABAergic activity in dopaminergic pathways may represent new treatment modality.
Assuntos
Corpo Estriado , Neurônios GABAérgicos , Mesencéfalo , Proteínas do Tecido Nervoso , Sinapses , Animais , Neurônios GABAérgicos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/deficiência , Mesencéfalo/metabolismo , Mesencéfalo/patologia , Sinapses/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Biomarcadores/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteínas dos Microfilamentos/deficiência , Glutamato Descarboxilase/metabolismo , Forma Celular , Ácido gama-Aminobutírico/metabolismo , Camundongos Endogâmicos C57BL , Camundongos , Masculino , Camundongos Knockout , Receptores de GABA-A/metabolismo , Proteínas de MembranaAssuntos
Gabapentina , Humanos , Gabapentina/efeitos adversos , Gabapentina/uso terapêutico , Analgésicos/efeitos adversos , Analgésicos/uso terapêutico , Ácido gama-Aminobutírico/efeitos adversos , Aminas/efeitos adversos , Pregabalina/efeitos adversos , Pregabalina/uso terapêutico , Ácidos Cicloexanocarboxílicos/efeitos adversos , Dor/tratamento farmacológico , Dor/induzido quimicamenteRESUMO
The risk of cardiovascular disease (CVD) is approximately doubled in subjects with hypercholesterolemia compared to those with normal blood cholesterol levels. Monacolin K (MK), the main active substance in rice fermented by the Monascus purpureus, acts on cholesterol metabolism. Rice also contains other bioactive compounds such as γ-oryzanol (OZ) and γ-aminobutyric acid (GABA). In a randomized, placebo-controlled, double-blind trial, the efficacy and tolerability of a food supplement (FS) based on an ingredient standardized to contain monacolins (4.5%), OZ, and GABA were evaluated in subjects with mild dyslipidemia. For the duration of the trial, enrolled subjects (n = 44, each group) received the FS or placebo and were instructed to use an isocaloric diet. Compared to the placebo group, after a 3 months of the FS, the mean low-density lipoprotein cholesterol and mean TC values were reduced by 19.3 and 8.3%, respectively, while the mean high-density lipoprotein cholesterol value increased by 29.3%. On average, the subjects shifted from very high to moderate CVD risk. Glucose metabolism and hepatic and renal parameters did not change after the treatment and no adverse events were reported. Guidelines to handle hypercholesterolemia with food supplements in specific clinical settings are needed to better manage mild dyslipidemia.
Assuntos
Suplementos Nutricionais , Dislipidemias , Fenilpropionatos , Ácido gama-Aminobutírico , Humanos , Método Duplo-Cego , Masculino , Feminino , Pessoa de Meia-Idade , Dislipidemias/tratamento farmacológico , Dislipidemias/sangue , Fenilpropionatos/uso terapêutico , Adulto , Lovastatina/uso terapêutico , LDL-Colesterol/sangue , Resultado do Tratamento , HDL-Colesterol/sangueRESUMO
Tea (Camellia sinensis) falls into the family Theaceae, is a valuable commercial crop, and tea products made from its buds and young leaves are favored by consumers all over the world. The more common Thea plant is Camellia sinensis (C. sinensis), but its most important relative, Camellia taliensis (C. taliensis), is also utilized by locals in the area of cultivation to manufacture tea. In this investigation, C. taliensis (DL) and C. sinensis (QJZ) were characterized in terms of their agronomic traits, physicochemical indices, metabolomics, and transcriptomics. The leaf area of DL is larger than that of QJZ; the color of DL's buds and leaves is yellowish-green, while that of QJZ's is green. DL's buds and leaves are more densely velvety than those of QJZ. The HPLC results indicated that the physicochemical contents varied considerably between the two samples, with DL having greater concentrations of EGCG and GABA than QJZ, while QJZ had remarkably higher concentrations of C, CA, and EGC than DL. A total of 2269 metabolites and 362,190,414 genes were positively identified, with the number of DAMs and DEGs being 1001 and 34,026, respectively. The flavonoids, phenolic acids, and alkaloid metabolites were dramatically different between the two tea group plants. Bioinformatics profiling revealed that the DAMs and DEGs of the two tea group plants interacted with each other and were involved in metabolic pathways, including "biosynthesis of secondary metabolites", "biosynthesis of amino acids", "biosynthesis of cofactors", "phenylpropanoid biosynthesis", and "flavonoid biosynthesis". Overall, these results provide statistical support for germplasm conservation and production for both C. taliensis and C. sinensis.
Assuntos
Camellia , Metabolômica , Folhas de Planta , Camellia/genética , Camellia/metabolismo , Folhas de Planta/metabolismo , Folhas de Planta/genética , Transcriptoma/genética , Catequina/metabolismo , China , Perfilação da Expressão Gênica , Camellia sinensis/genética , Camellia sinensis/metabolismo , Regulação da Expressão Gênica de Plantas , Metaboloma , Ácido gama-Aminobutírico/metabolismoRESUMO
Cognitive deficits are long-lasting consequences of drug use, yet the convergent mechanism by which classes of drugs with different pharmacological properties cause similar deficits is unclear. We find that both phencyclidine and methamphetamine, despite differing in their targets in the brain, cause the same glutamatergic neurons in the medial prefrontal cortex of male mice to gain a GABAergic phenotype and decrease expression of their glutamatergic phenotype. Suppressing drug-induced gain of GABA with RNA-interference prevents appearance of memory deficits. Stimulation of dopaminergic neurons in the ventral tegmental area is necessary and sufficient to produce this gain of GABA. Drug-induced prefrontal hyperactivity drives this change in transmitter identity. Returning prefrontal activity to baseline, chemogenetically or with clozapine, reverses the change in transmitter phenotype and rescues the associated memory deficits. This work reveals a shared and reversible mechanism that regulates the appearance of cognitive deficits upon exposure to different drugs.
Assuntos
Metanfetamina , Fenciclidina , Córtex Pré-Frontal , Área Tegmentar Ventral , Ácido gama-Aminobutírico , Animais , Masculino , Metanfetamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Camundongos , Fenciclidina/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo , Ácido gama-Aminobutírico/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Camundongos Endogâmicos C57BL , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Clozapina/farmacologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismoRESUMO
The Mongolian sheep, emblematic of the Inner Mongolian grasslands, is renowned for its exceptional stress resistance and adaptability to harsh environments, drawing considerable attention. Recent research has unveiled the novel role of γ-aminobutyric acid (GABA) in combating oxidative stress. This investigation examined how GABA impacts renal-cortex and medulla cells from Mongolian sheep exposed to high-glucose stress conditions, utilizing gene expression analysis and non-targeted metabolomics. Elevated glucose levels significantly reduced the viability of Mongolian sheep renal cells and increased reactive oxygen species (ROS) levels. Conversely, the introduction of GABA notably enhanced cell viability, reduced ROS production, and stimulated the expression of antioxidant genes (e.g., Gpx, SOD, CAT) in the renal cortex. In the renal medulla, CAT expression increased, while Gpx gene expression showed mixed responses. Metabolomics analysis indicated that high-glucose exposure altered various metabolites, whereas GABA alleviated the metabolic stress induced by high glucose through modulating glycolysis and the tricarboxylic acid cycle. In Mongolian sheep renal cells, GABA effectively mitigated oxidative damage triggered by high-glucose stress by upregulating antioxidant genes and regulating metabolic pathways, revealing insights into its potential mechanism for adapting to extreme environments. This finding offers a fresh perspective on understanding the stress resilience of Mongolian sheep and may provide valuable insights for research across diverse disciplines.
Assuntos
Glucose , Estresse Oxidativo , Espécies Reativas de Oxigênio , Ácido gama-Aminobutírico , Animais , Estresse Oxidativo/efeitos dos fármacos , Glucose/metabolismo , Ácido gama-Aminobutírico/metabolismo , Ovinos , Espécies Reativas de Oxigênio/metabolismo , Rim/metabolismo , Rim/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Metabolômica/métodosRESUMO
Contamination of agricultural products with Cadmium (Cd) is a global problem that should be considered for minimizing the risks to human health. Considering the potential effects of SiNPs in decreasing abiotic stress, a study was conducted to investigate the effect of SiNPs in the reduction of Cd stress on Solanum lycopersicum. SiNPs was used at 0, 25, 50 and 100 mg/l and CdCl2 at 0, 100 and 200 µM concentrations. The results showed that Cd stress caused a significant decrease in dry weight, content of GSH, ASA, significently increasing the activity of GR, APX, GST, SOD, as well as content of H2O2, MDA, proline, and GABA in shoots and roots compared to the control. SiNPs significantly increased shoot and root dry weight compared to the control. As a coenzyme, SiNPs induced the activity of antioxidant enzymes and significantly increased GST and GR gene expression compared to the control. SiNPs also caused a substantial increase in the content of ASA, GSH, proline and GABA compared to the control. By inducing the activity of antioxidant enzymes and metabolites of the ascorbate-glutathione (ASA-GSH) cycle, SiNPs removed a large content of H2O2 and significantly reduced the MDA content, and as a result led to the stability of cell membrane under Cd stress. Induction of ASA-GSH, GABA and SOD cycle by SiNPs clearly showed that SiNPs could be a potential tool to alleviate Cd stress in plants cultivated in areas contaminated with this heavy metal.
Assuntos
Cádmio , Glutationa , Silício , Solanum lycopersicum , Estresse Fisiológico , Ácido gama-Aminobutírico , Glutationa/metabolismo , Cádmio/toxicidade , Cádmio/metabolismo , Solanum lycopersicum/metabolismo , Solanum lycopersicum/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Silício/farmacologia , Silício/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Antioxidantes/metabolismo , Nanopartículas/química , Peróxido de Hidrogênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido Ascórbico/metabolismo , Raízes de Plantas/metabolismo , Raízes de Plantas/efeitos dos fármacosRESUMO
Gamma-aminobutyric acid (GABA) derivatives are a class of effective inhibitory neurotransmitters for treating neurodegenerative diseases, with an immense market demand. Chemical methods are currently the main synthetic strategies for GABA derivatives, facing challenges such as complex processes, low yields, low atom economy, and environmental burden. In recent years, chemoenzymatic synthesis of GABA derivatives has garnered increasing attention because of the high atom economy, high yields, and environmental friendliness. This article reviews the latest advances in the chemical synthesis and chemoenzymatic synthesis of GABA derivatives. Furthermore, it introduces the progress in the industrial synthesis of representative GABA derivatives such as gabapentin, pregabalin, and brivaracetam and prospects the future development of GABA derivatives.
Assuntos
Pregabalina , Ácido gama-Aminobutírico , Ácido gama-Aminobutírico/biossíntese , Ácido gama-Aminobutírico/síntese química , Ácido gama-Aminobutírico/metabolismo , Pregabalina/síntese química , Gabapentina , Aminas/química , Aminas/síntese química , Aminas/metabolismo , Técnicas de Química SintéticaRESUMO
BACKGROUND: High GABA levels and its conversion to succinate via the GABA shunt are known to be associated with abiotic and biotic stress tolerance in plants. The exact mode of action is still under debate and it is not yet clear whether GABA is a common component of the plant stress defense process or not. We hypothesized that if it is a common route for stress tolerance, activation of GABA-shunt by a biotic stressor might also function in increased abiotic stress tolerance. To test this, Brassica napus plants treated with Flagellin-22 (Flg-22) were exposed to drought stress and the differences in GABA levels along with GABA-shunt components (biosynthetic and catabolic enzyme activities) in the leaf and root samples were compared. In order to provide a better outlook, MYC2, MPK6 and ZAT12, expression profiles were also analyzed since these genes were recently proposed to function in abiotic and biotic stress tolerance. RESULTS: Briefly, we found that Flg treatment increased drought stress tolerance in B. napus via GABA-shunt and the MAPK cascade was involved while the onset was different between leaves and roots. Flg treatment promoted GABA biosynthesis with increased GABA content and GAD activity in the leaves. Better performance of the Flg treated plants under drought stress might be dependent on the activation of GABA-shunt which provides succinate to TCA since GABA-T and SSADH activities were highly induced in the leaves and roots. In the transcript analysis, Flg + drought stressed groups had higher MYC2 transcript abundances correlated well with the GABA content and GABA-shunt while, MPK6 expression was induced only in the roots of the Flg + drought stressed groups. ZAT12 was also induced both in leaves and roots as a result of Flg-22 treatment. However, correlation with GABA and GABA-shunt could be proposed only in Flg + drought stressed group. CONCLUSION: We provided solid data on how GABA-shunt and Fgl-22 are interacting against abiotic stress in leaf and root tissues. Fgl-22 induced ETI activated GABA-shunt with a plausible cross talk between MYC2 and ZAT12 transcription factors for drought stress tolerance in B. napus.
Assuntos
Brassica napus , Secas , Flagelina , Ácido gama-Aminobutírico , Brassica napus/genética , Brassica napus/fisiologia , Brassica napus/efeitos dos fármacos , Brassica napus/metabolismo , Ácido gama-Aminobutírico/metabolismo , Flagelina/farmacologia , Estresse Fisiológico/genética , Regulação da Expressão Gênica de Plantas , Raízes de Plantas/metabolismo , Raízes de Plantas/fisiologia , Raízes de Plantas/genética , Folhas de Planta/metabolismo , Folhas de Planta/fisiologia , Folhas de Planta/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genéticaRESUMO
OBJECTIVE: The study aimed to investigate changes in basal levels of the inhibitory γ-aminobutyric acid (GABA) neurotransmitter in the sensorimotor cortex (SMC) and cortical gyrification in patients with Parkinson's disease (PD), which could further identify potential imaging biomarkers for PD, particularly in patients with early-onset Parkinson's disease (EOPD). METHOD: Fifty patients with PD (EOPD: 10, late-onset Parkinson's disease [LOPD]: 40) and fifty-two age- and gender-matched healthy controls (HC) underwent GABA-edited 1H MRS of the SMC and high-resolution 3D T1-weighted brain imaging. GABA levels and local gyrification index (LGI) were calculated to assess GABAergic and cortical gyrification deficits in PD. RESULT: The Pearson correlation coefficients revealed significant negative associations between eight indicators, including GABA/Cr level and local gyrification index (LGI) of specific cortical regions (precentral, postcentral, entorhinal, superiortemporal, posteriorcingulate, cuneus, and transversetemporal cortex), and the likelihood of Parkinson's disease (r < -0.4, p < 0.001). Additionally, GABA levels were significantly lower in the SMC region of both EOPD and LOPD patients compared to healthy controls (mean ± SD [u.i.]: EOPD=0.081 ± 0.022 vs. Young-HC=0.112 ± 0.021, p = 0.003; LOPD=0.054 ± 0.024 vs. Old-HC=0.099 ± 0.021, p < 0.001). The logistic regression model was established by using multivariate analysis, identifying two statistically significant indicators: GABA/Cr and LGI of the transversetemporal. The combined model exhibited the highest AUC values in both younger and older populations. CONCLUSION: GABAergic dysfunction may play an important role in the pathogenesis of PD patients. Changes in neurotransmitter and morphological may serve as potential markers for the preclinical diagnosis and progression of PD, including EOPD.
Assuntos
Imageamento por Ressonância Magnética , Doença de Parkinson , Ácido gama-Aminobutírico , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Ácido gama-Aminobutírico/metabolismo , Idoso , Imageamento por Ressonância Magnética/métodos , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Biomarcadores , Adulto , Córtex Sensório-Motor/diagnóstico por imagem , Córtex Sensório-Motor/fisiopatologia , Córtex Sensório-Motor/metabolismoRESUMO
Several studies suggest that hearing loss results in changes in the balance between inhibition and excitation in the inferior colliculus (IC). The IC is an integral nucleus within the auditory brainstem. The majority of ascending pathways from the lateral lemniscus (LL), superior olivary complex (SOC), and cochlear nucleus (CN) synapse in the IC before projecting to the thalamus and cortex. Many of these ascending projections provide inhibitory innervation to neurons within the IC. However, the nature and the distribution of this inhibitory input have only been partially elucidated in the rat. The inhibitory neurotransmitter, gamma aminobutyric acid (GABA), from the ventral nucleus of the lateral lemniscus (VNLL), provides the primary inhibitory input to the IC of the rat with GABA from other lemniscal and SOC nuclei providing lesser, but prominent innervation. There is evidence that hearing related conditions can result in dysfunction of IC neurons. These changes may be mediated in part by changes in GABA inputs to IC neurons. We have previously used gene micro-arrays in a study of deafness-related changes in gene expression in the IC and found significant changes in GAD as well as the GABA transporters and GABA receptors (Holt 2005). This is consistent with reports of age and trauma related changes in GABA (Bledsoe et al., 1995; Mossop et al., 2000; Salvi et al., 2000). Ototoxic lesions of the cochlea produced a permanent threshold shift. The number, intensity, and density of GABA positive axon terminals in the IC were compared in normal hearing and deafened rats. While the number of GABA immunolabeled puncta was only minimally different between groups, the intensity of labeling was significantly reduced. The ultrastructural localization and distribution of labeling was also examined. In deafened animals, the number of immuno gold particles was reduced by 78 % in axodendritic and 82 % in axosomatic GABAergic puncta. The affected puncta were primarily associated with small IC neurons. These results suggest that reduced inhibition to IC neurons contribute to the increased neuronal excitability observed in the IC following noise or drug induced hearing loss. Whether these deafness diminished inhibitory inputs originate from intrinsic or extrinsic CNIC sources awaits further study.
Assuntos
Colículos Inferiores , Ratos Sprague-Dawley , Ácido gama-Aminobutírico , Animais , Colículos Inferiores/metabolismo , Colículos Inferiores/patologia , Ácido gama-Aminobutírico/metabolismo , Perda Auditiva Provocada por Ruído/metabolismo , Perda Auditiva Provocada por Ruído/fisiopatologia , Perda Auditiva Provocada por Ruído/patologia , Ototoxicidade/metabolismo , Ototoxicidade/etiologia , Masculino , Vias Auditivas/metabolismo , Vias Auditivas/patologia , Vias Auditivas/fisiopatologia , Modelos Animais de Doenças , Imuno-Histoquímica , Ratos , Glutamato Descarboxilase/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Inibição NeuralRESUMO
AIM: Molecular alterations of diabetic gastroenteropathy are poorly identified. This study investigates the effects of prolonged GABA supplementation on key protein expression levels of trypsin-1, PAR-1, PAR-2, PAR-3, PI3K, Akt, COX-2, GABAA, and GABAB receptors in the gastric tissue of type 2 diabetic rats (T2DM). METHOD: To induce T2DM, a 3-month high-fat diet and 35 mg/kg of streptozotocin was used. Twenty-four male Wistar rats were divided into 4 groups: (1) control, (2) T2DM, (3) insulin-treated (2.5 U/kg), and (4) GABA-treated (1.5 g/kg GABA). Blood glucose was measured weekly. The protein expressions were assessed using western blotting. Histopathological changes were examined by H&E and Masson's staining. RESULTS: Diabetic rats show reduced NOS1 and elevated COX-2 and trypsin-1 protein expression levels in gastric tissue. Insulin and GABA therapy restored the NOS1 and COX-2 levels to control values. Insulin treatment increased PI3K, Akt, and p-Akt and, decreased trypsin-1, PAR-1, PAR-2, and PAR-3 levels in the diabetic rats. Levels of GABAA and GABAB receptors normalized following insulin and GABA therapy. H&E staining indicated an increase in mucin secretion following GABA treatment. CONCLUSION: These results suggest that GABA by acting on GABA receptors may regulate the trypsin-1/PARs/Akt/COX-2 pathway and thereby improve complications of diabetic gastroenteropathy.
Assuntos
Ciclo-Oxigenase 2 , Diabetes Mellitus Experimental , Proteínas Proto-Oncogênicas c-akt , Ratos Wistar , Receptores de GABA , Ácido gama-Aminobutírico , Animais , Masculino , Ciclo-Oxigenase 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Receptores de GABA/metabolismo , Ácido gama-Aminobutírico/metabolismo , Tripsina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Transdução de Sinais/efeitos dos fármacos , Suplementos NutricionaisRESUMO
We studied the effect of enteral administration of GABA on the gastric mucosa in male Wistar rats (n=47) with modeled metabolic stress (food deprivation for 9 days with free access to water). The relative weights of the adrenal glands and thymus were determined, and histological examination of the stomach was performed. In control rats, modeling the metabolic stress was accompanied by the development of erosive damage to the gastric mucosa related to blood supply disturbances. Administration of GABA prevented erosions and exhibited a pronounced gastroprotective effect. Thus, administration of GABA can be a promising method for the prevention and treatment of erosive gastric lesions associated with metabolic stress.