Search Results (1,375)

Background: A growing body of research supports the role of the microbial communities residing in the digestive system in the host’s cognitive functioning. Most of these studies have been focused on the gut microbiome and its association with clinical phenotypes in middle-aged and older adults. There is an insufficiency of population-based research exploring the association of normative cognitive functioning with the microbiome particularly with the oral microbiota. Methods: In this study, using metagenomics and metabolomics, we characterized the salivary microbiome diversity in a sample of 51 males of Hispanic and African American origin aged 12–18 years and explored the associations between the microbiome and the youths’ cognitive performance captured with the Kaufman Assessment Battery for Children II (KABC-II). Results: Several bacterial species of the oral microbiota and related metabolic pathways were associated with cognitive function. In particular, we found negative associations between indicators of general intelligence and the relative abundance of Bacteroidetes and Lachnospiraceae and positive associations with Bifidobacteriaceae and Prevotella histicola sp. Among metabolic pathways, the super pathways related to bacterial cell division and GABA metabolism were linked to cognitive function. Conclusions: The results of our work are consistent with the literature reporting on the association between microbiota and cognitive function and support further population work to elucidate the potential for a healthy oral microbiome to improve cognitive health. Full article

Background: Boron is an essential micronutrient for plant growth and productivity, yet excessive boron leads to toxicity, posing significant challenges for agriculture. Fragrant rice is popular among consumers, but the impact of boron toxicity on qualitative traits of fragrant rice, especially aroma, remains largely unexplored. The individual potentials of melatonin and salicylic acid in reducing boron toxicity are less known, while their synergistic effects and mechanisms in fragrant rice remain unclear. Methods: Thus, this study investigates the combined application of melatonin and salicylic acid on fragrant rice affected by boron toxicity. One-week-old seedlings were subjected to boron (0 and 800 µM) and then treated with melatonin and salicylic acid (0 and 100 µM, for 3 weeks). Results: Boron toxicity significantly impaired photosynthetic pigments, plant growth, and chloroplast integrity while increasing oxidative stress markers such as hydrogen peroxide, malondialdehyde, methylglyoxal, and betaine aldehyde dehydrogenase. Likewise, boron toxicity abridged the precursors involved in the 2-acetyl-1-pyrroline (2-AP) biosynthesis pathway. However, individual as well as combined application of melatonin and salicylic acid ameliorated boron toxicity by strengthening the antioxidant defense mechanisms—including the enzymes involved during the ascorbate–glutathione (AsA–GSH) cycle and glyoxalase system—and substantially improved 2-AP precursors including proline, P5C, Δ1-pyrroline, and GABA levels, thereby restoring the 2-AP content and aroma. These findings deduce that melatonin and salicylic acid synergistically alleviate boron toxicity-induced disruptions on the 2-AP biosynthesis pathway by improving the 2-AP precursors and enzymatic activities, as well as modulating the physio-biochemical processes and antioxidant defense system of fragrant rice plants. Conclusions: The findings of this study have the potential to enhance rice productivity and stress tolerance, offering solutions to improve food security and sustainability in agricultural practices, particularly in regions affected by environmental stressors. Full article

γ-aminobutyric acid (GABA) and rare ginsenosides are good antioxidant and anti-fatigue active components that can be enriched via probiotic fermentation. In this study, ginseng and germinated brown rice were used as raw materials to produce six fermented purees using fermentation and non-fermentation technology. We tested the chemical composition of the purees and found that the content of GABA and rare ginsenoside (Rh₄, Rg₃, and CK) in the puree made of ginseng and germinated brown rice (FGB) increased significantly after fermentation. The antioxidant activity of the six purees was determined using cell-free experiments, and it was found that FGB had better ferric-ion-reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical scavenging rates, exhibiting better antioxidant effects. We then evaluated the antioxidant effect of FGB in HepG₂ cells induced by H₂O₂ and found that FGB can reduce the generation of reactive oxygen species (ROS) in HepG₂ cells and increase the membrane potential level, thereby improving oxidative damage in these cells. In vivo experiments also showed that FGB has good antioxidant and anti-fatigue activities, which can prolong the exhaustive swimming time of mice and reduce the accumulation of metabolites, and is accompanied by a corresponding increase in liver glycogen and muscle glycogen levels as well as superoxide dismutase and lactate dehydrogenase activities. Finally, we believe that the substances with good antioxidant and anti-fatigue activity found in FGB are derived from co-fermented enriched GABA and rare ginsenosides. Full article

Gut microbiota (GM), together with its metabolites (such as SCFA, tryptophan, dopamine, GABA, etc.), plays an important role in the functioning of the central nervous system. Various neurological and psychiatric disorders are associated with changes in the composition of GM and their metabolites, which puts them in the foreground as a potential adjuvant therapy. However, the molecular mechanisms behind this relationship are not clear enough. Therefore, before considering beneficial microbes and/or their metabolites as potential therapeutics for brain disorders, the mechanisms underlying microbiota–host interactions must be identified and characterized in detail. In this review, we summarize the current knowledge of GM alterations observed in prevalent neurological and psychiatric disorders, multiple sclerosis, major depressive disorder, Alzheimer’s disease, and autism spectrum disorders, together with experimental evidence of their potential to improve patients’ quality of life. We further discuss the main obstacles in the study of GM–host interactions and describe the state-of-the-art solution and trends in this field, namely “culturomics” which enables the culture and identification of novel bacteria that inhabit the human gut, and models of the gut and blood–brain barrier as well as the gut–brain axis based on induced pluripotent stem cells (iPSCs) and iPSC derivatives, thus pursuing a personalized medicine agenda for neuropsychiatric disorders. Full article

Oxidative stress emerges as a prominent factor in the onset and progression of intestinal inflammation, primarily due to its critical role in damaging cells and tissues. GABAergic signaling is important in the occurrence and development of various intestinal disorders, yet its effect on oxidative stress remains unclear. We attempted to assess whether GABAergic signaling participated in the regulation of oxidative stress during enteritis. The results showed that lipopolysaccharide (LPS) significantly decreased γ-aminobutyric acid (GABA) levels in the ileal tissues of mice. Interestingly, the application of GABA significantly repressed the shedding of intestinal mucosal epithelial cells and inflammatory cell infiltration, inhibited the expressions of proinflammatory factors, including granulocyte colony-stimulating factor and granulocyte-macrophage colony stimulating factor, and enhanced the levels of anti-inflammatory cytokines interleukin (IL)-4 and IL-10, indicating that GABA could alleviate enteritis in mice. This observation was further supported by transcriptome sequencing, revealing a total of 271 differentially expressed genes, which exhibited a marked enrichment of inflammatory and immune-related pathways, alongside a prominent enhancement of GABA B receptor (GABA_BR) signaling following GABA administration. Effectively, Baclofen pretreatment alleviated intestinal mucosal damage in LPS-induced mice, suppressed proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor alpha expressions, and boosted total antioxidant capacity, superoxide dismutase (SOD), and glutathione (GSH) levels. Moreover, Baclofen notably enhanced the viability of LPS-stimulated IPEC-J2 cells, contracted the proinflammatory secretion factors, and reinforced SOD, GSH, and catalase levels, emphasizing the anti-inflammatory and antioxidant effects associated with GABA_BR activation. Mechanistically, Baclofen restrained the mRNA and protein levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3), and inducible nitric oxide synthase, while elevating nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 in both mice and IPEC-J2 cells, indicating that activating GABA_BR strengthened antioxidant abilities by interrupting the TLR4/MyD88/NLRP3 pathway. Furthermore, 16S rDNA analysis demonstrated that Baclofen increased the relative abundance of probiotic, particularly Lactobacillus, renowned for its antioxidant properties, while reducing the relative richness of harmful bacteria, predominantly Enterobacteriaceae, suggesting that GABA_BR signaling may have contributed to reversing intestinal flora imbalances to relieve oxidative stress in LPS-induced mice. Our study identified previously unappreciated roles for GABA_BR signaling in constricting oxidative stress to attenuate enteritis, thus offering novel insights for the treatment of intestinal inflammation. Full article

Type-A γ-aminobutyric acid (GABA_A) receptors are channel proteins crucial to mediating neuronal balance in the central nervous system (CNS). The structure of GABA_A receptors allows for multiple binding sites and is key to drug development. Yet the formation mechanism of the receptor’s distinctive pentameric structure is still unknown. This study aims to investigate the role of three predominant subunits of the human GABA_A receptor in the formation of protein pentamers. Through purifying and refolding the protein fragments of the GABA_A receptor α1, β2, and γ2 subunits, the particle structures were visualised with negative staining electron microscopy (EM). To aid the analysis, AlphaFold2 was used to compare the structures. Results show that α1 and β2 subunit fragments successfully formed homo-oligomers, particularly homopentameric structures, while the predominant heteropentameric GABA_A receptor was also replicated through the combination of the three subunits. However, homopentameric structures were not observed with the γ2 subunit proteins. A comparison of the AlphaFold2 predictions and the previously obtained cryo-EM structures presents new insights into the subunits’ modular structure and polymerization status. By performing experimental and computational studies, a deeper understanding of the complex structure of GABA_A receptors is provided. Hopefully, this study can pave the way to developing novel therapeutics for neuropsychiatric diseases. Full article

Corticosteroids are frequently prescribed across medical disciplines, yet they are associated with various adverse effects, including neuropsychiatric symptoms, documented since their introduction over 60 years ago. The cellular mechanisms underlying neuropsychiatric symptoms are complex and somewhat obscure, involving multiple pathways. Notably, they include changes in excitability, cellular death of hippocampal and striatal neurons, and increased inflammation and oxidative stress. Clinical presentation varies, encompassing affective disorders (anxiety, euphoria, depression), psychotic episodes, and cognitive deficits. It is crucial to note that these manifestations often go unnoticed by treating physicians, leading to delayed detection of severe symptoms, complications, and underreporting. Discontinuation of corticosteroids constitutes the cornerstone of treatment, resolving symptoms in up to 80% of cases. Although the literature on this topic is scant, isolated cases and limited studies have explored the efficacy of psychotropic medications for symptomatic control and prophylaxis. Pharmacological intervention may be warranted in situations where corticosteroid reduction or withdrawal is not feasible or beneficial for the patient. Full article

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. Full article

Hemp seed protein (HSP), a by-product of hemp oil processing, was converted into a functional protein ingredient enriched with γ-aminobutyric acid (GABA) and peptides through a two-step microbial fermentation process. To enhance peptide and free amino acid production from HSP, it was hydrolyzed using alkaline protease produced by Bacillus subtilis HA. The HSP was hydrolyzed at a degree of 40% at 55 °C for 24 h, yielding a pH of 6.55, an acidity of 1.22%, and 205.45 mg% tyrosine equivalents. This process resulted in the production of low molecular-weight peptides. (<5000 Da) The total amino acid content and branched-chain amino acids (leucine, isoleucine, and valine) were 6.78 mg/g and 1.47 mg/g. Subsequently, the production of γ-aminobutyric acid (GABA) in the HSP hydrolysate was optimized through co-fermentation with lactic acid bacteria in the presence of 5% MSG at 30 °C for 5 days. The serial co-fermented HSP hydrolysate exhibited a GABA content of 33.98 mg/g and a viable bacterial count of 9.51 log CFU/mL for Lb. plantarum KS2020. This serial co-fermentation process, combining proteolysis and lactic acid fermentation, not only increased the peptide content but also promoted GABA accumulation, positioning HSP hydrolysate as a promising candidate for functional foods with potential health benefits. Full article

In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. Employing a human-relevant ex vivo ‘chip’, AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a significant survival benefit to mice bearing NSCLC intracranial tumors generated using a patient-derived metastatic line. GABA(A) receptor activation stimulates a selective-autophagic response via the multimerization of GABA(A) receptor-associated protein, GABARAP, the stabilization of mitochondrial receptor Nix, and the utilization of ubiquitin-binding protein p62. A high-affinity peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP–Nix multimerization axis that triggers autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity. Full article

The potassium–chloride cotransporter KCC2 is the main extruder of Cl^- in neurons. It plays a fundamental role in the activity of the inhibitory neurotransmitters (GABA and glycine) since low levels of KCC2 promote intracellular Cl^- accumulation, leading to the depolarizing activity of GABA and glycine. The downregulation of this cotransporter occurs in neurological disorders characterized by hyperexcitability, such as epilepsy, neuropathic pain, and spasticity. KCC2 is also downregulated after axotomy. If muscle reinnervation is allowed, the KCC2 levels recover in motoneurons. Therefore, we argued that target-derived neurotrophic factors might be involved in the regulation of KCC2 expression. For this purpose, we performed the axotomy of extraocular motoneurons via the monocular enucleation of adult rats, and a pellet containing either VEGF or BDNF was chronically implanted in the orbit. Double confocal immunofluorescence of choline acetyl-transferase (ChAT) and KCC2 was carried out in the brainstem sections. Axotomy led to a KCC2 decrease in the neuropil and somata of extraocular motoneurons, peaking at 15 days post-lesion, with the exception of the abducens motoneuron somata. VEGF administration prevented the axotomy-induced KCC2 downregulation. By contrast, BDNF either maintained or reduced the KCC2 levels following axotomy, suggesting that BDNF is involved in the axotomy-induced KCC2 downregulation in extraocular motoneurons. The finding that VEGF prevents KCC2 decrease opens up new possibilities for the treatment of neurological disorders coursing with neuronal hyperactivity due to KCC2 downregulation. Full article

Many studies have found that salted radishes offer various health benefits, such as enhancing antioxidant levels and increasing GABA. This study fermented a mixture of 20-year-old salted radishes (20-S. radishes), 2-year-old salted radishes (2-S. radishes), 20-year-old salted radishes combined with fresh radishes (R + 20-radishes), and fresh radishes with eight whole grains fermentation as a starter (EGS) for 8 weeks. EGS was derived from the saccharified fermentation of millet, wheat, sorghum, black rice, buckwheat, pearled rice, black glutinous rice, and quinoa, serving as a carbon source for microorganisms and replacing the traditional sugar-based fermentation method. During the fermentation process, the bacterial count of the 20-year-old salted radishes significantly increased to 11.08 ± 0.03 log CFU/mL, which was much higher than the other three groups. Pichia manshurica LYC1722 was identified in all four groups after isolation. After 8 weeks of fermentation, 20-S. radishes showed the highest concentrations of gamma-aminobutyric acid (GABA) and glucuronic acid in functional components, at 18.40 ± 0.69 ppm and 14,162.84 ± 48.22 ppm, respectively. In terms of antioxidant components, 20-S. radishes exhibited a total phenolic content (TPC) and total flavonoid content (TFC) of 0.81 ± 0.01 mg/mL and 42.78 ± 0.60 mg/L, respectively. Regarding antioxidant capability, 20-S. radishes displayed ABTS radical scavenging activity and DPPH radical scavenging activity at 184.42 ± 0.28 μg/mL and 9.13 ± 0.28 μg/mL, respectively. These values were the highest among the four groups evaluated. Fresh radishes exhibited the highest angiotensin-converting enzyme (ACE) inhibition after fermentation among the four groups, reaching 69.04 ± 2.82%, slightly higher than 20-S. radishes. These results show that 20-S. radishes are expected to become a novel health beverage in the future. Full article

Agarwood, a precious traditional medicinal herb and fragrant material, is known for its sedative and sleep-improving properties. This study explores the mechanisms underlying the aromatherapy effects of Chi-Nan agarwood and ordinary agarwood in improving sleep. Using a combination of gas chromatography–mass spectrometry (GC-MS), network pharmacology, and molecular docking techniques, we identified and c ompared the chemical compositions and potential molecular targets of both types of agarwood. The GC-MS analysis detected 87 volatile components across six types of agarwood aromatherapy, with 51 shared between Chi-Nan and ordinary agarwood, while each type also had 18 unique components. Ordinary agarwood was found to be richer in sesquiterpenes and small aromatic molecules, whereas Chi-Nan agarwood contained higher levels of chromones. These differences in chemical composition are likely responsible for the distinct sleep-improving effects observed between the two types of agarwood. Through network pharmacology, 100, 65, and 47 non-repetitive target genes related to sleep improvement were identified for components shared by both types of agarwood (CSBTs), components unique to common agarwood (CUCMs), and components unique to Chi-Nan agarwood (CUCNs), respectively. The constructed protein–protein interaction (PPI) networks revealed that key targets such as MAOA, MAOB, SLC6A4, and ESR1 are involved in the sleep-improving mechanisms of agarwood aromatherapy. Molecular docking further confirmed the strong binding affinities of major active components, such as 5-Isopropylidene-6-methyldeca-369-trien-2-one and 2-(2-Phenylethyl)chromone, with these core targets. The results suggest that agarwood aromatherapy enhances sleep quality through both hormonal and neurotransmitter pathways, with ordinary agarwood more deeply mediating hormonal regulation, while Chi-Nan agarwood predominantly influences neurotransmitter pathways, particularly those involving serotonin and GABA. This study provides valuable insights into the distinct therapeutic potentials of Chi-Nan and ordinary agarwood, highlighting their roles in sleep improvement and offering a foundation for future research in the clinical application of agarwood-based aromatherapy. Full article

Understanding the molecular mechanisms underlying the generation of absence seizures is crucial for developing effective, patient-specific treatments for childhood absence epilepsy (CAE). Currently, one-third of patients remain refractive to the antiseizure medications (ASMs), previously called antiepileptic drugs (AEDs), available to treat CAE. Additionally, these ASMs often produce serious side effects and can even exacerbate symptoms in some patients. Determining the precise cellular and molecular mechanisms directly responsible for causing this type of epilepsy has proven challenging as they appear to be complex and multifactorial in patients with different genetic backgrounds. Aberrant neuronal activity in CAE may be caused by several mechanisms that are not fully understood. Thus, dissecting the causal factors that could be targeted in the development of precision medicines without side effects remains a high priority and the ultimate goal in this field of epilepsy research. The aim of this review is to highlight our current understanding of potential causative mechanisms for absence seizure generation, based on the latest research using cutting-edge technologies. This information will be important for identifying potential targets for future therapeutic intervention. Full article

The Module-0 Demonstrator is a single-phase 600 kg liquid argon time projection chamber operated as a prototype for the DUNE liquid argon near detector. Based on the ArgonCube design concept, Module-0 features a novel 80k-channel pixelated charge readout and advanced high-coverage photon detection system. In this paper, we present an analysis of an eight-day data set consisting of 25 million cosmic ray events collected in the spring of 2021. We use this sample to demonstrate the imaging performance of the charge and light readout systems as well as the signal correlations between the two. We also report argon purity and detector uniformity measurements and provide comparisons to detector simulations. Full article