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The implication of 5-hydroxytryptamine 2C receptor (5-HT2CR) activity in depression is a topic of debate, and the underlying mechanisms remain largely unclear. Here, we elucidate how hippocampal excitation-inhibition (E/I) balance underlies the regulatory effects of 5-HT2CR in depression. Molecular biological analyses showed that chronic mild stress (CMS) reduced the expression of 5-HT2CR in hippocampus. We revealed that inhibition of 5-HT2CR induced depressive-like behaviours, reduced GABA release and shifted the E/I balance towards excitation in CA3 pyramidal neurons using behavioural analyses, microdialysis coupled with mass spectrometry and electrophysiological recordings. Moreover, 5-HT2CR modulated the neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction by influencing intracellular Ca2+ release, as determined by fibre photometry and coimmunoprecipitation. Notably, disruption of nNOS-CAPON with the specific small molecule compound ZLc-002 or AAV-CMV-CAPON-125C-GFP abolished 5-HT2CR inhibition-induced depressive-like behaviours, as well as the impairment in soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly-mediated GABA vesicle release and consequent E/I imbalance. Importantly, optogenetic inhibition of CA3 GABAergic neurons prevented the effects of AAV-CMV-CAPON-125C-GFP on depressive behaviours in the presence of a 5-HT2CR antagonist. Conclusively, our findings disclose the regulatory role of 5-HT2CR in depressive-like behaviours and highlight hippocampal nNOS-CAPON coupling-triggered E/I imbalance as a pivotal cellular event underpinning the behavioural consequences of 5-HT2CR inhibition. [ABSTRACT FROM AUTHOR]

Taste buds contain 2 types of GABA-producing cells: sour-responsive Type III cells and glial-like Type I cells. The physiological role of GABA, released by Type III cells is not fully understood. Here, we investigated the role of GABA released from Type III cells using transgenic mice lacking the expression of GAD67 in taste bud cells (Gad67-cKO mice). Immunohistochemical experiments confirmed the absence of GAD67 in Type III cells of Gad67-cKO mice. Furthermore, no difference was observed in the expression and localization of cell type markers, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2), gustducin, and carbonic anhydrase 4 (CA4) in taste buds between wild-type (WT) and Gad67-cKO mice. Short-term lick tests demonstrated that both WT and Gad67-cKO mice exhibited normal licking behaviors to each of the five basic tastants. Gustatory nerve recordings from the chorda tympani nerve demonstrated that both WT and Gad67-cKO mice similarly responded to five basic tastants when they were applied individually. However, gustatory nerve responses to sweet–sour mixtures were significantly smaller than the sum of responses to each tastant in WT mice but not in Gad67-cKO mice. In summary, elimination of GABA signalling by sour-responsive Type III taste cells eliminates the inhibitory cell–cell interactions seen with application of sour–sweet mixtures. [ABSTRACT FROM AUTHOR]

BACKGROUND: Gamma‐aminobutyric acid (GABA) is an important neurotransmitter in the human body, with several negative emotions reported as being associated with GABA dysregulation. This study investigates the safety and modulatory effects of GABA‐enriched milk, fermented by Streptococcus thermophilus GA8 and Lacticasebacillus rhamnosus HAO9, on the gut microbiota and neurotransmitter profiles in mice. RESULTS: Through rigorous culturing and fermentation processes, we achieved consistent GABA production in milk, with concentrations reaching 4.6 and 8.5 g L−1 for GA8‐fermented and co‐fermented milk, respectively, after 48 h. Using SPF male C57BL/6J mice, we administered either mono‐culture or combined‐culture milk treatments and monitored physiological impacts. The treatments did not affect mouse body weight but induced significant changes in gut microbiota composition. Beta diversity analysis revealed distinct microbial profiles between treatment groups, highlighting fermentation‐specific microbial shifts, such as an increase in Verrucomicrobia for the GA8 group and a modulation in Saccharibacteria_genera_incertae_sedis for the GA8 + HAO9 group. Serum neurotransmitter levels were elevated in both treatment groups, with significant increases in l‐glutamine, l‐tryptophan and, notably, serotonin hydrochloride in the GA8 + HAO9 group. Correlation analysis identified a positive association between specific bacterial genera and neurotransmitter levels, suggesting a probiotic effect on neuroactive substances. CONCLUSION: These findings suggest that fermented milk has potential as a probiotic supplement for mood improvement and stress relief, highlighting its role in modulating the gut–brain axis. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Wheat leaf rust, caused by Puccinia triticina, poses a growing threat to global wheat production, necessitating alternative strategies for effective disease management. This study investigated the potential of gamma-aminobutyric acid (GABA) to enhance resistance to leaf rust in two wheat cultivars: the susceptible Morocco and moderately resistant Sakha 94 cultivar. Our findings revealed that GABA significantly improved resistance in both cultivars to P. triticina, particularly in Morocco, by mitigating disease severity and reducing pustule density and size while extending both incubation and latent periods. This study assessed the effectiveness of two GABA application methods: plants received 1 mM GABA treatment, as a foliar spray, twenty-four hours prior to infection (pre-GABA), and plants received 1 mM GABA treatment both 24 h before and after infection (pre-/post-GABA), with the latter yielding significantly better results in reducing infection severity and improving plant resilience. Additionally, GABA application influenced stomatal behavior, promoting closure that may enhance resilience against leaf rust. GABA application on plants also modulated the production of reactive oxygen species (ROS). This led to a stronger oxidative burst in both susceptible and moderately resistant cultivars. GABA increased O2●− levels in guard cells and surrounding stomata, enhancing stomatal closure and the hypersensitive response. GABA enhanced the accumulation of soluble phenols and increased the activity of key antioxidant enzymes, catalase (CAT) and peroxidase (POX), which are vital for managing oxidative stress. To the best of our knowledge, this investigation represents the first report into the impact of GABA on wheat leaf rust disease. [ABSTRACT FROM AUTHOR]

Although peroxisomes are integral for both primary and secondary metabolism, how developmental changes affect activity of peroxisomes remains poorly understood. Here, we used published RNA‐seq data to analyze the expression patterns of genes encoding 21 peroxisome metabolic pathways at successive developmental stages of Zea mays and Oryza sativa. Photorespiration was the most represented pathway in adult leaf relative to the juvenile stages. Components of reactive oxygen species (ROS)/reactive nitrogen species (RNS) metabolism, NADPH regeneration, and catabolism of polyamines were also enriched at later stages of leaf differentiation. The most commonly upregulated gene in differentiated leaves across all datasets of both species was BETAINE ALANINE DEHYDROGENASE (BADH). BADH functions in catabolism of polyamines where it converts 4‐aminobutyraldehyde (ABAL) to 4‐aminobutyrate (GABA). We tested the outcome of RNA‐seq analysis by qRT‐PCR in developing Triticum monococcum ssp. monococcum (Einkorn) seedlings. Consistent with the outcomes of RNA‐seq analysis, transcription of BADH and CATALASE3 (CAT3) were upregulated in older seedlings. CAT3 is an essential peroxisome biogenesis factor and a key enzyme of ROS homeostasis. Furthermore, exogenous application of GABA resulted in higher peroxisome abundance and transcriptional upregulation of BADH and a gene encoding another peroxisome biogenesis factor responsible for peroxisome fission, PEROXIN11C (PEX11C), in leaves. We propose that GABA contributes to regulation of peroxisome fission machinery during leaf differentiation. [ABSTRACT FROM AUTHOR]

In this study, a functional fermented beverage enriched with gamma‐aminobutyric acid (GABA) was produced. To achieve this, the prebiotic abilities of pectin obtained from pomegranate peel and its enzymatic hydrolysates were evaluated. Additionally, a functional fermented beverage enriched with GABA was produced by fermenting carrot juice with pectin hydrolysates. First, pectin was obtained at a yield of 8.91% from pomegranate peels. Pectinase‐catalyzed hydrolysis of the obtained pectin was applied using different enzyme concentrations and hydrolysis times, and the effect of these hydrolysates on the growth of Levilactobacillus brevis was determined. Although the Fourier transform infrared (FT‐IR) spectra of the resulting hydrolysates were similar, their degree of esterification compared to that of pectin was statistically different (p <.05). Considering the viability analysis and GABA production of L. brevis in the liquid medium supplemented with pectin or its hydrolysate, the hydrolysate obtained by treatment with 400 μL enzyme for 2 h and having a high glucose content (216.80 mg/100 g) was selected for application in fermented carrot juice. During fermentation (24, 48, and 72 h), a remarkable change was observed, especially in the amounts of lactic acid and malic acid, while the amount of GABA in carrot juice varied between 25 and 46 mg/mL and increased with the increase in hydrolysate concentration. It was observed that the total phenolic content and antioxidant activity of carrot juice were highly affected by the hydrolysate concentration. This study demonstrated that pectin hydrolysate obtained from food waste could be a potential prebiotic and could be used in the production of a functional beverage with improved GABA content. [ABSTRACT FROM AUTHOR]

Gamma-aminobutyric acid (GABA) is considered an important stress metabolite with regulatory functions in plants. Exogenous GABA can enhance the tolerance of different plant species to drought and salt stress. However, its effects on the functioning of stress-protective systems in triticale, an intergeneric wheat-rye hybrid with specific adaptation strategies to abiotic stresses, remain completely understudied. We examined the effects of exogenous GABA (0.5 mM) on the growth, antioxidant, and osmoprotective systems of triticale seedlings (cv. 'Rarytet') under simulated drought (15% PEG 6000), salt stress (100 mM NaCl), or a combination of these two factors. GABA mitigated the growth-inhibitory effects of drought by approximately 15% and salt stress by approximately 23%. However, GABA's most noticeable impact was seen on biomass accumulation under combined stress: it decreased the biomass accumulation inhibition caused by a drought-salt stress combination by 67%; GABA also increased the water content in seedling tissues when subjected to each stressor separately and to the combination of the two. GABA considerably reduced drought- and salt-triggered enhancement of ROS generation and lipid peroxidation. GABA increased the activities of antioxidant enzymes, such as superoxide dismutase, catalase, and guaiacol peroxidase, under physiologically normal conditions under the influence of PEG 6000 or NaCl. Subjected to a drought-salt stress combination, GABA prevented a reduction in the activities of these enzymes. Under normal and stressful conditions, exogenous GABA also modulated the contents of proline, sugars, phenolic compounds, and anthocyanins in the seedlings. We concluded that the stress-protective systems of triticale were highly susceptible to GABA and that it was possible to use GABA to enhance the tolerance of this species to osmotic stresses, especially under a combined impact of drought and salinity. [ABSTRACT FROM AUTHOR]

Gamma‐aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the adult brain that binds to GABA receptors and hyperpolarizes the postsynaptic neuron. Gabazine acts as a competitive antagonist to type A GABA receptors (GABAAR), thereby causing diminished neuronal hyperpolarization and GABAAR‐mediated inhibition. However, the biochemical effects and the potential regulatory role of astrocytes in this process remain poorly understood. To address this, we investigated the neuronal responses of gabazine in rat cortical cultures containing varying ratios of neurons and astrocytes. Electrophysiological characterization was performed utilizing microelectrode arrays (MEAs) with topologically controlled microcircuit cultures that enabled control of neuronal network growth. Biochemical analysis of the cultures was performed using traditional dissociated cultures on coverslips. Our study indicates that, upon gabazine stimulation, astrocyte‐rich neuronal cultures exhibit elevated electrophysiological activity and tyrosine phosphorylation of tropomyosin receptor kinase B (TrkB; receptor for brain‐derived neurotrophic factor), along with distinct cytokine secretion profiles. Notably, neurons lacking proper astrocytic support were found to experience synapse loss and decreased mitogen‐activated protein kinase (MAPK) phosphorylation. Furthermore, astrocytes contributed to neuronal viability, morphology, vascular endothelial growth factor (VEGF) secretion, and overall neuronal network functionality, highlighting the multifunctional role of astrocytes. [ABSTRACT FROM AUTHOR]

Extensive studies on γ-aminobutyric acid (GABA) over decades highlight its significant physiological and pharmacological effects on humans. GABA produced using microbe is favoured compared to enzymatic and chemical methods due to operational ease and reduced harmful pollutant formation. This study focused on increasing γ-aminobutyric acid (GABA) biosynthesis from Lactiplantibacillus plantarum B7, employing a multi-step optimisation strategy. An unoptimised cultivation approach yielded a maximum GABA of 11.68 ± 0.04 g/L and viable cell count of 10.47 ± 0.01 log CFU/mL at 48 h. A nutrient-rich medium was developed through single-parameter optimisation, comprising 1%, 2.5% and 0.0002% of glucose, yeast extract and each trace element (CaCO3, KI, and Tween 80) respectively. Temperature, pH, incubation period, initial concentration of monosodium glutamate (MSG) and pyridoxal-5'-phosphate (PLP) demonstrated significant contributions towards GABA production and cell growth as determined using a two-level factorial design. Steepest ascent identified optimal conditions (36°C, pH 5.5, 370 mM MSG, and 0.7 mM PLP), resulting in 30.50 g/L GABA and 11.51 log CFU/mL at 60 h. Further refinement via a central composite experiment yielded optimal conditions (temperature-35.6°C, pH-5.66, initial MSG concentration-335.61 mM, PLP concentration-0.723 mM) with improved GABA production (32.18 g/L) and cell growth (11.52 log CFU/mL) over 63.66 h. Therefore, this approach utilising lactic acid bacteria capable of GABA synthesis holds promise for mass-produced, enhanced-functional foods. [ABSTRACT FROM AUTHOR]

Importance: Glutamic acid decarboxylase 67 (GAD67) is a gamma-aminobutyric acid (GABA) synthesis enzyme associated with the function of other neurotransmitter receptors, such as the N-methyl-D-aspartate (NMDA) receptor and cannabinoid receptor 1. However, the role of GAD67 in the development of different abused drug-induced reward behaviors remains unknown. In order to elucidate the mechanisms of substance use disorder, it is crucial to study changes in biomarkers within the brain's reward circuit induced by drug use. Objective: The study was designed to examine the effects of the downregulation of GAD67 expression in the dorsal striatum on reward behavior development. Methods: We evaluated the effects of GAD67 knockdown on depression-like behavior and anxiety using the forced swim test and elevated plus maze test in a mouse model. We further determined the effects of GAD67 knockdown on ketamine- and JWH-018-induced conditioned place preference (CPP). Results: Knockdown of GAD67 in the dorsal striatum of mice increased depression-like behavior, but it decreased anxiety. Moreover, the CPP score on the NMDA receptor antagonist ketamine was increased by GAD67 knockdown, whereas the administration of JWH-018, a cannabinoid receptor agonist, did not affect the CPP score in the GAD67 knockdown mice group compared with the control group. Conclusions and Relevance: These results suggest that striatal GAD67 reduces GABAergic neuronal activity and may cause ketamine-induced NMDA receptor inhibition. Consequently, GAD67 downregulation induces vulnerability to the drug reward behavior of ketamine. [ABSTRACT FROM AUTHOR]

Extensive studies on γ-aminobutyric acid (GABA) over decades highlight its significant physiological and pharmacological effects on humans. GABA produced using microbe is favoured compared to enzymatic and chemical methods due to operational ease and reduced harmful pollutant formation. This study focused on increasing γ-aminobutyric acid (GABA) biosynthesis from Lactiplantibacillus plantarum B7, employing a multi-step optimisation strategy. An unoptimised cultivation approach yielded a maximum GABA of 11.68 ± 0.04 g/L and viable cell count of 10.47 ± 0.01 log CFU/mL at 48 h. A nutrient-rich medium was developed through single-parameter optimisation, comprising 1%, 2.5% and 0.0002% of glucose, yeast extract and each trace element (CaCO3, KI, and Tween 80) respectively. Temperature, pH, incubation period, initial concentration of monosodium glutamate (MSG) and pyridoxal-5’-phosphate (PLP) demonstrated significant contributions towards GABA production and cell growth as determined using a two-level factorial design. Steepest ascent identified optimal conditions (36°C, pH 5.5, 370 mM MSG, and 0.7 mM PLP), resulting in 30.50 g/L GABA and 11.51 log CFU/mL at 60 h. Further refinement via a central composite experiment yielded optimal conditions (temperature-35.6°C, pH-5.66, initial MSG concentration-335.61 mM, PLP concentration-0.723 mM) with improved GABA production (32.18 g/L) and cell growth (11.52 log CFU/mL) over 63.66 h. Therefore, this approach utilising lactic acid bacteria capable of GABA synthesis holds promise for mass-produced, enhanced-functional foods.

On the industrial scale, the cost of commercial culture media for the production of gammaaminobutyric acid (GABA) is a very important factor. This study employed a low-cost substrates and byproduct from agri-food industry for GABA synthesis by Lact. futsaii CS3 at the fermenter-scale. Lact. futsaii CS3 cells were immobilized in 3 % (w/v) sodium alginate and employed for GABA synthesis in the optimal modified MRS medium (3.48 % (w/v) cane sugar, 3.84 % (w/v) tuna condensate waste and 10.77 % (w/v) monosodium glutamate (MSG)) with the initial pH medium of 5, fermentation temperature at 37 °C and agitation speed at 30 rpm. During the 60th h of batch fermentation without pH control, immobilized Lact. futsaii CS3 efficiently transformed MSG into the highest GABA of 19.05 g/L, achieving the volumetric productivity of 0.32 g/L/h with a bioconversion rate of 29.01 %. To further enhance GABA production, MSG (7.5 % w/v) was fed into the fermenter during the 48th h of fed-batch fermentation, aiming to amplify GABA synthesis. The maximum GABA (26.28 g/L) was synthesized at 84 h of fed-batch fermentation, and the volumetric productivity and a bioconversion rate of 0.31 g/L/h and 23.59 %, respectively, were obtained. Fed-batch fermentation significantly outperformed batch fermentation, resulting in a 37.95 % increase in GABA production. Moreover, immobilized Lact. futsaii CS3 cells could be reused in 2 batch cycles. In the 1st reusability, the maximum GABA synthesis reached 25.94 g/L, and the volumetric productivity and a bioconversion rate of 0.31 g/L/h and 23.29 %, respectively, were achieved at 84 h of fed-batch fermentation. While in the 2nd reusability, GABA synthesis decreased to 23.29 g/L, with the volumetric productivity and a bioconversion rate of 0.28 g/L/h and 20.91 %, respectively, at 84 h of fed-batch fermentation. [ABSTRACT FROM AUTHOR]

Introduction: Changpu Yujin Tang(CPYJT), a Chinese herbal compound, is an effective therapeutic strategy for pediatric patients with Tourette disorder (TD). Therefore, this work aims to investigate the therapeutic mechanisms of CPYJT. Methods: Behavioral and cellular ultrastructural evaluation of the therapeutic effects of CPYJT in TD model rats. Colorimetric methods, reverse transcription‑quantitative PCR, and Western Blot were used to measure the altered levels of GLU, GABA, and the levels of VGLUT1, GLUD1, GABRA3, and GAD65 in the cortex, striatum, and thalamus of the TD model rats after 7, 14, 21, and 28 days of CPYJT administration. Results: CPYJT significantly reduced stereotypic behavior and motor behavior scores in TD model rats. CPYJT ameliorates myelin structural damage in TD model rat neuronal cells. CPYJT decreased GLU content, elevated GABA content, decreased GLUD1 and VGLUT1 levels, and elevated GAD65 and GABRA3 levels in TD model rats' cortex, striatum, and thalamus. CPYJT has different regulatory time points in the cortex, striatum, and thalamus for critical factors of amino acid-based neurotransmission. Conclusion: CPYJT protects behavioral and structural damage of neuronal cells in multiple brain regions in TD model rats. [ABSTRACT FROM AUTHOR]

The probiotic fermentation of the bioactive substance gamma-aminobutyric acid (GABA) is an attractive research topic. There is still room for further improvement in reported GABA fermentation methods based on a single substrate (l-glutamic acid or l-monosodium glutamate). Here, we devised a pH auto-buffering strategy to facilitate the fermentation of GABA by Levilactobacillus brevis CD0817. This strategy features a mixture of neutral monosodium l-glutamate plus acidic l-glutamic acid as the substrate. This mixture provides a mild initial pH; moreover, the newly dissolved l-glutamic acid automatically offsets the pH increase caused by substrate decarboxylation, maintaining the acidity essential for GABA fermentation. In this study, a flask trial was first performed to optimize the GABA fermentation parameters of Levilactobacillus brevis CD0817. The optimized parameters were further validated in a 10 L fermenter. The flask trial results revealed that the appropriate fermentation medium was composed of powdery l-glutamic acid (750 g/L), monosodium l-glutamate (34 g/L [0.2 mol/L]), glucose (5 g/L), yeast extract (35 g/L), MnSO4·H2O (50 mg/L [0.3 mmol/L]), and Tween 80 (1.0 g/L). The appropriate fermentation temperature was 30 °C. The fermenter trial results revealed that GABA was slowly synthesized from 0–4 h, rapidly synthesized until 32 h, and finally reached 353.1 ± 8.3 g/L at 48 h, with the pH increasing from the initial value of 4.56 to the ultimate value of 6.10. The proposed pH auto-buffering strategy may be popular for other GABA fermentations. [ABSTRACT FROM AUTHOR]

Abstract Background Magnetic resonance spectroscopy (MRS) studies have indicated that the imbalance between gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels was the potential cause of migraine development. However, the changes in the GABA and Glx levels in patients with New daily persistent headache (NDPH) remain unclear. This study aimed to investigate the changes in GABA and Glx levels in the periaqueductal gray (PAG) and dentate nucleus (DN) in patients with NDPH using the MEGA-PRESS sequence. Methods Twenty-one NDPH patients and 22 age- and sex-matched healthy controls (HCs) were included and underwent a 3.0T MRI examination, using the MEGA-PRESS sequence to analyze GABA and Glx levels of PAG and DN. The correlations between these neurotransmitter levels and clinical characteristics were also analyzed. Results There were no significant differences in the GABA+/Water, GABA+/Cr, Glx/Water, and Glx/Cr levels in both PAG and DN between the two groups (all p > 0.05). Moderate-severe NDPH patients had lower levels of Glx/Water (p = 0.034) and Glx/Cr (p = 0.012) in DN than minimal-mild NDPH patients. In patients with NDPH, higher Glx/Water levels in the PAG (r=-0.471, p = 0.031, n = 21) and DN (r=-0.501, p = 0.021, n = 21) and higher Glx/Cr levels in DN (r=-0.483, p = 0.026, n = 21) were found to be correlated with lower Visual Analogue Scale scores. Additionally, a positive correlation was observed between the GABA+/Cr levels in the DN and the Generalized Anxiety Disorder-7 scores (r = 0.519, p = 0.039, n = 16). Conclusions The results of this study indicated that the GABA and Glx levels in the PAG and DN may not be the primary contributor to the development of NDPH. The correlations between certain clinical scales and the neurotransmitter levels may be derived from the NDPH related symptoms.

Abstract Gamma-aminobutyric acid (GABA), a ubiquitous non-protein 4-carbon amino acid present in both prokaryotic and eukaryotic organisms. It is conventionally recognized as a neurotransmitter in mammals and plays a crucial role in plants. The context of this review centers on the impact of GABA in mitigating abiotic stresses induced by climate change, such as drought, salinity, heat, and heavy metal exposure. Beyond its neurotransmitter role, GABA emerges as a key player in diverse metabolic processes, safeguarding plants against multifaceted abiotic as well as biotic challenges. This comprehensive exploration delves into the GABA biosynthetic pathway, its transport mechanisms, and its intricate interplay with various abiotic stresses. The discussion extends to the nuanced relationship between GABA and phytohormones during abiotic stress acclimation, offering insights into the strategic development of mitigation strategies against these stresses. The delineation of GABA's crosstalk with phytohormones underscores its pivotal role in formulating crucial strategies for abiotic stress alleviation in plants.

The current gold-standard management of hyperglycemia in individuals with type 1 diabetes mellitus (T1DM) is insulin therapy. However, this therapy is associated with a high incidence of complications, and delaying the onset of this disease produces a substantially positive impact on quality of life for individuals with a predisposition to T1DM, especially children. This review aimed to assess the use of gamma-aminobutyric acid (GABA) to delay the onset of T1DM in children. GABA produces protective and proliferative effects in 2 ways, β cell and immune cell modulation. Various in vitro and in vivo studies have shown that GABA induces proliferation of β cells, increases insulin levels, inhibits β-cell apoptosis, and suppresses T helper 1 cell activity against islet antigens. Oral GABA is safe as no serious adverse effects were reported in any of the studies included in this review. These findings demonstrate promising results for the use of GABA treatment to delay T1DM, specifically in genetically predisposed children, through immunoregulatory effects and the ability to induce β-cell proliferation.

Background: Magnetic resonance spectroscopy (MRS) studies have indicated that the imbalance between gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels was the potential cause of migraine development. However, the changes in the GABA and Glx levels in patients with New daily persistent headache (NDPH) remain unclear. This study aimed to investigate the changes in GABA and Glx levels in the periaqueductal gray (PAG) and dentate nucleus (DN) in patients with NDPH using the MEGA-PRESS sequence. Methods: Twenty-one NDPH patients and 22 age- and sex-matched healthy controls (HCs) were included and underwent a 3.0T MRI examination, using the MEGA-PRESS sequence to analyze GABA and Glx levels of PAG and DN. The correlations between these neurotransmitter levels and clinical characteristics were also analyzed. Results: There were no significant differences in the GABA+/Water, GABA+/Cr, Glx/Water, and Glx/Cr levels in both PAG and DN between the two groups (all p > 0.05). Moderate-severe NDPH patients had lower levels of Glx/Water (p = 0.034) and Glx/Cr (p = 0.012) in DN than minimal-mild NDPH patients. In patients with NDPH, higher Glx/Water levels in the PAG (r=-0.471, p = 0.031, n = 21) and DN (r=-0.501, p = 0.021, n = 21) and higher Glx/Cr levels in DN (r=-0.483, p = 0.026, n = 21) were found to be correlated with lower Visual Analogue Scale scores. Additionally, a positive correlation was observed between the GABA+/Cr levels in the DN and the Generalized Anxiety Disorder-7 scores (r = 0.519, p = 0.039, n = 16). Conclusions: The results of this study indicated that the GABA and Glx levels in the PAG and DN may not be the primary contributor to the development of NDPH. The correlations between certain clinical scales and the neurotransmitter levels may be derived from the NDPH related symptoms. [ABSTRACT FROM AUTHOR]

Gamma-aminobutyric acid (GABA), a ubiquitous non-protein 4-carbon amino acid present in both prokaryotic and eukaryotic organisms. It is conventionally recognized as a neurotransmitter in mammals and plays a crucial role in plants. The context of this review centers on the impact of GABA in mitigating abiotic stresses induced by climate change, such as drought, salinity, heat, and heavy metal exposure. Beyond its neurotransmitter role, GABA emerges as a key player in diverse metabolic processes, safeguarding plants against multifaceted abiotic as well as biotic challenges. This comprehensive exploration delves into the GABA biosynthetic pathway, its transport mechanisms, and its intricate interplay with various abiotic stresses. The discussion extends to the nuanced relationship between GABA and phytohormones during abiotic stress acclimation, offering insights into the strategic development of mitigation strategies against these stresses. The delineation of GABA's crosstalk with phytohormones underscores its pivotal role in formulating crucial strategies for abiotic stress alleviation in plants. [ABSTRACT FROM AUTHOR]

The transmission of nociceptive and pruriceptive signals in the spinal cord is greatly influenced by descending modulation from brain areas such as the rostral ventromedial medulla (RVM). Within the RVM three classes of neurons have been discovered which are relevant to spinal pain modulation, the On, Off, and Neutral cells. These neurons were discovered due to their functional response to nociceptive stimulation. On cells are excited, Off cells are inhibited, and Neutral cells have no response to noxious stimulation. Since these neurons are identified by functional response characteristics it has been difficult to molecularly identify them. In the present study, we leverage our ability to perform optotagging within the RVM to determine whether RVM On, Off, and Neutral cells are GABAergic. We found that 27.27% of RVM On cells, 47.37% of RVM Off cells, and 42.6% of RVM Neutral cells were GABAergic. These results demonstrate that RVM On, Off, and Neutral cells represent a heterogeneous population of neurons and provide a reliable technique for the molecular identification of these neurons. [ABSTRACT FROM AUTHOR]

Although classically recognized as a neurotransmitter, gamma aminobutyric acid (GABA) has also been identified in colonic tumors. Moreover, the gut microbiome represents another potential source of GABA. Both GABAA and GABAB receptors have been implicated in contributing to the effects of GABA in colorectal cancer, with both pro‐ and anti‐tumorigenic functions identified. However, their subunit composition is often overlooked. Studies to date have not addressed whether the GABA‐producing potential of the microbiome changes over the course of colon tumor development or whether receptor subunit expression patterns are altered in colon cancer. Therefore, we investigated the clusters of orthologous group frequencies of glutamate decarboxylase (GAD) in feces from two murine models of colon cancer and found that the frequency of microbial GAD was significantly decreased early in the tumorigenic process. We also determined that microbial‐derived GABA inhibited proliferation of colon cancer cells in vitro and that this effect of GABA on SW480 cells involved both GABAA and GABAB receptors. GABA also inhibited prostaglandin E2 (PGE2)‐induced proliferation and interleukin‐6 (IL‐6) expression in these cells. Gene expression correlations were assessed using the "Cancer Exploration" suite of the TIMER2.0 web tool and identified that GABA receptor subunits were differentially expressed in human colon cancer. Moreover, GABAA receptor subunits were predominantly positively associated with PGE2 synthase, cyclooxygenase‐2 and IL‐6. Collectively, these data demonstrate decreased potential of the microbiome to produce GABA during tumorigenesis, a novel anti‐tumorigenic pathway for GABA, and that GABA receptor subunit expression adds a further layer of complexity to GABAergic signaling in colon cancer. [ABSTRACT FROM AUTHOR]

Summary: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder of γ‐aminobutyrate (GABA) catabolism. Cerebral waste clearance along glymphatic perivascular spaces depends on aquaporin 4 (AQP4) water channels, the function of which was shown to be influenced by GABA. Sleep disturbances are associated independently with SSADHD and glymphatic dysfunction. This study aimed to determine whether indices of the hyperGABAergic state characteristic of SSADHD coincide with glymphatic dysfunction and sleep disturbances and to explicate the modulatory effect that GABA may have on the glymphatic system. The study included 42 individuals (21 with SSADHD; 21 healthy controls) who underwent brain MRIs and magnetic resonance spectroscopy (MRS) for assessment of glymphatic dysfunction and cortical GABA, plasma GABA measurements, and circadian clock gene expression. The SSADHD subjects responded to an additional Children's Sleep Habits Questionnaire (CSHQ). Compared with the control group, SSADHD subjects did not differ in sex and age but had a higher severity of enlarged perivascular spaces in the centrum semiovale (p < 0.001), basal ganglia (p = 0.01), and midbrain (p = 0.001), as well as a higher MRS‐derived GABA/NAA peak (p < 0.001). Within the SSADHD group, the severity of glymphatic dysfunction was specific for a lower MRS‐derived GABA/NAA (p = 0.04) and lower plasma GABA (p = 0.004). Additionally, the degree of their glymphatic dysfunction correlated with the CSHQ‐estimated sleep disturbances scores (R = 5.18, p = 0.03). In the control group, EPVS burden did not correlate with age or cerebral and plasma GABA values. The modulatory effect that GABA may exert on the glymphatic system has therapeutic implications for sleep‐related disorders and neurodegenerative conditions associated with glymphatic dysfunction. [ABSTRACT FROM AUTHOR]

The Sogatella furcifera (Horva'th) (Homoptera: Delphacidae) is a white-backed planthopper (WBPH) that causes "hopper burn" in rice, resulting in severe yield loss. Gamma-aminobutyric acid (GABA) is a well-known neurotransmitter that inhibits neurotransmission in insects by binding to specific receptors. In this study, we investigated the potential role of GABA in modulating rice resistance to WBPH and evaluated possible defense mechanisms. The experiment was conducted in green house in pots consist of four groups: control, GABAtreated, WBPH-infested, and WBPH-infested treated with GABA. Among the various tested concentration of GABA, 15 mM GABA was applied as a single treatment in water. The treatment was administered one week before WBPH infestation. The results revealed that 15 mM GABA treatment strongly increased WBPH resistance. A plate-based assay indicated that direct application of 15 mM GABA increased the mortality rate of WBPH and increased the damage recovery rate in rice plants. We found that GABA treatment increased the activation of antioxidant enzymes and reduced the reactive oxygen species content and malondialdehyde contents, and reduced the damage rate caused by WBPH. Interestingly, GABA-supplemented plants infested with WBPH exhibited increased phenylalanine ammonia-lyase and pathogenesis-related (PR) genes expression levels. GABA induced the accumulation of abscisic acid (ABA) and salicylic acid (SA) and enhanced the stomata closure and reduced leaf vessels to reduce water conductance during WBPH stress. Furthermore, we found that GABA application to the plant induced the expression of Jasmonic acid (JA) biosynthesis genes (LOX, AOS, AOC, and OPR) and melatonin biosynthesisrelated genes (TDC, T5H, ASMT, and SNAT). Our study suggested that GABA increases resistance against WBPH infestation by regulating antioxidant defense system, TCA cycle regulation, phytohormonal signaling, and PR gene regulation. [ABSTRACT FROM AUTHOR]

The need to increase food safety and improve human health has led to a worldwide increase in interest in gamma-aminobutyric acid (GABA), produced by lactic acid bacteria (LABs). GABA, produced from glutamic acid in a reaction catalyzed by glutamate decarboxylase (GAD), is a four-carbon, non-protein amino acid that is increasingly used in the food industry to improve the safety/quality of foods. In addition to the possible positive effects of GABA, called a postbiotic, on neuroprotection, improving sleep quality, alleviating depression and relieving pain, the various health benefits of GABA-enriched foods such as antidiabetic, antihypertension, and anti-inflammatory effects are also being investigated. For all these reasons, it is not surprising that efforts to identify LAB strains with a high GABA productivity and to increase GABA production from LABs through genetic engineering to increase GABA yield are accelerating. However, GABA's contributions to food safety/quality and human health have not yet been fully discussed in the literature. Therefore, this current review highlights the synthesis and food applications of GABA produced from LABs, discusses its health benefits such as, for example, alleviating drug withdrawal syndromes and regulating obesity and overeating. Still, other potential food and drug interactions (among others) remain unanswered questions to be elucidated in the future. Hence, this review paves the way toward further studies. [ABSTRACT FROM AUTHOR]

Gamma-aminobutyric acid is one of the major inhibitory neurotransmitters in the nervous system. Although gamma-aminobutyric acid is commonly synthesized by chemical methods, its microbial biosynthesis is regarded as one of the best production methods among the conventional techniques. This study aimed to optimize and model the production of gamma-aminobutyric acid from Lactobacillus plantarum subsp. plantarum IBRC (10,817) under the influence of heat and ultrasonic shock using the response surface methodology. Heat and ultrasonic shock were applied in the lag phase of bacterial growth. Heat shock variables included heat treatment, monosodium glutamate concentration, and incubation time. Also, ultrasonic shock variables were ultrasonic intensity, ultrasonic time, incubation time, and monosodium glutamate concentration. By applying the 30.9 h of incubation, 3.082 g/L of monosodium glutamate, and thermal shock of 49.958 °C for 30 min, the production of 295.04 mg/L of gamma amino butyric acid was predicted. As for ultrasonic shock, using 3.28 (g/L) monosodium glutamate, 70 h of bacterial incubation, 7.7 min ultrasound shock, and ultrasound frequency of 26.58 kHz, the highest amount of metabolite production was anticipated to be 215.19 mg/L. Overall, it was found that the actual values were consistent with the predicted values. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BP) is a recurring psychiatric condition characterized by alternating episodes of low energy (depressions) followed by manias (high energy). Cortical network activity produced by GABAergic interneurons may be critical in maintaining the balance in excitatory/inhibitory activity in the brain during development. Initially, GABAergic signaling is excitatory; with maturation, these cells undergo a functional switch that converts GABAA channels from depolarizing (excitatory) to hyperpolarizing (inhibitory), which is controlled by the intracellular concentration of two chloride transporters. The earliest, NKCC1, promotes chloride entry into the cell and depolarization, while the second (KCC2) stimulates movement of chloride from the neuron, hyperpolarizing it. Perturbations in the timing or expression of NKCC1/KCC2 may affect essential morphogenetic events including cell proliferation, migration, synaptogenesis and plasticity, and thereby the structure and function of the cortex. We derived induced pluripotent stem cells (iPSC) from BP patients and undiagnosed control (C) individuals, then modified a differentiation protocol to form GABAergic interneurons, harvesting cells at sequential stages of differentiation. qRT-PCR and RNA sequencing indicated that after six weeks of differentiation, controls transiently expressed high levels of NKCC1. Using multi-electrode array (MEA) analysis, we observed that BP neurons exhibit increased firing, network bursting and decreased synchrony compared to C. Understanding GABA signaling in differentiation may identify novel approaches and new targets for treatment of neuropsychiatric disorders such as BP. [ABSTRACT FROM AUTHOR]

Gamma-aminobutyric acid (GABA) serves as a pivotal neurotransmitter implicated in the pathogenesis of stress, anxiety, sleep-related disorders, and heart rate (HR) reactions. Heart-rate variability (HRV), modulated by the sympathetic and parasympathetic branches of the autonomic nervous system (ANS), offers insights into cardiac autonomic control and cardiovascular well-being. The present study aimed to explore the impact of GABA supplementation on emotional metrics, sleep quality, and HRV in sedentary women with overweight or obesity partaking in physical exercise. A randomized, double-blind, placebo-controlled clinical trial was undertaken involving 30 sedentary women with overweight or obesity. Volunteers were assigned randomly to two groups: the intervention group receiving GABA (200 mg) once daily for a total of 90 supplementation doses, and the placebo group. Both groups engaged in physical exercise, while the supplementation regimen spanned 90 days. Assessments were conducted at three intervals: baseline (T0), midway through the study (T45), and study culmination (T90). Following 90 days of GABA supplementation, the intervention group demonstrated enhancements in habitual sleep efficiency, as indicated by reductions in Pittsburgh Sleep Quality Index (PSQI) scores. Moreover, an improved emotional response was observed, characterized by diminished negative affect. GABA supplementation yielded ameliorations in depression scores as per the Depression, Anxiety, and Stress Scale (DASS-21). Notably, an augmented HRV was noted, attributed to heightened parasympathetic autonomic nervous system predominance. GABA supplementation elicited noteworthy enhancements in heart rate variability, emotional response, depression mitigation, and sleep efficiency following a 90-day supplementation. [ABSTRACT FROM AUTHOR]

Lowing blood lipid levels with probiotics has good application prospects. This study aimed to isolate probiotics with hypolipidemic efficacy from homemade na dish and investigate their mechanism of action. In vitro experiments were conducted to determine the cholesterol-lowering ability of five isolates, with results showing that Lactiplantibacillus plantarum N4 exhibited a high cholesterol-lowering rate of 50.27% and significant resistance to acid (87%), bile salt (51.97%), and pepsin (88.28%) in simulated gastrointestinal fluids, indicating promising application prospects for the use of probiotics in lowering blood lipids. The findings from the in vivo experiment demonstrated that the administration of N4 effectively attenuated lipid droplet accumulation and inflammatory cell infiltration in the body weight and liver of hyperlipidemic rats, leading to restoration of liver tissue morphology and structure, as well as improvement in lipid and liver biochemical parameters. 16S analysis indicated that the oral administration of N4 led to significant alterations in the relative abundance of various genera, including Sutterella, Bacteroides, Clostridium, and Ruminococcus, in the gut microbiota of hyperlipidemia rats. Additionally, fecal metabolomic analysis identified a total of 78 metabolites following N4 intervention, with carboxylic acids and their derivatives being the predominant compounds detected. The transcriptomic analysis revealed 156 genes with differential expression following N4 intervention, leading to the identification of 171 metabolic pathways through Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Notably, the glutathione metabolism pathway, PPAR signaling pathway, and bile secretion pathway emerged as the primary enrichment pathways. The findings from a comprehensive multi-omics analysis indicate that N4 influences lipid metabolism and diminishes lipid levels in hyperlipidemic rats through modulation of fumaric acid and γ-aminobutyric acid concentrations, as well as glutathione and other metabolic pathways in the intestinal tract, derived from both the gut microbiota and the host liver. This research offers valuable insights into the therapeutic potential of probiotics for managing lipid metabolism disorders and their utilization in the development of functional foods. [ABSTRACT FROM AUTHOR]

The current gold-standard management of hyperglycemia in individuals with type 1 diabetes mellitus (T1DM) is insulin therapy. However, this therapy is associated with a high incidence of complications, and delaying the onset of this disease produces a substantially positive impact on quality of life for individuals with a predisposition to T1DM, especially children. This review aimed to assess the use of gamma-aminobutyric acid (GABA) to delay the onset of T1DM in children. GABA produces protective and proliferative effects in 2 ways, β cell and immune cell modulation. Various in vitro and in vivo studies have shown that GABA induces proliferation of β cells, increases insulin levels, inhibits β-cell apoptosis, and suppresses T helper 1 cell activity against islet antigens. Oral GABA is safe as no serious adverse effects were reported in any of the studies included in this review. These findings demonstrate promising results for the use of GABA treatment to delay T1DM, specifically in genetically predisposed children, through immunoregulatory effects and the ability to induce β-cell proliferation. [ABSTRACT FROM AUTHOR]

Insomnia affects millions of people worldwide, prompting considerable interest in herbal remedies for its treatment. This review aims to assess the therapeutic potential of such remedies for insomnia by analyzing current scientific evidence. The analysis identified several herbs, including Rosmarinus officinalis, Crocus sativus, Rosa damascena, Curcuma longa, Valeriana officinalis, Lactuca sativa, Portulaca oleracea, Citrus aurantium, Lippia citriodora, and Melissa officinalis, which show promise in improving overall sleep time, reducing sleep latency, and enhancing sleep quality. These plants act on the central nervous system, particularly the serotonergic and gamma‐aminobutyric acid (GABA)ergic systems, promoting sedation and relaxation. However, further research is necessary to fully understand their mechanisms of action, optimal dosages, and treatment protocols. Combining herbal medicines with conventional treatments may offer an effective natural alternative for those seeking medication. Nevertheless, individuals should consult their healthcare provider before using herbal remedies for insomnia. While this review provides evidence supporting their use, additional high‐quality studies are needed to firmly establish their clinical efficacy. [ABSTRACT FROM AUTHOR]

Abstract Although peroxisomes are integral for both primary and secondary metabolism, how developmental changes affect activity of peroxisomes remains poorly understood. Here, we used published RNA‐seq data to analyze the expression patterns of genes encoding 21 peroxisome metabolic pathways at successive developmental stages of Zea mays and Oryza sativa. Photorespiration was the most represented pathway in adult leaf relative to the juvenile stages. Components of reactive oxygen species (ROS)/reactive nitrogen species (RNS) metabolism, NADPH regeneration, and catabolism of polyamines were also enriched at later stages of leaf differentiation. The most commonly upregulated gene in differentiated leaves across all datasets of both species was BETAINE ALANINE DEHYDROGENASE (BADH). BADH functions in catabolism of polyamines where it converts 4‐aminobutyraldehyde (ABAL) to 4‐aminobutyrate (GABA). We tested the outcome of RNA‐seq analysis by qRT‐PCR in developing Triticum monococcum ssp. monococcum (Einkorn) seedlings. Consistent with the outcomes of RNA‐seq analysis, transcription of BADH and CATALASE3 (CAT3) were upregulated in older seedlings. CAT3 is an essential peroxisome biogenesis factor and a key enzyme of ROS homeostasis. Furthermore, exogenous application of GABA resulted in higher peroxisome abundance and transcriptional upregulation of BADH and a gene encoding another peroxisome biogenesis factor responsible for peroxisome fission, PEROXIN11C (PEX11C), in leaves. We propose that GABA contributes to regulation of peroxisome fission machinery during leaf differentiation.

ABSTRACT Globally, appetite disorders have become an increasingly prominent public health issue. While short-term appetite loss may seem relatively harmless, prolonged instances can lead to serious physical and mental damage. In recent years, numerous studies have highlighted the significant role of the “microbiota-gut-brain” axis in the regulation of feeding behavior in organisms, suggesting that targeting the gut microbiota may be a novel therapeutic strategy for appetite disorders. However, the molecular mechanisms through which the gut microbiota mediates the increase in host appetite and the causal relationship between the two remain unclear. Based on this, we conducted 16S rRNA sequencing to analyze the gut microbiota of rabbits with high and low feed intake, followed by fecal microbiota transplantation (FMT) and metabolite gavage experiments to elucidate the underlying mechanisms. Our research indicates that the high feed intake group exhibited significant enrichment of the g__Bacteroides and gamma-aminobutyric acid (GABA), and intragastric administration of GABA effectively promoted the host’s feeding behavior. The underlying mechanism involves GABA derived from the gut microbiota inhibiting the secretion of satiety hormones to enhance the host’s feeding behavior. Furthermore, the results of FMT suggest that differences in gut microbiota composition may be a contributing factor to varying levels of feed intake in the host. In conclusion, these findings emphasize the role of the gut microbiota-derived GABA, in increasing host feed intake, offering a new target for the treatment of appetite disorders from the perspective of gut microbiota.IMPORTANCEThe incidence of anorexia is rapidly increasing and has become a global burden. Gut microbiota can participate in the regulation of host feeding behavior, yet the molecular mechanisms through which the gut microbiota mediates the increase in host appetite and the causal relationship between them remain unclear. In this study, we utilized 16S rRNA sequencing to investigate the composition of the gut microbiota in rabbits with varying levels of feed intake and employed fecal microbiota transplantation and gastric infusion experiments with gamma-aminobutyric acid (GABA) to elucidate the potential mechanisms involved. GABA derived from the gut microbiota can effectively enhance the host’s feeding behavior by inhibiting the secretion of satiety hormones. This discovery underscores the pivotal role of the gut microbiota in modulating host appetite, offering novel research avenues and therapeutic targets for appetite disorders.

Abstract Acute lung injury (ALI) is generally caused by severe respiratory infection and characterized by overexuberant inflammatory responses and inefficient pathogens-containing, the two major processes wherein alveolar macrophages (AMs) play a central role. Dysfunctional mitochondria have been linked with distorted macrophages and hence lung disorders, but few treatments are currently available to correct these defects. Plant-derive nanovesicles have gained significant attention because of their therapeutic potential, but the targeting cells and the underlying mechanism remain elusive. We herein prepared the nanovesicles from Artemisia annua, a well-known medicinal plant with multiple attributes involving anti-inflammatory, anti-infection, and metabolism-regulating properties. By applying three mice models of acute lung injury caused by bacterial endotoxin, influenza A virus (IAV) and SARS-CoV-2 pseudovirus respectively, we showed that Artemisia-derived nanovesicles (ADNVs) substantially alleviated lung immunopathology and raised the survival rate of challenged mice. Macrophage depletion and adoptive transfer studies confirmed the requirement of AMs for ADNVs effects. We identified that gamma-aminobutyric acid (GABA) enclosed in the vesicles is a major molecular effector mediating the regulatory roles of ADNVs. Specifically, GABA acts on macrophages through GABA receptors, promoting mitochondrial gene programming and bioenergy generation, reducing oxidative stress and inflammatory signals, thereby enhancing the adaptability of AMs to inflammation resolution. Collectively, this study identifies a promising nanotherapeutics for alleviating lung pathology, and elucidates a mechanism whereby the canonical neurotransmitter modifies AMs and mitochondria to resume tissue homeostasis, which may have broader implications for treating critical pulmonary diseases such as COVID-19.

Abstract GABA (Gamma-aminobutyric acid), a crucial neurotransmitter in the central nervous system, has gained significant attention in recent years due to its extensive benefits for human health. The review focused on recent advances in the biosynthesis and production of GABA. To begin with, the investigation evaluates GABA-producing strains and metabolic pathways, focusing on microbial sources such as Lactic Acid Bacteria, Escherichia coli, and Corynebacterium glutamicum. The metabolic pathways of GABA are elaborated upon, including the GABA shunt and critical enzymes involved in its synthesis. Next, strategies to enhance microbial GABA production are discussed, including optimization of fermentation factors, different fermentation methods such as co-culture strategy and two-step fermentation, and modification of the GABA metabolic pathway. The review also explores methods for determining glutamate (Glu) and GABA levels, emphasizing the importance of accurate quantification. Furthermore, a comprehensive market analysis and prospects are provided, highlighting current trends, potential applications, and challenges in the GABA industry. Overall, this review serves as a valuable resource for researchers and industrialists working on GABA advancements, focusing on its efficient synthesis processes and various applications, and providing novel ideas and approaches to improve GABA yield and quality. Graphical Abstract

There are many facts about the possible role of gamma-aminobutyric acid (GABA) in the development and differentiation of cells not only in nervous but also in muscle tissue. In the present study, a primary culture of rat skeletal muscle myocytes was used to evaluate the correlation between the content of GABA in the cytoplasm and the processes of myocyte division and their fusion into myotubes. The effect of exogenous GABA on the processes of culture development was also estimated. Since the classical protocol for working with myocyte cultures involves the use of fetal bovine serum (FBS) to stimulate cell division (growth medium) and horse serum (HS) to activate the differentiation process (differentiation medium), the studies were carried out both in the medium with FBS and with HS. It was found that cells grown in medium supplemented with FBS contain more GABA compared to cultures growing in medium supplemented with HS. Addition of exogeneous GABA leads to a decrease in the number of myotubes formed in both media, while the addition of an amino acid to the medium supplemented with HS had a more pronounced inhibitory effect. Thus, we have obtained data indicating that GABA is able to participate in the early stages of skeletal muscle myogenesis by modulating the fusion process. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is generally caused by severe respiratory infection and characterized by overexuberant inflammatory responses and inefficient pathogens-containing, the two major processes wherein alveolar macrophages (AMs) play a central role. Dysfunctional mitochondria have been linked with distorted macrophages and hence lung disorders, but few treatments are currently available to correct these defects. Plant-derive nanovesicles have gained significant attention because of their therapeutic potential, but the targeting cells and the underlying mechanism remain elusive. We herein prepared the nanovesicles from Artemisia annua, a well-known medicinal plant with multiple attributes involving anti-inflammatory, anti-infection, and metabolism-regulating properties. By applying three mice models of acute lung injury caused by bacterial endotoxin, influenza A virus (IAV) and SARS-CoV-2 pseudovirus respectively, we showed that Artemisia-derived nanovesicles (ADNVs) substantially alleviated lung immunopathology and raised the survival rate of challenged mice. Macrophage depletion and adoptive transfer studies confirmed the requirement of AMs for ADNVs effects. We identified that gamma-aminobutyric acid (GABA) enclosed in the vesicles is a major molecular effector mediating the regulatory roles of ADNVs. Specifically, GABA acts on macrophages through GABA receptors, promoting mitochondrial gene programming and bioenergy generation, reducing oxidative stress and inflammatory signals, thereby enhancing the adaptability of AMs to inflammation resolution. Collectively, this study identifies a promising nanotherapeutics for alleviating lung pathology, and elucidates a mechanism whereby the canonical neurotransmitter modifies AMs and mitochondria to resume tissue homeostasis, which may have broader implications for treating critical pulmonary diseases such as COVID-19. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate and compare the characteristics of non-treated and fermented [via submerged (SMF) and solid-state (SSF) fermentation using Pediococcus acidilactici] lentils (Lens culinaris) grown either in pure stands (L) or relay intercropped with winter rye (LR). It was observed that the lentils were suitable substrate for lacto-fermentation. Most of the free amino acid concentrations increased in lentils after both fermentations. The highest concentration of γ-aminobutyric acid was found in SSF LR samples. However, fermentation led to higher biogenic amines (BA) content in lentils. The most abundant fatty acid in lentils was C18:2. SSF lentils showed more complex volatile compound (VC) profiles (with between nine and seventeen new VCs formed), whereas, in SMF samples, between two and five newly VCs were formed. When comparing lentil grown types, L contained significantly higher concentrations of Na, K, Ca, P, Mn, and Se, while LR contained significantly higher concentrations of Fe and Ni. To sum up, fermentation with lactic acid bacteria (LAB) contributed to the improved biological value of lentils; still, the quantity of BA needs to be considered. Further investigations into the P. acidilactici metabolism of certain compounds (such as phenolic and antinutritional compounds) in lentils during fermentation ought to be carried out. [ABSTRACT FROM AUTHOR]

Sleep is an essential activity for the survival of mammals. Good sleep quality helps promote the performance of daily functions. In contrast, insufficient sleep reduces the efficiency of daily activities, causes various chronic diseases like Alzheimer's disease, and increases the risk of having accidents. The GABAergic system is the primary inhibitory neurotransmitter system in the central nervous system. It transits the gamma-aminobutyric acid (GABA) neurotransmitter via GABAA and GABAB receptors to counterbalance excitatory neurotransmitters, such as glutamate, noradrenaline, serotonin, acetylcholine, orexin, and dopamine, which release and increase arousal activities during sleep. Several studies emphasized that dysfunction of the GABAergic system is related to insomnia, the most prevalent sleep-related disorder. The GABAergic system comprises the GABA neurotransmitter, GABA receptors, GABA synthesis, and degradation. Many studies have demonstrated that GABA levels correlate with sleep quality, suggesting that modulating the GABAergic system may be a promising therapeutic approach for insomnia. In this article, we highlight the significance of sleep, the classification and pathology of insomnia, and the impact of the GABAergic system changes on sleep. In addition, we also review the medications that target the GABAergic systems for insomnia, including benzodiazepines (BZDs), non-BZDs, barbiturates, GABA supplements, and Chinese herbal medicines. [ABSTRACT FROM AUTHOR]

Saline water has been proposed as a solution to partially supply plants with their water requirements due to a lack of fresh water for cultivation in arid and semi-arid sites. Gamma-aminobutyric acid (GABA) is a non-protein amino acid participating in numerous metabolic processes to mitigate the undesirable effects of salinity. A pot experiment was carried out during 2021 and 2022 at Sakha Horticulture Research Station to investigate the effect of foliar application of GABA at 20 and 40 mM on vegetative growth and biochemical changes in French lavender under increasing levels of sea water salinity irrigation treatments (0, 1000, 2000, and 3000 ppm). Results indicated that increasing salinity concentration noticeably decreased plant height, number of branches, herb fresh and dry weight, root length, root fresh and dry weights, photosynthetic pigments, relative water content, and essential oil percentage. On the other hand, accumulation of proline and antioxidant enzymes was increased under increasing salinity concentrations. We conclude that foliar application of GABA acid at 40 mM can alleviate the adverse effects of salinity on the abovementioned French lavender plant characteristics by improving vegetative growth and root characteristics, as well as diminishing chlorophyll degradation, maintaining high leaf relative water content, increasing proline accumulation and antioxidant activity. [ABSTRACT FROM AUTHOR]

GABA (Gamma-aminobutyric acid), a crucial neurotransmitter in the central nervous system, has gained significant attention in recent years due to its extensive benefits for human health. The review focused on recent advances in the biosynthesis and production of GABA. To begin with, the investigation evaluates GABA-producing strains and metabolic pathways, focusing on microbial sources such as Lactic Acid Bacteria, Escherichia coli, and Corynebacterium glutamicum. The metabolic pathways of GABA are elaborated upon, including the GABA shunt and critical enzymes involved in its synthesis. Next, strategies to enhance microbial GABA production are discussed, including optimization of fermentation factors, different fermentation methods such as co-culture strategy and two-step fermentation, and modification of the GABA metabolic pathway. The review also explores methods for determining glutamate (Glu) and GABA levels, emphasizing the importance of accurate quantification. Furthermore, a comprehensive market analysis and prospects are provided, highlighting current trends, potential applications, and challenges in the GABA industry. Overall, this review serves as a valuable resource for researchers and industrialists working on GABA advancements, focusing on its efficient synthesis processes and various applications, and providing novel ideas and approaches to improve GABA yield and quality. [ABSTRACT FROM AUTHOR]

Focal epilepsy is associated with intermittent brief population discharges (interictal spikes), which resemble sentinel spikes that often occur at the onset of seizures. Why interictal spikes self-terminate whilst seizures persist and propagate is incompletely understood. We used fluorescent glutamate and GABA sensors in an awake rodent model of neocortical seizures to resolve the spatiotemporal evolution of both neurotransmitters in the extracellular space. Interictal spikes were accompanied by brief glutamate transients which were maximal at the initiation site and rapidly propagated centrifugally. GABA transients lasted longer than glutamate transients and were maximal ∼1.5 mm from the focus where they propagated centripetally. Prior to seizure initiation GABA transients were attenuated, whilst glutamate transients increased, consistent with a progressive failure of local inhibitory restraint. As seizures increased in frequency, there was a gradual increase in the spatial extent of spike-associated glutamate transients associated with interictal spikes. Neurotransmitter imaging thus reveals a progressive collapse of an annulus of feed-forward GABA release, allowing seizures to escape from local inhibitory restraint. [ABSTRACT FROM AUTHOR]

Abstract Although classically recognized as a neurotransmitter, gamma aminobutyric acid (GABA) has also been identified in colonic tumors. Moreover, the gut microbiome represents another potential source of GABA. Both GABAA and GABAB receptors have been implicated in contributing to the effects of GABA in colorectal cancer, with both pro‐ and anti‐tumorigenic functions identified. However, their subunit composition is often overlooked. Studies to date have not addressed whether the GABA‐producing potential of the microbiome changes over the course of colon tumor development or whether receptor subunit expression patterns are altered in colon cancer. Therefore, we investigated the clusters of orthologous group frequencies of glutamate decarboxylase (GAD) in feces from two murine models of colon cancer and found that the frequency of microbial GAD was significantly decreased early in the tumorigenic process. We also determined that microbial‐derived GABA inhibited proliferation of colon cancer cells in vitro and that this effect of GABA on SW480 cells involved both GABAA and GABAB receptors. GABA also inhibited prostaglandin E2 (PGE2)‐induced proliferation and interleukin‐6 (IL‐6) expression in these cells. Gene expression correlations were assessed using the “Cancer Exploration” suite of the TIMER2.0 web tool and identified that GABA receptor subunits were differentially expressed in human colon cancer. Moreover, GABAA receptor subunits were predominantly positively associated with PGE2 synthase, cyclooxygenase‐2 and IL‐6. Collectively, these data demonstrate decreased potential of the microbiome to produce GABA during tumorigenesis, a novel anti‐tumorigenic pathway for GABA, and that GABA receptor subunit expression adds a further layer of complexity to GABAergic signaling in colon cancer.

The Sogatella furcifera (Horváth) (Homoptera: Delphacidae) is a white-backed planthopper (WBPH) that causes “hopper burn” in rice, resulting in severe yield loss. Gamma-aminobutyric acid (GABA) is a well-known neurotransmitter that inhibits neurotransmission in insects by binding to specific receptors. In this study, we investigated the potential role of GABA in modulating rice resistance to WBPH and evaluated possible defense mechanisms. The experiment was conducted in green house in pots consist of four groups: control, GABA-treated, WBPH-infested, and WBPH-infested treated with GABA. Among the various tested concentration of GABA, 15 mM GABA was applied as a single treatment in water. The treatment was administered one week before WBPH infestation. The results revealed that 15 mM GABA treatment strongly increased WBPH resistance. A plate-based assay indicated that direct application of 15 mM GABA increased the mortality rate of WBPH and increased the damage recovery rate in rice plants. We found that GABA treatment increased the activation of antioxidant enzymes and reduced the reactive oxygen species content and malondialdehyde contents, and reduced the damage rate caused by WBPH. Interestingly, GABA-supplemented plants infested with WBPH exhibited increased phenylalanine ammonia-lyase and pathogenesis-related (PR) genes expression levels. GABA induced the accumulation of abscisic acid (ABA) and salicylic acid (SA) and enhanced the stomata closure and reduced leaf vessels to reduce water conductance during WBPH stress. Furthermore, we found that GABA application to the plant induced the expression of Jasmonic acid (JA) biosynthesis genes (LOX, AOS, AOC, and OPR) and melatonin biosynthesis-related genes (TDC, T5H, ASMT, and SNAT). Our study suggested that GABA increases resistance against WBPH infestation by regulating antioxidant defense system, TCA cycle regulation, phytohormonal signaling, and PR gene regulation.

Inflammation, reduced gamma-aminobutyric acidergic (GABAergic) function and altered neuroplasticity are co-occurring pathophysiologies in major depressive disorder (MDD). However, the link between these biological changes remains unclear. We hypothesized that inflammation induces deficits in GABAergic interneuron markers and that this effect is mediated by brain-derived neurotrophic factor (BDNF). We report here that systemic inflammation induced by intraperitoneal injection of lipopolysaccharide (LPS) (0.125, 0.25, 0.5, 1, 2 mg/kg) in the first cohort of C57BL/6 mice (n = 72; 10–11 weeks; 50% female) resulted in increased interleukin 1-beta and interleukin-6 in prefrontal cortex (PFC) and hippocampus (HPC), as measured using enzyme-linked immunosorbent assay (ELISA). Quantitative real-time polymerase reaction (qPCR) was used to explore the effect of LPS on the expression of GABAergic interneuron markers. In the PFC of the second cohort (n = 39; 10–11 weeks; 50% female), 2 mg/kg of LPS decreased the expression of somatostatin (Sst) (p = 0.0014), parvalbumin (Pv) (p = 0.0257), cortistatin (Cort) (p = 0.0003), neuropeptide Y (Npy) (p = 0.0033) and cholecystokinin (Cck) (p = 0.0041), and did not affect corticotropin-releasing hormone (Crh) and vasoactive intestinal peptide (Vip) expression. In the HPC, 2 mg/kg of LPS decreased the expression of Sst (p = 0.0543), Cort (p = 0.0011), Npy (p = 0.0001), and Cck (p

IntroductionKefir beverage has beneficial microorganisms that have health-giving properties; therefore, they have a good potential to be probiotic. This study evaluated the probiotic potential, technological, and safety characteristics of Enterococcus faecalis, Lactococcus lactis, and Pichia fermentans isolated from traditional kefir beverages.MethodFirst, isolates were evaluated in terms of resistance to acid, alkali, bile salts, trypsin, and pepsin of the gastrointestinal tract. The auto-aggregation and co-aggregation ability of isolates were measured using spectrophotometry. Antimicrobial activities were assayed against important food-borne pathogens using the agar well diffusion method. Moreover, gamma-aminobutyric acid (GABA) production was investigated by thin-layer chromatography (TLC).ResultAmong the isolates, P. fermentans had an 85% total survival rate, but its amount reached below 6 log CFU/ml which is considered non-resistant, and it showed the highest auto-aggregation (74.67%). Moreover, only L. lactis showed antimicrobial activity and had the highest co-aggregation with E. coli PTCC 1338 (54.33%) and L. monocytogenes ATCC 7644 (78%). Finally, an evaluation of the technological and safety characteristics of the strains showed that the strains produced GABA and were safe.DiscussionAlthough the isolates were not resistant to the gastrointestinal tract, their supernatant contained valuable natural compounds, including antioxidants, GABA, and antimicrobials, which can be used to produce functional foods and medicines. In addition, other approaches, such as increasing the initial number of strains, using foods as carriers of isolates, and encapsulating the isolates, can effectively increase the survivability of isolates in the gastrointestinal tract.

Sleep is an essential activity for the survival of mammals. Good sleep quality helps promote the performance of daily functions. In contrast, insufficient sleep reduces the efficiency of daily activities, causes various chronic diseases like Alzheimer's disease, and increases the risk of having accidents. The GABAergic system is the primary inhibitory neurotransmitter system in the central nervous system. It transits the gamma-aminobutyric acid (GABA) neurotransmitter via GABAA and GABAB receptors to counterbalance excitatory neurotransmitters, such as glutamate, noradrenaline, serotonin, acetylcholine, orexin, and dopamine, which release and increase arousal activities during sleep. Several studies emphasized that dysfunction of the GABAergic system is related to insomnia, the most prevalent sleep-related disorder. The GABAergic system comprises the GABA neurotransmitter, GABA receptors, GABA synthesis, and degradation. Many studies have demonstrated that GABA levels correlate with sleep quality, suggesting that modulating the GABAergic system may be a promising therapeutic approach for insomnia. In this article, we highlight the significance of sleep, the classification and pathology of insomnia, and the impact of the GABAergic system changes on sleep. In addition, we also review the medications that target the GABAergic systems for insomnia, including benzodiazepines (BZDs), non-BZDs, barbiturates, GABA supplements, and Chinese herbal medicines.