Gamma-aminobutyric Acid Research Articles

Systematic analysis of molecular mechanisms of action of essential macro- and micronutrients on the neurotransmitter and vasodilator molecule nitric oxide (NO)

Maintaining adequate levels of nitric oxide (NO) in the blood and other body tissues is necessary for the regulation of vascular tone, blood pressure, maintenance of oxygen metabolism and endothelial function. NO is also involved in regulating the balance of excitatory (glutamate) and inhibitory (gamma-aminobutyric acid) neurotransmission. Nutritional factors profoundly affect NO metabolism. Systematic computer analysis of 26,103 publications by methods of topological approach to recognition allowed to identify the most crucial fields of clinical research assessing relationships between NO metabolism and nutrients: arginine-derived NO synthase-driven NO production, nitrate-containing products, folates and vitamin B12 in NO homeostasis (including the effects of modifications of the vitamin B12 molecule), other B vitamins (B1, B2, B7), antioxidant vitamins (C and E), hormone-like vitamins D3 and A, electrolytes magnesium and calcium, participation of the microbiome in NO production.

Drug-Induced Myoclonus: A Systematic Review

Background and Objectives: Myoclonus is already associated with a wide variety of drugs and systemic conditions. As new components are discovered, more drugs are suspected of causing this disabling abnormal involuntary movement. This systematic review aims to assess the medications associated with drug-induced myoclonus (DIM). Materials and Methods: Two reviewers assessed the PubMed database using the search term “myoclonus”, without language restriction, for articles published between 1955 and 2024. The medications found were divided into classes and sub-classes, and the subclasses were graded according to their level of evidence. Results: From 12,097 results, 1115 were found to be DIM. The subclasses of medications with level A evidence were intravenous anesthetics (etomidate), cephalosporins (ceftazidime, cefepime), fluoroquinolones (ciprofloxacin), selective serotonin reuptake inhibitors (citalopram, escitalopram, paroxetine, sertraline), tricyclic antidepressant (amitriptyline), glutamate antagonist (amantadine), atypical antipsychotics (clozapine, quetiapine), antiseizure medications (carbamazepine, oxcarbazepine, phenytoin, gabapentin, pregabalin, valproate), pure opioid agonist (fentanyl, morphine), bismuth salts, and mood stabilizers (lithium). The single medication with the highest number of reports was etomidate. Drug-induced asterixis is associated with a specific list of medications. The neurotransmitters likely involved in DIM are serotonin, dopamine, gamma-aminobutyric acid (GABA), and glutamate. Conclusions: DIM may be reversible with management that can include drug discontinuation, dose adjustment, and the prescription of a medication used to treat idiopathic myoclonus. Based on the main clinical constellation of symptoms and pathophysiological mechanisms found in this study, DIM can be categorized into three types: type 1 (serotonin syndrome), type 2 (non-serotonin syndrome), and type 3 (unknown).

PpERF17 alleviates peach fruit postharvest chilling injury under elevated CO2 by activating jasmonic acid and γ-aminobutyric acid biosynthesis

Abstract Internal browning (IB) is a common chilling injury (CI) feature in peach fruit after prolonged cold storage. Our previous study demonstrated that low O2 and elevated CO2 (eCO2) condition of modified atmosphere (MA) storage alleviated CI by facilitating the accumulation of jasmonic acids (JAs) and γ-aminobutyric acid (GABA) in ‘Zhonghuashoutao’ (‘ZHST’) peach fruit. Here we show that 10 % CO2 alone can improve cold tolerance, with ethylene response factor 17 (PpERF17) identified as a pivotal transcription factor (TF) that promotes biosynthesis of JAs and GABA. Stable transformation of PpERF17 in tobacco resulted in reduced cold damage, attributed to decreased levels of hydrogen peroxide (H2O2) and malondialdehyde (MDA), as well as enhanced accumulation of JAs and GABA. Moreover, under eCO2, PpMYC2.1, the master regulator of JA signaling, was found to activate transcription of 13S-lipoxygenase (Pp13S-LOX), allene oxide synthase (PpAOS), 12-oxophytodienoate reductase 3 (PpOPR3) and glutamate decarboxylase (PpGAD), while also inducing the expression of the upstream TF PpERF17, thereby establishing positive feedback loops upregulating JA and GABA biosynthesis. Finally, application of methyl jasmonate (MeJA) to fruit before shelf transfer from cold storage alleviated chilling injury development, due to increased accumulation of JAs and GABA as a result of raised expression of related biosynthetic genes. Collectively, our results suggest that eCO2-induced PpERF17 enhances JAs and GABA accumulation while activating the JA signaling pathway. This contributes to a positive feedback loop mediated by PpMYC2.1, ultimately alleviating CI of peach fruit through the sustained accumulation of JAs and GABA.

Altered microbiome and metabolome profiling in fearful companion dogs: An exploratory study.

Behavioral dysfunctions in dogs represent one of the main social concerns, since they can endanger animals and human-dog relationship. Together with the trigger stimulus (human, animal, place, scent, auditory stimuli, objects), dogs can experience stressful conditions, either in multiple settings or unique situations, more often turning into generalized fear. Such a dysfunctional behavior can be associated with genetic susceptibility, environmental factors, traumatic experiences, and medical conditions. The available therapy, based on behavior approaches, environmental management, and neurochemical manipulation, through nutrition, supplements, medicines, and pheromones, represent the mainstays of the treatments currently accessible. Growing evidence in humans and animals highlight the importance of the gut-brain axis in the modulation of the brain physiology and behavior as well. Here, taking advantage of the next generation sequencing approach, we sought to investigate the potential connection between gut microbiota and microbiome in dogs suffering from generalized fear (n = 8), when compared to healthy subjects (n = 8), who all lived in different families. Faecal microbiota evaluation showed a differential abundance of taxa related to Proteobacteria and Firmicutes Phyla, between case and control dogs. Moreover, serum metabolomics documented significant alterations of molecules associated to GABA and glutamate neurotransmission in the patients, as well as bile acids metabolism. Overall, our preliminary and integrated investigations highlighted an intriguing role for the microbiome-metabolome network, allowing to further unveil the potential pathophysiology of relational issues in companion animals and paving the way for more effective therapeutical approaches.

Quantitative analysis of γ-aminobutyric acid in vegetables: effects of pretreatment methods

Quantitative analysis of γ-aminobutyric acid in vegetables: effects of pretreatment methods

Therapeutic potential of rutin in premenstrual depression: evidence from in vivo and in vitro studies

IntroductionPremenstrual dysphoric disorder (PMDD) is a cyclical mood disorder that severely affects the daily life of women of reproductive age. Most of the medications being used clinically have limitations such as low efficacy, side effects, and high cost, so there is an urgent need to discover safer and more effective medications. Rutin is a natural flavonol glycoside with various pharmacological properties including antidepressant. The study of the efficacy and mechanism of action of rutin in PMDD-depressed subtype model rats plays an important role in the discovery of new drugs for the treatment of PMDD.MethodsBinding of rutin to gamma-aminobutyric acid type A receptors (GABAA receptors) was probed using molecular docking, microscale thermophoresis, radioactive receptor ligand binding assay and cell membrane clamp experiment. Behavioral tests in mice were performed to screen the optimal dose of rutin. Behavioral tests were performed to evaluate the effects of rutin on depressed mood, memory impairment, and social impairment in PMDD-depressed subtype model rats. HE staining and Golgi staining were performed to observe the neuronal damage in rat hippocampus. UHPLC-MS/MS targeted metabolomics was performed to detect the changes of neurotransmitter content in rat hippocampus. PCR array to detect the effect of rutin on mRNA expression of GABAA receptor partial subunits in rat hippocampus.ResultsThe docking score of rutin with the GABAA receptor benzodiazepine site was −11.442 and the gliding score was −11.470. The Kd of rutin with the GABAA receptor (α1β2γ2) was 1.17 ± 0.89 μM. Rutin competed with [H3]-flunitrazepam for the GABAA receptor benzodiazepine site and inhibited the inward flow of chloride ions (P < 0.05). In PMDD-depressed subtype rats, rutin alleviated depressed mood, memory impairment and social impairment, ameliorated hippocampal neuronal damage and reduces gamma-aminobutyric acid (GABA) and acetylcholine (ACh) levels (P < 0.05). Moreover, we found that rutin did not affect the relative mRNA expression of GABAA receptor subunits in rat hippocampus.DiscussionOverall, rutin alleviated depressed mood, memory impairment and social impairment in PMDD-depressed subtype rats, which may be related to binding to GABAA receptor benzodiazepine sites, inhibiting chloride ions inward flow, ameliorating hippocampal neuronal damage and reducing GABA and ACh levels. The results of this study provide an experimental basis and scientific evidence for the development of new drugs for the treatment of PMDD.

Neurosteroids and neurological disorders.

Neurosteroids play an important role as endogenous neuromodulators that are locally produced in the central nervous system and rapidly change the excitability of neurons and the activation of microglial cells and astrocytes. Here we review the mechanisms of synthesis, metabolism, and actions of neurosteroids in the central nervous system. Neurosteroids are able to play a variety of roles in the central nervous system under physiological conditions by binding to membrane ion channels and receptors such as gamma-aminobutyric acid type A receptors, Nmethyl- D-aspartate receptors, L- and T-type calcium channels, and sigma-1 receptors. In addition, numerous neurological disorders, including persistent neuropathic pain, multiple sclerosis, and seizures, have altered the levels of neurosteroids in the central nervous system. Thus, we review how local synthesis and metabolism of neurosteroids are modulated in the central nervous system and describe the role of neurosteroids under pathological conditions. Furthermore, we discuss whether neurosteroids may play a role as a new therapeutic for the treatment of neurological disorders.

CEST imaging combined with 1H-MRS reveal the neuroprotective effects of riluzole by improving neurotransmitter imbalances in Alzheimer’s disease mice

BackgroundThe imbalance of glutamate (Glu) and gamma-aminobutyric acid (GABA) neurotransmitter system plays a crucial role in the pathogenesis of Alzheimer’s disease (AD). Riluzole is a Glu modulator originally approved for amyotrophic lateral sclerosis that has shown potential neuroprotective effects in various neurodegenerative disorders. However, whether riluzole can improve Glu and GABA homeostasis in AD brain and its related mechanism of action remain unknown. This study utilized chemical exchange saturation transfer (CEST) imaging combined with proton magnetic resonance spectroscopy (1H-MRS) to monitor the dynamic changes of Glu and GABA in riluzole-treated AD mice, aiming to evaluate the efficacy and mechanism of riluzole in AD treatment.MethodsGluCEST, GABACEST and 1H-MRS were used to longitudinally monitor Glu and GABA levels in 3xTg AD mice treated with riluzole (12.5 mg/kg/day) or vehicle for 20 weeks. Magnetic resonance measurements were performed at baseline, 6, 12, and 20 weeks post-treatment. Cognitive performance was assessed using the Morris Water Maze (MWM) at baseline, 10, and 20 weeks. At the study endpoint, immunohistochemistry, Nissl staining, and Western blot were used to evaluate the brain pathology, neuronal survival, and protein expression.ResultsGluCEST, GABACEST and 1H-MRS consistently revealed higher levels of Glu and GABA in the brain of riluzole-treated AD mice compared to untreated controls, which were associated with improvements in spatial learning and memory. The cognitive improvements significantly correlated with the increased GluCEST signals and Glu levels. Immunohistochemistry and Nissl staining demonstrated that riluzole treatment reduced amyloid-beta (Aβ) deposition, tau hyperphosphorylation, GFAP-positive astrocyte activation, and prevented neuronal loss. Moreover, riluzole upregulated the expression of excitatory amino acid transporter 2 (EAAT2), glutamic acid decarboxylase 65/67 (GAD65/67), and glutamine synthetase (GS), suggesting enhanced neurotransmitter metabolism.ConclusionsCEST imaging combined with 1H-MRS demonstrated the effectiveness of riluzole in modulating Glu- and GABA-related changes and improving cognitive function in 3xTg AD mice, potentially through regulating key proteins involved in neurotransmitter metabolism. These findings suggest riluzole as a therapeutic agent for Alzheimer’s disease and highlight the utility of multimodal MR imaging in monitoring treatment response and exploring disease mechanisms.

Role of the Dorsal Cortex of the Inferior Colliculus in the Precedence Effect.

BACKGROUND The precedence effect (PE) is a physiological phenomenon for accurate sound localization in a reverberant environment. Physiological studies of PE have mostly focused on the central nucleus of the inferior colliculus (CNIC), which receives ascending and descending projections, as well as projections from the shell of the inferior colliculus (IC) and contralateral IC. However, the role of the dorsal cortex of the IC (DCIC), which receives ascending and descending projections to ensure sound information processing and conduction on PE formation, remains unclear. Therefore, this study aimed to understand the role, if any, of the DCIC on PE formation in male Sprague Dawley rats. MATERIAL AND METHODS In vivo, 16-channel electrophysiological recordings were performed in anesthetized rats to investigate neuronal responses in the CNIC, after inducing electrolytic lesions in the DCIC. In vitro, the expression of inhibitory gamma-aminobutyric acid (GABA)ergic receptors in the CNIC was analyzed by Western blot. RESULTS After inducing electrolytic lesions in the DCIC, normalized neural responses of the CNIC to lagging stimuli were significantly increased (P<0.05), half-maximal inter-stimuli delays were shortened (P<0.05), and the expression of GABA A receptor a1 and GABA B receptor 2 decreased (P<0.05). Furthermore, neurons in the CNIC showed a contralateral preference when paired sounds in the free field were presented. CONCLUSIONS Our study suggests that the DCIC could modulate PE formation in the CNIC, potentially involving inhibitory GABAergic mechanisms. This study showed the role of the DCIC on PE formation and proposed a potential structure for identifying likely mechanisms of the PE in the IC.

Lacto-Fermented Fruits and Vegetables: Bioactive Components and Effects on Human Health.

Lacto-fermented fruits and vegetables (FVs) such as kimchi, sauerkraut, and fermented olives and nonalcoholic juices have a long history as dietary staples. Herein, the production steps and microbial ecology of lacto-fermented FVs are discussed alongside findings from human and laboratory studies investigating the health benefits of these foods. Lacto-fermented FVs are enriched in bioactive compounds, including lactic and acetic acids, phenolic compounds, amino acid derivatives such as indole-3-lactic acid, phenyl-lactic acid, γ-aminobutyric acid, and bacteriocins, and beneficial live microbes. At least 11 human studies have been performed on kimchi, whereas others have been investigated in only one or two trials. Besides exploring the health benefits, it is imperative to ensure that these foods made either commercially or at home have minimal risk for foodborne illness and exposure to undesired compounds like biogenic amines. Development of starter-culture strains and production protocols can lead to lacto-fermented FVs designed for specific health benefits.

Targeting the glymphatic system to promote α-synuclein clearance: a novel therapeutic strategy for Parkinson's disease.

The excessive buildup of neurotoxic α-synuclein plays a pivotal role in the pathogenesis of Parkinson's disease, highlighting the urgent need for innovative therapeutic strategies to promote α-synuclein clearance, particularly given the current lack of disease-modifying treatments. The glymphatic system, a recently identified perivascular fluid transport network, is crucial for clearing neurotoxic proteins. This review aims to synthesize current knowledge on the role of the glymphatic system in α-synuclein clearance and its implications for the pathology of Parkinson's disease while emphasizing potential therapeutic strategies and areas for future research. The review begins with an overview of the glymphatic system and details its anatomical structure and physiological functions that facilitate cerebrospinal fluid circulation and waste clearance. It summarizes emerging evidence from neuroimaging and experimental studies that highlight the close correlation between the glymphatic system and clinical symptom severity in patients with Parkinson's disease, as well as the effect of glymphatic dysfunction on α-synuclein accumulation in Parkinson's disease models. Subsequently, the review summarizes the mechanisms of glymphatic system impairment in Parkinson's disease, including sleep disturbances, aquaporin-4 impairment, and mitochondrial dysfunction, all of which diminish glymphatic system efficiency. This creates a vicious cycle that exacerbates α-synuclein accumulation and worsens Parkinson's disease. The therapeutic perspectives section outlines strategies for enhancing glymphatic activity, such as improving sleep quality and pharmacologically targeting aquaporin-4 or its subcellular localization. Promising interventions include deep brain stimulation, melatonin supplementation, γ-aminobutyric acid modulation, and non-invasive methods (such as exercise and bright-light therapy), multisensory γ stimulation, and ultrasound therapy. Moreover, identifying neuroimaging biomarkers to assess glymphatic flow as an indicator of α-synuclein burden could refine Parkinson's disease diagnosis and track disease progression. In conclusion, the review highlights the critical role of the glymphatic system in α-synuclein clearance and its potential as a therapeutic target in Parkinson's disease. It advocates for further research to elucidate the specific mechanisms by which the glymphatic system clears misfolded α-synuclein and the development of imaging biomarkers to monitor glymphatic activity in patients with Parkinson's disease. Findings from this review suggest that enhancing glymphatic clearance is a promising strategy for reducing α-synuclein deposits and mitigating the progression of Parkinson's disease.

Comparative effective dose of ciprofol and propofol in suppressing cardiovascular responses to tracheal intubation

Ciprofol, a novel γ-aminobutyric acid receptor agonist, outperforms propofol with minimal cardiovascular effects, higher potency, reduced injection pain, and a broader safety margin. Despite these advantages, ciprofol’s clinical research is still emerging. This study compares the median effective dose (ED50) and adverse reactions of ciprofol and propofol, in conjunction with sufentanil, for suppressing cardiovascular responses during tracheal intubation. Fifty-three adult patients scheduled for tracheal intubation under general anesthesia were enrolled and randomly assigned to receive either ciprofol (Group C) or propofol (Group P), according to a random number table. Tracheal intubation was performed using a standardized laryngoscope and endotracheal tube. The Dixon’s up-and-down method was employed to determine the ED50 and 95% effective dose (ED95) of ciprofol and propofol in inhibiting cardiovascular responses during tracheal intubation. Based on the pilot study, the initial dose for ciprofol was set at 0.35 mg/kg (with a 0.01 mg/kg increment) and for propofol at 2.0 mg/kg (with a 0.1 mg/kg increment). Probit analysis was applied to derive dose-response curves, while adverse reactions were continuously monitored. A total of 54 participants were included, with 24 in group C (1 excluded) and 30 in group P. Probit analysis revealed that the ED50 of ciprofol for inhibiting cardiovascular responses to tracheal intubation were 0.326 mg/kg (95% CI 0.304–0.337 mg/kg), and for propofol, 1.541 mg/kg (95% CI 1.481–1.599 mg/kg). The heart rate in group P was significantly higher than the group C at 1 minute (p = 0.026) and 3 minutes (p = 0.016) post-intubation. Systolic and diastolic blood pressures (SBP and DBP) decreased significantly before and after intubation compared to baseline values in both groups (p< 0.05). Group C experienced significantly less injection pain (p = 0.001), although the incidence of other adverse effects was not statistically different between groups (p > 0.05).Clinical Trial Registration: hppts://ClinicalTrials.gov; Identifier: NCT06095570(18/10/2023).

Acupuncture combined with bamboo-based medicinal moxibustion for chronic insomnia complicated with mild depressive state: a randomized controlled trial

To observe the clinical efficacy of acupuncture combined with bamboo-based medicinal moxibustion in the treatment of chronic insomnia complicated with mild depressive state. A total of 60 patients with chronic insomnia complicated with mild depressive state were randomly divided into an observation group and a control group, 30 cases in each group. The control group was treated with acupuncture at bilateral Zhaohai (KI6), Shenmen (HT7), Sanyinjiao (SP6), Anmian (Extra) and Sishencong (EX-HN1), Baihui (GV20), etc. The observation group was treated with bamboo-based medicinal moxibustion based on the treatment in the control group, on the abdomen，Shenque (CV8), Guanyuan (CV4), Zhongwan (CV12) and bilateral Tianshu (ST25) were selected , on the back, the acupoints of governer vessel from Dazhui (GV14) to Yaoshu (GV2) were selected. Both groups were treated once every other day, 3 times a week for 4 weeks. The Pittsburgh sleep quality index (PSQI) score, Hamilton depression scale-17 (HAMD-17) score, insomnia severity index (ISI) score, fatigue assessment instrument (FAI) score before and after treatment and after 2 weeks of treatment completion (follow-up) were observed in the two groups, and the serum level of γ-aminobutyric acid (GABA) before and after treatment was detected in the two groups, and the clinical efficacy and safety were evaluated. After treatment and in the follow-up, the sub-item scores and total scores of PSQI in both groups were reduced compared with those before treatment (P<0.001); except for the score of daytime dysfunction in the follow-up, the scores of sleep quality, sleep duration, daytime dysfunction, and total scores of PSQI in the observation group were lower than those in the control group (P<0.05). After treatment and in the follow-up, the HAMD-17, ISI and FAI scores in both groups were reduced compared with those before treatment (P<0.001); the scores in the observation group were lower than those in the control group (P<0.05). After treatment，the serum levels of GABA in both groups were increased compared with those before treatment (P<0.05); the level in the observation group was higher than that in the control group (P<0.05). The total effective rate of treating chronic insomnia in the observation group was 96.7% (29/30), which was higher than 80.0% (24/30) in the control group (P<0.05); and the total effective rate of improving mild depressive state was 93.3% (28/30), which was higher than 66.7% (20/30) in the control group (P<0.001). During the treatment period, no serious adverse reactions occurred in both groups. Acupuncture combined with bamboo-based medicinal moxibustion has definite efficacy in the treatment of chronic insomnia complicated with mild depressive state, and has synergistic efficacy in improving sleep quality, sleep duration, daytime dysfunction and depressive state, its action mechanism may be related to the increase of serum level of GABA.

Limosilactobacillus reuteri fermented brown rice alleviates anxiety improves cognition and modulates gut microbiota in stressed mice

Chronic stress disrupts gut microbiota homeostasis, contributing to anxiety and depression. This study explored the effects of Limosilactobacillus reuteri fermented brown rice (FBR) on anxiety using an ICR mouse chronic mild stress (CMS) model. Anxiety was assessed through body weight, corticosterone levels, neurotransmitter profiles, and behavioral tests. A four-week FBR regimen reduced corticosterone, restored neurotransmitters like gamma-aminobutyric acid (GABA) and serotonin, and improved anxiety-related behaviors. Metagenomic (16S rRNA) and metabolomic analyses revealed enhanced amino acid metabolism, energy metabolism, and short-chain fatty acid (SCFA) production in FBR-treated mice. FBR-enriched beneficial gut bacteria, aligning the microbiota profile with that of non-stressed mice. FBR also modulated GABA receptor-related gene expression, promoting relaxation. Network pharmacology identified quercetin, GABA, glutamic acid, phenylalanine, and ferulic acid as bioactive compounds with neuroprotective potential. These findings highlight FBR’s potential as a gut-brain axis-targeted therapeutic for anxiety and stress-related disorders.

Effect of Probiotics on the Symptomatology of Autism Spectrum Disorder and/or Attention Deficit/Hyperactivity Disorder in Children and Adolescents: Pilot Study.

The aim of this study is to investigate the impact of using probiotics with strains related to dopamine and gamma-aminobutyric acid production on clinical features of autism spectrum disorder (ASD) and/or attention deficit/hyperactivity disorder (ADHD). This randomized, controlled trial involved 38 children with ADHD and 42 children with ASD, aged 5-16years, who received probiotics (Lactiplantibacillus plantarum and Levilactobacillus brevis 109/cfu/daily) or placebo for 12weeks. Parent-reported symptoms were assessed using Conners' 3rd-Ed and the Social Responsiveness Scale Test, 2nd-Ed (SRS-2), and children completed the Conners Continuous Performance Test, 3rd-Ed (CPT 3) or Conners Kiddie CPT, 2nd-Ed (K-CPT 2). Executive functions, quality of life and sleep patterns were also parent-assessed. Intention-to-treat analyses, controlling for sociodemographic and nutritional covariates, revealed no significant inter-group differences in parent-reported or neuropsychological data after the probiotic intervention. However, age-stratified analyses showed improved hyperactivity-impulsivity symptoms in younger children with ASD (Cohen's d = 1.245) and ADHD (Cohen's d = 0.692). Intra-group analyses supported these findings in the aforementioned age and intervention group for both diagnoses. An improvement in impulsivity for children with ASD was also observed in the intra-group analysis of the CPT commissions scores (probiotic: p = 0.001, Cohen's d = -1.216; placebo: p = 0.013, Cohen's d = -0.721). A better comfort score (quality of life) was shown in children with ASD (probiotic: p = 0.010, Cohen's d = 0.722; placebo: p = 0.099, Cohen's d = 0.456). The probiotics used, may improve hyperactivity-impulsivity in children with ASD or/and ADHD and quality of life in children with ASD. Further research is warranted to explore probiotics as an adjunctive therapeutic intervention for NDs.Trial registration: clinicaltrials.gov Identifier: NCT05167110.

Metabolome and RNA-seq reveal discrepant metabolism and secretory metabolism profile in skeletal muscle between obese and lean pigs at different ages.

Metabolites and metabolism-related gene expression profiles in skeletal muscle change dramatically under obesity, aging and metabolic disease. Since obese and lean pigs are ideal models for metabolic research. Here, we compared metabolome and transcriptome of Longissimus dorsi (LD) muscle between Taoyuan black (TB, obese) and Duroc (lean) pigs at different ages. We defined the "window phase" of intramuscular fat (IMF) deposition in TB pig, which has significantly higher IMF than Duroc pig. Our results displayed discrepant lipid composition and different expression genes (DEGs) enriched in lipid metabolism, and both metabolome and transcriptome analyses revealed stronger energy expenditure and more active amino acid and protein metabolism in Duroc pig. 10 up- and 51 down-regulated biomarker metabolites with age- and breed-specificity were identified. Potential secretory metabolites, including organic acid (fumaric acid, succinate, malic acid, and gamma-aminobutyric acid), amino acid (L-lysine, and L-glutamic acid), lipid (2-hydroxyisovaleric acid, and L-carnitine) were demonstrated a significant correlation with IMF deposition. Our research highlights the huge difference of metabolic spectrum in skeletal muscle between obese and lean model and muscle-derived secretory metabolites might act as an ambassador of intercellular communication to regulate systematic metabolism.

Dynamic changes in primary and secondary metabolites of monascal brown rice through γ-aminobutyric acid microcapsule supplementation and untargeted metabolomic analysis

Abstract This study aimed to study the effect of modification of monascal brown rice (MBR) solid-state fermentation through supplementation of γ-aminobutyric acid (GABA) microcapsules from the emulsification/internal gelation technique on dynamic changes in primary and secondary metabolites during 25-day fermentation to conduct metabolomic analysis. During MBR fermentation, the d50 values of GABA microcapsules increased due to their swelling during the MBR fermentation. The lowest encapsulation efficiency (EE%) and highest cumulative release (CR%) of GABA microcapsules found after 25 days of the fermentation were 40.18% and 89.13%, respectively. It was an interesting point that supplementation of microencapsulated GABA into MBR substrate could expand the stationary phase (days 10–20 of the fermentation) of M. purpureus growth curve compared to the control (days 10–15 of the fermentation). During the stationary phase, the concentrations of alanine, phenylalanine, arginine, tyrosine, and tryptophan in MBR fermentation with GABA microcapsule supplementation rose by more than 1.2-fold relative to the control, whereas linolenic acid, linoleic acid, and oleic acid demonstrated increases of over 1.24, 1.31, and 1.42-fold, respectively. Following a 25-day fermentation period, the maximum concentration of GABA detected in the MBR supplemented with GABA microcapsules was 1,267.13 mg/kg, in comparison to the control. Considering HCA and variable importance in projection (VIP), the primary metabolites MBR from GABA microcapsule supplementation positively correlated with days 10 and 15 of the fermentation but days 20 and 25 of the fermentation for the secondary metabolites. The significant metabolic pathways based on the primary and secondary metabolites of MBR from GABA microcapsule supplementation were 1. starch and sucrose metabolism, 2. neomycin, kanamycin, and gentamicin biosynthesis, 3. biosynthesis of unsaturated fatty acids, 4. phenylalanine, tyrosine, and tryptophan biosynthesis, 5. arginine and proline metabolism, 6. citrate cycle (TCA cycle), 7. fructose and mannose metabolism, and 8. pyruvate metabolism.

Fusion of FDG and FMZ PET Reduces False Positive in Predicting Epileptogenic Zone.

Epilepsy, a globally prevalent neurological disorder, necessitates precise identification of the epileptogenic zone (EZ) for effective surgical management. While the individual utilities of FDG PET and FMZ PET have been demonstrated, their combined efficacy in localizing the epileptogenic zone remains underexplored. We aim to improve the non-invasive prediction of epileptogenic zone (EZ) in temporal lobe epilepsy (TLE) by combining FDG PET and FMZ PET with statistical feature extraction and machine learning. This study included 20 drug-resistant unilateral TLE patients (14 mesial TLE, 6 lateral TLE), and two control groups (N=29 for FDG, N=20 for FMZ). EZ of each patient was confirmed by post-surgical pathology, and one-year follow-up, while propagation zone (PZ) and non-involved zone (NIZ) were derived from the epileptogenicity index based on presurgical stereo-encephalography (SEEG) monitoring. Whole brain PET scans were obtained with dual tracers [18F]FDG and [18F]FMZ on separate days, from which standard uptake value ratio (SUVR) was calculated by global mean scaling. Low-order statistical parameters of SUVRs and t-maps derived against control groups were extracted. Additionally, fused FDG and FMZ features were created using arithmetic operations. Spearman correlation was used to investigate the associations between FDG and FMZ, while multiple linear regression analysis was used to explore the interaction effects of imaging features in predicting epileptogenicity. Crafted imaging features were used to train logistic regression models to predict EZ, whose performance was evaluated using 10-fold cross-validation at ROI-level, and leave-one-patient-out cross-validation at patient-level. FDG SUVR significantly decreased in EZ and PZ compared to NIZ, while FMZ SUVR in EZ significantly differed from PZ. Interaction effects were found between FDG and FMZ in their prediction of epileptogenicity. Fusion of FDG and FMZ provided the best prediction model with an area under the curve (AUC) of 0.86 [0.84-0.87] for EZ vs. NIZ and an AUC of 0.79 [0.77-0.81] for EZ vs. PZ, eliminating 100% false positives in 50% of patients, and ≥80% FPs in 90% patients at patient level. Combined FDG and FMZ offer a promising avenue for non-invasive localization of the epileptogenic zone in TLE, potentially refining surgical planning. AUC = Area under the curve; EI = Epileptogenicity index; EZ = Epileptogenic zone; FMZ = Flumazenil; GABAA = Gammaaminobutyric acid type A; NIZ = Not-involved zone; PZ = Propagation zone; SEEG = Stereo-electroencephalography; SUVR = Standard uptake value ratio; TLE = Temporal lobe epilepsy.

Ganaxolone: A Review in Epileptic Seizures Associated with Cyclin-Dependent Kinase-Like 5 Deficiency Disorder.

Oral ganaxolone (ZTALMY®), a synthetic analogue of the endogenous neuroactive steroid allopregnanolone, acts as a positive allosteric modulator of synaptic and extra-synaptic γ-aminobutyric acid(GABA) type A receptor function in the CNS. In the EU and the UK, it is approved for the adjunctive treatment of epileptic seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients aged 2-17 years. In a multinational phase III study (Marigold), 17weeks' therapy with adjunctive ganaxolone, administered orally three times daily with food, significantly reduced 28-day major motor seizure frequency from baseline versus placebo in patients aged 2-19years with CDD-associated refractory epilepsy. Antiepileptic efficacy was generally sustained through 2years of treatment. Ganaxolone was generally well tolerated in Marigold. While somnolence and sedation are related to the dose of ganaxolone, they appear early in treatment and may decrease with continued therapy. Thus, although current evidence is somewhat limited,adjunctive ganaxolone could be a valuable therapeutic option for patients aged 2-17years with epileptic seizures associated with CDD.

Adaptive sampling-based structural prediction reveals opening of a GABAA receptor through the αβ interface.

γ-Aminobutyric acid type A (GABAA) receptors are ligand-gated ion channels in the central nervous system with largely inhibitory function. Despite being a target for drugs including general anesthetics and benzodiazepines, experimental structures have yet to capture an open state of classical synaptic α1β2γ2 GABAA receptors. Here, we use a goal-oriented adaptive sampling strategy in molecular dynamics simulations followed by Markov state modeling to capture an energetically stable putative open state of the receptor. The model conducts chloride ions with comparable conductance as in electrophysiology measurements. Relative to experimental structures, our open model is relatively expanded at both the cytoplasmic (-2') and central (9') gates, coordinated with distinctive rearrangements at the transmembrane αβ subunit interface. Consistent with previous experiments, targeted substitutions disrupting interactions at this interface slowed the open-to-desensitized transition rate. This work demonstrates the capacity of advanced simulation techniques to investigate a computationally and experimentally plausible functionally critical of a complex membrane protein yet to be resolved by experimental methods.