Search Results (778)

Cancer progression and therapeutic resistance are shaped by reciprocal dynamic interactions between malignant cells and the metabolically altered tumor microenvironment (TME). Tumor-associated hypoxia, glucose and amino acid competition, extracellular acidity, lactate accumulation, adenosine, prostaglandin E2 (PGE2) and other metabolic signals can remodel immune cell function and determine whether inflammation is tumoricidal or tumor-supportive. Although B lymphocytes have traditionally been viewed as antibody-producing cells, tumor-infiltrating B (TIL-B) cells comprise functionally heterogeneous populations that can act as antigen-presenting cells, cytokine and chemokine producers, antibody-secreting cells, cytotoxic effectors, regulatory B cells (Bregs) and organizers of tertiary lymphoid structures (TLSs). Their functional state is strongly influenced by the metabolic and spatial context in which they reside. This review focuses on the intersection of B cell biology and tumor immunometabolism, emphasizing how hypoxia, lactate, nutrient limitation, adenosine, PGE2, kynurenine and B cell-derived γ-aminobutyric acid (GABA) may shape B cell states and their interactions with myeloid and lymphoid cells. We discuss how metabolically conditioned Bregs and immunoglobulin (Ig)A-skewed humoral responses can contribute to immune suppression, whereas metabolically competent antigen-presenting, IgG-biased and TLS-associated B cell responses may support effective anti-tumor immunity. Importantly, the effects are tumor type- and context-dependent: B cell/TLS signatures are associated with favorable outcomes in several breast, lung and other solid tumors, whereas B cell-centered immune landscapes can be suppressed or neutral in pancreatic cancer and IgA-dominated responses may be unfavorable in selected malignancies. We further examine how these states may influence sensitivity or resistance to immune checkpoint blockade, chemotherapy, radiotherapy and cellular therapies. Finally, we highlight B cell metabolic pathways as potential therapeutic entry points and identify priorities for spatial metabolomics and prospective interventional studies. Full article

Zeugodacus tau (Walker) is a polyphagous invasive tephritid capable of cross-family host shifts from ancestral Cucurbitaceae crops to phylogenetically divergent commercial fruits, causing severe horticultural economic losses. As an obligate fruit-boring pest, Z. tau largely relies on larval metabolic plasticity to achieve successful colonization of novel hosts during host shifts. However, few matched fruit–larva metabolomic studies integrate host chemistry to larval physiology, hindering sustainable pest control development. We performed untargeted LC–MS metabolomics on matched fruit and third-instar larval samples from eight hosts after multi-generational acclimation. Principal component analysis (PCA) split fruit and larval metabolomes into cucurbit and non-cucurbit clusters, indicating that larval metabolic profiles align with host fruit chemistry during host shifts. Cucurbit fruits contained uniformly high γ-aminobutyric acid (GABA), and their larvae exhibited enriched glutamate (Glu)-centred amino acid pathways. Non-cucurbit fruits showed heterogeneous chemical composition: larvae-fed banana, mango and pitaya all possessed high UDP-glucose (UDPG), whose levels correlated with fruit glucose-6-phosphate (G6P) enriched in banana and mango. Overall, larvae colonizing distinct non-cucurbit hosts deployed a suite of divergent carbohydrate metabolic modules to respond to variable fruit chemical microenvironments. Banana and pitaya larvae showed enhanced starch–sucrose turnover, whereas mango larvae featured prominent ascorbate and aldarate metabolism; both pathways are closely connected to carbohydrate homeostasis. Orange and guava larvae activated distinct gluconeogenic branches. Gluconeogenesis itself constitutes an important component of carbohydrate metabolism. This dual-metabolome profiling uncovered host-specific biomarkers and two divergent metabolic strategies underlying the host shift in Z. tau, characterizing host-linked metabolic variation after long-term laboratory acclimation, which delivers correlative biochemical clues for subsequent pest management research. Full article

GABA (γ-aminobutyric acid) is the most abundant inhibitory neurotransmitter in the central nervous system of insects. GABAergic signal transduction is involved in the control and modulation of various vital functions such as salivation, locomotion, vision and olfaction, circadian timekeeping and sleep, arousal as well as learning and memory. GABA exerts its effects by binding to specific receptors, which are divided into GABA_A and GABA_B receptors. GABA_A receptors are ligand-gated Cl⁻ channels and molecular targets for a variety of small-molecule insecticides (polychlorocycloalkanes such as dieldrin, phenylpyrazoles such as fipronil, isoxazolines, and meta-diamides) that are widely used in agriculture. GABA_B receptors are seven-transmembrane G-protein-coupled receptors. GABA_B receptors function as obligate heteromers consisting of the two subunits, GABA_B-R1 and GABA_B-R2, whereby GABA_B-R1 binds the ligand and GABA_B-R2 is coupled to the G protein. Usually, adenylyl cyclase activity is inhibited via the G_αi subunits of heterotrimeric G proteins; this leads to a reduction in the intracellular cAMP level. This review summarizes the current knowledge on the molecular and pharmacological properties of insect GABA receptors. Finally, two established model organisms for studying the effects of GABA in insects are presented as examples. The American cockroach (Periplaneta americana) has a long tradition as an object to study GABAergic circuits in the olfactory pathway and the role of GABA in the control of salivary secretion. The fruit fly (Drosophila melanogaster) has proven to be an unsurpassed model system to study the effects of GABA and specific GABA receptors on a variety of physiological functions and behavioral processes. In particular, D. melanogaster is used as a disease model for several human diseases in which GABAergic signaling is involved. Full article

Vespa basalis Smith venom (VBsV) causes painful and potentially severe systemic reactions, yet the relationships among its composition, bioactivity, and cytotoxicity remain poorly understood. Proteomic and metabolomic profiling was combined with ultrafiltration and gel filtration to characterize VBsV and obtain >3 kDa, operationally defined 700–3000 Da, and <700 Da fractions. The effect on LPS-induced NO production was evaluated by nitric oxide (NO) release in LPS-stimulated RAW264.7 cells, and cytotoxicity was assessed in tumor and THLE-2 liver cells. Five venom allergen proteins were identified, including two phospholipase A1 isoforms, hyaluronidase A, antigen 5, and venom dipeptidyl peptidase IV. Targeted profiling also detected several neurotransmitters and energy metabolites, including 5-hydroxytryptamine, L-glutamate, histamine, γ-aminobutyric acid, inosine, and adenosine. The 700–3000 Da fraction exhibited the strongest NO-suppressive and tumor-cell-viability effects among the tested fractions. The 700–3000 Da fraction suppressed NO release (IC₅₀, approximately 23 μg/mL) and reduced tumor-cell viability, while minimally affecting THLE-2 cells at 10–80 μg/mL; by contrast, the >3 kDa fraction showed greater THLE-2 cytotoxicity. These findings identify the 700–3000 Da fraction as a priority for direct compositional characterization and isolation of the responsible molecules. Full article

The increasing incidence of herbicide-resistant weeds and concerns over synthetic herbicides are driving the search for natural alternatives. This study evaluated the post-emergence bioherbicidal activity and mode of action of Santolina chamaecyparissus L. essential oil against Bidens pilosa L. seedlings. Gas chromatography–mass spectrometry revealed a chemically complex oil dominated by oxygenated monoterpenes, including cuminic alcohol, cis-carveol, cis-pinocarveol, α-phellandrene, and limonene. A preliminary dose–response assay identified an ED₅₀ of 0.82% (v/v). At this concentration, visible injury reached 75.9% at 72 h, while leaf relative water content declined to 40.0%. Electrolyte leakage reached 77.6% at 24 h, accompanied by a threefold increase in malondialdehyde, indicating severe membrane damage and lipid peroxidation. Chlorophyll fluorescence imaging showed impaired photosystem II function, reduced electron transport, altered energy dissipation, and loss of photosynthetic vitality. Photosynthetic pigments declined after 24 h, with chlorophyll a reduced by approximately 32.5%. Untargeted metabolomics revealed time-dependent depletion of soluble sugars, organic acids, ascorbate, and shikimate, together with accumulation of proline, γ-aminobutyric acid, trehalose, and branched-chain amino acids. Network analysis indicated loss of metabolic coordination. Overall, under the controlled experimental conditions used here, S. chamaecyparissus essential oil exhibited a rapid contact-type phytotoxic action characterised by membrane disruption, oxidative damage, dehydration, photosynthetic impairment, and extensive metabolic perturbation. Full article

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by core features of social communication deficits and high prevalence of gastrointestinal comorbidities. With its continuously rising global prevalence, current therapeutic modalities remain unable to target and ameliorate the core symptoms of ASD. The microbiota–gut–brain axis (MGBA), a critical pathway mediating crosstalk between the gut microbiota and the brain, has been extensively documented to be deeply involved in the pathological progression of ASD in recent years. However, prior studies have predominantly focused on the unidirectional regulation of the brain by gut microbiota, lacking an integrated account of the bidirectional regulation across immune, metabolic, and endocrine systems. Centered on the immune–metabolic–endocrine interactive network, this review systematically delineates the bidirectional regulatory mechanisms of the MGBA in ASD by integrating recent evidence from microbiota sequencing, animal models, and clinical intervention studies, with the aim of clarifying the bidirectional causal controversy between intestinal microecological disturbance and ASD behavioral abnormalities. This review proposes that in children with ASD, decreased abundance of beneficial intestinal bacteria and disrupted metabolic profiles of short-chain fatty acids synergistically impair intestinal barrier integrity, triggering peripheral chronic inflammation that further drives excessive microglial activation-mediated central neuroinflammation. Subsequently, disturbances in the homeostasis of multiple neurotransmitters including 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), histamine, and dopamine occur via the vagus nerve and hypothalamic–pituitary–adrenal (HPA) axis, ultimately driving ASD behavioral abnormalities. Conversely, chronic stress and behavioral characteristics associated with ASD reshape the intestinal microecology through neuroendocrine pathways, forming a vicious cycle of “microbiota dysbiosis—immune inflammation—HPA axis hyperactivity—further intestinal microecological imbalance”. This review summarizes the therapeutic efficacy and translational bottlenecks of three types of microecological interventions: fecal microbiota transplantation (FMT), probiotics, and ketogenic diet, and analyzes the current limitations in the field, including pronounced population heterogeneity, unclear cross-talk mechanisms among multiple pathways, and the scarcity of large-sample clinical evidence. Collectively, this review preliminarily elucidates the complete multi-system interactive framework of MGBA regulation in ASD, providing theoretical support for mechanistic research and gut-targeted individualized interventions for ASD. Full article

Temperature stress is a major constraint on the productivity of microalgae used in aquaculture. γ-Aminobutyric acid (GABA) is well-established as a key player in the stress tolerance of higher plants, yet its role in microalgae remains largely unexplored. Here, we examined the effects of low (15 °C), optimal (25 °C), and high (35 °C) temperatures on the GABA shunt in Isochrysis zhanjiangensis during the initial and mid-exponential growth phases. The results demonstrated that temperature stress significantly inhibited cell growth and photosynthetic efficiency (assessed by Fv/Fm and Fv’/Fm’), with soluble protein decreasing and soluble sugar accumulating. During the initial exponential phase, both low and high temperature stress triggered marked GABA accumulation, accompanied by coordinated increases in glutamate decarboxylase (GAD) and diamine oxidase (DAO) activities. Interestingly, the transcript levels of IzGAD and IzDAO decreased under these conditions, suggesting that GABA accumulation at this stage is predominantly governed by post-translational activation rather than transcriptional upregulation. Upon entry into the mid-exponential phase, a distinct phase-dependent shift in GABA biosynthetic regulation emerged. Under low temperature stress, GAD activity and IzGAD expression were both suppressed, whereas DAO activity and IzDAO transcripts increased significantly, indicating the transition to DAO-mediated GABA production as the dominant route. Under high temperature stress, both GAD and DAO activities increased, yet their corresponding gene transcription remained repressed, revealing a persistent asynchrony between enzyme activities and gene expression across both phases. Meanwhile, the expression of catabolic genes (IzGABA-T, IzSSADH1, and IzSSADH2) was consistently downregulated, further facilitating the net accumulation of GABA. Promoter analysis revealed multiple stress- and hormone-responsive cis-elements in these genes, implying a complex regulatory network. Collectively, our findings uncover a growth-phase-dependent reconfiguration of GABA biosynthetic pathways in I. zhanjiangensis under temperature stress. These insights provide a mechanistic basis for strain-specific temperature management in aquaculture applications. Full article

γ-aminobutyric acid (GABA), an inhibitory neurotransmitter, plays an important role in regulating stress responses through modulation of the hypothalamic–pituitary–adrenal axis, neuroendocrine activity, antioxidant defense, and immune function. Therefore, this study evaluated the effects of dietary rumen-protected γ-aminobutyric acid (RP-GABA) supplementation on alleviating long-distance transport-induced stress in beef cattle. Forty-eight healthy Simmental bulls were randomly assigned to four treatment groups: CON, G-L, G-M, and G-H, receiving RP-GABA at 0, 300, 500, and 700 mg/kg of concentrate dry matter, respectively. The experiment lasted 53 days, including a 21-day pre-transport feeding period, a 2-day transportation period, and a 30-day post-transport feeding period. Samples were collected on experimental Days 21, 23, and 54. The results showed that long-distance transport impaired antioxidant status, immune function, and stress hormone secretion in beef cattle. The responses to different dietary RP-GABA supplementation levels varied among serum parameters. Long-distance transport reduced triiodothyronine and thyroxine (T4) concentrations, while the G-L group alleviated these reductions and maintained higher levels than the CON group after transport (Day 23). The G-M group enhanced glutathione peroxidase (GSH-Px) activity after transport (Day 23) (p < 0.001) and promoted the elevation of interleukin (IL)-4 levels both before and after long-distance transport (Days 21 and 23). The G-H group significantly decreased serum cortisol concentration after transport (Day 23), while reducing epinephrine levels and increasing glutathione peroxidase activity (all p < 0.001). Moreover, the G-H group further enhanced the increases in IL-4 and total antioxidant capacity before and after transport (Days 21 and 23), and increased IL-6 concentrations before and after transport (Days 21 and 54). Regarding dose-specific effects, the G-L group showed limited effects on stress-related hormones, immune function, and antioxidant capacity, whereas the G-H group enhanced some antioxidant and immune-related responses but had higher pre-transport stress hormone concentrations. In contrast, the G-M group exhibited a relatively balanced response across stress hormone levels, antioxidant status, and immune regulation, characterized by higher T4 (p = 0.003), GSH-Px (p = 0.001), and IL-4 (p = 0.006) concentrations and lower alkaline phosphatase (p = 0.005) and tumor necrosis factor-alpha concentrations. Therefore, under the conditions of this study, dietary supplementation with 500 mg/kg RP-GABA in concentrate may represent a potential level for maintaining balanced physiological responses in beef cattle. Full article

Seed germination induces profound physiological and metabolic changes that promote the synthesis and accumulation of bioactive metabolites in cereal grains. However, the combined effects of germination time and temperature on these responses in black rice (Oryza sativa L.) remain poorly understood. This study investigated how controlled germination modulates the accumulation of GABA (γ-aminobutyric acid) and phenolic metabolites and identified optimal conditions for obtaining bioactive-rich water-soluble extracts. A central composite design was applied by varying germination time (24–96 h) and temperature (14–32 °C). Germinated flours and their corresponding water-soluble extracts were analyzed for GABA, total soluble phenolics, flavonoids, anthocyanins, proanthocyanidins, and oxygen radical absorbance capacity (ORAC). Response surface methodology, desirability analysis, principal component analysis, heatmap, and partial least squares discriminant analysis were used to characterize metabolic responses and optimize germination conditions. Germination significantly altered metabolite accumulation, with higher GABA levels observed at lower temperatures, whereas phenolic metabolites showed distinct responses to the interaction between time and temperature. Multivariate analyses revealed clear metabolic differentiation among germination treatments. Multi-response optimization identified 27 h and 19.7 °C as the optimal germination conditions. These findings demonstrate that controlled germination modulates the bioactive profile of black rice, enhancing phytochemical accumulation and supporting the production of bioactive-rich water-soluble extracts. Full article

3,4-dihydroxyphenethylamine, commonly known as dopamine (DA), is a neuromodulator that fine-tunes neuronal excitability, neurotransmitter release, and the effects of other neurotransmitters on postsynaptic neurons. DA, acting on D1 and D2 receptor families, is involved in myriad functions. In the striatum, it is mainly implicated in motor control, motivation, and reward mechanisms. In the cerebral cortex it participates in attention processes, working memory, long-term memory, etc. DA overproduction or deficits lead to neuronal circuit imbalance that underlies a number of neurological and psychiatric diseases, including Parkinson’s disease (PD), schizophrenia, Huntington’s disease (HD), and substance use disorders (SUDs), to name a few. DA regulates neuronal excitability by modulating ion channels, the release of excitatory (glutamate) and inhibitory (γ-aminobutyric acid, GABA) neurotransmitters, and postsynaptic interactions with glutamate and GABA receptors. Together, these pre- and postsynaptic actions of DA underlie a number of synergistic or antagonistic actions that have important implications for setting membrane potentials, improving the signal-to-noise ratio, and directing the sign of synaptic plasticity. In this review, I will first provide a historical overview of the many studies exploring DA actions in the brain, with particular focus on the striatum. Then, I will emphasize some of the contributions of our laboratory to the understanding of DA modulatory effects from an electrophysiological perspective. Finally, I will discuss the mechanistic and therapeutic implications of DA function and dysfunction. Full article

Mulberry (Morus spp.) leaves, fruits, branches, and root bark are rich in bioactive compounds, including 1-deoxynojirimycin (1-DNJ) and γ-aminobutyric acid (GABA), supporting their potential use in food, medicinal, and feed applications. Their high moisture content, however, makes fresh materials highly susceptible to postharvest quality deterioration, making drying essential for stabilization and high-value utilization. Drying technologies involve trade-offs among efficiency, energy consumption, sensory quality, rehydration, and bioactive-compound retention. This review provides a comprehensive overview of pretreatment and drying technologies for mulberry materials, with particular attention to differences in raw-material characteristics, processing conditions, analytical methods, and reporting bases that limit direct comparisons among studies. Current evidence suggests that low-temperature, low-oxygen, or short-duration technologies, including vacuum freeze-drying, microwave drying, and microwave-vacuum drying, may better preserve quality in certain thermosensitive products, although their benefits remain product- and process-dependent. Hot-air, solar, infrared, heat-pump, and hybrid drying remain practical options for bulk products but require optimization to balance quality, energy efficiency, and scalability. For juice and functional powders, carrier selection, powder properties, and bioaccessibility require further study. Overall, the available evidence is heterogeneous, and some conclusions rely on limited mulberry-specific data or extrapolation from related plant matrices. Future research should emphasize standardized quality evaluation, harmonized reporting, kinetic modeling, multi-objective optimization, online monitoring, energy and carbon-footprint assessment, and industrial-scale validation. Full article

Soil salinity restricts sugar beet growth and productivity, creating a need for effective agronomic approaches to improve plant performance under salt-affected conditions. However, the comparative responses of sugar beet to different foliar-applied exogenous substances under controlled NaCl stress and field saline–alkali conditions remain insufficiently understood. In this study, sugar beet (Beta vulgaris L.) cultivar ‘HI0479’ was used to evaluate the effects of different concentrations of PAA@Mn₃O₄ nanoparticles (PMO), methyl jasmonate (MeJA), and γ-aminobutyric acid (GABA). A pot experiment was first conducted under controlled NaCl stress to identify concentrations for subsequent field evaluation, followed by a one-season field experiment under non-saline–alkali and saline–alkali soil conditions. Based on the overall responses of growth and physiological traits, 100 mg L⁻¹ PMO, 100 mg L⁻¹ MeJA, and 1000 mg L⁻¹ GABA were selected for field evaluation. Under the imposed NaCl treatment, these foliar treatments improved growth and physiological performance and were associated with changes in photosynthetic characteristics, antioxidant enzyme activities, MDA content, osmolyte accumulation, and selected growth-related hormone levels. Under saline–alkali field conditions, PMO, MeJA, and GABA increased storage-root yield by 13.59%, 12.69%, and 12.37%, respectively, compared with the control. Although estimated storage-root sugar concentration decreased, the corresponding estimated sugar yields increased by 10.77%, 9.79%, and 7.41%, respectively. These results show that the three foliar treatments produced favorable growth- and yield-related responses under the experimental conditions evaluated while also revealing a trade-off between storage-root yield and estimated storage-root sugar concentration. The findings provide a basis for further agronomic evaluation of foliar PMO, MeJA, and GABA in sugar beet grown under salt-affected conditions. Full article

Free amino acids serve as a crucial hub connecting plant life activities with human nutrition. The fruits of Cucurbitaceae crops are natural nitrogen reservoirs, rich in free amino acids such as citrulline, arginine, and γ-aminobutyric acid (GABA). To investigate the spatial accumulation characteristics and differential distribution of free amino acids in cucurbit fruits, this study measured the contents of 19 free amino acids in the fruit stem, epicarp, endocarp, pulp, and seeds of 10 cucurbit species (12 varieties) at the mature stage. The results revealed that free amino acid accumulation exhibits significant tissue specificity and species specificity, forming diverse nitrogen metabolism hubs. Glutamine, aspartate, asparagine, arginine, and citrulline constitute a highly coordinated core module of nitrogen metabolism in Cucurbitaceae. Methionine, valine, and some other amino acids were consistently present at extremely low levels across tissues, indicating a competitive diversion of conserved metabolic pathways coexisting among species. Species classification based on free amino acids differed markedly from traditional taxonomy based on gene domestication, implying environmental selection pressures and non-linear gene-metabolite network relationships. Glutamine, GABA, citrulline, and arginine were identified as core hub metabolites supporting tissue type classification. This study revealed the allocation characteristics of free amino acids in fruits of various cucurbit crops and established a functional model integrating nitrogen assimilation, flavor/energy metabolism, stress tolerance/defense signaling, and storage across different tissue types of multiple cucurbit crops, providing new perspectives for precision breeding and domestication mechanism research in Cucurbitaceae. Full article

This study investigated non-conventional crops as raw materials for plant-based fermented functional products with potential neuromodulatory properties, assessing antioxidant activity, amino acid composition, neuroactive metabolites, and aroma profile. Antioxidant activity depended not only on total phenolic content but also on the composition and extractability of other bioactive and reducing constituents released during processing. Free amino acid and γ-aminobutyric acid (GABA) profiles differed markedly from the raw grains, reflecting the effects of enzymatic hydrolysis, formulation, and microbial fermentation. The naked oat fermented product (NOFP) had the highest total, essential and branched-chain free amino acid contents and contained serotonin (811 µg/kg). The triticale fermented product (TFP) showed high phenylethylamine (440 µg/kg), proline and glutamine, and the highest diacetyl content (502 ng/g), potentially contributing to its nutritional and sensory properties. The amaranth fermented product (AFP) was distinguished by high GABA (648.9 mg/kg DW) and L-DOPA (15,272 µg/kg). Kynurenine, kynurenic acid, indole-3-lactic acid, tryptamine, and other tryptophan and tyrosine metabolites were also detected. Volatile profiles were strongly matrix-dependent; AFP was the most diverse, with high levels of aldehydes, pyrazines, furans, and sulfur-containing compounds. Overall, the grain matrix and the processing and formulation sequence strongly influence the nutritional, antioxidant, neuroactive, and aroma characteristics of the products. Full article

The mechanisms underlying the symbiotic efficiency of arbuscular mycorrhizal (AM) fungi are actively debated, but comparative metabolomic studies with fungi of contrasting efficiency are scarce. This study aimed to evaluate the influence of effective (Rhizophagus irregularis RCAM00320) and ineffective (Glomus sp. 129.1Te) AM fungal strains on the root metabolome of the responsive Medicago lupulina line MlS-1 at two vegetative and two reproductive stages. Using GC-MS, over 150 metabolites (amino acids, carboxylic and fatty acids, sugars, etc.) were annotated. Effective AM symbiosis was associated with increased levels of phosphoric acid, trehalose, and free fatty acids 16:1, as well as a decreased pool of tricarboxylic acid cycle intermediates (citrate, malate, succinate) and a reduction in γ-aminobutyric acid from the branching stage to fruiting. The comparison revealed that the branching initiation stage, characterized by low arbuscule abundance in ineffective treatment, is likely a main critical metabolic transition determining symbiosis efficiency. Novel metabolic markers of effective AM were identified. Network analysis revealed a divergence of amino acid and fatty acid clusters under effective mycorrhization, whereas under ineffective mycorrhization these clusters were less separated and closely linked in the control. Thus, inoculation with strains of contrasting efficiency generates distinct phenotypes, with effective AM inducing the most pronounced metabolome rearrangements in development. Full article