Sucrose, cell wall, and polyamine metabolisms involve in preserving postharvest quality of 'Zaosu' pear fruit by L-glutamate treatment.

'Zaosu' pear fruit is prone to yellowing of the surface and softening of the flesh after harvest. This work was performed to assess the influences of L-glutamate treatment on the quality of 'Zaosu' pears and elucidate the underlying mechanisms involved. Results demonstrated that L-glutamate immersion reduced ethylene release, respiratory intensity, weight loss, brightness (L*), redness (a*), yellowness (b*), and total coloration difference (ΔE); enhanced ascorbic acid, soluble solids, and soluble sugar contents; maintained chlorophyll content and flesh firmness of pears. L-glutamate also restrained the activities of neutral invertase and acid invertase, while enhancing sucrose phosphate synthetase and sucrose synthase activities to facilitate sucrose accumulation. The transcriptions of PbSGR1, PbSGR2, PbCHL, PbPPH, PbRCCR, and PbNYC were suppressed by L-glutamate, resulting in a deceleration of chlorophyll degradation. L-glutamate concurrently suppressed the transcription levels and enzymatic activities of polygalacturonases, pectin methylesterases, cellulase, and ß-glucosidase. It restrained polygalacturonic acid trans-eliminase and pectin methyl-trans-eliminase activities as well as inhibited the transcription levels of PbPL and Pbß-gal. Moreover, the gene transcriptions and enzymatic activities of arginine decarboxylase, ornithine decarboxylase, S-adenosine methionine decarboxylase, glutamate decarboxylase, γ-aminobutyric acid transaminase, glutamine synthetase along with the PbSPDS transcription was promoted by L-glutamate. L-glutamate also resulted in the down-regulation of PbPAO, PbDAO, PbSSADH, PbGDH, and PbGOGAT transcription levels, while enhancing γ-aminobutyric acid, glutamate, and pyruvate acid contents in pears. These findings suggest that L-glutamate immersion can effectively maintain the storage quality of 'Zaosu' pears via modulating key enzyme activities and gene transcriptions involved in sucrose, chlorophyll, cell wall, and polyamine metabolism.

A neural circuit associated with anxiety-like behaviors induced by chronic inflammatory pain and the anxiolytic effects of electroacupuncture.

AIMS: Negative emotions induced by chronic pain are a serious clinical problem. Electroacupuncture (EA) is a clinically proven safe and effective method to manage pain-related negative emotions. However, the circuit mechanisms underlying the effect of EA treatment on negative emotions remain unclear. METHODS: Plantar injection of complete Freund's adjuvant (CFA) was performed to establish a rat model of chronic inflammatory pain-induced anxiety-like behaviors. Adeno-associated virus (AAV) tracing was used to identify excitatory synaptic transmission from the rostral anterior cingulate cortex (rACC) to the dorsal raphe nucleus (DRN). Employing chemogenetic approaches, we examined the role of the rACC-DRN circuit in chronic pain-induced anxiety-like behaviors and investigated whether EA could reverse chronic pain-induced dysfunctions of the rACC-DRN circuit and anxiety-like behaviors. RESULTS: We found that chemogenetic activation of the rACC-DRN circuit alleviated CFA-induced anxiety-like behaviors, while chemogenetic inhibition of the rACC-DRN circuit resulted in short-term CFA-induced anxiety-like behaviors. Further research revealed that the development of CFA-induced anxiety-like behaviors was attributed to the dysfunction of rACC CaMKII neurons projecting to DRN serotonergic neurons (rACCCaMKII-DRN5-HT neurons) but not rACC CaMKII neurons projecting to DRN GABAergic neurons (rACCCaMKII-DRNGABA neurons). This is supported by the findings that chemogenetic activation of the rACCCaMKII-DRN5-HT circuit alleviates anxiety-like behaviors in rats with chronic pain, whereas neither chemogenetic inhibition nor chemogenetic activation of the rACCCaMKII-DRNGABA circuit altered CFA chronic pain-evoked anxiety-like behaviors in rats. More importantly, we found that EA could reverse chronic pain-induced changes in the activity of rACC CaMKII neurons and DRN 5-HTergic neurons and that chemogenetic inhibition of the rACCCaMKII-DRN5-HT circuit blocked the therapeutic effects of EA on chronic pain-induced anxiety-like behaviors. CONCLUSIONS: Our data suggest that the reversal of rACCCaMKII-DRN5-HT circuit dysfunction may be a mechanism underlying the therapeutic effect of EA on chronic pain-induced anxiety-like behaviors.

Active peptides from Eupolyphaga sinensis walker attenuates experimental hyperlipidemia by regulating the gut microbiota and biomarkers in rats with dyslipidemia.

Eupolyphaga sinensis Walker (ESW) is a traditional Chinese medicine formulation used to treat hyperlipidemia. However, the hypolipidemic effect of the active peptides from E. sinensis Walker (APE) is incompletely understood. We studied the hypolipidemic effect of APE and explored the impact of APE on the gut microbiota (GM) in rats suffering from hyperlipidemia. APE was prepared by enzymatic digestion, and its structure was characterized using various methods. The anti-hyperlipidemic activity of APE was assessed using a high-fat diet (HFD)-induced model in zebrafish and rats. In rats, HFD administration caused abnormalities of lipid metabolism and disturbances of the GM and amino acid (AA) profile in plasma. The abundance of bacteria of the phyla Firmicutes and Bacteroides was increased significantly (p < 0.05), and the relative abundance of Lactobacillus species and Clostridium species was decreased significantly (p < 0.05). HFD therapy affected the levels of 12 AAs in vivo: 10 AAs showed increased levels and two AAs had decreased levels (p < 0.05). Similar results were demonstrated in an experiment on fecal microbiota transplantation. APE treatment dose-dependently decreased lipid factors and liver damage (p < 0.05). Sequencing of the 16 S rRNA gene indicated that APE improved the intestinal-flora structure of rats with HL markedly, and increased the relative abundance of Lactobacillus species and Clostridium species. Metabolomics analysis indicated that APE could alter the levels of 10 AAs affected by HFD consumption. Spearman correlation analysis revealed that gamma-aminobutyric acid (GABA) could be a crucial metabolite, and Lactobacillus species and Clostridium species might be important bacteria for the action of APE against hyperlipidemia. We speculate that APE exhibited an anti-hyperlipidemic effect by regulating GABA synthesis in the presence of Lactobacillus species and Clostridium species.

Electroacupuncture alleviates the relapse of pain-related aversive memory by activating KOR and inhibiting GABAergic neurons in the insular cortex.

Pain-related aversive memory is common in chronic pain patients. Electroacupuncture has been demonstrated to block pain-related aversive memory. The insular cortex is a key region closely related to aversive behaviors. In our study, a potential mechanism underlying the effect of electroacupuncture treatment on pain-related aversive memory behaviors relative to the insular cortex was investigated. Our study used the chemogenetic method, pharmacological method, electroacupuncture intervention, and behavioral detection. Our study showed that both inhibition of gamma-aminobutyric acidergic neurons and activation of the kappa opioid receptor in the insular cortex blocked the pain-related aversive memory behaviors induced by 2 crossover injections of carrageenan in mice; conversely, both the activation of gamma-aminobutyric acidergic neurons and inhibition of kappa opioid receptor in the insular cortex play similar roles in inducing pain-related aversive memory behaviors following 2 crossover injections of carrageenan. In addition, activation of gamma-aminobutyric acidergic neurons in the insular cortex reversed the effect of kappa opioid receptor activation in the insular cortex. Moreover, electroacupuncture effectively blocked pain-related aversive memory behaviors in model mice, which was reversed by both activation of gamma-aminobutyric acidergic neurons and inhibition of kappa opioid receptor in the insular cortex. The effect of electroacupuncture on blocking pain-related aversive memory behaviors may be related to the activation of the kappa opioid receptor and inhibition of gamma-aminobutyric acidergic neurons in the insular cortex.

Herb pair of Polygala tenuifolia Willd and Acorus tatarinowii Schott decoction attenuates seizures and alleviates anxiety in mice: Evidence for modulating inflammation, alleviating oxidative stress and mediating GABA pathway.

Currently, prolong use of standard anti-epileptics may cause tolerance and ineffective for about 30% of epileptic patients. Medicinal plants provide an attractive therapeutic effect in preventing and treating seizures in traditional and folk medicine. In this study, we investigate the antiepileptic effects of PTAT decoction on acute and chronic seizure models in mice and explore the potential mechanisms. PTAT decoction dose-dependently protected mice against MES and PTZ induced seizure. Meanwhile, it decreased the seizure severity and reduced seizure-caused anxious behavior in the PTZ-kindling mice, suggesting a significant antiepileptic activity and anxiolytic/anxiogenic potential. PTAT decoction dose-dependently increased the levels of GSH and the activity SOD and CAT, while decreased the level of MDA in the hippocampi of treated mice. Furthermore, a significant decrease in the proinflammatory cytokine levels, including TNF-α, IL-1ß, IL-6 and MCP-1 was found in treated mice compared with the mice in the vehicle + PTZ group. Moreover, PTAT decoction dose-dependently reversed the alterations induced by PTZ in GABA, GABA-T, L-GAD and glutamate levels in kindling mice, showing an effect on the modulation of the GABA neurotransmission. Thus, PTAT decoction has a promising anticonvulsant activity mediated via multiple mechanisms, which might be used as an up-and-coming phytotherapy strategy in the management of epilepsy and its complications.

Resilient and sustainable production of peanut (Arachis hypogaea) in phosphorus-limited environment by using exogenous gamma-aminobutyric acid to sustain photosynthesis.

Globally, many low to medium yielding peanut fields have the potential for further yield improvement. Low phosphorus (P) limitation is one of the significant factors curtailing Arachis hypogaea productivity in many regions. In order to demonstrate the effects of gamma-aminobutyric acid (GABA) on peanuts growing under P deficiency, we used a pot-based experiment to examine the effects of exogenous GABA on alleviating P deficiency-induced physiological changes and growth inhibition in peanuts. The key physiological parameters examined were foliar gas exchange, photochemical efficiency, proton motive force, reactive oxygen species (ROS), and adenosine triphosphate (ATP) synthase activity of peanuts under cultivation with low P (LP, 0.5 mM P) and control conditions. During low P, the cyclic electron flow (CEF) maintained the high proton gradient (∆pH) induced by low ATP synthetic activity. Applying GABA during low P conditions stimulated CEF and reduced the concomitant ROS generation and thereby protecting the foliar photosystem II (PSII) from photoinhibition. Specifically, GABA enhanced the rate of electronic transmission of PSII (ETRII) by pausing the photoprotection mechanisms including non-photochemical quenching (NPQ) and ∆pH regulation. Thus, GABA was shown to be effective in restoring peanut growth when encountering P deficiency. Exogenous GABA alleviated two symptoms (increased root-shoot ratio and photoinhibition) of P-deficient peanuts. This is possibly the first report of using exogenous GABA to restore photosynthesis and growth under low P availability. Therefore, foliar applications of GABA could be a simple, safe and effective approach to overcome low yield imposed by limited P resources (low P in soils or P-fertilizers are unavailable) for sustainable peanut cultivation and especially in low to medium yielding fields.

Ameliorative effects of Albizia adianthifolia aqueous extract against pentylenetetrazole-induced epilepsy and associated memory loss in mice: Role of GABAergic, antioxidant defense and anti-inflammatory systems.

Albizia adianthifolia (Schumach.) (Fabaceae) is a medicinal herb used for the treatment of epilepsy and memory impairment. This study aims to investigate the anticonvulsant effects of Albizia adianthifolia aqueous extract against pentylenetetrazole (PTZ)-induced spontaneous convulsions in mice; and determine whether the extract could mitigate memory impairment, oxidative/nitrergic stress, GABA depletion and neuroinflammation. Ultra-high performance liquid chromatography/mass spectrometry analysis was done to identify active compounds from the extract. Mice were injected with PTZ once every 48 h until kindling was developed. Animals received distilled water for the normal group and negative control groups, doses of extract (40, 80, or 160 mg/kg) for the test groups and sodium valproate (300 mg/kg) for the positive control group. Memory was measured using Y maze, novel object recognition (NOR) and open field paradigms, while the oxidative/nitrosative stresses (MDA, GSH, CAT, SOD and NO), GABAergic transmission (GABA, GABA-T and GAD) and neuro-inflammation (TNF-α, IFN-γ, IL- 1ß, and IL-6) were determined. Brain photomicrograph was also studied. Apigenin, murrayanine and safranal were identified in the extract. The extract (80-160 mg/kg) significantly protected mice against seizures and mortality induced by PTZ. The extract significantly increased the spontaneous alternation and the discrimination index in the Y maze and NOR tests, respectively. PTZ kindling induced oxidative/nitrosative stress, GABA depletion, neuroinflammation and neuronal cells death was strongly reversed by the extract. The results suggest that the anticonvulsant activity of Albizia adianthifolia extract is accompanied by its anti-amnesic property, and may be supported by the amelioration of oxidative stress, GABAergic transmission and neuroinflammation.

Effects of L-Cysteine and γ-Aminobutyric Acid Treatment on Postharvest Quality and Antioxidant Activity of Loquat Fruit during Storage.

Sichuan is the China's leading producer of loquat, with the largest cultivation area and yield ranked first in China. Loquat is a seasonal fruit highly appreciated by consumers; however, the fruit is prone to browning and lignification after harvest, affecting its storage quality. The effects of L-Cysteine (L-Cys, 0.01, 0.05, 0.1, 0.2%) and γ-aminobutyric acid (GABA, 0.025, 0.05, 0.075, 0.1%) on the sensory quality and antioxidant activity of loquat fruit during cold storage at 4 °C for 35 days and simulated shelf life for 5 days were investigated. The results showed that after 40 days of storage, compared with the control, 0.05% L-Cys and 0.05% GABA treatment of 'Zaozhong No. 6' loquat fruit effectively reduced the weight loss rate, browning index, decay index, respiratory rate, firmness, and lignin content and slowed the decreases in total soluble solids, soluble sugar, titratable acidityand vitamin C contents. The application of 0.05% L-Cys and 0.05% GABA significantly increased the contents of total phenols, total flavonoids, flavanols, and carotenoids; delayed the increase of relative electric conductivity, MDA, POD, and PPO activities; and significantly enhanced the activities of SOD and CAT, DPPH free radical scavenging ability, and FRAP, thereby improving antioxidant capacity. In summary, 0.05% L-Cys and 0.05% GABA treatment promotes the quality of loquat fruit after 40 days of storage, and significantly enhances antioxidant capacity, thus delaying senescence after harvest.

Heukharang lettuce (Lactuca sativa L.) leaf extract displays sleep-promoting effects through GABAA receptor.

ETHNOPHARMACOLOGICAL RELEVANCE: Although lettuce is traditionally known to have hypnotic and sedative effects, to date, only a few studies have documented its sleep-promoting effects and elucidated the related mechanisms. AIM OF THE STUDY: We aimed to investigate the sleep-promoting activity of Heukharang lettuce leaf extract (HLE) with increased lactucin content, known as a sleep-promoting substance in lettuce, in animal models. MATERIALS AND METHODS: To evaluate the effect of HLE on sleep behavior, analysis of electroencephalogram (EEG), gene expression of brain receptors, and activation mechanisms using antagonists were investigated in rodent models. RESULTS: High-performance liquid chromatography analysis showed that HLE contained lactucin (0.78 mg/g of extract) and quercetin-3-glucuronide (1.3 mg/g of extract). In the pentobarbital-induced sleep model, the group administered 150 mg/kg of HLE showed a 47.3% increase in sleep duration time as compared to the normal group (NOR). The EEG analysis showed that the HLE significantly increased non-rapid eye movement (NREM), where delta waves were improved by 59.5% when compared to the NOR, resulting in increased sleep time. In the caffeine-induced arousal model, HLE significantly decreased the awake time increased by caffeine administration (35.5%) and showed a similar level to NOR. In addition, HLE increased the gene and protein expression of gamma-aminobutyric acid receptor type A (GABAA), GABA type B, and 5-hydroxytryptamine (serotonin) receptor 1A. In particular, in comparison to the NOR, the group administered 150 mg/kg HLE showed an increase in expression levels of GABAA and protein by 2.3 and 2.5 times, respectively. When the expression levels were checked using GABAA receptor antagonists, HLE showed similar levels to NOR, as the sleep duration was reduced by flumazenil (45.1%), a benzodiazepine antagonist. CONCLUSIONS: HLE increased NREM sleep and significantly improved sleep behavior due to its action on the GABAA receptors. The collective findings suggest that HLE can be used as a novel sleep-enhancing agent in the pharmaceutical and food industries.

Zinc supplementation and light intensity affect 2-acetyl-1-pyrroline (2AP) formation in fragrant rice.

BACKGROUND: Improving the yield and aroma content of fragrant rice is the focus of fragrant rice research. Light and Zinc (Zn) management generally cause regulations in the 2-acetyl-1-pyrroline (2AP) accumulation in fragrant rice. In addition, Zn promotes rice growth and improves rice yield, which has the potential to compensate for the negative impact of low light on fragrant rice yield. However, the potential of Zn to improve fragrant rice yield and 2AP content under shading conditions has not been verified. METHODS: Field experiments were conducted in the rice season (May-September) in 2019 to 2021. Two light i.e., normal light (NL) and low light (LL) and four Zn levels i.e., 0 kg Zn ha- 1 (N0), 1 kg Zn ha- 1 (Zn1), 2 kg Zn ha- 1(Zn2), and 3 kg Zn ha- 1 (Zn3), which applied at booting stage was set up. The grain yield, 2AP contents, Zn content in polished rice, photosynthesis related indicators, MDA content, antioxidant enzyme activity and the biochemical parameters related to 2AP formation were investigated. RESULTS: Shading reduced yield by 8.74% and increased 2AP content by 24.37%. In addition, shading reduced net photosynthetic rate (Pn), superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), and increased proline, γ-aminobutyric acid (GABA), and pyrroline-5-carboxylic acid (P5C), proline dehydrogenase (PDH), △1-pyrroline-5-carboxylic acid synthetase (P5CS), malondialdehyde (MDA). With increasing Zn application levels, yield, 2AP, Zn content in polished rice, Pn, proline, P5C, GABA, PDH, P5CS, SOD, CAT and POD increased, and MDA decreased. Significant Light and Zn interaction effect on 2AP content was detected, and both shading and increasing Zn application increased the 2AP content. CONCLUSION: Shading can increase the 2AP content but reduce the yield of fragrant rice. Increasing Zn application under shading conditions can further promote the biosynthesis of 2AP, but the effect of improving yield is limited.

Exogenous γ-aminobutyric acid (GABA) alleviates nitrogen deficiency by mediating nitrate uptake and assimilation in Andrographis paniculata seedlings.

γ-Aminobutyric acid (GABA) plays significant metabolic and signaling roles in plant stress responses. Recent studies have proposed that GABA alleviates plant nitrogen (N) deficient stress; however, the mechanism by which GABA mediates plant N deficiency adaptation remains not yet well understood. Herein we found in a medicinal plant Andrographis paniculata that 5 mmol L-1 exogenous GABA promoted plant growth under N deficient (1 mmol L-1 NO3-) condition, with remarkably increments in total N and NO3- concentrations in plants. GABA increased N assimilation and protein synthesis by up-regulating the activities and expression of N metabolic enzymes. GABA also increased the accumulation of α-ketoglutarate and malate, which could facilitate the assimilation of NO3-. Inhibition of NR by Na2WO4 counteracted the promoting effects of GABA on plant growth, and the effects of GABA were not affected by L-DABA and 3-MP, the inhibitors of GABA transaminase (GABA-T) and glutamate decarboxylase (GAD), respectively. These results suggested that the nutritional role of GABA was excluded in promoting plant growth under low N condition. The results of 15N isotopic tracing and NRTs transcription indicated that exogenous GABA could up-regulate NRT2.4 and NRT3.2 to increase plant NO3- uptake under N deficient condition. Interestingly, primidone, an inhibitor of GABA receptor, impeded the effects of GABA on plant growth and N accumulation. Thus, our results revealed that exogenous GABA acted as a signal to up-regulate NRTs via its receptor to increase NO3- uptake, and subsequently promoted NO3- assimilation to alleviate N deficiency in A. paniculata.

Gamma-amino butyric acid (GABA) supplementation alleviates dexamethasone treatment-induced oxidative stress and inflammation response in broiler chickens.

This experiment was conducted to investigate the effect of Gamma-amino butyric acid (GABA) on growth performance, serum and liver antioxidant status, inflammation response and hematological changes, in male broiler chickens under experimentally induced stress via in-feed dexamethasone (DEX). A total of 300 male chicks (Ross 308) on day 7 after hatching, were randomly selected into four groups which were positive control group (PC, without any treatment), negative control (NC, with 1 mg/kg DEX), a third group received 1 mg/kg DEX and 100 mg/kg GABA (DG +) and the last one was (DG ++) which received 1 mg/kg DEX and 200 mg/kg GABA. Each group has five replicates (15 birds/replicate). Dietary GABA modulated DEX-induced adverse effects on body weight, feed intake, and feed conversion ratio. The DEX-induced effect of serum levels of IL-6 and IL-10 was reduced by dietary GABA supplementation. The activity of serum and liver superoxide dismutase, catalase, glutathione peroxidase were enhanced and malondialdehyde was reduced by GABA supplementation. The serum levels of total cholesterol & triglyceride were higher while low-density lipoprotein & high-density lipoprotein were lower in GABA groups than NC group. GABA supplementation also significantly decreased the heterophil, heterophil/lymphocyte ratio and elevated the activities of aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) than NC group. In conclusion, dietary GABA supplementation can alleviate DEX stress-induced oxidative stress and inflammation response.

Pharmacological evaluation of the anxiolytic-like effects of an aqueous extract of the Raphanus sativus L. sprouts in mice.

Raphanus sativus L. (Brassicaceae), commonly known as radish, is consumed worldwide as a vegetable. However, its benefits on mental health are unknown. The aim of this study was to evaluate its anxiolytic-like effects and safety using different experimental models. An aqueous extract of R. sativus sprouts (AERSS) was pharmacologically evaluated by intraperitoneal route (i.p.) at 10, 30, and 100 mg/kg and orally (p.o.) at 500 mg/kg on behavior by using open-field and plus-maze tests. In addition, its acute toxicity (LD50) was determined by the Lorke's method. Diazepam (1 mg/kg, i.p.) and buspirone (4 mg/kg, i.p.) were the reference drugs. A significant and anxiolytic-like dosage of AERSS (30 mg/kg, i.p.) resembling the effects of reference drugs was chosen to explore the involvement of GABAA/BDZs site (flumazenil, 5 mg/kg, i.p.) and serotonin 5-HT1A receptors (WAY100635, 1 mg/kg, i.p.) as a possible mechanism of action. A 500 mg/kg, p.o. dosage of AERSS produced an anxiolytic-like response equivalent to 100 mg/kg, i.p. No acute toxicity was observed since a LD50 > 2000 mg/kg, i.p. The phytochemical analysis allowed the identification and quantification of major presence of sulforaphene (2500 µM), sulforaphane (15 µM), iberin (0.75 µM), and indol-3-carbinol (0.75 µM), as major constituents. Both the GABAA/BDZs site and serotonin 5-HT1A receptors were involved in the anxiolytic-like activity of AERSS, depending on the pharmacological parameter or the experimental assay tested. Our results demonstrate that the anxiolytic activity of R. sativus sprouts involves GABAA/BDZs site and serotonin 5-HT1A receptors supporting its health benefits in the treatment of anxiety beyond the satisfaction of basic nutritional needs.

Exogenous γ-aminobutyric acid (GABA) improves salt-inhibited nitrogen metabolism and the anaplerotic reaction of the tricarboxylic acid cycle by regulating GABA-shunt metabolism in maize seedlings.

Salinity stress hampers the growth of most crop plants and reduces yield considerably. In addition to its role in metabolism, γ-aminobutyric acid (GABA) plays a special role in the regulation of salinity stress tolerance in plants, though the underlying physiological mechanism remains poorly understood. In order to study the physiological mechanism of GABA pathway regulated carbon and nitrogen metabolism and tis relationship with salt resistance of maize seedlings, we supplemented seedlings with exogenous GABA under salt stress. In this study, we showed that supplementation with 0.5 mmol·L-1 (0.052 mg·g-1) GABA alleviated salt toxicity in maize seedling leaves, ameliorated salt-induced oxidative stress, and increased antioxidant enzyme activity. Applying exogenous GABA maintained chloroplast structure and relieved chlorophyll degradation, thus improving the photosynthetic performance of the leaves. Due to the improvement in photosynthesis, sugar accumulation also increased. Endogenous GABA content and GABA transaminase (GABA-T) and succinate semialdehyde dehydrogenase (SSADH) activity were increased, while glutamate decarboxylase (GAD) activity was decreased, via the exogenous application of GABA under salt stress. Meanwhile, nitrogen metabolism and the tricarboxylic acid (TCA) cycle were activated by the supply of GABA. In general, through the regulation of GABA-shunt metabolism, GABA activated enzymes related to nitrogen metabolism and replenished the key substrates of the TCA cycle, thereby improving the balance of carbon and nitrogen metabolism of maize and improving salt tolerance.

Antidepressant- and anxiolytic-like actions of Cajanus cajan seed extract mediated through monoaminergic, nitric oxide-cyclic GMP and GABAergic pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: The seeds of Cajanus cajan (L) Millsp, are used in Traditional medicine for the treatment of anxiety and other neurological disorders. Hence, this study is designed to investigate the antidepressant- and anxiolytic-like properties of ethanol seed extract of Cajanus cajan (CC) in mice. MATERIALS AND METHODS: CC (50, 100 or 200 mg/kg, p.o.) was administered 1h before subjecting the animals to different behavioral models: forced swim test (FST) and tail suspension test (TST) (depressive-like behaviour), open field test (OFT), elevated plus maze (EPM), light-dark test (LDT) and hole-board test (HBT) for anxiety-like behaviour. To ascertain the pharmacodynamic of CC mice were pretreated with monoaminergic, nitrergic and GABAergic receptors antagonists. As well as molecular docking analysis of about 19 flavonoids present in CC on GABAA, α2 adrenoceptors and 5-HT2A receptors. RESULTS: CC (50, 100 or 200 mg/kg, p.o.) treatment significantly reduced immobile time in both FST and TST when compared with vehicle-treated control. However, the pretreatment of mice with prazosin/yohimbine (α1/2 adrenoceptor antagonists, respectively), WAY100635 (5-HT1A receptor antagonist), ketanserin (5-HT2A receptor antagonist), sulpiride (dopamine D2 receptor antagonist), L-NG-Nitro arginine methyl ester (L-NAME), or methylene blue reversed the antidepressant-like effect of CC. In anxiety model, CC produced significant (p < 0.05) increase in open arms exploration and head dipping behavior which was reversed by flumazenil (benzodiazepine receptor antagonist) in the EPM. Docking analysis showed significant binding affinity of orientin, vitexin, pinostrobin and quercetin with 5HT2A, α2-adrenoceptor and GABAA receptors. CONCLUSION: Findings from this study showed that C.cajan seeds extract exerts antidepressant-like effect through participation of monoaminergic systems (5-HT2 receptor, α1/α2-adrenoceptors, and dopamine D2-receptors), nitric oxide-cyclic GMP pathway and anxiolytic-like effect via GABAA benzodiazepine receptors. Moreso, presence of flavonoids with significant binding energies with monoaminergic and GABAergic systems support the potential of the extract in the management of mixed anxiety-depressive illness.

The effects of postnatal erythropoietin and nano-erythropoietin on behavioral alterations by mediating K-Cl co-transporter 2 in the valproic acid-induced rat model of autism.

In this study, based on the excitatory/inhibitory imbalance theory of autism, the time window of GABA switch, the role of K-Cl co-transporter 2 (KCC2) in adjustment GABA switch, and brain permeability to erythropoietin (EPO), the effects of postnatal -EPO and- nano- erythropoietin (NEPO) have been evaluated in the valproic acid (VPA) rat model of autism. The VPA was administered for animal modeling of autism at gestational day (GD) 12.5 (600 mg/kg). Male offsprings were injected with EPO and NEPO in a clinically proper postnatal dosing regimen on postnatal days (PND) 1-5, and autistic-like behaviors were tested at the end of the first month. Then animals were sacrificed, and neuron morphology and KCC2 expression were examined by Nissl staining and Western blot. According to our findings, high-dose NEPO improved autism-associated phenotypes. Neuroprotective effects of EPO and NEPO have been shown in the hippocampus. Postnatal NEPO treatment reversed KCC2 expression abnormalities induced by prenatal VPA. Our results might support the role of KCC2 in ASD and the excitatory/inhibitory imbalance hypothesis. We suggested Nano- erythropoietin and other KCC2 interventions as a new approach to the early treatment and prevention of autism.

Anxiolytic-like effects of citral in the mouse elevated plus maze: involvement of GABAergic and serotonergic transmissions.

Citral, a monoterpene which is a part of the essential oil of several medicinal plants, is generally regarded as safe for human and animal consumption. Studies have introduced citral as a functional component of some essential oils in anxiolytic and antidepressant therapies; however, the neuropharmacological characteristics of citral have not yet been reported. In the present study, we evaluated the anxiolytic activities of citral in comparison to two standard anxiolytics, diazepam and buspirone, in Swiss albino mice by intraperitoneal administration of 1, 2, 5, 10, and 20 mg/kg using elevated plus maze (EPM) and open-field test (OFT). Moreover, we also examined whether the GABAA-benzodiazepine and 5-HT1A receptor are involved in the anxiolytic-like effects of citral by pretreatment with flumazenil and WAY-100635, respectively. Citral dose-dependently decreased the number of border crossings and time spent in borders, and also the number of grooming and rearing in OFT without altering the exploratory behavior of mice. In the EPM, this monoterpene led to a significant increase in number of entries in open arms and time spent in open arms, as well as a decrease in time spent in closed arms. Pretreatment with flumazenil and WAY-100635 both could reverse the anxiolytic effects of the citral in the EPM. These results suggest that anxiolytic activity of citral occurs via the GABAA and 5-HT1A receptor modulation.

Red Ginseng Extract and γ-Aminobutyric Acid Synergistically Enhance Immunity Against Cancer Cells and Antitumor Metastasis Activity in Mice.

The effects of combined administration of red ginseng (RG) extracts and gamma-aminobutyric acid (GABA) on immunostimulatory activity and tumor metastasis inhibition were investigated in mice. For the immunostimulatory activity, splenocyte proliferation, natural killer (NK) cell activity, including the production of granzyme B (GrB) and interferon gamma (IFN-γ), and serum level of cytokine such as IFN-γ, interleukin (IL)-17, and IL-21 were assessed. Peyer's patch cells obtained from mice administered with RG+GABA were cultured, and the cytokine level in the culture supernatant and bone marrow (BM) cell proliferation activity were examined. The proliferative activity of splenocytes was significantly higher in the RG-GABA treatment group than in RG or GABA alone (P < .05). In the experimental tumor metastasis model, oral administration of RG+GABA showed a higher antitumor metastatic effect compared to that of RG or GABA alone. Oral administration of RG+GABA significantly augmented NK cell-mediated cytotoxicity against YAC-1 tumor cells. In addition, the production of GrB and IFN-γ was stimulated in the culture supernatant of NK cells and YAC-1 cells. Serum concentrations of IFN-γ, IL-17, and IL-21 in mice with RG+GABA were significantly higher compared to the corresponding blood levels in mice administered with RG or GABA alone. The RG+GABA group showed significant BM cell proliferation and increased production of IL-6 and granulocyte-macrophage colony-stimulating factor compared to that in the monotherapy groups. Therefore, RG may have a synergistic effect with GABA for enhancing the host defense system such as BM proliferation and NK cell activity in a tumor metastasis model.

TET3 epigenetically controls feeding and stress response behaviors via AGRP neurons.

The TET family of dioxygenases promote DNA demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Hypothalamic agouti-related peptide-expressing (AGRP-expressing) neurons play an essential role in driving feeding, while also modulating nonfeeding behaviors. Besides AGRP, these neurons produce neuropeptide Y (NPY) and the neurotransmitter GABA, which act in concert to stimulate food intake and decrease energy expenditure. Notably, AGRP, NPY, and GABA can also elicit anxiolytic effects. Here, we report that in adult mouse AGRP neurons, CRISPR-mediated genetic ablation of Tet3, not previously known to be involved in central control of appetite and metabolism, induced hyperphagia, obesity, and diabetes, in addition to a reduction of stress-like behaviors. TET3 deficiency activated AGRP neurons, simultaneously upregulated the expression of Agrp, Npy, and the vesicular GABA transporter Slc32a1, and impeded leptin signaling. In particular, we uncovered a dynamic association of TET3 with the Agrp promoter in response to leptin signaling, which induced 5hmC modification that was associated with a chromatin-modifying complex leading to transcription inhibition, and this regulation occurred in both the mouse models and human cells. Our results unmasked TET3 as a critical central regulator of appetite and energy metabolism and revealed its unexpected dual role in the control of feeding and other complex behaviors through AGRP neurons.

Differential sensitivity of metabolic pathways in sugar beet roots to combined salt, heat, and light stress.

Plants in nature commonly encounter combined stress scenarios. The response to combined stressors is often unpredictable from the response to single stresses. To address stress interference in roots, we applied salinity, heat, and high light to hydroponically grown sugar beet. Two main patterns of metabolomic acclimation were apparent. High salt of 300 mM NaCl considerably lowered metabolite amounts, for example, those of most amino acids, γ-amino butyric acid (GABA), and glucose. Very few metabolites revealed the opposite trend with increased contents at high salts, mostly organic acids such as citric acid and isocitric acid, but also tryptophan, tyrosine, and the compatible solute proline. High temperature (31°C vs. 21°C) also frequently lowered root metabolite pools. The individual effects of salinity and heat were superimposed under combined stress. Under high light and high salt conditions, there was a significant decline in root chloride, mannitol, ribulose 5-P, cysteine, and l-aspartate contents. The results reveal the complex interaction pattern of environmental parameters and urge researchers to elaborate in much more detail and width on combinatorial stress effects to bridge work under controlled growth conditions to growth in nature, and also to better understand acclimation to the consequences of climate change.