γ-Aminobutyric acid alleviates litchi thaumatin-like protein-induced inflammation and reduces gut microbial translocation

Previous research reported litchi thaumatin-like protein(LcTLP)could lead to inflammation,which is a factor causing the adverse reactions after excessive intake of litchi.As a main amino acid in litchi pulp,γ-aminobutyric acid(GABA)was found with anti-inflammatory effect.Therefore,this study aimed to investigate the effects of GABA on LcTLP-induced inflammation through RAW264.7 macrophages and C57BL mice models.In vitro study showed GABA could effectively regulate the level of inflammatory cytokines(interleukin(IL)-1β,IL-6,IL-10,and prostaglandin E2)and Ca2+in cells,and inhibit the phosphorylation of p65,IκB,p38,c-Jun N-terminal kinase(JNK)and extracellular signal-regulated kinase(ERK).These results indicate GABA alleviated inflammation through nuclear factor-κB and mitogen-activated protein kinase pathway signaling pathways.In vivo experiment was performed to verify the anti-inflammatory effect of GABA,and the results demonstrated that GABA reduced the inflammation and oxidative stress in the liver of LcTLP-treated mice,as it down-regulated the pro-inflammatory cytokines,malondialdehyde,aspartate transferase,and alanine transaminase.The relative expression of phosphorylated p38,JNK and ERK in mice liver with GABA treatment were reduced to 65%,39%and 80%of the control group,respectively.Furthermore,GABA treatment enriched probiotic bacteria and decreased pathogenic bacteria in mice gut,which reveals GABA could effectively reduce the translocation of gut microbiota.

Effects ofγ-aminobutyric Acid on Nitrogen Metabolism in Roots and Leaves of Cold-stressed Rice(Oryza sativa L.)During Early Vegetative Growth

Cold stress adversely affects rice growth,particularly at the early vegetative growth stage.In higher plants,nitrogen metabolism plays a central role in amino acid metabolism,plant defense mechanisms and productivity.This report investigated the effects of cold stress and supplementalγ-aminobutyric acid(GABA)under cold stress on nitrogen metabolism in rice seedlings.Cold stress resulted in a greater increase in the transformation to NH_(4)^(+)by nitrate reductase(NR)in roots,it further resulted in lower levels of NO_(3)^(-)content in roots,weakened glutamine glutamate(GOGAT/GS)pathway and elevated glutamate dehydrogenase(GDH)pathway of rice seedlings.Whereas,compared with cold stress,supplementation of GABA(2.5 mmol·L^(-1))could increase relative water content(79.43%)and biomass(34.15%)of rice seedlings.GABA could act as an amplifier of stress signal conduction/transduction to increase NR activity and promote NO_(3)^(-)assimilation in leaves.In addition,GABA elicited the Ca^(2+)signaling pathway which could promote the GDH pathway and GABA shunt,increase the activities of GS and GDH,and the expression of OsGAD2 and OsGDH family.The GABA might increase the ratio of the Glu family and avoid NH4+toxicity in order to raise the concentration of organic compounds and alleviate the harmful consequences of cold stress.Based on these observations,this study proposed that GABA mediated cold tolerance in rice seedlings by activating Ca^(2+)burst and subsequent crosstalk among Ca^(2+)signaling,GDH pathway and GABA shunt.

Synthesis and Anticonvulsant Activity of γ-Aminobutyric Acid Derivatives

Under physiological conditions, γ-aminobutyric acid poorly crosses the blood-brain barrier. It is likely that a non-toxic derivative of γ-aminobutyric acid which enters the brain easily will have useful anticonvulsant activity. 16 derivatives of γ-aminobutyric acid with an imine link to a lipophilic carrier were prepared and tested for anticonvulsant activity; six compounds show anticonvulsant activity.

Three novel dendritic chitosan derivatives for inhibiting acid corrosion of petroleum pipelines

In the process of exploration and development of oil and gas fields, the acidic environment of oil reservoir, production and transport processes cause corrosion of pipelines and equipment, resulting in huge economic losses and production safety risks. Corrosion inhibitors were widely used in oil industry because of simple operation process and economical. In this study, three environmentally friendly corrosion inhibitors were synthesized based on the natural polysaccharide chitosan. Corrosion inhibition of three dendritic chitosan derivatives (We name them BH, CH and DH) on mild steel in 1 mol/L HCl solution with natural ventilation system was evaluated by weight loss experiment, electrochemical analysis and surface morphology characterization. The experimental results showed that when the three dendritic chitosan derivatives added in the corrosive medium were 500 mg L^(−1), the corrosion inhibition efficiencies were all more than 80%. Based on quantum chemical calculation, inhibition mechanisms of three dendritic chitosan derivatives were investigated according to molecular structures. The results showed that the benzene ring, Schiff base and N atom contained in the molecule were the active centers of electron exchange, which were more likely to form a film on the carbon steel surface, thereby slowing or inhibiting corrosion. The results also predicted the corrosion inhibition effect BH > DH > CH, which was consistent with the experimental conclusion.

Study on the mechanism of cholic acid derivatives in traditional Chinese medicine based on the regulation of gene expression

Objective:To investigate the pharmacological action and mechanism of cholic acid derivatives in traditional Chinese medicine(TCM)based on the regulation of gene expression.Methods:Genome-wide gene expression profiles of Michigan Cancer Foundation-7(MCF-7)cells treated with or without 4 cholic acid derivatives were detected by gene chip technology.Similarities in upregulated and downregulated genes were analyzed using the Connectivity Map(CMap)database.The affinity between cholic acid derivatives and the potential target was confirmed by molecular docking.The cholic acid derivative-regulated pathway enrichment analysis was performed by the STRING database,and the potential pathway was confirmed by in vitro experiments on MD Anderson-Metastatic Breast-231(MDA-MB-231)cells.Results:Compared with the reference genome in the CMap database,the gene expression profiles of cholic acid derivatives were similar to those of antipsychotic,anticancer,anti-inflammatory,and antiinfective drugs.Among them,4 derivatives were associated with antianxiety drugs,and molecular docking results showed that these compounds may act by binding to the ligand-binding site of gammaaminobutyric acid(GABA)receptors.Moreover,the cytoskeletal pathway is one of the pathways enriched in the derivatives.Of them,ursodeoxycholic acid showed significant inhibitory activity on the cytoskeleton formation of MDA-MB-231 cells.Conclusion:The gene expression detection method,combined with CMap and pathway enrichment analysis,could be used to study the mechanism of the active ingredients of TCM.In addition,our research showed that cholic acid derivatives have a potential affinity for membrane receptors,where they can exert anxiolytic activity by modulating opioid receptor,GABA receptor,and dopamine receptor.Moreover,ursodeoxycholic and chenodeoxycholic acid inhibit cytoskeleton formation,probably by acting on membrane proteins to activate the corresponding cytoskeletal pathways.

Environmental cues associated with morphine modulate release of glutamate and γ-aminobutyric acid in ventral subiculum

Objective To investigate whether environmental cues associated with different properties of morphine could regulate the extracellular levels of glutamate and y-aminobutyric acid （GABA） in the hippocampal ventral subiculum, which play a critical role in the reinstatement of drug-seeking behavior induced by environmental cues. Methods Conditioning place preference （CPP） and conditioning place aversion （CPA） models were used to establish environment associated with rewarding and aversive properties of morphine respectively. Microdialysis and high performance liquid chromatography were used to measure the extracelluar level of glutamate and GABA in the ventral subiculum under these environmental cues. Results Exposure to the environmental cues associated with rewarding properties of morphine resulted in a decrease （approximately 11%） of extracellular level of GABA in ventral subiculum, and exposure to the environmental cues associated with aversive properties of morphine resulted in an increase （approximately 230%） of extracellular level of glutamate in ventral subiculum. Conclusion Environmental cues associated with different properties of morphine modulate the release of distinct neurotransmitters in the hippocampal ventral subiculum possibly through different neural circuit.

Effect of brain-derived neurotropic factor released from hypoxic astrocytes on gamma-aminobutyric acid type A receptor function in normal hippocampal neurons

Astrocytes can release increased levels of brain-derived neurotrophic factor during cerebral ischemia, but it is unclear whether brain-derived neurotrophic factor affects y-aminobutyric acid type A receptor function in normal neurons. Results from this study demonstrated that y-aminobutyric acid at 100 pmol/L concentration raised the intracellular calcium level in neurons treated with medium from cultured hypoxic astrocytes, and the rise in calcium level could be inhibited by y-aminobutyric acid type A receptor antagonist bicuculline or brain-derived neurotrophic factor receptor antagonist k252a, y-aminobutyric acid type A-gated current induced by 100 IJmol/L y-aminobutyric acid was in an inward direction in physiological conditions, but shifted to the outward direction in neurons when treated with the medium from cultured hypoxic astrocytes, and this effect could be inhibited by k252a. The reverse potential was shifted leftward to -93 mV, which could be inhibited by k252a and Na＋-K＋-CI cotransporter inhibitor bumetanide. Brain-derived neurotrophic factor was released from hypoxic astrocytes at a high level. It shifted the reverse potential of y-aminobutyric acid type A-gated currents leftward in normal neurons by enhancing the function of Na＋-K＋-CI- cotransporter, and caused y-aminobutyric acid to exert an excitatory effect by activating y-aminobutyric acid type A receptor.

Modulation of γ-aminobutyric acid on painful sense in central nervous system of morphine-dependent rats

Objective To observe the effects of y-aminobutyric acid （GABA） on the electric activities of pain-excited neurons （PEN） in nucleus accumbens （NAc） in central nervous system （CNS） of morphine-dependent rats. Methods After GABA or the GABAA-receptor antagonist, bicuculline （Bic）, was injected into cerebral ventricles or NAc, right sciatic nerve was stimulated by electrical pulses, which was considered as traumatic pain stimulation. Extracellular recordings methods were used to record the electric activities of PEN in NAc. Results When GABA was injected into intracerebroventricle （ICV） as well as NAc, it could decrease the pain-evoked discharge frequency and prolong the latency of PEN. Bic could interdict the above effects of GABA on the electric activities of PEN. Conclusion Exogenous GABA might have an inhibitory effect on the central pain adjustment. Furthermore, GABA and GABAA receptor participate and mediate the traumatic information transmission process in CNS.

Effects of Exogenous Salicylic Acid Derivative on the Resistance to TMV and Activity of Defense Enzymes of Tobacco

[Objective] This study aimed to evaluate the effects of exogenous salicylic acid derivatives on tobacco resistance to TMV and activity of defense enzymes. [Method] The tobboco leaves were treated by exogenous salicylic acid derivatives. Then, the disease occurrence was observed, and the activity of phenylalanin ammo- nia lyase （PAL） and peroxidase （POX） were measured. [Result] Exogenous salicylic acid derivative increased the activities of PAL and POX, while did not influence the resistance to TMV. [Conclusion] The result provides a theoretical basis for the study of plant disease resistance mechanisms.

Relationship of nocturnal concentrations of melatonin, gamma-aminobutyric acid and total antioxidants in peripheral blood with insomnia after stroke： study protocol for a prospective non-randomized controlled trial

Melatonin and gamma-aminobutyric acid（GABA） have been shown to regulate sleep. The nocturnal concentrations of melatonin, GABA and total antioxidants may relate to insomnia in stroke patients. In this prospective single-center non-randomized controlled clinical trial performed in the China Rehabilitation Research Center, we analyzed the relationship of nocturnal concentrations of melatonin, GABA and total antioxidants with insomnia after stroke. Patients during rehabilitation of stroke were recruited and assigned to the insomnia group or non-insomnia group. Simultaneously, persons without stroke or insomnia served as normal controls. Each group contained 25 cases. The primary outcome was nocturnal concentrations of melatonin, GABA and total antioxidants in peripheral blood. The secondary outcomes were Pittsburgh Sleep Quality Index, Insomnia Severity Index, Epworth Sleepiness Scale, Fatigue Severity Scale, Morningness-Eveningness Questionnaire（Chinese version）, and National Institute of Health Stroke Scale. The relationship of nocturnal concentrations of melatonin, GABA and total antioxidants with insomnia after stroke was analyzed and showed that they were lower in the insomnia group than in the non-insomnia group. The severity of stroke was higher in the insomnia group than in the non-insomnia group. Correlation analysis demonstrated that the nocturnal concentrations of melatonin and GABA were associated with insomnia after stroke. This trial was registered at Clinical Trials.gov, identifier： NCT03202121.

Overexpression of γ-aminobutyric acid transporter subtype I leads to susceptibility to Kainic acid-induced seizure in transgenic mice

γ-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter, and the GABAergic synaptic transmission is normally terminated by the rapid uptake through GABA transporters. With transgenic mice ubiquitously overexpressing GABA transporter subtype I (GAT1), the present study explored the pathophysiological role of GAT1 in epileptogenesis. Though displaying no spontaneous seizure activity, these mice exhibit altered electroencephalographic patterns and increased susceptibility to seizure induced by kainic acid. In addition, the GABAA receptor and glutamate transporters are up-regulated in transgenic mice, which perhaps reflects a compensatory or corrective change to the elevated level of GAT1. These preliminary findings support the hypothesis that excitatory and inhibitory neurotransmission, and seizure susceptibility can be altered by neurotransmitter transporters.

Synthesis and Anti-tumor Activity of Novel Amide Derivatives of Ursolic Acid

Ursolic acid was modified at C3 and C28 position to obtain fourteen derivatives including twelve novel compounds, and their chemical structures were characterized by IR, ^1H NMR and MS. Cell growth inhibitory effects of the derivatives against Hela cell were evaluated by MTT assay. All these derivatives were found to have stronger cell growth inhibitory than their parent compound, ursolic acid. The derivatives with a substituted acetyl group at C3 hydroxyl group show better activities than those with an unsubstituted hydroxyl group.

QSAR and Pharmacophore Studies of Thiazolidine-4-carboxylic Acid Derivatives as Novel Influenza Neuraminidase Inhibitors Using HQSAR, Topomer CoMFA and CoMSIA

In order to understand the chemical-biological interactions governing their activities toward neuraminidase （NA）, QSAR models of 28 thiazolidine-4-carboxylic acid derivatives with inhibitory influenza A virus were developed. The obtained HQSAR （hologram quantitative structure activity relationship）, Topomer CoMFA and CoMSIA （comparative molecular similarity indices analysis） models were robust and had good exterior predictive capabilities. Moreover, QSAR modeling results elucidated that hydrogen bonds highly contributed to the inhibitory activity, then electrostatic and hydrophobic factors. Squared multiple correlation coefficients （R2） of HQSAR, Topomer CoMFA and CoMSIA models were 0.994, 0.978 and 0.996, respectively. Squared cross-validated correlation coefficients （Q2） of HQSAR, Topomer CoMFA and CoMSIA models were in turn 0.951, 919 and 0.820. Furthermore, squared multiple correlation coefficients for the test set （R2test） of HQSAR, CoMFA and CoMSIA models were 0.879, 0.912 and 0.953, respectively. Squared cross-validated correlation coefficients for the test set （Q2ext） of HQSAR, Topomer CoMFA and CoMSIA models were 0.867, 0.884 and 0.899, correspondingly.

Synthesis of Tetrahydrofuran and Tetrahydropyran Derivatives Catalyzed by Tungstophosphoric Acid in Ionic Liquid

Synthesis of tetrahydrofuran and tetrahydropyran derivatives catalyzed by tungstophosphoric acid （H3PW12040） were conveniently performed with high yield from the corresponding unsaturated alcohols in ionic liquid. Sufuric acid （H2SO4）, trifluoromathanesulfonic acid （TfOH） and p-toluenesulfonic acid （TsOH） were also explored for preparing these products in ionic liquid. The catalysts and ionic liquid can be easily recovered and reused.

Synthesis and biological evaluation of novel N-(alkoxyphenyl)-aminocarbonylbenzoic acid derivatives as PTP1B inhibitors

Based on the fact that petroselinic acid showed good inhibitory activity（IC50 = 6.99μmol/L） against protein tyrosine phophatase 1B（PTP1B） in vitro,a series of novel N-（alkoxyphenyl）-aminocarbonylbenzoic acid derivatives were designed and synthesized.The results indicated that most of the derivatives showed more potent activities against PTP1B.Especially,compound 13 had obvious activity with an IC50 of 106 nmol/L in vitro.

Synthesis of phenol-class azo derivatives of 4-aminosalicylic acid

To explore the better prodrug of 4-aminosalicylic acid（4-ASA）with higher activity and less side effects against the inflammatory bowel disease.4-ASA,after a succession of synthesis process,was conjugated with various carder molecules to get seven azo derivatives of 4-ASA.All compounds were characterized by FT-IR,^1H NMR,^13C NMR spectras in detail.New derivatives of 4-ASA were definituded.

γ-Aminobutyric acid transporter (GAT1) overexpression in mouse affects the testicular morphology

γ-Aminobutyric acid and GABAergic receptors were previously reported to be distributed in reproductive systems besides CNS and predicted to participate in the modulation of testicular function. γ-Aminobutyric acid transporter was implicated to be involved in this process. However, the potential role of γ-aminobutyric transporter in testis has not been explored. In this study, we investigated the existence of mouse γ-aminobutyric acid transporter subtype I (mGAT1) in testis. Wild-type and transgenic mice, which overexpressing mGAT1 in a variety of tissues, especially in testis, were primarily studied to approach the profile of mGAT1 in testis. Mice with overexpressed mGAT1 develop normally but with reduced mass and size of testis as compared with wild-type. Testicular morphology of transgenic mice exhibited overt abnormalities including focal damage of the spermatogenic epithelium accompanied by capillaries proliferation and increased diameter of seminiferous tubules lumen. Reduced number of spermatids was also found in some seminiferous tubules. Our results clearly demonstrate the presence of GAT1 in mouse testis and imply that GAT1 is possibly involved in testicular function.

Anthranilic acid derivatives from Inula japonica

Three new anthranilic acid derivatives, N-heneicosanoylanthranilic acid （1b）, N-tricosanoylanthranilic acid （1d）, N-tetracosanoylanthranilic acid （1e）, and two known N-arachidylanthranilic acid （1a） and N-docosanoylanthranilic acid （1c） were isolated from the aerial parts of lnula japonica Thunb. Their structures were established by spectroscopic and chemical methods.

A green method for the synthesis of bis-indolylmethanes and 3,3'-indolyloxindole derivatives using cellulose sulfuric acid under solvent-free conditions

A highly efficient green protocol for the preparation of bis-indolylmethanes,bis-2-methylindolylmethanes,bis-1-methylindolylmethanes and 3,3 -diindolyloxindole derivatives from the reaction of indoles with various aldehydes and ketones in the presence of cellulose sulfuric acid under solvent-free conditions is reported.The significant features of this procedure are high yields of the products,mild reaction,solvent-free condition and non-toxicity of the catalyst.

Synthesis of azo derivatives of 4-aminosalicylic acid

For searching a better 4-aminosalicylic acid derivative with higher activity and less side effects against the inflammatory bowel disease, 4-aminosalicylic acid (4-ASA) was protected by benzyloxycarbonyl and acetyl, respectively. The resultant was hydrogenized to remove protective group of amino group, then the product was reacted with NaNO2 to give diazonium salt, which was conjugated with salicylic acid, hydroxybenzene, N-salicyloyl glycine acid to get azo derivatives of 4-ASA. The azo derivatives were hydrolyzed under the alkaline condition to get the target products. All compounds were characterized by FT-IR, (1)H NMR, (13)C NMR spectra in details. New derivatives of 4-ASA were characterized. The synthetic route was reasonable and feasible.