Bile acids and their receptors: Potential therapeutic targets in inflammatory bowel disease

Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel disease.As a result of the interaction between the liver and the gut microbiota,bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food absorption.With the development of genomics and metabolomics,more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their receptors.Bile acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora,epithelial barrier function,and intestinal immunology.Inflammatory bowel disease can be treated in new ways by using these potential molecules.This paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic applications.In addition,we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.

Methods for the Determination of Stable Isotopes of Carbon and Nitrogen Directly in Valine, Proline, Glutamine, and Glutamic Acid

Amino acids are very important compounds for the body and are involved in important functions that keep us healthy. Amino acids are essential components such as valine, proline, glutamine and glutamic acid. They can be synthesized either naturally or artificially. To examine the metabolism and regulate the synthesis process, compounds labeled with nitrogen or carbon isotopes need to be used. These isotopic compounds allow for more extensive research and enable studies that would otherwise be impossible. However, their use is dependent on the availability of simple, efficient methods for isotopic analysis. Currently, the determination of the atomic fraction of carbon and nitrogen isotopes is only possible through their conversion into molecular nitrogen or carbon monoxide or carbon dioxide. This leads to the loss of information about isotopic enrichment in specific centers of the molecule. This article explores a new direct approach to determining the atomic fraction of carbon and nitrogen isotopes in the isotope-modified or identical centers of these compounds. This method eliminates the transfer process and dilution due to nitrogen and carbon impurities. It is now possible to simultaneously determine the atomic fraction of nitrogen and carbon isotopes in the research substance. This method can be applied to amino acids, making it an effective tool for proposing new research methods. Several articles [1] [2] [3] have proposed similar methods for organic compounds and amino acids.

Metabotropic glutamate receptors(mGluRs)in epileptogenesis:an update on abnormal mGluRs signaling and its therapeutic implications

Epilepsy is a neurological disorder characterized by high morbidity,high recurrence,and drug resistance.Enhanced signaling through the excitatory neurotransmitter glutamate is intricately associated with epilepsy.Metabotropic glutamate receptors(mGluRs)are G protein-coupled receptors activated by glutamate and are key regulators of neuronal and synaptic plasticity.Dysregulated mGluR signaling has been associated with various neurological disorders,and numerous studies have shown a close relationship between mGluRs expression/activity and the development of epilepsy.In this review,we first introduce the three groups of mGluRs and their associated signaling pathways.Then,we detail how these receptors influence epilepsy by describing the signaling cascades triggered by their activation and their neuroprotective or detrimental roles in epileptogenesis.In addition,strategies for pharmacological manipulation of these receptors during the treatment of epilepsy in experimental studies is also summarized.We hope that this review will provide a foundation for future studies on the development of mGluR-targeted antiepileptic drugs.

Bile acid receptors and nonalcoholic fatty liver disease

With the high prevalence of obesity, diabetes, and otherfeatures of the metabolic syndrome in United States, nonalcoholic fatty liver disease(NAFLD) has inevitably become a very prevalent chronic liver disease and is now emerging as one of the leading indications for liver transplantation. Insulin resistance and derangement of lipid metabolism, accompanied by activation of the pro-inflammatory response and fibrogenesis, are essential pathways in the development of the more clinically significant form of NAFLD, known as nonalcoholic steatohepatitis(NASH). Recent advances in the functional characterization of bile acid receptors, such as farnesoid X receptor(FXR) and transmembrane G protein-coupled receptor(TGR) 5, have provided further insight in the pathophysiology of NASH and have led to the development of potential therapeutic targets for NAFLD and NASH. Beyond maintaining bile acid metabolism, FXR and TGR5 also regulate lipid metabolism, maintain glucose homeostasis, increase energy expenditure, and ameliorate hepatic inflammation. These intriguing features have been exploited to develop bile acid analogues to target pathways in NAFLD and NASH pathogenesis. This review provides a brief overview of the pathogenesis of NAFLD and NASH, and then delves into the biological functions of bile acid receptors, particularly with respect to NASH pathogenesis, with a description of the associated experimental data, and, finally, we discuss the prospects of bile acid analogues in the treatment of NAFLD and NASH.

Tanshinone IIa antagonizes spinal ischemia/reperfusion injury by interfering with upstream glutamic acid factors

Based on the hypothesis that upstream factor inhibition results in better treatment effects than downstream factor inhibition,the present study interfered with glutamic acid（Glu）-released upstream factors,such as Glu transporter function and Na＋-K＋-adenosine triphosphatases（ATPase）activity relativly.Rats with spinal cord ischemia/reperfusion injury received intraperitoneal injections of tanshinone Ila and Glu uptake and Na＋-K＋-ATPase activity were increased.Results showed that tanshinone Ila influenced Glu-released upstream factors following spinal ischemia/reperfusion injury and protected against spinal ischemia/reperfusion injury.

Granulocyte colony-stimulating factor increases extracellular glutamic acid uptake and suppresses free radicals in an experimental model of amyotrophic lateral sclerosis

Excitatory amino acid toxicity and free radical damage play important roles in amyotrophic lateral sclerosis. Granulocyte colony-stimulating factor （G-CSF） protects nerve cells exposed to high-concentrations of glutamic acid, suggesting positive effects in the treatment of amyotrophic lateral sclerosis. The present study induced in vitro motor neuron injury using glutamic acid excitotoxicity, and the biochemical effects of G-CSF on glutamic acid concentration were determined. In addition, the effects of G-CSF on superoxide dismutase, glutathione peroxidase activity in motor neurons, and malondialdehyde and nitric oxide contents were analyzed. Immunohistochemistry was performed to measure neuronal survival. Results revealed that G-CSF significantly suppressed free radical activity, inhibited excitotoxicity, and reduced apoptosis and loss of motor neurons in the anterior horn of the spinal cord.

Gamma-aminobutyric acid A receptors in Alzheimer＇s disease： highly localized remodeling of a complex and diverse signaling pathway

Alzheimer＇s disease （AD）, the predominant form of dementia, is a chronic, incurable neurodegenerative disorder presenting with symptoms includ- ing progressive memory loss and disturbed emotional state. It has been estimated that dementia affects over 47 million people worldwide （Prince et al., 2015）, and with 60-80% of cases attributable to AD.

In Vitro Biomineralization of Glutaraldehyde Crosslinked Chitosan/Glutamic Acid Films

In vitro biomineralization of glutaraldehyde crosslinked chitosan/glutamic acid films were studied. IR and ESCA （electron spectroscopy for chemical analysis） determinations confirm that chitosan and glutamic acid are successfully crosslinked by glutaraldehyde to form chitosan-glutamic acid surfaces. Composite films were soaked in saturated Ca（OH）2 solution for 8 d and then immersed in simulated body fluid （SBF） for more than 20 d. Morphological characterizations and structure of cal-cium phosphate coatings deposited on the films were studied by SEM, XRD, and EDAX （energy dispersive X-ray analysis）. Initially, the treatment in SBF results in the formation of single-layer cal-cium phosphate particles over the film surface. As immersion time increases, further nucleation and growth produce the simulated calcium-carbonate hydroxyapatite coating. ICP results show Ca/P ratio of calcium phosphate coating is a function of SBF immersion time. The inducing of glutamic acid improves the biomineralization property of chitosan films.

Double Labeling Immulloelectron Microscopic Study on the Synaptic Connections between Glutamic Acid Neurons and GABA Neurons in the Hippocampus of Rats

Summary: In order to explore the roles of different neurotransmitters in epileptic pathogenesis, the synaptic connections between glutamic acid (Gin) neurons and GABA neurons in normal rat hippocampus were studied by pre-embedding double labeling immunoelectron microscopy. The GABA immunoreaction was first demonstrated by chromogen DAB, then the Gin immunoreaction was demonstrated by molybdic acid-TAB method. After being stabilized by DAB-cobalt chloride. the sections were processed for electron microscopic embedding. Under electron microscope, there were many Gin immunoreaction-positive neurons in the pyramidal layer of hippocampal CA1 area and some GABA immunoreaction-positive neurons with pyramidal or polygonal perikarya in the pyramidal, polymorphic and radiant layer of CA1 area. There were also symmetric dendro-axonic synapses formed by GABA-positive dendrites and Glu-positive a-cons in the polymorphic layer and symmetric axo-dendritic synapses formed by GABA-positive axons and Glu-positive dendrites in the radiant layer. In addition, there were symmetric autoregulatory axo-dendritic synapses be- tween Gin-positive axons and dendrites and autoregulatory axo-axonic synapses (both symmetric and asymmetric) between GABA-positive axons. Above mentioned results, for the first time, showed that there were complex synaptic regulatory relationships between excitatory Glu neurons and inhibitory GABA neurons in the hippocampal CA1 area, thereby, providing ultrastructural evidence for different neurotransmitters participating in epileptic pathogenesis.

Determination of Enantiomeric Excess of Glutamic Acids by Lab-made Capillary Array Electrophoresis

Simulated enantiomeric excess of glutamic acid was determined by a lab-made sixteen-channel capillary array electrophoresis with confocal fluorescent rotary scanner. The experimental results indicated that the capillary array electrophoresis method can accurately determine the enanfiomefic excess of glutamic acid and can be used for high-throughput screening system for combinatorial asymmetric catalysis.

Tb(lll) and Ca(ll) Ion Equilibria in the Presence of Glutamic Acid and Glutamine

Tb(111) and Ca(11) ion equilibria in the presence of glutamic acid and glutamine were studied by potentiometric titration at 37'C and an ionic strength of 0. 15mol/L(NaCl) .The stability constants for Tb(111) and Ca(11)complexes in the systems were obtained. The species and their distribution in the systems were discussed.

Preparation and Characterization of Orally Fast-Disintegrating Mini-Tablets Containing Diphenhydramine Hydrochloride and Aspartic or Glutamic Acid as an Umami Amino Acid

The aim of this study was to prepare diphenhydramine hydrochloride (DPH)-loaded orally fast-disintegrating mini-tablets (OFDMTs) containing either L-aspartic acid (Asp) or L-glutamic acid (Glu) as bitterness-suppressant, to characterize the prepared tablets and to evaluate their bitterness under conditions mimicking those of the oral cavity. The preparation of five formulation batches of the OFDMTs involved mixing DPH, with or without two different concentrations of Asp or Glu, and a premix containing a disintegrating agent. When all ingredients were well mixed, the mixture was directly compacted to form small (4 mm diameter) DPH-loaded OFDMTs. There were only small differences between the tablets with respect to mass, diameter, width and hardness. The disintegration times of the five formulation batches of DPH-loaded OFDMTs were measured using the OD-mate, a disintegration test apparatus in which conditions resemble those of the oral cavity. The disintegration times were all within 10 s of exposure to a medium representing the inside of the oral cavity. Rapid release profiles were observed for DPH, Asp and Glu in these dissolution tests. The taste sensor outputs of samples taken at different times (5 - 30 s) from the dissolution test solutions of the four DPH-loaded OFDMTs containing Asp or Glu were significantly inhibited compared with those of control DPH-loaded OFDMT. These results suggest that the inclusion of Asp or Glu in DPH-loaded OFDMTs is sufficient to mask bitterness in the oral cavity for the first 30 s after the tablet is placed in the mouth. It is anticipated that swallowing will have taken place within 30 s.

Effects of Glutamic Acid on C-type Inactivation of Kv1.4ΔN Channel

Objectives Acidosis has an inhibitory effect on the inactivation of Kv1.4 ΔN channel through the position H508. So in order to show the effects of glutamic acid on the mutant Kv 1.4 channel that lacks N-type inactivation （Kv1.4 Δ2-146）, we studied in the expression system of the Xenopus oocytes. Methods The two-electrode voltage-clamp technique （TEV） was used to record the currents. Results Acidosis increased fKv1.4 Δ2-146 C-type inactivation. After application of glutamic acid （1 mmol/L） to Kv1.4 Δ2-146 increased C-type inactivation further, changed inactivation time constants from （2.02 ± 0.39 s ） to （1.71 ± 0.23 s） （P〈 0.05） at ＋50mv, and shifted the steady-state inactivation curves of Kv1.4 ΔN to positive potential, which was from （-44.30 ± 0.59 mV） to （-39.88 ± 0.29 mV）（P〈0.05）. and slowed the rate of recovery from inactivation, which was from （1.64 ± 0.19 s） to （1.91 ± 0.23 s）（P〈 0.05）. Conclusions Together, these results suggest that 1 mmol/L glutamic acid accelerates the C-type inactivation of Kv1.4 ΔN in pH 6.8.

Synthesis,Crystal Structure and Luminescent Properties of a Novel Zinc(II) Complex of N-Acetyl-L-glutamic Acid and Imidazole Ligands

A novel complex [Zn（Im）2（A-glu）]-0.5H2O（Im = imidazole, A-glu = N-acetyi- L-glutamic acid） has been synthesized from the reaction of A-glu with Zn（CH3COO）2·2H20 in the presence of Im at 65 ℃, and structurally characterized by single-crystal X-ray diffraction. The complex crystallizes in tetragonai, space group P43212 with a = b = 8.9078（6）, c = 43.458（6） A, C26H36N10O11Zn2, Mr = 795.39, V= 3448.3（6） A^3, De = 1.532 g/cm^3, Z = 4,μ（MoKα） = 1.461 mm^-1, F（000） = 1640, the final R = 0.0453 and wR = 0.0992. X-ray analysis reveals that the crystal structure is constructed by mixed iigands. A-glu adopts the bis-monodentate coordination mode linking two adjacent metal ions to form a one-dimensional chain. Zinc（Ⅱ） ions are four-coordinated with a distorted tetrahedral geometry. Luminescent properties of the complex have been inves- tigated.

Alterations in Retinoic Acid Receptors in Non-Small Cell Lung Cancer and Their Clinical Implications

The nuclear retinoic acid receptor may play a critical role in the process of lung carcinogenesis. Alteration or loss of nuclear retinoic acid receptors (RARs) has been associated with progression in premalignant and malignant tissues and it is associated with malignant transformation in human cells. Vitamin A derivates, such as retinoic acid, have emerged as adjuvant to therapy in several types of cancer with favorable effects. Retinoic acid regulates the expression of target genes through the binding and activation of RARs, inhibiting growth proliferation. Diverse studies have evaluated different retinoids alone or in combination with chemotherapy in lung cancer, from which results have been controversial with benefits observed only in the subpopulation with high levels of triglycerides. Additionally, several large randomized trials using retinoids to prevent tobacco-related cancer have failed;due to the latter the use of retinoids in clinical trials remains controversial. However they could reduce the risk of cancer development in non-smokers. There is evidence that retinoids have different effects on lung cancer;still the identification of biomarkers could determinate their benefits as preventive or therapy agents. This review describes the RAR alterations during the development of Non-Small Cell Lung Cancer and sets out the importance of several cancer treatments with retinoid compounds.

Evolution of neurotransmitter gamma-aminobutyric acid,glutamate and their receptors

Gamma-aminobutyric acid(GABA)and glutamate are two important amino acid neurotransmitters widely present in the nervous systems of mammals,insects,round worm,and platyhelminths,while their receptors are quite diversified across different animal phyla.However,the evolutionary mechanisms between the two conserved neurotransmitters and their diversified receptors remain elusive,and antagonistic interactions between GABA and glutamate signal transduction systems,in particular,have begun to attract significant attention.In this review,we summarize the extant results on the origin and evolution of GABA and glutamate,as well as their receptors,and analyze possible evolutionary processes and phylogenetic relationships of various GABAs and glutamate receptors.We further discuss the evolutionary history of Excitatory/Neutral Amino Acid Transporter(EAAT),a transport protein,which plays an important role in the GABA-glutamate“yin and yang”balanced regulation.Finally,based on current advances,we propose several potential directions of future research.

Effect of Xingnaojing Injection(醒脑静注射液)on Hippocampal N-methyl-D-aspartic Acid Receptors of Focal Cerebral Ischemia in Rats

Objective: To observe and elucidate the neuroprotective effect of Xingnaojing (XNJ) injection on hippocampal N-methyl-D-aspartic acid (NMDA) receptors of focal cerebral ischemia in rats. Methods: Cerebral ischemia was established by occluding the middle cerebral artery with an intraluminal suture technique in rats. Neurological deficit score, infarct volume and quantity of NMDA receptors were estimated in all groups and compared. Results: After being treated with XNJ, the score decreased in the initial 6 hours and infarct volume decreased in 24 hours. And within 24 hours, the quantity of NMDA receptors obviously decreased compared with the model group (P<0. 01) It indicated that XNJ could ameliorate neurological behavior of middle cerebral artery occlusion rats and down-regulate the expression of hippocampal NMDA receptors. Conclusion: The neuroprotective effect of XNJ on focal cerebral ischemia is possibly related to down-regulating the expression of NMDA receptors in rats.

Metal ion-binding properties of L-glutamic acid and L-aspartic acid, a comparative investigation

A comparative research has been developed for acidity and stability constants of M(Glu)1, M(Asp)2 and M(Ttr)3 complexes, which have been determined by potentiometric pH titration. Depending on metal ion-binding properties, vital differences in building complex were observed. The present study indicates that in M(Ttr) com-plexes, metal ions are arranged to the carboxyl groups, but in M(Glu) and M(Asp), some metal ions are able to build chelate over amine groups. The results mentioned-above demonstrate that for some M(Glu) and M(Asp) complexes, the stability constants are also largely determined by the affinity of metal ions for amine group. This leads to a kind of selectivity of metal ions, and transfers them through building complexes accompanied with glutamate and aspartate. For heavy metal ions, this building complex helps the absorption and filtration of the blood plasma, and consequently, the excursion of heavy metal ions takes place. This is an important method in micro-dialysis. In this study the different as-pects of stabilization of metal ion complexes regarding to Irving-Williams sequence have been investigated.

Effect of ω-3 Polyunsaturated Fatty Acid on Toll-like Receptors in Patients with Severe Multiple Trauma

This study examined the effects of ω-3 polyunsaturated fatty acid（ω-3PUFA） on the expression of toll-like receptor 2（TLR2）,toll-like receptor 4（TLR4） and some related inflammatory factors in peripheral blood mononuclear cells（PBMCs） of patients with early-stage severe multiple trauma.Thirty-two patients who were admitted to the Department of Traumatic Surgery,Tongji Hospital（Wuhan,China） between May 2010 and November 2010,and diagnosed as having severe multiple trauma with a injury severity score（ISS） no less than 16,were enrolled in the study and divided into two groups at random（n=16 in each）：ω-3PUFA group and control group in which routine parenteral nutrition supplemented with ω-3PUFA or not was administered to the patients in two groups for consecutive 7 days.Peripheral blood from these patients was collected within 2 h of admission（day 0）,and 1,3,5 and 7 days after the nutritional support.PBMCs were isolated and used for detection of the mRNA and protein expression of TLR2 and TLR4 by using real-time PCR and flow cytometry respectively,the levels of NF-κB by quantum dots-based immunofluorescence assay,the levels of TNF-α,IL-2,IL-6 and COX-2 by ELISA,respectively.The results showed that the mRNA and protein expression of TLR2 and TLR4 in PBMCs was significantly lower in ω-3PUFA group than in control group 5 and 7 days after nutrition support（both P0.05）.The levels of TNF-α,IL-2,IL-6 and COX-2 were found to be substantially decreased in PBMCs in ω-3PUFA group as compared with control group at 5th and 7th day（P0.05 for all）.It was concluded that ω-3PUFA can remarkably decrease the expression of TLR2,TLR4 and some related inflammatory factors in NF-κB signaling pathway in PBMCs of patients with severe multiple trauma,which suggests that ω-3PUFA may suppress the excessive inflammatory response meditated by the TLRs/NF-κB signaling pathway.