Histamine-bound magnesium porphyrins: diverse coordination modes, inhibitory role in photodegradation of chlorophyll a and antioxidant activity.

The neurotransmitter histamine exists in two isomeric forms and could be an interesting ligand due to three nitrogen atoms with the possibility of binding to metals in different ways besides its crucial role in biological systems. However, no metal-histamine interaction is known in the literature. Therefore, two histamine-bound magnesium porphyrins [MgT(4-Cl)PP(hist)2] 1 and [MgT(4-Br)PP(hist)] 2 have been synthesized and structurally characterized. Interestingly, 1 is a hexa-coordinated magnesium porphyrin due to the axial coordination of two histamine molecules via the nitrogen of the aliphatic amino group with the Mg-Nhistamine distance of 2.300 Å, while 2 is penta-coordinated due to the axial coordination of one histamine molecule through the imidazole nitrogen atom with the Mg-Nhistamine distance of 2.145 Å. The diverse coordination modes of this unique ligand are explored for the first time. Theoretical studies at the level of DFT supported the binding of histamine via imidazole nitrogen atoms for complex 2. Histamine-bound magnesium porphyrins are found to be stable against the photodegradation of magnesium porphyrin in the presence of light and oxygen. Freshly isolated chlorophyll a from spinach showed similar resistivity against photodegradation. Moreover, the histamine-bound complexes showed higher antioxidant activity for 1 (92.45%) compared to the free base porphyrin (73.11%) and MgT(4-Cl)PP (75.89%).

Imidazole and Derivatives Drugs Synthesis: A Review.

Imidazoles have long held a special place in heterocyclic chemistry, and their derivatives have piqued interest in recent years due to their diverse chemistry and pharmacology features. Imidazole is a biologically and pharmaceutically important nitrogen-containing heterocyclic ring. As a result, researchers have been interested in imidazole molecules. For a century and a half, purine, histamine, and other natural compounds all contained the imidazole ring. A number of imidazole drugs have been prepared and marketed for the treatment of various diseases. In view of this, we herein report a detailed account of synthetic procedures for various imidazole drugs.

Recent advances in the application of microbial diamine oxidases and other histamine-oxidizing enzymes.

The consumption of foods fraught with histamine can lead to various allergy-like symptoms if the histamine is not sufficiently degraded in the human body. The degradation occurs primarily in the small intestine, naturally catalyzed by the human diamine oxidase (DAO). An inherent or acquired deficiency in human DAO function causes the accumulation of histamine and subsequent intrusion of histamine into the bloodstream. The histamine exerts its effects acting on different histamine receptors all over the body but also directly in the intestinal lumen. The inability to degrade sufficient amounts of dietary histamine is known as the 'histamine intolerance'. It would be preferable to solve this problem initially by the production of histamine-free or -reduced foods and by the oral supplementation of exogenous DAO supporting the human DAO in the small intestine. For the latter, DAOs from mammalian, herbal and microbial sources may be applicable. Microbial DAOs seem to be the most promising choice due to their possibility of an efficient biotechnological production in suitable microbial hosts. However, their biochemical properties, such as activity and stability under process conditions and substrate selectivity, play important roles for their successful application. This review deals with the advances and challenges of DAOs and other histamine-oxidizing enzymes for their potential application as processing aids for the production of histamine-reduced foods or as orally administered adjuvants to humans who have been eating food fraught with histamine.

Why Monoamine Oxidase B Preferably Metabolizes N-Methylhistamine over Histamine: Evidence from the Multiscale Simulation of the Rate-Limiting Step.

Histamine levels in the human brain are controlled by rather peculiar metabolic pathways. In the first step, histamine is enzymatically methylated at its imidazole Nτ atom, and the produced N-methylhistamine undergoes an oxidative deamination catalyzed by monoamine oxidase B (MAO-B), as is common with other monoaminergic neurotransmitters and neuromodulators of the central nervous system. The fact that histamine requires such a conversion prior to oxidative deamination is intriguing since MAO-B is known to be relatively promiscuous towards monoaminergic substrates; its in-vitro oxidation of N-methylhistamine is about 10 times faster than that for histamine, yet this rather subtle difference appears to be governing the decomposition pathway. This work clarifies the MAO-B selectivity toward histamine and N-methylhistamine by multiscale simulations of the rate-limiting hydride abstraction step for both compounds in the gas phase, in aqueous solution, and in the enzyme, using the established empirical valence bond methodology, assisted by gas-phase density functional theory (DFT) calculations. The computed barriers are in very good agreement with experimental kinetic data, especially for relative trends among systems, thereby reproducing the observed MAO-B selectivity. Simulations clearly demonstrate that solvation effects govern the reactivity, both in aqueous solution as well as in the enzyme although with an opposing effect on the free energy barrier. In the aqueous solution, the transition-state structure involving histamine is better solvated than its methylated analog, leading to a lower barrier for histamine oxidation. In the enzyme, the higher hydrophobicity of N-methylhistamine results in a decreased number of water molecules at the active side, leading to decreased dielectric shielding of the preorganized catalytic electrostatic environment provided by the enzyme. This renders the catalytic environment more efficient for N-methylhistamine, giving rise to a lower barrier relative to histamine. In addition, the transition state involving N-methylhistamine appears to be stabilized by the surrounding nonpolar residues to a larger extent than with unsubstituted histamine, contributing to a lower barrier with the former.

New Histamine-Related Five-Membered N-Heterocycle Derivatives as Carbonic Anhydrase I Activators.

A series of histamine (HST)-related compounds were synthesized and tested for their activating properties on five physiologically relevant human Carbonic Anhydrase (hCA) isoforms (I, II, Va, VII and XIII). The imidazole ring of HST was replaced with different 5-membered heterocycles and the length of the aliphatic chain was varied. For the most interesting compounds some modifications on the terminal amino group were also performed. The most sensitive isoform to activation was hCA I (KA values in the low micromolar range), but surprisingly none of the new compounds displayed activity on hCA II. Some derivatives (1, 3a and 22) displayed an interesting selectivity for activating hCA I over hCA II, Va, VII and XIII.

Repurposing old drugs as novel inhibitors of human MIF from structural and functional analysis.

Human macrophage migration inhibitory factor (MIF) is an important pro-inflammatory cytokine that plays multiple pleiotropic functions. It is considered as a promising therapeutic target for the infectious, autoimmune, and cardiovascular diseases and cancers. The development of MIF inhibitors has not been translated into clinical success despite decades of research. Given the time and cost of developing new drugs, existing drugs with clarified safety and pharmacokinetics are explored for their potential as novel MIF inhibitors. This study identified five known drugs that could inhibit MIF's tautomerase activity and MIF-mediated cell chemotaxis in RAW264.7 cells. It was found that compounds D2 (histamine), D5 (metaraminol), and D8 (nebivolol) exhibited micromolar-range inhibition potency close to the positive control ISO-1. Kinetics and the mechanism for inhibition were subsequently determined. Moreover, the detailed inhibitor-binding patterns were investigated by X-ray crystallography, computational molecular docking, and structure-based analysis. Therefore, this study elucidates the molecular mechanism of repurposed drugs acting on MIF and provides a structural foundation for lead optimization to promote the clinical development of MIF-targeted drugs.

Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations.

G protein-coupled receptors (GPCRs) are targets of extracellular stimuli and hence occupy a key position in drug discovery. By specific and not yet fully elucidated coupling profiles with α subunits of distinct G protein families, they regulate cellular responses. The histamine H2 and H4 receptors (H2R and H4R) are prominent members of Gs- and Gi-coupled GPCRs. Nevertheless, promiscuous G protein and selective Gi signaling have been reported for the H2R and H4R, respectively, the molecular mechanism of which remained unclear. Using a combination of cellular experimental assays and Gaussian accelerated molecular dynamics (GaMD) simulations, we investigated the coupling profiles of the H2R and H4R to engineered mini-G proteins (mG). We obtained coupling profiles of the mGs, mGsi, or mGsq proteins to the H2R and H4R from the mini-G protein recruitment assays using HEK293T cells. Compared to H2R-mGs expressing cells, histamine responses were weaker (pEC50, Emax) for H2R-mGsi and -mGsq. By contrast, the H4R selectively bound to mGsi. Similarly, in all-atom GaMD simulations, we observed a preferential binding of H2R to mGs and H4R to mGsi revealed by the structural flexibility and free energy landscapes of the complexes. Although the mG α5 helices were consistently located within the HR binding cavity, alternative binding orientations were detected in the complexes. Due to the specific residue interactions, all mG α5 helices of the H2R complexes adopted the Gs-like orientation toward the receptor transmembrane (TM) 6 domain, whereas in H4R complexes, only mGsi was in the Gi-like orientation toward TM2, which was in agreement with Gs- and Gi-coupled GPCRs structures resolved by X-ray/cryo-EM. These cellular and molecular insights support (patho)physiological profiles of the histamine receptors, especially the hitherto little studied H2R function in the brain, as well as of the pharmacological potential of H4R selective drugs.

Interaction pattern of histidine, carnosine and histamine with methylglyoxal and other carbonyl compounds.

The ability of histidine to scavenge sugar-derived 1,2-dicarbonyl compounds was investigated using aqueous methanolic model systems containing histidine or histamine in the presence of glucose, methylglyoxal, or glyoxal. The samples were prepared either at room temperature (RT) or at 150 °C and analyzed using ESI-qTOF-MS/MS and isotope labeling technique. Replacing glucose with [U-13C6]glucose allowed the identification of glucose carbon atoms incorporated in the products. Various sugar-generated carbonyl compounds ranging in size from C1 to C6 were captured by histidine or histamine. The majority of the fragments incorporated were either C3 or C2 units originating from glyoxal (C2) or methylglyoxal (C3). The ESI-qTOF-MS/MS analysis indicated that histamine could react with either of the two carbonyl carbons of methylglyoxal utilizing the α-amino group and/or the imidazolium moiety. Furthermore, when histidine was added to 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) generating model system, it completely suppressed the formation of PhIP due to scavenging of phenylacetaldehyde.

Cryo-EM structure of the human histamine H1 receptor/Gq complex.

Histamine receptors play important roles in various pathophysiological conditions and are effective targets for anti-allergy treatment, however the mechanism of receptor activation remain elusive. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human H1R in complex with a Gq protein in an active conformation via a NanoBiT tethering strategy. The structure reveals that histamine activates receptor via interacting with the key residues of both transmembrane domain 3 (TM3) and TM6 to squash the binding pocket on the extracellular side and to open the cavity on the intracellular side for Gq engagement in a model of "squash to activate and expand to deactivate". The structure also reveals features for Gq coupling, including the interaction between intracellular loop 2 (ICL2) and the αN-ß junction of Gq/11 protein. The detailed analysis of our structure will provide a framework for understanding G-protein coupling selectivity and clues for designing novel antihistamines.

Selective post-column derivatization coupled to cation exchange chromatography for the determination of histamine and its precursor histidine in fish and Oriental sauce samples.

Histamine is a biogenic amine that is formed from histidine by action of the enzyme histidine decarboxylase and can be toxic at high intakes. Thus, the quantification of these analytes in foods constitutes a significant axis of food safety. In this study we present the development, validation and application of a new method for the determination of histamine and its precursor histidine in fish products and oriental sauces. The analytes were separated rapidly through a cation exchange column using an acidic mobile phase (7 mmol L-1 nitric acid) and reacted downstream with o-phthalaldehyde in post-column mode in the absence of nucleophilic reagents. The derivatives were detected spectrofluorimetrically at λex/λem. = 360/440 nm. Following investigation of the chromatographic and post-column conditions, the method was validated as for its intended applications. The limits of detection were 0.16 and 0.17 µmol L-1 for histidine and histamine respectively (ca. 0.1 mg kg-1) and the precision was better than 5%. Various food samples were successfully analyzed without matrix interferences following minimal pretreatment. The percent recoveries ranged between 91.3 and 117.9%.

Lactic acid bacterial exopolysaccharides strongly bind histamine and can potentially be used to remove histamine contamination in food.

The symptoms of foodborne histamine poisoning are similar to those of IgE-mediated food allergies. In this study, we investigated the histamine-binding capacity of lactic acid bacteria (LAB) strains as potential preventive agents against histamine poisoning. Histamine biosorption capacity was determined for 16 LAB strains. Leuconostoc mesenteroides TOKAI 51 m, Lactobacillus paracasei TOKAI 65 m, Lactobacillus plantarum TOKAI 111 m and Pediococcus pentosaceus TOKAI 759 m showed especially high biosorption rates and reached saturation within 30 min. Adsorption isotherms showed better conformance to the Freundlich model than to the Langmuir model. Analyses after heat, periodic acid and guanidine hydrochloride treatments suggested that histamine was bound to the bacterial cell surface. HPLC analysis revealed that exopolysaccharides produced by Lact. paracasei TOKAI 65 m strongly bound to histamine. In the detachment test with 1 mol l-1 HCl solution, the dissociation rate of histamine for Lact. paracasei TOKAI 65 m was <10 %. This strain is presumably a suitable candidate for use against histamine poisoning.

The Effect of Deuteration on the H2 Receptor Histamine Binding Profile: A Computational Insight into Modified Hydrogen Bonding Interactions.

We used a range of computational techniques to reveal an increased histamine affinity for its H2 receptor upon deuteration, which was interpreted through altered hydrogen bonding interactions within the receptor and the aqueous environment preceding the binding. Molecular docking identified the area between third and fifth transmembrane α-helices as the likely binding pocket for several histamine poses, with the most favorable binding energy of -7.4 kcal mol-1 closely matching the experimental value of -5.9 kcal mol-1. The subsequent molecular dynamics simulation and MM-GBSA analysis recognized Asp98 as the most dominant residue, accounting for 40% of the total binding energy, established through a persistent hydrogen bonding with the histamine -NH3+ group, the latter further held in place through the N-H∙∙∙O hydrogen bonding with Tyr250. Unlike earlier literature proposals, the important role of Thr190 is not evident in hydrogen bonds through its -OH group, but rather in the C-H∙∙∙π contacts with the imidazole ring, while its former moiety is constantly engaged in the hydrogen bonding with Asp186. Lastly, quantum-chemical calculations within the receptor cluster model and utilizing the empirical quantization of the ionizable X-H bonds (X = N, O, S), supported the deuteration-induced affinity increase, with the calculated difference in the binding free energy of -0.85 kcal mol-1, being in excellent agreement with an experimental value of -0.75 kcal mol-1, thus confirming the relevance of hydrogen bonding for the H2 receptor activation.

Removal of biogenic amines from wines by chemisorption on functionalized silica and effects on other wine components.

The effectiveness of several functionalized silica materials (cation-exchange materials) for the removal of biogenic amines from wines, and the effects on other wine components and organoleptic characteristics were evaluated. Results have shown that mesoporous silica material bi-functionalized with phosphonic and sulfonic acids allowed the removal of histamine, putrescine, cadaverine, spermine and spermidine from wines, although the dose must be adapted for each wine according to the removal requirements and wine characteristics. A plus of the adsorbent developed is that it can be recovered and re-used for at least 3 treatments. Immediately following the treatments, a decrease in the levels of linear ethyl esters (ethyl hexanoate, ethyl octanoate and ethyl decanoate) was observed, although these levels were re-equilibrated after several days reducing this undesired side effect. A slight, but perceptible, effect on wine color was observed, probably due to the slight decrease in the pH of the wine produced by the treatments. On the basis of the sensory analysis that focused only on the aroma of the wines, the proposed technique would be more adequate for wines aged in barrels than for young wines.

Extract of Boehmeria nivea Suppresses Mast Cell-Mediated Allergic Inflammation by Inhibiting Mitogen-Activated Protein Kinase and Nuclear Factor-κB.

Mast cells are effector cells that initiate allergic inflammatory immune responses by inducing inflammatory mediators. Boehmeria nivea (Linn.) Gaudich is a natural herb in the nettle family Urticaceae that possesses numerous pharmacological properties. Despite the various pharmacological benefits of Boehmeria nivea, its effects on allergic inflammation have not yet been determined. Here, we investigated the effect of the ethanol extract of Boehmeria nivea (BNE) on degranulation rat basophilic leukemia (RBL)-2H3 mast cells stimulated with anti-dinitrophenyl (anti-DNP) and bovine serum albumin (BSA) during immunoglobulin E (IgE)-mediated allergic immune response. The results showed inhibition of the release of ß-hexosaminidase and histamine from the cells. BNE suppressed pro-inflammatory cytokines (Tumor necrosis factor (TNF)-α, Interleukin (IL)-1ß, and IL-6) and reduced T helper (Th)2 cytokine IL-4 expression and/or secretion correlated with the downregulation of p38, extracellular signal-regulated kinases (ERK) mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) signaling pathways in treated RBL-2H3 mast cells. In passive cutaneous anaphylaxis, treatment with BNE during IgE-mediated local allergic reaction triggered a reduction in mouse ear pigmentation and thickness. Taken together, these results indicated that BNE suppressed mast cell-mediated inflammation, suggesting that BNE might be a candidate for the treatment of various allergic disorders.

Conformational Restriction of Histamine with a Rigid Bicyclo[3.1.0]hexane Scaffold Provided Selective H3 Receptor Ligands.

We designed and synthesized conformationally rigid histamine analogues with a bicyclo[3.1.0]hexane scaffold. All the compounds were selectively bound to the H3 receptor subtype over the H4 receptor subtype. Notably, compound 7 showed potent binding affinity and over 100-fold selectivity for the H3 receptors (Ki = 5.6 nM for H3 and 602 nM for H4). These results suggest that the conformationally rigid bicyclo[3.1.0]hexane structure can be a useful scaffold for developing potent ligands selective for the target biomolecules.

Discovery of Potent Charge-Reducing Molecules for Native Ion Mobility Mass Spectrometry Studies.

There is growing interest in the characterization of protein complexes and their interactions with ligands using native ion mobility mass spectrometry. A particular challenge, especially for membrane proteins, is preserving noncovalent interactions and maintaining native-like structures. Different approaches have been developed to minimize activation of protein complexes by manipulating charge on protein complexes in solution and the gas-phase. Here, we report the utility of polyamines that have exceptionally high charge-reducing potencies with some molecules requiring 5-fold less than trimethylamine oxide to elicit the same effect. The charge-reducing molecules do not adduct to membrane protein complexes and are also compatible with ion-mobility mass spectrometry, paving the way for improved methods of charge reduction.

Structural Similarity Image Analysis for Detection of Adenosine and Dopamine in Fast-Scan Cyclic Voltammetry Color Plots.

Fast-scan cyclic voltammetry (FSCV) is widely used for in vivo detection of neurotransmitters, but identifying analytes, particularly mixtures, is difficult. Data analysis has focused on identifying dopamine from cyclic voltammograms, but it would be better to analyze all the data in the three-dimensional FSCV color plot. Here, the goal was to use image analysis-based analysis of FSCV color plots for the first time, specifically the structural similarity index (SSIM), to identify rapid neurochemical events. Initially, we focused on identifying spontaneous adenosine events, as adenosine cyclic voltammograms have a primary oxidation at 1.3 V and a secondary oxidation peak that grows in over time. Using SSIM, sample FSCV color plots were compared with reference color plots, and the SSIM cutoff score was optimized to distinguish adenosine. High-pass digital filtering was also applied to remove the background drift and lower the noise, which produced a better LOD. The SSIM algorithm detected more adenosine events than a previous algorithm based on current versus time traces, with 99.5 ± 0.6% precision, 95 ± 3% recall, and 97 ± 2% F1 score (n = 15 experiments from three researchers). For selectivity, it successfully rejected signals from pH changes, histamine, and H2O2. To prove it is a broad strategy useful beyond adenosine, SSIM analysis was optimized for dopamine detection and is able to detect simultaneous events with dopamine and adenosine. Thus, SSIM is a general strategy for FSCV data analysis that uses three-dimensional data to detect multiple analytes in an efficient, automated analysis.

Gold nanoparticle aptamer assay for the determination of histamine in foodstuffs.

The development of a gold nanoparticle aptamer assay is persued for rapid and sensitive determination of histamine in foodstuffs, which could be deployed for on-site use. The assay is based on a histamine-specific aptamer and gold nanoparticles and the salt-induced aggregation of the particles in the presence of histamine indicated by the color change from red to blue. Gold nanoparticle size, salt type, and concentration as well as aptamer concentration were optimized, and using optimum conditions, a limit of detection of 8 nM (~ 0.05 mg/kg) was obtained. Finally, the aptamer AuNP assay was applied to the determination of histamine in quality control fish samples. The histamine levels of these samples had previously been determined using HPLC and commercial ELISA kits by numerous independent laboratories and a good correlation was obtained. The developed AuNP assay is rapid, sensitive, and reproducible. Graphical abstract.

Dinuclear Copper(II) Complexes with Schiff Bases Derived from 2-Hydroxy-5-Methylisophthalaldehyde and Histamine or 2-(2-Aminoethyl)pyridine and Their Application as Magnetic and Fluorescent Materials in Thin Film Deposition.

Two Cu(II) complexes, 1 and 2, with tridentate Schiff bases derived from 2-hydroxy-5-methylisophthalaldehyde and histamine HL1 or 2-(2-aminoethyl)pyridine HL2, respectively, were obtained and characterized by X-ray crystallography, spectroscopic (UV-vis, fluorescence, IR, and EPR), magnetic, and thermal methods. Despite the fact that the chelate formed by the NNO ligand donors (C26-C25H2-C24H2-N23=C23H-C22-C19Ph(O1)-C2(Ph)-C3H=N3-C4H2-C5H2-C6 fragment) are identical, as well as the synthesis of Cu(II) complexes (Cu:L = 2:1 molar ratio) was performed in the same manner, the structures of the complexes differ significantly. The complex 1, {[Cu2(L1)Cl2]2[CuCl4]}·2MeCN·2H2O, consists of [Cu2(L1)Cl2]+ units in which Cu(II) ions are bridged by the HL1 ligand oxygen and each of these Cu(II) ions is connected with Cu(II) ions of the next dimeric unit via two bridging Cl- ions to form a chain structure. In the dinuclear [Cu2(L2)Cl3]0.5MeCN complex 2, each Cu(II) is asymmetrically bridged by the ligand oxygen and chloride anions, whereas the remaining chloride anions are apically bound to Cu(II) cations. In contrast to the complex 1, the square-pyramidal geometry of the both Cu(II) centers is strongly distorted. The magnetic study revealed that antiferromagnetic interactions in the complex 2 are much stronger than in the complex 1, which was corresponded with magneto-structural examination. Thin layers of the studied Cu(II) complexes were deposited on Si(111) by the spin coating method and studied by scanning electron microscopy (SEM/EDS), atomic force microscopy (AFM), and fluorescence spectroscopy. The Cu(II) complexes and their thin layers exhibited fluorescence between 489-509 nm and 460-464 nm for the compounds and the layers, respectively. Additionally, DFT calculations were performed to explain the structures and electronic spectral properties of the ligands.