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Role of nicotinic and estrogen signaling during experimental acute and chronic bladder inflammation.The American Journal of Pathology Jan 2008Inflammation is a physiological process that characterizes many bladder diseases. We hypothesized that nicotinic and estrogen signaling could down-regulate bladder...
Inflammation is a physiological process that characterizes many bladder diseases. We hypothesized that nicotinic and estrogen signaling could down-regulate bladder inflammation. Cyclophosphamide was used to induce acute and chronic bladder inflammation. Changes in bladder inflammation were measured histologically and by inflammatory gene expression. Antagonizing nicotinic signaling with mecamylamine further aggravated acute and chronic inflammatory changes resulting from cyclophosphamide treatment. Estrogen and nicotinic signaling independently attenuated acute bladder inflammation by decreasing neutrophil recruitment and down-regulating elevated lipocalin-2 and cathepsin D expression. However, the combined signaling by the estrogen and nicotinic pathways, as measured by macrophage infiltration and up-regulation of interleukin-6 expression in the bladder, synergistically reduced chronic bladder inflammation. The elevated expression of p65 nuclear localization in bladders treated with cyclophosphamide or cyclophosphamide with mecamylamine suggested nuclear factor-kappa B activation in the chronic inflammatory process. The complementary treatment of 17 beta-estradiol and the nicotinic agonist anabasine resulted in the translocation of p65 to the cytoplasm, again greater than either alone. Activation of nuclear factor-kappaB can result in macrophage activation and/or elevation in epithelial proliferation. These data suggest that 17 beta-estradiol and anabasine reduce chronic bladder inflammation through reduction of nuclear translocation of p65 to suppress cytokine expression.
Topics: Animals; Antineoplastic Agents, Alkylating; Cell Nucleus; Cyclophosphamide; Cystitis; Estradiol; Female; Gene Expression Regulation; Inflammation; Mecamylamine; Mice; Mice, Inbred C57BL; Receptors, Nicotinic; Signal Transduction; Urinary Bladder
PubMed: 18079438
DOI: 10.2353/ajpath.2008.070529 -
Clinical and Experimental Rheumatology 2021At present, the pathogenesis of Sjögren's syndrome (SS) remains unclear. This research aimed to identify differential metabolites that contribute to SS diagnosis and...
OBJECTIVES
At present, the pathogenesis of Sjögren's syndrome (SS) remains unclear. This research aimed to identify differential metabolites that contribute to SS diagnosis and discover the disturbed metabolic pathways.
METHODS
Recent advances in mass spectrometry have allowed the identification of hundreds of unique metabolic signatures and the exploration of altered metabolite profiles in disease. In this study, 505 candidates including healthy controls (HCs) and SS patients were recruited and the serum samples were collected. A non-targeted gas chromatography-mass spectrometry (GC-MS) serum metabolomics method was used to explore the changes in serum metabolites.
RESULTS
We found SS patients and HCs can be distinguished by 21 significant metabolites. The levels of alanine, tryptophan, glycolic acid, pelargonic acid, cis-1-2-dihydro-1-2-naphthalenediol, diglycerol, capric acid, turanose, behenic acid, dehydroabietic acid, stearic acid, linoleic acid, heptadecanoic acid, valine, and lactic acid were increased in serum samples from SS patients, whereas levels of catechol, anabasine, 3-6-anhydro-D-galactose, beta-gentiobiose, 2-ketoisocaproic acid and ethanolamine were decreased. The significantly changed pathways included the following: Linoleic acid metabolism; unsaturated fatty acid biosynthesis; aminoacyl-tRNA biosynthesis; valine, leucine, and isoleucine biosynthesis; glycerolipid metabolism; selenocompound metabolism; galactose metabolism; alanine, aspartate and glutamate metabolism; glyoxylate and dicarboxylate metabolism; glycerophospholipid metabolism; and valine, leucine and isoleucine degradation.
CONCLUSIONS
These findings enhance the informative capacity of biochemical analyses through the identification of serum biomarkers and the analysis of metabolic pathways and contribute to an improved understanding of the pathogenesis of SS.
Topics: Biomarkers; Humans; Metabolomics; Sjogren's Syndrome
PubMed: 34251320
DOI: 10.55563/clinexprheumatol/ylte6v -
Frontiers in Microbiology 2021Orange-tufted sunbirds () feed on the nectar of the tobacco tree () which contains toxic pyridine alkaloids characterized by high concentrations of anabasine and much...
Orange-tufted sunbirds () feed on the nectar of the tobacco tree () which contains toxic pyridine alkaloids characterized by high concentrations of anabasine and much lower concentrations of nicotine. We aimed at determining whether the gut microbiota of sunbirds harbors bacterial species that enable the birds to cope with these toxic alkaloids. An experiment that included 12 birds showed that inducing dysbiosis in sunbirds' guts by the addition of sulfamethoxazole and trimethoprim, significantly reduced the birds' ability to degrade anabasine ( = 3) compared to control birds ( = 3) with undisturbed microbiota. Sunbirds whose gut bacterial communities were altered by the antibacterial agents and who were fed with added nicotine, also showed a lower percentage of nicotine degradation ( = 3) in their excreta compared to the sunbirds with undisturbed microbiota ( = 3), though this difference was not significant. In an experiment, we studied the ability of , , , , and that were isolated from sunbirds' excreta, to degrade anabasine and nicotine. By using gas chromatography-mass spectrometry (GC-MS) analysis, we successfully demonstrated, for the first time, the ability of these species to degrade the focal secondary metabolites. Our findings demonstrate the role of gut bacteria in detoxifying toxic secondary metabolites found in the nectar. The degradation products may supply the birds with nitrogen which is scarce in nectar-rich diets. These findings support another role of bacteria in mediating the interactions between plants and their pollinators.
PubMed: 33815326
DOI: 10.3389/fmicb.2021.639808 -
Nature Chemistry Feb 2018Cyclic amines are ubiquitous core structures of bioactive natural products and pharmaceutical drugs. Although the site-selective abstraction of C-H bonds is an...
Cyclic amines are ubiquitous core structures of bioactive natural products and pharmaceutical drugs. Although the site-selective abstraction of C-H bonds is an attractive strategy for preparing valuable functionalized amines from their readily available parent heterocycles, this approach has largely been limited to substrates that require protection of the amine nitrogen atom. In addition, most methods rely on transition metals and are incompatible with the presence of amine N-H bonds. Here we introduce a protecting-group-free approach for the α-functionalization of cyclic secondary amines. An operationally simple one-pot procedure generates products via a process that involves intermolecular hydride transfer to generate an imine intermediate that is subsequently captured by a nucleophile, such as an alkyl or aryl lithium compound. Reactions are regioselective and stereospecific and enable the rapid preparation of bioactive amines, as exemplified by the facile synthesis of anabasine and (-)-solenopsin A.
Topics: Alkaloids; Amines; Anabasine; Chemistry Techniques, Synthetic; Molecular Structure; Stereoisomerism
PubMed: 29359746
DOI: 10.1038/nchem.2871 -
PloS One 2014Tobacco use is a major contributor to premature morbidity and mortality. The measurement of nicotine and its metabolites in urine is a valuable tool for evaluating...
Tobacco use is a major contributor to premature morbidity and mortality. The measurement of nicotine and its metabolites in urine is a valuable tool for evaluating nicotine exposure and for nicotine metabolic profiling--i.e., metabolite ratios. In addition, the minor tobacco alkaloids--anabasine and anatabine--can be useful for monitoring compliance in smoking cessation programs that use nicotine replacement therapy. Because of an increasing demand for the measurement of urinary nicotine metabolites, we developed a rapid, low-cost method that uses isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) for simultaneously quantifying nicotine, six nicotine metabolites, and two minor tobacco alkaloids in smokers' urine. This method enzymatically hydrolyzes conjugated nicotine (primarily glucuronides) and its metabolites. We then use acetone pretreatment to precipitate matrix components (endogenous proteins, salts, phospholipids, and exogenous enzyme) that may interfere with LC-MS/MS analysis. Subsequently, analytes (nicotine, cotinine, hydroxycotinine, norcotinine, nornicotine, cotinine N-oxide, nicotine 1'-N-oxide, anatabine, and anabasine) are chromatographically resolved within a cycle time of 13.5 minutes. The optimized assay produces linear responses across the analyte concentrations typically found in urine collected from daily smokers. Because matrix ion suppression may influence accuracy, we include a discussion of conventions employed in this procedure to minimize matrix interferences. Simplicity, low cost, low maintenance combined with high mean metabolite recovery (76-99%), specificity, accuracy (0-10% bias) and reproducibility (2-9% C.V.) make this method ideal for large high through-put studies.
Topics: Alkaloids; Anabasine; Chromatography, Liquid; Cotinine; Humans; Nicotine; Pyridines; Smoking; Tandem Mass Spectrometry
PubMed: 25013964
DOI: 10.1371/journal.pone.0101816 -
The Journal of Clinical Investigation Jun 1986Epidemiologic studies suggest that women who smoke have lower endogenous estrogen than nonsmokers. To explore the possible link between cigarette smoking and decreased...
Epidemiologic studies suggest that women who smoke have lower endogenous estrogen than nonsmokers. To explore the possible link between cigarette smoking and decreased endogenous estrogens, we have examined the effects of constituents of tobacco on estrogen production in human choriocarcinoma cells and term placental microsomes. In choriocarcinoma cell cultures, nicotine, cotinine (a major metabolite of nicotine), and anabasine (a minor component of cigarette tobacco) all inhibited androstenedione conversion to estrogen in a dose-dependent fashion. Removal of nicotine, cotinine, and anabasine from the culture medium resulted in the complete reversal of the inhibition of aromatase. In the choriocarcinoma cell cultures, a supraphysiologic concentration of androstenedione (73 microM) in the culture medium blocked the inhibition of aromatase caused by nicotine, cotinine, and anabasine. In preparations of term placental microsomes, nicotine, cotinine, and anabasine inhibited the conversion of testosterone to estrogen. Kinetic analysis demonstrated the inhibition to be competitive with respect to the substrate. These findings suggest that some nicotinic alkaloids directly inhibit aromatase. This mechanism may explain, in part, the decreased estrogen observed in women who smoke.
Topics: Anabasine; Androstenedione; Aromatase Inhibitors; Carbachol; Cells, Cultured; Choriocarcinoma; Cotinine; Decamethonium Compounds; Dose-Response Relationship, Drug; Estradiol; Female; Hexamethonium Compounds; Humans; In Vitro Techniques; Kinetics; Microsomes; Nicotine; Piperidines; Placenta; Pregnancy; Pyrrolidinones; Smoking; Succinylcholine; Trophoblasts; Uterine Neoplasms
PubMed: 3711333
DOI: 10.1172/JCI112494 -
Journal of Heterocyclic Chemistry Nov 2009A straightforward and practical approach was established for the synthesis of nicotine and anabasine analogues by the cyclization of mesylated 1-(3-pyridinyl)-1,4, and...
A straightforward and practical approach was established for the synthesis of nicotine and anabasine analogues by the cyclization of mesylated 1-(3-pyridinyl)-1,4, and 1,5-diol derivatives to form the pyrrolidino or piperidino fragments. Nicotine analogue (S)-15 was prepared with good enantioselectivity using the developed azacyclization procedure of nonracemic (R)-1-pyridin-3-yl-butane-1,4-diol, which was obtained by the borane-mediated reduction of ketone 12 in the presence of the spiroborate ester derived from diphenyl prolinol and ethylene glycol.
PubMed: 20161612
DOI: 10.1002/jhet.233 -
Frontiers in Chemistry 2020Anabasine (ANA), a major piperidine alkaloid originally isolated from wild tobacco trees (), has been known to induce serious developmental toxicities such as skeletal...
Anabasine (ANA), a major piperidine alkaloid originally isolated from wild tobacco trees (), has been known to induce serious developmental toxicities such as skeletal deformities in livestock and humans. In this study, we thoroughly investigated the supramolecular nano-encapsulations of ANA by an artificial nanocontainer, cucurbit[7] uril (CB[7]), and examined the influences of the nano-encapsulation on ANA's inherent developmental toxicities on a zebrafish model. We have shown that CB[7] formed 1:1 host-guest inclusion complexes with ANA via a relatively high binding strength [ of (7.45 ± 0.31) × 10 M] in an aqueous solution, via UV-vis and H nuclear magnetic resonance spectroscopic titrations, as well as isothermal titration calorimetry titration. As a consequence, CB[7] significantly attenuated the developmental toxicity of ANA on zebrafish . In contrast, for a comparative purpose, β-CD didn't exert any influence on the toxicity of ANA due to its weak binding with ANA, which was not even measurable via either spectroscopic methods or ITC titration. This is the first head-to-head comparison of this pair of nanocontainers, CB[7] and β-CD, on their potential roles in influencing the toxicity of guest molecules and the results suggested that CB[7] could become a more promising functional excipient for reducing the inherent toxicities of active pharmaceutical ingredients, particularly alkaloids that may form relatively strong host-guest binding species with the host.
PubMed: 32185162
DOI: 10.3389/fchem.2020.00134 -
Heliyon May 2019N'-Nitrosonornicotine (NNN), a carcinogenic tobacco-specific N'-nitrosamine (TSNA), is on the FDA list of harmful and potentially harmful constituents (HPHCs)....
N'-Nitrosonornicotine (NNN), a carcinogenic tobacco-specific N'-nitrosamine (TSNA), is on the FDA list of harmful and potentially harmful constituents (HPHCs). Nornicotine, a product of the demethylation of nicotine, is the immediate alkaloid precursor for NNN formation. Nicotine, nornicotine and NNN are optically active. The accumulation of the isomers of nicotine, nornicotine, and NNN impacts their biological activity. In this paper, we report the determination of tobacco alkaloid enantiomers (including nicotine, nornicotine, anabasine, and anatabine) in samples of different tobacco lines using a reversed phase ultra-performance liquid chromatography-tandem mass spectrometer (UPLC/MS/MS) method. Current method demonstates excellent detection capability for all alkaloid enantiomers, with correlation coefficients (r) > 0.996 within their linear dynamic ranges. The limit of detection (LOD) and limit of quantitation (LOQ) of all analytes are less than 10 ng/mL and 30 ng/mL, respectively. In addition, their recovery and coefficient of variation (CV%) are within 100-115% and 0.2-3.7%, respectively. The method validated in this paper is simple, fast, and sensitive for the quantification of alkaloid enantiomers in tobacco leaf and has been applied to investigations of tobacco alkaloid enantiomer ratios in different tobacco lines and tobacco products.
PubMed: 31193304
DOI: 10.1016/j.heliyon.2019.e01719 -
Proceedings. Biological Sciences Mar 2015The synthesis of secondary metabolites is a hallmark of plant defence against herbivores. These compounds may be detrimental to consumers, but can also protect...
The synthesis of secondary metabolites is a hallmark of plant defence against herbivores. These compounds may be detrimental to consumers, but can also protect herbivores against parasites. Floral nectar commonly contains secondary metabolites, but little is known about the impacts of nectar chemistry on pollinators, including bees. We hypothesized that nectar secondary metabolites could reduce bee parasite infection. We inoculated individual bumblebees with Crithidia bombi, an intestinal parasite, and tested effects of eight naturally occurring nectar chemicals on parasite population growth. Secondary metabolites strongly reduced parasite load, with significant effects of alkaloids, terpenoids and iridoid glycosides ranging from 61 to 81%. Using microcolonies, we also investigated costs and benefits of consuming anabasine, the compound with the strongest effect on parasites, in infected and uninfected bees. Anabasine increased time to egg laying, and Crithidia reduced bee survival. However, anabasine consumption did not mitigate the negative effects of Crithidia, and Crithidia infection did not alter anabasine consumption. Our novel results highlight that although secondary metabolites may not rescue survival in infected bees, they may play a vital role in mediating Crithidia transmission within and between colonies by reducing Crithidia infection intensities.
Topics: Alkaloids; Anabasine; Animals; Bees; Crithidia; Disease Resistance; Glycosides; Host-Parasite Interactions; Plant Nectar; Secondary Metabolism; Terpenes
PubMed: 25694627
DOI: 10.1098/rspb.2014.2471