Apigenin in cancer therapy: anti-cancer effects and mechanisms of action. Cell Biosci. Actions of quercetin, a polyphenol, on blood pressure. Efficacy of morin as a potential therapeutic phytocomponent: insights into the mechanism of action. Lotito SB, Frei B. Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon?
Free Radic Biol Med. A week subchronic toxicity study of dietary administered morin in F rats. Food Chem Toxicol. Morin: a promising natural drug. Curr Med Chem. Morin, a flavonoid, on lipid peroxidation and antioxidant status in experimental myocardial ischemic rats.
Zingerone 4- 4-hydroxymethylphenyl butanone ameliorates renal function via controlling oxidative burst and inflammation in experimental diabetic nephropathy.
Arch Physiol Biochem. Therapeutic potential of morin against liver fibrosis in rats: modulation of oxidative stress, cytokine production and nuclear factor kappa B. Environ Toxicol Pharmacol. Fructose-rich diet leads to reduced aerobic capacity and to liver injury in rats. Lipids Health Dis. Flavonoid, morin inhibits oxidative stress, inflammation and enhances neurotrophic support in the brain of streptozotocin-induced diabetic rats.
Neurol Sci. Naderali EK, Williams G. Prolonged endothelial-dependent and -independent arterial dysfunction induced in the rat by short-term feeding with a high-fat, high-sucrose diet. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.
Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction.
Anal Biochem. Spectrophotometric determination of serum nitrite and nitrate by copper-cadmium alloy. Improved method for the determination of blood glutathione. J Lab Clin Med. Potential role of sugar fructose in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease.
Morin attenuates ovalbumin-induced airway inflammation by modulating oxidative stress-responsive MAPK signaling. Oxid Med Cell Longev. Alleviating effects of morin against experimentally-induced diabetic osteopenia. Diabetol Metab Syndr. Carrier A. Metabolic syndrome and oxidative stress: a complex relationship. Antioxid Redox Signal. Pathophysiology of the metabolic syndrome.
Clin Dermatol. Morin hydrate is a plant-derived and antioxidant-based hepatoprotector. Life Sci. Singlet oxygen reactions with flavonoids. A theoretical-experimental study. PLoS One. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. Downregulation of autophagy by herpesvirus Bcl-2 homologs. Effects of low-level light therapy on hepatic antioxidant defense in acute and chronic diabetic rats.
J Biochem Mol Toxicol. CuZn-SOD deficiency causes ApoB degradation and induces hepatic lipid accumulation by impaired lipoprotein secretion in mice. J Biol Chem. Effects of morin on blood pressure and metabolic changes in fructose-induced hypertensive rats. Biol Pharm Bull.
The insulin-mimetic effect of Morin: a promising molecule in diabetes treatment. Biochim Biophys Acta. Ghaffari MA, Mojab S. Influence of flavonols as in vitro on low density lipoprotein glycation. Iran Biomed J. Morin attenuates hepatic insulin resistance in high-fat-diet-induced obese mice. J Physiol Biochem. Clin Exp Pharmacol Physiol. Khitan Z, Kim DH. Fructose: a key factor in the development of metabolic syndrome and hypertension.
J Nutr Metab. Eur J Clin Invest. Morin attenuates blood pressure and oxidative stress in deoxycorticosterone acetate-salt hypertensive rats: a biochemical and histopathological evaluation.
The flavonoid morin restores blood pressure and lipid metabolism in DOCA-salt hypertensive rats. The impact of morin, a natural flavonoid, on cyclophosphamide-induced changes in the oxidative stress parameters in rat livers. Adv Clin Exp Med. Modulation of glucose transporter protein by dietary flavonoids in type 2 diabetes mellitus.
Int J Biol Sci. One category required. Select another before deselecting this one. See fewer ads everywhere on Yahoo, including your inbox Discover Yahoo Plus. Check the checkbox to filter stream by Politics category Politics Check the checkbox to filter stream by US News category US News Check the checkbox to filter stream by Celebrity category Celebrity Check the checkbox to filter stream by Lifestyle category Lifestyle Check the checkbox to filter stream by Sports category Sports Check the checkbox to filter stream by Business category Business Check the checkbox to filter stream by Entertainment category Entertainment Check the checkbox to filter stream by World News category World News Check the checkbox to filter stream by Health category Health Check the checkbox to filter stream by Style category Style Check the checkbox to filter stream by Science category Science Check the checkbox to filter stream by Technology category Technology Check the checkbox to filter stream by category Ads.
Atlanta Black Star. Thanks for your feedback! Good Housekeeping. Business Insider. The highest levels of H3R are found in the cerebral cortex, hippocampal formation, basal ganglia, and hypothalamus [12] , [13].
The H3R was first identified as a presynaptic autoreceptor that negatively regulated the synthesis and release of histamine from histaminergic neurons [9]. However, the H3R has also been shown to act as a presynaptic heteroreceptor on non-histaminergic neurons, inhibiting the release of other neurotransmitters such as acetylcholine, dopamine, norepinephrine, serotonin, and various neuropeptides in both the central and peripheral nervous system [15] , [16] , [17].
Therefore, the H3 receptor has long been recognized as a promising target for the treatment of various central and peripheral nervous system diseases. However, increasing evidence suggests H3R agonists could serve as potential therapeutics for obesity, diabetes mellitus, and liver cholestasis [22] , [23] , [24]. BP 2—94, one of the earliest explored agonists of H3R, displayed anti-inflammatory and anti-nociceptive properties in mice and was recognized as a promising drug for the treatment of asthma, migraines, related inflammatory diseases, and pain [25] , [26].
Therefore, it is reasonable to believe that H3R agonists could hold therapeutic value for the treatment of human diseases. Another major result of this study is that ZEL-H16 could induce intense internalization and delay recycling of internalized H3R to the cell surface compared with histamine.
Our results clearly demonstrate that ZEL-H16 is a potent, selective and non-imidazole agonist of H3R that could serve as a useful pharmacological tool for future studies or as a possible therapeutic agent.
We used CRE-driven reporter assay as primary assay to screen more than antagonist compounds in 6 serials of structures, and found several compounds with the activity in inhibition of forskolin-induced luciferase activity.
We then employed hH3R-GFP redistribution assay as a secondary assay to confirm the antagonistic activity. One of the compounds identified, ZEL-H16, whose chemical structure and synthetic routes are shown in Figure 1 , triggered a significant increase in receptor internalization as compared to the control compound histamine, behaving as an agonist on H3R internalization. Moreover, the inhibition of forskolin-induced luciferase activity by Histamine could be reduced by co-incubation with ZEL-H16 Fig.
We also performed the experiments to determine the CRE-driven luciferase activity in the response to ZEL-H16 and histamine in the presence of three different concentrations of antagonist thioperamide Fig.
The data suggested that it is likely for both ZEL-H16 and histamine to bind to the same binding site of H3 receptor. Reaction of indolepropionic acid with piperidine provided 2, which was alkylated with 1-bromochloropropane in the presence of NaH in anhydrous DMF to get 3.
A, Concentration inhibition curve of luciferase activity induced by ZEL-H16 with forskolin stimulation. D and E. As shown in Fig. ZEL-H16 showed no agonist or antagonist activities to these receptors in the experiments Table 1. Moreover, the receptor internalization induced by ZEL-H16 was more intense than the internalization induced by histamine and imetit Fig. This result was confirmed by experiments that quantified the levels of receptors on the surface of the cells following stimulation by compounds.
ELISA data are expressed as the percentage of receptors detected on the surface of agonist-untreated cells expressing H3R. Error bars represent the SEM for four replicates. Furthermore, we used the endosome marker Alexa Fluor labeled transferrin to assess whether internalized H3Rs induced by histamine or ZEL-H16 are generally recycled back to the plasma membrane via early and recycling endosomes.
Confocal microscopy analysis revealed that the internalized H3R receptors induced by histamine or ZEL-H16 were both colocalized with transferrin in endosomes Fig.
The recycling experiments showed that the internalized H3R receptors were recycled to the cell surface within 1 h after histamine removal, but within 3 h after ZEL-H16 removal Fig. The internalized receptors were recycled to the plasma membrane within 1 h after histamine removal and 3 h after ZEL-H16 removal. All pictures shown are representative of at least three independent experiments.
The signal at each point is expressed as the percentage of the maximal p-ERK signal induced by histamine. Concentration -dependent phosphorylation signals were quantified by densitometric analysis and p-ERK levels were normalized to total ERK levels. This EC 50 value was similar to the EC 50 induced by histamine, 1. The mouse H3 receptor protein is Neonatal mouse cortical neuron cultures were treated with ZEL-H16 after seven days of primary culture and analyzed by specific anti-phospho-ERK immunoblots.
In Guinea-pig ileum bioassay, ZEL-H16 produced concentration—dependent inhibition of the electrically induced twitch of the guinea-pig ileum just like Histamine Fig. Both ZEL-H16 and Histamine inhibit the contractions of the guinea pig ileum with a comparable efficacy The histamine H3 receptor, which is predominantly expressed in the CNS, has been known to modulate the release of various neurotransmitters including histamine, dopamine [27] , [28] , acetylcholine [29] , [30] , norepinephrine [31] , serotonin [32] , [33] , GABA [34] , glutamate [35] , and substance P [36].
Therefore, H3R has been identified as a potential therapeutic target for many nervous system diseases. Classical agonists of the histamine H3 receptor, e. The discovery of the histamne H4 receptor evoked strong interest of many pharmaceutical companies to develop H4R selective ligands for the regulation of immune functions with possible uses in allergy and asthma [41].
Consequently, many imidazole-based histamine H3 receptor agonists also possess a high affinity at the H4 receptor. As one of the most potent and selective H3 agonist, immepip also shows reasonable potency for the histamine H4 receptor with pKi values of 7.
In the current study, we have identified a new non-imidazole based H3 agonist, ZEL-H16, which exhibited approximately fold higher affinity for human H3R as compared to histamine.
In addition, ZEL-H16 also exhibited a characteristic feature of induction of intense H3 receptor internalization and delayed recycling to the cell surface as compared to that of control with treatment of histamine. Thus, ZEL-H16 is identified as a potent and highly selective histamine H3 receptor agonist, which will be useful as a tool in H3R research.
However, in Guinea-pig ileum bioassay, ZEL-H16 exhibited concentration—dependent inhibition of the electrically induced twitch of the guinea-pig ileum as a full agonist just like histamine. Previous studies have demonstrated that depending on the test model, iodoproxyfan and FUB have been described as antagonists, partial or even full agonists [44] , [45]. GT and proxyfan acted as full agonists in cAMP assays, but they displayed weak partial agonism in modulating neurotransmitter release examination [46].
Betahistine has been found to act as a nanomolar inverse agonist and a micromolar agonist at histamine H3 receptors on in vitro inhibition of cAMP formation and [ 3 H]arachidonic acid release, but to behave as a partial inverse agonist on in vivo measuring tele-methylhistamine levels in the brains of mice [47].
These differences in pharmacological action in different assays might be caused by a varying receptor reserve or species variants of the histamine H3-receptor protein as well as by different experimental conditions within the assays [48]. It is well established that rapid internalization of the agonist-activated receptor into the intracellular membrane compartments of target cell plays an important role in the regulation of GPCR signaling and desensitization [49].
To visualize the internalization and trafficking of human histamine H3 receptors, we constructed a vector to express a chimeric protein by fusing enhanced green fluorescent protein EGFP to the C terminal end of the H3 receptor H3R-GFP. Moreover, our observation using immunofluorescence indicated that the internalized H3 receptors induced by both ZEL-H16 and histamine were co-localized with early endosome containing the transferrin receptors.
However, these recycled CCR5 receptors are rapidly reinternalized [51]. The mechanism of slower recycling of internalized H3 receptors in the presence of ZEL-H16 remains for further elucidation. In conclusion, a new non-imidazole compound, ZEL-H16, was identified as a novel and selective agonist of histamine H3 receptor. It is interesting to note that exposure of cells to ZEL-H16 resulted in intensive H3 receptor internalization and delayed recycling to the cell surface as compared to control compound histamine.
As a novel agonist, ZEL-H16 and its derivatives might serve as useful pharmacological tool for future investigations regarding the molecular and pharmacological aspects of H3R or as a possible therapeutic agent for the treatment of human diseases.
The protocol was approved by the research ethics committee of Zhejiang University approval ID: Zju Forskolin, PTX, histamine, imetit, thioperamide, dopamine, serotonin and epinephrine were obtained from Sigma-Aldrich St. Louis, MO. Louis, MO , respectively. Primers were designed according to the published human histamine receptor gene sequences GenBank accession no.
Nanjing, Jiangsu. The cell pellet was homogenized with a Polytron PT set at rpm and centrifuged at 1, g for 5 min. The male rats g— g were killed by decapitation, and the cerebral cortex was rapidly removed in ice-cold 50 mM Tris-HCl pH 7. Protein concentration was determined using Bio-Rad protein assays.
0コメント