• Molecules and Cells
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• v.37 no.8
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• pp.585-591
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• 2014

The ${\beta}_2$ adrenergic receptor (ADRB2) is a G protein-coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder (COPD). Although a number of ADRB2 agonists have been developed for use in asthma therapy, indacaterol is the only ultra-long-acting inhaled ${\beta}_2$-agonist (LABA) approved by the FDA for relieving the symptoms in COPD patients. The precise molecular mechanism underlying the pharmacological effect of indacaterol, however, remains unclear. Here, we show that ${\beta}$-arrestin-2 mediates the internalization of ADRB2 following indacaterol treatment. Moreover, we demonstrate that indacaterol significantly inhibits tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$)-induced NF-${\kappa}B$ activity by reducing levels of both phosphorylated-IKK and -$I{\kappa}B{\alpha}$, thereby decreasing NF-${\kappa}B$ nuclear translocation and the expression of MMP-9, an NF-${\kappa}B$ target gene. Subsequently, we show that indacaterol significantly inhibits TNF-${\alpha}$/NF-${\kappa}B$-induced cell invasiveness and migration in a human cancer cell line. In conclusion, we propose that indacaterol may inhibit NF-${\kappa}B$ activity in a ${\beta}$-arrestin2-dependent manner, preventing further lung damage and improving lung function in COPD patients.

• Biomolecules & Therapeutics
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• v.26 no.2
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• pp.201-209
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• 2018

G protein-coupled receptor 119 (GPR119) is expressed in the pancreas and gastrointestinal tract, and its activation promotes insulin secretion in the beta cells of the pancreatic islets as well as the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells, consequently improving glucose-stimulated insulin secretion. Due to this dual mechanism of action, the development of small-molecule GPR119 agonists has received significant interest for the treatment of type 2 diabetes. We newly synthesized 1,2,4-triazolone derivatives of GPR119 agonists, which demonstrated excellent outcomes in a cyclic adenosine monophosphate (cAMP) assay. Among the synthesized derivatives, YH18968 showed cAMP=2.8 nM; in GLUTag cell, GLP-1secretion=2.3 fold; in the HIT-T15 cell, and insulin secretion=1.9 fold. Single oral administration of YH18968 improved glucose tolerance and combined treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor augmented the glucose lowering effect as well as the plasma level of active GLP-1 in normal mice. Single oral administration of YH18968 improved glucose tolerance in a diet induced obese mice model. This effect was maintained after repeated dosing for 4 weeks. The results indicate that YH18968 combined with a DPP-4 inhibitor may be an effective therapeutic candidate for the treatment of type 2 diabetes.

• Biomolecules & Therapeutics
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• v.31 no.3
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• pp.285-297
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• 2023

Alzheimer's disease (AD) is a neurodegenerative disease with progressive memory loss and the cognitive decline. AD is mainly caused by abnormal accumulation of misfolded amyloid β (Aβ), which leads to neurodegeneration via a number of possible mechanisms such as down-regulation of brain-derived neurotrophic factor-tropomyosin-related kinase B (BDNF-TRKB) signaling pathway. 7,8-Dihydroxyflavone (7,8-DHF), a TRKB agonist, has demonstrated potential to enhance BDNF-TRKB pathway in various neurodegenerative diseases. To expand the capacity of flavones as TRKB agonists, two natural flavones quercetin and apigenin, were evaluated. With tryptophan fluorescence quenching assay, we illustrated the direct interaction between quercetin/apigenin and TRKB extracellular domain. Employing Aβ folding reporter SH-SY5Y cells, we showed that quercetin and apigenin reduced Aβ-aggregation, oxidative stress, caspase-1 and acetylcholinesterase activities, as well as improved the neurite outgrowth. Treatments with quercetin and apigenin increased TRKB Tyr516 and Tyr817 and downstream cAMP-response-element binding protein (CREB) Ser133 to activate transcription of BDNF and BCL2 apoptosis regulator (BCL2), as well as reduced the expression of pro-apoptotic BCL2 associated X protein (BAX). Knockdown of TRKB counteracted the improvement of neurite outgrowth by quercetin and apigenin. Our results demonstrate that quercetin and apigenin are to work likely as a direct agonist on TRKB for their neuroprotective action, strengthening the therapeutic potential of quercetin and apigenin in treating AD.

• Asian-Australasian Journal of Animal Sciences
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• v.13 no.1
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• pp.86-95
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• 2000

Animal feed additives are used worldwide for many different reasons. Some help to cover the needs of essential nutrients and others to increase growth performance, feed intake and therefore optimize feed utilization. They can positively effect technological properties and product quality. The health status of animals with a high growth performance is a predominant argument in the choice of feed additives. In many countries the use of feed additives is more and more questioned by the consumers: substances such as antibiotics and $\beta$-agonists with expected high risks are banned in animal diets. Therefore, the feed industry is highly interested in valuable alternatives which could be accepted by the consumers. Probiotics, prebiotics, enzymes and highly available minerals as well as herbs can be seen as alternatives to metabolic modifiers and antibiotics.

• Tuberculosis and Respiratory Diseases
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• v.79 no.4
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• pp.241-247
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• 2016

Bronchodilators are the cornerstone of symptomatic chronic obstructive pulmonary disease (COPD) treatment. They are routinely recommended for symptom reduction, with a preference of long-acting over short-acting drugs. Bronchodilators are classified into two classes based on distinct modes of action, i.e., long-acting antimuscarinics (LAMA, once-daily and twice-daily), and long-acting ${\beta}2$-agonists (LABA, once-daily and twice-daily). In contrast to asthma management, evidence supports the efficacy of both classes of long-acting bronchodilators as monotherapy in preventing COPD exacerbations, with greater efficacy of LAMA drugs versus LABAs. Several novel LAMA/LABA fixed dose combination inhalers are currently approved for COPD maintenance treatment. These agents show superior symptom control to monotherapies, and some of these combinations have also demonstrated superior efficacy in exacerbation prevention versus monotherapies, or combinations of inhaled corticosteroids plus LABA. This review summarizes the current data on clinical effectiveness of bronchodilators alone or in combination to prevent exacerbations of COPD.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.17
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• pp.7001-7010
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• 2014

Isoflavones are phytoestrogens and natural plant compounds which are similar to 17-${\beta}$-estradiol in chemical structure. It is known that they can act as estrogen agonists or antagonists, depending on endocrine estrogenic levels, but actions of isoflavones are rather complex due to large number of variables such as chemical structures and mechanisms. Some hypotheses on biological mechanisms have not satisfactorily been confirmed to date and human epidemiological and experimental studies have been relatively limited. Nevertheless, isoflavones and isoflavone rich foods have become a focus onf interest due to positive health benefits on many diseases, especially prevention of hormone-related cancers, cardiovascular disease, osteoporosis, and adverse postmenopausal symptoms, and improvement of physiological condition such as maintaining cognitive function. This review provides an overview of chemistry, analytical techniques (focused on human biospecimens), functions including biological mechanisms, and effects of isoflavones, on the basis of the available meta-analysis and review articles and some original articles, on health and cancer.

• Journal of Nutrition and Health
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• v.57 no.2
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• pp.171-184
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• 2024

Purpose: Although activating thermogenic adipocytes is a promising strategy to reduce the risk of obesity and related metabolic disorders, emerging evidence suggests that it is difficult to induce adipocyte thermogenesis in obesity. Therefore, this study aimed to investigate the regulation of adipocyte thermogenesis in diet-induced obesity. Methods: Adipose progenitor cells were isolated from the white and brown adipose tissues of control diet (CD) or high-fat diet (HFD) fed mice, and fully differentiated white and brown adipocytes were treated with β-agonists or 18-carbon fatty acids for β-adrenergic activation or peroxisome proliferator-activated receptor (PPAR) activation. Results: Compared to the CD-fed mice, the expression of uncoupling protein 1 (Ucp1) was lower in the white adipose tissue of the HFD-fed mice; however, this was not observed in the brown adipose tissue. The expression of peroxisome proliferator-activated receptor gamma (Pparg) was lower in the brown adipose progenitor cells isolated from HFD-fed mice than in those isolated from the CD-fed mice. Norepinephrine (NE) treatment exerted lesser effect on peroxisome proliferator-activated receptor-γ coactivator (Pgc1a) upregulation in white adipocytes derived from HFD-fed mice than those derived from CD-fed mice. Regardless which 18-carbon fatty acids were treated, the expression levels of thermogenic genes including Ucp1, Pgc1a, and positive regulatory domain zinc finger region protein 16 (Prdm16) were higher in the white adipocytes derived from HFD-fed mice. Oleic acid (OLA) and γ-linolenic acid (GLA) upregulated Pgc1a expression in white adipocytes derived from HFD-fed mice. Brown adipocytes derived from HFD-fed mice had higher expression levels of Pgc1a and Prdm16 compared to their counterparts. Conclusion: These results indicate that diet-induced obesity may downregulate brown adipogenesis and NE-induced thermogenesis in white adipocytes. Also, HFD feeding may induce thermogenic gene expression in white and brown primary adipocytes, and OLA and GLA could augment the expression levels.

• Journal of Ginseng Research
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• v.40 no.1
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• pp.76-85
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• 2016

Background: Binding of adhesive proteins (i.e., fibrinogen, fibronectin, vitronectin) to platelet integrin glycoprotein IIb/IIIa (${\alpha}IIb/{\beta}3$) by various agonists (thrombin, collagen, adenosine diphosphate) involve in strength of thrombus. This study was carried out to evaluate the antiplatelet effect of total saponin from Korean Red Ginseng (KRG-TS) by investigating whether KRG-TS inhibits thrombin-induced binding of fibrinogen and fibronectin to ${\alpha}IIb/{\beta}3$. Methods: We investigated the effect of KRG-TS on phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and dephosphorylation of phosphatidylinositol 3-kinase (PI3K) and Akt, affecting binding of fibrinogen and fibronectin to ${\alpha}IIb/{\beta}3$, and clot retraction. Results: KRG-TS had an antiplatelet effect by inhibiting the binding of fibrinogen and fibronectin to ${\alpha}IIb/{\beta}3$ via phosphorylation of VASP ($Ser^{157}$), and dephosphorylation of PI3K and Akt on thrombin-induced platelet aggregation. Moreover, A-kinase inhibitor Rp-8-Br-cyclic adenosine monophosphates (cAMPs) reduced KRG-TS-increased VASP ($Ser^{157}$) phosphorylation, and increased KRG-TS-inhibited fibrinogen-, and fibronectin-binding to ${\alpha}IIb/{\beta}3$. These findings indicate that KRG-TS interferes with the binding of fibrinogen and fibronectin to ${\alpha}IIb/{\beta}3$ via cAMP-dependent phosphorylation of VASP ($Ser^{157}$). In addition, KRG-TS decreased the rate of clot retraction, reflecting inhibition of ${\alpha}IIb/{\beta}3$ activation. In this study, we clarified ginsenoside Ro (G-Ro) in KRG-TS inhibited thrombin-induced platelet aggregation via both inhibition of $[Ca^{2+}]_i$ mobilization and increase of cAMP production. Conclusion: These results strongly indicate that KRG-TS is a beneficial herbal substance inhibiting fibrinogen-, and fibronectin-binding to ${\alpha}IIb/{\beta}3$, and clot retraction, and may prevent platelet ${\alpha}IIb/{\beta}3$-mediated thrombotic disease. In addition, we demonstrate that G-Ro is a novel compound with antiplatelet characteristics of KRG-TS.

• The Korean Journal of Pharmacology
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• v.30 no.1
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• pp.1-9
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• 1994

It has been shown that there are several subtypes of ${\kappa}$ opioid receptor. We examined ligand binding profiles and the effects of various opioid agonists on high potassium-stimulated release of $[^3H]$ histamine. We have evaluated the properties of $non-{\mu},\;non-{\delta},$ binding of $[^3H]\;DIP\;([^3H]\;diprenorphine),$ anonselective opioid antagonist, in rat cortex membranes. Binding $to\;{\mu}\;and\;{\delta}$ sites was inhibited by the use of an excess of competing selective agonists (DAMGO, DPDPE) for these sites. (-) Ethylketocyclazocine (EKC), DIP and bremazocine inhibited $[^3H]$ DIP binding. However, arylacetamides (U69593 and U50488H) gave little inhibition Replacement of sodium by NMDG and the addition of guanine nucleotide influenced the inhibitory potency of (-) EKC, an agonist for {\kappa}_1-and-{\kappa}_2-binding site, but not of bremazocine. This result suggests that bremazocine can be an antagonist at this binding site. Also, we have examined the opioid modulation of $K^+(30mM)-induced\;[^3H]\;histamine$ release in rat frontal cortex slices labeled with $1-[^3H]\;histidine$. The $[^3H]\; histamine$ release from cortex slices was inhibited by EKC in a concentration-dependent manner. However, the ${\delta}$ receptor selective agonists, DPDPE and deltorphine II, ${\mu}$ receptor agonists, DAMGO and TAPS, ${\kappa}_1-agonists$, U69593 and U50488H, and ${\varepsilon}-agonist,\;{\beta}-endorphin,$ did not. The concentration-response curve of EKC was shifted to right in the presence of naloxone, nor-binaltorphimine and bremazocine, respectively. These results suggest that ${\kappa}_2$ opioid receptor regulates histamine release in the fromtal cortex of the rat.

• The Korean Journal of Physiology and Pharmacology
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• v.8 no.2
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• pp.69-76
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• 2004

A variety of G protein coupled receptors (GPCRs) are expressed in the presynaptic terminals of central and peripheral synapses and play regulatory roles in transmitter release. The patch-clamp whole-cell recording technique, applied to the calyx of Held presynaptic terminal in brainstem slices of rodents, has made it possible to directly examine intracellular mechanisms underlying the GPCR-mediated presynaptic inhibition. At the calyx of Held, bath-application of agonists for GPCRs such as $GABA_B$ receptors, group III metabotropic glutamate receptors (mGluRs), adenosine $A_1$ receptors, or adrenaline ${\alpha}2$ receptors, attenuate evoked transmitter release via inhibiting voltage-activated $Ca^{2+}$ currents without affecting voltage-activated $K^+$ currents or inwardly rectifying $K^+$ currents. Furthermore, inhibition of voltage-activated $Ca^{2+}$ currents fully explains the magnitude of GPCR-mediated presynaptic inhibition, indicating no essential involvement of exocytotic mechanisms in the downstream of $Ca^{2+}$ influx. Direct loadings of G protein ${\beta}{\gamma}$ subunit $(G{\beta}{\gamma})$ into the calyceal terminal mimic and occlude the inhibitory effect of a GPCR agonist on presynaptic $Ca^{2+}$ currents $(Ip_{Ca})$, suggesting that $G{\beta}{\gamma}$ mediates presynaptic inhibition by GPCRs. Among presynaptic GPCRs glutamate and adenosine autoreceptors play regulatory roles in transmitter release during early postnatal period when the release probability (p) is high, but these functions are lost concomitantly with a decrease in p during postnatal development.