• Biomolecules & Therapeutics
• /
• v.28 no.3
• /
• pp.267-271
• /
• 2020

Gut microbiota produce dietary metabolites such as short-chain fatty acids, which exhibit anti-inflammatory effects. Free fatty acid receptor 2 (FFA2, formerly known as GPR43) is a specific receptor for short-chain fatty acids, such as acetate that regulates inflammatory responses. However, the therapeutic potential of FFA2 agonists for treatment of atopic dermatitis has not been investigated. We investigated the efficacy of the FFA2 agonist, 4-chloro-α-(1-methylethyl)-N-2-thiazoylylbenzeneacetanilide (4-CMTB), for treatment of atopic dermatitis induced by 2,4-dinitrochlorobenzene (DNCB). Long-term application of DNCB to the ears of mice resulted in significantly increased IgE in the serum, and induced atopic dermatitis-like skin lesions, characterized by mast cell accumulation and skin tissue hypertrophy. Treatment with 4-CMTB (10 mg/kg, i.p.) significantly suppressed DNCB-induced changes in IgE levels, ear skin hypertrophy, and mast cell accumulation. Treatment with 4-CMTB reduced DNCB-induced increases in Th2 cytokine (IL-4 and IL-13) levels in the ears, but did not alter Th1 or Th17 cytokine (IFN-γ and IL-17) levels. Furthermore, 4-CMTB blocked DNCB-induced lymph node enlargement. In conclusion, activation of FFA2 ameliorated DNCB-induced atopic dermatitis, which suggested that FFA2 is a therapeutic target for atopic dermatitis.

• Biomolecules & Therapeutics
• /
• v.25 no.1
• /
• pp.80-90
• /
• 2017

Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, $S1P_{1-5}$. The molecular identification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors. Another unexpected finding that fingolimod (FTY720) modulates S1P receptors accelerated drug discovery in this field. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials. In addition, more selective S1P receptor modulators with better pharmacokinetic profiles and fewer side effects are under development. Some of them are being clinically tested in the contexts of multiple sclerosis and other autoimmune and inflammatory disorders, such as, psoriasis, Crohn's disease, ulcerative colitis, polymyositis, dermatomyositis, liver failure, renal failure, acute stroke, and transplant rejection. In this review, the authors discuss the state of the art regarding the status of drug discovery efforts targeting S1P receptors and place emphasis on potential clinical applications.

• Journal of Ginseng Research
• /
• v.17 no.2
• /
• pp.109-113
• /
• 1993

The effects of ginseng total saponins (GTS) on the action of U-50,488H, a $textsc{k}$-opioid receptor agonist, on the electrically induced twitch responses of mouse vats deferens were studied. U-50,488H ($10^9$~$10^{-5}$M) inhibited the twitch contractions in a dose-dependent manner, which were caused by adenosine 5'-triphosphate (ATP) released from the stimulated sympathetic nerve, and this effect was antagonized by naloxone ($10^6$ M). GTS, which itself induced the inhibition of the twitch contractions, acted additively to U-50,488H, GTS and U-50,488H had no effect on the tension of the unstimulated organs. The contractions elicited by ATP were not affected by U-50,488H, but inhibited by GTS. These results suggest that U-50,488H suppressed the twitch contractions by the inhibition of neurotransmitter release from presynaptic nerve terminals via action on opioid receptor, but G75, by inhibiting the action of the neurotransmitter on the smooth muscle.

• Archives of Pharmacal Research
• /
• v.12 no.4
• /
• pp.282-288
• /
• 1989

This study was investigated the effects of imipramine (IMI) and electroconvulsive shock (ECS), which are used as antidepressant therapy, on the central $\beta_1$or $\beta_2$ adrenergic receptor in anesthetized rats. The resting blood pressure and heart rate decreased in reserpinized group (5 mg/kg i. p., 24 hr before), but not in order 4 groups i. e. acute IMI (20 mg/kg i. p.. 3-5 hr before), chronic IMI (Same dose, twice a day for 14 days), siggle ECS (sinusoidal 20 Hz, 120 V for 2 sec) and repeated ECS (same condition, daily for 12 days). The increase of heart rate and hypotension evoked by 1 or 3 $\mu$g intracerebroventricular (i. c. v.) administration of (+) dobutamine, $\beta_2$-agonist, 1 or 3 $\mu$g i. c. v. was significantly attenuated in repeated ECS or reserpine treatment. And, the diminuation of pulse pressure of salbutamol also reduced by repeated ECS. These results suggest that IMI or ECS result in attenuation on tachycardia by (+) dobutamine or on hypotension by salbutamol, presumably by which the central $\beta_1$ or $\beta_2$receptor sensitivity may be suppressed, repectively.

• Biomedical Science Letters
• /
• v.23 no.3
• /
• pp.194-200
• /
• 2017

Bone-resorbing osteoclasts play a major role in maintaining bone homeostasis with bone-forming osteoblasts. Although it has been reported that A2B adenosine receptor (A2BAR) regulates osteoclast differentiation, its effects on apoptosis or proliferation of osteoclasts have been less-defined. Here, we demonstrate that A2BAR stimulation regulates macrophage-colony stimulating factor (M-CSF)-mediated osteoclast proliferation. Stimulation with a specific agonist of A2BAR, BAY 60-6583, significantly reduced M-CSF-mediated osteoclast proliferation in a time- and dose-dependent manner. In addition, A2BAR stimulation induced both apoptosis of the cells and cell arrest in the G1 phase with a decrease of cell number in the G2/M phase. Stimulation with BAY 60-6583 inhibited the activation of Akt by M-CSF, whereas M-CSF-induced ERK1/2 activation was not affected. These results suggest that the inhibition of M-CSF-mediated Akt activation by A2BAR stimulation increases apoptotic response of osteoclasts and induces cell cycle arrest in the G1 phase, thus contributing to the down-regulation of osteoclast proliferation.

• Biomolecules & Therapeutics
• /
• v.14 no.3
• /
• pp.125-131
• /
• 2006

The inhibitory effects of (-)-epigallocatechin gallate (EGCG), a major compound of green tea, on the development of locomotor sensitization, conditioned place preference (CPP) and dopamine receptor supersensitivity induced by the repeated administration of morphine were investigated in mice. A single administration of morphine produces hyperlocomotion. The repeated administration of morphine develops sensitization, a progressive enhancement of locomotion, which is used as a model for studying the craving and drug-seeking behaviors characterizing addiction, and CPP, which is used as a model for studying drug reinforcement, respectively. EGCG inhibited morphine-induced hyperlocomotion, sensitization and CPP. In addition, EGCG inhibited the development of postsynaptic dopamine receptors supersensitivity, which may be an underlying common mechanism that mediates the morphine-induced dopaminergic behaviors such as sensitization and CPP. Apomorphine (a dopamine agonist)-induced climbing behaviors also were inhibited by a single direct administration of EGCG These results provide evidence that EGCG has anti-dopaminergic activity, as inhibiting the development of dopamine receptor supersensitivity and apomorphine-induced climbing behaviors. Therefore, it is suggested that green tea may be useful for the prevention and therapy of these adverse actions of morphine.

• Korean Journal of Pharmacognosy
• /
• v.51 no.3
• /
• pp.186-191
• /
• 2020

In this study, we evaluated the anti-nociceptive activities of Sorbus alnifolia. To investigate the anti-nociceptive properties of the methanolic extract of Sorbus alnifolia (MSA), we conducted several tests using various experimental mouse pain models. Herein, MSA significantly delayed the latency time and writhing motion in the hotplate test and acetic acid test, respectively. These result indicated that MSA has an ability to manage both peripheral and central nociception. We could further confirm the analgesic effects of MSA by performing formalin test. In combination test using naloxone, a non-selective opioid receptor antagonist, analgesic activity of MSA was partly antagonized by naloxone, but not completely, indicating that the MSA acts as a partial opioid receptor agonist. Out results suggest that the S. alnifolia may be possibly used as valuable anti-nociceptive agent.

• Archives of Pharmacal Research
• /
• v.28 no.2
• /
• pp.238-242
• /
• 2005

Many reports demonstrate that extremely low frequency magnetic fields (ELF MFs, 60 Hz) may be involved in hyperalgesia. In a previous investigation, we suggested that MFs may produce hyperalgesia and such a response may be regulated by the benzodiazepine system. In order to further confirm this effect of MFs, we used diazepam and/or flumazenil with MFs exposure. When testing the pain threshold of rats using hot plate tests, MFs or diazepam ($0.5\;{\mu}g$, i.c.v.; a benzodiazepine receptor agonist) induced hyperalgesic effects with the reduction of latency. These effects were blocked by a pretreatment of flumazenil (1.5 mg/kg, i.p.; a benzodiazepine receptor antagonist). When the rats were exposed simultaneously to MFs and diazepam, the latency tended to decrease without statistical significance. The induction of hyperalgesia by co-exposure to MFs and diazepam was also blocked by flumazenil. However, the pretreatment of GABA receptor antagonists such as bicuculline ($0.1\;{\mu}g$, i.c.v.; a $GABA_A$ antagonist) or phaclofen ($10\;{\mu}g$, i.c.v.; a $GABA_B$ antagonist) did not antagonize the hyperalgesic effect of MFs. These results suggest that the benzodiazepine system may be involved in MFs-induced hyperalgesia.

• Journal of Veterinary Science
• /
• v.22 no.4
• /
• pp.53.1-53.13
• /
• 2021

Background: Canine adipose-derived stem cells (cADSCs) exhibit various differentiation properties and are isolated from the canine subcutaneous fat. Although cADSCs are valuable as tools for research on adipogenic differentiation, studies focusing on adipogenic differentiation methods and the underlying mechanisms are still lacking. Objectives: In this study, we aimed to establish an optimal method for adipogenic differentiation conditions of cADSCs and evaluate the role of peroxisome proliferator-activated receptor gamma (PPARγ) and estrogen receptor (ER) signaling in the adipogenic differentiation. Methods: To induce adipogenic differentiation of cADSCs, 3 different adipogenic medium conditions, MDI, DRI, and MDRI, using 3-isobutyl-1-methylxanthine (M), dexamethasone (D), insulin (I), and rosiglitazone (R) were tested. Results: MDRI, addition of PPARγ agonist rosiglitazone to MDI, was the most significantly facilitated cADSC into adipocyte. GW9662, an antagonist of PPARγ, significantly reduced adipogenic differentiation induced by rosiglitazone. Adipogenic differentiation was also stimulated when 17β-estradiol was added to MDI and DRI, and this stimulation was inhibited by the ER antagonist ICI182,780. Conclusions: Taken together, our results suggest that PPARγ and ER signaling are related to the adipogenic differentiation of cADSCs. This study could provide basic information for future research on obesity or anti-obesity mechanisms in dogs.

• Biomolecules & Therapeutics
• /
• v.29 no.1
• /
• pp.64-72
• /
• 2021

Renal cell carcinoma (RCC) is likely to metastasize to other organs, and is often resistant to conventional chemotherapies. Thymoquinone (TQ), a phytochemical derived from the seeds of Nigella sativa, has been shown to inhibit migration and metastasis in various cancers. In this study, we assessed the effect of TQ on the migratory activity of human RCC Caki-1 cells. We found that treatment with TQ reduced the proteolytic activity of matrix metalloproteinase-9 (MMP-9) in Caki-1 cells. TQ significantly repressed prostaglandin E2 (PGE2) production, its EP2 receptor expression as well as the activation of Akt and p38, the wellknown upstream signal proteins of MMP-9. In addition, treatment with butaprost, a PGE2 agonist, also induced MMP-9 activity and migration/invasion in Caki-1 cells. Moreover, pharmacological inhibitors of PI3K/Akt and p38 remarkably attenuated butaprost-induced Caki-1 cell migration and invasion, implying that activation of PI3K/Akt and p38 is a bridge between the PGE2-EP2 axis and MMP-9-dependent migration and invasion. Taken together, these data suggest that TQ is a promising anti-metastatic drug to treat advanced and metastatic RCC.