• Journal of the Korean Society of Food Science and Nutrition
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• v.46 no.2
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• pp.267-272
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• 2017

Piceatannol (PIC) is a natural hydroxylated analog of resveratrol (RSV), which is a polyphenol known to extend lifespan by stimulating sirtuins. The aim of this study was to investigate the effects of PIC and RSV on the toll-like receptor 4 (TLR4)-nuclear factor kappa B ($NF-{\kappa}B$) pathway in mouse hepatocytes and an obese/diabetic KK/HlJ mouse model. AML12 mouse hepatocytes in the absence or presence of palmitic acids (PA) were treated with PIC ($50{\mu}M$) or RSV ($50{\mu}M$). Male KK/HlJ mice at 20 weeks of age were divided into three subgroups as follows: 1) obese and diabetic control (KK), 2) KK_PIC, and 3) KK_RSV. PIC and RSV were administered orally at a dose of 10 mg/kg/d for 4 weeks. Four weeks of PIC and RSV treatment did not affect body weight or food intake in KK mice. Serum fasting blood glucose was significantly reduced in KK_PIC, and 2 h oral glucose tolerance test area under the curve was significantly reduced by PIC and RSV treatment in KK mice. PIC tended to improve homeostasis model assessment of the insulin resistance index (HOMA-IR) and HOMA beta-cells in diabetic KK mice. TLR4 and $NF-{\kappa}B$ were down-regulated by PIC and RSV treatments in hepatocytes in the absence or presence of PA. Insulin receptor, AMP-activated protein kinase, peroxisome proliferator-activated receptor gamma, nucleotide oligomerization domain-like receptor family pyrin domain-containing 3, interleukin-1, and $NF-{\kappa}B$ were altered in PIC-treated livers. Collectively, PIC and RSV inhibited the $TLR4-NF-{\kappa}B$ pathway, and PIC seems to be more effective than RSV in the regulation of analyzed targets, which are involved in insulin signaling and inflammation in vivo.

• BMB Reports
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• v.33 no.6
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• pp.454-462
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• 2000

Interleukin-4(IL-4) is known to be a major cytokine regulating immunoglobulin E(IgE) response by the induction of IgE production and type II IgE receptor(IgER II: CD23) expression. Recently, however, the role of neuroendocrine factors has been implicated in modulating the IgE response. Among various neuroendocrine growth factors, we investigated the effects of the insulin-like growth factor-1(IGF-1) since IL-4 and IGF-1 share common intracellular signaling molecules, such as the insulin receptor substrate-1/2(IRS-1/2) to induce a specific cellular response. In the human peripheral blood mononuclear cell (PBMC) cultures, IGF-1 was capable of inducing a substantial level of IgE production in a dose-dependent manner. It also noticeably upregulated the IL-4-induced or IL-4 plus anti-CD40-induced IgE production. Similarly, the IGF-1-induced IgE production was enhanced by IL-4 or anti-CD40 in an additive manner, which became saturated at high concentrations of IGF-1. Although IGF-1 alone did not induce IgER II (CD23) expression, it augmented the IL-4-induced surface CD23 expression in a manner similar to the action of anti-CD40. These results imply that IGF-1 is likely to utilize common signaling pathways with IL-4 and anti-CD40 to induce IgE and IgER II expression. In support of this notion, we observed that IGF-1 enhanced the IL-4-induced signal transducers and activators of transcription 6(STAT6) activation and independently induced $NF-{\kappa}B$ activation. Both of these bind to the IgE(C) or IgER II (CD23) promoters. Together, our data suggest that IL-4 and IGF-1 work cooperatively to activate STAT6 and $NF-{\kappa}B$. This leads to the subsequent binding of these transcription factors to the $C{\varepsilon}$ and CD23 promoters to enhance the expression of IgE and IgER II. The observed differential ability of IGF-1 on the induction of IgE vs. IgER II is discussed based on the different structure of the two promoters.

• Journal of Life Science
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• v.31 no.10
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• pp.954-959
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• 2021

Apoptosis is an important mechanism that regulates cellular populations to maintain homeostasis, and the caspases, a family of cysteine proteases, are key mediators of the apoptosis pathway. Caspase-8 is an initiator caspase of the extrinsic apoptotic pathway, which is initiated by extracellular stimuli. Caspase-8 have two conserved domains, N-terminal tandem death effector domains (DED) and C-terminal two catalytic domain, which are important for this extrinsic apoptosis pathway. In extrinsic apoptosis pathway, death receptors which members of TNF superfamily are activated by binding of death receptor specific ligands from cell outside. After the activated death receptors recruit adaptor protein Fas-associated death domain protein (FADD), death domains (DD) of death receptor and FADD bind to each other and FADD combined with death receptor recruits procaspase-8, a precursor form of caspase-8. The DED of FADD and procaspase-8 bind to one another and FADD-bound procaspase-8 is activated by cleavage of the prodomain. This death receptor-FADD-caspase-8 complex called death inducing signaling complex (DISC). Cellular FLICE-inhibitory proteins (c-FLIPs) regulate caspase-8 activation by acting both anti- and pro-apoptotically, and caspase-8 activation initiates the activation of executioner caspases such as caspase-3. Finally activated executioner caspases complete the apoptosis by acting critically DNA degradation, nuclear condensation, plasma membrane blebbing, and the proteolysis of certain caspase substrates.

• Journal of Life Science
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• v.33 no.11
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• pp.859-867
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• 2023

Lupeol is a type of pentacyclic triterpene that has been reported to have therapeutic effects for treating many diseases; however, its effect on insulin resistance is unclear clear. This study examined the inhibitory effect of lupeol on the serine phosphorylation of insulin receptor substrate-1 in insulin resistance-induced 3T3-L1 adipocytes. 3T3-L1 cells were cultured and treated with tumor necrosis factor-α (TNF-α) for 24 hours to induce insulin resistance. Cells treated with different concentrations of lupeol (15 μM or 30 μM) or 100 nM of rosiglitazone were incubated. Then, lysed cells underwent western blotting. Lupeol exhibited a positive effect on the negative regulator of insulin signaling and inflammation-activated protein kinase caused by TNF-α in adipocytes. Lupeol inhibited the activation of protein tyrosine phosphatase-1B (PTP-1B)-a negative regulator of insulin signaling-and c-Jun N-terminal kinase (JNK); it was also an inhibitor of nuclear factor kappa-B kinase (IKK) and inflammation-activated protein kinases. In addition, Lupeol downregulated serine phosphorylation and upregulated tyrosine phosphorylation in insulin receptor substrate-1. Then, the downregulated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway was activated, the translocation of glucose transporter type 4 was stimulated to the cell membrane, and intracellular glucose uptake increased in the insulin resistance-induced 3T3-L1 adipocytes. Lupeol may improve TNF-α-induced insulin resistance by downregulating the serine phosphorylation of insulin receptor substrate 1 by inhibiting negative regulators of insulin signaling and inflammation-activated protein kinases in 3T3-L1 adipocytes.

• Journal of Applied Biological Chemistry
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• v.66
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• pp.447-454
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• 2023

In the environment in which humans live, there are various antigens that invade the human body and interfere with humans leading a healthy life, so the immune system recognizes the antigen then removes them through a complex mechanism. Macrophages are widely distributed immune cells involved in the innate immune system, and produce various immune modulators such as inducible nitric oxide synthase-induced nitric oxide, cyclooxygenase-2 induced prostaglandin E2 and proinflammatory cytokines such as tumor necrosis factor-alpha. On the other hand, Protaetia brevitarsis seulensis larvae are a type of edible insect that have emerged as an alternative to the future food supply problem. The immuno-modulatory effect through the activation of murine macrophage RAW264.7 cell via mitogen-activated protein kinases (MAPKs)/nuclear factor-kappa B (NF-κB) signaling pathways has been reported. Based on this report, in this study, we confirmed how the expression of immune modulators induced by Protaetia brevitarsis seulensis larvae extracts in RAW264.7 cells was changed by treatment with pharmacological inhibitors of toll-like receptor 4 (TLR4), MAPKs and NF-κB signaling pathways. As a result, reduction of immune modulators was confirmed in the c-Jun N-terminal kinase (JNK) inhibitor treatment group and NF-κB inhibitor treatment group among the Protaetia brevitarsis seulensis larvae-treated RAW264.7 cell. Furthermore, in the TLR4 inhibitor-treated group, decreases in phosphorylation of JNK and NF-κB factors were confirmed in Protaetia brevitarsis seulensis larvae-treated RAW264.7 cell, as well as decreases in immune modulators. This results suggest that Protaetia brevitarsis seulensis larvae activates RAW264.7 cells by the engagement of TLR4-JNK/NF-κB signaling pathway.

• The Korean Journal of Nuclear Medicine
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• v.37 no.6
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• pp.402-417
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• 2003

Purpose: To evaluate the use of monoclonal antibody (MoAb) as a carrier of the receptor-binding ligand the receptor mediated uptake into liver and subsequent metabolism of $^{111}In-labeled$ galactosylated MoAb-chelator conjugates were investigated and compared with those of $^{111}In$ labeled MoAb. Materials and Methods : T101 MoAb, $IgG_2$ against human lymphocytic leukemic cell, conjugated with cyclic DTPA dianhydride (DTPA) or 2-p-isothiocyanatobenzyl-6-methyl-DTPA (1B4M) was galactosylated with 2-imino-2-methoxyethyl-1-thio-${\beta}$-D-galactose and then radiolabeled with $^{111}In$. Biodistribution and metabolism study was peformed with two $^{111}In-conjugates$ in mice and rats. Results: $^{111}In-labeled$ T101 and its galactosylated conjugates were taken to the liver by the time, mostly within 10 min. However DTPA conjugate was retained longer in the liver than the 1B4M conjugate (55% vs 20% of injected dose at 44 hr). During this time, the radiornetabolite of DTPA conjugate was excreted similarly into urine (24%) and feces (17%). The radiometabolite of 1B4M was excreted primarily into feces (68%) rather than urine (8%). Size exclusion HPLC analysis of the bile and supernatant of liver homogenate showed two peaks the first (35%) with the retention time (Rt) identical to IgG and the second (65%) with Rt similar to free $^{111}In$ at 3 hr post-injection for the 1B4M conjugate, indicating that the metabolite is rapidly excreted through the biliary system. in contrast to DTPA conjugate, the small $^{111}In-DTPA-like$ metabolite was the major radioindium component (90%) in the liver homogenate as early as 3 hour post-injection, but the cumulative radioindium activity in feces was only 17% at 44 hour, indicating that the metabolite from DTPA conjugate does not clear readily through the biliary tract. Conclusion: The galactosylation of the MoAb conjugates resulted in higher hepatocyte uptake and enhanced metabolism, compared to those without galactosylation. Metabolism of the MoAb-conjugates is different between compounds radiolabled with different chelators due to different characteristics of radiometabolites generated in the liver.

• Biomolecules & Therapeutics
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• v.25 no.4
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• pp.383-389
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• 2017

Dexmedetomidine is an ${\alpha}2$-adrenergic receptor agonist that exhibits a protective effect on ischemia-reperfusion injury of the heart, kidney, and other organs. In the present study, we examined the neuroprotective action and potential mechanisms of dexmedetomidine against ischemia-reperfusion induced cerebral injury. Transient focal cerebral ischemia-reperfusion injury was induced in Sprague-Dawley rats by middle cerebral artery occlusion. After the ischemic insult, animals then received intravenous dexmedetomidine of $1{\mu}g/kg$ load dose, followed by $0.05{\mu}g/kg/min$ infusion for 2 h. After 24 h of reperfusion, neurological function, brain edema, and the morphology of the hippocampal CA1 region were evaluated. The levels and mRNA expressions of interleukin-$1{\beta}$, interleukin-6 and tumor nevrosis factor-${\alpha}$ as well as the protein expression of inducible nitric oxide synthase, cyclooxygenase-2, nuclear factor-${\kappa}Bp65$, inhibitor of ${\kappa}B{\alpha}$ and phosphorylated of ${\kappa}B{\alpha}$ in hippocampus were assessed. We found that dexmedetomidine reduced focal cerebral ischemia-reperfusion injury in rats by inhibiting the expression and release of inflammatory cytokines and mediators. Inhibition of the nuclear factor-${\kappa}B$ pathway may be a mechanism underlying the neuroprotective action of dexmedetomidine against focal cerebral I/R injury.

• The Korean Journal of Nuclear Medicine
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• v.35 no.4
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• pp.258-267
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• 2001

Purpose/Methods: Repeated administration of methamphetamine (METH) produces high extracellular levels of dopamine (DA) and subsequent striatal DA terminal damage. The effect of MK-801, a noncompetitive N-methyl-D-aspartate receptor antagonist, on METH-induced changes in DA transporter (DAT) and DA release evoked by an acute METH challenge was evaluated in rodent striatum uslng $[^3H]$]WIN 38,428 ex vivo auto-radiography and in vivo microdialysis. Results: Four injections of METH (10 mg/kg, i.p.), each given 2 h apart, produced 71% decrease in DAT levels in mouse striatum 3 d after administration. Pretreatment with MK-801 (2.5 mg/kg, i.p.) 15 min before each of the four METH injections protected completely against striatal DAT depletions. Four injections of MK-801 alone did not significantly change striatal DAT levels. Striatal DA release evoked by an acute METH challenge (4 mg/kg, i.p.) at 3 d after repeated administration of METH in rats was decreased but significant compared with controls, which was attenuated by repeated pretreatment with MK-801. Also, repeated injections of MK-801 alone attenuated acute METH-induced striatal DA release 3 d after administration. Conclusion: These results suggest that repeated administration of MK-801 may exert a preventive effect against METH-induced DA terminal injury through long-term attenuation of DA release induced by METH and other stimuli.

• Biomolecules & Therapeutics
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• v.22 no.6
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• pp.525-531
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• 2014

In the present study, we investigated whether apigenin significantly affects tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$)-induced production and gene expression of MUC5AC mucin in airway epithelial cells. Confluent NCI-H292 cells were pretreated with apigenin for 30 min and then stimulated with TNF-${\alpha}$ for 24 h or the indicated periods. The MUC5AC mucin gene expression and mucin protein production were measured by reverse transcription - polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Apigenin significantly inhibited MUC5AC mucin production and down-regulated MUC5AC gene expression induced by TNF-${\alpha}$ in NCI-H292 cells. To elucidate the action mechanism of apigenin, effect of apigenin on TNF-${\alpha}$-induced nuclear factor kappa B (NF-${\kappa}B$) signaling pathway was also investigated by western blot analysis. Apigenin inhibited NF-${\kappa}B$ activation induced by TNF-${\alpha}$. Inhibition of inhibitory kappa B kinase (IKK) by apigenin led to the suppression of inhibitory kappa B alpha ($I{\kappa}B{\alpha}$) phosphorylation and degradation, p65 nuclear translocation. This, in turn, led to the down-regulation of MUC5AC protein production in NCI-H292 cells. Apigenin also has an influence on upstream signaling of IKK because it inhibited the expression of adaptor protein, receptor interacting protein 1 (RIP1). These results suggest that apigenin can regulate the production and gene expression of mucin through regulating NF-${\kappa}B$ signaling pathway in airway epithelial cells.

• Biomolecules & Therapeutics
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• v.32 no.2
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• pp.205-213
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• 2024

Hydroxychavicol, a primary active phenolic compound of betel leaves, previously inhibited bone loss in vivo by stimulating osteogenesis. However, the effect of hydroxychavicol on bone remodeling induced by osteoclasts is unknown. In this study, the anti-osteoclastogenic effects of hydroxychavicol and its mechanism were investigated in receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclasts. Hydroxychavicol reduced the number of tartrate resistance acid phosphatase (TRAP)-positive multinucleated, F-actin ring formation and bone-resorbing activity of osteoclasts differentiated from RAW264.7 cells in a concentration-dependent manner. Furthermore, hydroxychavicol decreased the expression of osteoclast-specific genes, including cathepsin K, MMP-9, and dendritic cell-specific transmembrane protein (DC-STAMP). For mechanistic studies, hydroxychavicol suppressed RANKL-induced expression of major transcription factors, including the nuclear factor of activated T-cells 1 (NFATc1), c-Fos, and c-Jun. At the early stage of osteoclast differentiation, hydroxychavicol blocked the phosphorylation of NF-κB subunits (p65 and Iκβα). This blockade led to the decrease of nuclear translocation of p65 induced by RANKL. In addition, the anti-osteoclastogenic effect of hydroxychavicol was confirmed by the inhibition of TRAP-positive multinucleated differentiation from human peripheral mononuclear cells (PBMCs). In conclusion, hydroxychavicol inhibits osteoclastogenesis by abrogating RANKL-induced NFATc1 expression by suppressing the NF-κB signaling pathway in vitro.