• BMB Reports
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• v.46 no.9
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• pp.454-459
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• 2013

LRRK2 (leucine-rich repeat kinase 2) has been identified as a gene corresponding to PARK8, an autosomal-dominant gene for familial Parkinson's disease (PD). LRRK2 pathogenic-specific mutants induce neurotoxicity and shorten neurites. To elucidate the mechanism underlying LRRK2 expression, we constructed the LRRK2-promoter-luciferase reporter and used it for promoter analysis. We found that the glucocorticoid receptor (GR) transactivated LRRK2 in a ligand-dependent manner. Using quantitative RT-PCR and Western analysis, we further showed that treatment with dexamethasone, a synthetic GR ligand, induced LRRK2 expression at both the transcriptional and translational levels, in dopaminergic MN9D cells. Dexamethasone treatment also increased expression of ${\alpha}$-synuclein, another PD causative gene, and enhanced transactivation of the ${\alpha}$-synuclein promoter-luciferase reporter. In addition, dexamethasone treatment to MN9D cells weakly induced cytotoxicity based on an LDH assay. Because glucocorticoid hormones are secreted in response to stress, our data suggest that stress might be a related factor in the pathogenesis of PD.

• YAKHAK HOEJI
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• v.47 no.5
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• pp.325-330
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• 2003

Solanum melongena L. (Solanaceae) has anti-oxidant, analgesic, and hypolipidemic effects. We previously showed that Solanum melongena (SM) aqueous extract inhibits mast cell-mediated allergic reactions. The activation of protease-activated receptor-2 (PAR-2) induces acute inflammation in rat hindpaw. In the present study, we investigated the effects of the SM aqueous extract on mouse paw edema induced by PAR2 agonists. Trypsin or trans-cinnamoyl-LIGRLO-NH$_2$ (tc-NH$_2$), PAR-2 agonists, was injected into the hind paw of mice to induce paw edema. SM aqueous extract (1, 5, 10, and 100 mg/kg) was orally administered 1 hr before induction of paw edema. SM aqueous extract (5, 10, and 100 mg/kg) significantly inhibited both paw edema and vascular permeability in the dose-dependent manner. Furthermore, SM aqueous extract (10 mg/kg) significantly inhibited PAR-2 agonist-induced myeloperoxidase (MPO) activity and tumor necrosis factor (TNF)-$\alpha$ expression in paw tissue compared to that of saline. These results suggest that SM aqueous extract may be useful for treatment of PAR-2-mediated inflammation.

• Journal of Yeungnam Medical Science
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• v.36 no.1
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• pp.26-35
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• 2019

Background: Dysregulation of hepatic glucose production (HGP) contributes to the development of type 2 diabetes mellitus. Telmisartan, an angiotensin II type 1 receptor blocker (ARB), has various ancillary effects in addition to common blood pressure-lowering effects. The effects and mechanism of telmisartan on HGP have not been fully elucidated and, therefore, we investigated these phenomena in hyperglycemic HepG2 cells and high-fat diet (HFD)-fed mice. Methods: Glucose production and glucose uptake were measured in HepG2 cells. Expression levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase ${\alpha}$ ($G6Pase-{\alpha}$), and phosphorylation levels of insulin receptor substrate-1 (IRS-1) and protein kinase C ${\zeta}$ ($PKC{\zeta}$) were assessed by western blot analysis. Animal studies were performed using HFD-fed mice. Results: Telmisartan dose-dependently increased HGP, and PEPCK expression was minimally increased at a $40{\mu}M$ concentration without a change in $G6Pase-{\alpha}$ expression. In contrast, telmisartan increased phosphorylation of IRS-1 at Ser302 ($p-IRS-1-Ser^{302}$) and decreased $p-IRS-1-Tyr^{632}$ dose-dependently. Telmisartan dose-dependently increased $p-PKC{\zeta}-Thr^{410}$ which is known to reduce insulin action by inducing IRS-1 serine phosphorylation. Ectopic expression of dominant-negative $PKC{\zeta}$ significantly attenuated telmisartan-induced HGP and $p-IRS-1-Ser^{302}$ and -inhibited $p-IRS-1-Tyr^{632}$. Among ARBs, including losartan and fimasartan, only telmisartan changed IRS-1 phosphorylation and pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor ${\gamma}$ ($PPAR{\gamma}$) antagonist, did not alter this effect. Finally, in the livers from HFD-fed mice, telmisartan increased $p-IRS-1-Ser^{302}$ and decreased $p-IRS-1-Tyr^{632}$, which was accompanied by an increase in $p-PKC{\zeta}-Thr^{410}$. Conclusion: These results suggest that telmisartan increases HGP by inducing $p-PKC{\zeta}-Thr^{410}$ that increases $p-IRS-1-Ser^{302}$ and decreases $p-IRS-1-Tyr^{632}$ in a $PPAR{\gamma}$-independent manner

• Natural Product Sciences
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• v.25 no.3
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• pp.200-207
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• 2019

Albizzia julibrissin (AJ) is an herbal medicine that shows low toxicity, promotes promoting blood circulation and mitigates the inflammation and has mild side effects. Benign prostate hyperplasia (BPH) is one of the most common diseases that occurs in older males and often results in lower urinary tract symptoms. This study was conducted to evaluate the protective effect of AJ against BPH using LNCaP cells and Sprague Dawley rats treated with testosterone. Treatment with AJ extract reduced the expression of androgen receptor (AR) and prostate-specific antigen (PSA) in vitro. In vivo, rats were divided into 6 groups: 1 (Normal Control); 2 (Testosterone propionate (TP) alone); 3 (TP + finasteride); 4 (TP + AJ 10 mg/kg); 5 (TP + AJ 50 mg/kg); 6 (TP + AJ 300 mg/kg). The groups treated with AJ showed reduced the relative prostate weights and BPH-related proteins were altered, with decreased AR, PSA and proliferating cell nuclear antigen (PCNA) observed by western blot. Histopathological analysis revealed the therapeutic effect of AJ, with a decreased thickness of epithelial cells and reduced level of PCNA and $5{\alpha}$-reductase type 2. These results suggest that AJ extract could ameliorate testosterone-induced benign prostatic hyperplasia.

• Archives of Reconstructive Microsurgery
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• v.18 no.1
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• pp.9-15
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• 2009

Whether a seven days course of anti-${\alpha}{\beta}$-T cell receptor-antibody (${\alpha}{\beta}$-TCRmAb) combined with FK506 therapy promotes survival of limb allografts in fully MHC-mismatched combination (Brown Norway $\rightarrow$ Lewis) was examined. Eight animals received 250 ${\mu}g$/kg/day of ${\alpha}{\beta}$-TCRmAb for 7 days and 2 mg/kg/day of FK506 postoperatively (Combination therapy group). Eight animals had FK506 only (Mono-therapy group) and five animals did not have treatment (Control group). Clinical signs of early rejection with edema or erythema in the skin occurred at an average of 8.6${\pm}$1.5 days postoperatively in Control group and 59.0${\pm}$8.3 days in Mono-therapy group, both of which proceeded to irreversible rejection with necrosis of the epidermis and finally mummification. In Combination therapy group, all animals showed evidence of early rejection at an average of 56.8${\pm}$12.6 days postoperatively, however, in 4 of 8 limbs, early rejection resolved without any treatment and limbs survived >1 year. At 9 months postoperatively, donor skin grafts were accepted and third-party skin grafts were rejected by all four survivors, demonstrating donor-specific tolerance. Little or no detectable chimerism was observed in any of the 4 surviving animals at one-year postoperatively. Combination therapy of ${\alpha}{\beta}$-TCRmAb and FK506 resulted in long-term survival in fully MHC-mismatched limb transplants.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.3
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• pp.169-176
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• 2010

The hyperosmotic stimulus is regarded as a mechanical factor for bone remodeling. However, whether the hyperosmotic stimulus affects $1{\alpha}$, 25-dihydroxyvitamin $D_3$ ($1{\alpha},25(OH)_2D_3$)-induced osteoclastogenesis is not clear. In the present study, the effect of the hyperosmotic stimulus on $1{\alpha},25(OH)_2D_3$-induced osteoclastogenesis was investigated in an osteoblast-preosteoclast co-culture system. Serial doses of sucrose were applied as a mechanical force. These hyperosmotic stimuli significantly evoked a reduced number of $1{\alpha},25(OH)_2D_3$-induced tartrate-resistant acid phosphatase-positive multinucleated cells and $1{\alpha},25(OH)_2D_3$-induced bone-resorbing pit area in a co-culture system. In osteoblastic cells, receptor activator of nuclear factor ${\kappa}B$ ligand (RANKL) and Runx2 expressions were down-regulated in response to $1{\alpha},25(OH)_2D_3$. Knockdown of Runx2 inhibited $1{\alpha},25(OH)_2D_3$-induced RANKL expression in osteoblastic cells. Finally, the hyperosmotic stimulus induced the overexpression of TonEBP in osteoblastic cells. These results suggest that hyperosmolarity leads to the down-regulation of $1{\alpha},25(OH)_2D_3$-induced osteoclastogenesis, suppressing Runx2 and RANKL expression due to the TonEBP overexpression in osteoblastic cells.

• BMB Reports
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• v.42 no.4
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• pp.189-193
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• 2009

During development lymphoid tissue inducer (LTi) cells are the first hematopoietic cells to enter the secondary lymphoid anlagen and induce lymphoid tissue neogenesis. LTi cells induce lymphoid tissue neogensis by expressing a wide range of proteins that are associated with lymphoid organogenesis. Among these proteins, membrane-bound lymphotoxin (LT) $\alpha1\beta2$ has been identified as a critical component to this process. LT$\alpha1\beta2$ interacts with the LT$\beta$-receptor on stromal cells and this interaction induces up-regulation of adhesion molecules and production of chemokines that are necessary for the attraction, retention and organization of other cell types. Constitutive expression of LT$\alpha1\beta2$ in adult LTi cells can result in the formation of a lymphoid-like structure called tertiary lymphoid tissue. In this review, we summarize the function of fetal and adult LTi cells and their involvement in secondary and tertiary lymphoid tissue development in murine models.

• Biomolecules & Therapeutics
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• v.24 no.2
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• pp.109-114
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• 2016

In Drosophila, rhomboid proteases are active cardinal regulators of epidermal growth factor receptor (EGFR) signaling pathway. iRhom1 and iRhom2, which are inactive homologs of rhomboid intramembrane serine proteases, are lacking essential catalytic residues. These are necessary for maturation and trafficking of tumor necrosis factor-alpha (TNF-${\alpha}$) converting enzyme (TACE) from endoplasmic reticulum (ER) to plasma membrane through Golgi, and associated with the fates of various ligands for EGFR. Recent studies have clarified that the activation or downregulation of EGFR signaling pathways by alteration of iRhoms are connected to several human diseases including tylosis with esophageal cancer (TOC) which is the autosomal dominant syndrom, breast cancer, and Alzheimer's disease. Thus, this review focuses on our understanding of iRhoms and the involved mechanisms in the cellular processes.

• Molecules and Cells
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• v.24 no.2
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• pp.247-254
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• 2007

Improvement in the pharmacokinetic properties of short interfering RNAs (siRNAs) is a prerequisite for the therapeutic application of RNA interference technology. When injected into mice as unmodified siRNAs complexed to DOTAP/Chol-based cationic liposomes, all 12 tested siRNA duplexes caused a strong induction of cytokines including interferon ${\alpha}$, indicating that the immune activation by siRNA duplexes is independent of sequence context. When modified by various combinations of 2'-OMe, 2'-F, and phosphorothioate substitutions, introduction of as little as three 2'-OMe substitutions into the sense strand was sufficient to suppress immune activation by siRNA duplexes, whereas the same modifications were much less efficient at inhibiting the immune response of single stranded siRNAs. It is unlikely that Toll-like receptor 3 (TLR3) signaling is involved in immune stimulation by siRNA/liposome complexes since potent immune activation by ds siRNAs was induced in TLR3 knockout mice. Together, our results indicate that chemical modification of siRNA provides an effective means to avoid unwanted immune activation by therapeutic siRNAs. This improvement in the in vivo properties of siRNAs should greatly facilitate successful development of siRNA therapeutics.

• YAKHAK HOEJI
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• v.33 no.6
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• pp.333-338
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• 1989

It has been postulated that abnormal characteristics of central noradrenergic nervous system has been implicated in the development and maintenance of hypertension in several modes of experimental hypertension including spontaneously hypertensive rats (SHR). In the present study, we attempt to determine if abnormal characteristics of central noradrenergic nervous system in SHR is caused by genetic factors or hypertensive phenomena by evaluating the changes of central adrenoceptors after long-term treatment of clonidine. Animals were divided into three groups; (1) 14 week-old SHR; (2) age-matched normotensive Wistar rats (NW); (3) DOCA-Salt induced hypertensive rats (DS). Clonidine (100 ug/kg) or vehicle was injected intraperitonealy twice a day for 15 days. Changes of ${\alpha}_1-$ and ${\alpha}_2-receptor$ desities following clonidine treatment were determiend in frontal corte, medulla oblongata and hypothalamus using 3H-WB4101 and 3H-clonidine, respectively. Densities of ${\alpha}_1$ and ${\alpha}_2-receptors$ following clonidine treatment were not changed in frontal cortex and medulla oblongate of SHR as well as DS, but increased in frontal cortex of NW and decreased in medulla oblongata of NW. On the other hand, densities of ${\alpha}_1-receptors$ were increased and densities of ${\alpha}_2-receptors$ were not changed in hypothalamus of SHR but densities of ${\alpha}_1-$ and ${\alpha}_2-receptors$ were decreased in hypothalamus of DS as well as NW. These results suggest that such differences in frontal cortex and medulla oblongata of SHR may be results of hypertensive phenomena whereas those in hypothalamus may be relevant to genetic factors of SHR.