• The Korean Journal of Physiology and Pharmacology
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• v.22 no.1
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• pp.23-33
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• 2018

Cushing's syndrome (CS) is a collection of symptoms caused by prolonged exposure to excess cortisol. Chronically elevated glucocorticoid (GC) levels contribute to hepatic steatosis. We hypothesized that histone deacetylase inhibitors (HDACi) could attenuate hepatic steatosis through glucocorticoid receptor (GR) acetylation in experimental CS. To induce CS, we administered adrenocorticotropic hormone (ACTH; 40 ng/kg/day) to Sprague-Dawley rats by subcutaneous infusion with osmotic mini-pumps. We administered the HDACi, sodium valproate (VPA; 0.71% w/v), in the drinking water. Treatment with the HDACi decreased steatosis and the expression of lipogenic genes in the livers of CS rats. The enrichment of GR at the promoters of the lipogenic genes, such as acetyl-CoA carboxylase (Acc), fatty acid synthase (Fasn), and sterol regulatory element binding protein 1c (Srebp1c), was markedly decreased by VPA. Pan-HDACi and an HDAC class I-specific inhibitor, but not an HDAC class II a-specific inhibitor, attenuated dexamethasone (DEX)-induced lipogenesis in HepG2 cells. The transcriptional activity of Fasn was decreased by pretreatment with VPA. In addition, pretreatment with VPA decreased DEX-induced binding of GR to the glucocorticoid response element (GRE). Treatment with VPA increased the acetylation of GR in ACTH-infused rats and DEX-induced HepG2 cells. Taken together, these results indicate that HDAC inhibition attenuates hepatic steatosis through GR acetylation in experimental CS.

• Tuberculosis and Respiratory Diseases
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• v.85 no.1
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• pp.18-24
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• 2022

Background: Neutrophilic asthma (NeuA) is usually resistant to corticosteroids. Tiotropium bromide (TIO) is a bronchodilator that is used as an add-on therapy to inhaled corticosteroid and long-acting β2 agonist in asthma treatment. However, the role of TIO in NeuA is not fully known. Thus, the aim of this study was to evaluate the effect of TIO on NeuA compared to that of corticosteroids. Methods: C57BL/6 female mice were sensitized with ovalbumin and lipopolysaccharide to induce neutrophilic inflammation. Dexamethasone (DEX) was administered on days 14, 17, 20, and 23. TIO was inhaled on days 21, 21, and 23. On day 24, mice were sacrificed. Airway hyper-responsiveness, levels of cytokines in bronchoalveolar lavage (BAL) and lung homogenates, and lung tissue histopathology were compared between the two groups. Results: Neutrophil counts, T helper 2 cells (T_H2)/T_H17 cytokines, and pro-inflammatory cytokine in BAL fluids were elevated in the NeuA group. TIO group showed lower total cells, neutrophil counts, and eosinophil counts in BAL fluids than the DEX group (p<0.001, p<0.05, and p<0.001, respectively). Airway resistance was attenuated in the TIO group but elevated in the NeuA group (p<0.001). Total protein, interleukin (IL)-5, and IL-17A levels in BAL fluids were lower in the TIO group than in the NeuA group (all p<0.05). Conclusion: TIO showed more potent effects than DEX in improving airway inflammation and attenuating airway resistance in NeuA.

• IMMUNE NETWORK
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• v.23 no.5
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• pp.40.1-40.14
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• 2023

Glucocorticoids suppress the vascular inflammation that occurs under hypercholesterolemia, as demonstrated in an animal model fed a high-cholesterol diet. However, the molecular mechanisms underlying these beneficial effects remain poorly understood. Because cholesterol is oxidized to form cholesterol oxides (oxysterols) that are capable of inducing inflammation, we investigated whether glucocorticoids affect the immune responses evoked by 7α-hydroxycholesterol (7αOHChol). The treatment of human THP-1 monocytic cells with dexamethasone (Dex) and prednisolone (Pdn) downregulated the expression of pattern recognition receptors (PRRs), such as TLR6 and CD14, and diminished 7αOHChol-enhanced response to FSL-1, a TLR2/6 ligand, and lipopolysaccharide, which interacts with CD14 to initiate immune responses, as determined by the reduced secretion of IL-23 and CCL2, respectively. Glucocorticoids weakened the 7αOHChol-induced production of CCL2 and CCR5 ligands, which was accompanied by decreased migration of monocytic cells and CCR5-expressing Jurkat T cells. Treatment with Dex or Pdn also reduced the phosphorylation of the Akt-1 Src, ERK1/2, and p65 subunits. These results indicate that both Dex and Pdn impair the expression of PRRs and their downstream products, chemokine production, and phosphorylation of signaling molecules. Collectively, glucocorticoids suppress the innate immune response and activation of monocytic cells to an inflammatory phenotype enhanced or induced by 7αOHChol, which may contribute to the anti-inflammatory effects in hypercholesterolemic conditions.

• Korean Journal of Pharmacognosy
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• v.40 no.1
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• pp.35-40
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• 2009

The immunomodulatory activities of the ethanol extract of Gynostemma pentaphyllum, termed hereafter as GPE, were examined in immunosuppressed mice as well as in normal mice in the present study. Oral administration of GPE into mice prevented dexamethasone (DEX)-induced immunosuppression as determined by the mitogen-induced proliferation of the splenocytes and the the cytokine production (TNF-$\alpha$, IL-$1{\beta}$) in the whole blood culture. In addition, oral administration of GPE increased antitumor host defense in mice implanted with sarcoma-180 tumor cells. The immunoaugmenting activity of orally administered GPE was also confirmed in mice immunized with ovalbumin (OVA). Mice that were orally administered with GPE generated much more potent OVA-specific cytotoxic T lymphocyte (CTL) responses upon intravenous OVA injection compared to the untreated controls. These results demonstrate that oral administration of the ethanol extract of Gynostemma pentaphyllum could be useful to increase host defense in immunocompromised situations such as stress- or tumor-induced immunosuppression.

• Korean Journal of Biological Psychiatry
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• v.17 no.2
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• pp.86-93
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• 2010

Objectives : The aim of this research is to determine the effects of depression and anxiety symptoms of schizophrenic psychopathology on the HPA axis. Methods : Twenty patients with schizophrenia were included and divided into the medication non-exposed group(n = 10) and the medication exposed group(n = 10). Evaluated scales were the Positive and Negative Syndrome Scale(PANSS), Scale for the Assessment of Negative Symptoms(SANS), Scale for the Assessment of Positive Symptoms(SAPS), Hamilton Depression Inventory(HAM-D) and Hamilton Anxiety Inventory (HAM-A), and then the combined Dexamethasone/Corticotropin Releasing Hormone(DEX/CRH) test was conducted to determine the basal level, the peak level and the area under the curve(AUC) of cortisol and adrenocorticotropic hormone(ACTH). Results : When the correlations between each psychopathology and cortisol level or ACTH AUC value were analyzed, HAM-D showed a negative correlation, whereas HAM-A showed a positive correlation. Also, the non-depression group(HAM-D ${\leq}$ 18) showed higher cortisol and ACTH concentrations than the depression group(HAM-D > 18), and the anxiety group(HAM-A ${\geq}$ 14) showed significantly higher concentrations than the non-anxiety group(HAM-D < 14)(p < 0.05). Also, as for the comparison between the medication non-exposed group and the medication exposed group, the non-exposed group showed significantly higher cortisol and ACTH concentration than exposed group(p < 0.05). Conclusion : This study suggest that anxiety symptoms rather than depression symptoms are related to the increased activity of the HPA axis of schizophrenics.

• Molecules and Cells
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• v.38 no.10
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• pp.866-875
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• 2015

COPI vesicles are essential to the retrograde transport of proteins in the early secretory pathway. The COPI coatomer complex consists of seven subunits, termed ${\alpha}-$, ${\beta}-$, ${\beta}^{\prime}-$, ${\gamma}-$, ${\delta}-$, ${\varepsilon}-$, and ${\zeta}$-COP, in yeast and mammals. Plant genomes have homologs of these subunits, but the essentiality of their cellular functions has hampered the functional characterization of the subunit genes in plants. Here we have employed virus-induced gene silencing (VIGS) and dexamethasone (DEX)-inducible RNAi of the COPI subunit genes to study the in vivo functions of the COPI coatomer complex in plants. The ${\beta}^{\prime}-$, ${\gamma}-$, and ${\delta}$-COP subunits localized to the Golgi as GFP-fusion proteins and interacted with each other in the Golgi. Silencing of ${\beta}^{\prime}-$, ${\gamma}-$, and ${\delta}$-COP by VIGS resulted in growth arrest and acute plant death in Nicotiana benthamiana, with the affected leaf cells exhibiting morphological markers of programmed cell death. Depletion of the COPI subunits resulted in disruption of the Golgi structure and accumulation of autolysosome-like structures in earlier stages of gene silencing. In tobacco BY-2 cells, DEX-inducible RNAi of ${\beta}^{\prime}$-COP caused aberrant cell plate formation during cytokinesis. Collectively, these results suggest that COPI vesicles are essential to plant growth and survival by maintaining the Golgi apparatus and modulating cell plate formation.

• Journal of Ginseng Research
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• v.48 no.2
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• pp.181-189
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• 2024

Background: Cigarette smoke is generally accepted as a major contributor to chronic obstructive pulmonary disease (COPD), which is characterized by emphysematous lesions. In this study, we investigated the protective effects of Korean Red Ginseng (KRG) against cigarette smoke condensate (CSC)-induced emphysema. Methods: Mice were instilled with 50 mg/kg of CSC intranasally once a week for 4 weeks, KRG was administered to the mice once daily for 4 weeks at doses of 100 or 300 mg/kg, and dexamethasone (DEX, positive control) was administered to the mice once daily for 2 weeks at 3 mg/kg. Results: KRG markedly decreased the macrophage population in bronchoalveolar lavage fluid and reduced emphysematous lesions in the lung tissues. KRG suppressed CSC-induced apoptosis as revealed by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling staining and Caspase 3 immunohistochemistry. Additionally, KRG effectively inhibited CSC-mediated activation of Bcl-2-associated X protein/Caspase 3 signaling, followed by the induction of cell survival signaling, including vascular endothelial growth factor/phosphoinositide 3-kinase/protein kinase B in vivo and in vitro. The DEX group also showed similar improved results in vivo and in vitro. Conclusion: Taken together, KRG effectively inhibits macrophage-mediated emphysema induced by CSC exposure, possibly via the suppression of pro-apoptotic signaling, which results in cell survival pathway activation. These findings suggest that KRG has therapeutic potential for the prevention of emphysema in COPD patients.

• Journal of Korean Medicine Rehabilitation
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• v.29 no.2
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• pp.101-113
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• 2019

Objectives Bogol-tang has clinically been used to protect joint cartilage and to treat osteoarthritis. Our objective was to study the protective effect of Bogol-tang extract (BGT) in functional impairment, behavioral disorders, cartilage loss and pathological changes in a monoiodoacetate (MIA)-induced murine osteoarthritis (OA) model and interleukin (IL)-$1{\beta}$ -treated primary rat chondrocytes. Methods Mouse knee joints were injected with MIA, a chemical that inhibits glycolysis and causes joint inflammation and matrix loss. MIA-OA induced mice orally administered BGT or acetaminophen (AAP) for 18 days by daily. Primary rat chondrocytes were pretreated with BGT or dexamethasone (DEX) and followed by co-incubation with IL-$1{\beta}$ (10 ng/mL). Results In MIA-OA mice model, BGT led to delayed response on hot plate analysis, and suppressed the cartilage loss and damages in joint tissues. BGT suppressed the elevated levels of inflammatory mediators, nitrite and $PGE_2$, the gene expression of matrix degrading enzymes, and extracellular-signal-regulated kinases 1/2 and c-JunN-terminal kinase phosphorylation in IL-$1{\beta}$-treated primary rat chondrocytes. Conclusions Our results suggest that BGT improve the knee joint function and delay the cartilage damages by anti-nociceptive, anti-inflammatory and ant-catabolic effects, which indicate BGT could be a potential candidate for osteoarthritis treatment.

• Journal of Korean Medicine Rehabilitation
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• v.24 no.3
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• pp.71-85
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• 2014

Objectives In this study, we investigated the inhibitory effects of Samhwangsasim-tang (S.H) on the allergic response caused by ovalbumin(OVA) sensitization and challenge in BALB/c mice. Methods The experimental animals were divided into five groups; 1) normal as negative control, 2) OVA-sensitized mice, 3) OVA-sensitized mice treated with 200 mg/kg of S.H 200, 4) OVA-sensitized mice treated with 400 mg/kg of S.H 400, and 5) OVA-sensitized mice treated with 5 mg/kg of Dexamethasone (Dex). Antigen sensitization for allergic mouse model was performed with twice injection of OVA for 2 weeks. After secondary injection, S.H was administrated orally into mice every day for 13 days and the inhibitory effect of S.H on allergic responses was evaluated. Results Treatment of S.H into allergic mice reduced significantly ear edema and infiltration of immune cells in ear tissues induced with OVA challenge in a dose-dependent manner. S.H reduced significantly the serum levels of Total Immunoglobulin(Ig)G and IgE, and particularly inhibited the production of OVA-specific IgE, but not OVA-specific IgG. The serum level of proinflammatory cytokine TNF-${\alpha}$ and Th2-associated cytokine IL-4 also were significantly decreased by S.H adminstration in a dose denpendent manner. S.H attenuated OVA-induced secretion of IFN-${\gamma}$, but not IL-12 which is a cytokine inducing the development of Th1 cells. It also reduced significantly the secretion of IL-4, which is a cytokine inducing the development of Th2 cells, after splenocytes were stimulated with OVA. However the secretion of IL-5 and IL-13 was influenced weakly or a little. Conclusions These results indicate that S.H could reduce the allergic response through inhibition of antigen-specific IgE and Th2-inducing cytokines. It suggest that S.H may be available clinically for the treatment of allergic patients.

• Journal of Life Science
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• v.18 no.8
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• pp.1023-1030
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• 2008

NtMEK2, which is the tobacco MAPK kinase that is upstream of SIPK and WIPK, was identified using the dexamethasone (DEX)-inducible gain-of-function transgenic system. Expression of $NtNEK2^{DD}$, a constitutively active mutant of NtNEK2, leads to HR-like cell death, which indicates that the NtMEK2-SIPK/WIPK cascade controls defense responses in tobacco. However, little is known about the downstream target substrates or defense-related genes that are regulated by the NtMEK2-SIPK/ WIPK cascade. In this study, ACP-based differential display RT-PCR was used to isolate the downstream effectors mediated by the NtMEK2-SIPK/WIPK cascade in $NtNEK2^{DD}$ transgenic plants. The results identified 6 novel differentially expressed genes (DEGs). These included pathogen induced protein 2-4 (pI2-4), monoterpene synthase 2 (MTS2), seven in absentia protein (SINA), cell death marker protein 1 (CDM1), hydroxyproline-rich glycoprotein (HRGP) and unknown genes (DEG45). The induction of these genes was confirmed by RT-PCR of samples obtained from $NtNEK2^{DD}$ plants. Additionally, when compared with other isolated DEGs, the pI2-4, CDM1 and HRGP genes were significantly up-regulated in response to treatment with salicylic acid and tobacco mosaic virus. Taken together, these results suggest that three novel DEGs were regulated by the NtMEK2-SIPK/WIPK cascade involved in disease resistance in tobacco.