• Journal of Ginseng Research
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• v.45 no.2
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• pp.264-272
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• 2021

Background: Gintonin is a ginseng-derived exogenous G-protein-coupled lysophosphatidic acid (LPA) receptor ligand, which exhibits in vitro and in vivo functions against Alzheimer disease (AD) through lysophosphatidic acid 1/3 receptors. A recent study demonstrated that systemic treatment with gintonin enhances paracellular permeability of the blood-brain barrier (BBB) through the LPA1/3 receptor. However, little is known about whether gintonin can enhance brain delivery of donepezil (DPZ) (Aricept), which is a representative cognition-improving drug used in AD clinics. In the present study, we examined whether systemic administration of gintonin can stimulate brain delivery of DPZ. Methods: We administered gintonin and DPZ alone or coadministered gintonin with DPZ intravenously or orally to rats. Then we collected the cerebral spinal fluid (CSF) and serum and determined the DPZ concentration through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Results: Intravenous, but not oral, coadministration of gintonin with DPZ increased the CSF concentration of DPZ in a concentration- and time-dependent manner. Gintonin-mediated enhancement of brain delivery of DPZ was blocked by Ki16425, a LPA1/3 receptor antagonist. Coadministration of vascular endothelial growth factor (VEGF) + gintonin with DPZ similarly increased CSF DPZ concentration. However, gintonin-mediated enhancement of brain delivery of DPZ was blocked by axitinip, a VEGF receptor antagonist. Mannitol, a BBB disrupting agent that increases the BBB permeability, enhanced gintonin-mediated enhancement of brain delivery of DPZ. Conclusions: We found that intravenous, but not oral, coadministration of gintonin facilitates brain delivery of DPZ from plasma via LPA1/3 and VEGF receptors. Gintonin is a potential candidate as a ginseng-derived novel agent for the brain delivery of DPZ for treatment of patients with AD.

• The Korean Journal of Pharmacology
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• v.31 no.1 s.57
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• pp.27-37
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• 1995

In anesthetized rats, we examined the possibility that endothelium-derived relaxing factor (EDRF) or nitric oxide (NO) released in response to cholinergic mechanism may contribute to the reflex autoregulation of cerebral blood flow. Suffusion with mock cerebrospinal fluid (CSF), containing acetylcholine (ACh, $10^{-9}{\sim}10^{-6}M$) evoked concentration-dependent vasodilatation of the resting pial artery (mean, $19.3{\pm}1.7{\mu}m$, n=36), which was significantly inhibited not only by $N{\omega}$-nitro-L-arginine (L-NNA, $10^{-5}M$) but also by methylene blue ($10^{-6}M$) and oxyhemoglobin ($10^{-6}M$). The muscarinic receptors in the endothelium of pial artery implicated in the release of EDRF were considered to be $M_1\;and\;M_3$ subtypes. When suffused with mock CSF containing L-arginine it caused a transient vasodilatation, which was strongly inhibited by LY 83583 ($10^{-5}M$), but not by L-NNA ($10^{-5}M$). Additionally, both ACh- and L-arginine-induced vasodilation were significantly inhibited by glibenclamide, a specific ATP-sensitive $K^+$ channel blocker. On the other hand, changes in pial arterial diameter were plotted as a function of changes in systemic arterial blood pressure. The slopes of regression lines for vasodilation and vasoconstriction were not affected by pretreatment with $10^{-5}M$ L-NNA, but significantly reduced by $3{\times}10^{-6}M$ glibenclamide. Thus it is suggested that the reflex vasodilation of rat pial arteries in response to a transient hypotension is not mediated by EDRF (NO).

• Journal of Animal Science and Technology
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• v.55 no.2
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• pp.95-101
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• 2013

The present study was conducted to test a hypothesis that pork quality traits would be influenced by the systemic and/or local bioavailability of insulin-like growth factor-I (IGF-I), transforming growth factor-${\beta}1$ (TGF-${\beta}1$), or epidermal growth factor (EGF) before or at slaughter. To this end, 60 cross-bred female market pigs weighing approximately 110 kg were slaughtered, after which Longissimus dorsi muscle (LM) samples taken at slaughter (D 0) and blood samples taken at D -7 and D 0 were analyzed. The 60 carcasses rendered 36 RFN (reddish-pink, firm, and non-exudative), 16 RSE (reddish-pink, soft, and exudative), and 6 PSE (pale, soft, and exudative); 2 DFD (dark, firm, and dry) also were found but were excluded in subsequent experiments. The $L^*$ and drip loss were greater in PSE vs. RFN and RSE and in PSE and RSE vs. RFN, respectively, as they should (P<0.05). The $pH_{45min}$ was less in PSE vs. RFN (P<0.05); $pH_{24h}$ tended to be less in the former (P=0.09). The LM IGF-I and TGF-${\beta}1$ as well as serum EGF concentrations were less in PSE than in RFN. None of the other LM and serum concentrations of the three growth factors differed across the three pork quality categories. The LM IGF-I and TGF-${\beta}1$ concentrations and serum EGF concentration at D 0 were negatively correlated with drip loss [r = -0.36(P<0.01), -0.44 (P<0.01), and -0.32 (P<0.05), respectively]. However, none of the serum and LM growth factor variables was correlated with $L^*$ or $a^*$ (redness) of LM. Taken together, results suggest that locally expressed IGF-I and TGF-${\beta}1$ and blood-borne EGF may have a beneficial effect on postmortem water holding capacity of the muscle and that pork quality traits could be predicted to some extent from concentrations of IGF-I and TGF-${\beta}1$ in muscle and EGF in serum at slaughter.

• Journal of the Korean Society of Laryngology, Phoniatrics and Logopedics
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• v.32 no.1
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• pp.15-23
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• 2021

Background and Objectives During speech, the vocal folds oscillate at frequencies ranging from 100-200 Hz with amplitudes of a few millimeters. Mechanical stimulation is an essential factor which affects metabolism of human vocal folds. The effect of mechanical vibration on the cellular response in the human vocal fold fibroblasts cells (hVFFs) was evaluated. Materials and Method We created a culture systemic device capable of generating vibratory stimulations at human phonation frequencies. To establish optimal cell culture condition, cellular proliferation and viability assay was examined. Quantitative real time polymerase chain reaction was used to assess extracellular matrix (ECM) related and growth factors expression on response to changes in vibratory frequency and amplitude. Western blot was used to investigate ECM and inflammation-related transcription factor activation and its related cellular signaling transduction pathway. Results The cell viability was stable with vibratory stimulation within 24 h. A statistically significant increase of ECM genes (collagen type I alpha 1 and collagen type I alpha 2) and growth factor [transforming growth factor β1 (TGF-β1) and fibroblast growth factor 1 (FGF-1)] observe under the experimental conditions. Vibratory stimulation induced transcriptional activation of NF-κB by phosphorylation of p65 subunit through cellular Mitogen-activated protein kinases activation by extracellular signal regulated kinase and p38 mitogen-activated protein kinases (MAPKs) phosphorylation on hVFFs. Conclusion This study confirmed enhancing synthesis of collagen, TGF-β1 and FGF was testified by vibratory stimulation on hVFFs. This mechanism is thought to be due to the activation of NF-κB and MAPKs. Taken together, these results demonstrate that vibratory bioreactor may be a suitable alternative to hVFFs for studying vocal folds cellular response to vibratory vocalization.

• Korean Journal of Clinical Laboratory Science
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• v.55 no.4
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• pp.306-313
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• 2023

Sepsis is a systemic inflammatory response, with manifestations in multiple organs by pathogenic infection. Currently, there are no promising therapeutic strategies. Signal transducer and activator of transcription 3 (STAT3) is a cell signaling transcription factor. Niclosamide is an anti-helminthic drug approved by the Food and Drug Administration (FDA) as a potential STAT3 inhibitor. C57BL/6 mice were treated with an intraperitoneal injection of lipopolysaccharide (LPS). Niclosamide was administered orally 2 hours after the LPS injection. This study found that Niclosamide improved the survival and lung injury of LPS-induced mice. Niclosamide decreased the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) in serum. The effects of Niclosamide on phosphoinositide 3-kinase (PI3K), AKT, nuclear factor-κB (NF-κB), and STAT3 signaling pathways were determined in the lung tissue by immunoblot analysis. Niclosamide reduced phosphorylation of PI3K, AKT, NF-κB, and STAT3 significantly. Furthermore, it reduced the phosphorylation of STAT3 by LPS stimulation in RAW 264.7 macrophages. Niclosamide also reduced the LPS-stimulated expression of proinflammatory mediators, including IL-6, TNF-α, and IL-1β. Niclosamide provides a new therapeutic strategy for murine sepsis models by suppressing the inflammatory response through STAT3 inhibition.

• Tuberculosis and Respiratory Diseases
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• v.53 no.4
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• pp.379-388
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• 2002

Background : Although patients with stage IV non-small cell lung cancer are known to have a poor prognosis, the prognostic factors for survival have not been well evaluated. Such factors may be different from those for overall survival. This study was performed to analyze the prognostic factors for survuval and the variation of survival according to metastatic organ, in patients with stage IV non-small cell lung cancer. Materials and Methods : From January 1997 to December 2000, 151 patients with confirmed stage IV non-small cell lung cancer were enrolled into this study retrospectively. The clinical and laboratory data were analyzed using univareate Kaplan-Meied and Multivariate Cox regression models. Results : On univariate analysis, age, performance status, serum albumin level, weight loss, forced expiratory volume in one second (FEV1), systemic chemotherapy, the number of metastatic organs and serum lactate dehydrogenase (LDH) level were significant factors (p<0.05). In multivariate analysis, important factors for survival were ECOG performance (relative risk of death [RR]: 2.709), systemic chemotherapy (RR: 1.944), serum LDH level (RR: 1.819) and FEV1 (RR: 1.774) (p<0.05), Metastasis to the brain and liver was also a significant factor on univariate analysis). The presence of single lung metastasis was associated with better survival than that of other metastatic organs (p=0.000). Conclusion : We confirmed that performance status and systemic chemotherapy were independent prognostic factors, as has been recognized. The survival of stage IV non-small cell lung cancer patients was different according to the metastatic organs. Among the metastatic sites, only patients with metastasis to the lung showed bettrer survival than that of other sites, while metastasis of the brain or liver was associated with worse survival than that of other sites.

• Tuberculosis and Respiratory Diseases
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• v.40 no.5
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• pp.474-482
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• 1993

Background: As a physiologic plasminogen activator, tissue-type plasminogen activator (t-PA) could induce effective thrombolysis in massive pulmonary embolism, without the risk of systemic hemorrhage. However, therapeutic doses of t-PA has been associated with systemic lytic state, and fibrin selectivity may be influenced by the dosing regimen of t-PA. To investigate the effects of duration of t-PA infusion on blood coagulation system, we performed this study. Method: In a canine model of pulmonary embolism, which was induced by injection of autologous blood clots, we administered equal doses of t-PA (1 mg/kg) over 15 minutes in $t-PA_{15}$ group, over 180 minutes in $t-PA_{180}$ group, and only saline in control group. Then serial blood samplings were made to check complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, fibrin, plasminogen, ${\alpha}_2$-antiplasmin, coagulation factor V and VIII, and fibrin(ogen) degradation products. Results: 1) In all 3 groups, complete blood count showed same changes. Hemoglobin, hematocrit and platelet count decreased, but WBC count increased. 2) Prothrombin time, activated partial thromboplastin time, and thrombin time were prolonged during 15-60 minutes after t-PA administration in $t-PA_{15}$ group, and from 30 minutes through 180 minutes after administration in $t-PA_{180}$ gorup. 3) Fibrin, ${\alpha}_2$-antiplasmin, and cogulation factor V and VIII decreased in both $t-PA_{15}$ and $t-PA_{180}$ group, but returned to basal levels earlier in $t-PA_{15}$ group. 4) Fibrin(ogen) degradation products increased after pulmonary embolism in all groups, and further increased in both $t-PA_{15}$ and $t-PA_{180}$ groups after t-PA infusion. But more pronounced increment was noted in $t-PA_{180}$ gorup. Conclusion: In pulmonary embolism, the shorter (15 minutes) infusion of t-PA would have less risk of systemic hemorrhage than the longer (180 minutes) infusion when the doses is equal. And, this suggests that manipulating the duration of t-PA infusion can reduce the risk of major bleeding.

• Natural Product Sciences
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• v.13 no.3
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• pp.263-267
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• 2007

The mast cell-mediated immediate-type allergic reaction is involved in many allergic diseases such as asthma, allergic rhinitis, and sinusitis. The discovery of drugs for the treatment of mast cell-mediated immediate-type allergic diseases is a very important subject in human health. In this study, we investigated the effect of small black soybean (Glycine max Merr.) (Leguminosae) on mast cell-mediated allergic reaction and pro-inflammatory cytokine secretion. Small black soybean (SBS) inhibited compound 48/80-induced systemic reaction. SBS attenuated immunoglobulin (Ig) E-mediated local allergic reaction. In addition, SBS decreased the phorbol 12-myristate 13-acetate plus calcium ionophore A23187-stimulated tumor necrosis factor $(TNF)-{\alpha}$ and interleukin (IL)-8 secretion in human mast cells. These results indicate that SBS may be beneficial in the treatment of mast cell-mediated immediate-type allergic reactions.

• The Korean Journal of Food And Nutrition
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• v.21 no.4
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• pp.430-435
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• 2008

The main cause of diabetic neuropathy, one of the most debilitating complications, is the chronic hyperglycemia, the increase sorbitol or the decrease of nerve growth factor(NGF). NGF, a protein, plays a major role in the development and maintenance of peripheral nervous system. Systemic administration of NGF prevents manifestations of neuropathy in rodent models of diabetic neuropathy. In the previous investigation, we report the hypoglycemia effect of Dioscorea rhizoma extract(DRE) in diabetic mice. The present study shows protective effect of DRE on diabetic neuropathy by induction of NGF protein. We investigated the NGF level in salivary gland and sciatic nerve of normal mouse and the effect of DRE on sciatic nerve conductivity and thermal hyperalgesia test in Type 2 db/db mouse. DRE increased endogenous NGF level in salivary gland and sciatic nerve of mouse. And sensory nerve conductivity velocity(SNCV), motor nerve conductivity velocity(MNCV) and thermal hyperalgesia increased in DRE treatment mice compared with control group. On the basis of our results, we conclude that DRE increase induction of endogenous NGF level and have protective effect on diabetic neuropathy by induction of NGF. Therefore, we propose that long-term use of DRE might help prevention of diabetes-associated complication; diabetic neuropathy.

• Journal of Gastric Cancer
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• v.20 no.3
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• pp.233-244
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• 2020

Purpose: For unresectable or initially metastatic gastric cancer, conversion surgery (CVS), after systemic chemotherapy, has received attention as a treatment strategy. This study evaluated the prognostic value of ypTNM stage and the oncologic outcomes in patients receiving CVS. Materials and Methods: A retrospective review of clinicopathologic findings and oncologic outcomes of 116 patients who underwent CVS with curative intent, after combination chemotherapy, between January 2000 and December 2015, has been reported here. Results: Twenty-six patients (22.4%) underwent combined resection of another organ and 12 patients received para-aortic lymphadenectomy (10.3%). Pathologic complete remission (CR) was confirmed in 11 cases (9.5%). The median overall survival (OS) and disease-free survival (DFS) times were 35.0 and 21.3 months, respectively. In multivariate analysis, ypTNM stage was the sole independent prognostic factor for DFS (P=0.042). Tumors invading an adjacent organ or involving distant lymph nodes showed better survival than those with peritoneal seeding or solid organ metastasis (P=0.084). Kaplan-Meier curves showed that the 3-year OS rate of patients with pathologic CR and those with CR of the primary tumor but residual node metastasis was 81.8% and 80.0%, respectively. OS was 65.8% for stage 1 patients, 49.8% for those at stage 2, and 36.3% for those at stage 3. Conclusions: The ypTNM staging is a significant prognostic factor in patients who underwent CVS for localized unresectable or stage IV gastric cancers. Patients with locally advanced but unresectable lesions or with tumors with distant nodal metastasis may be good candidates for CVS.