• The Korea Journal of Herbology
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• v.34 no.3
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• pp.1-7
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• 2019

Objectives : Amyloid ${\beta}(A{\beta})$ could induce cognitive deficits through oxidative stress, inflammation, and neuron death in Alzheimer's disease (AD). This study was investigated the effect of Angelica keiskei KOIDZUMI (AK) on memory in $A{\beta}$-induced an AD model. Methods : AK was extracted uses 70% ethanol solvent. Total polyphenol and flavonoids content were obtained by the Folin-Ciocalteu and the Ethylene glycol colorimetric methods, respectively. The antioxidant activities were assessed through free radical scavenging assays using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazolin-6-sulfonic acid) (ABTS) methods. Intracerebroventrical (i.c.v) injection of $A{\beta}$ 1-42 was used to induce AD in male ICR mice, followed by administrations of 5, 10 or 20 mg/kg AK on a daily. Animals were subjected to short and long term memory behavior in Y-maze and passive avoidance test. Results : The total polyphenol and flavonoids contents of the AK extract were $88.73{\pm}6.36mg$ gallic acid equivalent/g, $84.21{\pm}5.04mg$ rutin equivalent/g, respectively. The assays of DPPH and ABTS revealed that AK extract in treated concentrations (31.25, 62.5, 125, 250, 500, $1000{\mu}g/m{\ell}$) increased antioxidant activity in a dose-dependent manner. Oral administration of AK extract significantly reversed the $A{\beta}$ 1-42-induced decreasing of the spontaneous alternation in the Y-maze test and $A{\beta}$ 1-42-induced shorting of the step-through latency in the passive avoidance test. Conclusions : The findings suggest that AK indicated the antioxidant protective effects against $A{\beta}$-induced memory deficits, and therefore a potential lead natural therapeutic drug or agent for AD.

• Biomolecules & Therapeutics
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• v.30 no.4
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• pp.360-367
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• 2022

Tropomyosin receptor kinase A (TrkA) protein is a receptor tyrosine kinase encoded by the NTRK1 gene. TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its ligand, the nerve growth factor. Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion protein, which is known to cause deregulation of TrkA signaling. Targeting TrkA activity represents a promising strategy for the treatment of cancers that harbor the TrkA fusion protein. In this study, we evaluated the TrkA-inhibitory activity of the benzoxazole compound KRC-108. KRC-108 inhibited TrkA activity in an in vitro kinase assay, and suppressed the growth of KM12C colon cancer cells harboring an NTRK1 gene fusion. KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy. KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt, phospholipase Cγ, and ERK1/2. Furthermore, KRC-108 exhibited antitumor activity in vivo in a KM12C cell xenograft model. These results indicate that KRC-108 may be a promising therapeutic agent for Trk fusion-positive cancers.

• Korean Journal of Agricultural Science
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• v.49 no.1
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• pp.137-149
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• 2022

We investigated the effects of Cirsium japonicum var. maackii (CJM) against oxidative stress-induced C6 glial cells and cognitive impairment in mice. To evaluate the anti-oxidative effect of the extract and fractions from CJM, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), reactive oxygen species (ROS), and nitric oxide (NO) assays were conducted in H₂O₂-treated C6 glial cells. Furthermore, we identified the protective mechanisms of CJM with a scopolamine-treated mice model. The results revealed that H₂O₂ decreased the cell viability in C6 glial cells, indicating that H₂O₂ induced oxidative stress in glial cells. However, CJM fractions significantly increased cell viability in H₂O₂-treated C6 glial cells, which suggested that CJM protected against oxidative stress. CJM extract and fractions also reduced ROS and NO production, which were increased by H₂O₂ in C6 glial cells. In particular, the EtOAc fraction from CJM (EACJM) effectively protected against oxidative stress by increasing the cell viability and decreasing ROS and NO. Therefore, we carried out further in vivo experiments with EACJM. Scopolamine caused increases of ROS, thiobarbituric acid reactive substances (TBARS), and NO production. However, EACJM effectively alleviated ROS, TBARS, and NO levels compared to scopolamine-injected mice. In addition, EACJM up-regulated protein expressions of superoxide dismutase and glutathione peroxidase, indicating that EACJM enhanced the antioxidative system. Our results demonstrated that CJM had protective effects against oxidative stress in glial cells and memory dysfunction in mice. Based on these results, we propose that CJM could be a potential AD preventive and therapeutic agent.

• Biomolecules & Therapeutics
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• v.31 no.2
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• pp.200-209
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• 2023

Patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) amplification or sensitive mutations initially respond to the tyrosine kinase inhibitor gefitinib, however, the treatment becomes less effective over time by resistance mechanism including mesenchymal-epithelial transition (MET) overexpression. A therapeutic strategy targeting MET and EGFR may be a means to overcoming resistance to gefitinib. In the present study, we found that picropodophyllotoxin (PPT), derived from the roots of Podophyllum hexandrum, inhibited both EGFR and MET in NSCLC cells. The antitumor efficacy of PPT in gefitinib-resistant NSCLC cells (HCC827GR), was confirmed by suppression of cell proliferation and anchorage-independent colony growth. In the targeting of EGFR and MET, PPT bound with EGFR and MET, ex vivo, and blocked both kinases activity. The binding sites between PPT and EGFR or MET in the computational docking model were predicted at Gly772/Met769 and Arg1086/Tyr1230 of each ATP-binding pocket, respectively. PPT treatment of HCC827GR cells increased the number of annexin V-positive and subG1 cells. PPT also caused G2/M cell-cycle arrest together with related protein regulation. The inhibition of EGFR and MET by PPT treatment led to decreases in the phosphorylation of the downstream-proteins, AKT and ERK. In addition, PPT induced reactive oxygen species (ROS) production and GRP78, CHOP, DR5, and DR4 expression, mitochondrial dysfunction, and regulated involving signal-proteins. Taken together, PPT alleviated gefitinib-resistant NSCLC cell growth and induced apoptosis by reducing EGFR and MET activity. Therefore, our results suggest that PPT can be a promising therapeutic agent for gefitinib-resistant NSCLC.

• Journal of Audiology & Otology
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• v.23 no.2
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• pp.69-75
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• 2019

Background and Objectives: The antioxidant ebselen will be able to limit or prevent the ototoxicity arising from 2-hydroxypropyl-β-cyclodextrin (HPβCD). Niemann-Pick Type C (NPC) disease is a disorder of lysosomal storage manifested in sphingolipidosis. Recently, it was noted that experimental use of HPβCD could partially resolve the symptoms in both animals and human patients. Despite its desirable effect, HPβCD can induce hearing loss, which is the only major side effect noted to date. Understanding of the pathophysiology of hearing impairment after administration of HPβCD and further development of preventive methods are essential to reduce the ototoxic side effect. The mechanisms of HPβCD-induced ototoxicity remain unknown, but the resulting pathology bears some resemblance to other ototoxic agents, which involves oxidative stress pathways. To indirectly determine the involvement of oxidative stress in HPβCD-induced ototoxicity, we tested the efficacy of an antioxidant reagent, ebselen, on the extent of inner ear side effects caused by HPβCD. Materials and Methods: Ebselen was applied prior to administration of HPβCD in mice. Auditory brainstem response thresholds and otopathology were assessed one week later. Bilateral effects of the drug treatments also were examined. Results: HPβCD-alone resulted in bilateral, severe, and selective loss of outer hair cells from base to apex with an abrupt transition between lesions and intact areas. Ebselen co-treatment did not ameliorate HPβCD-induced hearing loss or alter the resulting histopathology. Conclusions: The results indirectly suggest that cochlear damage by HPβCD is unrelated to reactive oxygen species formation. However, further research into the mechanism(s) of HPβCD otopathology is necessary.

• Biomolecules & Therapeutics
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• v.31 no.1
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• pp.27-39
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• 2023

Extensive research supported the therapeutic potential of curcumin, a naturally occurring compound, as a promising cytokine-suppressive anti-inflammatory drug. This study aimed to investigate the synergistic anti-inflammatory and anti-cytokine activities by combining 6-shogaol and 10-shogaol to curcumin, and associated mechanisms in modulating lipopolysaccharides and interferon-γ-induced proinflammatory signaling pathways. Our results showed that the combination of 6-shogaol-10-shogaolcurcumin synergistically reduced the production of nitric oxide, inducible nitric oxide synthase, tumor necrosis factor and interlukin-6 in lipopolysaccharides and interferon-γ-induced RAW 264.7 and THP-1 cells assessed by the combination index model. 6-shogaol-10-shogaol-curcumin also showed greater inhibition of cytokine profiling compared to that of 6-shogaol-10-shogaol or curcumin alone. The synergistic anti-inflammatory activity was associated with supressed NFκB translocation and downregulated TLR4-TRAF6-MAPK signaling pathway. In addition, SC also inhibited microRNA-155 expression which may be relevant to the inhibited NFκB translocation. Although 6-shogaol-10-shogaol-curcumin synergistically increased Nrf2 activity, the anti-inflammatory mechanism appeared to be independent from the induction of Nrf2. 6-shogaol-10-shogaol-curcumin provides a more potent therapeutic agent than curcumin alone in synergistically inhibiting lipopolysaccharides and interferon-γ induced proinflammatory mediators and cytokine array in macrophages. The action was mediated by the downregulation of TLR4/TRAF6/MAPK pathway and NFκB translocation.

• Journal of the Korean Society for Geothermal and Hydrothermal Energy
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• v.18 no.4
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• pp.12-21
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• 2022

Steam assisted gravity drainage(SAGD) is a process that drills well in the underground oil sands layer, injects hightemperature steam, lowers the viscosity of buried bitumen, and recovers it to the ground. Recently, direct contact steam generator(DCSG) is being developed to maximize steam efficiency for SAGD process. The DCSG requires high technology to achieve pressurized combustion and steam generation in accordance with underground pressurized conditions. Therefore, it is necessary to develop a combustion technology that can control the heat load and exhaust gas composition. In this study, process analysis of high-pressurized DCSG was conducted to apply oxygen enrichment technology in which nitrogen of the air was partially removed for increasing steam production and reducing fuel consumption. As the process analysis conditions, methane as the fuel and normal air or oxygen enriched air as the oxidizing agent were applied to high-pressurized DCSG process model. A simple combustion reaction program was used to calculate the property variations for combustion temperature, steam ratio and residual heat in exhaust gas. As a major results, the steam production efficiency of DCSG using the pure oxygen was about 6% higher than that of the normal air due to the reducing nitrogen in the air. The results of this study will be used as operating data to test the demonstration device.

• The Journal of Korean Medicine
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• v.43 no.3
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• pp.1-15
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• 2022

Objectives: Myrrh have been used as a traditional remedy to treat infectious and inflammatory diseases. However, it is largely unknown whether myrrh ethanol extract could exhibit the inhibitory activities against particulate matter (PM)-induced skin injury on human keratinocytes, HaCaT cells. Therefore, this study was aimed to investigate the inhibitory activity of myrrh ethanol extract on PM-induced skin injury in HaCaT cells. Methods: To investigate the inhibitory effects of myrrh ethanol extract in HaCaT cells, the skin injury model of HaCaT cells was established under PM treatment. HaCaT keratinocyte cells were pre-treated with myrrh ethanol extract for 1 h, and then stimulated with PM. Then, the cells were harvested to measure the cell viability, reactive oxygen species (ROS), pro-inflammatory cytokines including interleukin (IL) 1-beta, IL-6, and tumor necrosis factor (TNF)-𝛼, hyaluronidase, collagen, MMPs. In addition, we examined the mitogen activated protein kinases (MAPKs) and inhibitory kappa B alpha (I𝜅-B𝛼) as inhibitory mechanisms of myrrh ethanol extract. Results: The treatment of myrrh ethanol extract inhibited the PM-induced cell death and ROS production in HaCaT cells. In addition, myrrh ethanol extract treatment inhibited the PM-induced elevation of IL-1beta, IL-6, and TNF-𝛼. Also, myrrh ethanol extract treatment inhibited the increase of hyaluronidase, MMP and decrease of collagen. Furthermore, myrrh ethanol extract treatment inhibited the activation of MAPKs and the degradation of I𝜅-B𝛼. Conclusions: Our result suggest that treatment of myrrh ethanol extract could inhibit the PM-induced skin injury via deactivation of MAPKs and nuclear factor (NF)-𝜅B in HaCaT cells. This study could suggest that myrrh ethanol extract could be a beneficial agent to prevent skin damage or inflammation.

• Korean Journal of Veterinary Research
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• v.63 no.1
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• pp.6.1-6.9
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• 2023

Stroke is a major cause of death and long-term disability. Chlorogenic acid is a phenolic compound with a potent neuroprotective effect. γ-enolase is a phosphopyruvate hydratase found in mature neurons and plays an important role in neuronal survival. This study investigated whether chlorogenic acid regulates the expression of γ-enolase during cerebral ischemia. Middle cerebral artery occlusion (MCAO) was performed to induce cerebral ischemia. Adult male rats were used and chlorogenic acid (30 mg/kg) or phosphate buffered saline (PBS) was injected intraperitoneally 2 hours after MCAO surgery. Cerebral cortical tissues were collected 24 hours after MCAO surgery. Our proteomic approach identified the reduction of γ-enolase caused by MCAO damage and the mitigation of this reduction by chlorogenic acid treatment. Results of reverse transcription-polymerase chain reaction and Western blot analyses showed a decrease in γ-enolase expression in the PBS-treated MCAO group. However, chlorogenic acid treatment attenuated this decrease. Results of immunofluorescence staining showed the change of γ-enolase by chlorogenic acid treatment. These results demonstrated that chlorogenic acid regulates the γ-enolase expression during MCAO-induced ischemia. Therefore, we suggest that chlorogenic acid mediates the neuroprotective function by regulating the γ-enolase expression in cerebral ischemia and may be used as a therapeutic agent for brain diseases including stroke.

• Korean Journal of Pharmacognosy
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• v.53 no.1
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• pp.49-56
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• 2022

The present study was designed to evaluate the anti-inflammatory and anti-nociceptive potential of the ethyl acetate fraction of Lindera glauca (ELG). We found that ELG significantly suppressed NO production through decreased enzyme activity and expression of iNOS in the IFN-γ/LPS-activated murine peritoneal macrophages. The treatment of ELG also down-regulated the expression of COX-2. Our western blot data revealed that inhibitory effects of ELG on these pro-inflammatory mediators were attributed to inactivation of NF-κB. In addition, ELG-fed mice showed a marked decrease in paw edema induced by subplantar injection of trypsin, suggesting in vivo anti-inflammatory potential of ELG. We further investigated the anti-nociceptive properties of ELG using thermal and chemical nociception model. We found that ELG has a strong anti-nociceptive activities in both central and peripheral mechanism. An additional combination test with naloxone revealed that opioid receptor was not involved in the ELG-mediated anti-nociception. In conclusion, ELG may possibly be used as valuable anti-inflammatory and anti-nociceptive agent for the treatment of inflammatory diseases and pains.