• Journal of Life Science
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• v.33 no.11
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• pp.944-949
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• 2023

The purpose of this study was to identify conserved metabolic pathways and conserved genes in 122 archaeal species. Using the Clusters of Orthologous Groups of Proteins (COG) database of conserved genes, we analyzed whether 122 species had 63 COG metabolic pathways, the 822 COGs that compose them, and a total of 4,877 COGs. Archaeal ribosomal proteins were the most conserved in metabolic pathways. 46 COGs in seven COG pathways among 63 COG pathways and 20 COGs in others were conserved in 122 species. Some genes involved in cell wall and extracellular matrix synthesis, replication, transcription, translation, and protein metabolism were common to all 122 species. When the distance value of the phylogenetic tree was analyzed at the phylum level or class level, the average was the lowest at the class Halobacteria of the phylum Euryarchaeota. Standard deviation was high for the class Nitosospharia of the phylum Thaumarchaeota, the unclassified members of phylum Thaumarchaeota, the class Halobacteria of the phylum Euryarchaeota, the class Thermoprotei of the phylum Crenarchaeota, and other archaea. Furthermore, the phylogenetic tree analysis revealed six commonalities. The results of this study, along with data on conserved genes, could be used for drug development and gene selection for strain improvement.

• Molecules and Cells
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• v.46 no.10
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• pp.592-610
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• 2023

The Hippo kinase cascade functions as a central hub that relays input from the "outside world" of the cell and translates it into specific cellular responses by regulating the activity of Yes-associated protein 1 (YAP1). How Hippo translates input from the extracellular signals into specific intracellular responses remains unclear. Here, we show that transforming growth factor β (TGFβ)-activated TAK1 activates LATS1/2, which then phosphorylates YAP1. Phosphorylated YAP1 (p-YAP1) associates with RUNX3, but not with TEAD4, to form a TGFβ-stimulated restriction (R)-point-associated complex which activates target chromatin loci in the nucleus. Soon after, p-YAP1 is exported to the cytoplasm. Attenuation of TGFβ signaling results in re-localization of unphosphorylated YAP1 to the nucleus, where it forms a YAP1/TEAD4/SMAD3/AP1/p300 complex. The TGFβ-stimulated spatiotemporal dynamics of YAP1 are abrogated in many cancer cells. These results identify a new pathway that integrates TGFβ signals and the Hippo pathway (TGFβ→TAK1→LATS1/2→YAP1 cascade) with a novel dynamic nuclear role for p-YAP1.

• Biomolecules & Therapeutics
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• v.32 no.1
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• pp.84-93
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• 2024

Rosmarinic acid (RA) is a phenolic ester that protects human keratinocytes against oxidative damage induced by ultraviolet B (UVB) exposure, however, the mechanisms underlying its effects remain unclear. This study aimed to elucidate the cell signaling mechanisms that regulate the antioxidant activity of RA and confirm its cyto-protective role. To explore the signaling mechanisms, we used the human keratinocyte cell line HaCaT and SKH1 hairless mouse skin. RA enhanced glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione synthetase (GSS) expression in HaCaT cells in a dose- and time-dependent manner. Moreover, RA induced nuclear factor erythroid-2-related factor 2 (NRF2) nuclear translocation and activated the signaling kinases protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, the ERK inhibitor U0126, and small interfering RNA (siRNA) gene silencing suppressed RA-enhanced GCLC, GSS, and NRF2 expression, respectively. Cell viability tests showed that RA significantly prevented UVB-induced cell viability decrease, whereas the glutathione (GSH) inhibitors buthionine sulfoximine, LY294002, and U0126 significantly reduced this effect. Moreover, RA protected against DNA damage and protein carbonylation, lipid peroxidation, and apoptosis caused by UVB-induced oxidative stress in a concentration-dependent manner in SKH1 hairless mouse skin tissues. These results suggest that RA protects against UVB-induced oxidative damage by activating AKT and ERK signaling to regulate NRF2 signaling and enhance GSH biosynthesis. Thus, RA treatment may be a promising approach to protect the skin from UVB-induced oxidative damage.

• Journal of the Society of Cosmetic Scientists of Korea
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• v.50 no.1
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• pp.67-75
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• 2024

Skin aging progresses due to external factors such as ultraviolet rays and infections. These factors cause skin fibroblasts to secrete proteolytic enzymes, matrix metalloproteinases (MMPs). MMPs induce the degradation of collagen located in the extracellular matrix, directly influencing aging. The stems of Akebia quinata Decaisne have been reported to have antioxidant and anti-inflammatory effects. However, the anti-aging effect of Akebia quinata Decaisne stem ethanol extract (AQSEE) is not known. Therefore, we studied the TNF-α-induced MMP-1 inhibitory effect in human fibroblasts. When the cell viability of AQSEE was confirmed through MTT asaay, it showed no toxicity up to 400 ㎍/mL. The inhibition of MMP-1 mRNA and protein secretion was confirmed through RT-qPCR and ELISA, and results showed a significant decrease at concentrations of 100, 200, 400 ㎍/mL. We also confirmed by Western blotting that phosphorylation of MAPKs signaling pathway and transcription factors was reduced. As a result, phosphorylation of p38, c-Jun, p65 was significantly decreased at all concentrations. DPPH and ABTS assays were performed to confirm the radical scavenging ability of AQSEE, and the results showed a significant decrease at all concentrations. The results of this study confirmed the MMP-1 inhibitory effect and radical scavenging ability, which suggests that it can be used as an anti-aging substance.

• Korean Journal of Radiology
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• v.24 no.10
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• pp.983-995
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• 2023

Objective: To compare the diagnostic performance and interobserver agreement between contrast-enhanced computed tomography (CECT) and contrast-enhanced magnetic resonance imaging (CE-MRI) with magnetic resonance cholangiopancreatography (MRCP) for evaluating the resectability in patients with extrahepatic cholangiocarcinoma (eCCA). Materials and Methods: This retrospective study included treatment-naïve patients with pathologically confirmed eCCA, who underwent both CECT and CE-MRI with MRCP using extracellular contrast media between January 2015 and December 2020. Among the 214 patients (146 males; mean age ± standard deviation, 68 ± 9 years) included, 121 (56.5%) had perihilar cholangiocarcinoma. R0 resection was achieved in 108 of the 153 (70.6%) patients who underwent curative-intent surgery. Four fellowship-trained radiologists independently reviewed the findings of both CECT and CE-MRI with MRCP to assess the local tumor extent and distant metastasis for determining resectability. The pooled area under the receiver operating characteristic curve (AUC), sensitivity, and specificity of CECT and CE-MRI with MRCP were compared using clinical, surgical, and pathological findings as reference standards. The interobserver agreement of resectability was evaluated using Fleiss kappa (κ). Results: No significant differences were observed between CECT and CE-MRI with MRCP in the pooled AUC (0.753 vs. 0.767), sensitivity (84.7% [366/432] vs. 90.3% [390/432]), and specificity (52.6% [223/424] vs. 51.4% [218/424]) (P > 0.05 for all). The AUC for determining resectability was higher when CECT and CE-MRI with MRCP were reviewed together than when CECT was reviewed alone in patients with discrepancies between the imaging modalities or with indeterminate resectability (0.798 [0.754-0.841] vs. 0.753 [0.697-0.808], P = 0.014). The interobserver agreement for overall resectability was fair for both CECT (κ = 0.323) and CE-MRI with MRCP (κ = 0.320), without a significant difference (P = 0.884). Conclusion: CECT and CE-MRI with MRCP showed no significant differences in the diagnostic performance and interobserver agreement in determining the resectability in patients with eCCA.

• Korean Journal of Radiology
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• v.24 no.11
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• pp.1081-1092
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• 2023

Objective: To investigate the incidence of microvascular myocardial ischemia in diabetic patients without obstructive coronary artery disease (CAD) and its relationship with angina. Materials and Methods: Diabetic patients and an intermediate-to-high pretest probability of CAD were prospectively enrolled. Non-diabetic patients but with an intermediate-to-high pretest probability of CAD were retrospectively included as controls. The patients underwent dynamic computed tomography-myocardial perfusion imaging (CT-MPI) and coronary computed tomography angiography (CCTA) to quantify coronary stenosis, myocardial blood flow (MBF), and extracellular volume (ECV). The proportion of patients with microvascular myocardial ischemia, defined as any myocardial segment with a mean MBF ≤ of 100 mL/min/100 mL, in patients without obstructive CAD (Coronary Artery Disease-Reporting and Data System [CAD-RADS] grade 0-2 on CCTA) was determined. Various quantitative parameters of the patients with and without diabetes without obstructive CAD were compared. Multivariable analysis was used to determine the association between microvascular myocardial ischemia and angina symptoms in diabetic patients without obstructive CAD. Results: One hundred and fifty-two diabetic patients (mean age: 59.7 ± 10.7; 77 males) and 266 non-diabetic patients (62.0 ± 12.3; 167 males) were enrolled; CCTA revealed 113 and 155 patients without obstructive CAD, respectively. For patients without obstructive CAD, the mean global MBF was significantly lower for those with diabetes than for those without (152.8 mL/min/100 mL vs. 170.4 mL/min/100 mL, P < 0.001). The mean ECV was significantly higher for diabetic patients (27.2% vs. 25.8%, P = 0.009). Among the patients without obstructive CAD, the incidence of microvascular myocardial ischemia (36.3% [41/113] vs. 10.3% [16/155], P < 0.001) and interstitial fibrosis (69.9% [79/113] vs. 33.3% [8/24], P = 0.001) were significantly higher in diabetic patients than in the controls. The presence of microvascular myocardial ischemia was independently associated with angina symptoms (adjusted odds ratio = 3.439, P = 0.037) in diabetic patients but without obstructive CAD. Conclusion: Dynamic CT-MPI + CCTA revealed a high incidence of microvascular myocardial ischemia in diabetic patients without obstructive CAD. Microvascular myocardial ischemia is strongly associated with angina.

• Korean Journal of Radiology
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• v.24 no.9
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• pp.838-848
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• 2023

Objective: To quantitatively analyze the cardiac magnetic resonance imaging (CMR) characteristics of chemotherapy-related cardiac dysfunction (CTRCD) and explore their prognostic value for major adverse cardiovascular events (MACE). Materials and Methods: A total of 145 patients (male:female = 76:69, mean age = 63.0 years) with cancer and heart failure who underwent CMR between January 2015 and January 2021 were included. CMR was performed using a 3T scanner (Siemens). Biventricular functions, native T1 T2, extracellular volume fraction (ECV) values, and late gadolinium enhancement (LGE) of the left ventricle (LV) were compared between those with and without CTRCD. These were compared between patients with mild-to-moderate CTRCD and those with severe CTRCD. Cox proportional hazard regression analysis was used to evaluate the association between the CMR parameters and MACE occurrence during follow-up in the CTRCD patients. Results: Among 145 patients, 61 had CTRCD and 84 did not have CTRCD. Native T1, ECV, and T2 were significantly higher in the CTRCD group (1336.9 ms, 32.5%, and 44.7 ms, respectively) than those in the non-CTRCD group (1303.4 ms, 30.5%, and 42.0 ms, respectively; P = 0.013, 0.010, and < 0.001, respectively). They were not significantly different between patients with mild-to-moderate and severe CTRCD. Indexed LV mass was significantly smaller in the CTRCD group (65.0 g/m² vs. 78.9 g/mm²; P < 0.001). According to the multivariable Cox regression analysis, T2 (hazard ratio [HR]: 1.14, 95% confidence interval [CI]: 1.01-1.27; P = 0.028) and quantified LGE (HR: 1.07, 95% CI: 1.01-1.13; P = 0.021) were independently associated with MACE in the CTRCD patients. Conclusion: Quantitative parameters from CMR have the potential to evaluate myocardial changes in CTRCD. Increased T2 with reduced LV mass was demonstrated in CTRCD patients even before the development of severe cardiac dysfunction. T2 and quantified LGE may be independent prognostic factors for MACE in patients with CTRCD.

• Journal of The Korean Society of Integrative Medicine
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• v.12 no.1
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• pp.1-10
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• 2024

Purpose: Lycopene is abundantly contained in Tomatoes and is known for diverse biological activities such as antioxidant, anti-inflammatory, and anticancer effects. In this study, the antioxidative potential of lycopene was investigated through the induction of hemeoxygenase (HO)-1 by nuclear factor-erythroid 2 p45-related factor2 (Nrf2) and upstream signaling molecules, mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Aktin RAW 264.7 cells. Methods: The antioxidative potential of lycopene against oxidative stress and its molecular mechanisms were determined by the cell viability assay, intracellular reactive oxygen species (ROS) formation assay, and Western blot analysis in RAW 264.7 cells. Results: Lycopene treatment significantly attenuated tert-butyl hydroperoxide (t-BHP) induced intracellular ROS formation in a dose-dependent manner without any cytotoxicity. In addition, 50 µM of lycopene for 6 h treatment induced potent HO-1 expression and its transcription factor, Nrf2. MAPK and PI3K/Aktwere also analyzed due to their critical roles in the regulation of cellular redox homeostasis against oxidative damage. As a result, phosphorylation of extracellular regulated kinase (ERK) was significantly induced by lycopene treatment while the activated status of c-Jun NH2-terminal kinase (JNK), p38, and Akt, were not given any effect. To confirm the antioxidative mechanism of HO-1 mediated by ERK activation, each selective inhibitor was employed in a protection assay, in which oxidative damage occurred by t-BHP. Lycopene, SnPP, and CoPP treatments reflected accelerated HO-1 expression could be a protective role against oxidative damage-initiated cell death. A selective inhibitor for ERK significantly inhibited the lycopene-induced cytoprotective effect but selective inhibitors for other signaling molecules did not attenuate the rate of t-BHP-induced cell death. Conclusion: In conclusion, lycopene potently scavenged intracellular ROS formation and enhanced the HO-1 mediated antioxidative potential through the modulation of Nrf2, MAPK signaling pathway in RAW 264.7 cells.

• Journal of The Korean Society of Integrative Medicine
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• v.12 no.1
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• pp.63-71
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• 2024

Purpose : Skin is the primary barrier to protect the body from various exogenous factors. Among them, UVB exposure can cause the induction of not only excessive inflammatory responses but also the degradation of extracellular matrix (ECM), including collagen and elastin. This study tried to investigate the ameliorative effect of Persicaria perfoliata ethanol extract (PPEE) on UVB-irradiated photodamage through the regulation of activator protein (AP)-1, phosphoinositide 3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) signaling molecules in HaCaT cells. Methods : The cytotoxicity of PPEE on HaCaT cells was evaluated by the WST-1 assay. The 80 mJ/cm² of UVB (312 nm) was irradiated on HaCaT cells to induce the photodamage. Western blot analysis was conducted to investigate the protein expression levels of cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-9, and heme oxygenase (HO)-1 for ameliorative status by PPEE treatment in UVB-exposed HaCaT cells. In addition, the activated status of the inflammatory transcription factor, AP-1, as well as upstream signaling molecules, PI3K/Akt, and MAPK, were also evaluated by Western blot analysis. Results : Any cytotoxic effect was not induced at the concentration up to 200 ㎍/ml by PPEE treatment. Protein expression levels of COX-2 and MMP-9 were significantly down- and up-regulated by PPEE treatment. The inflammatory transcription factor AP-1, stimulated by UVB irradiation, was also significantly attenuated by PPEE treatment. The phosphorylated status of PI3K/Akt and MAPK were mitigated by PPEE treatment in UVB-exposed HaCaT cells. Moreover, PPEE treatment potently accelerated the expression of HO-1 and its transcription factor, nuclear factor-erythroid 2-related factor (Nrf)2, which is known for its anti-inflammatory activity. Conclusion : Consequently, PPEE treatment significantly regulated COX-2 and MMP-9 expressions in UVB-irradiated HaCaT cells. The inflammatory transcription factor AP-1, along with upstream signaling molecules PI3K/Akt and MAPKs, were also attenuated by PPEE treatment in UVB-exposed HaCaT cells. Additionally, PPEE treatment exaggerated HO-1 expression and Nrf2 activation, which might have contributed to the anti-inflammatory activity of PPEE. These results indicate that PPEE could be a candidate for attenuating UVB-induced photodamage in human skin.

• Journal of Life Science
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• v.34 no.2
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• pp.94-104
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• 2024

β-Lapachone is a natural quinone compound originally obtained from the bark of the lapacho tree (Tabebuia vellanedae), which has been used in traditional medicine in several South and Central American countries for treating various diseases. Although β-lapachone has been reported to have potent anticancer activity in many types of cancer cells, its effect on the proliferation of hepatocellular carcinoma (HCC) cells is still unclear. Therefore, in this study, we investigated the effect of β-lapachone on the proliferation of human HCC Hep3B cells. According to our results, the decrease in cell viability of Hep3B cells caused by β-lapachone was closely related to the induction of apoptosis, which was confirmed through changes in nuclear morphology and flow cytometry. In addition, in Hep3B cells treated with β-lapachone, the expression of Bcl-2, an anti-apoptotic factor, was decreased, while the expression of Bax, an apoptosis inducer, was increased, and the activity of the caspase cascade was also increased. However, in the presence of a pan-caspase inhibitor, β-lapachone-induced apoptosis was weakened, indicating that the induction of apoptosis by β-lapachone was caspase-dependent. Moreover, β-lapachone treatment activated extracellular-regulated kinase (ERK) signaling while inhibiting activation of the phosphoinositide 3 kinase (PI3K)/Akt pathway. Furthermore, the effect of the ERK inhibitor on suppressing the induction of apoptosis by β-lapachone was minimal, and the PI3K inhibitor significantly increased β-lapachone-induced apoptosis. The findings from this study will contribute to a better understanding of the anticancer activity of β-lapachone in HCC cells.