Publications by authors named "Yung Hyun Choi"

668 Publications

Emotional Labor, Burnout, Medical Error, and Turnover Intention among South Korean Nursing Staff in a University Hospital Setting.

Int J Environ Res Public Health 2021 Sep 26;18(19). Epub 2021 Sep 26.

Department of Biochemistry, Dongeui University College of Korean Medicine, Busan 47227, Korea.

Nurses are vulnerable to mental health challenges, including burnout, as they are exposed to adverse job conditions such as high workload. The mental health of this population can relate not only to individual well-being but also to patient safety outcomes. Therefore, there is a need for a mental health improvement strategy that targets this population. This cross-sectional survey study investigates emotional labor, burnout, turnover intention, and medical error levels among 117 nursing staff members in a South Korean university hospital; it also analyzes correlations among outcomes and conduct correlation analysis and multiple regression analysis to determine relationships among these factors. The participants had moderate to high levels of emotional labor and burnout, and 23% had experienced medical errors within the last six months. Save for medical errors, all outcomes significantly and positively correlated with each other. These results can be used to improve the mental health outcomes of nurses working in the hospital and their consequences. Specifically, the job positions of nursing personnel may be a major consideration in such a strategy, and job-focused emotional labor and employee-focused emotional labor may be promising targets in ameliorating turnover intention and client-related burnout, respectively.
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http://dx.doi.org/10.3390/ijerph181910111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507784PMC
September 2021

The Protective Effect of Oral Application of Corni Fructus on the Disorders of the Cornea, Conjunctiva, Lacrimal Gland and Retina by Topical Particulate Matter 2.5.

Nutrients 2021 Aug 27;13(9). Epub 2021 Aug 27.

Department of Biochemistry, College of Korean Medicine, Dong-Eui University, Busan 47227, Korea.

Particulate matter 2.5 (PM) may aggravate dry eye disease (DED). Corni Fructus (CF), which is fruit of Sieb. et Zucc., has been reported to have various beneficial pharmacological effects, whereas the effect of CF on the eye is still unknown. Therefore, in this study, we investigated the effect of oral administration of water extract of CF (CFW) on the eye, hematology, and biochemistry in a DED model induced by topical exposure to PM. Furthermore, the efficacy of CFW compared with cyclosporine (CsA), an anti-inflammatory agent, and lutein, the posterior eye-protective agent. Sprague-Dawley rats were topically administered 5 mg/mL PM in both eyes four times daily for 14 days. During the same period, CFW (200 mg/kg and 400 mg/kg) and lutein (4.1 mg/kg) were orally administered once a day. All eyes of rats in the 0.05% cyclosporine A (CsA)-treated group were topically exposed to 20 μL of CsA, twice daily for 14 days. Oral administration of CFW attenuated the PM-induced reduction of tear secretion and corneal epithelial damage. In addition, CFW protected against goblet cell loss in conjunctiva and overexpression of inflammatory factors in the lacrimal gland following topical exposure to PM. Furthermore, CFW markedly prevented PM-induced ganglion cell loss and recovered the thickness of inner plexiform layer. Meanwhile, CFW treatment decreased the levels of total cholesterol and low-density lipoprotein cholesterol in serum induced by PM. Importantly, the efficacy of CFW was superior or similar to that of CsA and lutein. Taken together, oral administration of CFW may have protective effects against PM-induced DED symptoms via stabilization of the tear film and suppression of inflammation. Furthermore, CFW may in part contribute to improving retinal function and lipid metabolism disorder.
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http://dx.doi.org/10.3390/nu13092986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464674PMC
August 2021

The Protective Effect of Topical Spermidine on Dry Eye Disease with Retinal Damage Induced by Diesel Particulate Matter2.5.

Pharmaceutics 2021 Sep 10;13(9). Epub 2021 Sep 10.

Department of Biochemistry, College of Korean Medicine, Dong-Eui University, Busan 47227, Korea.

Air pollutants, especially ambient fine particulate matter2.5, may contribute to various ocular surface disorders, including dry eye disease, keratitis and conjunctivitis. A natural polyamine spermidine has a protective effect on the retina and optic nerve; however, no study has been conducted on the application of spermidine in particulate matter2.5-induced dry eye disease. In the present study, we investigated the effect of spermidine eye drops in topically exposed particulate matter2.5-induced dry eye models of Sprague-Dawley rats, by hematological, biochemical and histological evaluation. Spermidine eye drops attenuated the particulate matter2.5 exposure-induced reduction of tear secretion and corneal epithelial damage. Furthermore, spermidine protected against conjunctival goblet cell loss and retinal ganglion cell loss induced by particulate matter2.5. Additionally, spermidine markedly prevented particulate matter2.5-induced infiltration of cluster of differentiation3 and cluster of differentiation4 T lymphocytes and F4/80 macrophages on lacrimal gland. Moreover, over expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6 and interleukin-17 in the lacrimal gland and cornea. Meanwhile, the levels of serum total cholesterol and low-density lipoprotein cholesterol were markedly increased by topical exposure to particulate matter2.5, but this change in the lipid profile was decreased by spermidine. Taken together, spermidine may have protective effects against particulate matter2.5-induced dry eye symptoms via stabilization of the tear film and suppression of inflammation and may in part contribute to improving retinal function and lipid metabolism disorder.
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http://dx.doi.org/10.3390/pharmaceutics13091439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468149PMC
September 2021

Fisetin Protects HaCaT Human Keratinocytes from Fine Particulate Matter (PM)-Induced Oxidative Stress and Apoptosis by Inhibiting the Endoplasmic Reticulum Stress Response.

Antioxidants (Basel) 2021 Sep 18;10(9). Epub 2021 Sep 18.

Department of Marine Life Science, Jeju National University, Jeju 63243, Korea.

Fine particulate matter (PM) originates from the combustion of coal and is found in the exhaust of fumes of diesel vehicles. PM readily penetrates the skin via the aryl hydrocarbon receptor, causing skin senescence, inflammatory skin diseases, DNA damage, and carcinogenesis. In this study, we investigated whether fisetin, a bioactive flavonoid, prevents PM-induced apoptosis in HaCaT human keratinocytes. The results demonstrated that fisetin significantly downregulated PM-induced apoptosis at concentrations below 10 μM. Fisetin strongly inhibited the production of reactive oxygen species (ROS) and the expression of pro-apoptotic proteins. The PM-induced apoptosis was associated with the induction of the endoplasmic reticulum (ER) stress response, mediated via the protein kinase R-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4)-CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP) axis. Additionally, the cytosolic Ca levels were markedly increased following exposure to PM. However, fisetin inhibited the expression of ER stress-related proteins, including 78 kDa glucose-regulated protein (GRP78), phospho-eIF2α, ATF4, and CHOP, and reduced the cytosolic Ca levels. These data suggest that fisetin inhibits PM-induced apoptosis by inhibiting the ER stress response and production of ROS.
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http://dx.doi.org/10.3390/antiox10091492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467638PMC
September 2021

Anthocyanin-enriched polyphenols from Hibiscus syriacus L. (Malvaceae) exert anti-osteoporosis effects by inhibiting GSK-3β and subsequently activating β-catenin.

Phytomedicine 2021 Oct 17;91:153721. Epub 2021 Aug 17.

Department of Marine Life Science, Jeju National University, Jeju 63243, Republic of Korea; Research Institute for Basic Sciences, Jeju National University, Jeju 63243, Republic of Korea. Electronic address:

Background: The bark and petal of Hibiscus syriacus L. (Malvaceae) have been used to relieve pain in traditional Korean medicine. Recently, we identified anthocyanin-enriched polyphenols from the petal of H. syriacus L. (AHs) and determined its anti-melanogenic, anti-inflammatory, and anti-oxidative properties. Nevertheless, the osteogenic potential of AHs remains unknown.

Purpose: This study was aimed to investigating the effect of AHs on osteoblast differentiation and osteogenesis in osteoblastic cell lines and zebrafish larvae. Furthermore, we investigated whether AHs ameliorates prednisolone (PDS)-induced osteoporosis.

Study Design And Methods: Cell viability was assessed by cellular morphology, MTT assay, and flow cytometry analysis, and osteoblast differentiation was measured alizarin red staining, alkaline phosphatase (ALP) activity, and osteoblast-specific marker expression. Osteogenic and anti-osteoporotic effects of AHs were determined in zebrafish larvae.

Results: AHs enhanced calcification and ALP activity concomitant with the increased expression of osterix (OSX), runt-related transcription factor 2 (RUNX2), and ALP in MC3T3-E1 preosteoblast and MG-63 osteosarcoma cells. Additionally, AHs accelerated vertebral formation and mineralization in zebrafish larvae, concurrent with the increased expression of OSX, RUNX2a, and ALP. Furthermore, PDS-induced loss of osteogenic activity and vertebral formation were restored by treatment with AHs, accompanied by a significant recovery of calcification, ALP activity, and osteogenic marker expression. Molecular docking studies showed that 16 components in AHs fit to glucagon synthase kinase-3β (GSK-3β); particularly, isovitexin-4'-O-glucoside most strongly binds to the peptide backbone of GSK-3β at GLY47(O), GLY47(N), and ASN361(O), with a binding score of -7.3. Subsequently, AHs phosphorylated GSK-3β at SER9 (an inactive form) and released β-catenin into the nucleus. Pretreatment with FH535, a Wnt/β-catenin inhibitor, significantly inhibited AH-induced vertebral formation in zebrafish larvae.

Conclusion: AHs stimulate osteogenic activities through the inhibition of GSK-3β and subsequent activation of β-catenin, leading to anti-osteoporosis effects.
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http://dx.doi.org/10.1016/j.phymed.2021.153721DOI Listing
October 2021

The Effectiveness and Safety of Mind-Body Modalities for Mental Health of Nurses in Hospital Setting: A Systematic Review.

Int J Environ Res Public Health 2021 08 23;18(16). Epub 2021 Aug 23.

Department of Oriental Neuropsychiatry, College of Korean Medicine, Dong-eui University, Busan 47227, Korea.

The mental health of nurses including burnout is an important issue. The purpose of this systematic review was to evaluate whether mind-body modalities improve burnout and other mental health aspects of nurses. A comprehensive search was conducted using six electronic databases. Randomized controlled trials using mind-body modalities on the mental health of nurses, up to January 2021, were included. The methodological quality of the included studies was assessed using the Cochrane Risk of Bias tool. Seventeen studies were included in the review. Data on mindfulness-based interventions (MBIs) and yoga were available for burnout, and there was no evidence that multimodal resilience programs including MBIs statistically significantly improved burnout levels compared to no intervention or active control groups. However, one study reported that yoga could significantly improve emotional exhaustion and depersonalization, which are subscales of burnout, compared to usual care. In addition, the effects of MBIs, relaxation, yoga, and music on various mental health outcomes and stress-related symptoms have been reported. In conclusion, there was some evidence that yoga was helpful for improvement in burnout of nurses. However, due to the heterogeneity of interventions and outcomes of the studies included, further high-quality clinical trials are needed on this topic in the future.
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http://dx.doi.org/10.3390/ijerph18168855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393251PMC
August 2021

Fisetin Inhibits NLRP3 Inflammasome by Suppressing TLR4/MD2-Mediated Mitochondrial ROS Production.

Antioxidants (Basel) 2021 Jul 28;10(8). Epub 2021 Jul 28.

Department of Marine Life Science, Jeju National University, Jeju 63243, Korea.

Fisetin has numerous therapeutic properties, such as anti-inflammatory, antioxidative, and anticancer effects. However, the mechanism by which fisetin inhibits NLRP3 inflammasome remains unclear. In this study, we observed that fisetin bound to TLR4 and occluded the hydrophobic pocket of MD2, which in turn inhibited the binding of LPS to the TLR4/MD2 complex. This prevented the initiation of scaffold formation by the inhibition of MyD88/IRAK4 and subsequently downregulated the NF-κB signaling pathway. The result also demonstrated that fisetin downregulated the activation of the NLRP3 inflammasome induced by LPS and ATP (LPS/ATP) and the subsequent maturation of IL-1β. Fisetin also activated mitophagy and prevented the accumulation of damaged mitochondria and the excessive production of mitochondrial reactive oxygen species. The transient knockdown of reversed the inhibitory activity of fisetin on the LPS/ATP-induced formation of the NLRP3 inflammasome. This indicated that fisetin induces p62-mediated mitophagy for eliminating damaged mitochondria. Recently, the existence of inflammasomes in non-mammalian species including zebrafish have been identified. Treatment of an LPS/ATP-stimulated zebrafish model with fisetin aided the recovery of the impaired heart rate, decreased the recruitment of macrophage to the brain, and gradually downregulated the expression of inflammasome-related genes. These results indicated that fisetin inhibited the TLR4/MD2-mediated activation of NLRP3 inflammasome by eliminating damaged mitochondria in a p62-dependent manner.
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http://dx.doi.org/10.3390/antiox10081215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389007PMC
July 2021

Rare minisatellite alleles of MUC2-MS8 influence susceptibility to rectal carcinoma.

Genes Genomics 2021 Aug 26. Epub 2021 Aug 26.

Department of Biomedical Science, Dong-A University, Busan, 49315, Korea.

Background: Previously, we identified eight novel minisatellites in the MUC2, of which allelic variants in MUC2-MS6 were examined to influence susceptibility to gastric cancer. However, studies on the susceptibility to gastrointestinal cancer of other minisatellites in the MUC2 region still remain unprogressive.

Objective: In this study, we investigated whether polymorphic variations in the MUC2-MS8 region are related to susceptibility to gastrointestinal cancer.

Methods: We assessed the association between MUC2-MS8 and gastrointestinal cancers by a case-control study with 1229 controls, 486 gastric cancer cases, 220 colon cancer cases and 278 rectal cancer cases. To investigate whether intronic minisatellites affect gene expression, various minisatellites were inserted into the luciferase-reporter vector and their expression levels were examined. We also examined the length of MUC2-MS8 alleles in blood and cancer tissue matching samples of 107 gastric cancer patients, 125 colon cancer patients, and 85 rectal cancer patients, and investigated whether the repeat sequence affects genome instability.

Results: A statistically significant association was identified between rare MUC2-MS8 alleles and the occurrence of rectal cancer: odds ratio (OR), 6.66; 95% confidence interval (CI), 1.11-39.96; and P = 0.0165. In the younger group (age, < 55), rare alleles were significant associated with an increased risk of rectal cancer (odds ratio, 24.93 and P = 0.0001). Suppression of expression was found in the reporter vector inserted with minisatellites, and loss of heterozygosity (LOH) of the MUC2-MS8 region was confirmed in cancer tissues of gastrointestinal cancer patients (0.8-5.9%).

Conclusion: Our results suggest that the rare alleles of MUC2-MS8 could be used to identify the risk of rectal cancer and that this repeat region is related to genomic instability.
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http://dx.doi.org/10.1007/s13258-021-01158-0DOI Listing
August 2021

Proteome profile of spleen in rock bream (Oplegnathus fasciatus) naturally infected with rock bream iridovirus (RBIV).

Genes Genomics 2021 Nov 24;43(11):1259-1268. Epub 2021 Aug 24.

Department of Parasitology and Genetics, Kosin University College of Medicine, Busan, Republic of Korea.

Background: Rock bream iridovirus (RBIV) is one of the most dangerous pathogens that causes the highest mortality in the aquaculture of rock bream (Oplegnathus fasciatus). Even though RBIV infection leads to huge economic loss, proteome studies on RBIV-infected rock bream have not been conducted to provide information about the differential protein expression pattern by the host protection system.

Objective: The purpose of this study was to investigate the protein expression patterns in spleens of rock bream olive after infection by RBIV or mixed infection by RBIV and bacteria.

Methods: Depending on the infection intensity and sampling time point, fish were divided into five groups: uninfected healthy fish at week 0 as the control (0C), heavily infected fish at week 0 (0H), heavily mixed RBIV and bacterial infected fish at week 0 (0MH), uninfected healthy fish at week 3 (3C), and lightly infected fish at week 3 (3L). Proteins were extracted from the spleens of infected rock bream. We used 2-DE analysis with LC-MS/MS to investigate proteome changes in infected rock bream.

Results: The results of the LC-MS/MS analyses showed different protein expression profiles after infection. Proteins related to oxygen transport and energy generation, such as hemoglobin, beta-globin, and ATP synthase, were mostly expressed in the infected spleen. Whereas proteins involved in structure and cell movement, such as tubulin, myosin, actin binding proteins, and intermediate filament proteins, were down-regulated in the infected spleens. The protein expression profiles between infection by RBIV and mixed infection by RBIV and bacteria showed similar patterns.

Conclusions: Our results indicated that infection by RBIV or mixed infection by RBIV and bacteria triggered energy generation and oxygen-transport, but cell migration and constructional changes in the spleen were extremely decreased.
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http://dx.doi.org/10.1007/s13258-021-01149-1DOI Listing
November 2021

Gamma-Aminobutyric Acid (GABA) Inhibits α-Melanocyte-Stimulating Hormone-Induced Melanogenesis through GABA and GABA Receptors.

Int J Mol Sci 2021 Jul 31;22(15). Epub 2021 Jul 31.

Department of Marine Life Science, Jeju National University, Jeju 63243, Korea.

Gamma-aminobutyric acid (GABA) is considered the primary inhibitory neurotransmitter in the human cortex. However, whether GABA regulates melanogenesis has not been comprehensively elucidated. In this study, we reveal that GABA (20 mM) significantly inhibited α-melanocyte-stimulating hormone (α-MSH)-induced extracellular (from 354.9% ± 28.4% to 126.5% ± 16.0%) and intracellular melanin contents (from 236.7% ± 11.1% to 102.7% ± 23.1%) in B16F10 melanoma cells, without inducing cytotoxicity. In addition, α-MSH-induced hyperpigmentation in zebrafish larvae was inhibited from 246.3% ± 5.4% to 116.3% ± 3.1% at 40 mM GABA, displaying no apparent cardiotoxicity. We also clarify that the GABA-mediated antimelanogenic properties were related to the direct inhibition of microphthalmia-associated transcription factor () and expression by inhibiting cyclic adenosine monophosphate (cAMP) and cAMP response element-binding protein (CREB). Furthermore, under α-MSH stimulation, GABA-related antimelanogenic effects were mediated through the GABA and GABA receptors, with subsequent inhibition of Ca accumulation. In B16F10 melanoma cells and zebrafish larvae, pretreatment with bicuculline, a GABA receptor antagonist, and CGP 46381, a GABA receptor antagonist, reversed the antimelanogenic effect of GABA following α-MSH treatment by upregulating Ca accumulation. In conclusion, our results indicate that GABA inhibits α-MSH-induced melanogenesis. Hence, in addition to the health benefits of GABA in the central nervous system, it could ameliorate hyperpigmentation disorders.
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http://dx.doi.org/10.3390/ijms22158257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347673PMC
July 2021

Flavonoid Glycosides from var. (Bunge) Rehder Seeds Inhibit α-Melanocyte-Stimulating Hormone-Mediated Melanogenesis.

Int J Mol Sci 2021 Jul 19;22(14). Epub 2021 Jul 19.

Department of Marine Life Science, Jeju National University, Jeju 63243, Korea.

extracts possess a broad spectrum of biological activities, such as antioxidant and anticancer activities in melanoma cancers. Nevertheless, the compounds contain high antioxidant capacities and anticancer activities in melanoma cells, shown to be effective in hyperpigmentation disorders, but whether flavonoid glycosides from . regulate anti-melanogenesis remains unclear. In this study, we evaluated the anti-melanogenic activity of five flavonoid glycosides from var. (Bunge) Rehder seeds, including jujuboside A (JUA), jujuboside B (JUB), epiceanothic acid (EPA), betulin (BTL), and 6'''-feruloylspinosin (FRS), in B16F10 melanoma cells and zebrafish larvae. According to our results, JUB, EPA, and FRS potently inhibited α-melanocyte-stimulating hormone (α-MSH)-induced melanogenesis and prevented hyperpigmentation in zebrafish larvae. In particular, under α-MSH-stimulated conditions, FRS most significantly inhibited α-MSH-induced intracellular and extracellular melanin content in B16F10 melanoma cells. Additionally, JUB, EPS, and FRS remarkably downregulated melanogenesis in α-MSH-treated zebrafish larvae, with no significant change in heart rate. Neither JUA nor BTA were effective in downregulating melanogenesis in B16F10 melanoma cells and zebrafish larvae. Furthermore, JUB, EPA, and FRS directly inhibited in vitro mushroom tyrosinase enzyme activity. JUB, EPA, and FRS also downregulated cyclic adenosine monophosphate (cAMP) levels and the phosphorylation of cAMP-response element-binding protein (CREB), and subsequent microphthalmia transcription factor (MITF) and tyrosinase expression. In conclusion, this study demonstrated that JUB, EPA, and FRS isolated from var. (Bunge) Rehder seeds exhibit potent anti-melanogenic properties by inhibition of the cAMP-CERB-MITF axis and consequent tyrosinase activity.
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http://dx.doi.org/10.3390/ijms22147701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304508PMC
July 2021

Nargenicin A1 attenuates lipopolysaccharide-induced inflammatory and oxidative response by blocking the NF-κB signaling pathway.

EXCLI J 2021 28;20:968-982. Epub 2021 May 28.

Anti-Aging Research Center, Dong-eui University, Busan, Republic of Korea.

Inflammation caused by the excessive production of pro-inflammatory mediators and cytokines in abnormally activated macrophages promotes the initiation and progression of many diseases along with oxidative stress. Previous studies have suggested that nargenicin A1, an antibacterial macrolide isolated from sp. may be a potential treatment for inflammatory responses and oxidative stress, but the detailed mechanisms are still not well studied. In this study, we investigated the inhibitory effect of nargenicin A1 on inflammatory and oxidative stress in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and zebrafish () models. Our results indicated that nargenicin A1 treatment significantly inhibited LPS-induced release of pro-inflammatory mediators including nitric oxide (NO) and prostaglandin E, which was associated with decreased inducible NO synthase and cyclooxygenase-2 expression. In addition, nargenicin A1 attenuated the LPS-induced expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and monocyte chemotactic protein-1, reducing their extracellular secretion. Nargenicin A1 also suppressed LPS-induced generation of reactive oxygen species. Moreover, nargenicin A1 abolished the LPS-mediated nuclear translocation of nuclear factor-kappa B (NF-κB) and the degradation of inhibitor IκB-α, indicating that nargenicin A1 exhibited anti-inflammatory effects by inhibiting the NF-κB signaling pathway. Furthermore, nargenicin A1 showed strong protective effects against NO and ROS production in LPS-injected zebrafish larvae. In conclusion, our findings suggest that nargenicin A1 ameliorates LPS-induced anti-inflammatory and antioxidant effects by downregulating the NF-κB signaling pathway, and that nargenicin A1 can be a potential functional agent to prevent inflammatory- and oxidative-mediated damage.
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http://dx.doi.org/10.17179/excli2021-3506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278209PMC
May 2021

Fisetin promotes osteoblast differentiation and osteogenesis through GSK-3β phosphorylation at Ser9 and consequent β-catenin activation, inhibiting osteoporosis.

Biochem Pharmacol 2021 Oct 10;192:114676. Epub 2021 Jul 10.

Department of Marine Life Science, Jeju National University, Jeju 63243, Republic of Korea; Research Institute for Basic Sciences, Jeju National University, Jeju 63243, Republic of Korea. Electronic address:

Fisetin is a bioactive flavonol that inhibits osteoclastogenesis and promotes osteoblastogenesis. However, the osteogenic activity of fisetin needs to be comprehensively elucidated. In the present study, we observed that fisetin significantly increased alkaline phosphatase (ALP) activity and bone mineralization in MC3T3-E1 preosteoblasts, accompanied by a significant increase in runt-related transcription factor 2 (RUNX2), ALP, collagen type Ⅰ alpha 1 (Col1α1), osterix (OSX), osteocalcin (OCN), and bone morphogenetic protein 4 (BMP4) expression. Furthermore, fisetin promoted vertebral formation in zebrafish larvae, with the highest fisetin concentration comparable with that observed in β-glycerophosphate treatment. Fisetin also inhibited prednisolone (PDS)-induced anti-osteoblastic genes, including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), tartrate-resistant acid phosphatase-6 (ACP6), dendritic cell-specific transmembrane protein (DC-STAMP), and cathepsin K (CTSK). Fisetin potently mitigated the PDS-induced inhibition of ALP activity and bone mineralization, as well as vertebral resorption in zebrafish larvae. Moreover, we confirmed that fisetin-induced osteogenic effect was activated through phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9, consequently releasing β-catenin from the destructive complex to promote its nuclear translocation. β-Catenin inhibition by FH535 and the stabilization of GSK-3β by DOI hydrochloride remarkably inhibited fisetin-induced osteogenic activities, indicating that the GSK-3β/β-catenin signaling pathway plays a vital role in fisetin-induced osteogenesis. Collectively, our findings suggest that fisetin stimulates osteogenic activity and could be used as an effective strategy to prevent bone resorption.
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http://dx.doi.org/10.1016/j.bcp.2021.114676DOI Listing
October 2021

The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis.

Anim Cells Syst (Seoul) 2021 23;25(2):119-127. Epub 2021 Apr 23.

Anti-Aging Research Center, Dong-eui University, Busan, Republic of Korea.

Although previous studies have shown anti-cancer activity of betulinic acid (BA), a pentacyclic triterpenoid, against various cancer lines, the underlying molecular mechanisms are not well elucidated. In this study, we evaluated the mechanisms involved in the anti-cancer efficacy of BA in U937 human myeloid leukemia cells. BA exerted a significant cytotoxic effect on U937 cells through blocking cell cycle arrest at the G2/M phase and inducing apoptosis, and that the intracellular reactive oxygen species (ROS) levels increased after treatment with BA. The down-regulation of cyclin A and cyclin B1, and up-regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 revealed the G2/M phase arrest mechanism of BA. In addition, BA induced the cytosolic release of cytochrome by reducing the mitochondrial membrane potential with an increasing Bax/Bcl-2 expression ratio. BA also increased the activity of caspase-9 and -3, and subsequent degradation of the poly (ADP-ribose) polymerase. However, quenching of ROS by -acetyl-cysteine, an ROS scavenger, markedly abolished BA-induced G2/M arrest and apoptosis, indicating that the generation of ROS plays a key role in inhibiting the proliferation of U937 cells by BA treatment. Taken together, our results provide a mechanistic rationale that BA exhibits anti-cancer properties in U937 leukemia cells through ROS-dependent induction of cell cycle arrest at G2/M phase and apoptosis.
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http://dx.doi.org/10.1080/19768354.2021.1915380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118407PMC
April 2021

Inhibition of Lipopolysaccharide-Induced Inflammatory and Oxidative Responses by -cinnamaldehyde in C2C12 Myoblasts.

Int J Med Sci 2021 23;18(12):2480-2492. Epub 2021 Apr 23.

Anti-Aging Research Center, Dong-eui University, Busan 47340, Republic of Korea.

-cinnamaldehyde (tCA), a bioactive component found in , has been reported to exhibit anti-inflammatory and antioxidant effects, but its efficacy in muscle cells has yet to be found. In this study, we investigated the inhibitory effect of tCA on inflammatory and oxidative stress induced by lipopolysaccharide (LPS) in C2C12 mouse skeletal myoblasts. To investigate the anti-inflammatory and antioxidant effects of tCA in LPS-treated C2C12 cells, we measured the levels of pro-inflammatory mediator, cytokines, and reactive oxygen species (ROS). To elucidate the mechanism underlying the effect of tCA, the expression of genes involved in the expression of inflammatory and oxidative regulators was also investigated. We further evaluated the anti-inflammatory and antioxidant efficacy of tCA against LPS in the zebrafish model. tCA significantly inhibited the LPS-induced release of pro-inflammatory mediators and cytokines, which was associated with decreased expression of their regulatory genes. tCA also suppressed the expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor, and attenuated the nuclear translocation of nuclear factor-kappa B (NF-κB) and the binding of LPS to TLR4 on the cell surface in LPS-treated C2C12 cells. Furthermore, tCA abolished LPS-induced generation of ROS and expression levels of ROS producing enzymes, NADPH oxidase 1 (NOX1) and NOX2. However, tCA enhanced the activation of nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1) in LPS-stimulated C2C12 myoblasts. In addition, tCA showed strong protective effects against NO and ROS production in LPS-injected zebrafish larvae. Our findings suggest that tCA exerts its inhibitory ability against LPS-induced inflammatory and antioxidant stress in C2C12 myoblasts by targeting the TLR4/NF-κB, which might be mediated by the NOXs and Nrf2/HO-1 pathways.
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http://dx.doi.org/10.7150/ijms.59169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176176PMC
April 2021

Loganin Inhibits Lipopolysaccharide-Induced Inflammation and Oxidative Response through the Activation of the Nrf2/HO-1 Signaling Pathway in RAW264.7 Macrophages.

Biol Pharm Bull 2021 ;44(6):875-883

Anti-Aging Research Center, Dong-eui University.

Inflammation caused by the excessive secretion of inflammatory mediators in abnormally activated macrophages promotes many diseases along with oxidative stress. Loganin, a major iridoid glycoside isolated from Cornus officinalis, has recently been reported to exhibit anti-inflammatory and antioxidant effects, whereas the underlying mechanism has not yet been fully clarified. Therefore, the aim of the present study is to investigate the effect of loganin on inflammation and oxidative stress in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Our results indicated that loganin treatment markedly attenuated the LPS-mediated phagocytic activity and release of nitric oxide (NO) and prostaglandin E, which was associated with decreased the expression of inducible NO synthase and cyclooxygenase-2. In addition, loganin suppressed the expression and their extracellular secretion of LPS-induced pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-1β. Furthermore, loganin abolished reactive oxygen species (ROS) generation, and promoted the activation of nuclear factor-E2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1) in LPS-stimulated macrophages. However, zinc protoporphyrin, a selective HO-1 inhibitor, reversed the loganin-mediated suppression of pro-inflammatory cytokines in LPS-treated macrophages. In conclusion, our findings suggest that the upregulation of the Nrf2/HO-1 signaling pathway is concerned at least in the protective effect of loganin against LPS-mediated inflammatory and oxidative stress, and that loganin can be a potential functional agent to prevent inflammatory and oxidative damage.
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http://dx.doi.org/10.1248/bpb.b21-00176DOI Listing
January 2021

Anti-Inflammatory Effect of Auranofin on Palmitic Acid and LPS-Induced Inflammatory Response by Modulating TLR4 and NOX4-Mediated NF-κB Signaling Pathway in RAW264.7 Macrophages.

Int J Mol Sci 2021 May 31;22(11). Epub 2021 May 31.

Department of Biochemistry, Dong-eui University College of Korean Medicine, Busan 47227, Korea.

Chronic inflammation, which is promoted by the production and secretion of inflammatory mediators and cytokines in activated macrophages, is responsible for the development of many diseases. Auranofin is a Food and Drug Administration-approved gold-based compound for the treatment of rheumatoid arthritis, and evidence suggests that auranofin could be a potential therapeutic agent for inflammation. In this study, to demonstrate the inhibitory effect of auranofin on chronic inflammation, a saturated fatty acid, palmitic acid (PA), and a low concentration of lipopolysaccharide (LPS) were used to activate RAW264.7 macrophages. The results show that PA amplified LPS signals to produce nitric oxide (NO) and various cytokines. However, auranofin significantly inhibited the levels of NO, monocyte chemoattractant protein-1, and pro-inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor-α, and IL-6, which had been increased by co-treatment with PA and LPS. Moreover, the expression of inducible NO synthase, IL-1β, and IL-6 mRNA and protein levels increased by PA and LPS were reduced by auranofin. In particular, the upregulation of NADPH oxidase (NOX) 4 and the translocation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) induced by PA and LPS were suppressed by auranofin. The binding between the toll-like receptor (TLR) 4 and auranofin was also predicted, and the release of NO and cytokines was reduced more by simultaneous treatment with auranofin and TLR4 inhibitor than by auranofin alone. In conclusion, all these findings suggested that auranofin had anti-inflammatory effects in PA and LPS-induced macrophages by interacting with TLR4 and downregulating the NOX4-mediated NF-κB signaling pathway.
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http://dx.doi.org/10.3390/ijms22115920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198732PMC
May 2021

The Root Extract of Induces Apoptosis in EGFR TKI-Resistant Human Lung Cancer Cells by Inactivation of STAT3.

Int J Mol Sci 2021 May 13;22(10). Epub 2021 May 13.

Department of Pathology, College of Korean Medicine, Dong-eui University, Busan 47227, Korea.

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) is a major obstacle in managing lung cancer. The root of (SB) traditionally used for fever clearance and detoxification possesses various bioactivities including anticancer effects. The purpose of this study was to investigate whether SB exhibited anticancer activity in EGFR TKI-resistant lung cancer cells and to explore the underlying mechanism. We used four types of human lung cancer cell lines, including H1299 ( wildtype; EGFR TKI-resistant), H1975 (acquired TKI-resistant), PC9/ER (acquired erlotinib-resistant), and PC9/GR (acquired gefitinib-resistant) cells. The ethanol extract of SB (ESB) decreased cell viability and suppressed colony formation in the four cell lines. ESB stimulated nuclear fragmentation and the cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-3. Consistently, the proportion of sub-G1 phase cells and annexin V+ cells were significantly elevated by ESB, indicating that ESB induced apoptotic cell death in EGFR TKI-resistant cells. ESB dephosphorylated signal transducer and activator of transcription 3 (STAT3) and downregulated the target gene expression. The overexpression of constitutively active STAT3 reversed ESB-induced apoptosis, suggesting that ESB triggered apoptosis in EGFR TKI-resistant cells by inactivating STAT3. Taken together, we propose the potential use of SB as a novel therapeutic for lung cancer patients with EGFR TKI resistance.
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http://dx.doi.org/10.3390/ijms22105181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153615PMC
May 2021

The regulation of the TLR4/NF-κB and Nrf2/HO-1 signaling pathways is involved in the inhibition of lipopolysaccharide-induced inflammation and oxidative reactions by morroniside in RAW 264.7 macrophages.

Arch Biochem Biophys 2021 07 23;706:108926. Epub 2021 May 23.

Anti-Aging Research Center, Dong-eui University, Busan, 47340, Republic of Korea; Department of Biochemistry, Dong-eui University College of Korean Medicine, Busan, 47227, Republic of Korea. Electronic address:

Morroniside, a major iridoid glycoside isolated from Cornus officinalis, has a variety of beneficial pharmacological properties. Although morroniside has recently been reported to exhibit anti-inflammatory and antioxidant effects, the detailed mechanism has not yet been fully elucidated. In this study, we investigated the inhibitory effect of morroniside on inflammatory and oxidative stress activated by lipopolysaccharide (LPS) in RAW 264.7 macrophages. Our results indicated that morroniside pretreatment significantly inhibited the LPS-induced phagocytic activity and release of pro-inflammatory factors, which was associated with blocking the expression of their regulatory genes. Morroniside also markedly suppressed the expression of myeloid differentiation factor 88 as well as Toll-like receptor 4 (TLR4), and attenuated the translocation of nuclear factor-κB (NF-κB) to the nucleus in LPS-treated RAW 264.7 macrophages. Furthermore, morroniside prevented the binding of LPS to the TLR4 on the cell surface. In addition, morroniside abolished reactive oxygen species (ROS) generation, and enhanced the expression of heme oxygenase-1 (HO-1) following activation of nuclear factor-E2-related factor 2 (Nrf2) in LPS-stimulated RAW 264.7 macrophages. However, zinc protoporphyrin, a specific inhibitor of HO-1, reversed the morroniside-mediated inhibition of inflammatory response in LPS-treated RAW 264.7 macrophages. In conclusion, our findings suggest that morroniside exerts LPS-induced anti-inflammatory and antioxidant effects by targeting the TLR4/NF-κB and Nrf2/HO-1 signaling pathways in RAW 264.7 macrophages. Taken together, our findings suggest that morroniside interacted structurally and electrochemically with TLR4/MD2 complex, consequently can be a potential functional agent to prevent inflammatory and oxidative damage.
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http://dx.doi.org/10.1016/j.abb.2021.108926DOI Listing
July 2021

Collagen type VI‑α1 and 2 repress the proliferation, migration and invasion of bladder cancer cells.

Int J Oncol 2021 Jul 13;59(1). Epub 2021 May 13.

Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Chungcheongbuk 28644, Republic of Korea.

The bladder cancer (BCa) microenvironment comprises heterogeneous tumor cell populations, the surrounding stroma and the extracellular matrix (ECM). Collagen, the scaffold of the tumor microenvironment, regulates ECM remodeling to promote tumor infiltration, angiogenesis, invasion and migration. The present study examined how collagen type VI‑α (COL6A) 1 and 2 function during BCa pathogenesis and progression, with the aim of facilitating the development of precision therapeutics, risk stratification and molecular diagnosis. and mRNA expression in non‑muscle invasive BCa (NMIBC) and MIBC tissue samples was measured using reverse transcription‑quantitative PCR. In addition, the tumor‑suppressive effects of and in human BCa EJ cells (MGH‑U1) were assessed. Compared with normal controls, and mRNA expression was downregulated in both NMIBC and MIBC tissue samples (P<0.05, respectively). and effectively inhibited the proliferation of human BCa EJ cells (MGH‑U1) and induced cell cycle arrest at the G phase. Additionally, and served roles in MAPK and AKT signaling by increasing p38 MAPK phosphorylation and decreasing AKT phosphorylation. Finally, and inhibited wound healing and invasion by suppressing the activity of matrix metalloproteinase (MMP)‑2 and MMP‑9. In conclusion, COL6A1 and COL6A2 may act as classical collagens by forming a physical barrier to inhibit BCa tumor growth and invasion.
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http://dx.doi.org/10.3892/ijo.2021.5217DOI Listing
July 2021

VNTR polymorphism in the breakpoint region of ABL1 and susceptibility to bladder cancer.

BMC Med Genomics 2021 05 5;14(1):121. Epub 2021 May 5.

Department of Biomedical Sciences, Dong-A University, Busan, 49315, Korea.

Background: ABL1 is primarily known as a leukemia-related oncogene due to translocation, but about 2.2% of ABL1 mutations have been identified in bladder cancer, and high expression in solid cancer has also been detected.

Methods: Here, we used the NCBI database, UCSC genome browser gateway and Tandem repeat finder program to investigate the structural characterization of the ABL1 breakpoint region and to identify the variable number of tandem repeats (VNTR). To investigate the relationship between ABL1-MS1 and bladder cancer, a case-controlled study was conducted in 207 controls and 197 bladder cancer patients. We also examined the level of transcription of the reporter gene driven by the ABL1 promoter to determine if the VNTR region affects gene expression.

Results: In our study, one VNTR was identified in the breakpoint region, the intron 1 region of ABL1, and was named ABL1-MS1. In the control group, only two common alleles (TR13, TR15) were detected, but an additional two rare alleles (TR14, TR16) were detected in bladder cancer. A statistically significant association was identified between the rare ABL1-MS1 allele and bladder cancer risk: P = 0.013. Investigating the level of transcription of the reporter gene driven by the ABL1 promoter, VNTR showed inhibition of ABL1 expression in non-cancer cells 293 T, but not in bladder cancer cells. In addition, ABL1-MS1 was accurately passed on to offspring according to Mendelian inheritance through meiosis.

Conclusions: Therefore, the ABL1-MS1 region can affect ABL1 expression of bladder cancer. This study provides that ABL1-MS1 can be used as a DNA fingerprinting marker. In addition, rare allele detection can predict susceptibility to bladder cancer.
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http://dx.doi.org/10.1186/s12920-021-00968-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097952PMC
May 2021

ROS-Mediated Anti-Tumor Effect of Coptidis Rhizoma against Human Hepatocellular Carcinoma Hep3B Cells and Xenografts.

Int J Mol Sci 2021 Apr 30;22(9). Epub 2021 Apr 30.

Anti-Aging Research Center, Dongeui University, Busan 47340, Korea.

Coptidis Rhizoma is the dried rhizome from the Franch. that has been shown to have a number of beneficial pharmacological properties including antioxidant, anti-inflammatory, and anti-cancer effects. However, the anti-cancer effects of Coptidis Rhizoma on hepatocellular carcinoma (HCC) remain unclear. In this study, we investigated the anti-cancer properties of Coptidis Rhizoma ethanol extract (CR) in HCC Hep3B cells and in a xenograft mouse model. Our results showed that the CR significantly inhibited cell growth and induced apoptosis in Hep3B cells through increased expression of Bcl-2 associated x-protein (Bax) and cleavage of poly-ADP ribose polymerase (PARP), reduced expression of Bcl-2, and activated caspases. CR also increased the generation of intracellular reactive oxygen species (ROS), which caused a loss of mitochondrial membrane potential (MMP, ΔΨm) and activation of the mitochondria-mediated intrinsic apoptosis pathway. Moreover, -acetylcysteine (NAC), a ROS inhibitor, markedly blocked the effects of CR on apoptotic pathways. CR also induced the expression of light chain 3 (LC3)-I/II, a key autophagy regulator, whereas CR-mediated autophagy was significantly suppressed by NAC. In addition, pre-treatment with NAC perfectly attenuated the inhibition of cell invasion and migration of CR-stimulated Hep3B cells. Furthermore, oral administration of CR suppressed Hep3B tumor growth in xenograft mice without toxicity, alterations to body weight, or changes in hematological and biochemical profiles. Taken together, our findings suggest that CR has anti-tumor effects that result from ROS generation, and may be a potential pharmacological intervention for HCC.
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http://dx.doi.org/10.3390/ijms22094797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124566PMC
April 2021

LCT-3d Induces Oxidative Stress-Mediated Apoptosis by Upregulating Death Receptor 5 in Gastric Cancer Cells.

Front Oncol 2021 16;11:658608. Epub 2021 Apr 16.

Key Laboratory of Advanced Technology for Drug Preparation, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.

Gastric cancer is a global health problem. In this study, we investigate the role of a novel Indole derivative, named LCT-3d, in inhibiting the growth of gastric cancer cells by MTT assay. The Western blotting results showed that LCT-3d modulated the mitochondrial-related proteins and Cleaved-Caspases 3/9, to induce cell apoptosis. The up-regulation of Death receptor 5 (DR5) in MGC803 cells was observed with LCT-3d treatment. Knockdown of DR5 on MGC803 cells partially reversed the LCT-3d-induced mitochondrial apoptosis. The level of Reactive Oxygen Species (ROS) in MGC803 cells was increased with LCT-3d treatment and could be blocked with the pretreatment of the ROS inhibitor N-Acetylcysteine (NAC). The results demonstrate that the elevating ROS can up-regulate the expression of DR5, resulting in apoptosis mitochondrial pathway. Although the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway served an important role in protecting gastric cancer cells against the injury of ROS, it can't reverse LCT-3d-induced cell apoptosis. Taken together, our study showed that LCT-3d induced apoptosis DR5-mediated mitochondrial apoptotic pathway in gastric cancer cells. LCT-3d could be a novel lead compound for development of anti-cancer activity in gastric cancer.
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http://dx.doi.org/10.3389/fonc.2021.658608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085419PMC
April 2021

Human Endogenous Retrovirus (HERV)-K Gene Knockout Affects Tumorigenic Characteristics of Gene in DLD-1 Colorectal Cancer Cells.

Int J Mol Sci 2021 Apr 11;22(8). Epub 2021 Apr 11.

Department of Parasitology and Genetics, Kosin University College of Medicine, Busan 49267, Korea.

Human endogenous retroviruses (HERVs) are suggested to be involved in the development of certain diseases, especially cancers. To elucidate the function of HERV-K Env protein in cancers, an HERV-K gene knockout (KO) in DLD-1 colorectal cancer cell lines was generated using the CRISPR-Cas9 system. Transcriptome analysis of HERV-K KO cells using next-generation sequencing (NGS) was performed to identify the key genes associated with the function of HERV-K Env protein. The proliferation of HERV-K KO cells was significantly reduced in in vitro culture as well as in in vivo nude mouse model. Tumorigenic characteristics, including migration, invasion, and tumor colonization, were also significantly reduced in HERV-K KO cells. Whereas, they were enhanced in HERV-K over-expressing DLD-1 cells. The expression of nuclear protein-1 (NUPR1), an ER-stress response factor that plays an important role in cell proliferation, migration, and reactive oxygen species (ROS) generation in cancer cells, significantly reduced in HERV-K KO cells. ROS levels and ROS-related gene expression was also significantly reduced in HERV-K KO cells. Cells transfected with NUPR1 siRNA (small interfering RNA) exhibited the same phenotype as HERV-K KO cells. These results suggest that the HERV-K gene affects tumorigenic characteristics, including cell proliferation, migration, and tumor colonization through NUPR1 related pathway.
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http://dx.doi.org/10.3390/ijms22083941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070087PMC
April 2021

Protective Effect of Anthocyanin-Enriched Polyphenols from L. (Malvaceae) against Ultraviolet B-Induced Damage.

Antioxidants (Basel) 2021 Apr 9;10(4). Epub 2021 Apr 9.

Department of Marine Life Science, Jeju National University, Jeju 63243, Korea.

Anthocyanin-enriched polyphenols from the flower petals of L. (Malvaceae, AHs) possess anti-septic shock, anti-oxidant, and anti-melanogenic properties. However, whether AHs positively or negatively regulate ultraviolet B (UVB)-mediated photoaging and photodamage remains unclear. This study aims to investigate the protective effect of AHs against UVB-induced damage. We examined the photoprotective effects of AHs on UVB-induced apoptosis, endoplasmic reticulum (ER) stress, and mitochondrial reactive oxygen species (mtROS). AHs prevented UVB irradiation-induced apoptosis of HaCaT keratinocytes by inhibiting caspase activation and ROS production. Moreover, AHs restored the survival rate and the hatchability of UVB-irradiated zebrafish larvae without any abnormalities. Furthermore, AHs inhibited UVB-induced ER stress, resulting in a decrease in mtROS production via the stabilization of the mitochondrial membrane potential. Our results indicate that AHs inhibit UVB-induced apoptosis by downregulating total cytosolic ROof cytosolic CaS and ER-mediated mitoROS production in both HaCaT keratinocytes and zebrafish larvae. These findings provide evidence for the applications of AHs to protect skin from UVB-induced photodamage.
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http://dx.doi.org/10.3390/antiox10040584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069133PMC
April 2021

Fisetin inhibits lipopolysaccharide-induced inflammatory response by activating β-catenin, leading to a decrease in endotoxic shock.

Sci Rep 2021 04 16;11(1):8377. Epub 2021 Apr 16.

Department of Marine Life Science, Jeju National University, Jeju, 63243, Republic of Korea.

Fisetin is a naturally occurring flavonoid that possesses several pharmacological benefits including anti-inflammatory activity. However, its precise anti-inflammatory mechanism is not clear. In the present study, we found that fisetin significantly inhibited the expression of proinflammatory mediators, such as nitric oxide (NO) and prostaglandin E (PGE), and cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Additionally, fisetin attenuated LPS-induced mortality and abnormalities in zebrafish larvae and normalized the heart rate. Fisetin decreased the recruitment of macrophages and neutrophils to the LPS-microinjected inflammatory site in zebrafish larvae, concomitant with a significant downregulation of proinflammatory genes, such as inducible NO synthase (iNOS), cyclooxygenase-2a (COX-2a), IL-6, and TNF-α. Fisetin inhibited the nuclear localization of nuclear factor-kappa B (NF-κB), which reduced the expression of pro-inflammatory genes. Further, fisetin inactivated glycogen synthase kinase 3β (GSK-3β) via phosphorylation at Ser9, and inhibited the degradation of β-catenin, which consequently promoted the localization of β-catenin into the nucleus. The pharmacological inhibition of β-catenin with FH535 reversed the fisetin-induced anti-inflammatory activity and restored NF-κB activity, which indicated that fisetin-mediated activation of β-catenin results in the inhibition of LPS-induced NF-κB activity. In LPS-microinjected zebrafish larvae, FH535 promoted the migration of macrophages to the yolk sac and decreased resident neutrophil counts in the posterior blood island and induced high expression of iNOS and COX-2a, which was accompanied by the inhibition of fisetin-induced anti-inflammatory activity. Altogether, the current study confirmed that the dietary flavonoid, fisetin, inhibited LPS-induced inflammation and endotoxic shock through crosstalk between GSK-3β/β-catenin and the NF-κB signaling pathways.
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http://dx.doi.org/10.1038/s41598-021-87257-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052411PMC
April 2021

Differential proteome profile of gill and spleen in three pathogen-infected Paralichthys olivaceus.

Genes Genomics 2021 Jul 13;43(7):701-712. Epub 2021 Apr 13.

Department of Parasitology and Genetics, Institute for Medical Science, Kosin University College of Medicine, Busan, Republic of Korea.

Background: Olive flounder (Paralichthys olivaceus) is one of the major cultured fish species in Asia including Korea. However, the mass mortality of olive flounder caused by various pathogens leads to huge economic loss. The pathogens that lead to fish mortality include parasites, bacteria, and viruses that can cause various kinds of diseases.

Objective: The purpose of this study was to investigate the protein expression patterns in the gills and spleens of olive flounder after artificial infection. We hypothesized that proteomics levels in gills and spleen may be differentially expressed depending on infectious agents.

Methods: To investigate the expression pattern of proteins in gills and spleens, olive flounders were experimentally infected with VHSV (virus), S. parauberis (bacteria), or M. avidus (pathogenic ciliate). Proteins were extracted from the gills and spleens of infected olive flounder. We used 2-DE analysis with LC-MS/MS to investigate proteome changes in infected olive flounders.

Results: The results of the LC-MS/MS analyses showed different protein expression profiles depending on pathogenic sources and target organs. Proteins related to cytoskeletal structure like keratin, calmodulin and actin were mostly expressed in the infected gills. Proteins involved in the metabolism pathway like glycolysis were expressed mainly in the spleens. The protein profiles of S. parauberis and VHSV infection groups had many similarities, but the profile of the M. avidus infection group was greatly different in the gill and spleen.

Conclusion: Our results indicate that measures according to the characteristics of each pathogen are necessary for disease prevention and treatment of farmed fish.
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http://dx.doi.org/10.1007/s13258-021-01097-wDOI Listing
July 2021

Urinary microRNA-1913 to microRNA-3659 expression ratio as a non-invasive diagnostic biomarker for prostate cancer.

Investig Clin Urol 2021 05 16;62(3):340-348. Epub 2021 Mar 16.

Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea.

Purpose: MicroRNAs (miRNAs) are small non-coding RNAs and are involved in the development, proliferation, and pathogenesis of prostate cancer (PCa). Urinary miRNAs are promising non-invasive biomarkers for PCa diagnosis because of their stability in urine. Here, we evaluated the diagnostic value of urinary miR-1913 to miR-3659 ratio in PCa patients and benign prostate hyperplasia (BPH) controls.

Materials And Methods: Candidate miRNAs were identified from urinary microarray data and tested by real-time PCR. The urinary miR-1913 to miR-3659 expression ratio was selected and tested in 83 urine samples (44 PCa and 39 BPH) to confirm its validity as a non-invasive diagnostic biomarker for PCa.

Results: The expression ratio of urinary miR-1913 to miR-3659 was significantly higher in PCa than in BPH (p=0.002) and showed a higher area under the receiver operating characteristic curve than prostate-specific antigen (PSA; 0.821 vs. 0.518) in patients within the PSA gray zone (tPSA: 3-10 ng/mL), with sensitivity of 75.0% and specificity of 78.6% (p=0.003).

Conclusions: The urinary miR-1913 to miR-3659 expression ratio was increased in PCa and may serve as a useful supplemental biomarker to PSA for the diagnosis of PCa, particularly in patients within the PSA gray zone.
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http://dx.doi.org/10.4111/icu.20200488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100013PMC
May 2021

Suppression of Lipopolysaccharide-Induced Inflammatory and Oxidative Response by 5-Aminolevulinic Acid in RAW 264.7 Macrophages and Zebrafish Larvae.

Biomol Ther (Seoul) 2021 Apr 6. Epub 2021 Apr 6.

Anti-Aging Research Center, Dong-eui University, Busan 47340, Republic of Korea.

In this study, we investigated the inhibitory effect of 5-aminolevulinic acid (ALA), a heme precursor, on inflammatory and oxidative stress activated by lipopolysaccharide (LPS) in RAW 264.7 macrophages by estimating nitric oxide (NO), prostaglandin E2 (PGE2), cytokines, and reactive oxygen species (ROS). We also evaluated the molecular mechanisms through analysis of the expression of their regulatory genes, and further evaluated the anti-inflammatory and antioxidant efficacy of ALA against LPS in the zebrafish model. Our results indicated that ALA treatment significantly attenuated the LPS-induced release of pro-inflammatory mediators including NO and PGE2, which was associated with decreased inducible NO synthase and cyclooxygenase-2 expression. ALA also inhibited the LPS-induced expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, reducing their extracellular secretion. Additionally, ALA abolished ROS generation, improved the mitochondrial mass, and enhanced the expression of heme oxygenase-1 (HO-1) and the activation of nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) in LPS-stimulated RAW 264.7 macrophages. However, zinc protoporphyrin, a specific inhibitor of HO-1, reversed the ALA-mediated inhibition of pro-inflammatory cytokines production and activation of mitochondrial function in LPS-treated RAW 264.7 macrophages. Furthermore, ALA significantly abolished the expression of LPS-induced pro-inflammatory mediators and cytokines, and showed strong protective effects against NO and ROS production in zebrafish larvae. In conclusion, our findings suggest that ALA exerts LPS-induced anti-inflammatory and antioxidant effects by upregulating the Nrf2/HO-1 signaling pathway, and that ALA can be a potential functional agent to prevent inflammatory and oxidative damage.
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http://dx.doi.org/10.4062/biomolther.2021.030DOI Listing
April 2021

Apoptotic Effects of Anthocyanins from Are Enhanced by Augmented Enhancer of the Rudimentary Homolog (ERH) in Human Gastric Carcinoma MKN28 Cells.

Int J Mol Sci 2021 Mar 16;22(6). Epub 2021 Mar 16.

Department of Biochemistry, Dong-eui University College of Korean Medicine, Busan 47227, Korea.

Evidence suggests that augmented expression of a certain gene can influence the efficacy of targeted and conventional chemotherapies. Here, we tested whether the high expression of enhancer of the rudimentary homolog (ERH), which serves as a prognostic factor in some cancers, can influence the efficacy of anthocyanins isolated from fruits of , Meoru in Korea (AIMs) on human gastric cancer cells. The anticancer efficacy of AIMs was augmented in ERH-transfected MKN28 cells (E-MKN28 cells). Molecularly, ERH augmented AIM-induced caspase-dependent apoptosis by activating caspase-3 and -9. The ERH-augmented apoptotic effect was related to mitochondrial depolarization and inhibition of antiapoptotic proteins, XIAP, and Bcl-2. In addition, reactive oxygen species (ROS) generation was augmented in AIMs-treated E-MKN28 cells compared to AIMs-treated naïve MKN28 cells. In conclusion, ERH augmented AIM-induced caspase-dependent mitochondrial-related apoptosis in MKN28 cells. A decrease in expression of Bcl-2 and subsequent excessive ROS generation would be the mechanism for ERH-augmented mitochondrial-related apoptosis in AIMs-treated MKN28 cells. A decrease in expression of XIAP would be another mechanism for ERH-augmented caspase-dependent apoptosis in AIMs-treated MKN28 cells.
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http://dx.doi.org/10.3390/ijms22063030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002340PMC
March 2021
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