Publications by authors named "Cheol Park"

909 Publications

Protection against Oxidative Stress-Induced Apoptosis by Fermented Sea Tangle ( Aresch) in Osteoblastic MC3T3-E1 Cells through Activation of Nrf2 Signaling Pathway.

Foods 2021 Nov 15;10(11). Epub 2021 Nov 15.

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

The purpose of the present study was to explore the efficacy of fermented extract of sea tangle ( Aresch, FST) with on DNA damage and apoptosis in hydrogen peroxide (HO)-stimulated osteoblastic MC3T3-E1 cells and clarify related signaling pathways. Our results showed that exposure to FST significantly improved cell viability, inhibited apoptosis, and suppressed the generation of reactive oxygen species (ROS) in HO-stimulated cells. In addition, HO triggered DNA damage in MC3T3-E1 cells was markedly attenuated by FST pretreatment. Moreover, HO-induced mitochondrial dysfunctions associated with apoptotic events, including loss of mitochondrial membrane potential (MMP), decreased Bcl-2/Bcl-2 associated x-protein (Bax) ratio, and cytosolic release of cytochrome , were reduced in the presence of FST. FST also diminished HO-induced activation of caspase-3, which was associated with the ability of FST to protect the degradation of poly (ADP-ribose) polymerase. Furthermore, FST notably enhanced nuclear translocation and phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2) in the presence of HO with concomitant upregulation of heme oxygenase-1 (HO-1) expression. However, artificial blockade of this pathway by the HO-1 inhibitor, zinc protoporphyrin IX, greatly abolished the protective effect of FST against HO-induced MC3T3-E1 cell injury. Taken together, these results demonstrate that FST could protect MC3T3-E1 cells from HO-induced damage by maintaining mitochondrial function while eliminating ROS along with activation of the Nrf2/HO-1 antioxidant pathway.
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http://dx.doi.org/10.3390/foods10112807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8623046PMC
November 2021

Inflammasome-Dependent Peroxiredoxin 2 Secretion Induces the Classical Complement Pathway Activation.

Immune Netw 2021 Oct 7;21(5):e36. Epub 2021 Oct 7.

Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, Korea.

Peroxiredoxins (Prxs) are ubiquitously expressed peroxidases that reduce hydrogen peroxide or alkyl peroxide production in cells. Prxs are released from cells in response to various stress conditions, and they function as damage-associated molecular pattern molecules. However, the secretory mechanism of Prxs and their roles have not been elucidated. Thus, we aimed to determine whether inflammasome activation is a secretory mechanism of Prxs and subsequently identify the effect of the secreted Prxs on activation of the classical complement pathway. Using J774A.1, a murine macrophage cell line, we demonstrated that NLRP3 inflammasome activation induces Prx1, Prx2, Prx5, and Prx6 secretion in a caspase-1 dependent manner. Using HEK293T cells with a transfection system, we revealed that the release of Prx1 and Prx2 relies on gasdermin-D (GSDMD)-mediated secretion. Next, we confirmed the binding of both Prx1 and Prx2 to C1q; however, only Prx2 could induce the C1q-mediated classical complement pathway activation. Collectively, our results suggest that inflammasome activation is a secretory mechanism of Prxs and that GSDMD is a mediator of their secretion. Moreover, secreted Prx1 and Prx2 bind with C1q, but only Prx2 mediates the classical complement pathway activation.
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http://dx.doi.org/10.4110/in.2021.21.e36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568911PMC
October 2021

Intraoperative Assessment of Gap Balancing in Total Knee Arthroplasty Using Navigation with Joint Stability Graphs.

J Knee Surg 2021 Nov 18. Epub 2021 Nov 18.

Department of Orthopaedic Surgery, College of Medicine, Kyung Hee University, Seoul, Korea.

The purpose of this study was to assess continuous gaps in the replaced knee throughout the full range of motion (ROM) after total knee arthroplasty (TKA) using a joint stability graph, and to analyze the gap laxity in the mid-flexion range. Ninety-three TKAs were performed using imageless navigation with a joint stability graph. While positioning guides for each respective cut, the surgeon can safely preview the resection's impact for the resulting joint gaps and control the soft tissue balance at the knee flexion of 0° (extension) and 90° (flexion). The gaps between the femoral component and insert were evaluated throughout the full ROM using the joint stability graph. The mechanical axis (MA) and change of joint line height were radiographically evaluated. Posthoc power analyses using a significant α value of 0.05 were performed on the proportion of the mid-flexion instability as a primary outcome to determine whether the sample had sufficient power. The power was determined to be sufficient (100%). The flexion-extension gap differences in each medial and lateral compartment and the mediolateral gap differences in flexion and extension were all ≤3 mm. None of the knees had mid-flexion instability, which is defined by a peak mid-flexion gap that is 3 mm greater than the smaller value of flexion or extension gap. The average MA was well corrected from varus 11.4° to varus 1.0° postoperatively. The proportion of postoperative well-aligned knees (MA ≤ 3°) was 87.1%. The joint line height was well preserved (14.7 vs. 14.8 mm,  = 0.751). The joint stability graph in TKA using the navigation can effectively evaluate the continuous gap throughout the ROM, including the mid-flexion range. Mid-flexion instability was uncommon in primary TKAs with appropriate alignment and proper preservation of the joint line. The Level of evidence for the study is IV.
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http://dx.doi.org/10.1055/s-0041-1739200DOI Listing
November 2021

Mori Ramulus Suppresses Hydrogen Peroxide-Induced Oxidative Damage in Murine Myoblast C2C12 Cells through Activation of AMPK.

Int J Mol Sci 2021 Oct 29;22(21). Epub 2021 Oct 29.

Department of Pharmacology, College of Korean Medicine, Daegu Haany University, Daegu 42158, Korea.

Mori Ramulus, the dried twigs of L., has been attracting attention for its potent antioxidant activity, but its role in muscle cells has not yet been elucidated. The purpose of this study was to evaluate the protective effect of aqueous extracts of Mori Ramulus (AEMR) against oxidative stress caused by hydrogen peroxide (HO) in C2C12 mouse myoblasts, and in dexamethasone (DEX)-induced muscle atrophied models. Our results showed that AEMR rescued HO-induced cell viability loss and the collapse of the mitochondria membrane potential. AEMR was also able to activate AMP-activated protein kinase (AMPK) in HO-treated C2C12 cells, whereas compound C, a pharmacological inhibitor of AMPK, blocked the protective effects of AEMR. In addition, HO-triggered DNA damage was markedly attenuated in the presence of AEMR, which was associated with the inhibition of reactive oxygen species (ROS) generation. Further studies showed that AEMR inhibited cytochrome release from mitochondria into the cytoplasm, and Bcl-2 suppression and Bax activation induced by HO. Furthermore, AEMR diminished HO-induced activation of caspase-3, which was associated with the ability of AEMR to block the degradation of poly (ADP-ribose) polymerase, thereby attenuating HO-induced apoptosis. However, compound C greatly abolished the protective effect of AEMR against HO-induced C2C12 cell apoptosis, including the restoration of mitochondrial dysfunction. Taken together, these results demonstrate that AEMR could protect C2C12 myoblasts from oxidative damage by maintaining mitochondrial function while eliminating ROS, at least with activation of the AMPK signaling pathway. In addition, oral administration of AEMR alleviated gastrocnemius and soleus muscle loss in DEX-induced muscle atrophied rats. Our findings support that AEMR might be a promising therapeutic candidate for treating oxidative stress-mediated myoblast injury and muscle atrophy.
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http://dx.doi.org/10.3390/ijms222111729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583786PMC
October 2021

HOXD10 expression as a prognostic factor for hepatocellular carcinoma treated with curative resection.

J BUON 2021 Sep-Oct;26(5):1942-1949

Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: HOXD10 downregulation resulting from epigenetic changesas well as its role as a tumor suppressor have been reported in several cancers including hepatocellular carcinomas (HCCs). However, the prognostic role of HOXD10 expression in HCC tissue samples has not been evaluated.

Methods: HOXD10 expression was investigated in 278 curatively resected HCC samples using immunohistochemistry and its effectiveness in predicting patient outcome was analyzed.

Results: Low expression of HOXD10 was observed in 82.7% of HCC samples, and this was associated with increased age, large tumor size and advanced stage.HOXD10 was an independent predictive factor for early tumor recurrence at less than 2 years. Patients with low HOXD10 expression showed shorter recurrence-free survival (RFS) (p=0.024) and disease-specific survival (DSS) (p=0.016) than those with high expression. Multivariate analysis confirmed that low HOXD10 expression was an independent predictor of shorter RFS (hazard ratio 1.873, p=0.006) and DSS (hazard ratio2.504, p=0.012) than high HOXD10 expression.

Conclusions: The present study provides clinical evidence supporting the use of HOXD10 as a prognostic biomarker in curatively resected HCCs, and suggests that HOXD10 could also be a potential therapeutic target in HCC.
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November 2021

Appropriate determination of the surgical transepicondylar axis can be achieved following distal femur resection in navigation-assisted total knee arthroplasty.

Knee Surg Relat Res 2021 Nov 10;33(1):41. Epub 2021 Nov 10.

Department of Orthopaedic Surgery, College of Medicine, Kyung Hee University, 23 Kyunghee-daero, Dongdaemun-gu, Seoul, 130-872, South Korea.

Background: Many surgeons have determined the surgical transepicondylar axis (sTEA) after distal femur resection in total knee arthroplasty (TKA). However, in most navigation systems, the registration of the sTEA precedes the distal femur resection. This sequential difference can influence the accuracy of intraoperative determination for sTEA when considering the proximal location of the anatomical references for sTEA and the arthritic environment. We compared the accuracy and precision in determinations of the sTEA between before and after distal femur resection during navigation-assisted TKA.

Methods: Ninety TKAs with Attune posterior-stabilized prostheses were performed under imageless navigation. The sTEA was registered before distal femur resection, then reassessed and adjusted after distal resection. The femoral component was implanted finally according to the sTEA determined after distal femur resection. Computed tomography (CT) was performed postoperatively to analyze the true sTEA (the line connecting the tip of the lateral femoral epicondyle to the lowest point of the medial femoral epicondylar sulcus on axial CT images) and femoral component rotation (FCR) axis. The FCR angle after distal femur resection (FCRA-aR) was defined as the angle between the FCR axis and true sTEA on CT images. The FCR angle before distal resection (FCRA-bR) could be presumed to be the value of FCRA-aR minus the difference between the intraoperatively determined sTEAs before and after distal resection as indicated by the navigation system. It was considered that the FCRA-bR or FCRA-aR represented the differences between the sTEA determined before or after distal femur resection and the true sTEA, respectively.

Results: The FCRA-bR was -1.3 ± 2.4° and FCRA-aR was 0.3 ± 1.7° (p < 0.001). The range of FCRA-bR was from -6.6° to 4.1° and that of FCRA-aR was from -2.7° to 3.3°. The proportion of appropriate FCRA (≤ ±3°) was significantly higher after distal femur resection than that before resection (91.1% versus 70%; p < 0.001).

Conclusions: The FCR was more appropriate when the sTEA was determined after distal femur resection than before resection in navigation-assisted TKA. The reassessment and adjusted registration of sTEA after distal femur resection could improve the rotational alignment of the femoral component in navigation-assisted TKA.

Level Of Evidence: IV.
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http://dx.doi.org/10.1186/s43019-021-00123-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579642PMC
November 2021

Role of Aberrantly Activated Lysophosphatidic Acid Receptor 1 Signaling Mediated Inflammation in Renal Aging.

Cells 2021 09 28;10(10). Epub 2021 Sep 28.

Transplant Research Center, The Catholic University of Korea, Seoul 06591, Korea.

The increasing load of senescent cells is a source of aging, and chronic inflammation plays a pivotal role in cellular senescence. In addition, senescent renal tubular epithelial cells are closely associated with renal aging. Lysophosphatidic acid (LPA) is a bioactive lipid mainly produced by the catalytic action of autotaxin (ATX), and its ligation to LPA receptor-1 (LPAR1) is associated with chronic inflammation and renal fibrosis; however, its role in renal aging is unclear. Male 2-, 12-, and 24-month-old C57BL/6 mice and Human renal proximal tubular epithelial cells (HRPTEpiC) were used in the present study. DNA damage and oxidative stress-induced senescence were simulated using doxorubicin (DOXO) and HO, respectively. The aged kidney showed decreased renal function, increased fractional mesangial area, and tubulointerstitial fibrosis. Both aged kidney and senescent cells showed increased levels of LPAR1, Nuclear factor κB (NF-κB), and inflammatory cytokines. In addition, knockdown reduced NF-κB and subsequent inflammatory cytokine induction, and -knockdown resulted in decreased LPAR1 expression. Our study revealed a positive feedback loop between LPAR1 and NF-κB, which reinforces the role of inflammatory response, suggesting that blocking of aberrantly activated LPAR1 may reduce excessive inflammation, thereby providing a new possible therapeutic strategy to attenuate renal aging.
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http://dx.doi.org/10.3390/cells10102580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534041PMC
September 2021

Induction of Apoptosis by Isoalantolactone in Human Hepatocellular Carcinoma Hep3B Cells through Activation of the ROS-Dependent JNK Signaling Pathway.

Pharmaceutics 2021 Oct 6;13(10). Epub 2021 Oct 6.

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

Isoalantolactone (IALT) is one of the isomeric sesquiterpene lactones isolated from the roots of L. IALT is known to possess various biological and pharmacological activities, but its anti-cancer mechanisms are not well understood. The aim of the present study was to investigate the anti-proliferative effects of IALT in human hepatocellular carcinoma (HCC) cells and to evaluate the potential anti-cancer mechanisms. Our results demonstrated that IALT treatment concentration-dependently suppressed the cell survival of HCC Hep3B cells, which was associated with the induction of apoptosis. IALT increased the expression of death-receptor-related proteins, activated caspases, and induced Bid truncation, subsequently leading to cleavage of poly (ADP-ribose) polymerase. In addition, IALT contributed to the cytosolic release of cytochrome c by destroying mitochondrial integrity, following an increase in the Bax/Bcl-2 expression ratio. However, IALT-mediated growth inhibition and apoptosis were significantly attenuated in the presence of a pan-caspase inhibitor, suggesting that IALT induced caspase-dependent apoptosis in Hep3B cells. Moreover, IALT activated the mitogen-activated protein kinases signaling pathway, and the anti-cancer effect of IALT was significantly diminished in the presence of a potent c-Jun N-terminal kinase (JNK) inhibitor. IALT also improved the generation of intracellular reactive oxygen species (ROS), whereas the ROS inhibitor significantly abrogated IALT-induced growth reduction, apoptosis, and JNK activation. Furthermore, ROS-dependent apoptosis was revealed as a mechanism involved in the anti-cancer activity of IALT in a 3D multicellular tumor spheroid model of Hep3B cells. Taken together, our findings indicate that IALT exhibited anti-cancer activity in HCC Hep3B cells by inducing ROS-dependent activation of the JNK signaling pathway.
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http://dx.doi.org/10.3390/pharmaceutics13101627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540929PMC
October 2021

Differences in genomic profile of high-grade urothelial carcinoma according to tumor location.

Urol Oncol 2021 Oct 15. Epub 2021 Oct 15.

Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Objectives: To establish targeted therapies based on the molecular landscape in upper urinary tract urothelial carcinoma (UTUC), we tried to investigate the molecular characteristics of UTUC compared with those of bladder urothelial carcinoma (BLUC) by next-generation sequencing (NGS).

Materials And Methods: We selected 71 high-grade infiltrating urothelial carcinoma tissue specimens from 33 UTUC and 38 BLUC patients. NGS analysis was performed with the Illumina TruShigt Oncology-500 panel.

Results: Both UTUC and BLUC showed similar clinicopathologic characteristics, as well as morphologic similarities. The median tumor mutation burden (TMB) of all cases was 7.8 mutations/Mb. The majority of alterations were missense mutations. TP53 (40/71, 56.3%), KDM6A (30/71, 42.3%), and TERT promoter mutations (23/71, 32.4%) were observed regardless of tumor location. Compared with UTUC, BLUC showed frequent mutations in several genes: ARID1A (P = 0.001), ASXL1 (P = 0.017), ERBB3 (P = 0.005), PRKDC (P = 0.004) and RB1 (P = 0.041). On the contrary, copy number loss of FGFR3 was observed more in UTUC than BLUC (P = 0.018). Also, 6 cases showed oncogenic fusions: 3 cases with FGFR2 fusion in UTUC and 3 cases with FGFR3-TACC3 fusion in BLUC.

Conclusion: Despite the small cohort size, we identified genetic differences between UTUC and BLUC in Korean patients by NGS. An understanding of the comprehensive molecular characteristics of UTUC and BLUC may be helpful in detecting candidates for targeted therapy.
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http://dx.doi.org/10.1016/j.urolonc.2021.08.019DOI Listing
October 2021

Substrate-independent three-dimensional polymer nanosheets induced by solution casting.

Chem Sci 2021 Sep 9;12(35):11748-11755. Epub 2021 Aug 9.

Department of Chemical and Biomolecular Engineering, Yonsei University 50 Yonsei-ro, Seodaemun-gu Seoul 03722 Republic of Korea

Nanosheets are important structures usually composed of inorganic materials, such as metals, metal oxides, and carbon. Their creation typically involves hydrothermal, electrochemical or microwave processes. In this study, we report a novel formation mechanism of 3D polymer nanosheets facile solution casting using a comb copolymer consisting of poly(ethylene glycol) behenyl ether methacrylate and poly(oxyethylene) methacrylate (PEGBEM-POEM). Controlling the composition of comb copolymer yielded nanosheets with different packing density and surface coverage. Interestingly, the structure exhibits substrate independence as confirmed by glass, inorganic wafer, organic filter paper, and porous membrane. The formation of 3D nanosheets was investigated in detail using coarse-grained molecular dynamics simulations. The obtained polymer nanosheets were further utilized as templates for inorganic nanosheets, which exhibit high conductivity owing to interconnectivity, and hence have promising electronic and electrochemical applications.
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http://dx.doi.org/10.1039/d1sc03232aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442678PMC
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

Renal Outcome of IgM Nephropathy: A Comparative Prospective Cohort Study.

J Clin Med 2021 Sep 16;10(18). Epub 2021 Sep 16.

Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.

Immunoglobulin M nephropathy (IgMN) is an idiopathic glomerulonephritis characterized by diffuse deposits of IgM in the glomerular mesangium. However, its renal prognosis remains unknown. We compared renal outcomes of IgMN patients with those of patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or mesangial proliferative glomerulonephritis (MsPGN) from a prospective observational cohort, with 1791 patients undergoing native kidney biopsy in eight hospitals affiliated with The Catholic University of Korea between December 2014 and October 2020. IgMN had more mesangial proliferation and matrix expansion than MsPGN and more tubular atrophy and interstitial fibrosis than MCD. IgMN patients had decreased eGFR than MCD patients in the earlier follow-up. However, there was no significant difference in urine protein or eGFR among all patients at the last follow-up. When IgMN was divided into three subtypes, patients with FSGS-like IgMN tended to have lower eGFR than those with MCD-like or MsPGN-like IgMN but higher proteinuria than MsPGN-like IgMN without showing a significant difference. The presence of hypertension at the time of kidney biopsy predicted ≥20% decline of eGFR over two years in IgMN patients. Our data indicate that IgMN would have a clinical course and renal prognosis similar to MCD, FSGS, and MsPGN.
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http://dx.doi.org/10.3390/jcm10184191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466757PMC
September 2021

Post-renal transplant pulmonary haemorrhage in a patient with Goodpasture syndrome without renal involvement and anti-glomerular basement membrane antibody: A case report.

Nephrology (Carlton) 2021 Sep 8. Epub 2021 Sep 8.

Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, Seoul, South Korea.

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http://dx.doi.org/10.1111/nep.13965DOI Listing
September 2021

Changes in Cyclin D1, cdk4, and Their Associated Molecules in Ischemic Pyramidal Neurons in Gerbil Hippocampus after Transient Ischemia and Neuroprotective Effects of Ischemic Preconditioning by Keeping the Molecules in the Ischemic Neurons.

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

Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon 24252, Korea.

Inadequate activation of cell cycle proteins including cyclin D1 and cdk4 is involved in neuronal cell death induced by diverse pathological stresses, including transient global brain ischemia. The neuroprotective effect of ischemic preconditioning is well-established, but the underlying mechanism is still unknown. In this study, we examined changes in cyclin D1, cdk4, and related molecules in cells or neurons located in Cornu Ammonis 1 (CA1) of gerbil hippocampus after transient ischemia for 5 min (ischemia and reperfusion) and investigated the effects of IPC on these molecules after ischemia. Four groups were used in this study as follows: sham group, ischemia group, IPC plus (+) sham group, and IPC+ischemia group. IPC was developed by inducing 2-min ischemia at 24 h before 5-min ischemia (real ischemia). Most pyramidal cells located in CA1 of the ischemia group died five days after ischemia. CA1 pyramidal cells in the IPC+ischemia group were protected. In the ischemia group, the expressions of cyclin D1, cdk4, phosphorylated retinoblastoma (-Rb), and E2F1 (a transcription factor regulated by -Rb) were significantly altered in the pyramidal cells with time after ischemia; in the IPC+ischemia group, they were controlled at the level shown in the sham group. In particular, the expression of p16 (an endogenous cdk inhibitor) in the ischemia group was reversely altered in the pyramidal cells; in the IPC+TI group, the expression of p16 was not different from that shown in the sham group. Our current results indicate that cyclin D1/cdk4-related signals may have important roles in events in neurons related to damage/death following ischemia and reperfusion. In particular, the preservation of p16 by IPC may be crucial in attenuating neuronal death/damage or protecting neurons after brain ischemic insults.
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http://dx.doi.org/10.3390/biology10080719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389197PMC
July 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

Frist observation and effect of fishery of seabed litter on sea bed by trawl survey Korea waters.

Mar Pollut Bull 2021 Sep 8;170:112228. Epub 2021 Jul 8.

Fisheries Resources Research Center, National Institute of Fisheries Science, 2-17 Tongyeonghaean-ro, Tongyeong-si, Gyeongsangnam-do 53064, Republic of Korea. Electronic address:

Fisheries activities for supplying marine productions were excessively overwhelming. Furthermore in the competitive industrialization, the impact on marine ecosystems and fisheries resources are severe due to the increase of various seabed litter such as plastic materials, styrofoam and plastic bottles and the deterioration of the marine environment. Despite these seriously situation, very few studies of some sea of Korea have been carried out on sedimentary waste fishing. Also some fisheries and there are few reports on plastics present on the seabed of around Korea. This study investigated the distribution of seabed litter collected from the seabed and characteristics of each area by using the trawl gear of the survey vessel from February to November 2018. The weight of all seabed litter collected during the investigation was 62,541.5 kg km, with a range of 0.2-15,019.7 kg km. The most amount of seabed litter was collected from sea block 106 in the South Sea, followed by sea blocks 76 and 82 in the East Sea. Through this study, which was conducted for the first time in all sea in around Korea, it can be used as basic data to understand the current status of seabed litter in the seabed and to establish effective policies at the led by the government.
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http://dx.doi.org/10.1016/j.marpolbul.2021.112228DOI Listing
September 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

Revisiting extraprostatic extension based on invasion depth and number for new algorithm for substaging of pT3a prostate cancer.

Sci Rep 2021 07 6;11(1):13952. Epub 2021 Jul 6.

Department of Pathology, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Extraprostatic extension (EPE) is a factor in determining pT3a stage in prostate cancer. However, the only distinction in EPE is whether it is focal or non-focal, causing diagnostic and prognostic ambiguity. We substaged pT3a malignancies using classification of EPE to improve personalized prognostication. We evaluated 465 radical prostatectomy specimens with a digital image analyzer by measuring the number, radial distance and two-dimensional square area of the EPE. The most significant cut-off value was proposed as an algorithm for the pT3a substaging system to predict biochemical recurrence (BCR). A combination of the radial distance and the number of EPEs predicted BCR the most effectively. The optimal cut-off criteria were 0.75 mm and 2 mm in radial distance and multifocal EPE (hazard ratio: 2.526, C-index 0.656). The pT3a was subdivided into pT3a1, < 0.75 mm and any number of EPEs; pT3a2, 0.75-2 mm and one EPE; and pT3a3, > 2 mm and any number of EPEs or 0.75-2 mm and ≥ 2 EPEs. This combined tier was highly significant in the prediction of BCR-free survival. The combination of radial distance and number of EPEs could be used to subdivide pT3a prostate cancer and may aid in the prediction of BCR.
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http://dx.doi.org/10.1038/s41598-021-93340-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260727PMC
July 2021

Revisiting extraprostatic extension based on invasion depth and number for new algorithm for substaging of pT3a prostate cancer.

Sci Rep 2021 07 6;11(1):13952. Epub 2021 Jul 6.

Department of Pathology, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Extraprostatic extension (EPE) is a factor in determining pT3a stage in prostate cancer. However, the only distinction in EPE is whether it is focal or non-focal, causing diagnostic and prognostic ambiguity. We substaged pT3a malignancies using classification of EPE to improve personalized prognostication. We evaluated 465 radical prostatectomy specimens with a digital image analyzer by measuring the number, radial distance and two-dimensional square area of the EPE. The most significant cut-off value was proposed as an algorithm for the pT3a substaging system to predict biochemical recurrence (BCR). A combination of the radial distance and the number of EPEs predicted BCR the most effectively. The optimal cut-off criteria were 0.75 mm and 2 mm in radial distance and multifocal EPE (hazard ratio: 2.526, C-index 0.656). The pT3a was subdivided into pT3a1, < 0.75 mm and any number of EPEs; pT3a2, 0.75-2 mm and one EPE; and pT3a3, > 2 mm and any number of EPEs or 0.75-2 mm and ≥ 2 EPEs. This combined tier was highly significant in the prediction of BCR-free survival. The combination of radial distance and number of EPEs could be used to subdivide pT3a prostate cancer and may aid in the prediction of BCR.
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http://dx.doi.org/10.1038/s41598-021-93340-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260727PMC
July 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

Effect of food intake on the pharmacokinetics of rivoceranib in healthy subjects.

Fundam Clin Pharmacol 2021 Jun 8. Epub 2021 Jun 8.

Elevar Therapeutics, Inc., Salt Lake City, UT, USA.

Rivoceranib is a selective inhibitor of VEGFR-2 being developed for the treatment of solid tumor. The objective of the study was to evaluate the effect of food on bioavailability as well as single- and multiple-dose pharmacokinetics (PKs) of 81 and 201 mg doses of rivoceranib. The study was conducted as a two-part study. In Part 1 (single ascending dose (SAD), open-label, crossover study design), 2 oral doses of rivoceranib (81 mg or 201 mg) were given to all healthy subjects with a minimum 3-day washout period between dosing. Part 2 was a multiple ascending dose (MAD), open-label, crossover design where subjects were divided based on 81 and 201 mg doses. Both doses were administered with and without food in a crossover manner for the SAD and MAD parts. 24 healthy subjects completed Part 1 and 20 subjects completed Part 2. For the 81 mg dose in the SAD and MAD parts of the study, their food effect was not observed. For the 201 mg dose in both parts, food appeared to increase bioavailability by 20%-30% in Part 1, and 30%-40% in Part 2. Median t value was delayed when rivoceranib was administered with food at each dose level in both parts of the study. Dose proportionality was confirmed only for the AUC  value from Part 1-fasted cohort but inconclusive for C  and AUC parameters under other dosing regimens. In conclusion, rivoceranib when taken with food delays t appears to increase bioavailability at 201 mg dose.
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http://dx.doi.org/10.1111/fcp.12707DOI Listing
June 2021

Erratum to "Sensor-Assisted Total Knee Arthroplasty: A Narrative Review".

Clin Orthop Surg 2021 Jun 18;13(2):286. Epub 2021 May 18.

Department of Orthopaedic Surgery, Kyung Hee University College of Medicine, Seoul, Korea.

[This corrects the article on p. 1 in vol. 13, PMID: 33747371.].
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http://dx.doi.org/10.4055/cios20034errDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173241PMC
June 2021

Comparison of Patellofemoral-Specific Clinical and Radiographic Results after Total Knee Arthroplasty Using a Patellofemoral Design-Modified Prosthesis and Its Predecessor.

Clin Orthop Surg 2021 Jun 2;13(2):175-184. Epub 2021 Feb 2.

Department of Orthopaedic Surgery, Kyung Hee University College of Medicine, Seoul, Korea.

Backgroud: One recently developed total knee arthroplasty (TKA) prosthesis was designed to alter the patellofemoral geometry and optimize patellar tracking compared to its predecessor. Despite an expectation that the improved design would contribute to optimal patellofemoral compatibility, its effect has not been confirmed with patellofemoral-specific clinical scoring systems and radiographic parameters. Our purpose was to compare patellofemoral-specific clinical and radiographic results after TKA using a patellofemoral design-modified prosthesis and its predecessor.

Methods: The results of 200 TKAs with Attune (group A) were compared to those of 200 TKAs with PFC Sigma (group B). Clinically, the presence of anterior knee pain (AKP), patellar crepitation, and Kujala score were checked. Radiographically, anterior femoral offset (AFO), posterior femoral offset (PFO), position of patellar ridge, and patellar tilt and translation were compared.

Results: In group A, AKP and patellar crepitation occurred less frequently (AKP: 3% vs. 8%, = 0.028; patellar crepitation: 2.5% vs. 9%, = 0.005) and Kujala score was higher (81.8 vs. 77.9, < 0.001), when compared to group B. The AFO decreased in group A postoperatively but increased in group B (-1.2 vs. 1.1 mm, < 0.001). The change in PFO was smaller in group A than group B (-1.2 vs. -3.6 mm, < 0.001). The change in patellar ridge after TKA was smaller in group A than group B (1.4% vs. 8.3%, < 0.001). The postoperative patella of group A was more laterally tilted (5.9° vs. 2.2°, < 0.001) and less laterally translated (0.9 vs. 2.6 mm, < 0.001). The proportion of incompatible patella tilt angle (≥ ± 10°) was greater in group A than group B (21.7% vs. 4.5%, < 0.001).

Conclusions: TKA using Attune provided better patellofemoral-specific clinical results and favorable radiographic parameters related with patellar ridge, AFO, and PFO than TKA using PFC Sigma did. However, the current prosthesis did not provide better radiographic patellar tracking, which might be due to the medial location of the patellar ridge.
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http://dx.doi.org/10.4055/cios20188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173230PMC
June 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
November 2021

Exosome-based delivery of super-repressor IκBα ameliorates kidney ischemia-reperfusion injury.

Kidney Int 2021 09 27;100(3):570-584. Epub 2021 May 27.

Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, South Korea. Electronic address:

Ischemia-reperfusion injury is a major cause of acute kidney injury. Recent studies on the pathophysiology of ischemia-reperfusion-induced acute kidney injury showed that immunologic responses significantly affect kidney ischemia-reperfusion injury and repair. Nuclear factor (NF)-ĸB signaling, which controls cytokine production and cell survival, is significantly involved in ischemia-reperfusion-induced acute kidney injury, and its inhibition can ameliorate ischemic acute kidney injury. Using EXPLOR, a novel, optogenetically engineered exosome technology, we successfully delivered the exosomal super-repressor inhibitor of NF-ĸB (Exo-srIĸB) into B6 wild type mice before/after kidney ischemia-reperfusion surgery, and compared outcomes with those of a control exosome (Exo-Naïve)-injected group. Exo-srIĸB treatment resulted in lower levels of serum blood urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin in post-ischemic mice than in the Exo-Naïve treatment group. Systemic delivery of Exo-srIĸB decreased NF-ĸB activity in post-ischemic kidneys and reduced apoptosis. Post-ischemic kidneys showed decreased gene expression of pro-inflammatory cytokines and adhesion molecules with Exo-srIĸB treatment as compared with the control. Intravital imaging confirmed the uptake of exosomes in neutrophils and macrophages. Exo-srIĸB treatment also significantly affected post-ischemic kidney immune cell populations, lowering neutrophil, monocyte/macrophage, and T cell frequencies than those in the control. Thus, modulation of NF-ĸB signaling through exosomal delivery can be used as a novel therapeutic method for ischemia-reperfusion-induced acute kidney injury.
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http://dx.doi.org/10.1016/j.kint.2021.04.039DOI Listing
September 2021

Cardiovascular Risk Comparison between Expanded Hemodialysis Using Theranova and Online Hemodiafiltration (CARTOON): A Multicenter Randomized Controlled Trial.

Sci Rep 2021 05 24;11(1):10807. Epub 2021 May 24.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.

Expanded hemodialysis (HDx) with medium cutoff (MCO) membranes, which remove middle-to-large molecules well, may be a good option to replace online hemodiafiltration (online-HDF). To provide more evidence, this randomized controlled trial compared several cardiovascular parameters between patients undergoing HDx and online-HDF. Eighty patients undergoing thrice-weekly hemodialysis were randomly assigned to receive either HDx with a Theranova membrane (n = 43) or online-HDF (n = 37). The primary endpoints were changes in brachial-ankle pulse wave velocity (baPWV), echocardiographic parameters, and coronary artery calcium (CAC) scores over 1 year, and the secondary endpoints included blood cardiovascular biomarkers, mortality, and patient-reported outcomes. A linear mixed model and log-rank test were used to estimate the group differences. 65 patients had completed the trial. The changes in baPWV and echocardiographic parameters did not differ between the two groups. The CAC scores remained stable in the online-HDF group, whereas an increasing trend was shown in the HDx group (P = 0.012). Other endpoints, including cardiovascular and all-cause mortalities, were similar between the two groups. The changes in cardiovascular parameters did not differ between HDx with an MCO membrane and online-HDF. However, attention may be needed in patients with high CAC scores or scores with an increasing tendency when online-HDF is replaced with HDx with an MCO membrane.
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http://dx.doi.org/10.1038/s41598-021-90311-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144214PMC
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

Fabry disease exacerbates renal interstitial fibrosis after unilateral ureteral obstruction via impaired autophagy and enhanced apoptosis.

Kidney Res Clin Pract 2021 Jun 21;40(2):208-219. Epub 2021 May 21.

Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Background: Fabry disease is a rare X-linked genetic lysosomal disorder caused by mutations in the GLA gene encoding alpha-galactosidase A. Despite some data showing that profibrotic and proinflammatory cytokines and oxidative stress could be involved in Fabry disease-related renal injury, the pathogenic link between metabolic derangement within cells and renal injury remains unclear.

Methods: Renal fibrosis was triggered by unilateral ureteral obstruction (UUO) in mice with Fabry disease to investigate the pathogenic mechanism leading to fibrosis in diseased kidneys.

Results: Compared to kidneys of wild-type mice, lamellar inclusion bodies were recognized in proximal tubules of mice with Fabry disease. Sirius red and trichrome staining revealed significantly increased fibrosis in all UUO kidneys, though it was more prominent in obstructed Fabry kidneys. Renal messenger RNA levels of inflammatory cytokines and profibrotic factors were increased in all UUO kidneys compared to sham-operated kidneys but were not significantly different between UUO control and UUO Fabry mice. Protein levels of Nox2, Nox4, NQO1, catalase, SOD1, SOD2, and Nrf2 were not significantly different between UUO control and UUO Fabry kidneys, while the protein contents of LC3-II and LC3-I and expression of Beclin1 were significantly decreased in UUO kidneys of Fabry disease mouse models compared with wild-type mice. Notably, TUNEL-positive cells were elevated in obstructed kidneys of Fabry disease mice compared to wild-type control and UUO mice.

Conclusion: These findings suggest that impaired autophagy and enhanced apoptosis are probable mechanisms involved in enhanced renal fibrosis under the stimulus of UUO in Fabry disease.
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http://dx.doi.org/10.23876/j.krcp.20.264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237117PMC
June 2021

Bioinspired Adenosine Triphosphate as an "All-In-One" Green Flame Retardant via Extremely Intumescent Char Formation.

ACS Appl Mater Interfaces 2021 May 5;13(19):22935-22945. Epub 2021 May 5.

School of Advanced Materials Science and Engineering, Sungkyunkwan University (SKKU), Suwon 16419, South Korea.

The development of eco-friendly flame retardants is crucial due to the hazardous properties of most conventional flame retardants. Herein, adenosine triphosphate (ATP) is reported to be a highly efficient "all-in-one" green flame retardant as it consists of three essential groups, which lead to the formation of char with extreme intumescence, namely, three phosphate groups, providing an acid source; one ribose sugar, working as a char source; and one adenine, acting as a blowing agent. Polyurethane foam was used as a model flammable material to demonstrate the exceptional flame retardancy of ATP. The direct flammability tests have clearly shown that the ATP-coated polyurethane (PU) foam almost did not burn upon exposure to the torch flame. Importantly, ATP exhibits an extreme volume increase, whereas general phosphorus-based flame retardants show a negligible increase in volume. The PU foam coated with 30 wt % of ATP (PU-ATP 30 wt %) exhibits a significant reduction in the peak heat release rate (94.3%) with a significant increase in the ignition time, compared to bare PU. In addition, PU-ATP 30 wt % exhibits a high limiting oxygen index (LOI) value of 31% and HF-1 rating in the UL94 horizontal burning foamed material test. Additionally, we demonstrated that ATP's flame retardancy is sufficient for other types of matrices such as cotton, as confirmed from the results of the standardized ASTM D6413 test; cotton-ATP 30 wt % exhibits an LOI value of 32% and passes the vertical flame test. These results strongly suggest that ATP has great potential to be used as an "all-in-one" green flame retardant.
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http://dx.doi.org/10.1021/acsami.1c02021DOI Listing
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
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