Publications by authors named "Min Jung Park"

285 Publications

Programmed Death-Ligand 1 Expression Potentiates the Immune Modulatory Function Of Myeloid-Derived Suppressor Cells in Systemic Lupus Erythematosus.

Front Immunol 2021 27;12:606024. Epub 2021 Apr 27.

The Rheumatism Research Center, The Catholic University of Korea, Seoul, South Korea.

Multiple studies have explored the potential role of programmed death-ligand 1 (PD-L1) as a mediator of Myeloid-derived suppressor cells (MDSCs) effects in various cancers. However, the role PD-L1 expression in MDSCs on autoimmune disease is still largely unknown.This study was undertaken to whether MDSC expressing PD-L1 have more potent immunoregulatory activity and control autoimmunity more effectively in two murine models of lupus (MRL/ mice and Roquin mice). The populations of MDSC were increased in peripheral blood of lupus patients. The mRNA levels of immunosuppressive molecules were profoundly decreased in MDSCs from lupus patients and mice. Co-culture with splenocytes showed that PD-L1 expressing MDSCs from control mice expand both Treg cells and regulatory B cells more potently. Infusion of PD-L1 expressing MDSCs reduced autoantibody levels and degree of proteinuria and improved renal pathology of two animal models of lupus. Moreover, PD-L1 expressing MDSCs therapy can suppress double negative (CD4-CD8-CD3+) T cells, the major pathogenic immune cells and follicular helper T cells in MRL/ mice, and podocyte damage. Our results indicate PD-L1 expressing MDSCs have more potent immunoregualtory activity and ameliorate autoimmunity more profoundly. These findings suggest PD-L1 expressing MDSCs be a promising therapeutic strategy targeting systemic autoimmune diseases.
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http://dx.doi.org/10.3389/fimmu.2021.606024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110929PMC
June 2021

Effects of coenzyme Q10 on ovarian surface epithelium-derived ovarian stem cells and ovarian function in a 4-vinylcyclohexene diepoxide-induced murine model of ovarian failure.

Reprod Biol Endocrinol 2021 Apr 22;19(1):59. Epub 2021 Apr 22.

Department of Obstetrics and Gynecology, Pusan National University School of Medicine, Busan, Republic of Korea.

Background: Several studies have shown that coenzyme Q10 (CoQ10) can rescue ovarian aging and that ovarian surface epithelium (OSE)-derived ovarian stem cells (OSCs) are useful for treating infertility due to ovarian aging. However, few studies have examined the effect of CoQ10 on OSCs. This study was aimed to investigate whether CoQ10 activates OSCs and recovers ovarian function in a 4-vinylcyclohexene diepoxide (VCD)-induced mouse model of ovarian failure.

Methods: Forty female C57BL/6 mice aged 6 weeks were randomly divided into four groups (n = 10/group): a control group administered saline orally, a CoQ10 group administered 150 mg/kg/day of CoQ10 orally in 1 mL of saline daily for 14 days, a VCD group administered 160 mg/kg/day of VCD i.p. in 2.5 mL of saline/kg for 5 days, and a VCD + CoQ10 group administered VCD i.p. for 5 days injection and CoQ10 (150 mg/kg/day) orally for 14 days. After treatment, follicle counts were evaluated by hematoxylin and eosin (H&E) staining, and ovarian mRNA expressions of Bmp-15, Gdf-9, and c-Kit were examined by quantitative real-time PCR. Serum FSH, AMH, and ROS levels were also measured. Oocyte-like structure counts and the expressions of Oct-4 and MVH were also evaluated after culturing OSE for 3 weeks. In a second experiment, 32 female mice were administered CoQ10 as described above, induced to superovulate using PMSG and hCG, and mated. Numbers of zygotes and embryo development rate were examined.

Results: Postcultured OSE showed significant increases in the numbers of oocyte-like structure and that the expression of Oct-4 and MVH were higher in the VCD + CoQ10 group than in the VCD group (p < 0.05). Numbers of surviving follicles from primordial to antral follicles, numbers of zygotes retrieved and embryo development rate to blastocyst were significantly greater in the VCD + CoQ10 group than in the VCD group (p < 0.01). Serum AMH level and ovarian expressions of Bmp-15, Gdf-9 and c-Kit were also significantly greater in the VCD + CoQ10 group than in the VCD group (p < 0.05). In contrast, serum ROS level was significantly lower in the VCD + CoQ10 group than in the VCD group (p < 0.05).

Conclusion: This study shows that CoQ10 stimulates the differentiation of OSE-derived OSCs and confirms that CoQ10 can reduce ROS levels and improve ovarian function and oocyte quality in mice with VCD-induced ovarian failure.
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http://dx.doi.org/10.1186/s12958-021-00736-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061220PMC
April 2021

Melatonin Inhibits Osteoclastogenesis and Bone Loss in Ovariectomized Mice by Regulating PRMT1-Mediated Signaling.

Endocrinology 2021 Jun;162(6)

Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea.

Melatonin, a pineal gland hormone, has been suggested to treat postmenopausal osteoporosis due to its inhibitory effect on osteoclast differentiation. We previously reported that protein arginine methyltransferase 1 (PRMT1) was an important mediator of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. However, the relationship between melatonin and PRMT1 in osteoclast differentiation and estrogen deficiency-induced osteoporosis is unclear. In this study, we investigated the inhibitory mechanisms of melatonin in vitro and in vivo by focusing on PRMT1. Melatonin treatment effectively blocked RANKL-induced osteoclastogenesis by inhibiting PRMT1 and asymmetric dimethylarginine (ADMA) expression. RANKL-induced tumor necrosis factor receptor-associated factor 6 (TRAF6) and the phosphorylation of JNK were also suppressed by melatonin, and TRAF6 siRNA attenuated RANKL-induced p-JNK and PRMT1 production. Melatonin inhibited the transcriptional activity of NF-κB by interfering with the binding of PRMT1 and NF-κB subunit p65 in RANKL-treated bone marrow-derived macrophages. Our results also revealed that melatonin inhibits RANKL-induced PRMT1 expression through receptors-independent pathway. Thus, the anti-osteoclastogenic effect of melatonin was mediated by a cascade of inhibition of RANKL-induced TRAF6, JNK, PRMT1, and NF-κB signaling in melatonin receptors-independent pathway. In vivo, ovariectomy caused significant decreases in bone mineral density, but melatonin treatment alleviated the ovariectomized (OVX)-induced bone loss by inhibiting bone resorption. Furthermore, the expression PRMT1 and TRAP mRNA was upregulated in OVX-femurs, but effectively suppressed by melatonin injection. These findings suggest that melatonin inhibited osteoclast differentiation and estrogen deficiency-induced osteoporosis by suppressing RANKL-induced TRAF6, JNK, PRMT1, and NF-κB signaling cascades in melatonin receptors-independent pathway.
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http://dx.doi.org/10.1210/endocr/bqab057DOI Listing
June 2021

Short-chain fatty acid butyrate induces IL-10-producing B cells by regulating circadian-clock-related genes to ameliorate Sjögren's syndrome.

J Autoimmun 2021 May 22;119:102611. Epub 2021 Feb 22.

Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea; Laboratory of Immune Network, Catholic Research Institute of Medical Science, College of Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; Department of Medical Life Science, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea. Electronic address:

Objectives: Sjögren's syndrome (SS) is an autoimmune disease caused by inflammation of the exocrine gland. The pathological hallmark of SS is the infiltration of lymphocytes into the salivary glands. Increased infiltration of T and B cells into salivary glands exacerbates symptoms of SS. Several recent studies have identified the role of gut microbiota in SS. Butyrate, one of the metabolites of the gut microbiota, regulates T cells; however, its effects on B cells and SS remain unknown. This study determined the therapeutic effect of butyrate on regulating B cells in SS.

Methods: Various concentrations of butyrate were intraperitoneally injected three times per week in NOD/ShiLtJ (NOD) mice, the prototype animal model for SS, and observed for more than 10 weeks. Whole salivary flow rate and the histopathology of salivary glands were investigated. Human submandibular gland (HSG) cells and B cells in mouse spleen were used to confirm the anti-inflammatory and immunomodulatory effects of butyrate.

Results: Butyrate increased salivary flow rate in NOD mice and reduced inflammation of salivary gland tissues. It also regulated cell death and the expression of circadian-clock-related genes in HSG cells. Butyrate induced B cell regulation by increasing IL-10-producing B (B10) cells and decreasing IL-17-producing B cells, through the circadian clock genes RAR-related orphan receptor alpha and nuclear receptor subfamily 1 group D member 1.

Conclusion: The findings of this study imply that butyrate may ameliorate SS via reciprocal regulation of IL-10- and IL-17-producing B cells.
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http://dx.doi.org/10.1016/j.jaut.2021.102611DOI Listing
May 2021

Combination Treatment With Metformin and Tacrolimus Improves Systemic Immune Cellular Homeostasis by Modulating Treg and Th17 Imbalance.

Front Immunol 2020 8;11:581728. Epub 2021 Jan 8.

Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.

We examined the effect of combination therapy with metformin and tacrolimus on immune parameters including T regulatory (Treg) and type 17 helper T (Th17) cells and in mice and in liver transplantation (LT) patients. T cell proliferation and subtypes after T cell activation or allogeneic stimulation were evaluated. RNA sequencing and microarray analysis were used to evaluate differences in gene expression. Metformin and tacrolimus were administered to mice with graft-versus-host disease (GVHD) and the effects were assessed. Five LT patients were treated with metformin and the changes in Treg and Th17 cells examined. Combination therapy decreased Type 1 helper T (Th1) and Th17 cells present after T cell activation, whereas genes associated with Treg were overexpressed. During allogeneic stimulation, combination therapy increased Treg cells and decreased T cell proliferation and pro-inflammatory markers. In mice with GVHD, combination treatment decreased the clinical and pathological severity of GVHD. In LT patients, addition of metformin increased the peripheral percentage of CD4+Treg and CD8+Treg cells and decreased CD4+Th17. Our study suggests that the addition of metformin to tacrolimus may improve immunological balance by increasing Treg cells and decreasing Th17 cells.
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http://dx.doi.org/10.3389/fimmu.2020.581728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821164PMC
June 2021

Myeloid-derived suppressor cells therapy enhance immunoregulatory properties in acute graft versus host disease with combination of regulatory T cells.

J Transl Med 2020 12 14;18(1):483. Epub 2020 Dec 14.

The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-040, South Korea.

Background: Myeloid-derived suppressor cells (MDSCs) play a critical role in modulating the immune response and promoting immune tolerance in models of autoimmunity and transplantation. Regulatory T cells (Tregs) exert therapeutic potential due to their immunomodulatory properties, which have been demonstrated both in vitro and in clinical trials. Cell-based therapy for acute graft-versus-host disease (aGVHD) may enable induction of donor-specific tolerance in the preclinical setting.

Methods: We investigated whether the immunoregulatory activity of the combination of MDSCs and Tregs on T cell and B cell subset and alloreactive T cell response. We evaluated the therapeutic effects of combined cell therapy for a murine aGVHD model following MHC-mismatched bone marrow transplantation. We compared histologic analysis from the target tissues of each groups were and immune cell population by flow cytometric analysis.

Results: We report a novel approach to inducing immune tolerance using a combination of donor-derived MDSCs and Tregs. The combined cell-therapy modulated in vitro the proliferation of alloreactive T cells and the Treg/Th17 balance in mice and human system. Systemic infusion of MDSCs and Tregs ameliorated serverity and inflammation of aGVHD mouse model by reducing the populations of proinflammatory Th1/Th17 cells and the expression of proinflammatory cytokines in target tissue. The combined therapy promoted the differentiation of allogeneic T cells toward Foxp3 + Tregs and IL-10-producing regulatory B cells. The combination treatment control also activated human T and B cell subset.

Conclusions: Therefore, the combination of MDSCs and Tregs has immunomodulatory activity and induces immune tolerance to prevent of aGVHD severity. This could lead to the development of new clinical approaches to the prevent aGVHD.
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http://dx.doi.org/10.1186/s12967-020-02657-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734831PMC
December 2020

Abdominal Imaging Findings in Critically Ill Children With Multisystem Inflammatory Syndrome Associated With COVID-19.

Pediatr Infect Dis J 2021 02;40(2):e82-e83

Department of Radiology, Newark Beth Israel Medical Center, Robert Wood Johnson Barnabas Health, Rutgers New Jersey Medical School, New Jersey.

We report findings on abdominal imaging in critically ill children admitted with MIS-C. On sonography, hepatomegaly, nephromegaly, gallbladder wall edema, ascites, intestinal inflammation and mesenteric lymphadenopathy were seen, while CT showed fluid-filled small bowel loops, mural thickening of the terminal ileum, diffuse lymphadenopathy, and moderate ascites.
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http://dx.doi.org/10.1097/INF.0000000000002967DOI Listing
February 2021

One-Stage Extension Shortening Osteotomy for Syndromic Camptodactyly.

J Clin Med 2020 Nov 20;9(11). Epub 2020 Nov 20.

Division of Pediatric Orthopaedic Surgery, Severance Children's Hospital, Yonsei University College of Medicine, Seoul 03722, Korea.

Syndromic camptodactyly often affects multiple fingers, and severe deformities are common compared to idiopathic camptodactyly. This study aimed to evaluate the use of a one-stage extension shortening osteotomy of the proximal phalanx for patients with syndromic camptodactyly without tendon surgery. Forty-nine cases of syndromic camptodactyly were included. Forty fingers (81.6%) were associated with arthrogryposis multiplex congenita, and nine (18.4%) with other syndromes. Six fingers presented with a moderate form (30° to 60°) of camptodactyly, whereas 43 fingers manifested the severe form (>60°). The mean age at the time of surgery was 8.5 years, and the patients were followed for a mean of 3.9 years. The mean length of the shortening of the proximal phalanx was 4.9 mm, which averaged 17.8% of the proximal phalanx's original preoperative length. The mean operative time was 25.8 min, and the PIP joint was fixed using Kirschner wires with an average flexion position of 7.6°. The mean flexion contracture improved from 76° preoperatively to 41° postoperatively. The mean preoperative active arc of motion was 23°, which improved to 49° postoperatively. A one-stage extension shortening osteotomy is a straightforward and effective technique for the improvement of finger function through the indirect lengthening of volar structures without the flexor tendon lengthening. The osteotomy could simultaneously correct bony abnormalities. This simple procedure is especially suitable for surgery on multiple fingers in patients with syndromic camptodactyly.
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http://dx.doi.org/10.3390/jcm9113731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699896PMC
November 2020

Aqueous green tea infusion extracted by ultra-sonication method, but not by conventional method, facilitates GLUT4 membrane translocation in adipocytes which potently ameliorates high-fat diet-induced obesity.

J Food Biochem 2021 01 11;45(1):e13561. Epub 2020 Nov 11.

Department of Food Science and Technology, Graduate School of Chonnam National University, Gwangju, Korea.

Green tea contains bioactive compounds, such as polyphenols, responsible for its health-promoting effects, including antiobesity and antidiabetic effects. We previously reported that ultra-sonication extraction (UE) could efficiently increase the extraction yield of green tea compounds. In the present study, we found that the extract obtained using UE contained higher phenolic and flavonoid contents than that obtained using the conventional method. We therefore considered the extract as a bioactive metabolite-rich functional green tea extract (BMF-GTE), and tested its glucose-lowering effect by generating an adipocyte cell line stably expressing 7myc-GLUT4-GFP. We found that BMF-GTE treatment increased GLUT4 translocation to the plasma membrane. Moreover, BMF-GTE administration attenuated weight gain in mice fed a high-fat diet (HFD). Importantly, HFD-induced glucose tolerance was ameliorated in the mice receiving BMF-GTE. Therefore, we conclude that BMF-GTE worked against obesity and diabetes, at least partially, by enhancing GLUT4 translocation in adipocytes. PRACTICAL APPLICATIONS: As green tea is one of the most consumed beverages worldwide, its health effects have been widely tested. In our previous studies, we found that ultra-sonication extraction (UE) has the potential to increase the aqueous extraction yield of green tea compounds compared to conventional extraction techniques. In this study, we examined the biological effect of bioactive metabolite-rich functional green tea extract (BMF-GTE) obtained using UE; we observed that administering BMF-GTE lowered the body weight and increased insulin sensitivity in mice fed a high-fat diet, potentially by facilitating the membrane translocation of GLUT4 in adipocytes. Therefore, this study suggests that the extract obtained with UE had antiobesity and antidiabetic properties, indicative of a potential application of UE in maximizing the beneficial effects of green tea on human health.
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http://dx.doi.org/10.1111/jfbc.13561DOI Listing
January 2021

TC-E 5003, a protein methyltransferase 1 inhibitor, activates the PKA-dependent thermogenic pathway in primary murine and human subcutaneous adipocytes.

FEBS Lett 2020 09 29;594(17):2923-2930. Epub 2020 Aug 29.

Department of Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.

We previously reported the involvement of protein arginine methyltransferase 1 (PRMT1) in adipocyte thermogenesis. Here, we investigate the effects of PRMT1 inhibitors on thermogenesis. Unexpectedly, we find that the PRMT1 inhibitor TC-E 5003 (TC-E) induces the thermogenic properties of primary murine and human subcutaneous adipocytes. TC-E treatment upregulates the expression of Ucp1 and Fgf21 significantly and activates protein kinase A signaling and lipolysis in primary subcutaneous adipocytes from both mouse and humans. We further find that the thermogenic effects of TC-E are independent of PRMT1 and beta-adrenergic receptors. Our data indicate that TC-E exerts strong effects on murine and human subcutaneous adipocytes by activating beige adipocytes via PKA signaling.
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http://dx.doi.org/10.1002/1873-3468.13900DOI Listing
September 2020

improves ovarian function and oocyte quality in aged female mice.

Anim Reprod 2020 Jul 1;17(2):e20200013. Epub 2020 Jul 1.

The Korea Institute for Public Sperm Bank, Busan, Repuplic of Korea.

Although ovarian aging is a key cause of decreased ovarian function and oocyte quality, it remains a problem in infertility treatment. Therefore, this study is aimed to investigate whether (PL), a herb improves ovarian function and oocyte quality using aged female mice. C57BL/6 female mice aged 8 months were treated orally every day with PL of 26.5 mg/kg (n=7) and 53 mg/kg (n=7) of body weight for 4 weeks using an oral zoned needle. The control group (n=7) was treated with normal saline. Ovaries and serum were collected for the H&E stain and the evaluation of reactive oxygen species (ROS) levels, respectively. In the second experiment, female mice were orally administered with PL (26.5 mg/kg: n=12, 53 mg/kg: n=12, control: n=12) and then superovulated with PMSG and hCG, and mated with male mice. Zygotes were retrieved and cultured for 4 days. Ovaries were provided for examination of expressions of genes associated with angiogenesis (VEGF and visfatin), anti-aging (Sirt1 and Sirt2), and follicular development (c-Kit, BMP-15, and GDF-9). PL significantly increased numbers of surviving follicles (primordial, primary, secondary, and antral), numbers of zygotes retrieved, embryo development rate, and ovarian expression of VEGF, visfatin, c-Kit, BMP-15, and GDF-9 at both doses. However, ovarian expression of Sirt1 and Sirt2 was increased at 53.0 mg/kg of PL. ROS levels were not affected by PL. These results suggest that PL may possess beneficial effects regarding ovarian function and oocyte quality, possibly by activation of ovarian angiogenesis and follicular development.
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http://dx.doi.org/10.1590/1984-3143-AR2020-0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375873PMC
July 2020

Protein arginine methyltransferase-1 stimulates dopaminergic neuronal cell death in a Parkinson's disease model.

Biochem Biophys Res Commun 2020 09 10;530(2):389-395. Epub 2020 Jun 10.

School of Biological Sciences and Technology, College of Natural Sciences, Chonnam National University, Gwangju, 61186, Republic of Korea; College of Medicine, Chonnam National University, Gwangju, 61469, Republic of Korea. Electronic address:

Recent studies have revealed that protein arginine methyltransferases (PRMTs) are responsible for diverse neurodegenerative diseases. However, their pathophysiological role in dopaminergic neuronal death in Parkinson's disease (PD) has not been evaluated. In this study, we demonstrated that 1-Methyl-4-phenylpyridinium iodide (MPP), rotenone and paraquat, which cause dopaminergic neuronal cell death, increased PRMT1 expression in dopaminergic cell line. Dopaminergic neuronal cell death was increased by PRMT1 overexpression. MPP-induced cell death was attenuated by PRMT1 knockdown. Poly (ADP-ribose) polymerase-1 (PARP1) expression and activity, poly-ADP-ribosylation (PARylation), were elevated by MPP. Moreover, we found that PRMT1 positively regulates nuclear translocation of apoptosis-inducing factor (AIF). Elevated PRMT1 expression was observed in the substantia nigra pars compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injected mice. Furthermore, MPTP-induced dopaminergic neuronal death was reduced in PRMT1 haploinsufficient (prmt1) mice. These data suggest that PRMT1 is implicated in PARP1/AIF-mediated dopaminergic neuronal cell death, which might be involved in the pathology of PD. Therefore, our results propose PRMT1 as a new target to develop a potential treatment of PD.
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http://dx.doi.org/10.1016/j.bbrc.2020.05.016DOI Listing
September 2020

FTY720 ameliorates GvHD by blocking T lymphocyte migration to target organs and by skin fibrosis inhibition.

J Transl Med 2020 06 6;18(1):225. Epub 2020 Jun 6.

The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Background: Fibrosis is the formation of excess connective tissue in an organ or tissue during a reparative or reactive process. Graft-versus-host disease (GvHD) is a medical complication of allogeneic tissue transplantation with transplanted donor T cell-mediated inflammatory response; it is characterized by a severe immune response with fibrosis in the final stage of the inflammatory process. T helper 17 cells play a critical role in the pathogenesis of GvHD. Fingolimod (FTY720), an analogue of sphingosine-1-phosphate (S1P), is an effective immunosuppressive agent in experimental transplantation models.

Methods: In this study, we evaluated the effects of FTY720 as a treatment for an animal GvHD model with inflammation and fibrosis. The splenocytes, lymph nodes, blood, tissues from Syngeneic mice and GvHD-induced mice treated vehicle or FTY720 were compared using flow cytometry, hematological analyses, histologic analyses.

Results: FTY720 reduced clinical scores based on the following five clinical parameters: weight loss, posture, activity, fur texture, and skin integrity. FACS data showed that T lymphocyte numbers increased in mesenteric lymph nodes and decreased in splenocytes of FTY720-treated mice. Tissue analysis showed that FTY720 reduced skin, intestinal inflammation, and fibrotic markers. FTY720 dramatically decreased α-smooth muscle actin, connective tissue growth factor, and fibronectin protein levels in keloid skin fibroblasts.

Conclusions: Thus, FTY720 suppressed migration of pathogenic T cells to target organs, reducing inflammation. FTY720 also inhibited fibrogenesis marker expression in vitro and in vivo. Together, these results suggest that FTY720 prevents GvHD progression via immunosuppression of TH17 and simultaneously acts an anti-fibrotic agent.
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http://dx.doi.org/10.1186/s12967-020-02386-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276082PMC
June 2020

Mitochondrial Damage and Necroptosis in Aging Cochlea.

Int J Mol Sci 2020 Apr 3;21(7). Epub 2020 Apr 3.

Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Korea.

Age-related hearing loss (ARHL) is an irreversible, progressive neurodegenerative disorder and is presently untreatable. Previous studies using animal models have suggested mitochondrial damage and programmed cell death to be involved with ARHL. Thus, we further investigated the pathophysiologic role of mitochondria and necroptosis in aged C57BL/6J male mice. Aged mice (20 months old) exhibited a significant loss of hearing, number of hair cells, neuronal fibers, and synaptic ribbons compared to young mice. Ultrastructural analysis of aged cochleae revealed damaged mitochondria with absent or disorganized cristae. Aged mice also showed significant decrease in cochlear blood flow, and exhibited increase in gene expression of proinflammatory cytokines (IL-1β, IL-6, and TNF-α), receptor-interacting serine/threonine-protein kinase 1 and 3 (RIPK1 and RIPK3) and the pseudokinase mixed-lineage kinase domain-like (MLKL). Immunofluorescence (IF) assays of cytochrome C oxidase I (COX1) confirmed mitochondrial dysfunction in aged cochleae, which correlated with the degree of mitochondrial morphological damage. IF assays also revealed localization and increased expression of RIPK3 in sensorineural tissues that underwent significant necroptosis (inner and outer hair cells and stria vascularis). Together, our data shows that the aging cochlea exhibits damaged mitochondria, enhanced synthesis of proinflammatory cytokines, and provides new evidence of necroptosis in the aging cochlea in in vivo.
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http://dx.doi.org/10.3390/ijms21072505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177801PMC
April 2020

Prediction of ovarian aging using ovarian expression of BMP15, GDF9, and C-KIT.

Exp Biol Med (Maywood) 2020 04 29;245(8):711-719. Epub 2020 Mar 29.

Korea Institute for Public Sperm Bank, Busan 49241, Korea.

Impact Statement: Ovarian aging is becoming a more important issue in terms of fertility preservation and infertility treatment. Serum anti-Mullerian hormone (AMH) level and antral follicle count (AFC) are being practically used as markers of ovarian aging as well as ovarian reserve in human. However, these factors have some drawbacks in assessing ovarian aging and reserve. Therefore, the identification of ovarian expressions of BMP15, GDF9, and C-KIT according to female could be applied as a potent predictor of ovarian aging. This work provides new information on the development of diagnosis and treatment strategy of age-related fertility decline and premature ovarian insufficiency.
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http://dx.doi.org/10.1177/1535370220915826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221484PMC
April 2020

Role of Visfatin in Restoration of Ovarian Aging and Fertility in the Mouse Aged 18 Months.

Reprod Sci 2020 02 15;27(2):681-689. Epub 2020 Jan 15.

Department of Obstetrics and Gynecology, Pusan National University School of Medicine, Gudeok-Ro 187, Seo-Gu, Busan, 49241, Republic of Korea.

The activation of dormant primordial follicles and ovarian angiogenesis has been attempted as a new treatment strategy for age-related ovarian aging. This study examined whether visfatin rescues age-related fertility decline in female mice aged 18 months, and whether this effect relates to the mTOR/PI3K signaling pathways for activation of primordial follicles and ovarian angiogenesis. Female mice were intraperitoneally injected with 0.1 ml of 500 ng/ml or 1000 ng/ml of visfatin three times at intervals of 2 days, and both ovaries were provided for H&E staining. In another experiment, the mice were superovulated with pregnant mare's serum gonadotropin and human chorionic gonadotropin, and were mated with males. After 18 h, zygotes were collected and cultured for 4 days, and numbers and embryo developmental competency of zygotes retrieved were evaluated. The expression of mTOR/PI3K signaling pathway regulated genes (4EBP1, S6K1, and RPS6) and angiogenic factors (VEGF, visfatin, and SDF-1α) in the ovary were examined. As well, visfatin-treated mice were mated with male mice for 2 weeks, and the pregnancy outcome was monitored up to 3 weeks. Visfatin significantly increased the total numbers of follicles compared with control. Numbers of zygotes retrieved, blastocyst formation rate, and pregnancy rate were significantly increased at 500 ng/ml of visfatin (2.83%, 40.0%, and 80%, respectively) compared with control (0, 0, and no pregnancy). Ovarian expressions of S6K1, RPS6, VEGF, visfatin, and SDF-1α were significantly stimulated at 500 ng/ml of visfatin. These results show that visfatin treatment of an optimal dose rescues age-related decline in fertility, possibly by stimulating mTOR/PI3K signaling.
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http://dx.doi.org/10.1007/s43032-019-00074-9DOI Listing
February 2020

Combination of Korean Red Ginseng Extract and Hydrogen-Rich Water Improves Spermatogenesis and Sperm Motility in Male Mice.

Chin J Integr Med 2020 May 10;26(5):361-369. Epub 2020 Jan 10.

The Korea Institute for Public Sperm Bank, Busan, 49241, Republic of Korea.

Objective: To investigate the effect of hydrogen-rich Korean Red Ginseng (KRG) water (HRGW) mixture on the spermatogenesis and sperm motility of mice of different ages.

Methods: Eighty young (3 month-old) and aged (12 month-old) male mice were randomly assigned to 4 groups (n =10 per group) including control group, hydrogen-rich water (HRW) group (10 mL/kg daily), KRG group (50 mg/kg daily) and HRGW group (10 mL/kg and 50 mg/kg daily) by an oral zoned needle for 4 weeks. Sperm count and motility were measured using sperm suspension released from cauda epididymis. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and reactive oxygen species (ROS) in serum have also been estimated. Tubular changes were examined through histological hematoxylin and eosin staining. Expression of antioxidation (PPx3, PPx4, GSTm5 and GPx4), spermatogenesis (inhibin-a, neptin-2 and CREM), antiaging (SIRT1 and SIRT2), and angiogenesis [visfatin and vascular endothelial growth factor (VEGF)] related genes were examined through real-time polymerase chain reaction.

Results: HRW and KRG treatment stimulated spermatogenesis followed by increasing sperm production and sperm motility (P <0.05). These effects were strengthened synergistically by a HRGW mixture (P <0.05 or P <0.01). HRGW greatly increased the expressions of antioxidation, antiaging, spermatogenesis related genes and VEGF especially in aged mice (P <0.05). Serum testosterone and FSH levels also increased, while serum ROS level decreased (all P <0.05).

Conclusion: HRGW increases sperm production and motility by enhancing antioxidation and stimulating spermatogenesis and sex hormone production, particularly in aged mice.
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http://dx.doi.org/10.1007/s11655-019-3047-1DOI Listing
May 2020

Reproductive Senescence and Ischemic Stroke Remodel the Gut Microbiome and Modulate the Effects of Estrogen Treatment in Female Rats.

Transl Stroke Res 2020 08 16;11(4):812-830. Epub 2019 Dec 16.

Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, 8447 Riverside Pkwy, Bryan, TX, 77807, USA.

Our previous work has shown that reproductively senescent (or middle-aged; 10-12-month-old) Sprague-Dawley female rats, that are naturally estrogen-deficient, have worse stroke outcomes as compared to normally estrous-cycling adult (5-6-month-old) females. Paradoxically, estrogen replacement to this middle-aged group exacerbates stroke outcomes, while it is neuroprotective in adult females. Recent studies reveal an important role for the gut microbiome and gut metabolites in cardiovascular health, including stroke outcomes. To determine whether gut dysbiosis underlies stroke severity in reproductive senescent females, and underlies the anomalous effects of estrogen on stroke, we compared the gut microbiota and gut metabolites pre and post stroke in (a) gonadally intact adult and middle-aged females, (b) in ovariectomized and estrogen-treated (OVX+E) adult and OVX+E middle-aged females, and (c) in middle-aged OVX+E females after fecal microbiome transfer. Our data show significant gut dysbiosis in reproductive senescent females at baseline and after stroke as indicated by an elevated ratio of the major phyla, Firmicutes/Bacteroidetes (F:B), reduced alpha diversity, and significant shifts in beta diversity as compared with adult females. Specific bacterial families were also altered as a result of reproductive aging, as well as gut metabolites, including elevated serum endotoxin levels and decreased short-chain fatty acids (SCFAs), with a concomitant increase in IL-17A, indicating that reproductive senescence significantly affects gut communities under pathologic conditions. Despite the differences in gonadally intact adult and middle-aged females, estrogen-treated ovariectomized (OVX+E) females of either age group displayed no differences in the major phyla, but there was increased abundance in specific bacterial taxa, including Prevotella and Lactobacillus. The SCFA butyrate was significantly reduced at baseline in the middle-aged OVX+E females, while circulating endotoxin LPS were elevated in this group after stroke, suggesting that gut metabolites were differently affected by estrogen treatment in the two age groups. A fecal transfer from adult OVX+E females to middle-aged OVX+E females significantly reduced infarct volume, improved behavioral recovery and transiently reduced IL-17A expression. These data provide the first evidence that microbial gut communities and metabolites are altered by reproductive senescence in female rats at baseline and after stroke, and suggest that estrogen may impact stroke recovery differently in adult and reproductive senescent females due to an age-specific effect on gut microbiota and metabolites.
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http://dx.doi.org/10.1007/s12975-019-00760-5DOI Listing
August 2020

Japanese government research grants for Kampo medicine: aAn overview of 10 years (1997-2017).

Integr Med Res 2019 Dec 14;8(4):279-283. Epub 2019 Nov 14.

National Development Institute of Korean Medicine, Seoul, Republic of Korea.

Background: Japan has its own traditional medicine called Kampo medicine, but it is relatively unknown in compared to Traditional Chinese Medicine. Therefore, this study examined the current status of the research related to Kampo medicine supported by Japanese government research grants (JGRG).

Methods: Three databases were searched on October 2019: National Institute of Public Health, Grant-in-Aid for Scientific Research and Japan Agency for Medical Research and Development. The search keywords were Kampo medicine, acupuncture, integrative medicine, oriental medicine, and traditional medicine. The final research that satisfied the inclusion criteria were selected and analyzed.

Results: After a comprehensive search of the three database and removing any duplication research, 2246 JGRG (985 new proposal) that met the inclusion criteria were selected. The number and amount of JGRG have been increasing steadily. The basic research conducted by academic research institutes was mainstream, and the proportion of development research of new Kampo medical technology was low. Most J-research was non-clinical research and 21 % were clinical research. The largest research institute was the Toyama University and there were many non-clinical, cancer, and Juzentaihoto research. On the other hand, government grants were funded relatively evenly without bias to specific fields or institutions.

Conclusions: After analyzing the Japanese government research grants from 1973 to 2017, research on Kampo medicine, which barely had any interest previously, was revived in the 2000s. In particular, it increased sharply in the 2010s, and the research fields were relatively diverse.
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http://dx.doi.org/10.1016/j.imr.2019.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889039PMC
December 2019

An easy method for the clear detection of beige fat UCP1 by Western blotting.

Adipocyte 2019 12;8(1):357-361

Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.

Beige adipocytes, which consume energy mainly in an uncoupling protein 1 (UCP1)-dependent manner, are risen in white adipose tissue (WAT) depots. Since beige adipocyte development is gaining attention as a potential strategy for conquering obesity, worldwide researchers are making efforts to study its biological aspects. However, assessing UCP1 protein levels in beige adipocytes is challenging because of the high level of lipid contaminants in WAT. This study showed that an acetone precipitation method had advantages over conventional methods for eliminating lipid contaminants, achieving clear Western blot bands for WAT proteins, especially UCP1. Our results suggest that the acetone precipitation cleaning method could be useful for the clear analysis and precise evaluation of WAT proteins.
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http://dx.doi.org/10.1080/21623945.2019.1693746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948967PMC
December 2019

Acoustic Trauma Modulates Cochlear Blood Flow and Vasoactive Factors in a Rodent Model of Noise-Induced Hearing Loss.

Int J Mol Sci 2019 Oct 25;20(21). Epub 2019 Oct 25.

Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Korea.

Noise exposure affects the organ of Corti and the lateral wall of the cochlea, including the stria vascularis and spiral ligament. Although the inner ear vasculature and spiral ligament fibrocytes in the lateral wall consist of a significant proportion of cells in the cochlea, relatively little is known regarding their functional significance. In this study, 6-week-old male C57BL/6 mice were exposed to noise trauma to induce transient hearing threshold shift (TTS) or permanent hearing threshold shift (PTS). Compared to mice with TTS, mice with PTS exhibited lower cochlear blood flow and lower vessel diameter in the stria vascularis, accompanied by reduced expression levels of genes involved in vasodilation and increased expression levels of genes related to vasoconstriction. Ultrastructural analyses by transmission electron microscopy revealed that the stria vascularis and spiral ligament fibrocytes were more damaged by PTS than by TTS. Moreover, mice with PTS expressed significantly higher levels of proinflammatory cytokines in the cochlea (e.g., IL-1β, IL-6, and TNF-α). Overall, our findings suggest that cochlear microcirculation and lateral wall pathologies are differentially modulated by the severity of acoustic trauma and are associated with changes in vasoactive factors and inflammatory responses in the cochlea.
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http://dx.doi.org/10.3390/ijms20215316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862585PMC
October 2019

Protein Arginine Methyltransferase 1 Interacts With PGC1α and Modulates Thermogenic Fat Activation.

Endocrinology 2019 12;160(12):2773-2786

Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.

Protein arginine methyltransferases (PRMTs) are enzymes that regulate the evolutionarily conserved process of arginine methylation. It has been reported that PRMTs are involved in many metabolic regulatory pathways. However, until now, their roles in adipocyte function, especially browning and thermogenesis, have not been evaluated. Even though Prmt1 adipocyte-specific-deleted mice (Prmt1fl/flAQcre) appeared normal at basal level, following cold exposure or β-adrenergic stimulation, impaired induction of the thermogenic program was observed in both the interscapular brown adipose tissue and inguinal white adipose tissue of Prmt1fl/flAQcre mice compared with littermate controls. Different splicing variants of Prmt1 have been reported. Among them, PRMT1 variant 1 and PRMT1 variant 2 (PRMT1V2) are well conserved between humans and mice. Both variants contribute to the activation of thermogenic fat, with PRMT1V2 playing a more dominant role. Mechanistic studies using cultured murine and human adipocytes revealed that PRMT1V2 mediates thermogenic fat activation through PGC1α, a transcriptional coactivator that has been shown to play a key role in mitochondrial biogenesis. To our knowledge, our data are the first to demonstrate that PRMT1 plays a regulatory role in thermogenic fat function. These findings suggest that modulating PRMT1 activity may represent new avenues to regulate thermogenic fat and mediate energy homeostasis. This function is conserved in human primary adipocytes, suggesting that further investigation of this pathway may ultimately lead to therapeutic strategies against human obesity and associated metabolic disorders.
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http://dx.doi.org/10.1210/en.2019-00504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853686PMC
December 2019

Validation of a smartphone-based, computer-assisted sperm analysis system compared with laboratory-based manual microscopic semen analysis and computer-assisted semen analysis.

Investig Clin Urol 2019 09 6;60(5):380-387. Epub 2019 Aug 6.

Department of Urology, Pusan National University School of Medicine, Busan, Korea.

Purpose: This study aimed to evaluate the clinical efficacy of a portable smartphone-based system for computer-assisted semen analysis (CASA) compared with the results of manual microscopic semen analysis (SA) and laboratory-based CASA for self-evaluation of semen parameters by a male partner.

Materials And Methods: From July 2017 to February 2018, a total of 28 samples were analyzed for concentration and motility with a smartphone-based CASA system and the results compared with those from laboratory-based CASA and manual microscopic SA with a Makler Counting Chamber (SEFI Medical Instruments, Israel).

Results: Sperm concentration and motility measured with the smartphone-based CASA system were positively correlated with the microscopic-based results. Likewise, sperm motility calculated with smartphone-based CASA was positively correlated with the laboratory-based CASA results. These results suggest that the smartphone-based CASA system can be used for clinical semen diagnosis.

Conclusions: A portable smartphone-based CASA system can play a role in motivating infertile males to visit clinics, thus resulting in early diagnosis and treatment with cost-effectiveness. The device can be used for easy follow-up on a screening basis by the male partner before visiting a clinic for fertility evaluation or by infertile males after receiving medical management. Additionally, future software advancements and post-marketing consumer surveys will make possible wider applications, including assessment of sperm morphology, in the coming future.
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http://dx.doi.org/10.4111/icu.2019.60.5.380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722405PMC
September 2019

Herbal Phytotherapy in Chronic Nonbacterial Prostatitis.

World J Mens Health 2019 Sep 3. Epub 2019 Sep 3.

The Korea Institute for Public Sperm Bank, Busan, Korea.

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http://dx.doi.org/10.5534/wjmh.190091DOI Listing
September 2019

Cochlear Glucocorticoid Receptor and Serum Corticosterone Expression in a Rodent Model of Noise-induced Hearing Loss: Comparison of Timing of Dexamethasone Administration.

Sci Rep 2019 09 2;9(1):12646. Epub 2019 Sep 2.

Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.

Glucocorticoid (GC) is a steroid hormone secreted from the adrenal cortex in response to stress, which acts by binding to cytoplasmic glucocorticoid receptors (GRs). Dexamethasone (DEX) is a synthetic GC exhibiting immunosuppressive effects in both human and rodent models of hearing loss. While clinical evidence has shown the effectiveness of DEX for treatment of various inner ear diseases, its mechanisms of action and the optimal timing of treatment are not well understood. In the present study, intergroup comparisons were conducted based on the time point of treatment with DEX: (1) pretreatment; (2) posttreatment; and (3) pre&post-noise. The pre&post DEX treatment group showed a significant improvement in threshold shift at 1 day post-noise exposure as compared to the TTS (transient threshold shift)-only group at 8 and 16 kHz. Both TTS and PTS (permanent threshold shift) significantly reduced cochlear GR mRNA expression and increased serum corticosterone and cochlear inflammatory cytokines. The pre&post DEX treatment group showed a significant decrease in serum corticosterone level as compared to other DEX treatment groups and TTS-treated group at 3 days after acoustic trauma. Our results suggest that the timing of DEX administration differentially modulates systemic steroid levels, GR expression and cochlear cytokine expression.
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http://dx.doi.org/10.1038/s41598-019-49133-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718671PMC
September 2019

Daurinol Attenuates Autoimmune Arthritis via Stabilization of Nrp1-PTEN-Foxp3 Signaling in Regulatory T Cells.

Front Immunol 2019 17;10:1526. Epub 2019 Jul 17.

The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea.

Optimizing Treg function and improving Treg stability are attractive treatment strategies for treating autoimmune rheumatoid arthritis (RA). However, the limited number of circulating Tregs and questions about the functional stability of -expanded Tregs are potential limitations of Treg-based cell therapy. The aim of this study was to analyze the regulatory effect of daurinol, a catalytic inhibitor of topoisomerase IIα, on Th cell differentiation and to evaluate their therapeutic potential in a preclinical experimental model of RA. We investigated the effect of daurinol on T cell differentiation by flow cytometry. Foxp3 stability and methylation were analyzed by suppression assays and bisulfite pyrosequencing. Daurinol was treated in the collagen-induced arthritis (CIA) model, and the effects were determined. We found that daurinol can promote Treg differentiation and reciprocally inhibit Th17 differentiation. This Treg-inducing property of daurinol was associated with decreased activity of Akt-mTOR and reciprocally increased activity of neuropilin-1 (Nrp1)-PTEN. Daurinol treatment inhibited aerobic glycolysis in Th17 conditions, indicating the metabolic changes by daurinol. We found that the daurinol increase the Treg stability was achieved by Foxp3 hypomethylation. daurinol treatment in CIA mice reduced the clinical arthritis severity and histological inflammation. The Treg population frequency increased and the Th17 cells decreased in the spleens of arthritis mice treated with daurinol. These results showed the anti-arthritic and immunoregulating properties of daurinol is achieved by increased differentiation and stabilization of Tregs. Our study provides first evidence for daurinol as a treatment for RA.
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http://dx.doi.org/10.3389/fimmu.2019.01526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651269PMC
September 2020

Current Status of Management on Pharmacopuncture in Korea through Introduction of an Accreditation System.

J Pharmacopuncture 2019 Jun 30;22(2):75-82. Epub 2019 Jun 30.

Division of Clinical Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612, South Korea.

Objectives: Pharmacopuncture is a new form of acupuncture treatment that injects herbal medicine into acupuncture points. This paper introduces the management status of pharmacopuncture through accreditation, and examines the effect of accreditation on pharmacopuncture management.

Methods: The Accreditation System of External Herbal Dispensaries (EHDs) of traditional Korean medicine clinics announced by the Ministry of Health and Welfare in September 2018 were investigated.

Results: The Accreditation System of EHDs assesses and certifies herbal medicine and pharmacopuncture preparations. Regular components for the 'pharmacopuncture' certification consist of nine standards, 30 categories, and 165 items. The nine standards include: herbal dispensary facilities, clean room management, management and organization operation, employee management, document management, continuous quality control, herbal medicine management, management of preparation, and pavement management.

Conclusion: Through EHD accreditation and certification system, traditional Korean medicine clinics and EHDs can now manage pharmacopuncture medicine quality and promise safe pharmacopuncture treatment for the people.
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http://dx.doi.org/10.3831/KPI.2019.22.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6645342PMC
June 2019

Contrast-enhanced US with Perfluorobutane for Hepatocellular Carcinoma Surveillance: A Multicenter Diagnostic Trial (SCAN).

Radiology 2019 09 9;292(3):638-646. Epub 2019 Jul 9.

From the Department of Radiology, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea (J.H.P., S.S.L.); Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea (M.S.P., M.J.P.); Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea (S.J.L., S.H.P.); Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea (W.K.J.); Department of Radiology and Institute of Radiation Medicine, Seoul National University Hospital, Seoul, Republic of Korea (J.Y.L.); Department of Radiology, Health Promotion Center, Samsung Medical Center, Seoul, Republic of Korea (M.J.P.); Yonsei Biomedical Research Institute, Department of Radiology, Research Institute of Radiological Science (K.H.) and Department of Preventive Medicine (C.M.N.), Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Radiology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea (K.H.L.); and Program in Biomedical Radiation Sciences, Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Interdisciplinary Program in Bioengineering, Seoul National University, Seoul, Republic of Korea (K.H.L.).

Background US has served as a standard surveillance tool for hepatocellular carcinoma (HCC); however, the detection rate and false referral rate with this modality are suboptimal. Purpose To evaluate the added value of perfluorobutane-enhanced US when combined with conventional B-mode US as an HCC surveillance tool in participants with liver cirrhosis. Materials and Methods This prospective multi-institution diagnostic trial (, NCT02188901) used an intraindividual comparison design in a single arm of study participants and was conducted at five referral hospitals. Eligible participants who had liver cirrhosis related to viral hepatitis and were undergoing US for HCC surveillance were enrolled from October 2014 to August 2016. Immediately after completion of B-mode US but before performance of perfluorobutane-enhanced US, operating radiologists entered the results of B-mode US. After completion of subsequent perfluorobutane-enhanced US (Kupffer phase with or without vascular-phase US), the radiologists recorded the results. The presence of HCC was confirmed either with pathologic analysis or radiologically by using dynamic contrast material-enhanced CT or gadoxetic acid-enhanced MRI. The primary end points were the detection rate of early-stage HCC (Barcelona Clinic Liver Cancer staging system stage 0 or A) and false referral rate. The primary end points were compared in a per-participant manner by using the McNemar test. Results A total of 524 participants (mean age, 54 years ± 9 [standard deviation]) were included. Of these, 493 (94.1%) had liver cirrhosis related to the hepatitis B virus. Ten HCCs were confirmed in eight participants. The detection rate of early-stage HCC was not significantly improved by adding perfluorobutane-enhanced US to conventional B-mode US (difference, 0.4% [95% confidence interval: -0.3%, 1.1%]; = .16). The false referral rate was significantly reduced (difference, -3.2% [95% confidence interval: -5.0%, -1.4%]; < .001). Conclusion The addition of perfluorobutane-enhanced US to conventional B-mode US reduced the false referral rate without a significant improvement in the detection rate of early-stage hepatocellular carcinoma for surveillance in a population in which the hepatitis B virus predominated. © RSNA, 2019
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http://dx.doi.org/10.1148/radiol.2019190183DOI Listing
September 2019

Metformin Augments Anti-Inflammatory and Chondroprotective Properties of Mesenchymal Stem Cells in Experimental Osteoarthritis.

J Immunol 2019 07 29;203(1):127-136. Epub 2019 May 29.

The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-701, South Korea;

Mesenchymal stem cells (MSCs) can protect against cartilage breakdown in osteoarthritis (OA) via their immunomodulatory capacities. However, the optimization strategy for using MSCs remains challenging. This study's objective was to identify the in vivo effects of metformin-stimulated adipose tissue-derived human MSCs (Ad-hMSCs) in OA. An animal model of OA was established by intra-articular injection of monosodium iodoacetate into rats. OA rats were divided into a control group and two therapy groups (treated with Ad-hMSCs or metformin-stimulated Ad-hMSCs). Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Our data show that metformin increased IL-10 and IDO expression in Ad-hMSCs and decreased high-mobility group box 1 protein, IL-1β, and IL-6 expression. Metformin increased the migration capacity of Ad-hMSCs with upregulation of chemokine expression. In cocultures, metformin-stimulated Ad-hMSCs inhibited the mRNA expression of RUNX2, COL X, VEGF, MMP1, MMP3, and MMP13 in IL-1β-stimulated OA chondrocytes and increased the expression of TIMP1 and TIMP3. The antinociceptive activity and chondroprotective effects were greater in OA rats treated with metformin-stimulated Ad-hMSCs than in those treated with unstimulated Ad-hMSCs. TGF-β expression in subchondral bone of OA joints was attenuated more in OA rats treated with metformin-stimulated Ad-hMSCs. Our findings suggest that metformin offers a promising option for the clinical application of Ad-hMSCs as a cell therapy for OA.
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http://dx.doi.org/10.4049/jimmunol.1800006DOI Listing
July 2019

Constitutive release of CPS1 in bile and its role as a protective cytokine during acute liver injury.

Proc Natl Acad Sci U S A 2019 04 12;116(18):9125-9134. Epub 2019 Apr 12.

Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109;

Carbamoyl phosphate synthetase-1 (CPS1) is the major mitochondrial urea cycle enzyme in hepatocytes. It is released into mouse and human blood during acute liver injury, where is has a short half-life. The function of CPS1 in blood and the reason for its short half-life in serum are unknown. We show that CPS1 is released normally into mouse and human bile, and pathologically into blood during acute liver injury. Other cytoplasmic and mitochondrial urea cycle enzymes are also found in normal mouse bile. Serum, bile, and purified CPS1 manifest sedimentation properties that overlap with extracellular vesicles, due to the propensity of CPS1 to aggregate despite being released primarily as a soluble protein. During liver injury, CPS1 in blood is rapidly sequestered by monocytes, leading to monocyte M2-polarization and homing to the liver independent of its enzyme activity. Recombinant CPS1 (rCPS1), but not control r-transferrin, increases hepatic macrophage numbers and phagocytic activity. Notably, rCPS1 does not activate hepatic macrophages directly; rather, it activates bone marrow and circulating monocytes that then home to the liver. rCPS1 administration prevents mouse liver damage induced by Fas ligand or acetaminophen, but this protection is absent in macrophage-deficient mice. Moreover, rCPS1 protects from acetaminophen-induced liver injury even when given therapeutically after injury induction. In summary, CPS1 is normally found in bile but is released by hepatocytes into blood upon liver damage. We demonstrate a nonenzymatic function of CPS1 as an antiinflammatory protective cytokine during acute liver injury.
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http://dx.doi.org/10.1073/pnas.1822173116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500125PMC
April 2019