Publications by authors named "Sun Yeou Kim"

288 Publications

Chemical constituents of twigs and their biological activity.

Beilstein J Org Chem 2020 17;16:3078-3085. Epub 2020 Dec 17.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.

A new megastigmane-type norsesquiterpenoid glycoside, chaemeloside (), was isolated from the twigs of together with 11 known phytochemicals through chromatographic methods. The chemical structure of the new isolate was determined by conventional 1D and 2D NMR data analysis, ECD experiment, hydrolysis followed by a modified Mosher's method, and LC-MS analysis. The characterized compounds' biological effects including cytotoxicity against cancer cell lines, antineuroinflammatory activity, and potential neurotrophic effect were evaluated.
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http://dx.doi.org/10.3762/bjoc.16.257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753107PMC
December 2020

Glyoxalase System in the Progression of Skin Aging and Skin Malignancies.

Int J Mol Sci 2020 Dec 30;22(1). Epub 2020 Dec 30.

College of Pharmacy, Gachon University, 191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.

Dicarbonyl compounds, including methylglyoxal (MGO) and glyoxal (GO), are mainly formed as byproducts of glucose metabolism. The main glyoxalase system consists of glyoxalase I and II (Glo1 and Glo2) and is the main enzyme involved in the detoxification of dicarbonyl stress, which occurs as an accumulation of MGO or GO due to decreased activity or expression of Glo1. Dicarbonyl stress is a major cause of cellular and tissue dysfunction that causes various health issues, including diabetes, aging, and cancer. The skin is the largest organ in the body. In this review, we discuss the role of the glyoxalase system in the progression of skin aging, and more importantly, skin malignancies. We also discuss the future prospects of the glyoxalase system in other skin abnormalities such as psoriasis and vitiligo, including hyperpigmentation. Finally, in the present review, we suggest the role of glyoxalase in the progression of skin aging and glyoxalase system as a potential target for anticancer drug development for skin cancer.
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http://dx.doi.org/10.3390/ijms22010310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794849PMC
December 2020

Trifostigmanoside I, an Active Compound from Sweet Potato, Restores the Activity of MUC2 and Protects the Tight Junctions through PKCα/β to Maintain Intestinal Barrier Function.

Int J Mol Sci 2020 Dec 30;22(1). Epub 2020 Dec 30.

College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.

Sweet potato () is considered a superfood among vegetables and has been consumed for centuries. Traditionally, sweet potato is used to treat several illnesses, including diarrhea and stomach disorders. This study aimed to explore the protective effect of sweet potato on intestinal barrier function, and to identify the active compounds of sweet potato and their underlying mechanism of action. To this purpose, bioactivity-guided isolation, Western blotting, and immunostaining assays were applied. Interestingly, our bioactivity-guided approach enabled the first isolation and identification of trifostigmanoside I (TS I) from sweet potato. TS I induced mucin production and promoted the phosphorylation of PKCα/β in LS174T human colon cancer cells. In addition, it protected the function of tight junctions in the Caco-2 cell line. These findings suggest that TS I rescued the impaired abilities of MUC2, and protected the tight junctions through PKCα/β, to maintain intestinal barrier function.
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http://dx.doi.org/10.3390/ijms22010291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794767PMC
December 2020

Structure-Activity Relationship of Phytoestrogen Analogs as ERα/β Agonists with Neuroprotective Activities.

Chem Pharm Bull (Tokyo) 2021 ;69(1):99-105

College of Pharmacy, Sookmyung Women's University.

A set of isoflavononid and flavonoid analogs was prepared and evaluated for estrogen receptor α (ERα) and ERβ transactivation and anti-neuroinflammatory activities. Structure-activity relationship (SAR) study of naturally occurring phytoestrogens, their metabolites, and related isoflavone analogs revealed the importance of the C-ring of isoflavonoids for ER activity and selectivity. Docking study suggested putative binding modes of daidzein 2 and dehydroequol 8 in the active site of ERα and ERβ, and provided an understanding of the promising activity and selectivity of dehydroequol 8. Among the tested compounds, equol 7 and dehydroequol 8 were the most potent ERα/β agonists with ERβ selectivity and neuroprotective activity. This study provides knowledge on the SAR of isoflavonoids for further development of potent and selective ER agonists with neuroprotective potential.
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http://dx.doi.org/10.1248/cpb.c20-00706DOI Listing
January 2021

Downregulation of dihydrolipoyl dehydrogenase by UVA suppresses melanoma progression via triggering oxidative stress and altering energy metabolism.

Free Radic Biol Med 2021 Jan 3;162:77-87. Epub 2020 Dec 3.

College of Pharmacy, Gachon University, 191, Hambakmoero, Yeonsu-gu, Incheon, 21936, Republic of Korea; Gachon Institute of Pharmaceutical Science, Gachon University, Yeonsu-gu, Incheon, 21565, Republic of Korea. Electronic address:

Melanoma, the most severe form of skin cancer, has poor prognosis and is resistant to chemotherapy. Targeting cancer metabolism is a promising approach in cancer therapeutics. Dihydrolipoyl dehydrogenase (DLD) is a mitochondrial enzyme with diaphorase activity. Here we report a pivotal role of DLD in melanoma cell progression and proliferation. Suppression DLD expression by low intensity UVA (125 mJ/cm) increased intracellular ROS production and decreased mitochondrial membrane potential thereby inducing autophagy cell death which were confirmed by increased LC3BII and decreased p62 expression in melanoma cells. Knockdown of DLD in melanoma cells also showed similar results. More so, suppression of DLD significantly inhibits in vivo melanoma growth and tumor proliferation. In addition, suppression of DLD increased the NAD+/NADH ratio in melanoma cells and also inhibits TCA cycle related metabolites. DLD downregulation markedly increased α-ketoglutarate and decreased succinic acid suggesting that DLD suppression may have decreased TCA cycle downstream metabolites, resulting in the alteration of mitochondrial energy metabolism Thus the downregulation of DLD induced autophagic cell death in melanoma cells and inhibits in vivo tumor growth and proliferation by increasing ROS production and altering energy metabolism. Our findings suggest that DLD plays a pivotal role in melanoma progression and proliferation.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.11.037DOI Listing
January 2021

Positioning of an unprecedented spiro[5.5]undeca ring system into kinase inhibitor space.

Sci Rep 2020 12 4;10(1):21265. Epub 2020 Dec 4.

Gachon Institute of Pharmaceutical Science and Department of Pharmacy, College of Pharmacy, Gachon University, Yeonsu-gu, Incheon, Republic of Korea.

In-house 1,5-oxaza spiroquinone 1, with spiro[5.5]undeca ring system, was announced as an unprecedented anti-inflammatory scaffold through chemistry-oriented synthesis (ChOS), a chemocentric approach. Herein, we studied how to best position the spiro[5.5]undeca ring system in kinase inhibitor space. Notably, late-stage modification of the scaffold 1 into compounds 2a-r enhanced kinase-likeness of the scaffold 1. The improvement could be depicted with (1) selectivity with target shift (from JNK-1 into GSK-3) and (2) potency (> 20-fold). In addition, ATP independent IC of compound 2j suggested a unique binding mode of this scaffold between ATP site and substrate site, which was explained by docking based optimal site selection and molecular dynamic simulations of the optimal binding site. Despite the shift of kinase profiling, the anti-inflammatory activity of compounds 2a-r could be retained in hyperactivated microglial cells.
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http://dx.doi.org/10.1038/s41598-020-78158-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719162PMC
December 2020

Repurposing of FDA approved ring systems through bi-directional target-ring system dual screening.

Sci Rep 2020 12 3;10(1):21133. Epub 2020 Dec 3.

Gachon Institute of Pharmaceutical Science and Department of Pharmacy, College of Pharmacy, Gachon University, 191 Hambakmoeiro, Yeonsu-gu, Inchon, Republic of Korea.

In drug repurposing approaches, the chemically diverse and potentially safe molecules can be explored as therapeutic potential beyond those originally targeted indications. However, accessible information on a limited number of drug pipelines can lead to competitive over-heating issues, and intellectual property rights also restrict the free investigation in chemical space. As a complementary approach to the drawbacks, ring systems of approved drugs (instead of clinical drugs) can be optimized and used for repurposing purposes. In this study, bi-directional target (T) and ring system (R) dual screening (TR screening) was developed for the repurposing of their rarely used ring systems from FDA approved drugs. The TR screening suggested RAR β and cyproheptadine as the best pair of target and ring system to escape a saddle point. The selected ring system was virtually grown and elaborated with the defined criteria: synthesizability, drug-likeness, and docking pose showing the top scores. The achieved compounds were synthesized and biologically tested with an acceptable ADME/T profile.
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http://dx.doi.org/10.1038/s41598-020-78077-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713353PMC
December 2020

Neurotrophic isoindolinones from the fruiting bodies of Hericium erinaceus.

Bioorg Med Chem Lett 2021 Jan 25;31:127714. Epub 2020 Nov 25.

College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea. Electronic address:

Four compounds, hericerin (1), isohericerinol A (2), N-de-phenylethyl isohericerin (3) and corallocin A (4) were isolated from the fruiting bodies of Hericium erinaceus, a lion's mane mushroom (Hericiaceae). Among them, isohericerinol A (2) was newly reported in nature. Further investigation of the neurotrophic effect of isolated compounds demonstrated that isohericerinol A (2) strongly increased the nerve growth factor (NGF) production in C6 glioma cells followed by corallocin A (4) and hericerin (1). Increased NGF production by these compounds promoted the neurite outgrowth in N2a neuronal cells. Western blot analysis also showed the increased protein expression of NGF, brain-derived neurotrophic factor (BDNF) and synaptophysin (SYP) in C6-N2a cells. Taken together, our present study characterized the neurotrophic constituents of H. erinaceus, which may support the potential use of memory improvement.
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http://dx.doi.org/10.1016/j.bmcl.2020.127714DOI Listing
January 2021

Neurotrophic and anti-neuroinflammatory constituents from the aerial parts of Coriandrum sativum.

Bioorg Chem 2020 12 1;105:104443. Epub 2020 Nov 1.

Natural Products Laboratory, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea. Electronic address:

In the course of our continuing search for biologically active compounds from medicinal sources, we investigated the MeOH extract of the aerial parts of Coriandrum sativum Linn. An extended phytochemical investigation of the aerial parts of C. sativum led to the isolation and identification of seven compounds (1-7) including two new isocoumarin glycosides (1-2) and a new phenolic glycoside (5). The chemical structures of the new compounds (1, 2, and 5) were elucidated by analysis of 1D and 2D NMR (H and C NMR, COSY, HSQC, and HMBC) and HRESIMS data as well as by using chemical methods. All the isolates were evaluated not only for their potential neurotrophic activity by means of induction of nerve growth factor (NGF) in C6 glioma cells but also for production of nitric oxide (NO) levels in lipopolysaccharide (LPS)-activated murine microglia BV-2 cells to assess their anti-neuroinflammatory activity. Compounds 1-3 and 7 were stimulants of NGF release, with levels of NGF stimulated at 127.23 ± 1.89%, 128.22 ± 5.45%, 121.23 ± 6.66%, and 120.94 ± 3.97%, respectively. Furthermore, the aglycones of 1 and 2 (1a and 2a) showed more potent NGF secretion activity and anti-neuroinflammatory effect than did their glycosides (1a : 130.81 ± 5.45% and 2a : 134.44 ± 5.45%).
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http://dx.doi.org/10.1016/j.bioorg.2020.104443DOI Listing
December 2020

Naphthoquinones from promote skin wound healing through Sirt3 regulation.

Iran J Basic Med Sci 2020 Sep;23(9):1139-1145

Department of Biological Sciences, National University of Medical Sciences, C/O Military Hospital, Mall Road Rawalpindi, Pakistan.

Objectives: Lapachone is a natural naphthoquinone-derived compound found in . It is well-known for its analgesic, anti-inflammatory, anti-microbial, diuretic, and anti-cancerous effects. However, the wound-healing effects of this compound are not known yet. The aim of this study was to investigate the wound healing activity of naphthoquinones (α-lapachone and β-lapachone) from .

Materials And Methods: Expression of Sirt3, migration-related proteins (Rac1, Cdc42, α-Pak) and angiogenesis-related protein of vascular endothelial growth factor (VEGF) was monitored using western blot analysis. Blood vessel formation and tissue development were monitored by angiogenesis assay and hematoxylin & eosin (H & E) staining, respectively on mouse skin tissue samples. Both α-lapachone and β-lapachone increased Sirt3 expression , but only β-lapachone increased Sirt3 expression

Results: Both the compounds accelerated wound healing in cultured skin cells as well as mouse skin; however, β-lapachone was more effective at lower concentrations. Both of the compounds increased the expression of migration-related proteins both and . Similarly, α-lapachone and β-lapachone increased VEGF expression, tissue development and blood vessel formation in mouse skin.

Conclusion: These findings indicated that α-lapachone and β-lapachone are novel Sirt3 activators, and Sirt3 has a role in wound healing. Thus, Sirt3 and its regulators come out as a novel target and potential drug candidates, respectively in the important field of cutaneous wound healing.
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http://dx.doi.org/10.22038/ijbms.2020.43706.10275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491501PMC
September 2020

Sulforaphane Inhibits MGO-AGE-Mediated Neuroinflammation by Suppressing NF-κB, MAPK, and AGE-RAGE Signaling Pathways in Microglial Cells.

Antioxidants (Basel) 2020 Aug 26;9(9). Epub 2020 Aug 26.

College of Pharmacy, Gachon University, #191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.

Advanced glycation end products (AGEs) are produced through the binding of glycated protein or lipid with sugar, and they are known to be involved in the pathogenesis of both age-dependent and independent neurological complications. Among dicarbonyl compounds, methylglyoxal (MGO), which is produced from glucose breakdown, is a key precursor of AGE formation and neurotoxicity. Several studies have shown the toxic effects of bovine serum albumin (BSA)-AGE (prepared with glucose, sucrose or fructose) both in in vitro and in vivo. In fact, MGO-derived AGEs (MGO-AGEs) are highly toxic to neurons and other cells of the central nervous system. Therefore, we aimed to investigate the role of MGO-AGEs in microglial activation, a key inflammatory event, or secondary brain damage in neuroinflammatory diseases. Interestingly, we found that sulforaphane (SFN) as a potential candidate to downregulate neuroinflammation induced by MGO-AGEs in BV2 microglial cells. SFN not only inhibited the formation of MGO-AGEs, but it did not show breaking activity on the MGO-mediated AGEs cross-links with protein, indicating that SFN could potentially trap MGO or inhibit toxic AGE damage. In addition, SFN significantly attenuated the production of neuroinflammatory mediators induced by MGO-AGEs in BV2 microglial cells. SFN also lowered the expression levels of AGE receptor (RAGE) in microglial cells, suggesting that SFN could downregulate MGO-AGE-mediated neurotoxicity at the receptor activation level. Altogether, our current study revealed that SFN might show neuropharmacological potential for downregulating MGO-AGEs-mediated neuronal complications thorough attenuating AGE formation and neuroinflammatory responses induced by MGO-AGEs in vitro.
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http://dx.doi.org/10.3390/antiox9090792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554773PMC
August 2020

Three New Oleanane-Type Triterpenoidal Glycosides from and Their Biological Activity.

Plants (Basel) 2020 Aug 24;9(9). Epub 2020 Aug 24.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

Three new oleanane-type triterpenoidal glycosides, imbalosides A-C (-), were isolated from the white flowers of . The structures of these phytochemical constituents (-) were elucidated through 1D and 2D Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS) data analyses followed by chemical methods. All the characterized compounds (-) were evaluated for their antiproliferative activity against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and BT549) and their anti-neuroinflammatory activity on the basis of inhibition levels of nitric oxide (NO) in the lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cell lines.
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http://dx.doi.org/10.3390/plants9091083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570163PMC
August 2020

UP256 Inhibits Hyperpigmentation by Tyrosinase Expression/Dendrite Formation via Rho-Dependent Signaling and by Primary Cilium Formation in Melanocytes.

Int J Mol Sci 2020 Jul 28;21(15). Epub 2020 Jul 28.

College of Pharmacy, Gachon University 191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.

Skin hyperpigmentation is generally characterized by increased synthesis and deposition of melanin in the skin. UP256, containing bakuchiol, is a well-known medication for acne vulgaris. Acne sometimes leaves dark spots on the skin, and we hypothesized that UP256 may be effective against hyperpigmentation-associated diseases. UP256 was treated for anti-melanogenesis and melanocyte dendrite formation in cultured normal human epidermal melanocytes as well as in the reconstituted skin and zebrafish models. Western blot analysis and glutathione S-transferase (GST)-pull down assays were used to evaluate the expression and interaction of enzymes related in melanin synthesis and transportation. The cellular tyrosinase activity and melanin content assay revealed that UP256 decreased melanin synthesis by regulating the expression of proteins related on melanogenesis including tyrosinase, TRP-1 and -2, and SOX9. UP256 also decreased dendrite formation in melanocytes via regulating the Rac/Cdc42/α-PAK signaling proteins, without cytotoxic effects. UP256 also inhibited ciliogenesis-dependent melanogenesis in normal human epidermal melanocytes. Furthermore, UP256 suppressed melanin contents in the zebrafish and the 3D human skin tissue model. All things taken together, UP256 inhibits melanin synthesis, dendrite formation, and primary cilium formation leading to the inhibition of melanogenesis.
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http://dx.doi.org/10.3390/ijms21155341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432859PMC
July 2020

Development and characterization of a superabsorbing hydrogel film containing var. root bark and pullulan for skin wound healing.

Saudi Pharm J 2020 Jul 3;28(7):791-802. Epub 2020 Jun 3.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju, Gyeongnam 52828, Republic of Korea.

var. (UD) has widely been used in Korean traditional medicine for the treatment of various types of diseases including inflammation and skin wounds. The UD root bark powders possess gelling activity with an excellent capacity for absorbing water. This distinct property could make the UD root bark powders to be a great material for manufacturing a gel film specifically for the healing of large and highly exudating wounds (e.g., pressure sores and diabetic ulcers). In this research, we separated the UD root bark powder into 4 different samples based on their sizes and then tested their water absorption capacity and flowability. Based on these results, 75-150 μm sized and below 75 μm sized samples of UD root bark powders were chosen, and UD gel films were prepared. The UD gel films showed good thermal stability and mechanically improved properties compared with pullulan only gel film with excellent swelling capacity and favorable skin adhesiveness. Further, in the animal studies with the skin wound mice model, the UD gel films exhibited significant therapeutic effects on accelerating wound closure and dermal regeneration. Overall, this study demonstrated the applicability of UD root bark powders for hydrogel wound dressing materials, and the potential of UD gel films to be superior wound dressings to currently available ones.
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http://dx.doi.org/10.1016/j.jsps.2020.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335722PMC
July 2020

Isosamidin from Roots Prevents Methylglyoxal-Induced Glucotoxicity in Human Umbilical Vein Endothelial Cells via Suppression of ROS-Mediated Bax/Bcl-2.

Antioxidants (Basel) 2020 Jun 17;9(6). Epub 2020 Jun 17.

College of Pharmacy, Gachon University, #191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.

Methylglyoxal (MGO) is a highly reactive metabolite of glucose. Elevated levels of MGO induce the generation of reactive oxygen species (ROS) and cause cell death in endothelial cells. Vascular endothelial cell damage by ROS has been implicated in the progression of diabetic vascular complications, cardiovascular diseases, and atherosclerosis. In this study, the protective effect of isosamidin, isolated from roots, on MGO-induced apoptosis was investigated using human umbilical vein endothelial cells (HUVECs). Among the 20 compounds isolated from , isosamidin showed the highest effectiveness in inhibiting MGO-induced apoptosis of HUVECs. Pretreatment of HUVECs with isosamidin significantly prevented the generation of ROS and cell death induced by MGO. Isosamidin prevented MGO-induced apoptosis in HUVECs by downregulating the expression of Bax and upregulating the expression of Bcl-2. MGO treatment activated mitogen-activated protein kinases (MAPKs), such as p38, c-Jun N terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). In contrast, pretreatment with isosamidin strongly inhibited the activation of p38 and JNK. Furthermore, isosamidin caused the breakdown of the crosslinks of the MGO-derived advanced glycation end products (AGEs). These findings suggest that isosamidin from may be used as a preventive agent against MGO-mediated endothelial dysfunction in diabetes. However, further study of the therapeutic potential of isosamidin on endothelial dysfunction needs to explored in vivo models.
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http://dx.doi.org/10.3390/antiox9060531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346203PMC
June 2020

Antineurodegenerative Labdane Diterpenoid Glycosides from the Twigs of .

J Nat Prod 2020 06 10;83(6):1794-1803. Epub 2020 Jun 10.

Natural Products Laboratory, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.

Eleven new labdane-type diterpenoid glycosides, koraiensides A-K (-), together with two known analogues were isolated from the twigs of . Their structures were elucidated via NMR, HRMS, and ECD data, DP4+ statistical analysis, and hydrolysis. The metabolites were tested for induction of nerve growth factor in C6 glioma cells to evaluate their potential neuroprotective activity. The compounds were measured for production of nitric oxide levels in lipopolysaccharide (LPS)-activated murine microglia BV2 cells to assess their antineuroinflammatory activity. Compounds and showed NGF secretion inducing effects from C6 glioma cells (162.3 ± 13.9% and 162.7 ± 6.9%, respectively). Compound showed an IC value of 24.1 μM, implying significant inhibition of NO production.
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http://dx.doi.org/10.1021/acs.jnatprod.9b01158DOI Listing
June 2020

Five New Pregnane Glycosides from and Their α-Glucosidase and α-Amylase Inhibitory Activities.

Molecules 2020 May 28;25(11). Epub 2020 May 28.

Yonsei Institute of Pharmaceutical Science, College of Pharmacy, Yonsei University, Incheon 21983, Korea.

, a medicinal plant, has been used in Indian ayurvedic traditional medicine for the treatment of diabetes. Phytochemical investigation of led to the isolation of five new pregnane glycosides, gymsylosides A-E (-) and four known oleanane saponins, 3β-β-D-glucopyranosyl (1→6)-β-D-glucopyranosyl oleanolic acid 28-β-D-glucopyranosyl ester (), gymnemoside-W1 (), 3β-β-D-xylopyranosyl-(1→6)-β-D- glucopyranosyl-(1→6)-β-D-glucopyranosyl oleanolic acid 28-β-D-glucopyranosyl ester (), and alternoside XIX (). Their structures were identified based on spectroscopic evidence and comparison with those reported in the literature. All compounds were evaluated for their α-glucosidase and α-amylase inhibitory activities. Compounds - showed significant α-amylase inhibitory activity, with IC values ranging from 113.0 to 176.2 µM.
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http://dx.doi.org/10.3390/molecules25112525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321224PMC
May 2020

Effect of Extract Supplementation on Oxidative Stress and Inflammation on Hyperglycemia-Induced Renal Damage in Type 2 Diabetic Mice.

Antioxidants (Basel) 2020 May 27;9(6). Epub 2020 May 27.

Department of Food and Nutrition, Kyung Hee Univerity, 26 Kyung Hee-Daero, Dongdamun-Gu, Seoul 02447, Korea.

Type 2 diabetes mellitus (T2DM) is caused by abnormalities of controlling blood glucose and insulin homeostasis. Especially, hyperglycemia causes hyper-inflammation through activation of NLRP3 inflammasome, which can lead to cell apoptosis, hypertrophy, and fibrosis. (QA), one of the annual winders, has been shown ameliorative effects on diabetes. The current study investigated whether the QA extract (QAE) attenuated hyperglycemia-induced renal inflammation related to NLRP inflammasome and oxidative stress in high fat diet (HFD)-induced diabetic mice. After T2DM was induced, the mice were treated with QAE (5 or 10 mg/kg/day) by gavage for 12 weeks. The QAE supplementation reduced homeostasis model assessment insulin resistance (HOMA-IR), kidney malfunction, and glomerular hypertrophy in T2DM. Moreover, the QAE treatment significantly attenuated renal NLRP3 inflammasome dependent hyper-inflammation and consequential renal damage caused by oxidative stress, apoptosis, and fibrosis in T2DM. Furthermore, QAE normalized aberrant energy metabolism (downregulation of p-AMPK, sirtuin (SIRT)-1, and PPARγ-coactivator α (PGC-1 α)) in T2DM mice. Taken together, the results suggested that QAE as a natural product has ameliorative effects on renal damage by regulation of oxidative stress and inflammation in T2DM.
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http://dx.doi.org/10.3390/antiox9060459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346142PMC
May 2020

Molecular mechanisms of methylglyoxal-induced aortic endothelial dysfunction in human vascular endothelial cells.

Cell Death Dis 2020 05 28;11(5):403. Epub 2020 May 28.

College of Pharmacy, Gachon University, #191, Hambakmoero, Yeonsu-Gu, Incheon, 21936, Republic of Korea.

Methylglyoxal (MGO)-induced cellular apoptosis, oxidative stress, inflammation, and AGE formation are specific events that induce vascular endothelial cell (EC) toxicity in endothelial dysfunction (ED). MGO accumulates quickly in various tissues and plays a prominent role in the pathogeneses of several diabetic complications. Unbalanced angiogenesis is a gateway to the development of diabetic complications. EC apoptosis and autophagy work together to regulate angiogenesis by interacting with different angiogenic factors. In addition to understanding the deep mechanism regarding MGO-dependent autophagy/apoptosis may provide new therapeutic applications to treat diabetes and diabetic complications. Therefore, the present study aimed to investigate the regulatory effects of MGO-induced autophagy and apoptosis on angiogenesis in HAoEC and to elucidate the molecular mechanisms to discover new target base therapy for diabetes and diabetic complications. In MGO-stimulated HAoEC, protein expression was identified using a western blot, autophagosomes were observed by bio-transmission electron microscopy (TEM), and cell autophagic vacuoles and flux were measured using a confocal microscope. We found that MGO significantly induced autophagy, declined the pro-angiogenic effect, decreased proliferation, migration, and formation of tube-like structures, and increased autophagic vacuoles, flux and autophagosomes in the HAoEC in a dose-dependent manner. We observed that MGO-induced autophagic cell death and inhibited the ROS-mediated Akt/mTOR signaling pathway. MGO also triggered apoptosis by elevating the cleaved caspase-3 to Bax/Bcl-2 ratio and through activation of the ROS-mediated MAPKs (p-JNK, p-p38, and p-ERK) signaling pathway. Collectively, these findings suggest that autophagy and apoptosis inhibit angiogenesis via the ROS-mediated Akt/mTOR and MAPKs signaling pathways, respectively, when HAoEC are treated with MGO.
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http://dx.doi.org/10.1038/s41419-020-2602-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256048PMC
May 2020

The Mixture of Gotu Kola, Cnidium Fruit, and Goji Berry Enhances Memory Functions by Inducing Nerve-Growth-Factor-Mediated Actions Both In Vitro and In Vivo.

Nutrients 2020 May 11;12(5). Epub 2020 May 11.

College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, 191, Hambakmoe-ro, Yeonsu-gu, Incheon 21936, Korea.

Nerve growth factor (NGF), a typical neurotrophin, has been characterized by the regulation of neuronal cell differentiation and survival involved in learning and memory functions. NGF has a main role in neurite extension and synapse formation by activating the cyclic adenosine monophosphate-response-element-binding protein (CREB) in the hippocampus. The purpose of this study was to determine whether a mixture of Gotu Kola, Cnidium fruit, and Goji berry (KYJ) enhances memory function by inducing NGF-mediated actions both in vitro and in vivo. The KYJ combination increased NGF concentration and neurite length in C6 glioma and N2a neuronal cells, respectively. Additionally, we discovered memory-enhancing effects of KYJ through increased NGF-mediated synapse maturation, CREB phosphorylation, and cell differentiation in the mouse hippocampus. These findings suggest that this combination may be a potential nootropic cognitive enhancer via the induction of NGF and NGF-dependent activities.
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http://dx.doi.org/10.3390/nu12051372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285178PMC
May 2020

NED416, a novel synthetic Sirt1 activator, promotes cutaneous wound healing via the MAPK/Rho pathway.

Int J Mol Med 2020 Jul 3;46(1):149-158. Epub 2020 Apr 3.

College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea.

Cutaneous wound healing is a highly complex biological process involving major events such as cell migration, angiogenesis, and tissue development. Sirtuin 1 (Sirt1) and its regulators have been suggested to play a role in cell migration and tissue repair. The aim of the present study was to determine the effects of a novel Sirt1 activator, the piper amide derivative (E)‑3‑(2,4‑dichlorophenyl)‑N‑phenylacrylamide, also known as NED416, on cutaneous wound healing. The effects of NED416 on Sirt1 activity, Sirt1 expression, and angiogenesis were measured in skin and endothelial cells (epidermal keratinocytes, dermal fibroblasts and vascular endothelial cells) using a Sirt1 activity assay kit, western blot analysis and tube formation assays, respectively. The effects of NED416 on the rate of wound closure and collagen deposition were measured via H&E staining and Masson's trichrome staining, respectively. Levels of migration‑related [Rac1, cell division cycle 42 (Cdc42) and α‑p21‑activated kinase] and mitogen‑activated protein kinase (MAPK) signaling pathway proteins were measured in hairless mice via western blot analysis. NED416 significantly increased Sirt1 activity in dermal fibroblasts and epidermal keratinocytes to a greater extent than resveratrol, leading to increased cell migration and angiogenesis through Rac1/Cdc42 and ERK/JNK activation. Furthermore, NED416 accelerated wound closure, macrophage infiltration, and epithelium and collagen formation in vivo. The present study demonstrated a role of Sirt1 in cutaneous wound healing, and suggested that NED416 as a Sirt1 activator is more potent than resveratrol in promoting wound healing through Rac1/Cdc42 and MAPK signaling without toxicity, thus serving as a promising candidate for treatment.
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http://dx.doi.org/10.3892/ijmm.2020.4564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255464PMC
July 2020

DA-9801, a standardized Dioscorea extract, improves memory function via the activation of nerve growth factor-mediated signaling.

Nutr Neurosci 2020 Mar 27:1-12. Epub 2020 Mar 27.

Department of Oriental Pharmaceutical Science, College of Pharmacy and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, Dongdaemun-gu, Republic of Korea.

Nerve growth factor (NGF) is a neurotrophin that plays a critical role in mammalian learning and memory functions. NGF also regulates neuronal cell differentiation and neurite outgrowth by activating ERK/CREB signaling. This present study examined the effects of a standardized Dioscorea extract (DA-9801), which is composed of Thunb and Makino on memory function via its NGF-potentiating activities using an and paradigm. Cells were incubated with or without different concentrations of DA-9801 (10, 25, and 50 μg/ml) extract for 24 h. The cultured conditioned medium from C6 glioma cells was used for NGF production assay, and neurite length in N2a cells was measured after every 2 h. Mice were orally treated with DA-9801 (10 and 100 mg/kg/day) once daily for 7 days. They were subjected to passive avoidance test to evaluate memory functions. The question of whether DA-9801 induced NGF synthesis was assessed by measuring the levels of NGF in the mouse cortical and hippocampal tissues. Hippocampal cell differentiation and NGF-mediated ERK/CREB signaling were evaluated by performing immunohistochemical analysis using BrdU, ki67, DCX, phosphorylated ERK and CREB in the mouse hippocampus. DA-9801 treatment increased the NGF contents and neurite length, respectively. Mice with DA-9801 administration showed memory enhancement in the passive avoidance test. DA-9801 also increased newborn cell differentiation, neurite length, NGF secretion, and ERK/CREB phosphorylation in the mouse hippocampus. These results suggest that DA-9801 treatment could improve memory function by inducing hippocampal NGF synthesis and ERK/CREB signaling.
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http://dx.doi.org/10.1080/1028415X.2020.1743916DOI Listing
March 2020

Four new pregnane glycosides from and their -glucosidase and -amylase inhibitory activities.

Nat Prod Res 2020 Feb 21:1-8. Epub 2020 Feb 21.

Institute of Marine Biochemistry, Vietnam Academy of Science and Technology (VAST), Hanoi, Viet Nam.

Four new pregnane glycosides, gymlatifosides A - D () and one known pregnane glycoside, verticilloside J () were isolated from the leaves of Wall. ex Wight. Their chemical structures were elucidated on the basis of extensive spectroscopic methods, including 1D, 2D NMR, HR-ESI-MS, and in comparison with the reported data. All these compounds were tested for -glucosidase and -amylase inhibitory activities. Compound exhibited the most anti -glucosidase activity with inhibitory percentage of 37.8 ± 1.5% at the concentration of 200 μM. Compounds showed moderate anti -glucosidase activity with inhibitory percentage ranging from 7.0 to 30.1%. In addition, all compounds showed moderate/weak anti -amylase activity in the investigated test.
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http://dx.doi.org/10.1080/14786419.2020.1729153DOI Listing
February 2020

Extract Ameliorated Renal Inflammation by Regulation of NLRP3 Inflammasome-Associated Hyperinflammation in Type 2 Diabetic Mice.

Antioxidants (Basel) 2020 Feb 10;9(2). Epub 2020 Feb 10.

Department of Food and Nutrition, Kyung Hee Univerity, 26 Kyung Hee-Daero, Dongdamun-Gu, Seoul 02447, Korea.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia. The chronic hyperglycemic condition causes hyperinflammation via activation of nucleotide-binding oligomerization domain-like pyrin domain containing receptor 3 (NLRP3) inflammasome and abnormally leads to morphological and functional changes in kidney. A previous study showed a protective effect of extract (LBE) on endothelial dysfunction induced by methylglyoxal glucotoxicity. We aimed to investigate whether LBE ameliorated renal damage through regulation of NLRP3 inflammasome-dependent hyper-inflammation in T2DM mice. After T2DM induction by a high fat diet and low dose of streptozotocin (30 mg/kg), the mice were administered with different dosages of LBE (100 or 250 mg/kg/day) by gavage for 12 weeks. LBE supplementation ameliorated kidney dysfunction demonstrated by urine albumin-creatinine at a low dose and plasma creatinine, blood urea nitrogen (BUN), and glomerular hypertrophy at a high dose. Furthermore, a high dose of LBE supplementation significantly attenuated renal hyper-inflammation associated with NLRP3 inflammasome and oxidative stress related to nuclear factor erythroid 2-related factor 2 (Nrf-2) in T2DM mice. Meanwhile, a low dose of LBE supplementation up-regulated energy metabolism demonstrated by phosphorylation of adenosine monophosphate kinase (AMPK) and Sirtuin (SIRT)-1 in T2DM mice. In conclusion, the current study suggested that LBE, in particular, at a high dose could be used as a beneficial therapeutic for hyperglycemia-induced renal damage in T2DM.
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http://dx.doi.org/10.3390/antiox9020148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071116PMC
February 2020

Phytochemicals against TNFα-Mediated Neuroinflammatory Diseases.

Int J Mol Sci 2020 Jan 24;21(3). Epub 2020 Jan 24.

College of Pharmacy, Gachon University, #191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.

Tumor necrosis factor-alpha (TNF-α) is a well-known pro-inflammatory cytokine responsible for the modulation of the immune system. TNF-α plays a critical role in almost every type of inflammatory disorder, including central nervous system (CNS) diseases. Although TNF-α is a well-studied component of inflammatory responses, its functioning in diverse cell types is still unclear. TNF-α functions through its two main receptors: tumor necrosis factor receptor 1 and 2 (TNFR1, TNFR2), also known as p55 and p75, respectively. Normally, the functions of soluble TNF-α-induced TNFR1 activation are reported to be pro-inflammatory and apoptotic. While TNF-α mediated TNFR2 activation has a dual role. Several synthetic drugs used as inhibitors of TNF-α for diverse inflammatory diseases possess serious adverse effects, which make patients and researchers turn their focus toward natural medicines, phytochemicals in particular. Phytochemicals targeting TNF-α can significantly improve disease conditions involving TNF-α with fewer side effects. Here, we reviewed known TNF-α inhibitors, as well as lately studied phytochemicals, with a role in inhibiting TNF-α itself, and TNF-α-mediated signaling in inflammatory diseases focusing mainly on CNS disorders.
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http://dx.doi.org/10.3390/ijms21030764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037901PMC
January 2020

Effect of Cysteine on Methylglyoxal-Induced Renal Damage in Mesangial Cells.

Cells 2020 01 17;9(1). Epub 2020 Jan 17.

College of Pharmacy, Gachon University, #191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.

Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is a key precursor of the formation of advanced glycation end products (AGEs). MGO and MGO-AGEs were reportedly increased in patients with diabetic dysfunction, including diabetic nephropathy. The activation of glyoxalase-I (GLO-I) increases MGO and MGO-AGE detoxification. MGO-mediated glucotoxicity can also be ameliorated by MGO scavengers such as -acetylcysteine (NAC), aminoguanidine (AG), and metformin. In this study, we noted that l-cysteine demonstrated protective effects against MGO-induced glucotoxicity in renal mesangial cells. l-cysteine prevented MGO-induced apoptosis and necrosis, together with a reduction of reactive oxygen species (ROS) production in MES13 cells. Interestingly, l-cysteine significantly reduced MGO-AGE formation and also acted as an MGO-AGE crosslink breaker. Furthermore, l-cysteine treatment accelerated MGO catabolism to D-lactate via the upregulation of GLO-I. The reduction of AGE formation and induction of AGE breakdown, following l-cysteine treatment, further supports the potential use of l-cysteine as an alternative for the therapeutic control of MGO-induced renal complications in diabetes, especially against diabetic nephropathy.
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http://dx.doi.org/10.3390/cells9010234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016887PMC
January 2020

Accelerates Skin Wound Healing by Regulating the Expression of MMPs and TGF-β.

J Clin Med 2019 Dec 26;9(1). Epub 2019 Dec 26.

College of Pharmacy, Gachon University 191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.

is one of the medicinal plants used traditionally for treatment of wounds. We intended to investigate the wound healing effect of the powder of (UP) root bark in a mouse wound healing model. We also determined the mechanisms of effects of in skin and skin wound healing effects using a keratinocyte model. Animal experiments showed that the wound lesions in the mice decreased with 200 mesh root bark powder and were significantly reduced with treatment by UP, compared with those treated with (UM). Results from in vitro experiments also revealed that UP extract promoted the migration of human skin keratinocytes. UP powder treatment upregulated the expression of the matrix metalloproteinase-2 and -9 protein and significantly increased transforming growth factor (TGF)-β levels. We confirmed that topical administration of the bark powder exerted a significant effect on skin wound healing by upregulating the expression of MMP and transforming growth factor-β. Our study suggests that may be a potential candidate for skin wound healing including epidermal skin rejuvenation.
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http://dx.doi.org/10.3390/jcm9010059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019489PMC
December 2019

A Stilbenoid Isorhapontigenin as a Potential Anti-Cancer Agent against Breast Cancer through Inhibiting Sphingosine Kinases/Tubulin Stabilization.

Cancers (Basel) 2019 Dec 5;11(12). Epub 2019 Dec 5.

College of Pharmacy, Gachon University, #191, Hambakmoero, Yeonsu-gu, Incheon 21936, Korea.

Isorhapontigenin (ISO), a tetrahydroxylated stilbenoid, is an analog of resveratrol (Rsv). The various biological activities of Rsv and its derivatives have been previously reported in the context of both cancer and inflammation. However, the anti-cancer effect of ISO against breast cancer has not been well established, despite being an orally bioavailable dietary polyphenol. In this study, we determine the anti-cancer effects of ISO against breast cancer using MCF7, T47D, and MDA-MB-231 cell lines. We observed that ISO induces breast cancer cell death, cell cycle arrest, oxidative stress, and the inhibition of cell proliferation. Additionally, sphingosine kinase inhibition by ISO controlled tubulin polymerization and cancer cell growth by regulating MAPK/PI3K-mediated cell cycle arrest in MCF7 cells. Interestingly, SPHK1/2 gene silencing increased oxidative stress, cell death, and tubulin destabilization in MCF7 cells. This suggests that the anti-cancer effect of ISO can be regulated by SPHK/tubulin destabilization pathways. Overall, ISO successfully induced breast cancer cell death and cell growth arrest, suggesting this phytochemical is a better alternative for breast cancer treatment. Further studies in animal models could confirm the potency and usability of ISO over Rsv for targeting breast cancer, potentially posing an alternative candidate for improved therapy in the near future.
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http://dx.doi.org/10.3390/cancers11121947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966567PMC
December 2019

Effects of Extract on Regulation of AMPK Associated Hepatic Lipid Metabolism in Type 2 Diabetic Mice.

Antioxidants (Basel) 2019 Nov 29;8(12). Epub 2019 Nov 29.

Department of Food and Nutrition, Kyung Hee Univerity, 26 Kyung Hee-Daero, Dongdamun-Gu, Seoul 02447, Korea.

(LB) is one of the ornamental plants used for the treatment of inflammation caused by oxidative damage. However, its beneficial effects on hyperglycemia-induced hepatic damage and the related molecular mechanisms remain unclear. We hypothesized that extract (LBE) would attenuate hyperglycemia-induced liver injury in type 2 diabetes mellitus (T2DM). Diabetes was induced by a low dosage of streptozotocin (STZ) injection (30 mg/kg) with a high fat diet in male C57BL/6J mice. LBE was administered orally at 100 mg/kg or 250 mg/kg for 12 weeks. LBE supplementation regardless of dosage ameliorated plasma levels of hemoglobin A1c (HbA1c) in diabetic mice. Moreover, both LBE supplementations upregulated AMP-activation kinase (AMPK), which may activate sirtuin1 (SIRT) associated pathway accompanied by decreased lipid synthesis at low dose of LBE supplementation. These changes were in part explained by reduced protein levels of oxidative stress (nuclear factor erythroid 2-related factor 2 (Nrf2) and catalase), inflammation (nuclear factor kappa B (NF-κB), interleukin-1β (IL-1β), interleukin-6 (IL-6), and nitric oxide synthases (iNOS)), and fibrosis (α-smooth muscle actin (α-SMA) and protein kinase C (PKC)) in diabetic liver. Taken together, LBE might be a potential nutraceutical to ameliorate hepatic damage by regulation of AMPK associated pathway via oxidative stress, inflammation, and fibrosis in T2DM.
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http://dx.doi.org/10.3390/antiox8120599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943630PMC
November 2019

Corrigendum to "6-Shogaol, an active constituent of ginger, attenuates neuroinflammation and cognitive deficits in animal models of dementia" [BBRC 449 (2014) 8-13].

Biochem Biophys Res Commun 2020 Jan 1;521(2):545. Epub 2019 Nov 1.

Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Science, Graduate School and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, Republic of Korea. Electronic address:

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http://dx.doi.org/10.1016/j.bbrc.2019.10.150DOI Listing
January 2020