The differential expression patterns of Atg9a and Atg9b in cells of the reproductive organs.

Objective: Autophagy is a major intracellular catabolic pathway governed by the sequential actions of proteins encoded by autophagy-related genes (Atg). ATG9, the only transmembrane protein involved in this process, regulates phospholipid translocation to autophagosomes during the early phases of autophagy. In mammals, two Atg9 isoforms have been reported: Atg9a and Atg9b. In this study, we examined whether the molecular and cellular characteristics of these two isoforms differed in mice. Methods: Whole uteri were collected on days 1, 4, and 8 of pregnancy and from ovariectomized mice injected with vehicle, progesterone, or 17ß-estradiol. Cells from reproductive tissues, such as granulosa cells, uterine epithelial cells (UECs), uterine stromal cells (USCs), and oocytes were collected. Two human uterine cell lines were also used in this analysis. Reverse transcription-polymerase chain reaction tests, Western blotting, and immunofluorescence staining were performed. Serum starvation conditions were used to induce autophagy in primary cells. Results: Atg9a and Atg9b were expressed in multiple mouse tissues and reproductive cells. Neither Atg9A nor Atg9B significantly changed in response to steroid hormones. Immunofluorescence staining of the UECs and USCs showed that ATG9A was distributed in a punctate-like pattern, whereas ATG9B exhibited a pattern of elongated tubular shapes in the cytoplasm. In human cancer cell lines, ATG9B was undetectable, whereas ATG9A was found in all cell types examined. Conclusion: The Atg9 isoforms exhibited distinct subcellular localizations in UECs and may play different roles in autophagy. Notably, human uterine cells exhibited reduced ATG9B expression, suggesting that this suppression may be due to epigenetic regulation.

Complete genome sequence of tulip virus X, a Korean isolate from Tulipa gesneriana.

In this study, the presence of tulip virus X (TVX) in Korean tulips was confirmed through high-throughput RNA sequencing. Its complete genome sequence of 6,056 nucleotides was determined via Sanger sequencing, exhibiting a 99.24% nucleotide identity with TVX-J isolate. This signifies a previously unreported presence of TVX outside Japan.

Learning goal orientation and promotive voice: A moderated mediation model.

Drawing on the broaden-and-build theory and trait-activation theory, this study investigates the mediating effect of thriving at work on the relationship between learning goal orientation (LGO) and promotive voice behavior, as well as the moderating effect of intrinsic career growth (ICG) on the relationship between employees' LGO and thriving at work. Using the two-wave design with a 4-month time lag involving 279 employees, the results demonstrate that employees' LGO is positively associated with promotive voice behavior by thriving at work. Furthermore, ICG moderates the relationship between LGO and thriving at work. ICG also moderates the mediating effect of thriving at work on the relationship between LGO and promotive voice behavior, such that the mediating effect is only significant when employees perceive high ICG.

Effects of Chronic Diseases on All-Cause Mortality in People with Mental Illness: A Retrospective Cohort Study Using the Korean National Health Insurance Service-Health Screening.

The aim of this study was to compare mortality and the prevalence of chronic diseases between people with mental illness and the general population, and to explore which chronic diseases increase the risk of all-cause mortality, especially in people with mental illness. This study assessed data from the 2002-2019 Korean National Health Insurance Service-Health Screening sample cohort. Results revealed that all-cause mortality was higher in people with mental illness compared to people without mental illness (11.40% vs. 10.28%, p = 0.0022). Several chronic diseases have a higher prevalence and risk of all-cause mortality in individuals with mental illness than the general population. Among people with the same chronic disease, those with mental disorders had a higher risk of all-cause mortality. Cancer (aHR 2.55, 95% CI 2.488-2.614), liver cirrhosis (aHR 2.198, 95% CI 2.086-2.316), and arrhythmia (aHR 1.427, 95% CI 1.383-1.472) were the top three chronic diseases that increased the risk of all-cause mortality in people with mental illness compared to people without mental illness. Our results suggest the need for more attention to chronic diseases for people with mental illness in clinical practice by explaining the effect of chronic disease on all-cause mortality in people with mental illness.

The first national scale evaluation of total nitrogen stocks and burial rates of intertidal sediments along the entire coast of South Korea.

The regulating ecosystem services, such as water purification, that tidal flats provide by nitrogen (N) burial are being increasingly recognized; yet, quantitative estimates remain limited. Here, we first present nationwide evaluation of total N stocks and burial rates in the Korean tidal flats, based on a 3 year long monitoring assessment combined with remote sensing approach. A total of 20 intertidal flats representing 7 provinces of South Korea were extensively surveyed in 2018-20. The sediment textural type (sand, mixed, and mud) classified from remotely sensed imagery was significantly correlated to that identified from field data (p < 0.01), warranting a nationwide estimate of total N stocks. The estimated total N stocks and burial rates in the tidal flats of Korea were 1.5 Tg N and 8,192 Mg N yr-1, respectively. Total N stocks significantly varied by region, province, morphology, salinity, and land use type adjacent to the corresponding tidal flats. In general, the N stocks of tidal flats were influenced by the degree of terrestrial N inputs to the ocean. The N stocks were significantly correlated with several physical parameters, such as precipitation (p < 0.05) and tide (p < 0.01). Among the sediment properties, the mud content was found to be the key factor determining the total N stocks across the 20 intertidal flats (p < 0.01). Finally, by applying the environmental value for N removal (USD km-2 yr-1) to the tidal flat area (km2), the economic value of the total N removal was estimated as ~233 Million USD yr-1 in Korea and ~15 Billion USD yr-1 globally. Overall, the present work confirms the valuable ecosystem service of tidal flat's cost-efficient N removal capacity, highlighting marine ecosystem service.

The first national scale evaluation of organic carbon stocks and sequestration rates of coastal sediments along the West Sea, South Sea, and East Sea of South Korea.

Blue carbon science requires the estimates of organic carbon stock and sequestration rate; however, holistic data analysis remains limited in South Korea. The present study reports current organic carbon stocks and sequestration rates in the coastal areas of West Sea, South Sea, and East Sea of South Korea, encompassing entire intertidal areas using long-term field survey combined with remote sensing technology. Twenty-one intertidal flats were targeted across seven provinces (Gyeonggi, Chungnam, Jeonbuk, Jeonnam, Gyeongnam, Gyeongbuk, Gangwon). Out of the evaluated environmental parameters, mud content represented a significant factor controlling sedimentary organic carbon stocks across target areas, and was significantly positively correlated to the total organic carbon (p < 0.05). Organic carbon stocks measured in salt marshes (i.e., upper intertidal zone) reflected the high carbon fixation capacity of halophytes through primary production. Sediment textural type was classified using analysis of remotely sensed imagery, and was closely correlated to field-based classification data (p < 0.05). Using field and remote sensing results, we estimated total organic carbon stocks (13,142,149 Mg C) and sequestration rates (71,383 Mg C yr-1) in the tidal flats of South Korea. This study presents the first report on blue carbon potential in the Korean tidal flats, providing baseline information on the carbon dynamics of intertidal sediments in this region and, potentially, elsewhere.

Novel ß-phenylacrylic acid derivatives exert anti-cancer activity by inducing Src-mediated apoptosis in wild-type KRAS colon cancer.

Many stress conditions including chemotherapy treatment is known to activate Src and under certain condition Src can induce the apoptotic signal via c-Jun N-terminal kinase (JNK) activation. Here we report that the newly synthesized ß-phenylacrylic acid derivatives, MHY791 and MHY1036 (MHYs), bind to epidermal growth factor receptor (EGFR) tyrosine kinase domains and function as EGFR inhibitors, having anti-cancer activities selectively in wild-type KRAS colon cancer. Mechanistically, MHYs-induced Src/JNK activation which enhanced their pro-apoptotic effects and therefore inhibition of Src by the chemical inhibitor PP2 or Src siRNA abolished the response. In addition, MHYs generated reactive oxygen species and increased ER stress, and pretreatment with antioxidant-inhibited MHY-induced ER stress, Src activation, and apoptosis. Furthermore, the irreversible EGFR inhibitor PD168393 also activated Src while the reversible EGFR inhibitor gefitinib showed the opposite effect, indicating that MHYs are the irreversible EGFR inhibitor. Collectively, Src can play a key role in apoptosis induced by the novel EGFR inhibitor MHYs, suggesting that activation of Src might prove effective in treating EGFR/wild-type KRAS colon cancer.

2-(3, 4-dihydroxybenzylidene)malononitrile as a novel anti-melanogenic compound.

Tyrosinase is a key player in ultraviolet-induced melanogenesis. Because excessive melanin accumulation in the skin can induce hyperpigmentation, the development of tyrosinase inhibitors has attracted attention in cosmetic-related fields. However, side effects including toxicity and low selectivity have limited the use of many tyrosinase inhibitors in cosmetics. We synthesized 12 novel 2-(substituted benzylidene)malononitrile derivatives and investigated their anti-melanogenic activities. Of these 12 compounds, 2-(3, 4-dihydroxy benzylidene)malononitrile (BMN11) exhibited the strongest inhibitory activity against tyrosinase (IC50 = 17.05 µM). In parallel with this, BMN11 treatment notably decreased alpha-melanocyte-stimulating hormone-induced melanin accumulation in B16F10, cells without toxicity and also decreased melanin accumulation in a human skin model. As a mechanism underlying the BMN11-mediated anti-melanogenic effect, docking simulation showed that BMN11 can directly bind to tyrosinase by forming two hydrogen bonds with GLY281 and ASN260 residues, and via three hydrophobic interactions with VAL283, PHE264, and ALA286 residues in the tyrosinase binding pocket, and this likely contributes to its inhibitory effect on tyrosinase. Consistently, Lineweaver-Burk and Cornish-Bowden plots showed that BMN11 is a competitive inhibitor of tyrosinase. We concluded that BMN11 may be a novel tyrosinase inhibitor that could be used in cosmetics.

PPARα activation by MHY908 attenuates age-related renal inflammation through modulation of the ROS/Akt/FoxO1 pathway.

2-[4-(5-Chlorobenzothiazothiazol-2-yl)phenoxy]-2-methyl-propionic acid (MHY908) has been shown to prevent insulin resistance-induced hyperinsulinemia in aged rats. However, the mechanism underlying MHY908-mediated amelioration of renal inflammation with insulin resistance during aging remains unknown. This study investigated the effects of MHY908 on age-related changes in the IRS/Akt/forkhead box (FoxO) 1 signaling pathway in the kidneys of aged rats and HEK293T cells. Experiments were performed in young, old, and MHY908-fed old rats (1mg or 3mg/kg/day MHY908 for 4 weeks). We found that MHY908-fed old rats suppressed phosphorylation of IRS/Akt and induced FoxO1 activation, leading to increased expression of MnSOD and catalase. In addition, in insulin-treated cells, MHY908 prevented the FoxO1 inactivation and increased the expression of MnSOD and catalase by inactivating IRS and Akt. In contrast, NF-κB signaling pathway decreased with MHY908 treatment in insulin-treated cells. Furthermore, MHY908 exclusively activated peroxisome proliferator-activated receptor (PPAR) α in the kidneys, leading to the inhibition of insulin-induced NADPH oxidase subunit 4 (NOX4)-derived reactive oxygen species (ROS) generation and FoxO1 inactivation. In conclusion, MHY908 improved the hyperinsulinemia-induced pro-inflammatory response through NF-κB inactivation and FoxO1 activation in aged rat kidneys. These phenomena suggest that PPARα activation by MHY908 attenuates NOX4-derived ROS generation in response to insulin.

(Z)-5-(2,4-Dihydroxybenzylidene)thiazolidine-2,4-dione Prevents UVB-Induced Melanogenesis and Wrinkle Formation through Suppressing Oxidative Stress in HRM-2 Hairless Mice.

Background. Uncontrolled melanogenesis and wrinkle formation are an indication of photoaging. Our previous studies demonstrated that (Z)-5-(2,4-dihydroxybenzylidene)thiazolidine-2,4-dione (MHY498) inhibited tyrosinase activity and melanogenesis in vitro. Objective. To examine in vivo effects of MHY498 as an antiaging compound on UVB-induced melanogenesis and wrinkle formation, we topically applied MHY498 on dorsal skin of HRM-2 hairless mice. Methods. Using histological analysis, we evaluated effects of MHY498 on melanogenesis and wrinkle formation after UVB exposure. In addition, related molecular signaling pathways were examined using western blotting, fluorometric assay, and enzyme-linked immunosorbent assay. Results. MHY498 suppressed UVB-induced melanogenesis by inhibiting phosphorylation of CREB and translocation of MITF protein into the nucleus, which are key factors for tyrosinase expression. Consistently, tyrosinase protein levels were notably reduced in the dorsal skin of the hairless mice by MHY498 treatment. Furthermore, MHY498 inhibited UVB-induced wrinkle formation and collagen fiber destruction by increasing type 1 procollagen concentration and decreasing protein expression levels of MMPs, which play an essential role in collagen fiber degradation. As a mechanism, MHY498 notably ameliorated UVB-induced oxidative stress and NF-κB activation in the dermal skin of the hairless mice. Conclusion. Our study suggests that MHY498 can be used as a therapeutic or cosmetic agent for preventing uncontrolled melanogenesis and wrinkle formation.

Tyrosinase inhibitors: a patent review (2011-2015).

INTRODUCTION: Tyrosinase is responsible for melanin production. The overproduction of melanin causes many skin disorders. The inhibition of tyrosinase activity would appear to be the most rational and explicit way of overcoming these issues. AREAS COVERED: Thirty eight patents on synthetic tyrosinase inhibitors issued since 2011 were reviewed. Inhibitors were categorized by chemical structure and assigned to eight classes. Information on potent inhibitors in each class is provided. EXPERT OPINION: Many tyrosinase inhibitors of natural or synthetic origin have been identified, but very few are qualified for clinical use. Thus medicinal scientists have to work more on the identification of potent and safe tyrosinase inhibitors. Various chemical scaffolds have been explored. Among them, the scaffolds such as resorcinol, biaryl, imidazolethione, ß-phenyl-α,ß-unsaturated carbonyl, and some double strand oligonucleotides have shown high tyrosinase inhibition, low toxicities, and great potencies. Detail structure activity relationship studies of these potential scaffolds could provide directions for a new and potent tyrosinase inhibitors. Furthermore new trends, such as the use of synergistic phenomena, salt formation, drug repositioning and designing of multi-targeted tyrosinase inhibitors could expand search areas for much improved tyrosinase inhibitors.

(E)-2-Cyano-3-(substituted phenyl)acrylamide analogs as potent inhibitors of tyrosinase: A linear ß-phenyl-α,ß-unsaturated carbonyl scaffold.

In this study, we synthesized (E)-2-cyano-3-(substituted phenyl)acrylamide (CPA) derivatives which possess a linear ß-phenyl-α,ß-unsaturated carbonyl scaffold and examined their inhibitory activities against tyrosinase. CPA analogs exerted inhibitory activity against mushroom tyrosinase. Results from the docking simulation indicated that CPA2 could bind directly to the active site of mushroom tyrosinase and the binding affinity of CPA2 for tyrosinase might be higher than that of kojic acid, a well-known potent tyrosinase inhibitor. In B16F10 cells, CPA2 significantly suppressed tyrosinase activity and melanogenesis in a dose-dependent manner. At the concentration of 25µM, CPA2 exhibited tyrosinase inhibitory activity comparable to that of kojic acid with no cytotoxic effect. Results from the present study suggest that CPA2 bearing a linear ß-phenyl-α,ß-unsaturated carbonyl scaffold may be the potential candidate for treatment of diseases associated with hyperpigmentation and that a linear ß-phenyl-α,ß-unsaturated carbonyl scaffold might be closely related to potent tyrosinase inhibition.

Design, synthesis, and anti-melanogenic effects of (E)-2-benzoyl-3-(substituted phenyl)acrylonitriles.

BACKGROUND: Tyrosinase is the most prominent target for inhibitors of hyperpigmentation because it plays a critical role in melaninogenesis. Although many tyrosinase inhibitors have been identified, from both natural and synthetic sources, there remains a considerable demand for novel tyrosinase inhibitors that are safer and more effective. METHODS: (E)-2-Benzoyl-3-(substituted phenyl)acrylonitriles (BPA analogs) with a linear ß-phenyl-α,ß-unsaturated carbonyl scaffold were designed and synthesized as potential tyrosinase inhibitors. We evaluated their effects on cellular tyrosinase activity and melanin biosynthesis in murine B16F10 melanoma cells and their ability to inhibit mushroom tyrosinase activity. RESULTS: BPA analogs exhibited inhibitory activity against mushroom tyrosinase. In particular, BPA13 significantly suppressed melanin biosynthesis and inhibited cellular tyrosinase activity in B16F10 cells in a dose-dependent manner. A docking study revealed that BPA13 had higher binding affinity for tyrosinase than kojic acid. CONCLUSION: BPA13, which possesses a linear ß-phenyl-α,ß-unsaturated carbonyl scaffold, is a potential candidate skin-whitening agent and treatment for diseases associated with hyperpigmentation.

A Novel Peroxisome Proliferator-activated Receptor (PPAR)γ Agonist 2-Hydroxyethyl 5-chloro-4,5-didehydrojasmonate Exerts Anti-Inflammatory Effects in Colitis.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease with increasing incidence and prevalence worldwide. Here we investigated the newly synthesized jasmonate analogue 2-hydroxyethyl 5-chloro-4,5-didehydrojasmonate (J11-Cl) for its anti-inflammatory effects on intestinal inflammation. First, to test whether J11-Cl can activate peroxisome proliferator-activated receptors (PPARs), we performed docking simulations because J11-Cl has a structural similarity with anti-inflammatory 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2), one of the endogenous ligands of PPARγ. J11-Cl bound to the ligand binding domain of PPARγ in the same manner as 15d-PGJ2 and rosiglitazone, and significantly increased transcriptional activity of PPARγ. In animal experiments, colitis was significantly reduced in mice with J11-Cl treatment, determined by analyses of survival rate, body weight changes, clinical symptoms, and histological evaluation. Moreover, J11-Cl decreased production of pro-inflammatory cytokines including IL-6, IL-8, and G-CSF as well as chemokines including chemokine (C-C motif) ligand (CCL)20, chemokine (C-X-C motif) ligand (CXCL)2, CXCL3, and chemokine (C-X3-C motif) ligand 1 (CX3CL1) in colon tissues, and LPS or TNF-α-stimulated macrophages and epithelial cells. In contrast, production of anti-inflammatory cytokines including IL-2 and IL-4 as well as the proliferative factor, GM-CSF, was increased by J11-Cl. Furthermore, inhibition of MAPKs and NF-κB activation by J11-Cl was also observed. J11-Cl reduced intestinal inflammation by increasing the transcriptional activity of PPARγ and modulating inflammatory signaling pathways. Therefore, our study suggests that J11-Cl may serve as a novel therapeutic agent against IBD.

(Z)-2-(Benzo[d]thiazol-2-ylamino)-5-(substituted benzylidene)thiazol-4(5H)-one Derivatives as Novel Tyrosinase Inhibitors.

Inhibiting tyrosinase is an important goal to prevent melanin accumulation in skin and thereby to inhibit pigmentation disorders. Therefore, tyrosinase inhibitors are an attractive target in cosmetics and treatments for pigmentation disorders. However, only a few tyrosinase inhibitors are currently available because of their toxic effects to skin or lack of selectivity and stability. Here, we newly synthesized thirteen (Z)-2-(benzo[d]thiazol-2-ylamino)-5-(substituted benzylidene)thiazol-4(5H)-one derivatives and examined their effect on melanogenesis. Of these compounds, MHY2081 had the strongest inhibitory effect on tyrosinase without cytotoxicity in B16F10 melanoma cells. Consistently, melanogenesis was notably decreased by MHY2081 treatment. As an underlying mechanism, docking simulation showed that compared to kojic acid, a well-known competitive tyrosinase inhibitor which forms a hydrogen bond and aromatic interaction with tyrosinase, MHY2081 has stronger affinity with tyrosinase by forming three hydrogen bonds and a hydrophobic interaction with residues of tyrosinase. In parallel with this, Lineweaver-Burk plot analysis showed that MHY2081 is a strong competitive inhibitor of tyrosinase. In conclusion, MHY2081 may be a novel tyrosinase inhibitor for prevention and treatment of pigmentation disorders.

Inhibition of melanogenesis by 2-[4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy]-2-methylpropanoic acid (MHY908).

Tyrosinase inhibitors might have potential use in cosmetic and medicinal products for the prevention of pigmentation disorders. However, only a few inhibitors are currently used due to their cytotoxicity, and lack of selectivity and stability. In this study, we synthesized several tyrosinase inhibitors and investigated their activity. To investigate the action of 2-[4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy]-2-methylpropanoic acid (MHY908) specifically in the inhibition of melanogenesis, a mushroom tyrosinase activity assay was performed. We confirmed the inhibitory effect of MHY908 at various melanin concentrations using α-MSH-induced melanoma cells. Our results indicate that MHY908 potently inhibited mushroom tyrosinase activity (IC50 = 8.19 µM) in a dose-dependent manner. Through a docking simulation, we also analyzed its binding mode to inhibit tyrosinase activity. MHY908 also decreased melanin synthesis without inducing cytotoxicity. These results suggest that MHY908 is a good candidate for prevention and treatment of pigmentation disorders.