Synthesis and anti-prion aggregation activity of acylthiosemicarbazide analogues.

Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrPSc) that forms insoluble amyloids to impair brain function. PrPSc interacts with the non-pathogenic, cellular prion protein (PrPC) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrPSc but no pharmacological intervention was well established thus far. We, here, report that acylthiosemicarbazides inhibit the prion aggregation. Compounds 7x and 7y showed almost perfect inhibition (EC50 = 5 µM) in prion aggregation formation assay. The activity was further confirmed by atomic force microscopy, semi-denaturing detergent agarose gel electrophoresis and real-time quaking induced conversion assay (EC50 = 0.9 and 2.8 µM, respectively). These compounds also disaggregated pre-existing aggregates in vitro and one of them decreased the level of PrPSc in cultured cells with permanent prion infection, suggesting their potential as a treatment platform. In conclusion, hydroxy-2-naphthoylthiosemicarbazides can be an excellent scaffold for the discovery of anti-prion therapeutics.

Synthesis and activity of N-(5-hydroxy-3,4,6-trimethylpyridin-2-yl)acetamide analogues as anticolitis agents via dual inhibition of TNF-α- and IL-6-induced cell adhesions.

Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are the critical pro-inflammatory cytokines involved in the pathogenesis of inflammatory bowel disease (IBD). Inhibition of these cytokines and related signaling pathways has been a target for the development of IBD therapeutics. In the current study, 6-acetamido-2,4,5-trimethylpyridin-3-ol (1) and various analogues with the amido scaffold were synthesized and examined for their inhibitory activities in in vitro and in vivo IBD models. The parent compound 1 (1 µM) showed an inhibitory activity against TNF-α- and IL-6-induced adhesion of monocytes to colon epithelial cells, which was similar to tofacitinib (1 µM), a JAK inhibitor, but much better than mesalazine (1,000 µM). All the analogues showed a positive relationship (R2 = 0.8943 in a linear regression model) between the inhibitory activities against TNF-α-induced and those against IL-6-induced adhesion. Compound 2-19 turned out to be the best analogue and showed much better inhibitory activity against TNF-α- and IL-6-induced adhesion of the cells than tofacitinib. In addition, oral administration of compound 1 and 2-19 resulted in a significant suppression of clinical signs of TNBS-induced rat colitis, including weight loss, colon tissue edema, and myeloperoxidase activity, a marker for inflammatory cell infiltration in colon tissues. More importantly, compound 2-19 (1 mg/kg) was more efficacious in ameliorating colitis than compound 1 and sulfasalazine (300 mg/kg), the commonly prescribed oral IBD drug. Taken together, the results suggest that compound 2-19 can be a novel platform for dual-acting IBD drug discovery targeting both TNF-α and IL-6 signaling.

3,4-dihydroxytoluene, a metabolite of rutin, suppresses the progression of nonalcoholic fatty liver disease in mice by inhibiting p300 histone acetyltransferase activity.

3,3',4',5,7-Pentahydroxyflavone-3-rhamnoglucoside (rutin) is a flavonoid with a wide range of pharmacological activities. Dietary rutin is hardly absorbed because the microflora in the large intestine metabolize rutin into a variety of compounds including quercetin and phenol derivatives such as 3,4-dihydroxyphenolacetic acid (DHPAA), 3,4-dihydroxytoluene (DHT), 3,4-hydroxyphenylacetic acid (HPAA) and homovanillic acid (HVA). We examined the potential of rutin and its metabolites as novel histone acetyltransferase (HAT) inhibitors. DHPAA, HPAA and DHT at the concentration of 25 µM significantly inhibited in vitro HAT activity with DHT having the strongest inhibitory activity. Furthermore, DHT was shown to be a highly efficient inhibitor of p300 HAT activity, which corresponded with its high degree of inhibition on intracellular lipid accumulation in HepG2 cells. Docking simulation revealed that DHT was bound to the p300 catalytic pocket, bromodomain. Drug affinity responsive target stability (DARTS) analysis further supported the possibility of direct binding between DHT and p300. In HepG2 cells, DHT concentration-dependently abrogated p300-histone binding and induced hypoacetylation of histone subunits H3K9, H3K36, H4K8 and H4K16, eventually leading to the downregulation of lipogenesis-related genes and attenuating lipid accumulation. In ob/ob mice, administration of DHT (10, 20 mg/kg, iv, every other day for 6 weeks) dose-dependently improved the NAFLD pathogenic features including body weight, liver mass, fat mass, lipid accumulation in the liver, and biochemical blood parameters, accompanied by the decreased mRNA expression of lipogenic genes in the liver. Our results demonstrate that DHT, a novel p300 histone acetyltransferase inhibitor, may be a potential preventive or therapeutic agent for NAFLD.

Antioxidant Analogue 6-Amino-2,4,5-Trimethylpyridin-3-ol Ameliorates Experimental Colitis in Mice.

BACKGROUND: Oxidative stress has been suggested to be a factor contributing to the disease severity of inflammatory bowel disease (IBD). BJ-1108, a derivative of 6-amino-2,4,5-trimethylpyridin-3-ol, is reported to significantly inhibit the generation of reactive oxygen species (ROS) in vitro. However, whether this molecule affects intestinal inflammation is largely unknown. We aimed to investigate the effect of BJ-1108 on dextran sulfate sodium (DSS)-induced experimental colitis in mice. METHODS: Colitis was induced in mice with DSS, and disease severity was estimated by evaluating body weight, colon length, histology, immune cell infiltration, and intestinal permeability. We examined the protective effects of BJ-1108 on barrier function using Caco-2 cells. Last, we estimated the impact of BJ-1108 on the phosphorylation of NF-kB, PI3K/AKT, and mitogen-activated protein kinases. RESULTS: Mice treated with BJ-1108 exhibited improved disease severity, as indicated by evaluations of body weight, histological scores, spleen weight, and infiltrates of T cells and macrophages. The administration of BJ-1108 inhibited the colonic mRNA expression of IL-6 and IL-1ß in vivo. Additionally, BJ-1108 limited intestinal permeability and enhanced the expression of tight junction (TJ) proteins such as claudin-1 and claudin-3 in the DSS-induced colitis model. In an in vitro model using Caco-2 cells, BJ-1108 ameliorated cytokine-induced ROS generation in a dose-dependent manner and remarkably recovered barrier dysfunction as estimated by evaluating transepithelial electrical resistance and TJ protein expression. BJ-1108 suppressed the NF-kB/ERK/PI3K pathway. CONCLUSIONS: This study demonstrated that BJ-1108 ameliorated intestinal inflammation in an experimental colitis mouse model, suggesting possible therapeutic implications for IBD.

Optimization and validation for quantification for allulose of jelly candies using response surface methodology.

A simple, rapid and reliable extraction method for allulose content in jelly were optimized using response surface methodology. The extraction method was selected based on preliminary experiments, with a three-factor, three-level central complex design including 20 experimental runs to optimize the extraction parameters. The optimum extraction factors predicted were temperature of 66 °C, solvent of 74% (v/v) ethanol, and extraction time of 24 min under shaking water bath extraction. The measured parameters were in accordance with the predicted values. The developed analytical method was validated with regard to linearity, accuracy and precision presenting recovery level from 90.79 to 95.18% and detection limits varying from 0.53 to 1.62 mg/mL. Finally, the method will be potentially applicable to a commercial jelly food using optimum extraction.

Inhibition of colitis by ring-modified analogues of 6-acetamido-2,4,5-trimethylpyridin-3-ol.

6-Aminopyridin-3-ol scaffold has shown an excellent anti-inflammatory bowel disease activity. Various analogues with the scaffold were synthesized in pursuit of the diversity of side chains tethering on the C(6)-position. Structure-activity relationship among the analogues was investigated to understand the effects of the side chains and their linkers on their anti-inflammatory activities. In this study, structural modification moved beyond side chains on the C(6)-position and reached to pyridine ring itself. It expedited us to synthesize diverse ring-modified analogues of a representative pyridine-3-ol, 6-acetamido-2,4,5-trimethylpyridin-3-ol (9). In the evaluation of compounds on their inhibitory actions against TNF-α-induced adhesion of monocytic cells to colonic epithelial cells, an in vitro model mimicking colon inflammation, the effects of compounds 9, 17, and 19 were greater than tofacitinib, an orally available anti-colitis drug, and compound 17 showed the greatest activity. In addition, TNF-α-induced angiogenesis, which permits more inflammatory cell migration into inflamed tissues, was significantly blocked by compounds 17 and 19 in a concentration-dependent manner. In the comparison of in vivo therapeutic effects of compounds 9, 17, and 19 on dextran sulfate sodium (DSS)-induced colitis in mice, compound 17 was the most potent and efficacious, and compound 19 was better than compound 9 which showed a similar degree of inhibitory effect to tofacitinib. Taken together, it seems that either the trimethyl system or the hydroxyl group on the pyridinol ring is essential to the activity. This finding might become a new milestone in the development of pyridinol-based anti-inflammatory bowel disease agents.

Synthesis, activity and mechanism of alkoxy-, carbamato-, sulfonamido-, thioureido-, and ureido-derivatives of 2,4,5-trimethylpyridin-3-ol against inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic immuno-inflammation in gastrointestinal tract. We have evaluated the activity of the compounds to inhibit the adhesion of monocytes to colon epithelial cells is triggered by a pro-inflammatory cytokine, tumour necrosis factor (TNF)-α. The in vitro activity of the compounds, 13b (an ureido-derivative), 14c, 14j, 14k, 14n (thioureido-), 18c and 18d (sulfonamido-), was in correlation with in vivo anti-colitis activity revealed as significant recovery in body- and colon-weights and colon myeloperoxidase level, a biochemical marker of inflammation reflecting neutrophil infiltration. In vivo, TNBS-induced changes in the expression of inflammatory cytokines (TNF-α, IL-6, IL-1ß, IL-10, and TGF-ß), NLRP3 inflammasome components (NLRP-3, Caspase-1, and IL-18), and epithelial junction molecules (E-cadherin, claudin2/3, and ZO-1) were blocked and recovered by oral administration of the compounds (1 mg/kg). Compound 14n which showed the best efficacy can be a promising lead for orally available therapeutics for pathology of IBD.

Enrichment of Polyglucosylated Isoflavones from Soybean Isoflavone Aglycones Using Optimized Amylosucrase Transglycosylation.

Isoflavones in soybeans are well-known phytoestrogens. Soy isoflavones present in conjugated forms are converted to aglycone forms during processing and storage. Isoflavone aglycones (IFAs) of soybeans in human diets have poor solubility in water, resulting in low bioavailability and bioactivity. Enzyme-mediated glycosylation is an efficient and environmentally friendly way to modify the physicochemical properties of soy IFAs. In this study, we determined the optimal reaction conditions for Deinococcus geothermalis amylosucrase-mediated α-1,4 glycosylation of IFA-rich soybean extract to improve the bioaccessibility of IFAs. The conversion yields of soy IFAs were in decreasing order as follows: genistein > daidzein > glycitein. An enzyme quantity of 5 U and donor:acceptor ratios of 1000:1 (glycitein) and 400:1 (daidzein and genistein) resulted in high conversion yield (average 95.7%). These optimal reaction conditions for transglycosylation can be used to obtain transglycosylated IFA-rich functional ingredients from soybeans.

Comparative evaluation of spoilage-related bacterial diversity and metabolite profiles in chilled beef stored under air and vacuum packaging.

Microbial spoilage is a complex event to which different bacterial populations and metabolites can contribute depending on the storage conditions. This study explored the evolution of spoilage and related volatile organic compounds (VOCs) in chilled beef under air and vacuum packaging (VP). The results suggested that different storage conditions affected changes in bacterial communities and metabolites in beef and consequently affected the odor properties of the stored beef, thereby leading to spoilage. Bacterial species belonging to Pseudomonadaceae (Pseudomonas spp.) and lactic acid bacteria (Lactobacillus sp.) dominated the bacterial communities in beef stored under air and VP, respectively, with several VOCs associated with off-odors of the stored beef and most likely produced by both bacteria. Our results suggested several microbial VOCs that could be used as potential spoilage indicators, including acetic acid, butanoic acid, and 2-butanone in VP-stored beef and 3-methylbutan-1-ol, ethyl acetate, acetoin, 2-butanone, and diacetyl in air-stored beef. These findings might provide valuable information regarding the quality monitoring of beef during storage.

Cilostazol Improves HFD-Induced Hepatic Steatosis by Upregulating Hepatic STAMP2 Expression through AMPK.

Nonalcoholic fatty liver disease (NAFLD) is an increasingly studied condition that can progress to end-stage liver disease. Although NAFLD was first described in 1980, a complete understanding of the mechanism and causes of this disease is still lacking. Six-transmembrane protein of prostate 2 (STAMP2) plays a role in integrating inflammatory and nutritional signals with metabolism. Our previous study suggested that STAMP2 may be a suitable target for treating NAFLD. In the current study, we performed a focused drug-screening and found that cilostazol could be a potential STAMP2 enhancer. Thus, we examined whether cilostazol alleviates NAFLD through STAMP2. The in vivo and in vitro pharmacological efficacies of cilostazol on STAMP2 expression and lipid accumulation were analyzed in NAFLD mice induced by high-fat diet (HFD) and in HepG2 cell lines treated by oleic acid (OA), respectively. Cilostazol increased the expression of STAMP2 through transcriptional regulation in vivo and in vitro. Cilostazol also dampened the STAMP2 downregulation caused by the HFD and by OA in vivo and in vitro, respectively. Cilostazol activated AMP-activated protein kinase (AMPK) in vivo and in vitro, and AMPK functions upstream of STAMP2, and reversed downregulation of STAMP2 expression through AMPK in the NAFLD model. Cilostazol ameliorates hepatic steatosis by enhancing hepatic STAMP2 expression through AMPK. Enhancing STAMP2 expression with cilostazol represents a potential therapeutic avenue for treatment of NAFLD.

Protective effects of 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ols against 4-hydroxynonenal-induced cell death in adult retinal pigment epithelial-19 cells.

Dysfunction or progressive degeneration of retinal pigment epithelium (RPE) contributes in the initial pathogenesis of age-related macular degeneration (AMD) causing irreversible vision loss, which makes RPE the prime target of the disease. The present study aimed to identify compounds to protect 4-hydroxynonenal (4-HNE)-induced RPE cell death by inhibiting NADPH oxidase 4 (NOX4) activity, not just as free radical scavengers, using ARPE-19, a human adult retinal pigment epithelial cell line, as a RPE representative. Novel thirty-two 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ol derivatives 17 were synthesized and tested. We found that there was a strong correlation between level of protective effect of compounds 17 against 4-HNE-induced APRE-19 cell death and that of inhibitory activity against 4-HNE-induced superoxide production, and that most of the compounds 17 showed minimal DPPH radical scavenging activity. Compound 17-28 showed the best protective activity against 4-HNE-induced superoxide production (79.5% inhibition) and cell death (85.1% recovery) at 10 µM concentration, which was better than that of VAS2870, a NOX2/4 inhibitor. In addition, compound 17-28 blocked 4-HNE-induced apoptosis of ARPE-19 cells in a concentration-dependent manner. The results indicate that compound 17-28 may be a lead compound to develop AMD therapeutics.

Dispersive liquid-liquid microextraction with in situ derivatization coupled with gas chromatography and mass spectrometry for the determination of 4-methylimidazole in red ginseng products containing caramel colors.

A rapid analytical method was developed for the determination of 4-methylimidazole from red ginseng products containing caramel colors by using dispersive liquid-liquid microextraction with in situ derivatization followed by gas chromatography with mass spectrometry. Chloroform and acetonitrile were selected as the extraction and dispersive solvents, and based on the extraction efficiency, their optimum volumes were 200 and 100 µL, respectively. The optimum volumes of the derivatizing agent (isobutyl chloroformate) and catalyst (pyridine), pH, and concentration of NaCl in the sample solution were determined to be 25 and 100 µL, pH 7.6, and 0% w/v, respectively. Validation of the optimized method showed good linearity (R2  > 0.999), accuracy (≥89.86%), intra- (≤6.70%) and interday (≤4.17%) repeatability, limit of detection (0.96 µg/L), and limit of quantification (5.79 µg/L). The validated method was applied to quantify 4-methylimidazole in red ginseng juices and concentrates, 4-methylimidazole was only found in red ginseng juices containing caramel colorant (42.91-2863.4 µg/L) and detected in red ginseng concentrates containing >1% caramel colorant.

Hypervalent iodine-mediated Ritter-type amidation of terminal alkenes: The synthesis of isoxazoline and pyrazoline cores.

Hypervalent iodine-mediated olefin functionalization provides a rapid gateway towards accessing both various heterocyclic cores and functional groups. In this regard, we have developed a Ritter-type alkene functionalization utilizing a PhI(OAc)2 ((diacetoxyiodo)benzene, PIDA)/Lewis acid combination in order to access isoxazoline and pyrazoline cores. Based on allyl ketone oximes and allyl ketone tosylhydrazones, we have developed an alkene oxyamidation and amido-amidation protocol en route to accessing both isoxazoline and pyrazoline cores. Additionally, acetonitrile serves as both the solvent and an amine source in the presence of this PIDA/Lewis acid combination. This operationally straightforward and metal-free protocol provides an easy access to isoxazoline and pyrazoline derivatives.

BJ-1108, a 6-Amino-2,4,5-trimethylpyridin-3-ol analogue, regulates differentiation of Th1 and Th17 cells to ameliorate experimental autoimmune encephalomyelitis.

BACKGROUND: CD4+ T cells play an important role in the initiation of an immune response by providing help to other cells. Among the helper T subsets, interferon-γ (IFN-γ)-secreting T helper 1 (Th1) and IL-17-secreting T helper 17 (Th17) cells are indispensable for clearance of intracellular as well as extracellular pathogens. However, Th1 and Th17 cells are also associated with pathogenesis and contribute to the progression of multiple inflammatory conditions and autoimmune diseases. RESULTS: In the current study, we found that BJ-1108, a 6-aminopyridin-3-ol analogue, significantly inhibited Th1 and Th17 differentiation in vitro in a concentration-dependent manner, with no effect on proliferation or apoptosis of activated T cells. Moreover, BJ-1108 inhibited differentiation of Th1 and Th17 cells in ovalbumin (OVA)-specific OT II mice. A complete Freund's adjuvant (CFA)/OVA-induced inflammatory model revealed that BJ-1108 can reduce generation of proinflammatory Th1 and Th17 cells. Furthermore, in vivo studies showed that BJ-1108 delayed onset of disease and suppressed experimental autoimmune encephalomyelitis (EAE) disease progression by inhibiting differentiation of Th1 and Th17 cells. CONCLUSIONS: BJ-1108 treatment ameliorates inflammation and EAE by inhibiting Th1 and Th17 cells differentiation. Our findings suggest that BJ-1108 is a promising novel therapeutic agent for the treatment of inflammation and autoimmune disease.

Tryptophan hydroxylase 1 and 5-HT7 receptor preferentially expressed in triple-negative breast cancer promote cancer progression through autocrine serotonin signaling.

BACKGROUND: Triple-negative breast cancer (TNBC) has a high risk of relapse and there are few chemotherapy options. Although 5-hydroxytryptamine (5-HT, serotonin) signaling pathways have been suggested as potential targets for anti-cancer drug development, the mechanism responsible for the action of 5-HT in TNBC remains unknown. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to measure mRNA and protein levels, respectively. Cell proliferation was measured using CellTiter 96 Aqueous One Solution. siRNA transfection was used to assess involvement of genes in cancer invasion, which were identified by Matrigel transwell invasion assay. Levels of 5-HT and vascular endothelial growth factor (VEGF) were measured using ELISA kits. Chick chorioallantoic membrane (CAM) assay and mouse tumor model were used to investigate the in vivo effects of SB269970, a 5-HT7 receptor antagonist, and BJ-1113, a novel synthetic compound. RESULTS: TNBC cell lines (MDA-MB-231, HCC-1395, and Hs578T) expressed higher levels of tryptophan hydroxylase 1 (TPH1) than hormone-responsive breast cancer cell lines (MCF-7 and T47D). In MDA-MB-231 cells, 5-HT promoted invasion and proliferation via 5-HT7 receptor, and interestingly, the stimulatory effect of 5-HT on MDA-MB-231 cell invasion was stronger than its effect on proliferation. Likewise, downstream signaling pathways of 5-HT7 differed during invasion and proliferation, that is, Gα-activated cAMP and Gßγ-activated kinase signaling during invasion, and Gßγ-activated PI3K/Akt signaling during proliferation. Also, 5-HT increased the protein expressions of TPH1 and VEGF in MDA-MB-231 cells. These results provide insight of the stimulatory effect of 5-HT on breast cancer progression; 5-HT was found to act more strongly during the first stage of metastasis (during invasion and migration) than during the later proliferative phase after local invasion. Interestingly, these actions of 5-HT were inhibited by BJ-1113, a 6-amino-2,4,5-trimethylpyridin-3-ol analog. BJ-1113 blocked intracellular signaling pathways initiated by 5-HT7 receptor activation, and exhibited anti-proliferative and anti-invasive activities against MDA-MB-231 cells. Furthermore, the inhibitory effect of BJ-1113 against MDA-MB-231 tumor growth was greater than that of SB269970, a 5-HT7 receptor antagonist. CONCLUSIONS: 5-HT7 receptor which mediates 5-HT-induced cancer progression is a potential therapeutic target in TNBC, and BJ-1113 offers a novel scaffold for the development of anti-cancer agents against TNBC.

In vitro and in vivo inhibitory activity of 6-amino-2,4,5-trimethylpyridin-3-ols against inflammatory bowel disease.

Although the pathogenesis of inflammatory bowel disease (IBD) is complex, attachment and infiltration of leukocytes to gut epithelium induced by pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) represents the initial step of inflammation in IBD. Previously, we have reported that some 6-amino-2,4,5-trimethylpyridin-3-ols have significant levels of antiangiogenic activity via PI3K inhibition. Based on the reports that angiogenesis is involved in the aggravation of IBD and that PI3K is a potential target for IBD therapy, we investigated whether the scaffold has inhibitory activity against in vitro and in vivo models of colitis. Many analogues showed >80% inhibition against TNF-α-induced monocyte adhesion to colon epithelial cells at 1µM. Compound 8m showed IC50=0.19µM, which is about five orders of magnitude better than that of 5-aminosalicylic acid (5-ASA, IC50=18.1mM), a positive control. In a rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis, orally administered 8m dramatically ameliorated TNBS-induced colon inflammation. It was demonstrated by a high level of suppression in myeloperoxidase (MPO), a surrogate marker of colitis, as well as almost perfect recovery of colon and body weights in a dose-dependent manner. Compared to sulfasalazine, a prodrug of 5-ASA, compound 8m showed >300-fold better efficacy in those parameters. Taken together, 6-amino-2,4,5-trimethylpyridin-3-ols can provide a novel platform for anti-IBD drug discovery.

5-Hydroxy-7-azaindolin-2-one, a novel hybrid of pyridinol and sunitinib: design, synthesis and cytotoxicity against cancer cells.

Angiogenesis plays important roles in tumor growth and metastasis. Sunitinib (Sutent®) is an antitumor agent targeting receptor tyrosine kinases which are involved in angiogenesis as well as cancer cell growth and survival. Using the pyridin-3-ol scaffold, which was previously reported as an excellent antioxidant and antiangiogenic platform, we have synthesized sunitinib mimics 6 by hybridizing bicyclic pyridinol 4 as a key scaffold and pyrrole-2-carbaldehydes 7 as side chains. Cytotoxicity assays showed that compounds 6 have comparable to better anticancer activity than sunitinib against five different cancer cell lines. In addition, compounds 6 showed even lower levels of cytotoxicity against normal cells, resulting in up to 26-fold better safety windows, than sunitinib. Signaling pathway-associated transcription factor reporter assay and western blot analyses revealed that apoptosis induction in MDA-MB-231 human breast cancer cells by 6F is mainly mediated through the p53 increase and down-regulation of phospho-signal transducer and activator of transcription 3 (STAT3) and its target gene products, cyclin D, Bcl-2, and survivin. The data strongly suggest that our hybrid compounds can provide a novel anticancer scaffold with improved and safer cytotoxicity profiles than sunitinib.

Natural, semisynthetic and synthetic tyrosinase inhibitors.

Tyrosinase plays a pivotal role in the synthesis of melanin pigment synthesis on skin utilizing tyrosine as a substrate. Melanin is responsible for the protection against harmful ultraviolet irradiation, which can cause significant pathological conditions, such as skin cancers. However, it can also create esthetic problems when accumulated as hyperpigmented spots. Various skin-whitening ingredients which inhibit tyrosinase activity have been identified. Some of them, especially ones with natural product origins, possess phenolic moiety and have been employed in cosmetic products. Semi-synthetic and synthetic inhibitors have also been developed under inspiration of the natural inhibitors yet some of which have no phenolic groups. In this review, tyrosinase inhibitors with natural, semi-synthetic and synthetic origins are listed up with their structures, activities and characteristics. Further, a recent report on the adverse effect of a natural melanin synthesis inhibitor which was included in skin-whitening cosmetics is also briefly discussed.

Estimated daily intake of phenolics and antioxidants from green tea consumption in the Korean diet.

To estimate daily intake of total phenolics and flavonoids from green tea and the contribution of green tea to the antioxidant intake from the Korean diet, 24 commercial brands of green tea were selected and analyzed. Data from the Korea National Health and Nutrition Examination Survey (KNHANES) from 2008 and 2011 indicate that the green tea consumption in these 2 years was 2.8 g/tea drinker/day and 2.9 g/tea drinker/day, respectively. Based on data derived from direct measurements of green tea phenolics and the dataset of the 2008 KNHANES, we estimated the daily per tea drinker phenolics intake to be 172 mg gallic acid equivalents (GAE), the total flavonoids to be 43 mg catechin equivalents (CE) and the total antioxidants to be 267 mg vitamin C equivalents (VCE; 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay) and 401 mg VCE (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) assay). In 2011, we estimated the daily per tea drinker total phenolics intake to be 246 mg GAE, the total flavonoids to be 60 mg CE and the antioxidants to be 448 mg VCE (DPPH assay) and 630 mg VCE (ABTS assay). The daily intake of total phenolics, total flavonoids and antioxidants from green tea consumption increased from 2008 to 2011.

Retraction: Lee, D.-S. et al. The Aminopyridinol Derivative BJ-1201 Protects Murine Hippocampal Cells against Glutamate-Induced Neurotoxicity via Heme Oxygenase-1. Molecules 2016, 21, 594.

n/a.