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The inhibition of soluble epoxide hydrolase (sEH) can reduce the level of dihydroxyeicosatrienoic acids (DHETs) effectively maintaining endogenous epoxyeicosatrienoic acids (EETs) levels, resulting in the amelioration of inflammation and pain. Consequently, the development of sEH inhibitors has been a prominent research area for over two decades. In the present study, we synthesized and evaluated sulfonyl urea derivatives for their potential to inhibit sEH. These compounds underwent extensive in vitro investigation, revealing their potency against human and mouse sEH, with 4f showing the most promising sEH inhibitory potential. When subjected to lipopolysaccharide (LPS)-induced acute lung injury (ALI) in studies in mice, compound 4f manifested promising antiinflammatory efficacy. We investigated the analgesic efficacy of sEH inhibitor 4f in a murine pain model of tail-flick reflex. These results validate the role of sEH inhibition in inflammatory diseases and pave the way for the rational design and optimization of sEH inhibitors based on a sulfonyl urea template. [ABSTRACT FROM AUTHOR]

Nymphoides indica, an aquatic plant, is used as folk medicine in some countries. Our previous study demonstrated that the methanol extract of N. indica inhibited the activity of tyrosinases, tyrosine related protein (TRP)1 and TRP2, and microphthalmia-associated transcription factor, as well as the activity of protein kinase A, by effectively inhibiting cyclic adenosine monophosphate. Although the biological activities of N. indica extract have been reported, there are no reports on the skin bioactivity of the main compound(s) on human keratinocytes. This study investigated the anti-inflammatory and moisturizing effects of quercetin 3,7-dimethyl ether 4'-glucoside (QDG) isolated from N. indica. In brief, ultraviolet B irradiated keratinocytes were pretreated with different concentrations of QDG, and the effects of QDG on various inflammatory markers were determined. QDG significantly inhibited inflammation-related cytokines and chemokines and enhanced the activation of skin barrier factors. Additionally, QDG also attenuated phosphorylation inhibition of the upstream cytokines and nuclear factor-κB expression. These results suggest that QDG isolated from N. indica may serve as a potential source of bioactive substances for chronic inflammatory skin diseases. [ABSTRACT FROM AUTHOR]

Antioxidants are suggested to decrease risk of type 2 diabetes (T2D) by preventing progressive impairment of pancreatic β-cell and endothelial function. This study was aimed to investigate the association between dietary antioxidants and risk of T2D in Korean adults based on a national representative data. A total of 24,377 adults (19-74 years) who completed one-day 24 h dietary recall and health examination were included. Dietary antioxidant intakes including α-carotene (p < 0.0001), lycopene (p = 0.0107), flavan-3-ols (p < 0.0001), and proanthocyanidins (p = 0.0075) were significantly higher in non-diabetic subjects than in diabetic subjects. After adjusting for confounding variables, the highest quartile group of α-carotene intake was associated with a 48% reduced risk of T2D in men (OR: 0.52, 95% CI: 0.34-0.80, p for trend = 0.0037) and a 39% reduced risk in women (OR: 0.61, 95% CI: 0.38-0.996, p for trend = 0.0377) compared to the lowest quartile group. Men in the highest quartile of β-carotene intake showed lower risk of T2D (OR: 0.64, 95% CI: 0.42-0.97), but no significant decreasing trend. However, the intakes of total carotenoids and other antioxidants showed no significant association with the risk of T2D. These findings suggest that a further comprehensive approach which considers overall dietary pattern is required. [ABSTRACT FROM AUTHOR]

The search for natural inhibitors with anti-diabetes properties has gained increasing attention. Among four selected Smilacaceae family plants, Smilax china L. stems (SCS) showed significant in vitro anti-glycation and rat lens aldose reductase inhibitory activities. Bioactivity-guided isolation was performed with SCS and four solvent fractions were obtained, which in turn yielded 10 compounds, including one phenolic acid, three chlorogenic acids, four flavonoids, one stilbene, and one phenylpropanoid glycoside; their structures were elucidated using nuclear magnetic resonance and mass spectrometry. All solvent fractions, isolated compounds, and stem extracts from plants sourced from six different provinces of South Korea were next tested for their inhibitory effects against advanced glycation end products, as well as aldose reductase. α-Glucosidase, and lipase assays were also performed on the fractions and compounds. Since compounds 3, 4, 6, and 8 appeared to be the superior inhibitors among the tested compounds, a comparative study was performed via high-performance liquid chromatography with photodiode array detection using a self-developed analysis method to confirm the relationship between the quantity and bioactivity of the compounds in each extract. The findings of this study demonstrate the potent therapeutic efficacy of SCS and its potential use as a cost-effective natural alternative medicine against type 2 diabetes and its complications. [ABSTRACT FROM AUTHOR]

A new phenolic glucoside, isoconiferoside (1), was isolated from the seeds of Panax ginseng (Araliaceae). The structure was determined to be 9-O-[β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyl]-trans-coniferyl alcohol based on spectroscopic analyses (1H- and 13C-NMR, DEPT, COSY, HMQC, and HMBC) and acid hydrolysis. [ABSTRACT FROM AUTHOR]

The inhibition of soluble epoxide hydrolase (sEH) can reduce the level of dihydroxyeicosatrienoic acids (DHETs) effectively maintaining endogenous epoxyeicosatrienoic acids (EETs) levels, resulting in the amelioration of inflammation and pain. Consequently, the development of sEH inhibitors has been a prominent research area for over two decades. In the present study, we synthesized and evaluated sulfonyl urea derivatives for their potential to inhibit sEH. These compounds underwent extensive in vitro investigation, revealing their potency against human and mouse sEH, with 4f showing the most promising sEH inhibitory potential. When subjected to lipopolysaccharide (LPS)-induced acute lung injury (ALI) in studies in mice, compound 4f manifested promising anti-inflammatory efficacy. We investigated the analgesic efficacy of sEH inhibitor 4f in a murine pain model of tail-flick reflex. These results validate the role of sEH inhibition in inflammatory diseases and pave the way for the rational design and optimization of sEH inhibitors based on a sulfonyl urea template.

A catalyst-free, additive-free, and eco-friendly method for synthesizing 1,2,4-triazolo[1,5-a]pyridines under microwave conditions has been established. This tandem reaction involves the use of enaminonitriles and benzohydrazides, a transamidation mechanism followed by nucleophilic addition with nitrile, and subsequent condensation to yield the target compound in a short reaction time. The methodology demonstrates a broad substrate scope and good functional group tolerance, resulting in the formation of products in good-to-excellent yields. Furthermore, the scale-up reaction and late-stage functionalization of triazolo pyridine further demonstrate its synthetic utility. A plausible reaction pathway, based on our findings, has been proposed.

Liver damage caused by various factors results in fibrosis and inflammation, leading to cirrhosis and cancer. Fibrosis results in the accumulation of extracellular matrix components. The role of STAT proteins in mediating liver inflammation and fibrosis has been well documented; however, approved therapies targeting STAT3 inhibition against liver disease are lacking. This study investigated the anti-fibrotic and anti-inflammatory effects of STAT3 decoy oligodeoxynucleotides (ODN) in hepatocytes and liver fibrosis mouse models. STAT3 decoy ODN were delivered into cells using liposomes and hydrodynamic tail vein injection into 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice in which liver injury was induced. STAT3 target gene expression changes were verified using qPCR and Western blotting. Liver tissue fibrosis and bile duct proliferation were assessed in animal experiments using staining techniques, and macrophage and inflammatory cytokine distribution was verified using immunohistochemistry. STAT3 decoy ODN reduced fibrosis and inflammatory factors in liver cancer cell lines and DDC-induced liver injury mouse model. These results suggest that STAT3 decoy ODN may effectively treat liver fibrosis and must be clinically investigated.

The enzyme tyrosinase plays a key role in the early stages of melanin biosynthesis. This study evaluated the inhibitory activity of anthocyanidin (1) and anthocyanins (2–6) on the catalytic reaction. Of the six derivatives examined, 1–3 showed inhibitory activity with IC50 values of 3.7 ± 0.1, 10.3 ± 1.0, and 41.3 ± 3.2 μM, respectively. Based on enzyme kinetics, 1–3 were confirmed to be competitive inhibitors with Ki values of 2.8, 9.0, and 51.9 μM, respectively. Molecular docking analysis revealed the formation of a binary encounter complex between 1–3 and the tyrosinase catalytic site. Luteolinidin (1) and petunidin 3-O-glucoside (2) may serve as tyrosinase inhibitors to block melanin production.

The solubility of glibenclamide was evaluated in DMSO, NMP, 1,4-dioxane, PEG 400, Transcutol® HP, water, and aqueous mixtures (T = 293.15~323.15 K). It was then recrystallized to solvate and compressed into tablets, of which 30-day stability and dissolution was studied. It had a higher solubility in 1,4-dioxane, DMSO, NMP (Xexp = 2.30 × 103, 3.08 × 104, 2.90 × 104) at 323.15 K, its mixture (Xexp = 1.93 × 103, 1.89 × 104, 1.58 × 104) at 298.15 K, and 1,4-dioxane (w) + water (1−w) mixture ratio of w = 0.8 (Xexp = 3.74 × 103) at 323.15 K. Modified Apelblat (RMSD ≤ 0.519) and CNIBS/R-K model (RMSD ≤ 0.358) suggested good comparability with the experimental solubility. The minimum value of ΔG° vs ΔH° at 0.70 < x2 < 0.80 suggested higher solubility at that molar concentration. Based on the solubility, it was recrystallized into the solvate, which was granulated and compressed into tablets. Among the studied solvates, the tablets of glibenclamide dioxane solvate had a higher initial (95.51%) and 30-day (93.74%) dissolution compared to glibenclamide reference (28.93%). There was no stability issue even after granulation, drying, or at pH 7.4. Thus, glibenclamide dioxane solvate could be an alternative form to improve the molecule’s properties.

LW6, an (aryloxyacetylamino)benzoic acid derivative, was recently identified to be an inhibitor of hypoxia-inducible factor-1α (HIF-1α), which is an attractive target for cancer therapeutics. Although LW6 is known to act by inhibiting the accumulation of HIF-1α, pharmacokinetics needs to be evaluated to assess its potential as an anti-tumor agent. Here, we investigated the plasma pharmacokinetics and metabolism of LW6 in mice. LW6 exhibited a small volume of distribution (0.5 ± 0.1 L/kg), and a short terminal half-life (0.6 ± 0.1 h). Following intravenous or oral administration, LW6 was rapidly converted to its active metabolite, (4-adamantan-1-yl-phenoxy)acetic acid (APA). Although LW6 was rapidly absorbed, its oral bioavailability, estimated using AUClast values, was low (1.7 ± 1.8%). It was slowly degraded in mouse liver microsomes (t1/2 > 1 h) and serum (t1/2 > 6 h). About 54% or 44.8% of LW6 was available systemically as APA in the mouse after a single intravenous or oral administration, respectively. Thus, our results indicated the need to simultaneously consider the active metabolite as well as the parent compound for successful evaluation during lead optimization.

A novel HIF (hypoxia-inducible factor)-1α inhibitor, the (aryloxyacetylamino)benzoic acid derivative LW6, is an anticancer agent that inhibits the accumulation of HIF-1α. The aim of this study was to characterize and determine the structures of the metabolites of LW6 in ICR mice. Metabolite identification was performed using a predictive multiple reaction monitoring-information dependent acquisition-enhanced product ion (pMRM-IDA-EPI) method in negative ion mode on a hybrid triple quadrupole-linear ion trap mass spectrometer (QTRAP). A total of 12 metabolites were characterized based on their MS/MS spectra, and the retention times were compared with those of the parent compound. The metabolites were divided into five structural classes based on biotransformation reactions: amide hydrolysis, ester hydrolysis, mono-oxidation, glucuronidation, and a combination of these reactions. From this study, 2-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)acetic acid (APA, M7), the metabolite produced via amide hydrolysis, was found to be a major circulating metabolite of LW6 in mice. The results of this study can be used to improve the pharmacokinetic profile by lowering the clearance and increasing the exposure relative to LW6.

The solubility and dissolution thermodynamics of new c-Met inhibitor, ABN401, were determined in eleven solvents and Transcutol® HP–water mixture (TWM) from 298.15 to 318.15 K. The experimental solubilities were validated using five mathematical models, namely modified Apelblat, van’t Hoff, Buchowski–Ksiazaczak λh, Yalkowsky, and Jouyban–Acree van’t Hoff models. The experimental results were correlated and utilized further to investigate the feasibility of nanosuspension formation using liquid anti-solvent precipitation. Thermodynamic solubility of ABN401 increased significantly with the increase in temperature and maximum solubility was obtained with Transcutol® HP while low solubility in was obtained water. An activity coefficient study indicated that high molecular interaction was observed in ABN401–Transcutol® HP (THP). The solubility increased proportionately as the mole fraction of Transcutol® HP increased in TWM, which was also supported by a solvent effect study. The result suggested endothermic and entropy-driven dissolution. Based on the solubility, nanosuspension was designed with Transcutol® HP as solvent, and water as anti-solvent. The mean particle size of nanosuspension decreased to 43.05 nm when the mole fraction of ABN401 in THP, and mole fraction of ABN401 in TWM mixture were decreased to 0.04 and 0.1. The ultrasonicated nanosuspension appeared to give comparatively higher dissolution than micronized nanosuspension and provide a candidate formulation for in vivo purposes.

Patrinia villosa (Thunb.) Juss is a traditional herb commonly used in East Asia including Korea, Japan, and China. It has been administered to reduce and treat inflammation in Donguibogam, Korea. The mechanism for its anti-inflammatory effects has already been reported. In this study, we confirmed the efficacy of Patrinia villosa (Thunb.) Juss ethanol extract (Pv-EE) for inducing autophagy and investigate its anti-melanogenic properties. Melanin secretion and content were investigated using cells from the melanoma cell line B16F10. Pv-EE inhibited melanin in melanogenesis induced by α-melanocyte-stimulating hormone (α-MSH). The mechanism of inhibition of Pv-EE was confirmed by suppressing the mRNA of microphthalmia-associated transcription factor (MITF), decreasing the phosphorylation level of CREB, and increasing the phosphorylation of ERK. Finally, it was confirmed that Pv-EE induces autophagy through the autophagy markers LC3B and p62, and that the anti-melanogenic effect of Pv-EE is inhibited by the autophagy inhibitor 3-methyl adenine (3-MA). These results suggest that Pv-EE may be used as a skin protectant due to its anti-melanin properties including autophagy.