Dietary supplement of tomato can accelerate urinary aMT6s level and improve sleep quality in obese postmenopausal women.

The aim of this study was to investigate the effect of the ingestion of tomato before bed on obese postmenopausal women's urinary 6-sulphatoxymelatonin (aMT6s) level and sleep quality. We quantified melatonin concentrations in beefsteak tomato, black tomato, and two commercial tomato juices and found that beefsteak tomato contained the highest level of melatonin. In this 8-week open-label, randomized controlled dietary intervention trial, 36 subjects completed the entire trial. The tomato group ate 250 g of beefsteak tomatoes 2 h before sleep for 8 weeks. Blood and urine samples were collected at the baseline and in the 8th week and were analyzed. The Pittsburgh Sleep Quality Index (PSQI) in the tomato group significantly decreased with time (p for trend = 0.0297). After 8 weeks of the beefsteak intervention, all components of the PSQI in tomato group had significantly improved, and their aMT6s level was 10-fold significantly higher than that of the control group. Therefore, supplementation with beefsteak tomato before sleep can increase circulating melatonin and improve sleep quality in obese postmenopausal women.

A novel finding of nalbuphine-6-glucuronide, an active opiate metabolite, possessing potent antinociceptive effects: Synthesis and biological evaluation.

Nalbuphine, a partial agonist/antagonist opioid analgesic, is structurally related to morphine. It is equipotent to morphine and has no serious side effects. In the past few decades, studies focusing on morphine metabolism have indicated that one of its sugar-conjugated metabolites, morphine-6-glucuronide, exerts a higher analgesic effect than its parent drug. Considering that nalbuphine is a morphine analog that follows a similar metabolic scheme, nalbuphine glucuronides were synthesized in this study and their potential analgesic effects were assessed. Nalbuphine-3-glucuronide (N3G) and nalbuphine-6-glucuronide (N6G) were synthesized based on Schmidt's glycosylation with OPiv protections on the glycosyl donor. In a pharmacodynamic study, paw pressure and cold-ethanol tail-flick tests were conducted in rats to evaluate the analgesic response after intracisternal and intraperitoneal administrations of nalbuphine, N3G, or N6G. The antinociceptive response was evaluated for each compound by calculating the area under the curve and the duration spent at greater than 50% maximum possible analgesia. In conclusion, intracisternal administration of N6G exhibited a stronger analgesic response than nalbuphine in the pain tests after both cold and mechanical stimuli, but N3G had no obvious effect. Similar to that of morphine, the glucuronide metabolite of nalbuphine at the 6-O-position exerted at least three-fold higher antinociceptive potency and five-fold longer analgesic duration than nalbuphine.

Melatonin Improves Fatty Liver Syndrome by Inhibiting the Lipogenesis Pathway in Hamsters with High-Fat Diet-Induced Hyperlipidemia.

The aim of this study was to investigate the effect of melatonin on hepatic lipid metabolism in hamsters with high-fat diet (HFD)-induced dyslipidemia. Male Syrian hamsters were kept on either a chow control (C) or HFD for four weeks. After four weeks, animals fed the HFD were further randomly assigned to four groups: high-fat only (P), melatonin low-dosage (L), medium-dosage (M), and high-dosage (H) groups. The L, M, and H groups, respectively, received 10, 20, and 50 mg/kg/day of a melatonin solution, while the P and C groups received the ethanol vehicle. After eight weeks of the intervention, results showed that a low dose of melatonin significantly reduced HFD-induced hepatic cholesterol and triglycerides; decreased plasma cholesterol, triglycerides, and low-density lipoprotein cholesterol; and increased plasma high-density lipoprotein cholesterol (p < 0.05). In addition, melatonin markedly decreased activities of the hepatic lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) (p < 0.05), and elevated the relative hepatic carnitine palmitoyltransferase-1α expression in hamsters with HFD-induced hyperlipidemia. Consequently, melatonin reduced activities of the hepatic lipogenic enzymes, ACC and FAS. In summary, chronic melatonin administration improved HFD-induced dyslipidemia and hepatic lipid accumulation in Syrian hamsters with HFD-induced dyslipidemia, which might have occurred through inhibiting the lipogenesis pathway.

Structural optimization and evaluation of novel 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole derivatives as potential VEGFR-2/PDGFRß inhibitors.

BACKGROUND: Tumor angiogenesis, essential for tumor growth and metastasis, is tightly regulated by VEGF/VEGFR and PDGF/PDGFR pathways, and therefore blocking those pathways is a promising therapeutic target. Compared to sunitinib, the C(5)-Br derivative of 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole has significantly greater in vitro activities against VEGFR-2, PDGFRß, and tube formation. RESULTS AND DISCUSSION: The objective of this study was to perform further structural optimization, which revealed certain new products with even more potent anti-tumor activities, both cellularly and enzymatically. Of these, 15 revealed ten- and eightfold stronger potencies against VEGFR-2 and PDGFRß than sunitinib, respectively, and showed selectivity against HCT116 with a favorable selective index (SI > 4.27). The molecular docking results displayed that the ligand-protein binding affinity to VEGFR-2 could be enhanced by introducing a hydrogen-bond-donating (HBD) substituent at C(5) of (2-oxoindolin-3-ylidene)methylpyrrole such as 14 (C(5)-OH) and 15 (C(5)-SH). CONCLUSIONS: Among newly synthetic compounds, 7 and 13-15 exhibited significant inhibitory activities against VEGFR-2 and PDGFRß. Of these, the experimental results suggest that 15 might be a promising anti-proliferative agent. Graphical abstract IC50 comparison of sunitinib, 14, and 15 against VEGFR-2 and PDGFRß.

Synthesis and Evaluation of Novel 2-Pyrrolidone-Fused (2-Oxoindolin-3-ylidene)methylpyrrole Derivatives as Potential Multi-Target Tyrosine Kinase Receptor Inhibitors.

Signaling pathways of VEGFs and PDGFs are crucial in tumor angiogenesis, which is essential in solid tumor progression and metastasis. This study reports our strategy for designing and synthesizing a series of novel 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole derivatives as potential multi-target tyrosine kinase receptor inhibitors. The target compounds were obtained by condensation of 5-substituted oxindoles with N-substituted 2-pyrrolidone aldehyde 7 in satisfactory yields. Of these, 11 and 12 had the highest potency and, compared to sunitinib, showed: (1) significant increase in anti-proliferation of various cancer cells with a favorable selective index (SI); (2) higher inhibitory potency against both VEGFR-2 and PDGFRß. The molecular modeling results showed that, in terms of VEGFR-2 binding, the synthesized products had a similar binding mode to sunitinib but with tighter interaction.