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It has been hypothesized that consumption of citrus, a group of foods particularly rich in a class of photoactive compounds known as furocoumarins, may increase the risk of malignant melanoma. However, this hypothesis has not been rigorously studied in a general sample of US men and women. This study examined the relationship between citrus intake and melanoma risk in subjects of the NIH-AARP Diet and Health Study. Among 388,467 adults, 3,894 melanoma cases were identified during a median follow-up of 15.5 years. After adjustment for relevant potential confounders, total citrus consumption was not significantly associated with melanoma risk in this cohort. Among those with higher estimated exposure to ultraviolet radiation, and among those aged 60+ years at baseline, there were significant trends toward increased melanoma risk associated with whole citrus fruit consumption ( P trends = 0.01 and 0.02, respectively), but the hazard ratios of the top consumers (2+ cups per week) vs. nonconsumers were nonsignificant. Further research is needed to explore associations of citrus with melanoma risk among older adults and those with high sun exposure.

Due to deleterious side effects of currently available medications, the search for novel, safe, and effective preventive agents for improving bone health in aging continues and is urgently needed. This study aimed to determine whether dietary blackcurrants (BC), an anthocyanin-rich berry, can improve bone mass in a mouse model of age-related bone loss. Thirty-five female C57BL/6J mice, 3 months old ( n = 20) and 18 months old ( n = 15), were randomized to consume either a standard chow diet or a standard chow diet with 1% ( w / w ) BC for four months. Dual-energy X-ray absorptiometry, Micro computed tomography (µCT), and histomorphometric analyses were conducted to assess bone parameters on femurs. Biochemical assays were conducted to determine bone resorption, antioxidant activity, and inflammation in humerus homogenates. Trabecular bone volume (BV/TV) was significantly lower in aged mice compared to young mice (young control, 3.7 ± 0.4% vs aged control, 1.5 ± 0.5%, mean ± SEM (standard error of mean), p < 0.01; young BC, 5.3 ± 0.6% vs aged BC, 1.1 ± 0.3%, p < 0.001). µCT analysis revealed that BC supplementation increased trabecular BV/TV in young mice by 43.2% ( p < 0.05) compared to controls. Histomorphometric analysis revealed a 50% increase, though this effect was not statistically significant ( p = 0.07). The osteoblast surface increased by 82.5% in aged mice with BC compared to controls ( p < 0.01). In humerus homogenates of young mice, BC consumption reduced C-telopeptide of type I collagen by 12.4% ( p < 0.05) and increased glutathione peroxidase by 96.4% ( p < 0.05). In humerus homogenates of aged mice, BC consumption increased catalase by 12% ( p = 0.09). Aged mice had significantly elevated concentrations of tumor necrosis factor α (TNF-α), a pro-inflammatory cytokine contributing to bone resorption, which was reduced by 43.3% with BC consumption ( p = 0.06). These results suggest that early consumption of BC may protect from aging-associated bone loss.

Preclinical Research & Development MR1704 is a selective G protein-coupled receptor 40/free fatty acid receptor 1 agonist, which exhibited favorable pharmacokinetic profiles and glucose-lowering effects in animal models. We studied the effects of MR1704 in a sulfonylurea-desensitized Sprague-Dawley rat model and evaluated the risk of pancreatic β-cell exhaustion compared to that of glibenclamide in Zucker fatty rats. Rats fed ad libitum a diet containing 0.03% glibenclamide exhibited lower non-fasting blood glucose levels compared to those in rats fed a control diet during the first 6 days. However, the response to glibenclamide disappeared on day 9. In a rat oral glucose tolerance test (OGTT), MR1704 reduced the plasma glucose excursion, whereas glibenclamide did not show this effect. In Zucker fatty rats, oral administration of MR1704 reduced glucose excursion during the OGTT, and the effects of MR1704 were maintained after 2-week treatment. In contrast, the glucose-lowering effects of glibenclamide were diminished, and glucose tolerance was aggravated after 2-week treatment. These results indicated that MR1704 provided more sustainable effects compared to those of the sulfonylurea, glibenclamide suggesting that MR1704 may be an attractive therapeutic option for diabetic patients who are unresponsive to sulfonylurea treatment., (© 2017 Wiley Periodicals, Inc.)

Activation of G protein-coupled receptor 40/Free fatty acid receptor 1 (GPR40/FFAR1), which is highly expressed in pancreatic β cells, is considered an important pharmacologic target for the treatment of type 2 diabetes mellitus. The aim of this study was to determine the effect of MR1704, a novel GPR40/FFAR1 agonist, on glucose homeostasis in rats. MR1704 is a highly potent and selective, orally bioavailable agonist with similar in vitro potencies among humans, mice, and rats. Treatment of rat islets with MR1704 increased glucose-dependent insulin secretion. Augmentation of glucose-dependent insulin secretion was abolished by adding a GPR40/FFAR1 antagonist. In mouse, insulinoma MIN6 cells, palmitic acid induced the activity of caspase 3/7 after a 72-h exposure, while pharmacologically active concentrations of MR1704 did not. In an oral glucose tolerance test in normal Sprague-Dawley rats, orally administered MR1704 (1-10 mg·kg -1 ) reduced plasma glucose excursion and enhanced insulin secretion, but MR1704 did not induce hypoglycemia, even at 300 mg·kg -1 , in fasted Sprague-Dawley rats. In addition, orally administered MR1704 reduced plasma glucose excursion and enhanced insulin secretion in diabetic Goto-Kakizaki rats. Oral administration of MR1704 once daily to Goto-Kakizaki rats reduced their blood glucose levels during a 5-week treatment period without reducing pancreatic insulin content; as a result, hemoglobin A1C levels significantly decreased. These results suggest that MR1704 improves glucose homeostasis through glucose-dependent insulin secretion with a low risk of hypoglycemia and pancreatic toxicity. MR1704 shows promise as a new, glucose-lowering drug to treat type 2 diabetes mellitus., (© 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Objective: Investigation was conducted to understand the mechanism of action of diacylglycerol acyltransferase 1 (DGAT1) using small molecules DGAT1 inhibitors, compounds K and L., Design and Methods: Biochemical and stable-label tracer approaches were applied to interrogate the functional activities of compounds K and L on TG synthesis and changes of carbon flow. Energy homeostasis and gut peptide release upon DGAT1 inhibition was conducted in mouse and dog models., Results: Compounds K and L, dose-dependently inhibits post-prandial TG excursion in mouse and dog models. Weight loss studies in WT and Dgat1(-/-) mice, confirmed that the effects of compound K on body weight loss is mechanism-based. Compounds K and L altered incretin peptide release following oral fat challenge. Immunohistochemical studies with intestinal tissues demonstrate lack of detectable DGAT1 immunoreactivity in enteroendocrine cells. Furthermore, (13) C-fatty acid tracing studies indicate that compound K inhibition of DGAT1 increased the production of phosphatidyl choline (PC)., Conclusion: Treatment with DGAT1 inhibitors improves lipid metabolism and body weight. DGAT1 inhibition leads to enhanced PC production via alternative carbon channeling. Immunohistological studies suggest that DGAT1 inhibitor's effects on plasma gut peptide levels are likely via an indirect mechanism. Overall these data indicate a translational potential towards the clinic., (Copyright © 2012 The Obesity Society.)

We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.

Cathepsin S inhibitors are well-known to be an attractive target as immunological therapeutic agents. Recently, our gene expression analysis identified that cathepsin S inhibitors could also be effective for neuropathic pain. Herein, we describe the efficacy of selective cathepsin S inhibitors as antihyperalgesics in a model of neuropathic pain in rats after oral administration.

We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine.

Nonpeptidic, selective, and potent cathepsin S inhibitors were derived from an in-house pyrrolopyrimidine cathepsin K inhibitor by modification of the P2 and P3 moieties. The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats.

Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core intermediate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11-20.

Synthesis and structure-activity relationship of RXR antagonists employing a diazepinylbenzoic acid scaffold are described. Of those antagonists, sulfonamide derivatives (6v and 6w) reveal a high antagonistic activity and good pharmacokinetic properties.

A series of diazepinylbenzoic acid derivatives were synthesized and tested in the inhibition assay of the transactivation of RXR. Oral treatment of cyano derivatives (16f) was found to show anti-diabetic and anti-obesity effects in KK-A(y) mice.