Differences in the response of Sprague-Dawley and Lewis rats to bezafibrate: The hypolipidemic effect and the induction of peroxisomal enzymes

The effects of bezafibrate administered at 10 and 50 mg/kg/day for 7 days to male Sprague-Dawley (SD) and Lewis rats were investigated in order to determine the interrelation between the changes in serum and hepatic lipid contents and activities of selected peroxisomal, microsomal and mitochondrial enzymes in the two rat strains. In both strains, bezafibrate effectively reduced serum and hepatic lipids, increased the liver weight, induced a proliferation of peroxisomes, and selectively elevated the activities of carnitine acetyltransferase and of the enzymes of the peroxisomal -oxidation system. Moreover, immunoblotting revealed that the drug specifically enhanced the concentration of only those peroxisomal enzymes involved in fatty acid -oxidation. The data obtained demonstrate that although the responses initiated by bezafibrate are qualitatively similar in both strains, they differ in their magnitude in a dose-dependent manner, with the Lewis strain exhibiting a more pronounced response than the SD rats. These results show that dose-dependent strain differences as well as the generally known species differences should be taken into account in pharmacological and toxicological evaluations of fibrates in rodents. Furthermore, generalization and extrapolation from rodent studies should be treated with great caution.     

Dietary intake of fish, ω‐3 and ω‐6 fatty acids and risk of colorectal cancer: A prospective study in U.S. men and women

The association between fish, ω‐3 and ω‐6 polyunsaturated fatty acid (PUFA) intake and risk of colorectal cancer (CRC) remains inconclusive. Recent prospective studies suggest that the relationship may vary by gender, subsite and duration of follow‐up. We followed 123,529 US adults (76,386 women and 47,143 men) without a history of cancer at baseline for 24 to 26 years. Fish and PUFA intake was assessed at baseline and updated every 4 years by using a validated food‐frequency questionnaire. We found no overall association between fish, ω‐3 and ω‐6 PUFA intake and CRC risk with hazard ratio (HR) of 1.03 [95% confidence interval (CI): 0.89–1.20] comparing marine ω‐3 intake of ≥0.30 g/d versus <0.15 g/d among women and 1.05 (95% CI: 0.85–1.30) comparing intake of ≥0.41 g/d versus <0.16 g/d among men. However, fish and marine ω‐3 PUFA intake appeared to be positively associated with risk of distal colon cancer in both men and women and inversely with risk of rectal cancer in men. In an analysis based on a limited number of cases, marine ω‐3 PUFA intake assessed 12–16 years before diagnosis tended to be inversely associated with CRC risk in men (HR: 0.76; 95% CI: 0.52–1.10). In conclusion, although no overall association between fish, ω‐3 or ω‐6 PUFA intake was observed with CRC risk, marine ω‐3 PUFA may be differentially associated with risk of distal colon and rectal cancers and a long latency may be needed for its protection against CRC in men.     

Enhanced antitumor effect of targeted nanoliposomal bleomycin

Folate receptor (FR)‐mediated drug delivery is a promising approach for active targeting of drugs to the FR‐positive tumor cells. Bleomycin (BLM) is an antitumor antibiotic with poor therapeutic activity as a result of its limited diffusion into tumor cells. The aim of this study was to investigate whether FR‐targeted PEGylated nanoliposomes (FPNL) can effectively deliver BLM to tumor cells and enhance its in vitro and in vivo efficacy. FPNL and PNL (non‐targeted) were prepared by thin film hydration method, and their physiochemical properties, cellular uptake, tissue distribution and tumor inhibitory effects were investigated. In Lewis lung cancer (LLC1) cells, FPNL containing BLM showed 2.38‐fold and 3.26‐fold higher cytotoxicity compared to PNL‐BLM and free BLM, respectively. Moreover, the uptake of FPNL by these cells was increased as compared to the PNL. Furthermore, FPNL showed significantly higher tumor distribution of BLM in the LLC1 cells and more tumor inhibition efficacy compared to free BLM and PNL. Both formulations of nanoliposomes had longer plasma half‐life than that of free BLM. Therefore, FPNL may be suitable carriers for targeted drug delivery to FR‐positive tumor cells.     

Inhibitory effect of Crocus sativus L. ethanol extract on adjuvant-induced arthritis

Saffron is a well-known spice produced from dried stigmas of Crocus sativus L. flowers. Apart from its wide use in food preparations, it also has a broad range of medical properties. We examined the potential anti-inflammatory effects of saffron ethanolic extract (SEE) using an animal model of arthritis. Adjuvant-induced arthritis was induced in Wistar rats by injection of Complete Freund's Adjuvant. The rats were then injected intraperitoneally every other day with 25–600 mg SEE/kg or dexamethasone (DEX, 2 mg/kg). Changes in body weight, paw oedema and arthritis indices were recorded over the subsequent 12 days of treatment. Results revealed that SEE particularly at the higher concentrations significantly reduced paw and tibiotarsal joint diameters and comparing with DEX caused no significant change in body weight. These observations suggest that SEE displays a considerable anti-inflammatory potency and could potentially be used as an anti-arthritic agent in control of inflammation in rheumatoid arthritis.     

Deconvolution analysis of rapid insulin pulses before and after six weeks of continuous subcutaneous administration of glucagon-like peptide-1 in elderly patients with type 2 diabetes

CONTEXT: Insulin is secreted in a pulsatile fashion with measurable orderliness (low entropy). Normal aging and diabetes in middle-aged patients is characterized by alterations in pulsatile insulin release. OBJECTIVES: We undertook the current studies to determine whether disruptions in pulsatile insulin release also accompany diabetes in the elderly. DESIGN: Two studies were performed. In the first study, insulin values were sampled every minute for 1 h under fasting conditions. In the second study, subjects underwent a 2-h hyperglycemic glucose clamp (glucose 5.4 mm above basal). From 60-120 min, insulin was sampled every 1 min. Secretory pulse analysis was conducted using a multiparameter deconvolution technique. SETTING: The study was conducted in a general clinical research center and during outpatient visits. PATIENTS: Volunteers were healthy young [n = 10; body mass index (BMI), 23 +/- 1 kg/m2; age, 23 +/- 1 yr] and elderly (n = 10; BMI, 24 +/- 1 kg/m2; age, 78 +/- 2 yr) volunteers and elderly patients with diabetes (n = 8; BMI, 28 +/- 1 kg/m2; age, 73 +/- 2 yr). Intervention: Five of the older patients with type 2 diabetes (BMI, 29 +/- 1 kg/m2; age, 72 +/- 2 yr) were treated with continuous sc glucagon-like peptide-1 (GLP-1) (7-36) amide infusion for 6 wk, and a second 2-h hyperglycemic clamp was performed. MAIN OUTCOME MEASURES: Insulin burst mass, pulsatile insulin secretion, and entropy were measured. RESULTS: Under fasting conditions, elderly patients with diabetes had a reduction in insulin burst mass (P < 0.05) that was similar to normal elderly. During hyperglycemia, elderly patients with diabetes had an even greater impairment in insulin burst mass (P < 0.05) and basal (P < 0.05) and pulsatile insulin secretion (P < 0.05) than normal elderly. Approximate entropy, a measure of irregularity of insulin release, was increased to a greater extent in older diabetes patients than normal elderly, signifying loss of orderliness of insulin secretion (P < 0.05). In response to treatment with GLP-1, insulin burst mass (P < 0.05) and pulsatile insulin secretion (P < 0.05) improved significantly in elderly patients with diabetes. CONCLUSIONS: We conclude that alterations in pulsatile insulin release can be improved in elderly patients with diabetes by the administration of sc GLP-1.