The Effect of Carbohydrate Restriction on Lipids, Lipoproteins, and Nuclear Magnetic Resonance-Based Metabolites: CALIBER, a Randomised Parallel Trial.

Low-carbohydrate high-fat (LCHF) diets can be just as effective as high-carbohydrate, lower-fat (HCLF) diets for improving cardiovascular disease risk markers. Few studies have compared the effects of the UK HCLF dietary guidelines with an LCHF diet on lipids and lipoprotein metabolism using high-throughput NMR spectroscopy. This study aimed to explore the effect of an ad libitum 8-week LCHF diet compared to an HCLF diet on lipids and lipoprotein metabolism and CVD risk factors. For 8 weeks, n = 16 adults were randomly assigned to follow either an LCHF (n = 8, <50 g CHO p/day) or an HCLF diet (n = 8). Fasted blood samples at weeks 0, 4, and 8 were collected and analysed for lipids, lipoprotein subclasses, and energy-related metabolism markers via NMR spectroscopy. The LCHF diet increased (p < 0.05) very small VLDL, IDL, and large HDL cholesterol levels, whereas the HCLF diet increased (p < 0.05) IDL and large LDL cholesterol levels. Following the LCHF diet alone, triglycerides in VLDL and HDL lipoproteins significantly (p < 0.05) decreased, and HDL phospholipids significantly (p < 0.05) increased. Furthermore, the LCHF diet significantly (p < 0.05) increased the large and small HDL particle concentrations compared to the HCLF diet. In conclusion, the LCHF diet may reduce CVD risk factors by reducing triglyceride-rich lipoproteins and improving HDL functionality.

Omega-3 fatty acids - A review of existing and innovative delivery methods.

Omega-3 fatty acids are generally under-consumed in Western diets; a factor that may largely be attributed to low intake of oily fish. Although supplementation strategies offer one approach in terms of improving blood fatty acid levels, rates of compliance are generally low due to difficulties in swallowing capsules, or unfavorable aftertastes. Consequently, new approaches, including food-based strategies, may be an alternative approach to improving omega-3 status and the health of public sectors. This paper sets out to discuss and review how the use of novel food vehicle and delivery advancements may be used to improve omega-3 status, which may have wider benefits for public health and well-being.

Cytotoxic constituents of the roots of Ekmanianthe longiflora.

Bioactivity-directed fractionation of the CHCl(3) extract of the roots of Ekmanianthe longiflora resulted in the isolation of three new natural products, (2R,3R,4R)-3,4-dihydro-3, 4-dihydroxy-2-(3-methyl-2-butenyl)-1(2H)-naphthalenone (1), (2S,3R, 4R)-3,4-dihydro-3, 4-dihydroxy-2-(3-methyl-2-butenyl)-1(2H)-naphthalenone (2), and (2R, 3aR,9R,9aR)-9-hydroxy-2-(1-hydroxy-1-methylethyl)-2,3,3a,4,9 , 9a-hexahydro-naphtho[2,3-b]furan-4-one (3), together with the known compounds 2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-quinone (4), 2-acetylnaphtho[2,3-b]furan-4,9-quinone (5), dehydro-iso-alpha-lapachone (6), alpha-lapachone (7), catalponol, and epi-catalponol. The structures of 1-3 were determined using a combination of NMR spectroscopic techniques, and the absolute configurations of compounds 1 and 2 were obtained using Mosher ester methodology. Compounds 4-6 showed significant cytotoxicity in a panel of human cancer cells. alpha-Lapachone (7) exhibited only marginal activity, and catalponol and epi-catalponol were inactive in this regard. When tested at 72 mg/kg/injection in an in vivo mouse P-388 leukemia system, compound 4 was inactive (110% T/C).

Cytotoxic sesquiterpenoids from Ratibida columnifera.

Bioassay-directed fractionation of the flowers and leaves of Ratibida columnifera using a hormone-dependent human prostate (LNCaP) cancer cell line led to the isolation of 10 cytotoxic substances, composed of five novel xanthanolide derivatives (2-4, 7, and 8), a novel nerolidol derivative (9), and three known sesquiterpene lactones, 9alpha-hydroxy-seco-ratiferolide-5alpha-O-angelate+ ++ (1), 9alpha-hydroxy-seco-ratiferolide-5alpha-O-(2-methylbut yrate) (5), 9-oxo-seco-ratiferolide-5alpha-O-(2-methylbutyrate) (6), as well as a known flavonoid, hispidulin (10). On the basis of its cytotoxicity profile, compound 5 was selected for further biological evaluation, and was found to induce G1 arrest and slow S traverse time in parental wild type p53 A2780S cells, but only G2/M arrest in p53 mutant A2780R cells, with strong apoptosis shown for both cell lines. The activity of 5 was not mediated by the multidrug resistance (MDR) pump, and it was not active against several anticancer molecular targets (i.e., tubulin polymerization/depolymerization, topoisomerases, and DNA intercalation). While these results indicate that compound 5 acts as a cytotoxic agent via a novel mechanism, this substance was inactive in in vivo evaluations using the murine lung carcinoma (M109) and human colon carcinoma (HCT116) models.

Suppression of testosterone and estradiol-17beta-induced dysplasia in the dorsolateral prostate of Noble rats by bromocriptine.

We, and others, have previously described the histological changes that occur in the prostate gland of intact Noble (NBL) rats following prolonged hormonal treatment. Dysplasia, a pre-neoplastic lesion, develops specifically in the dorsolateral prostates (DLPs) of NBL rats treated for 16 weeks with a combined regimen of testosterone (T) and estradiol-17beta (E2) (T + E2-treated rats). Concurrent with DLP dysplasia induction, the dual hormone regimen also elicits hyperprolactinemia, in addition to an elevation of nuclear type II estrogen binding sites (type II EBS), no alteration in estrogen receptors (ER), and marked epithelial cell proliferation in the dysplastic foci. The aim of this study was to investigate whether the dual hormone action is mediated via E2-induced hyperprolactinemia. Bromocriptine (Br), at a dose of 4 mg/kg body wt per day, was used to suppress pituitary prolactin (PRL) release. Serum PRL levels were lowered from values of 341 +/- 50 ng/ml in T + E2-treated rats to 32 +/- 10 ng/ml in Br co-treated animals. The latter values were comparable to those in untreated control rats. In addition, Br co-treatment effectively inhibited the evolution of dysplasia (six out of eight rats) and the often associated inflammation (five out of eight rats) in most animals. In contrast, Br co-treatment did not suppress the T + E2-induced type II EBS elevation nor alter ER levels in the DLPs of these rats, when compared with T + E2-treated rats. These data extend the many previous studies that have detailed marked influences of PRL on rat prostatic functions. However, the current study is the first to implicate PRL in prostatic dysplasia induction in vivo.

Effect of combined testosterone and estradiol-17 beta treatment on the metabolism of E2 in the prostate and liver of noble rats.

BACKGROUND: Long-term treatment of Noble (NBL) rats with testosterone (T) and estradiol-17 beta (E2) induces dysplasia in the dorsolateral lobe (DLP) but not in the ventral lobe (VP) of the rat prostate. The aim of this study was to determine whether metabolic conversion of E2 to catechol estrogens (CEs), which are potentially genotoxic, is a mechanism of estrogen carcinogenicity in this tissue. METHODS: Male NBL rats were treated simultaneously with T and E2, or left untreated, for 16 weeks after which time the liver, VP, and DLP were excised for microsomal preparations. 3H-E2 metabolites generated in microsomal incubates were separated by high-performance liquid chromatography (HPLC) and identified by coelution with known E2 metabolites. RESULTS: 2- and 4-hydroxyestrogens were detected at high levels in hepatic microsomal incubates, and at extremely low levels in prostatic microsomal incubates. T + E2 treatment of rats did not increase the formation of these prostatic and hepatic metabolites. CONCLUSIONS: These results do not support CE formation as a mediating step in estrogen-induced tumorigenesis in the rat prostate.

Intravenous self-administration of cathinone by rats.

Cathinone is the principal psychoactive constituent in leaves of the khat shrub. In some parts of the world, khat leaves are commonly chewed for their stimulant effects. While it has been demonstrated that rhesus monkeys will self-administer cathinone, there has been no demonstration of cathinone self-administration in rats. Two experiments were therefore conducted on rats fitted with intravenous catheters. On an FR 1 reinforcement schedule, the dose response curve for cathinone was shifted to the left of that for cocaine by a factor of approximately two. Within the sessions, cocaine infusions tended to be spaced evenly, whereas cathinone infusions were generally more frequent in the early portions of the session than later. In a second experiment, pretreatment with the dopamine D1-type receptor antagonist SCH 23390, at 10mg/kg, significantly increased the number of infusions obtained. Pretreatment with the D2-type receptor antagonist spiperone caused only a slight, non-significant increase in cathinone self-administration. These results demonstrate that cathinone is a potent reinforcer in rats and suggest a role for D1-type dopamine receptors in mediating its reinforcing effects.

Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat.

We asked whether the well known starvation-induced impairment of glucose-stimulated insulin secretion (GSIS) seen in isolated rat pancreas preparations also applies in vivo. Accordingly, fed and 18-24-h-fasted rats were subjected to an intravenous glucose challenge followed by a hyperglycemic clamp protocol, during which the plasma-insulin concentration was measured. Surprisingly, the acute (5 min) insulin response was equally robust in the two groups. However, after infusion of the antilipolytic agent, nicotinic acid, to ensure low levels of plasma FFA before the glucose load, GSIS was essentially ablated in fasted rats, but unaffected in fed animals. Maintenance of a high plasma FFA concentration by coadministration of Intralipid plus heparin to nicotinic acid-treated rats (fed or fasted), or further elevation of the endogenous FFA level in nonnicotinic acid-treated fasted animals by infusion of etomoxir (to block hepatic fatty acid oxidation), resulted in supranormal GSIS. The in vivo findings were reproduced in studies with the perfused pancreas from fed and fasted rats in which GSIS was examined in the absence and presence of palmitate. The results establish that in the rat, the high circulating concentration of FFA that accompanies food deprivation is a sine qua non for efficient GSIS when a fast is terminated. They also serve to underscore the powerful interaction between glucose and fatty acids in normal beta cell function and raise the possibility that imbalances between the two fuels in vivo could have pathological consequences.

Intravenous morphine self-administration by rats with low versus high saccharin preferences.

An experiment was performed to determine the relationship between saccharin preference and the self-administration of morphine via the oral and intravenous routes. On the basis of voluntary intake of a saccharin solution by male rats, low and high preference groups were formed. Rats selected for high saccharin preference self-administered more morphine intravenously than rats selected for low preference. The two groups did not differ in oral morphine intake. The positive relationship between the intake of saccharin and intravenous morphine self-administration may be due to their mediation by a common mechanism. Measures of taste sensitivity or preference may be useful in identifying individuals at risk for drug abuse.

Rotational behavior as a classically conditioned response to pentobarbital administration.

Pentobarbital stimulus control of rotational behavior was investigated in rats with unilateral 6-hydroxydopamine lesions of substantia nigra. In conditioning trials, lesioned rats were injected simultaneously with 10 mg/kg pentobarbital and 0.05 mg/kg apomorphine and their rotational (circling) behavior observed and counted. Subsequent to three consecutive daily conditioning sessions, animals were re-introduced to the rotation environment and tested with saline or pentobarbital. Pentobarbital, but not saline, administration was followed by a brief epoch of rapid contralateral rotation. After additional conditioning trials in which pentobarbital and apomorphine administration were paired, test sessions with 1 g/kg ethanol and with 10 mg/kg chlordiazepoxide were conducted. Most animals did not rotate in response to ethanol administration and most did rotate in response to chlordiazepoxide. Finally, in order to determine the persistence of the conditioned effect, animals were tested with pentobarbital 15 weeks after their last conditioning session and were found to rotate actively in response.