Effects of casoxin 4 on morphine inhibition of small animal intestinal contractility and gut transit in the mouse

Glen S Patten1,2, Richard J Head1, Mahinda Y Abeywardena1,21CSIRO Preventative Health National Research Flagship, Adelaide, Australia; 2CSIRO Food and Nutritional Sciences, Adelaide, AustraliaBackground and aims: Chronic opioid analgesia has the debilitating side-effect of constipation in human patients. The major aims of this study were to: 1) characterize the opioid-specific antagonism of morphine-induced inhibition of electrically driven contraction of the small intestine of mice, rats, and guinea pigs; and 2) test if the oral delivery of small milk-derived opioid antagonist peptides could block morphine-induced inhibition of intestinal transit in mice.Methods: Mouse, rat, and guinea pig intact ileal sections were electrically stimulated to contract and inhibited with morphine in vitro. Morphine inhibition was then blocked by opioid subtype antagonists in the mouse and guinea pig. Using a polymeric dye, Poly R-478, the opioid antagonists casoxin 4 and lactoferroxin A were tested orally for blocking activity of morphine inhibition of gut transit in vivo by single or double gavage techniques.Results: The guinea pig tissue was more sensitive to morphine inhibition compared with the mouse or the rat (IC50 [half maximal inhibitory concentration] values as nmol/L ± SEM were 34 ± 3, 230 ± 13, and 310 ± 14 respectively) (P < 0.01). The inhibitory influence of opioid agonists (IC50) in electrically driven ileal mouse preparations were DADLE ([D-Ala2, D-Leu5]-enkephalin) ≥ met-enkephalin ≥ dynorphin A ≥ DAMGO ([D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin) > morphine > morphiceptin as nmol/L 13.9, 17.3, 19.5, 23.3, 230, and 403 respectively. The mouse demonstrated predominantly Κ- and δ-opioid receptor activity with a smaller µ-opioid receptor component. Both mouse and guinea pig tissue were sensitive to casoxin 4 antagonism of morphine inhibition of contraction. In contrast to naloxone, relatively high oral doses of the µ-opioid receptor antagonists, casoxin 4 and lactoferroxin A, applied before and after morphine injection were unable to antagonize morphine inhibition of gut transit.Conclusions: Casoxin 4 reverses morphine-induced inhibition of contraction in mice and guinea pigs in vitro but fails to influence morphine inhibition of mouse small intestinal transit by the oral route.Keywords: lactoferroxin A, µ-opioid receptor antagonist, opioid agonist

Dietary fish oil preserves cardiac function in the hypertrophied rat heart

Regular fish or fish oil intake is associated with a low incidence of heart failure clinically, and fish oil-induced reduction in cardiac remodelling seen in hypertrophy models may contribute. We investigated whether improved cardiac energy efficiency in non-hypertrophied hearts translates into attenuation of cardiac dysfunction in hypertrophied hearts. Male Wistar rats (n 33) at 8 weeks of age were sham-operated or subjected to abdominal aortic stenosis to produce pressure-overload cardiac hypertrophy. Starting 3 weeks post-operatively to follow initiation of hypertrophy, rats were fed a diet containing 10% olive oil (control) or 5% fish oil (ROPUFA® 30 (17% EPA, 10% DHA))+5% olive oil (FO diet). At 15 weeks post-operatively, ventricular haemodynamics and oxygen consumption were evaluated in the blood-perfused, isolated working heart. Resting and maximally stimulated cardiac output and external work were >60% depressed in hypertrophied control hearts but this was prevented by FO feeding, without attenuating hypertrophy. Cardiac energy efficiency was lower in hypertrophy, but greater in FO hearts for any given cardiac mass. Coronary blood flow, restricted in hypertrophied control hearts, increased with increasing work in hypertrophied FO hearts, revealing a significant coronary vasodilator reserve. Pronounced cardiac dysfunction in hypertrophied hearts across low and high workloads, indicative of heart failure, was attenuated by FO feeding in association with membrane incorporation of n-3 PUFA, principally DHA. Dietary fish oil may offer a new approach to balancing the high oxygen demand and haemodynamic requirements of the failing hypertrophied heart independently of attenuating hypertroph

Lipid-Induced Insulin Resistance in Skeletal Muscle: The Chase for the Culprit Goes from Total Intramuscular Fat to Lipid Intermediates, and Finally to Species of Lipid Intermediates

The skeletal muscle is the largest organ in the body. It plays a particularly pivotal role in glucose homeostasis, as it can account for up to 40% of the body and for up to 80%–90% of insulin-stimulated glucose disposal. Hence, insulin resistance (IR) in skeletal muscle has been a focus of much research and review. The fact that skeletal muscle IR precedes β-cell dysfunction makes it an ideal target for countering the diabetes epidemic. It is generally accepted that the accumulation of lipids in the skeletal muscle, due to dietary lipid oversupply, is closely linked with IR. Our understanding of this link between intramyocellular lipids (IMCL) and glycemic control has changed over the years. Initially, skeletal muscle IR was related to total IMCL. The inconsistencies in this explanation led to the discovery that particular lipid intermediates are more important than total IMCL. The two most commonly cited lipid intermediates for causing skeletal muscle IR are ceramides and diacylglycerol (DAG) in IMCL. Still, not all cases of IR and dysfunction in glycemic control have shown an increase in either or both of these lipids. In this review, we will summarise the latest research results that, using the lipidomics approach, have elucidated DAG and ceramide species that are involved in skeletal muscle IR in animal models and human subjects

Investigating the Impact of Dragon Fruit Peel Waste on Starch Digestibility, Pasting, and Thermal Properties of Flours Used in Asia

As a by-product of dragon fruit consumption, dragon fruit peel (DFP) was developed into powder as a natural ingredient. Nevertheless, the effect of DFP on the physicochemical properties of flours used in Asian food processing and cooking remains unknown. In this study, starch digestibility, thermal, pasting, and physicochemical properties of DFP and flours (potato, rice, glutinous rice, and wheat) were characterized. It was found that DFP contained 65.2% dietary fiber together with phenolic compounds, betacyanins, and antioxidant activity. The results demonstrated that DFP (from 125 to 500 mg) reduced starch digestibility of flours, rapidly digestible starch, and slowly digestible starch, along with an increased proportion of undigested starch. A marked increase in phenolic compounds, betacyanins, and antioxidant activity occurred when DFP and flour were incubated for 180 min under simulated gastrointestinal digestion. The results indicate that bioactive compounds in DFP were highly bioaccessible and remained intact after digestion. Moreover, DFP exerted a significantly lower gelatinization enthalpy of flours with increasing peak viscosity and setback with decreasing pasting temperature. FTIR confirmed the decreased ratio at 1047/1022 cm−1, indicating the disruption of short-range orders of starch and DFP. These findings would expand the scope of DFP food applications and provide a knowledge basis for developing DFP flour-based products

Rise in DPA Following SDA-Rich Dietary Echium Oil Less Effective in Affording Anti-Arrhythmic Actions Compared to High DHA Levels Achieved with Fish Oil in Sprague-Dawley Rats

Stearidonic acid (SDA; C18:4n-3) has been suggested as an alternative to fish oil (FO) for delivering health benefits of C ≥ 20 long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA). Echium oil (EO) represents a non-genetically-modified source of SDA available commercially. This study compared EO and FO in relation to alterations in plasma and tissue fatty acids, and for their ability to afford protection against ischemia-induced cardiac arrhythmia and ventricular fibrillation (VF). Rats were fed (12 weeks) diets supplemented with either EO or FO at three dose levels (1, 3 and 5% w/w; n = 18 per group). EO failed to influence C22:6n-3 (DHA) but increased C22:5n-3 (DPA) in tissues dose-dependently, especially in heart tissue. Conversely, DHA in hearts of FO rats showed dose-related elevation; 14.8%–24.1% of total fatty acids. Kidney showed resistance for incorporation of LC n-3 PUFA. Overall, FO provided greater cardioprotection than EO. At the highest dose level, FO rats displayed lower (p < 0.05) episodes of VF% (29% vs. 73%) and duration (22.7 ± 12.0 vs. 75.8 ± 17.1 s) than the EO group but at 3% EO was comparable to FO. We conclude that there is no endogenous conversion of SDA to DHA, and that DPA may be associated with limited cardiac benefit

Effects of casoxin 4 on morphine inhibition of small animal intestinal contractility and gut transit in the mouse

Conclusions: Casoxin 4 reverses morphine-induced inhibition of contraction in mice and guinea pigs in vitro but fails to influence morphine inhibition of mouse small intestinal transit by the oral route.

Dietary fish oil increases acetylcholine- and eicosanoid-induced contractility of isolated rat ileum

Patten, Glen S. ; Abeywardena, Mahinda Y. ; Mcmurchie, Edward J. ; Jahangiri, Anis