Popis: |
Cancer cachexia is a wasting disease which leads to poor disease prognosis and survival. Cachexia affects about 80% of advanced cancer patients and causes up to one-third of all cancer-related deaths. To date, effective treatment that directly targets cancer cachexia to improve longevity and quality of life is lacking. Metabolic disturbance is the underlying driver of the pathogenesis and progression of cancer cachexia. Common observations in cancer patients presenting cachexia include elevated inflammation, insulin resistance, dyslipidemia, and increased energy expenditure resulting in body weight loss that is irreversible by nutrition therapies. The use of metabolic modulators to improve these metabolic disturbances in some studies successfully slowed cachexia development, suggesting the importance of metabolic regulation in cancer cachexia treatment.Naringenin is a flavonoid found primarily in citrus fruits. Stemming from several epidemiological findings of the inverse associations of consumption of naringenin-containing foods and cancer incidence, a number of studies have explored anticancer activities and other bioactivities of naringenin. Naringenin has shown anti-cancer properties in many human cell lines and has successfully improved the inflammatory status, insulin tolerance, plasma glucose, and lipid profiles in mice. The results of some animal studies have suggested that naringenin supplementation during weight loss may help maintain lean body mass while regulating diet-induced metabolic disturbances. These observations have pointed to the potential use of naringenin to combat cachexia, a disease of metabolic disturbance, in cancer population by attenuation of tumor growth and metabolic disturbances, as well as the protection of the lean body mass.The first objective of this study was to determine the effect of dietary naringenin on the well-established C-26 cancer cachexia mouse model. We hypothesized that two-percent dietary naringenin would improve the metabolic disturbances in the C-26 model, slowing the progression of cachexia symptoms. Male CD2F1 mice were provided with either a control diet or a two percent naringenin diet, and each diet group was divided into a tumor and a no-tumor group. To our surprise, naringenin fed tumor mice exhibited weight loss and anorexia earlier than the control diet tumor mice. However, the early onset of anorexia and weight loss was not a predictor of worse outcomes in this study, since naringenin improved the inflammatory status, insulin sensitivity, activity, muscle function, and survival. These results confirmed naringenin's positive metabolism-regulating effects and its favorable impact on the outcomes of disease in the C-26 model.The second objective was to begin to provide a method for translation of the beneficial health effects of naringenin suggested by animal studies to human application. Although the first part of the study observed positive effects of naringenin on metabolic regulation, the concentration of naringenin used in our C-26 study was not directly translatable to the quantity that a human can achieve by consuming regular naringenin-containing foods. We hypothesized that the use of lyophilized naringenin-rich grapefruit juice and cyclodextrin in a confection would improve the naringenin bioavailability and increase its concentration. Cyclodextrin is a cyclic compound that has the ability to surround a hydrophobic, poorly soluble compound inside its cavity. By doing so, cyclodextrin encapsulation can improve the solubility and the bioavailability of naringenin. Since there is no universal food-safe complexation method for naringenin and β-cyclodextrin, two different methods were tested to encapsulate naringenin and naringin: the stirring method and the kneading method. The analyses of complexation efficiency by differential scanning calorimetry (DSC) and proton nuclear magnetic resonance (H-NMR) revealed that the stirring method was more efficient for the complexation of β-cyclodextrin with both naringin and naringenin. As a preliminary study for the future bioavailability tests, mice were fed with four different types of confections (sucrose, grapefruit confection (GFC), GFC with three percent naringenin, GFC with naringin equivalent to three percent naringenin) after a 12-hour fast and monitored for 2.5 hours. None of the mice finished consuming 1.6 grams of confection in 2.5 hours, and voluntary ingestion of the confection was found to be not suitable for a bioavailability studies, suggesting the need to oral gavage mice or to utilize a larger animal model. |