Showing papers by "Cynthia J. Meininger published in 2014"

Involvement of histamine in endothelium-dependent relaxation of mesenteric lymphatic vessels.

Abstract: Objectives The knowledge of the basic principles of lymphatic function, still remains, to a large degree, rudimentary and will require significant research efforts. Recent studies of the physiology of the MLVs suggested the presence of an EDRF other than NO. In this study, we tested the hypothesis that lymphatic endothelium-derived histamine relaxes MLVs. Methods We measured and analyzed parameters of lymphatic contractility in isolated and pressurized rat MLVs under control conditions and after pharmacological blockade of NO by l-NAME (100 μM) or/and histamine production by α-MHD (10 μM). Effectiveness of α-MHD was confirmed immunohistochemically. We also used immunohistochemical labeling and Western blot analysis of the histamine-producing enzyme, HDC. In addition, we blocked HDC protein expression in MLVs by transient transfection with vivo-morpholino oligos. Results We found that only combined pharmacological blockade of NO and histamine production completely eliminates flow-dependent relaxation of lymphatic vessels, thus confirming a role for histamine as an EDRF in MLVs. We also confirmed the presence of HDC and histamine inside lymphatic endothelial cells. Conclusions This study supports a role for histamine as an EDRF in MLVs.

Analysis of energy expenditure in diet-induced obese rats

Abstract: Development of obesity in animals is affected by energy intake, dietary composition, and metabolism. Useful models for studying this metabolic problem are Sprague-Dawley rats fed low-fat (LF) or high-fat (HF) diets beginning at 28 days of age. Through experimental design, their dietary intakes of energy, protein, vitamins, and minerals per kg body weight (BW) do not differ in order to eliminate confounding factors in data interpretation. The 24-h energy expenditure of rats is measured using indirect calorimetry. A regression model is constructed to accurately predict BW gain based on diet, initial BW gain, and the principal component scores of respiratory quotient and heat production. Time-course data on metabolism (including energy expenditure) are analyzed using a mixed effect model that fits both fixed and random effects. Cluster analysis is employed to classify rats as normal-weight or obese. HF-fed rats are heavier than LF-fed rats, but rates of their heat production per kg non-fat mass do not differ. We conclude that metabolic conversion of dietary lipids into body fat primarily contributes to obesity in HF-fed rats.

Effects of short-term ingestion of Russian Tarragon prior to creatine monohydrate supplementation on whole body and muscle creatine retention and anaerobic sprint capacity: a preliminary investigation

Abstract: Extracts of Russian Tarragon (RT) have been reported to produce anti-hyperglycemic effects and influence plasma creatine (Cr) levels while supplementing with creatine monohydrate (CrM). The purpose of this preliminary study was to determine if short-term, low-dose aqueous RT extract ingestion prior to CrM supplementation influences whole body Cr retention, muscle Cr or measures of anaerobic sprint performance. In a double-blind, randomized, and crossover manner; 10 recreationally trained males (20 ± 2 yrs; 179 ± 9 cm; 91.3 ± 34 kg) ingested 500 mg of aqueous RT extract (Finzelberg, Andernach, Germany) or 500 mg placebo 30-minutes prior to ingesting 5 g of CrM (Creapure®, AlzChem AG, Germany) twice per day for 5-days then repeated after a 6-week wash-out period. Urine was collected at baseline and during each of the 5-days of supplementation to determine urine Cr content. Whole body Cr retention was estimated from urine samples. Muscle biopsies were obtained for determination of muscle free Cr content. Participants also performed two 30-second Wingate anaerobic capacity tests prior to and following supplementation for determination of peak power (PP), mean power (MP), and total work (TW). Data were analysed by repeated measures MANOVA. Whole body daily Cr retention increased in both groups following supplementation (0.0 ± 0.0; 8.2 ± 1.4, 6.5 ± 2.4, 5.6 ± 3.2, 6.1 ± 2.6, 4.8 ± 3.2 g · d-1; p = 0.001) with no differences observed between groups (p = 0.59). After 3 and 5-days of supplementation, respectively, both supplementation protocols demonstrated a significant increase in muscle free Cr content from baseline (4.8 ± 16.7, 15.5 ± 23.6 mmol · kg-1 DW, p = 0.01) with no significant differences observed between groups (p = 0.34). Absolute change in MP (9 ± 57, 35 ± 57 W; p = 0.031), percent change in MP (2.5 ± 10.5, 6.7 ± 10.4%; p = 0.026), absolute change in TW (275 ± 1,700, 1,031 ± 1,721 J; p = 0.032), and percent change in TW (2.5 ± 10.5, 6.6 ± 10.4%; p = 0.027) increased over time in both groups with no differences observed between groups. Short-term CrM supplementation (10 g · d-1 for 5-days) significantly increased whole body Cr retention and muscle free Cr content. However, ingesting 500 mg of RT 30-min prior to CrM supplementation did not affect whole body Cr retention, muscle free Cr content, or anaerobic sprint capacity in comparison to ingesting CrM with a placebo.

In-vivo evaluation of human recombinant Co-arginase against A375 melanoma xenografts.

Abstract: Metastatic melanoma is a deadly form of cancer with few therapeutic options and the cause of more than 9480 deaths annually in the USA alone. Novel treatment options for this disease are urgently needed. Here we test the efficacy of a novel melanoma drug, the human recombinant Co-arginase (CoArgIPEG), against an aggressive A375 melanoma mouse model. CoArgIPEG is a modification of the naturally occurring human enzyme with improved stability, catalytic activity, and potentially lower immunogenicity compared with current amino acid-depleting drugs. Marked tumor growth reductions (mean P=0.0057) with apoptosis induction and proliferation inhibition are noted with CoArgIPEG treatment, both in the presence and in the absence of supplemental citrulline. Further, improved therapeutic efficacy has been noted against A375 xenografts relative to the naturally occurring human recombinant arginase enzyme at lower doses of CoArgIPEG. Unfortunately, after 1 month, half of the relapsing tumors showed argininosuccinate synthase induction, which correlated with Ser62-phosphorylated cMyc. Although argininosuccinate synthase induction could not be induced in vitro, a drug targeting pathway previously demonstrated to be associated with Ser62 cMyc phosphorylation - U0126 - in combination with CoArgIPEG demonstrated an in-vitro synergistic response (combination indices 0.13±0.10 and 0.14±0.10 with or without citrulline, respectively). Overall, favorable efficacy and potential synergy with other antimelanoma drugs support CoArgIPEG as a potent, novel cancer therapeutic.