Mechanisms and treatment of cardiac atrophy secondary to cancer cachexia

 This project found that oxidative stress and activation of pro-inflammatory molecules is a feature of heart protein loss secondary to cancer wasting. Treatment with an omega-3 fatty acid is able to protect against heart muscle loss in cancer by reducing gene transcripts of both pro-inflammatory and oxidative molecules.

Lipid profiles, in vitro digestion and oxidative stability of mutton bird oil

The lipid profile, in vitro digestion and oxidative stability of mutton bird oil were investigated. Wax ester, triacylglycerol and sterol were the major lipids present as determined using capillary chromatography with flame ionisation detector (Iatroscan). Fatty acid analysis by gas chromatography (GC) showed that wax esters had a higher total omega-3 fatty acids content including EPA, DPA and DHA than TAGs (31 % and 24 %, respectively). In TAGs, 13C nuclear magnetic resonance (NMR) data showed that EPA was statistically positioned at sn-1,3 and sn-2, while DHA was preferentially at sn-2. In vitro digestion using porcine pancreatic lipase resulted in 75 % of TAG and 10 % wax ester hydrolysis in 120 min. As reflected in the measured conjugated dienes (CD) and thiobarbituric acid reactive substances (TBARS) values during accelerated oxidation at 60 °C for 5 days, the oil was relatively stable against oxidation considering its high omega-3 content.

Changes in lipid class content and composition of Isochrysis sp. (T-Iso) grown in batch culture

© 2015, Springer International Publishing Switzerland. For decades, the microalgae Isochrysis spp. have been widely utilised as a live feed in aquaculture practices. This species possesses a number of favourable characteristics, notably its long-chain omega-3 polyunsaturated fatty acid (LC n-3 PUFA) content; primarily docosahexaenoic acid (DHA, 22:6n-3). This article describes the lipid class content and composition of this microalga grown in batch culture, covering the entirety of lag, log and stationary growth phases. The total lipid was highest in the lag phase (27 pg/cell). Total lipid significantly decreased in the exponential growth (7 pg/cell), then steadily increasing for the remainder of growth. The increase in total lipid was due to the accumulation of neutral lipid in the form of triacylglycerides. The DHA content (pg/cell) of the neutral lipid remained relatively unchanged for the duration of growth, with the influx of fatty acids being primarily myristic and palmitic acids. DHA (pg/cell) was found at relatively uniform amounts across all lipid classes. However, the DHA content as a percentage differed greatly between classes. The polar lipid class had a significantly higher DHA content, which peaked at 38 % of all polar lipid in log growth. The primary PUFA species present in the glycolipid class was stearidonic acid (18:4n-3). This work gives an overview of the lipid content and composition of Isochrysis sp. (T-Iso) over the entirety of its growth under batch culture. The lipid profile for this species at different stages of culture provides a basal data set that is useful for comparative studies using this organism.

Bead milling for lipid recovery from thraustochytrid cells and selective hydrolysis of Schizochytrium DT3 oil using lipase

Marine microalgae present a renewable alternative source for sustainable production of omega-3 fatty acids, as compared to conventional sources such as krill oil and fish oil. In this study, we optimised a method for lipid extraction from marine thraustochytrids using a bead mill and enzymatic concentration of omega-3 fatty acids from the thraustochytrid oil. The optimised lipid extraction conditions were, bead size 0.4-0.6μm, 4500rpm, 4min of processing time at 5g biomass concentration. The maximum lipid yield (% dry weight basis) achieved at optimum conditions were 40.5% for Schizochytrium sp. S31 (ATCC) and 49.4% for Schizochytrium sp. DT3 (in-house isolate). DT3 oil contained 39.8% docosahexaenoic acid (DHA) as a percentage of lipid, a higher DHA percentage than S31. Partial hydrolysis of DT3 oil using Candida rugosa lipase was performed to enrich omega-3 polyunsaturated fatty acids (PUFAs) in the glyceride portion. Total omega-3 fatty acid content was increased to 88.7%.

Understanding response surface optimisation to the modeling of Astaxanthin extraction from a novel strain Thraustochytrium sp. S7

A fast growing, highly orange color pigmented strain of Thraustochytrids was isolated from New Zealand marine waters. This strain showed efficient utilization of glycerol as carbon source and produced significant amount of cell dry biomass (2.08gL-1), TFA (30.15% of dry cell weight), DHA (27.83% of TFA) and astaxanthin (131.56μgg-1). Astaxanthin is the dominant constituent in the carotenoid profile of Thraustochytrium sp. S7 and is an important antioxidant. Different cell disruption methods were applied for efficient astaxanthin extraction. Mechanical disruption of cells via ultrasonication resulted in the highest astaxanthin yield, from 26.78±1.25μgg-1 to 156.07±4.16μgg-1. Optimization of ultrasonication process using response surface methodology resulted into significant decrease in lysis time from 30min to 10min. This strain can be used for concurrent production of lipids and high value co-products such as DHA and astaxanthin.

Comparison of cell disruption methods for improving lipid extraction from thraustochytrid strains

Lipid extraction is an integral part of biodiesel production, as it facilitates the release of fatty acids from algal cells. To utilise thraustochytrids as a potential source for lipid production. We evaluated the extraction efficiency of various solvents and solvent combinations for lipid extraction from Schizochytrium sp. S31 and Thraustochytrium sp. AMCQS5-5. The maximum lipid extraction yield was 22% using a chloroform:methanol ratio of 2:1. We compared various cell disruption methods to improve lipid extraction yields, including grinding with liquid nitrogen, bead vortexing, osmotic shock, water bath, sonication and shake mill. The highest lipid extraction yields were obtained using osmotic shock and 48.7% from Schizochytrium sp. S31 and 29.1% from Thraustochytrium sp. AMCQS5-5. Saturated and monounsaturated fatty acid contents were more than 60% in Schizochytrium sp. S31 which suggests their suitability for biodiesel production.

Complex coacervation between flaxseed protein isolate and flaxseed gum

Flaxseed protein isolate (FPI) and flaxseed gum (FG) were extracted, and the electrostatic complexation between these two biopolymers was studied as a function of pH and FPI-to-FG ratio using turbidimetric and electrophoretic mobility (zeta potential) tests. The zeta potential values of FPI, FG, and their mixtures at the FPI-to-FG ratios of 1:1, 3:1, 5:1, 10:1, 15:1 were measured over a pH range 8.0-1.5. The alteration of the secondary structure of FPI as a function of pH was studied using circular dichroism. The proportion of a-helical structure decreased, whereas both β-sheet structure and random coil structure increased with the lowering of pH from 8.0 to 3.0. The acidic pH affected the secondary structure of FPI and the unfolding of helix conformation facilitated the complexation of FPI with FG. The optimum FPI-to-FG ratio for complex coacervation was found to be 3:1. The critical pH values associated with the formation of soluble (pHc) and insoluble (pHΦ1) complexes at the optimum FPI-to-FG ratio were found to be 6.0 and 4.5, respectively. The optimum pH (pHopt) for the optimum complex coacervation was 3.1. The instability and dissolution of FPI-FG complex coacervates started (pHΦ2) at pH2.1. These findings contribute to the development of FPI-FG complex coacervates as delivery vehicles for unstable albeit valuable nutrients such as omega-3 fatty acids.

Downstream processing of lipids and lipases from thraustochytrids

Thraustochytrids are a group of marine microbes well known for production of omega-3 fatty acids and other bioactive compounds. The purpose of this research project was to develop “downstream processing methods to extract lipids and lipases” from thraustochytrids and understanding their suitability in production of biofuels and nutraceuticals.

Uncoupling EPA and DHA in fish nutrition: dietary demand is limited in atlantic salmon and effectively met by DHA alone

Due to the scarcity of marine fish oil resources, the aquaculture industry is developing more efficient strategies for the utilization of dietary omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA). A better understanding of how fish utilize EPA and DHA, typically provided by fish oil, is needed. However, EPA and DHA have different physiological functions, may be metabolized and incorporated into tissues differently, and may vary in terms of their importance in meeting the fatty acid requirements of fish. To address these questions, Atlantic salmon were fed experimental diets containing, as the sole added dietary lipid source, fish oil (positive control), tallow (negative control), or tallow supplemented with EPA, DHA, or both fatty acids to ~50 or 100 % of their respective levels in the positive control diet. Following 14 weeks of feeding, the negative control diet yielded optimum growth performance. Though surprising, these results support the notion that Atlantic salmon requirements for n-3 LC-PUFA are quite low. EPA was largely β-oxidized and inefficiently deposited in tissues, and increasing dietary levels were associated with potential negative effects on growth. Conversely, DHA was completely spared from catabolism and very efficiently deposited into flesh. EPA bioconversion to DHA was largely influenced by substrate availability, with the presence of preformed DHA having little inhibitory effect. These results clearly indicate EPA and DHA are metabolized differently by Atlantic salmon, and suggest that the n-3 LC-PUFA dietary requirements of Atlantic salmon may be lower than reported and different, if originating primarily from EPA or DHA.

Cancer cachexia: a molecular nutrition approach to cancer-related muscle loss

The project identified changes in molecular markers of antioxidant status and muscle atrophy during cancer-associated weight-loss, and confirmed omega-3 EPA as an effective treatment for muscle-loss in experimental cancer cachexia. The project also identified the PG-SGA nutrition tool as a powerful predictor of patient outcomes and survival in clinical cachexia.

Cognitive remission: a novel objective for the treatment of major depression?

BACKGROUND: Cognitive dysfunction in major depressive disorder (MDD) encompasses several domains, including but not limited to executive function, verbal memory, and attention. Furthermore, cognitive dysfunction is a frequent residual manifestation in depression and may persist during the remitted phase. Cognitive deficits may also impede functional recovery, including workforce performance, in patients with MDD. The overarching aims of this opinion article are to critically evaluate the effects of available antidepressants as well as novel therapeutic targets on neurocognitive dysfunction in MDD.

DISCUSSION: Conventional antidepressant drugs mitigate cognitive dysfunction in some people with MDD. However, a significant proportion of MDD patients continue to experience significant cognitive impairment. Two multicenter randomized controlled trials (RCTs) reported that vortioxetine, a multimodal antidepressant, has significant precognitive effects in MDD unrelated to mood improvement. Lisdexamfetamine dimesylate was shown to alleviate executive dysfunction in an RCT of adults after full or partial remission of MDD. Preliminary evidence also indicates that erythropoietin may alleviate cognitive dysfunction in MDD. Several other novel agents may be repurposed as cognitive enhancers for MDD treatment, including minocycline, insulin, antidiabetic agents, angiotensin-converting enzyme inhibitors, S-adenosyl methionine, acetyl-L-carnitine, alpha lipoic acid, omega-3 fatty acids, melatonin, modafinil, galantamine, scopolamine, N-acetylcysteine, curcumin, statins, and coenzyme Q10. The management of cognitive dysfunction remains an unmet need in the treatment of MDD. However, it is hoped that the development of novel therapeutic targets will contribute to 'cognitive remission', which may aid functional recovery in MDD.

Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis

OBJECTIVE: Inflammation has been implicated in the risk, pathophysiology, and progression of mood disorders and, as such, has become a target of interest in the treatment of bipolar disorder (BD). Therefore, the objective of the current qualitative and quantitative review was to determine the overall antidepressant effect of adjunctive anti-inflammatory agents in the treatment of bipolar depression. METHODS: Completed and ongoing clinical trials of anti-inflammatory agents for BD published prior to 15 May 15 2015 were identified through searching the PubMed, Embase, PsychINFO, and Clinicaltrials.gov databases. Data from randomized controlled trials (RCTs) assessing the antidepressant effect of adjunctive mechanistically diverse anti-inflammatory agents were pooled to determine standard mean differences (SMDs) compared with standard therapy alone. RESULTS: Ten RCTs were identified for qualitative review. Eight RCTs (n = 312) assessing adjunctive nonsteroidal anti-inflammatory drugs (n = 53), omega-3 polyunsaturated fatty acids (n = 140), N-acetylcysteine (n = 76), and pioglitazone (n = 44) in the treatment of BD met the inclusion criteria for quantitative analysis. The overall effect size of adjunctive anti-inflammatory agents on depressive symptoms was -0.40 (95% confidence interval -0.14 to -0.65, p = 0.002), indicative of a moderate and statistically significant antidepressant effect. The heterogeneity of the pooled sample was low (I² = 14%, p = 0.32). No manic/hypomanic induction or significant treatment-emergent adverse events were reported. CONCLUSIONS: Overall, a moderate antidepressant effect was observed for adjunctive anti-inflammatory agents compared with conventional therapy alone in the treatment of bipolar depression. The small number of studies, diversity of agents, and small sample sizes limited interpretation of the current analysis.

Adjunctive nutraceuticals for depression: a systematic review and meta-analyses

OBJECTIVE: There is burgeoning interest in augmentation strategies for improving inadequate response to antidepressants. The adjunctive use of standardized pharmaceutical-grade nutrients, known as nutraceuticals, has the potential to modulate several neurochemical pathways implicated in depression. While many studies have been conducted in this area, to date no specialized systematic review (or meta-analysis) has been conducted. METHOD: A systematic search of PubMed, CINAHL, Cochrane Library, and Web of Science was conducted up to December 2015 for clinical trials using adjunctive nutrients for depression. Where sufficient data were available, a random-effects model analyzed the standard mean difference between treatment and placebo in the change from baseline to endpoint, combining the effect size data. Funnel plot and heterogeneity analyses were also performed. RESULTS: Primarily positive results were found for replicated studies testing S-adenosylmethionine (SAMe), methylfolate, omega-3 (primarily EPA or ethyl-EPA), and vitamin D, with positive isolated studies for creatine, folinic acid, and an amino acid combination. Mixed results were found for zinc, folic acid, vitamin C, and tryptophan, with nonsignificant results for inositol. No major adverse effects were noted in the studies (aside from minor digestive disturbance). A meta-analysis of adjunctive omega-3 versus placebo revealed a significant and moderate to strong effect in favor of omega-3. Conversely, a meta-analysis of folic acid revealed a nonsignificant difference from placebo. Marked study heterogeneity was found in a Higgins test for both omega-3 and folic acid studies; funnel plots also revealed asymmetry (reflecting potential study bias). CONCLUSIONS: Current evidence supports adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants to reduce depressive symptoms.

Increased erythrocyte eicosapentaenoic acid and docosahexaenoic acid are associated with improved attention and behavior in children with ADHD in a randomized controlled three-way crossover trial

OBJECTIVE: To investigate effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on attention, literacy, and behavior in children with ADHD.

METHOD: Ninety children were randomized to consume supplements high in EPA, DHA, or linoleic acid (control) for 4 months each in a crossover design. Erythrocyte fatty acids, attention, cognition, literacy, and Conners' Parent Rating Scales (CPRS) were measured at 0, 4, 8, 12 months.

RESULTS: Fifty-three children completed the treatment. Outcome measures showed no significant differences between the three treatments. However, in children with blood samples (n = 76-46), increased erythrocyte EPA + DHA was associated with improved spelling (r = .365, p < .001) and attention (r = -.540, p < .001) and reduced oppositional behavior (r = -.301, p < .003), hyperactivity (r = -.310, p < .001), cognitive problems (r = -.326, p < .001), Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) hyperactivity (r = -.270, p = .002) and DSM-IV inattention (r = -.343, p < .001).

CONCLUSION: Increasing erythrocyte DHA and EPA via dietary supplementation may improve behavior, attention, and literacy in children with ADHD.

The effect of the apolipoprotein E genotype on response to personalized dietary advice intervention: findings from the Food4Me randomized controlled trial

BACKGROUND: The apolipoprotein E (APOE) risk allele (ɛ4) is associated with higher total cholesterol (TC), amplified response to saturated fatty acid (SFA) reduction, and increased cardiovascular disease. Although knowledge of gene risk may enhance dietary change, it is unclear whether ɛ4 carriers would benefit from gene-based personalized nutrition (PN). OBJECTIVES: The aims of this study were to 1) investigate interactions between APOE genotype and habitual dietary fat intake and modulations of fat intake on metabolic outcomes; 2) determine whether gene-based PN results in greater dietary change than do standard dietary advice (level 0) and nongene-based PN (levels 1-2); and 3) assess the impact of knowledge of APOE risk (risk: E4+, nonrisk: E4-) on dietary change after gene-based PN (level 3). DESIGN: Individuals (n = 1466) recruited into the Food4Me pan-European PN dietary intervention study were randomly assigned to 4 treatment arms and genotyped for APOE (rs429358 and rs7412). Diet and dried blood spot TC and ω-3 (n-3) index were determined at baseline and after a 6-mo intervention. Data were analyzed with the use of adjusted general linear models. RESULTS: Significantly higher TC concentrations were observed in E4+ participants than in E4- (P < 0.05). Although there were no significant differences in APOE response to gene-based PN (E4+ compared with E4-), both groups had a greater reduction in SFA (percentage of total energy) intake than at level 0 (mean ± SD: E4+, -0.72% ± 0.35% compared with -1.95% ± 0.45%, P = 0.035; E4-, -0.31% ± 0.20% compared with -1.68% ± 0.35%, P = 0.029). Gene-based PN was associated with a smaller reduction in SFA intake than in nongene-based PN (level 2) for E4- participants (-1.68% ± 0.35% compared with -2.56% ± 0.27%, P = 0.025). CONCLUSIONS: The APOE ɛ4 allele was associated with higher TC. Although gene-based PN targeted to APOE was more effective in reducing SFA intake than standard dietary advice, there was no difference between APOE "risk" and "nonrisk" groups. Furthermore, disclosure of APOE nonrisk may have weakened dietary response to PN. This trial was registered at clinicaltrials.gov as NCT01530139.