An umbrella review of systematic reviews of ß-hydroxy-ß-methyl butyrate supplementation in ageing and clinical practice.

The compound ß-hydroxy-ß-methyl butyrate (HMB) is proposed to increase or mitigate the loss of skeletal muscle and improve muscle function. We undertook a review of systematic reviews of HMB supplementation to promote gains or mitigate muscle loss in ageing and clinical populations. Following PRISMA guidelines, we searched for systematic reviews reporting the effect of HMB in our target populations. Dual-energy X-ray absorptiometry (DXA) measured lean soft-tissue mass (LSTM) was accepted as a proxy for muscle. We identified 15 systematic reviews that met our inclusion criteria, which were independently evaluated. The methodological quality of the reviews was assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR), and standardized effectiveness statements were generated. Five of 15 studies found some evidence that HMB augmented LSTM; the remaining 10 studies reported some evidence favouring no difference (6/10 studies) or insufficient evidence to determine an effect (4/10 studies). Of the 12 studies that evaluated strength, 4/12 found some evidence, 5/12 found some evidence of no effect with one article finding some evidence in favour of patients in peri-hospitalized and no evidence for those that are community-dwelling, 4/12 had insufficient evidence to determine an effect, and 1/12 had insufficient evidence. No]study reported a positive effect of HMB on physical function; however, 2/10 studies found some evidence favouring no effect, and 7/10 studies reported insufficient evidence to determine an effect. The effectiveness of HMB supplementation in augmenting LSTM was heterogeneous, with most reviews finding no effect or inconclusive evidence to determine an effect. Most reviews concluded that HMB supplementation did not affect strength outcome measures or studies were inconclusive. The current evidence is insufficient to assess the impact of HMB supplementation on functional outcome measures. Our analysis shows minor, inconsistent support for HMB as part of an oral nutritional supplement or as a stand-alone supplement (or combined with other amino acids) to increase or promote retention of LSTM, improve strength, and no evidence that it improves physical function in older persons or clinical populations.

Nitrate consumption preserves HFD-induced skeletal muscle mitochondrial ADP sensitivity and lysine acetylation: A potential role for SIRT1.

Dietary nitrate supplementation, and the subsequent serial reduction to nitric oxide, has been shown to improve glucose homeostasis in several pre-clinical models of obesity and insulin resistance. While the mechanisms remain poorly defined, the beneficial effects of nitrate appear to be partially dependent on AMPK-mediated signaling events, a central regulator of metabolism and mitochondrial bioenergetics. Since AMPK can activate SIRT1, we aimed to determine if nitrate supplementation (4 mM sodium nitrate via drinking water) improved skeletal muscle mitochondrial bioenergetics and acetylation status in mice fed a high-fat diet (HFD: 60% fat). Consumption of HFD induced whole-body glucose intolerance, and within muscle attenuated insulin-induced Akt phosphorylation, mitochondrial ADP sensitivity (higher apparent Km), submaximal ADP-supported respiration, mitochondrial hydrogen peroxide (mtH2O2) production in the presence of ADP and increased cellular protein carbonylation alongside mitochondrial-specific acetylation. Consumption of nitrate partially preserved glucose tolerance and, within skeletal muscle, normalized insulin-induced Akt phosphorylation, mitochondrial ADP sensitivity, mtH2O2, protein carbonylation and global mitochondrial acetylation status. Nitrate also prevented the HFD-mediated reduction in SIRT1 protein, and interestingly, the positive effects of nitrate ingestion on glucose homeostasis and mitochondrial acetylation levels were abolished in SIRT1 inducible knock-out mice, suggesting SIRT1 is required for the beneficial effects of dietary nitrate. Altogether, dietary nitrate preserves mitochondrial ADP sensitivity and global lysine acetylation in HFD-fed mice, while in the absence of SIRT1, the effects of nitrate on glucose tolerance and mitochondrial acetylation were abrogated.

A higher energy-adjusted Dietary Inflammatory Index is positively associated with total and visceral body fat in young male adults.

BACKGROUND: The energy-adjusted Dietary Inflammatory Index (E-DII™) has been associated with a high body mass index and markers of chronic diseases. Also, pro-inflammatory diets with a high E-DII have been positively associated with metabolic disturbances such as glucose intolerance and type II diabetes mellitus. However, it is unclear whether E-DII scores are positively associated with body fat percentage and visceral fat per se. This cross-sectional study aimed to evaluate whether the E-DII is associated with body fat content and metabolic health indicators in lean and obese young men. METHODS: The present study was conducted on 59 participants, without comorbidities, not using tobacco, medication and nutritional supplements. Dietary data were obtained by 3-day food records to calculate E-DII scores based on 28 food parameters. Body composition was assessed by dual X-ray absorptiometry (DXA). Blood samples were taken to measure fasting glucose, insulin, triacylglycerols, total cholesterol, and low- and high-density lipoprotein cholesterol. An oral glucose tolerance test also was performed. Associations were determined by mixed-effects linear regression. RESULTS: E-DII scores ranged from -3.48 to +3.10. Energy intake was similar across E-DII tertiles. After adjusting for covariates, the highest E-DII tertile was associated with increased body fat, visceral adipose tissue and waist circumference. There was no association between E-DII scores and glycaemic parameters. CONCLUSIONS: In young participants, a dietary pattern with a higher E-DII (i.e., pro-inflammatory) score was associated with high body fat and markers of central adiposity assessed by DXA, regardless of body mass.

Systematic review and meta-analysis of protein intake to support muscle mass and function in healthy adults.

We performed a systematic review, meta-analysis, and meta-regression to determine if increasing daily protein ingestion contributes to gaining lean body mass (LBM), muscle strength, and physical/functional test performance in healthy subjects. A protocol for the present study was registered (PROSPERO, CRD42020159001), and a systematic search of Medline, Embase, CINAHL, and Web of Sciences databases was undertaken. Only randomized controlled trials (RCT) where participants increased their daily protein intake and were healthy and non-obese adults were included. Research questions focused on the main effects on the outcomes of interest and subgroup analysis, splitting the studies by participation in a resistance exercise (RE), age (<65 or ≥65 years old), and levels of daily protein ingestion. Three-level random-effects meta-analyses and meta-regressions were conducted on data from 74 RCT. Most of the selected studies tested the effects of additional protein ingestion during RE training. The evidence suggests that increasing daily protein ingestion may enhance gains in LBM in studies enrolling subjects in RE (SMD [standardized mean difference] = 0.22, 95% CI [95% confidence interval] 0.14:0.30, P < 0.01, 62 studies, moderate level of evidence). The effect on LBM was significant in subjects ≥65 years old ingesting 1.2-1.59 g of protein/kg/day and for younger subjects (<65 years old) ingesting ≥1.6 g of protein/kg/day submitted to RE. Lower-body strength gain was slightly higher by additional protein ingestion at ≥1.6 g of protein/kg/day during RE training (SMD = 0.40, 95% CI 0.09:0.35, P < 0.01, 19 studies, low level of evidence). Bench press strength is slightly increased by ingesting more protein in <65 years old subjects during RE training (SMD = 0.18, 95% CI 0.03:0.33, P = 0.01, 32 studies, low level of evidence). The effects of ingesting more protein are unclear when assessing handgrip strength and only marginal for performance in physical function tests. In conclusion, increasing daily protein ingestion results in small additional gains in LBM and lower body muscle strength gains in healthy adults enrolled in resistance exercise training. There is a slight effect on bench press strength and minimal effect performance in physical function tests. The effect on handgrip strength is unclear.

Insulin rapidly increases skeletal muscle mitochondrial ADP sensitivity in the absence of a high lipid environment.

Reductions in mitochondrial function have been proposed to cause insulin resistance, however the possibility that impairments in insulin signaling negatively affects mitochondrial bioenergetics has received little attention. Therefore, we tested the hypothesis that insulin could rapidly improve mitochondrial ADP sensitivity, a key process linked to oxidative phosphorylation and redox balance, and if this phenomenon would be lost following high-fat diet (HFD)-induced insulin resistance. Insulin acutely (60 min post I.P.) increased submaximal (100-1000 µM ADP) mitochondrial respiration ∼2-fold without altering maximal (>1000 µM ADP) respiration, suggesting insulin rapidly improves mitochondrial bioenergetics. The consumption of HFD impaired submaximal ADP-supported respiration ∼50%, however, despite the induction of insulin resistance, the ability of acute insulin to stimulate ADP sensitivity and increase submaximal respiration persisted. While these data suggest that insulin mitigates HFD-induced impairments in mitochondrial bioenergetics, the presence of a high intracellular lipid environment reflective of an HFD (i.e. presence of palmitoyl-CoA) completely prevented the beneficial effects of insulin. Altogether, these data show that while insulin rapidly stimulates mitochondrial bioenergetics through an improvement in ADP sensitivity, this phenomenon is possibly lost following HFD due to the presence of intracellular lipids.

The Influence of Omega-3 Fatty Acids on Skeletal Muscle Protein Turnover in Health, Disuse, and Disease.

Ingestion of omega-3 fatty acids is known to exert favorable health effects on a number of biological processes such as improved immune profile, enhanced cognition, and optimized neuromuscular function. Recently, data have emerged demonstrating a positive influence of omega-3 fatty acid intake on skeletal muscle. For instance, there are reports of clinically-relevant gains in muscle size and strength in healthy older persons with omega-3 fatty acid intake as well as evidence that omega-3 fatty acid ingestion alleviates the loss of muscle mass and prevents decrements in mitochondrial respiration during periods of muscle-disuse. Cancer cachexia that is characterized by a rapid involuntary loss of lean mass may also be attenuated by omega-3 fatty acid provision. The primary means by which omega-3 fatty acids positively impact skeletal muscle mass is via incorporation of eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) into membrane phospholipids of the sarcolemma and intracellular organelles. Enrichment of EPA and DHA in these membrane phospholipids is linked to enhanced rates of muscle protein synthesis, decreased expression of factors that regulate muscle protein breakdown, and improved mitochondrial respiration kinetics. However, exactly how incorporation of EPA and DHA into phospholipid membranes alters these processes remains unknown. In this review, we discuss the interaction between omega-3 fatty acid ingestion and skeletal muscle protein turnover in response to nutrient provision in younger and older adults. Additionally, we examine the role of omega-3 fatty acid supplementation in protecting muscle loss during muscle-disuse and in cancer cachexia, and critically evaluate the molecular mechanisms that underpin the phenotypic changes observed in skeletal muscle with omega-3 fatty acid intake.

Equivalent Hypertrophy and Strength Gains in ß-Hydroxy-ß-Methylbutyrate- or Leucine-supplemented Men.

Ingestion of proteins with high leucine content during resistance training (RT) can augment hypertrophy. Some data suggest that a leucine metabolite, ß-hydroxy, ß-methylbutyrate (HMB), is substantially more anabolically efficacious than leucine. PURPOSE: We aimed to test whether supplementation with HMB versus leucine, added to whey protein, would result in differential muscle hypertrophy and strength gains in young men performing RT. METHODS: Twenty-six resistance-trained men (23 ± 2 yr) performed 12 wk of RT with three phases. Phase 1: 8 wk of periodized RT (three training sessions per week). Phase 2: 2 wk overreaching period (five sessions per week). Phase 3: 2 wk taper (three sessions per week). Participants were randomly assigned to twice daily ingestion of: whey protein (25 g) plus HMB (1.5 g) (whey+HMB; n = 13) or whey protein (25 g) plus leucine (1.5 g) (whey+leu; n = 13). Skeletal muscle biopsies were performed before and after RT. Measures of fat- and bone-free mass, vastus lateralis (VL) muscle thickness and muscle cross-sectional area (CSA) (both by ultrasound), muscle fiber CSA, and 1-repetition maximum (1-RM) strength tests were determined. RESULTS: We observed increases in fat- and bone-free mass, VL muscle thickness, muscle CSA and fiber type CSA and 1-RM strength with no differences between groups at any phase. We observed no differences between groups or time-group interactions in hormone concentrations at any phase of the RT program. CONCLUSIONS: ß-Hydroxy-ß-methylbutyrate added to whey did not result in greater increases in any measure of muscle mass, strength, or hormonal concentration compared to leucine added to whey. Our results show that HMB is no more effective in stimulating RT-induced hypertrophy and strength gains than leucine.

Effects of cotreatment with omega-3 polyunsaturated fatty acids and anticancer agents on oxidative stress parameters: a systematic review of in vitro, animal, and human studies.

Context: Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid and eicosapentaenoic acid, demonstrate possible beneficial effects as adjuvants in cancer treatment. One mechanism seems to be related to alterations in the redox status of cancer cells. Such alterations are thought to act in synergy with conventional anticancer agents. Objective: This review examines published data on the effects of cotreatment with anticancer agents and n-3 PUFAS on oxidative stress parameters to determine whether any patterns of oxidative stress alterations can be identified. Data Sources: A systematic search of MEDLINE (via PubMed) was conducted to identify articles published in English, Spanish, or Portuguese until November 2017. Study Selection: The following inclusion criteria were applied: (1) individuals or animals with cancer or malignant cell lines supplemented with some source of n-3 PUFAs; (2) concomitant use of anticancer treatment; and (3) evaluation of oxidative stress-related variables. Data Extraction: A standardized outline was used to extract the following data: study type, supplement used, type of cells, tumor or patient characteristics, study design, anticancer treatment used, and oxidative stress-related outcomes. Results: After the literature search and screening of 1563 citations, 28 studies were included for data extraction and evaluation: 16 in vitro studies (2 of which also used in vivo studies), 8 animal studies, and 4 human studies (3 clinical trials and 1 case series). In most in vitro and animal studies, intervention groups receiving cotreatment with n-3 PUFAs showed enhanced lipid peroxidation and cytotoxicity compared with groups receiving anticancer treatment alone. Eleven of the 12 studies that investigated the effect of vitamin E on the sensitivity of cancer cells to the oxidative stress caused by n-3 PUFAs showed that vitamin E abolished the positive effects of cotreatment. Conclusions: Alterations in oxidative stress caused by cotreatment with anticancer agents and n-3 PUFAs can exert positive effects on the efficacy of conventional treatment. This seems to occur in most cells and tumors tested thus far, but not all. Identifying tumors that are sensitive to these oxidative effects may provide support for the rational use of n-3 PUFAs as an adjuvant treatment in specific types of cancer.

Assessing the mechanistic target of rapamycin complex-1 pathway in response to resistance exercise and feeding in human skeletal muscle by multiplex assay.

The mechanistic target of rapamycin complex-1 (mTORC-1) is a key nutrient and contraction-sensitive protein that regulates a pathway leading to skeletal muscle growth. Utilizing a multiplex assay, we aimed to examine the phosphorylation status of key mTORC-1-related signalling molecules in response to protein feeding and resistance exercise. Eight healthy men (age, 22.5 ± 3.1 years; mass, 80 ± 9 kg; 1-repetition maximum leg extension, 87 ± 5 kg) performed 4 sets of unilateral leg extensions until volitional failure. Immediately following the final set, all participants consumed a protein-enriched beverage. A single skeletal muscle biopsy was obtained from the vastus lateralis before (Pre) with further bilateral biopsies at 1 h (1 h exercised legs (FEDEX) and 1 h nonexercised legs (FED)) and 3 h (3 h FEDEX and 3 h FED) after drink ingestion. Phosphorylated AktSer473 was significantly elevated from Pre at 1 h FEDEX. Phosphorylated p70S6K1Thr412 was significantly increased above Pre at 1 h FEDEX and 1 h FED and was still significantly elevated at 3 h FEDEX but not 3 h FED. Phosphorylated rpS6Ser235/236 was also significantly increased above Pre at 1 h FEDEX and 1 h FED with 1 h FEDEX greater than 1 h FED. Our data highlight the utility of a multiplex assay to assess anabolic signalling molecules in response to protein feeding and resistance exercise in humans. Importantly, these changes are comparable with those as previously reported using standard immunoblotting and protein activity assays.

Glucose homeostasis in two degrees of sepsis lethality induced by caecum ligation and puncture in mice.

Sepsis is associated with high mortality. Both critically ill humans and animal models of sepsis exhibit changes in their glucose homeostasis, that is, hypoglycaemia, with the progression of infection. However, the relationship between basal glycaemia, glucose tolerance and insulin sensitivity is not well understood. Thus, we aimed to evaluate this glucose homeostasis triad at the late stage of sepsis (24 h after surgery) in male Swiss mice subjected to lethal and sublethal sepsis by the caecal ligation and puncture (CLP) model. The percentage of survival 24 h after CLP procedure in the Lethal and Sublethal groups was around 66% and 100% respectively. Both Lethal and Sublethal groups became hypoglycaemic in fasting and fed states 24 h after surgery. The pronounced fed hypoglycaemia in the Lethal group was not due to worsening anorexic behaviour or hepatic inability to deliver glucose in relation to the Sublethal group. Reduction in insulin sensitivity in CLP mice occurred in a lethality-dependent manner and was not associated with glucose intolerance. Analysis of oral and intraperitoneal glucose tolerance tests, as well as the gastrointestinal motility data, indicated that CLP mice had reduced intestinal glucose absorption. Altogether, we suggest cessation of appetite and intestinal glucose malabsorption are key contributors to the hypoglycaemic state observed during experimental severe sepsis.

Impact of Fish Oil Supplementation and Interruption of Fructose Ingestion on Glucose and Lipid Homeostasis of Rats Drinking Different Concentrations of Fructose.

Background. Continuous fructose consumption may cause elevation of circulating triacylglycerol. However, how much of this alteration is reverted after the removal of fructose intake is not known. We explored this question and compared the efficacy of this approach with fish oil supplementation. Methods. Male Wistar rats were divided into the following groups: control (C), fructose (F) (water intake with 10% or 30% fructose for 9 weeks), fish oil (FO), and fructose/fish oil (FFO). Fish oil was supplemented only for the last 33 days of fructose ingestion. Half of the F group remained for additional 8 weeks without fructose ingestion (FR). Results. Fructose ingestion reduced food intake to compensate for the increased energy obtained through water ingestion, independent of fructose concentration. Fish oil supplementation exerted no impact on these parameters, but the removal of fructose from water recovered both ingestion behaviors. Plasma triacylglycerol augmented significantly during the second and third weeks (both fructose groups). Fish oil supplementation did not attenuate the elevation in triacylglycerol caused by fructose intake, but the interruption of sugar consumption normalized this parameter. Conclusion. Elevation in triacylglyceridemia may be recovered by removing fructose from diet, suggesting that it is never too late to repair improper dietary habits.

Does Oil Rich in Alpha-Linolenic Fatty Acid Cause the Same Immune Modulation as Fish Oil in Walker 256 Tumor-Bearing Rats?

OBJECTIVE: Polyunsaturated fatty acids n-3 (PUFA n-3) have shown effects in reducing tumor growth, in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) abundantly present in fish oil (FO). When these fatty acids are provided in the diet, they alter the functions of the cells, particularly in tumor and immune cells. However, the effects of α-linolenic fatty acid (ALA), which is the precursor of EPA and DHA, are controversial. Thus, our objective was to test the effect of this parental fatty acid. METHODS: Non-tumor-bearing and tumor-bearing Wistar rats (70 days) were supplemented with 1 g/kg body weight of FO or Oro Inca® (OI) oil (rich in ALA). Immune cells function, proliferation, cytokine production, and subpopulation profile were evaluated. RESULTS: We have shown that innate immune cells enhanced phagocytosis capacity, and increased processing and elimination of antigens. Moreover, there was a decrease in production of pro-inflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6)) by macrophages. Lymphocytes showed decreased proliferation capacity, increased cluster of differentiation 8 (CD8+) subpopulation, and increased TNF-α production. CONCLUSIONS: Oil rich in ALA caused similar immune modulation in cancer when compared with FO.

Effects of Prebiotic and Synbiotic Supplementation on Inflammatory Markers and Anthropometric Indices After Roux-en-Y Gastric Bypass: A Randomized, Triple-blind, Placebo-controlled Pilot Study.

BACKGROUND: Studies have shown that prebiotics and synbiotics modulate the intestinal microbiota and may have beneficial effects on the immune response and anthropometric indices; however, the impact of the use of these supplements after bariatric surgery is not yet known. GOALS: This study investigated the effects of prebiotic and synbiotic supplementation on inflammatory markers and anthropometric indices in individuals undergoing open Roux-en-Y gastric bypass (RYGB). STUDY: In this randomized, controlled, and triple-blind trial conducted as a pilot study, individuals undergoing RYGB (n=9) and healthy individuals (n=9) were supplemented with 6 g/d of placebo (maltodextrin), prebiotic (fructo-oligosaccharide, FOS), or synbiotic (FOS+Lactobacillus and Bifidobacteria strains) for 15 days. RESULTS: Interleukin-1ß, interleukin-6, tumor necrosis factor-α, C-reactive protein, albumin, and the C-reactive protein/albumin ratio showed no significant changes on comparison between groups after supplementation. The reduction in the body weight of patients undergoing RYGB was 53.8% higher in the prebiotic group compared with the placebo group (-0.7 kg, P=0.001), whereas the reduction in the BMI and the increase in the percentage of excess weight loss were higher in the placebo and the prebiotic groups compared with the synbiotic group (P<0.05). CONCLUSIONS: Supplementation of FOS increased weight loss, whereas both prebiotics and synbiotics were not able to promote significant changes in inflammatory markers, although in most analyses, there was a reduction in their absolute values. The use of FOS may represent a potential adjunct in the treatment of obesity.

Fish oil supplementation improves neutrophil function during cancer chemotherapy.

Cancer chemotherapy is associated with neutropenia and impaired neutrophil function. This study aimed to investigate whether supplementation with low dose fish oil (FO), providing n-3 polyunsaturated fatty acids, in cancer patients receiving chemotherapy after surgical tumor (mainly gastrointestinal) removal is able to improve the function of blood neutrophils. Patients (n = 38) receiving chemotherapy (5-fluorouracil and leucovorin) were randomized into two groups; one group (control) did not receive a supplement, while the other group (FO) received 2 g FO/day for 8 weeks; the FO provided 0.3 g eicosapentaenoic acid plus 0.4 g docosahexaenoic acid per day. Patients in the control group lost an average of 2.5 kg of weight over the 8 weeks of the study. The number of blood polymorphonuclear cells (PMNC), mainly neutrophils, and their functions (phagocytosis and hydrogen peroxide production) decreased in the control group (average decreases of approximately 30, 45 and 17%, respectively). FO prevented these decreases and actually increased body weight (average of 1.7 kg weight gain; p < 0.002 vs. control group), PMNC number (average 29% increase), phagocytosis (average 14% increase) and superoxide production (average 28% increase). FO may be useful in preventing chemotherapy-induced decline in neutrophil number and function.

Low fish oil intake improves insulin sensitivity, lipid profile and muscle metabolism on insulin resistant MSG-obese rats.

BACKGROUND: Obesity is commonly associated with diabetes, cardiovascular diseases and cancer. The purpose of this study was to determinate the effect of a lower dose of fish oil supplementation on insulin sensitivity, lipid profile, and muscle metabolism in obese rats. METHODS: Monosodium glutamate (MSG) (4 mg/g body weight) was injected in neonatal Wistar male rats. Three-month-old rats were divided in normal-weight control group (C), coconut fat-treated normal weight group (CO), fish oil-treated normal weight group (FO), obese control group (Ob), coconut fat-treated obese group (ObCO) and fish oil-treated obese group (ObFO). Obese insulin-resistant rats were supplemented with fish oil or coconut fat (1 g/kg/day) for 4 weeks. Insulin sensitivity, fasting blood biochemicals parameters, and skeletal muscle glucose metabolism were analyzed. RESULTS: Obese animals (Ob) presented higher Index Lee and 2.5 fold epididymal and retroperitoneal adipose tissue than C. Insulin sensitivity test (Kitt) showed that fish oil supplementation was able to maintain insulin sensitivity of obese rats (ObFO) similar to C. There were no changes in glucose and HDL-cholesterol levels amongst groups. Yet, ObFO revealed lower levels of total cholesterol (TC; 30%) and triacylglycerol (TG; 33%) compared to Ob. Finally, since exposed to insulin, ObFO skeletal muscle revealed an increase of 10% in lactate production, 38% in glycogen synthesis and 39% in oxidation of glucose compared to Ob. CONCLUSIONS: Low dose of fish oil supplementation (1 g/kg/day) was able to reduce TC and TG levels, in addition to improved systemic and muscle insulin sensitivity. These results lend credence to the benefits of n-3 fatty acids upon the deleterious effects of insulin resistance mechanisms.

ß-Hydroxy-ß-methylbutyrate modifies human peripheral blood mononuclear cell proliferation and cytokine production in vitro.

OBJECTIVE: The main objective was to investigate the potential immunomodulatory effects of ß-hydroxy-ß-methylbutyrate (HMB) in human cells. METHODS: Peripheral blood mononuclear cells were isolated from the blood of eight volunteers and assayed for proliferation, cell cycle progression, surface expression of CD25, intracellular expression of pERK1/2, and cytokine production after in vitro exposure to a range of HMB concentrations (0.1 to 10 mM). RESULTS: Above 1 mM, HMB decreased the extent of proliferation normally observed after stimulation by concanavalin A. The decrease was evident at 10 mM HMB, when the proliferation index was 50% reduced when compared with the absence of HMB. Cell cycle analysis demonstrated an increase in the proportion of cells at the G0-G1 phase at 10 mM HMB. CD25 and pERK1/2 expression were not related to the observed effect on proliferation. HMB affected the concentrations of all five cytokines measured following stimulation. Tumor necrosis factor-α concentration in the culture medium was reduced by ~35% at all HMB concentrations. Th1/Th2 cytokine production was modified toward a Th2 profile when HMB was at 1 or 10 mM. Thus, HMB at 10 mM impairs lymphocyte proliferation and progression through the cell cycle. The lowest concentration used here (0.1 mM) exerted some actions on cytokine production, including decreasing TNF-α production, but not on proliferation and cell cycle progression. CONCLUSION: HMB may be a useful agent to consider for modulation of immune function in specific situations.

Walker-256 tumor growth is inhibited by the independent or associative chronic ingestion of shark liver and fish oil: a response linked by the increment of peritoneal macrophages nitrite production in Wistar rats.

Fish oil (FO) is widely known by its capacity to positively modulate immune parameters and decrease the growth of some tumors. Despite the enormous number of studies addressing the effects of FO, there are few reports showing similar results using other marine sources of lipid compounds with biologic importance. This study aimed to compare the effects of shark liver oil (SLO), which is a source of omega-3 fatty acids and alkylglycerols, with those obtained with FO administration, or the association of both, on tumor growth and the innate immune system in Walker-256 tumor-bearing rats. Beginning at 21 days of age, Wistar rats were fed regular chow and/or FO and/or SLO supplement (1 g/kg body weight per day) for 14 weeks. Walker-256 tumor cells were inoculated on the 90th day. As expected, 14 days after inoculation, rats fed with FO presented tumor weights that were 50% lower than the control tumors (P < .05). The association of both FO and SLO and ingestion of SLO alone also reached the same reduction level. Except for adhesion, all macrophage parameters assayed were 200% higher in rats fed with FO and those supplemented with both FO and SLO compared with control rats. Only reactive nitrogen species production was increased by SLO. These results suggest that SLO might also have indirect antitumor properties. Conversely, there were no additive effects when SLO was administered with FO. Therefore, SLO is another marine compound with in vivo antitumor effects, but its action mechanisms seem not to be related to major modifications on macrophage function.

Glutamine concentration and immune response of spinal cord-injured rats.

BACKGROUND/OBJECTIVES: Glutamine plays a key role in immune response. Spinal cord injury (SCI) leads to severe loss of muscle mass and to a high incidence of infections. This study investigated the acute effect of SCI (2 and 5 days) on the plasma glutamine and skeletal muscle concentrations and immune responses in rats. METHODS: A total of 29 adult male Wistar rats were divided as follows: control (C; n = 5), sham-operated (S2; n = 5) and spinal cord-transected (T2; n = 7). They were killed on day 2 after surgery/transection (acute phase). Another set was sham-operated (S5; n = 5), spinal cord-transected (T5; n = 7), and killed at day 5 after surgery/transection (secondary phase). Blood was collected; the white portion of the epitrochlearis and gastrocnemius muscles and the red portion of soleus muscles were dissected to measure the glutamine concentration. Gut-associated lymphocytes and peritoneal macrophages were obtained for immune parameters measurements. RESULTS: Glutamine concentration in the plasma, gastrocnemius, and soleus muscles in rats with SCI were significantly reduced but not in the epitrochlearis muscle in the acute (2 days) and secondary (5 days) phases. Phagocytic response was reduced in the acute phase but increased in the secondary phase in rats with SCI. Superoxide production, on the other hand, was significantly increased at days 2 and 5 after SCI, and CD8+ lymphocytes subset decreased significantly on days 2 and 5. CONCLUSIONS: Our results showed reduction in plasma glutamine and skeletal muscle concentrations after spinal cord transection. They also suggest that SCI and glutamine reduction contribute to an alteration in immune competence.

Decreased tumor growth in Walker 256 tumor-bearing rats chronically supplemented with fish oil involves COX-2 and PGE2 reduction associated with apoptosis and increased peroxidation.

Many studies have shown that addition of fish oil (FO) to the diet reduces tumor growth but the mechanism(s) of action involved is (are) still unknown. In this study, we examine some possible mechanisms in tumor-bearing rats chronically supplemented with FO. Male Wistar rats (21 days old) were fed with regular chow and supplemented with coconut or FO (1g/kg body weight) until they reached 70 days of age. Then, they were inoculated with a suspension of Walker 256 ascitic tumor cells (2 x 10(7)ml) and after 14 days they were killed. Supplementation with FO resulted in significantly lower tumor weight, greater tumor cell apoptosis, lower ex vivo tumor cell proliferation, a higher tumor content of lipid peroxides, lower expression of cyclooxygenase-2 (COX-2) in tumor tissue and a lower plasma concentration of prostaglandin E2 than observed in rats fed regular chow or supplemented with coconut oil. These results suggest that reduction of tumor growth by FO involves an increase in apoptosis and of lipid peroxidation in tumor tissue, with a reduction in tumor cell proliferation ex vivo, COX-2 expression and PGE2 production. Thus, FO may act simultaneously through multiple effects to reduce tumor growth. Whether these effects are connected through a single underlying mechanism remains to be seen.

Fish oil alters T-lymphocyte proliferation and macrophage responses in Walker 256 tumor-bearing rats.

OBJECTIVE: We investigated the effect of the dietary ratio of omega-6 to omega-3 polyunsaturated fatty acids (PUFAs) from postweaning until adulthood on T-lymphocyte proliferation, T-lymphocyte subpopulations (helper and cytotoxic), and production of cytotoxic mediators by macrophages in tumor-bearing rodents. METHODS: Weanling male Wistar rats received a normal low-fat (40 g/kg of diet) chow diet or a high-fat (300 g /kg) diet that included fish or sunflower oil or blends of fish and sunflower oils to yield omega-6:omega-3 PUFA ratios of approximately 6:1, 30:1, and 60:1 ad libitum. After 8 wk, 50% of rats in each group were inoculated with 1 mL of 2 x 10(7) Walker 256 cells. Fourteen days after tumor inoculation, animals were killed and lymphocytes and macrophages were obtained for study. RESULTS: The diets richest in omega-6 PUFA resulted in higher proliferation of thymus, spleen, and gut-associated lymphocytes compared with the chow diet irrespective of tumor burden. In contrast, the fish oil diet resulted in lower proliferation of thymus and spleen lymphocytes compared with the chow diet. Diets rich in omega-6 PUFA decreased the proportion of CD8+ lymphocytes. In non-tumor-bearing and tumor-bearing rats, hydrogen peroxide production by macrophages was highest in rats that consumed diets high in omega-3 PUFAs. Superoxide and nitric oxide production were little affected by the dietary ratio of omega-6 to omega-3 PUFAs. CONCLUSION: Dietary omega-6 and omega-3 PUFA contents alter immune function in non-tumor-bearing and tumor-bearing rats. The omega-3 PUFAs decreased T-cell proliferation but increased hydrogen peroxide production compared with omega-6 PUFAs. Decreased tumor growth and cachexia and increased survival previously reported for fish oil in Walker 256 tumor-bearing rats may be related to improved macrophage function rather than to improved T-cell function.