Effects of Chronic Ochratoxin A Exposure on p53 Heterozygous and p53 Homozygous Mice.

Exposure to the mycotoxin ochratoxin A (OTA) causes nephropathy in domestic animals and rodents and renal tumors in rodents and poultry. Humans are exposed to OTA by consuming foods made with contaminated cereal grains and other commodities. Management of human health risks due to OTA exposure depends, in part, on establishing a mode of action (MOA) for OTA carcinogenesis. To further investigate OTA's MOA, p53 heterozygous (p53+/-) and p53 homozygous (p53+/+) mice were exposed to OTA in diet for 26 weeks. The former are susceptible to tumorigenesis upon chronic exposure to genotoxic carcinogens. OTA-induced renal damage but no tumors were observed in either strain, indicating that p53 heterozygosity conferred little additional sensitivity to OTA. Renal changes included dose-dependent increases in cellular proliferation, apoptosis, karyomegaly, and tubular degeneration in proximal tubules, which were consistent with ochratoxicosis. The lowest observed effect level for renal changes in p53+/- and p53+/+ mice was 200 µg OTA/kg bw/day. Based on the lack of tumors and the severity of renal and body weight changes at a maximum tolerated dose, the results were interpreted as suggestive of a primarily nongenotoxic (epigenetic) MOA for OTA carcinogenesis in this mouse model.

The effect of a diet containing 70% protein from plants on mineral metabolism and musculoskeletal health in chronic kidney disease.

BACKGROUND: Chronic Kidney Disease (CKD) is associated with alterations in phosphorus excretion, and increases in fibroblast growth factor (FGF23) and parathyroid hormone (PTH). Plant protein-based phytate-bound phosphorus, is less bioavailable than that from animal sources. Our one-week study that was conducted previously showed that a nearly 100% plant protein-based diet benefits mineral metabolism in CKD; however, this diet may not be acceptable to patients. Here we hypothesize that a diet containing 70% protein from plants has similar efficacy and is tolerated by CKD patients. METHODS: Thirteen subjects with CKD 3-4 received an omnivorous diet containing 70% protein from plants for 4 weeks. The primary outcome was change in 24 h urine phosphorus. Secondary outcomes were changes in serum phosphorus, FGF23, PTH, urine sodium excretion, grip strength and fat free mass. Repeated measures analysis of variance (ANOVA) was used to test differences in parameters over the 4 weeks. RESULTS: Mean age of subjects was 54.8 years. Median eGFR was 26 (IQR 14.7) ml/min/1.73 m(2). Over the 4-week period, urine phosphorus significantly decreased by 215 ± 232 mg/day (p < 0.001). No significant changes in serum FGF23, phosphorus or PTH were noted. Urine sodium and titratable acid decreased significantly on the diet. Hand grip strength and fat-free mass did not change. There were two hyperkalemia events both 5.8 mEq/l, corrected by food substitutions. No other adverse events were observed. CONCLUSIONS: A 70% plant protein diet is safe, tolerated, and efficacious in lowering urine phosphorus excretion and may be an alternative to phosphate binders.

Resistance exercise training-induced decrease in circulating inflammatory CD14+CD16+ monocyte percentage without weight loss in older adults.

PURPOSE: Exercise training reduces systemic inflammation in weight-stable people, but concurrent diet-induced body weight loss is not well studied. We hypothesized that resistance training would decrease inflammatory monocyte percentage and improve biomarkers associated with disease risk, independent of weight loss. METHODS: Forty physically inactive (PI) subjects (58.0 ± 5.7 years; BMI 30.1 ± 4.3 kg m(-2)) completed baseline testing, and 26 of these subjects completed 12-week of resistance training exercises while consuming either their usual, weight-maintenance diet (RE, n = 14) or an energy-restricted diet (RE-ER, n = 12). Nine physically active (PA) subjects served as a comparison group (60.1 ± 6.1 years; BMI 25.8 ± 3.1 kg m(-2)). RESULTS: At baseline, circulating CD14+CD16+ monocyte percentage, C-reactive protein, and cholesterol were higher in PI vs. PA. Post-intervention, RE subjects had a ~35 % decrease in circulating CD14+CD16+, and a lower LPS-stimulated TNFα and IL-6 production, while RE-ER subjects had lower cholesterol than RE. CONCLUSIONS: These findings indicate that resistance training is an effective means for older, overweight adults to reduce systemic inflammation. The unexpected lack of response with concurrent energy restriction underscores the need for further research on the use of resistance training and diet to reduce inflammation.

Parent/caregiver's role in nutrition, physical activity, and food access among children diagnosed with spina bifida.

PURPOSE: This pilot study aimed to determine the parent/caregiver's role in nutrition/eating habits, physical activity behaviors, and food access among children diagnosed with spina bifida (SB). METHODS: Parents/caregivers of children with SB were asked to participate at a single, outpatient SB clinic. Demographic, biomedical data, parent/caregiver nutrition knowledge, family nutrition and physical activity (FNPA), and food security survey scores were compared. Descriptive, regression, and correlational statistics were conducted for analysis via SPSS 29. RESULTS: Of the 117 parents/caregivers surveyed, completed data suggested most were overweight/obese (average body mass index [BMI] of 30.63 kg/m2±8.40; n = 99) with an average nutrition knowledge score of 71% (17.83±3.33). As FNPA scores decreased, the patient/child's maximum BMI z scores increased (ß= -0.043; confidence interval -0.079, -0.007; p = 0.020), suggesting the less active and/or less healthy eating habits, the higher body mass was noted for the child. Forty four percent of children (n = 99) were in the overweight/obese weight range based on maximum BMI z score. CONCLUSION: These findings suggest there is a need for parental/caregiver nutrition education to assist children with SB with meal and activity planning to achieve optimal health.

Altered cord blood gammadelta T cell repertoire in Nigeria: possible impacts of environmental factors on neonatal immunity.

Infectious diseases during pregnancy can impact the development of fetal immunity, leading to reduced neonatal resistance to infection and decreased responses to pediatric vaccines. Plasmodium falciparum causes placental infection in low parity pregnant women and is among the pathogens that affect fetal immunity. Recognizing the relationship between malaria and gammadelta T lymphocytes in adults, we asked whether neonatal gammadelta T cells would be altered in malaria-endemic regions as a marker for changes in fetal immunity. Our initial studies compared cord blood gammadelta T cells from deliveries to HIV- mothers in Jos (Nigeria) where malaria is endemic, or in Rome (Italy). We noted substantial differences in the Vgamma2 repertoire for cord blood collected in Jos or Rome; differences were consistent with a negative selection mechanism operating on the fetal Vgamma2 chain repertoire in neonates from Jos. A specific disruption affected the fraction of gammadelta T cells that we expect will respond to Bacille Calmette-Guerin (BCG). Fetal gammadelta T cell depletion might be a mechanism for impaired neonatal immunity and lowered responses to pediatric vaccines.

Effects of Dietary Protein Source and Quantity during Weight Loss on Appetite, Energy Expenditure, and Cardio-Metabolic Responses.

Higher protein meals increase satiety and the thermic effect of feeding (TEF) in acute settings, but it is unclear whether these effects remain after a person becomes acclimated to energy restriction or a given protein intake. This study assessed the effects of predominant protein source (omnivorous, beef/pork vs. lacto-ovo vegetarian, soy/legume) and quantity (10%, 20%, or 30% of energy from protein) on appetite, energy expenditure, and cardio-metabolic indices during energy restriction (ER) in overweight and obese adults. Subjects were randomly assigned to one protein source and then consumed diets with different quantities of protein (4 weeks each) in a randomized crossover manner. Perceived appetite ratings (free-living and in-lab), TEF, and fasting cardio-metabolic indices were assessed at the end of each 4-week period. Protein source and quantity did not affect TEF, hunger, or desire to eat, other than a modestly higher daily composite fullness rating with 30% vs. 10% protein diet (p = 0.03). While the 20% and 30% protein diets reduced cholesterol, triacylglycerol, and APO-B vs. 10% protein (p < 0.05), protein source did not affect cardio-metabolic indices. In conclusion, diets varying in protein quantity with either beef/pork or soy/legume as the predominant source have minimal effects on appetite control, energy expenditure and cardio-metabolic risk factors during ER-induced weight loss.

TWEAK activation of the non-canonical NF-κB signaling pathway differentially regulates melanoma and prostate cancer cell invasion.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that binds with high affinity to a plasma membrane-anchored receptor named Fn14. Both TWEAK and Fn14 expression has been detected in human cancer tissue, and studies have shown that TWEAK/Fn14 signaling can promote either "pro-cancer" or "anti-cancer" cellular effects in vitro, depending on the cancer cell line under investigation. In this study, we engineered murine B16 melanoma cells to secrete high levels of soluble TWEAK and examined their properties. TWEAK production by B16 cells preferentially activated the non-canonical NF-κB signaling pathway and increased the expression of several previously described TWEAK-inducible genes, including Fn14. TWEAK overexpression in B16 cells inhibited both cell growth and invasion in vitro. The TWEAK-mediated reduction in B16 cell invasive capacity was dependent on activation of the non-canonical NF-κB signaling pathway. Finally, we found that this same signaling pathway was also important for TWEAK-stimulated human DU145 prostate cancer cell invasion. Therefore, even though TWEAK:Fn14 binding activates non-canonical NF-κB signaling in both melanoma and prostate cancer cells, this shared cellular response can trigger a very different downstream outcome (inhibition or stimulation of cell invasiveness, respectively).

The apéritif effect: Alcohol's effects on the brain's response to food aromas in women.

OBJECTIVE: Consuming alcohol prior to a meal (an apéritif) increases food consumption. This greater food consumption may result from increased activity in brain regions that mediate reward and regulate feeding behavior. Using functional magnetic resonance imaging, we evaluated the blood oxygenation level dependent (BOLD) response to the food aromas of either roast beef or Italian meat sauce following pharmacokinetically controlled intravenous infusion of alcohol. METHODS: BOLD activation to food aromas in non-obese women (n = 35) was evaluated once during intravenous infusion of 6% v/v EtOH, clamped at a steady-state breath alcohol concentration of 50 mg%, and once during infusion of saline using matching pump rates. Ad libitum intake of roast beef with noodles or Italian meat sauce with pasta following imaging was recorded. RESULTS: BOLD activation to food relative to non-food odors in the hypothalamic area was increased during alcohol pre-load when compared to saline. Food consumption was significantly greater, and levels of ghrelin were reduced, following alcohol. CONCLUSIONS: An alcohol pre-load increased food consumption and potentiated differences between food and non-food BOLD responses in the region of the hypothalamus. The hypothalamus may mediate the interplay of alcohol and responses to food cues, thus playing a role in the apéritif phenomenon.

Ventral frontal satiation-mediated responses to food aromas in obese and normal-weight women.

BACKGROUND: Sensory properties of foods promote and guide consumption in hunger states, whereas satiation should dampen the sensory activation of ingestive behaviors. Such activation may be disordered in obese individuals. OBJECTIVE: Using functional magnetic resonance imaging (fMRI), we studied regional brain responses to food odor stimulation in the sated state in obese and normal-weight individuals targeting ventral frontal regions known to be involved in coding for stimulus reward value. DESIGN: Forty-eight women (25 normal weight; 23 obese) participated in a 2-day (fed compared with fasting) fMRI study while smelling odors of 2 foods and an inedible, nonfood object. Analyses were conducted to permit an examination of both general and sensory-specific satiation (satiation effects specific to a given food). RESULTS: Normal-weight subjects showed significant blood oxygen level-dependent responses in the ventromedial prefrontal cortex (vmPFC) to food aromas compared with responses induced by the odor of an inedible object. Normal-weight subjects also showed general (but not sensory-specific) satiation effects in both the vmPFC and orbitofrontal cortex. Obese subjects showed no differential response to the aromas of food and the inedible object when fasting. Within- and between-group differences in satiation were driven largely by changes in the response to the odor of the inedible stimulus. Responses to food aromas in the obese correlated with trait negative urgency, the tendency toward negative affect-provoked impulsivity. CONCLUSIONS: Ventral frontal signaling of reward value may be disordered in obesity, with negative urgency heightening responses to food aromas. The observed nature of responses to food and nonfood stimuli suggests that future research should independently quantify each to fully understand brain reward signaling in obesity.

TWEAK/Fn14 Axis-Targeted Therapeutics: Moving Basic Science Discoveries to the Clinic.

The TNF superfamily member TWEAK (TNFSF12) is a multifunctional cytokine implicated in physiological tissue regeneration and wound repair. TWEAK is initially synthesized as a membrane-anchored protein, but furin cleavage within the stalk region can generate a secreted TWEAK isoform. Both TWEAK isoforms bind to a small cell surface receptor named Fn14 (TNFRSF12A) and this interaction stimulates various cellular responses, including proliferation and migration. Fn14, like other members of the TNF receptor superfamily, is not a ligand-activated protein kinase. Instead, TWEAK:Fn14 engagement promotes Fn14 association with members of the TNFR associated factor family of adapter proteins, which triggers activation of various signaling pathways, including the classical and alternative NF-κB pathways. Numerous studies have revealed that Fn14 gene expression is significantly elevated in injured tissues and in most solid tumor types. Also, sustained Fn14 signaling has been implicated in the pathogenesis of cerebral ischemia, chronic inflammatory diseases, and cancer. Accordingly, several groups are developing TWEAK- or Fn14-targeted agents for possible therapeutic use in patients. These agents include monoclonal antibodies, fusion proteins, and immunotoxins. In this article, we provide an overview of some of the TWEAK/Fn14 axis-targeted agents currently in pre-clinical animal studies or in human clinical trials and discuss two other potential approaches to target this intriguing signaling node.

Normal vs. high-protein weight loss diets in men: effects on body composition and indices of metabolic syndrome.

OBJECTIVE: This study assessed the effectiveness of a prescribed weight-loss diet with 0.8 versus 1.4 g protein·kg(-1) day(-1) on changes in weight, body composition, indices of metabolic syndrome, and resting energy expenditure (REE) in overweight and obese men. DESIGN AND METHODS: Men were randomized to groups that consumed diets containing 750 kcal day(-1) less than daily energy needs for weight maintenance with either normal protein (NP, n = 21) or higher protein (HP, n = 22) content for 12 weeks. The macronutrient distributions of the NP and HP diets were 25:60:15, and 25:50:25 percent energy from fat, carbohydrate, and protein, respectively. Assessments were made pre and post intervention. The subjects were retrospectively subgrouped into overweight and obese groups. RESULTS AND CONCLUSION: Both diet groups lost comparable body weight and fat. The HP group lost less lean body mass than the NP group (-1.9 ± 0.3 vs. -3.0 ± 0.4 kg). The effects of protein and BMI status on lean body mass loss were additive. The reductions in total cholesterol, HDL-C, triacylglycerol, glucose, and insulin, along with LDL-C, total cholesterol-to-HDL-C ratio, and HOMA-IR, were not statistically different between NP and HP. Likewise, macronutrient distributions of the diet did not affect the reductions in REE, and blood pressure. In conclusion, energy restriction effectively improves multiple clinical indicators of cardiovascular health and glucose control, and consumption of a higher-protein diet and accomplishing weight loss when overweight versus obese help men preserve lean body mass over a short period of time.

The effects of consuming frequent, higher protein meals on appetite and satiety during weight loss in overweight/obese men.

The purpose of this study was to determine the effects of dietary protein and eating frequency on perceived appetite and satiety during weight loss. A total of 27 overweight/obese men (age 47 ± 3 years; BMI 31.5 ± 0.7 kg/m(2)) were randomized to groups that consumed an energy-restriction diet (i.e., 750 kcal/day below daily energy need) as either higher protein (HP, 25% of energy as protein, n = 14) or normal protein (NP, 14% of energy as protein, n = 13) for 12 weeks. Beginning on week 7, the participants consumed their respective diets as either 3 eating occasions/day (3-EO; every 5 h) or 6 eating occasions/day (6-EO; every 2 h), in randomized order, for 3 consecutive days. Indexes of appetite and satiety were assessed every waking hour on the third day of each pattern. Daily hunger, desire to eat, and preoccupation with thoughts of food were not different between groups. The HP group experienced greater fullness throughout the day vs. NP (511 ± 56 vs. 243 ± 54 mm · 15 h; P < 0.005). When compared to NP, the HP group experienced lower late-night desire to eat (13 ± 4 vs. 27 ± 4 mm, P < 0.01) and preoccupation with thoughts of food (8 ± 4 vs. 21 ± 4 mm; P < 0.01). Within groups, the 3 vs. 6-EO patterns did not influence daily hunger, fullness, desire to eat, or preoccupation with thoughts of food. The 3-EO pattern led to greater evening and late-night fullness vs. 6-EO but only within the HP group (P < 0.005). Collectively, these data support the consumption of HP intake, but not greater eating frequency, for improved appetite control and satiety in overweight/obese men during energy restriction-induced weight loss.

The influence of higher protein intake and greater eating frequency on appetite control in overweight and obese men.

The purpose of this study was to determine the effects of dietary protein intake and eating frequency on perceived appetite, satiety, and hormonal responses in overweight/obese men. Thirteen men (age 51 +/- 4 years; BMI 31.3 +/- 0.8 kg/m(2)) consumed eucaloric diets containing normal protein (79 +/- 2 g protein/day; 14% of energy intake as protein) or higher protein (138 +/- 3 g protein/day; 25% of energy intake as protein) equally divided among three eating occasions (3-EO; every 4 h) or six eating occasions (6-EO; every 2 h) on four separate days in randomized order. Hunger, fullness, plasma glucose, and hormonal responses were assessed throughout 11 h. No protein x eating frequency interactions were observed for any of the outcomes. Independent of eating frequency, higher protein led to greater daily fullness (P < 0.05) and peptide YY (PYY) concentrations (P < 0.05). In contrast, higher protein led to greater daily ghrelin concentrations (P < 0.05) vs. normal protein. Protein quantity did not influence daily hunger, glucose, or insulin concentrations. Independent of dietary protein, 6-EO led to lower daily fullness (P < 0.05) and PYY concentrations (P < 0.05). The 6-EO also led to lower glucose (P < 0.05) and insulin concentrations (P < 0.05) vs. 3-EO. Although the hunger-related perceived sensations and hormonal responses were conflicting, the fullness-related responses were consistently greater with higher protein intake but lower with increased eating frequency. Collectively, these data suggest that higher protein intake promotes satiety and challenge the concept that increasing the number of eating occasions enhances satiety in overweight and obese men.

Impact of age, gender, and race on circulating γδ T cells.

A major subset of human peripheral blood γδ T cells expresses the Vγ2Vδ2 T cell receptor and responds to malignant or infectious diseases. We noted significant differences in the numbers of Vγ2Vδ2 T cells in blood samples from healthy Caucasian CA or African American (AA) donors. On average, CA donors had 3.71% ± 4.37% Vδ2 cells (as a percentage of total lymphocytes) compared with 1.18% ± 2.14% Vδ2 cells for AA donors (p < 0.0001). Age and race had the greatest impact on Vδ2 cell levels; the effect of age was similar for both racial groups. The Vδ2 cell population was dominated, for both donor groups, by cells expressing the Vγ2-Jγ1.2 Vδ2 T cell receptor, an apparent result of strong positive selection and there was substantial overlap in the public Vγ2 clonotypes from both racial groups. Mechanisms for selection and amplification of Vδ2 cells are nearly identical for both groups, despite the significant difference in baseline levels. These data show that appropriate controls, matched for age and race, may be required for clinical studies of Vγ2Vδ2 T cells in infectious disease or cancer and raise important questions about the mechanisms regulating the levels of circulating Vδ2 cells.

Natural viral suppressors of HIV-1 have a unique capacity to maintain gammadelta T cells.

OBJECTIVE: To evaluate Vgamma2Vdelta2 T cells in a group of HIV-infected patients who suppress HIV replication without antiretroviral therapy (natural viral suppressors, NVSs). DESIGN: : It is a cross-sectional study. METHODS: We compared Vgamma2Vdelta2 T-cell frequency, T-cell repertoire, and responses to isopentenyl pyrophosphate stimulation between NVSs (n = 21) and HIV-uninfected controls (n = 27) and between NVSs and HIV-infected patients taking HAART with suppressed viral replication (HIV-P; n = 25). RESULTS: NVSs had a mean frequency of 1.06 +/- 0.82% CD3Vdelta2+ cells among total lymphocytes, which was significantly higher than both control groups (HIV-negative: 0.50 +/- 0.53%, P = 0.042; HIV-P: 0.34 +/- 0.37%, P = 0.002). The proportion of Vgamma2 chains correlating with the Vgamma2-Jgamma1.2 rearrangement was reduced among NVSs compared with HIV-negative controls (0.57 +/- 0.06 vs. 0.32 +/- 0.04; P = 0.016) but was increased compared with HIV-P patients (0.32 +/- 0.04 vs. 0.22 +/- 0.03; P = 0.03). NVSs had a similar baseline frequency of CD27/CD45RA effector cells (19.6 +/- 4.2%) compared with HIV-negative controls (20.8 +/- 12.9%; P = 0.35). CONCLUSION: The altered gammadelta T-cell receptor repertoire among NVS was consistent with the known effect of HIV-1 on these cells. Uniquely among all HIV-infected groups, NVS reconstituted the gammadelta T-cell population, eventually reaching levels significantly above controls. This capacity to recover gammadelta T-cell numbers and function distinguishes individuals who control HIV-1 with and without HAART.